Skip main navigation

Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure

Originally published 2003;42:1206–1252


The National High Blood Pressure Education Program presents the complete Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Like its predecessors, the purpose is to provide an evidence-based approach to the prevention and management of hypertension. The key messages of this report are these: in those older than age 50, systolic blood pressure (BP) of greater than 140 mm Hg is a more important cardiovascular disease (CVD) risk factor than diastolic BP; beginning at 115/75 mm Hg, CVD risk doubles for each increment of 20/10 mm Hg; those who are normotensive at 55 years of age will have a 90% lifetime risk of developing hypertension; prehypertensive individuals (systolic BP 120–139 mm Hg or diastolic BP 80–89 mm Hg) require health-promoting lifestyle modifications to prevent the progressive rise in blood pressure and CVD; for uncomplicated hypertension, thiazide diuretic should be used in drug treatment for most, either alone or combined with drugs from other classes; this report delineates specific high-risk conditions that are compelling indications for the use of other antihypertensive drug classes (angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, beta-blockers, calcium channel blockers); two or more antihypertensive medications will be required to achieve goal BP (<140/90 mm Hg, or <130/80 mm Hg) for patients with diabetes and chronic kidney disease; for patients whose BP is more than 20 mm Hg above the systolic BP goal or more than 10 mm Hg above the diastolic BP goal, initiation of therapy using two agents, one of which usually will be a thiazide diuretic, should be considered; regardless of therapy or care, hypertension will be controlled only if patients are motivated to stay on their treatment plan. Positive experiences, trust in the clinician, and empathy improve patient motivation and satisfaction. This report serves as a guide, and the committee continues to recognize that the responsible physician’s judgment remains paramount.

For more than 3 decades, the National Heart, Lung, and Blood Institute (NHLBI) has administered the National High Blood Pressure Education Program (NHBPEP) Coordinating Committee, a coalition of 39 major professional, public, and voluntary organizations and 7 federal agencies. One important function is to issue guidelines and advisories designed to increase awareness, prevention, treatment, and control of hypertension (high blood pressure).

Data from the National Health and Nutrition Examination Survey (NHANES) have indicated that 50 million or more Americans have high blood pressure (BP) warranting some form of treatment.1,2 Worldwide prevalence estimates for hypertension may be as much as 1 billion individuals, and approximately 7.1 million deaths per year may be attributable to hypertension.3 The World Health Organization reports that suboptimal BP (>115 mm Hg SBP) is responsible for 62% of cerebrovascular disease and 49% of ischemic heart disease, with little variation by sex. In addition, suboptimal blood pressure is the number one attributable risk for death throughout the world.3

Considerable success has been achieved in the past in meeting the goals of the program. The awareness of hypertension has improved from a level of 51% of Americans in the period 1976 to 1980 to 70% in 1999 to 2000 (Table 1). The percentage of patients with hypertension receiving treatment has increased from 31% to 59% in the same period, and the percentage of persons with high BP controlled to below 140/90 mm Hg has increased from 10% to 34%. Between 1960 and 1991, median systolic BP (SBP) for individuals 60 to 74 years old declined by approximately 16 mm Hg (Figure 1). These changes have been associated with highly favorable trends in the morbidity and mortality attributed to hypertension. Since 1972, age-adjusted death rates from stroke and coronary heart disease (CHD) have declined by approximately 60% and 50%, respectively (Figures 2 and 3). These benefits have occurred independent of gender, age, race, or socioeconomic status. Within the last 2 decades, better treatment of hypertension has been associated with a considerable reduction in the hospital case-fatality rate for heart failure (HF) (Figure 4). This information suggests that there have been substantial improvements.

TABLE 1. Trends in Awareness, Treatment, and Control of High Blood Pressure 1976–2000

National Health and Nutrition Examination Survey, %
Percentage of adults aged 18 to 74 years with systolic blood pressure (SBP) of 140 mm Hg or greater, diastolic blood pressure (DBP) of 90 mm Hg or greater, or taking antihypertensive medication.
*SBP below 140 mm Hg and DBP below 90 mm Hg and on antihypertensive medication.

Figure 1. Smoothed weighted frequency distribution, median, and 90th percentile of SBP for ages 60 to 74 years, United States, 1960 to 1991. Source: Burt et al. Hypertension 1995;26:60–69. Erratum in: Hypertension 1996;27:1192.

Figure 2. Percentage decline in age-adjusted mortality rates for stroke by gender and race: United States, 1970 to 2000. Source: Prepared by T. Thom, National Heart, Lung, and Blood Institute from Vital Statistics of the United States, National Center for Health Statistics. Death rates are age-adjusted to the 2000 US census population.

Figure 3. Percentage decline in age-adjusted mortality rates for CHD by gender and race: United States, 1970 to 2000. Source: Prepared by T. Thom, National Heart, Lung, and Blood Institute from Vital Statistics of the United States, National Center for Health Statistics. Death rates are age-adjusted to the 2000 US census population.

Figure 4. Hospital case-fatality rates for congestive heart failure, ages <65 and 65+: United States, 1981 to 2000. Source: National Heart, Lung, and Blood Institute. Morbidity and Mortality: 2002 Chart Book on Cardiovascular, Lung, and Blood Disease. Chart 3–36. Accessed September 2003.

However, these improvements have not been extended to the total population. Current control rates for hypertension in the United States are clearly unacceptable. Approximately 30% of adults are still unaware of their hypertension, more than 40% of individuals with hypertension are not on treatment, and two thirds of hypertensive patients are not being controlled to BP levels less than 140/90 mm Hg (Table 1). Furthermore, the rates of decline of deaths from CHD and stroke have slowed in the past decade. In addition, the prevalence and hospitalization rates of HF, wherein the majority of patients have hypertension before developing heart failure, have continued to increase (Figures 5 and 6). Moreover, there is an increasing trend in end-stage renal disease (ESRD) by primary diagnosis. Hypertension is second only to diabetes as the most common antecedent for this condition (Figure 7). Undiagnosed, untreated, and uncontrolled hypertension clearly places a substantial strain on the health care delivery system.

Figure 5. Prevalence of CHF by race and gender, ages 25 to 74: United States, 1971 to 1974 to 1999 to 2000. Age-adjusted to 2000 US census population. White and African American in 1999 to 2000 excludes Hispanics. Source: National Heart, Lung, and Blood Institute. Morbidity and Mortality: 2002 Chart Book on Cardiovascular, Lung, and Blood Disease. Accessed September 2003. and 1999 to 2000 unpublished data computed by M. Wolz and T. Thom, National Heart, Lung, and Blood Institute. June 2003.

Figure 6. Hospitalization rates for congestive heart failure, ages 45 to 64 and 65+: United States, 1971 to 2000. Source: National Heart, Lung, and Blood Institute. Morbidity and Mortality: 2002 Chart Book on Cardiovascular, Lung, and Blood Disease. Chart 3–35. Accessed September 2003.

Figure 7. Trends in incident rates of ESRD, by primary diagnosis (adjusted for age, gender, race). Disease categories were treated as being mutually exclusive. Source: United States Renal Data System. 2002. Figure 1.14. Accessed September, 2003.


The decision to appoint a committee for The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) was based on 4 factors: the publication of many new hypertension observational studies and clinical trials since the last report was published in 19974; the need for a new clear and concise guideline that would be useful to clinicians; the need to simplify the classification of BP; and a clear recognition that the JNC reports did not result in maximum benefit to the public. This JNC report is presented in 2 separate publications. The initial “Express” version, a succinct practical guide, was published in the May 21, 2003, issue of the Journal of the American Medical Association.5 The current, more comprehensive report provides a broader discussion and justification for the recommendations made by the committee. As with prior JNC reports, the committee recognizes that the responsible physician’s judgment is paramount in managing his or her patients.

Since the publication of the JNC 6 report, the NHBPEP Coordinating Committee, chaired by the director of the NHLBI, has regularly reviewed and discussed studies on hypertension. To conduct this task, the Coordinating Committee is divided into 4 subcommittees: Science Base; Long Range Planning; Professional, Patient, and Public Education; and Program Organization. The subcommittees work together to review the hypertension scientific literature from clinical trials, epidemiology, and behavioral science. In many instances, the principal investigator of the larger studies has presented the information directly to the Coordinating Committee. The committee reviews are summarized and posted on the NHLBI web site.6 This ongoing review process keeps the committee apprised of the current state of the science, and the information is also used to develop program plans for future activities, such as continuing education.

During fall 2002, the NHBPEP Coordinating Committee chair solicited opinions regarding the need to update the JNC 6 report. The entire Coordinating Committee membership provided, in writing, a detailed rationale explaining the necessity for updating JNC 6, outlined critical issues, and provided concepts to be addressed in the new report. Thereafter, the NHBPEP Coordinating Committee chair appointed the JNC 7 chair and an Executive Committee derived from the Coordinating Committee membership. The Coordinating Committee members served on 1 of 5 JNC 7 writing teams, which contributed to the writing and review of the document.

The concepts for the new report identified by the NHBPEP Coordinating Committee membership were used to create the report outline. On the basis of these critical issues and concepts, the Executive Committee developed relevant medical subject headings (MeSH) terms and keywords to further review the scientific literature. These MeSH terms were used to generate MEDLINE searches that focused on English-language, peer-reviewed scientific literature from January 1997 through April 2003. Various systems of grading the evidence were considered, and the classification scheme used in JNC 6 and other NHBPEP clinical guidelines was selected.4,7–10 This scheme classifies studies according to a process adapted from Last and Abramson (see the section Scheme Used for Classification of the Evidence).11

In reviewing the exceptionally large body of research literature in hypertension, the Executive Committee focused its deliberations on evidence pertaining to outcomes of importance to patients and with effects of sufficient magnitude to warrant changes in medical practice (“patient oriented evidence that matters” [POEMs]).12,13 Patient-oriented outcomes include not only mortality but also other outcomes that affect patients’ lives and well-being, such as sexual function, ability to maintain family and social roles, ability to work, and ability to carry out activities of daily living. These outcomes are strongly affected by nonfatal stroke, HF, coronary heart disease, and renal disease; hence, these outcomes were considered along with mortality in the committee’s evidence-based deliberations. Studies of physiological end points (disease-oriented evidence [DOEs]) were used to address questions where POEMs were not available.

The Coordinating Committee began the process of developing the JNC 7 Express report in December 2002, and the report was submitted to the Journal of the American Medical Association in April 2003. It was published in an electronic format on May 14, 2003, and in print on May 21, 2003. During this time, the Executive Committee met on 6 occasions, 2 of which included meetings with the entire Coordinating Committee. The writing teams also met by teleconference and used electronic communications to develop the report. Twenty-four drafts were created and reviewed repeatedly. At its meetings, the Executive Committee used a modified nominal group process14 to identify and resolve issues. The NHBPEP Coordinating Committee reviewed the penultimate draft and provided written comments to the Executive Committee. In addition, 33 national hypertension leaders reviewed and commented on the document. The NHBPEP Coordinating Committee approved the JNC 7 Express report. To complete the longer JNC 7 version, the Executive Committee members met via teleconferences and in person and circulated sections of the larger document via e-mail. The sections were assembled and edited by the JNC 7 chair and were circulated among the Coordinating Committee members for review and comment. The JNC 7 chair synthesized the comments, and the longer version was submitted to the journal Hypertension in November, 2003.

Lifetime Risk of Hypertension

Hypertension is an increasingly important medical and public health issue. The prevalence of hypertension increases with advancing age to the point where more than half of people aged 60 to 69 years old and approximately three-fourths of those aged 70 years and older are affected.1 The age-related rise in SBP is primarily responsible for an increase in both incidence and prevalence of hypertension with increasing age.15

Whereas the short-term absolute risk for hypertension is conveyed effectively by incidence rates, the long-term risk is best summarized by the lifetime risk statistic, which is the probability of developing hypertension during the remaining years of life (either adjusted or unadjusted for competing causes of death). Framingham Heart Study investigators recently reported the lifetime risk of hypertension to be approximately 90% for men and women who were nonhypertensive at 55 or 65 years old and survived to age 80 to 85 (Figure 8).16 Even after adjusting for competing mortality, the remaining lifetime risks of hypertension were 86 to 90% in women and 81 to 83% in men.

Figure 8. Residual lifetime risk of hypertension in women and men aged 65 years. Cumulative incidence of hypertension in 65-year-old women and men. Data for 65-year-old men in the 1952 to 1975 period are truncated at 15 years since there were few participants in this age category who were followed up beyond this time interval. Source: JAMA 2002;287:1003–1010. Copyright 2002, American Medical Association. All rights reserved.

The impressive increase of BP to hypertensive levels with age is also illustrated by data indicating that the 4-year rates of progression to hypertension are 50% for those 65 years and older with BP in the 130 to 139/85 to 89 mm Hg range and 26% for those with BP in the 120 to 129/80 to 84 mm Hg range.17

Blood Pressure and Cardiovascular Risk

Data from observational studies involving more than 1 million individuals have indicated that death from both ischemic heart disease and stroke increases progressively and linearly from BP levels as low as 115 mm Hg systolic and 75 mm Hg diastolic upward (Figures 9 and 10).18 The increased risks are present in all age groups ranging from 40 to 89 years old. For every 20 mm Hg systolic or 10 mm Hg diastolic increase in BP, there is a doubling of mortality from both ischemic heart disease and stroke.

Figure 9. Ischemic heart disease (IHD) mortality rate in each decade of age versus usual blood pressure at the start of that decade. Source: Reprinted with permission from Elsevier (The Lancet, 2002;360:1903–1913).

Figure 10. Stroke mortality rate in each decade of age versus usual blood pressure at the start of that decade. Source: Reprinted with permission from Elsevier (The Lancet, 2002;360:1903–1913).

In addition, longitudinal data obtained from the Framingham Heart Study have indicated that BP values in the 130 to 139/85 to 89 mm Hg range are associated with a more than 2-fold increase in relative risk from cardiovascular disease (CVD) compared with those with BP levels below 120/80 mm Hg (Figure 11).19

Figure 11. Impact of high normal blood pressure on the risk of cardiovascular disease. Cumulative incidence of cardiovascular events in women (A) and men (B) without hypertension, according to blood-pressure category at the baseline examination. Vertical bars indicate 95% confidence intervals. Optimal BP is defined here as a systolic pressure of less than 120 mm Hg and a diastolic pressure of less than 80 mm Hg. Normal BP is a systolic pressure of 120 to 129 mm Hg or a diastolic pressure of 80 to 84 mm Hg. High-normal BP is a systolic pressure of 130 to 139 mm Hg or a diastolic pressure of 85 to 89 mm Hg. If the systolic and diastolic pressure readings for a subject were in different categories, the higher of the two categories was used. Source: N Engl J Med 2001;345:1291–1297. Copyright © 2001, Massachusetts Medical Society. All rights reserved.

Basis for Reclassification of Blood Pressure

Because of the new data on lifetime risk of hypertension and the impressive increase in the risk of cardiovascular complications associated with levels of BP previously considered to be normal, the JNC 7 report has introduced a new classification that includes the term “prehypertension” for those with BPs ranging from 120 to 139 mm Hg systolic and/or 80 to 89 mm Hg diastolic blood pressure (DBP). This new designation is intended to identify those individuals in whom early intervention by adoption of healthy lifestyles could reduce BP, decrease the rate of progression of BP to hypertensive levels with age, or prevent hypertension entirely.

Another change in classification from JNC 6 is the combining of stage 2 and stage 3 hypertension into a single stage 2 category. This revision reflects the fact that the approach to the management of the former two groups is similar (Table 2).

TABLE 2. Changes in Blood Pressure Classification

Classification of Blood Pressure

Table 3 provides a classification of BP for adults aged 18 and older. The classification is based on the average of 2 or more properly measured, seated BP readings on each of 2 or more office visits.

TABLE 3. Classification of Blood Pressure for Adults

BP ClassificationSBP mm HgDBP mm Hg
Normal<120and <80
Prehypertension120–139or 80–89
Stage 1 hypertension140–159or 90–99
Stage 2 hypertension≥160or ≥100

Prehypertension is not a disease category. Rather it is a designation chosen to identify individuals at high risk of developing hypertension, so that both patients and clinicians are alerted to this risk and encouraged to intervene and prevent or delay the disease from developing. Individuals who are prehypertensive are not candidates for drug therapy on the basis of their level of BP and should be firmly and unambiguously advised to practice lifestyle modification in order to reduce their risk of developing hypertension in the future (see the section Lifestyle Modifications). Moreover, individuals with prehypertension who also have diabetes or kidney disease should be considered candidates for appropriate drug therapy if a trial of lifestyle modification fails to reduce their BP to 130/80 mm Hg or less.

This classification does not stratify hypertensives by the presence or absence of risk factors or target organ damage in order to make different treatment recommendations, if either or both are present. JNC 7 suggests that all people with hypertension (Stages 1 and 2) be treated. The treatment goal for individuals with hypertension and no other compelling conditions is <140/90 mm Hg (see the section Compelling Indications). The goal for individuals with prehypertension and no compelling indications is to lower BP to normal with lifestyle changes and prevent the progressive rise in BP using the recommended lifestyle modifications (See the section Lifestyle Modification).

Cardiovascular Disease Risk

The relationship between BP and risk of CVD events is continuous, consistent, and independent of other risk factors. The higher the BP, the greater is the chance of heart attack, HF, stroke, and kidney diseases. The presence of each additional risk factor compounds the risk from hypertension, as illustrated in Figure 12.20 The easy and rapid calculation of a Framingham CHD risk score using published tables21 may assist the clinician and patient in demonstrating the benefits of treatment. Management of these other risk factors is essential and should follow the established guidelines for controlling these coexisting problems that contribute to overall cardiovascular risk.

Figure 12. Ten-year risk for CHD by SBP and presence of other risk factors. Source: Derived from K.M. Anderson, P.W.F. Wilson, P.M. Odell, W.B. Kannel. An updated coronary risk profile. A statement for health professionals. Circulation 1991;83:356–362.

Importance of Systolic Blood Pressure

Impressive evidence has accumulated to warrant greater attention to the importance of SBP as a major risk factor for CVDs. Changing patterns of BP occur with increasing age. The rise in SBP continues throughout life, in contrast to DBP, which rises until approximately 50 years old, tends to level off over the next decade, and may remain the same or fall later in life (Figure 13).1,15 Diastolic hypertension predominates before 50 years of age, either alone or in combination with SBP elevation. The prevalence of systolic hypertension increases with age, and above the age of 50 years, systolic hypertension represents the most common form of hypertension. DBP is a more potent cardiovascular risk factor than SBP until age 50; thereafter, SBP is more important (Figure 14).22

Figure 13. Changes in systolic and diastolic blood pressure with age. SBP and DBP by age and race or ethnicity for men and women over 18 years of age in the US population. Data from NHANES III, 1988 to 1991. Source: Burt VL et al. Hypertension 1995;23:305–313.

Figure 14. Difference in CHD prediction between systolic and diastolic blood pressure as a function of age. The strength of the relationship as a function of age is indicated by an increase in the β coefficient. Difference in β coefficients (from Cox proportional-hazards regression) between SBP and DBP is plotted as function of age, obtaining this regression line: β (SBP)−β (DBP)=1.4948+0.0290 × age (P=0.008). A β coefficient level <0.0 indicates a stronger effect of DBP on CHD risk, while levels >0.0 suggest a greater importance of systolic pressure. Source: Circulation 2001;103:1247.

Clinical trials have demonstrated that control of isolated systolic hypertension reduces total mortality, cardiovascular mortality, stroke, and HF events.23–25 Both observational studies and clinical trial data suggest that poor SBP control is largely responsible for the unacceptably low rates of overall BP control.26,27 In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) and Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial, DBP control rates exceeded 90%, but SBP control rates were considerably less (60 to 70%).28,29 Poor SBP control is at least in part related to physician attitudes. A survey of primary care physicians indicated that three-fourths of them failed to initiate antihypertensive therapy in older individuals with SBP of 140 to 159 mm Hg, and most primary care physicians did not pursue control to less than 140 mm Hg.30,31 Most physicians have been taught that the diastolic pressure is more important than SBP and thus treat accordingly. Greater emphasis must clearly be placed on managing systolic hypertension. Otherwise, as the US population becomes older, the toll of uncontrolled SBP will cause increased rates of cardiovascular and renal diseases.

Prevention of Hypertension: Public Health Challenges

The prevention and management of hypertension are major public health challenges for the United States. If the rise in BP with age could be prevented or diminished, much of hypertension, cardiovascular and renal disease, and stroke might be prevented. A number of important causal factors for hypertension have been identified, including excess body weight; excess dietary sodium intake; reduced physical activity; inadequate intake of fruits, vegetables, and potassium; and excess alcohol intake.10,32 The prevalence of these characteristics is high. One hundred twenty-two million Americans are overweight or obese.33 Mean sodium intake is approximately 4100 mg per day for men and 2750 mg per day for women, 75% of which comes from processed foods.34,35 Fewer than 20% of Americans engage in regular physical activity,36 and fewer than 25% consume 5 or more servings of fruits and vegetables daily.37

Because the lifetime risk of developing hypertension is very high (Figure 8), a public health strategy that complements the hypertension treatment strategy is warranted. In order to prevent BP levels from rising, primary prevention measures should be introduced to reduce or minimize these causal factors in the population, particularly in individuals with prehypertension. A population approach that decreases the BP level in the general population by even modest amounts has the potential to substantially reduce morbidity and mortality or at least delay the onset of hypertension. For example, it has been estimated that a 5 mm Hg reduction of SBP in the population would result in a 14% overall reduction in mortality due to stroke, a 9% reduction in mortality due to CHD, and a 7% decrease in all-cause mortality (Figure 15).10,38

Figure 15. Systolic blood pressure distributions. Source: Whelton PK et al. JAMA 2002;288:1884.

Barriers to prevention include cultural norms; insufficient attention to health education by health care practitioners; lack of reimbursement for health education services; lack of access to places to engage in physical activity; larger servings of food in restaurants; lack of availability of healthy food choices in many schools, worksites, and restaurants; lack of exercise programs in schools; large amounts of sodium added to foods by the food industry and restaurants; and the higher cost of food products that are lower in sodium and calories.10 Overcoming the barriers will require a multipronged approach directed not only to high-risk populations but also to communities, schools, worksites, and the food industry. The recent recommendations by the American Public Health Association and the NHBPEP Coordinating Committee that the food industry, including manufacturers and restaurants, reduce sodium in the food supply by 50% over the next decade is the type of approach that, if implemented, would reduce BP in the population.39,40

Community Programs

Healthy People 2010 has identified the community as a significant partner and vital point of intervention for attaining healthy goals and outcomes.41 Partnerships with community groups such as civic, philanthropic, religious, and senior citizen organizations provide locally focused orientation to the health needs of diverse populations. The probability of success increases as interventional strategies more aptly address the diversity of racial, ethnic, cultural, linguistic, religious, and social factors in the delivery of medical services. Community service organizations can promote the prevention of hypertension by providing culturally sensitive educational messages and lifestyle support services and by establishing cardiovascular risk factor screening and referral programs. Community-based strategies and programs have been addressed in prior NHLBI publications and other documents (Facts About the DASH Eating Plan,42 Your Guide to Lowering High Blood Pressure,43 National High Blood Pressure Education Month,44 The Heart Truth: A National Awareness Campaign for Women About Heart Disease,45Mobilizing African American Communities To Address Disparities in Cardiovascular Health: The Baltimore City Health Partnership Strategy Development Workshop Summary Report,46 NHLBI Healthy People 2010 Gateway,47 Cardiovascular Disease Enhanced Dissemination and Utilization Centers [EDUCs] Awardees,48 Hearts N’ Parks,49 Healthbeat Radio Network,50 Salud para su Corazón [For the Health of Your Heart]).51

Calibration, Maintenance, and Use of Blood Pressure Devices

The potential of mercury spillage contaminating the environment has led to the decreased use or elimination of mercury in sphygmomanometers as well as in thermometers52 However, concerns regarding the accuracy of nonmercury sphygmomanometers have created new challenges for accurate BP determination.53,54 When mercury sphygmomanometers are replaced, the new equipment, including all home BP measurement devices, must be appropriately validated and checked regularly for accuracy.55

Accurate Blood Pressure Measurement in the Office

The accurate measurement of BP is the sine qua non for successful management. The equipment, whether aneroid, mercury, or electronic, should be regularly inspected and validated. The operator should be trained and regularly retrained in the standardized technique, and the patient must be properly prepared and positioned.4,56,57 The auscultatory method of BP measurement should be used.58 Persons should be seated quietly for at least 5 minutes in a chair (rather than on an examination table), with feet on the floor, and arm supported at heart level. Caffeine, exercise, and smoking should be avoided for at least 30 minutes prior to measurement. Measurement of BP in the standing position is indicated periodically, especially in those at risk for postural hypotension, prior to necessary drug dose or adding a drug, and in those who report symptoms consistent with reduced BP on standing. An appropriately sized cuff (cuff bladder encircling at least 80% of the arm) should be used to ensure accuracy. At least two measurements should be made and the average recorded. For manual determinations, palpated radial pulse obliteration pressure should be used to estimate SBP; the cuff should then be inflated 20 to 30 mm Hg above this level for the auscultatory determinations; the cuff deflation rate for auscultatory readings should be 2 mm Hg per second. SBP is the point at which the first of two or more Korotkoff sounds is heard (onset of phase 1), and the disappearance of Korotkoff sound (onset of phase 5) is used to define DBP. Clinicians should provide to patients, verbally and in writing, their specific BP numbers and the BP goal of their treatment.

Follow-up of patients with various stages of hypertension is recommended as shown in Table 4.

TABLE 4. Recommendations for Follow-Up Based on Initial Blood Pressure Measurements for Adults Without Acute End Organ Damage

Initial Blood Pressure, mm Hg*Follow-Up Recommended
*If systolic and diastolic categories are different, follow recommendations for shorter time follow-up (e.g., 160/86 mm Hg should be evaluated or referred to source of care within 1 month).
†Modify the scheduling of follow-up according to reliable information about past BP measurements, other cardiovascular risk factors, or target organ disease.
‡Provide advice about lifestyle modifications (see Lifestyle Modifications section).
NormalRecheck in 2 years
PrehypertensionRecheck in 1 year
Stage 1 hypertensionConfirm within 2 months
Stage 2 hypertensionEvaluate or refer to source of care within 1 month. For those with higher pressures (eg, >180/110 mm Hg), evaluate and treat immediately or within 1 week depending on clinical situation and complications.

Ambulatory Blood Pressure Monitoring

Ambulatory blood pressure monitoring (ABPM) provides information about BP during daily activities and sleep.59 BP has a reproducible circadian profile, with higher values while awake and mentally and physically active, much lower values during rest and sleep, and early morning increases for 3 or more hours during the transition of sleep to wakefulness.60 These devices use either a microphone to measure Korotkoff sounds or a cuff that senses arterial waves using oscillometric techniques. Twenty-four-hour BP monitoring provides multiple readings during all of a patient’s activities. While office BP values have been used in the numerous studies that have established the risks associated with an elevated BP and the benefits of lowering BP, office measurements have some shortcomings. For example, a white-coat effect (increase in BP primarily in the medical care environment) is noted in as many as 20 to 35% of patients diagnosed with hypertension.61

Ambulatory BP values are usually lower than clinic readings. Awake hypertensive individuals have an average BP of >135/85 mm Hg and during sleep, >120/75 mm Hg. The level of BP measurement using ABPM correlates better than office measurements with target organ injury.15 ABPM also provides a measure of the percentage of BP readings that are elevated, the overall BP load, and the extent of BP fall during sleep. In most people, BP drops by 10 to 20% during the night; those in whom such reductions are not present appear to be at increased risk for cardiovascular events. In addition, it was reported recently that ABPM patients whose 24-hour BP exceeded 135/85 mm Hg were nearly twice as likely to have a cardiovascular event as those with 24-hour mean BPs less than 135/85 mm Hg, irrespective of the level of the office BP.62,63

Indications for the use of ABPM are listed in Table 5. Medicare reimbursement for ABPM is now provided to assess patients with suspected white-coat hypertension.

TABLE 5. Clinical Situations in Which Ambulatory Blood Pressure Monitoring May Be Helpful

Suspected white-coat hypertension in patients with hypertension and no target organ damage
Apparent drug resistance (office resistance)
Hypotensive symptoms with antihypertensive medication
Episodic hypertension
Autonomic dysfunction


Self-monitoring of BP at home and work is a practical approach to assess differences between office and out-of-office BP prior to consideration of ambulatory monitoring. For those whose out-of-office BPs are consistently <130/80 mm Hg despite an elevated office BP and who lack evidence of target organ disease, 24-hour monitoring or drug therapy can be avoided.

Self-measurement or ambulatory monitoring may be particularly helpful in assessing BP in smokers. Smoking raises BP acutely, and the level returns to baseline in about 15 minutes after stopping.

Patient Evaluation

Evaluation of hypertensive patients has three objectives: (1) to assess lifestyle and identify other cardiovascular risk factors or concomitant disorders that may affect prognosis and guide treatment (Table 6); (2) to reveal identifiable causes of high BP (Table 7); and (3) to assess the presence or absence of target organ damage and CVD.

TABLE 6. Cardiovascular Risk Factors

GFR indicates glomerular filtration rate.
*Components of the metabolic syndrome. Reduced HDL and elevated triglycerides are components of the metabolic syndrome. Abdominal obesity is also a component of metabolic syndrome.
†Increased risk begins at approximately 55 and 65 for men and women, respectively. Adult Treatment Panel III used earlier age cutpoints to suggest the need for earlier action.
Major risk factors
    Age (older than 55 for men, 65 for women)
    Diabetes mellitus*
    Elevated LDL (or total) cholesterol or low HDL cholesterol*
    Estimated GFR <60 mL/min
    Family history of premature cardiovascular disease (men aged <55 or  women aged <65)
    Obesity* (body mass index ≥30 kg/m2)
    Physical inactivity
    Tobacco usage, particularly cigarettes
Target organ damage
        Left ventricular hypertrophy
        Angina/prior myocardial infarction
        Prior coronary revascularization
        Heart failure
        Stroke or transient ischemic attack
    Chronic kidney disease
    Peripheral arterial disease

TABLE 7. Identifiable Causes of Hypertension

Chronic kidney disease
Coarctation of the aorta
Cushing syndrome and other glucocorticoid excess states including chronic steroid therapy
Drug-induced or drug-related (see Table 18)
Obstructive uropathy
Primary aldosteronism and other mineralocorticoid excess states
Renovascular hypertension
Sleep apnea
Thyroid or parathyroid disease

Patient evaluation is made through medical history, physical examination, routine laboratory tests, and other diagnostic procedures. The physical examination should include an appropriate measurement of BP, with verification in the contralateral arm; examination of the optic fundi; calculation of body mass index (BMI) (measurement of waist circumference is also very useful); auscultation for carotid, abdominal, and femoral bruits; palpation of the thyroid gland; thorough examination of the heart and lungs; examination of the abdomen for enlarged kidneys, masses, distended urinary bladder, and abnormal aortic pulsation; palpation of the lower extremities for edema and pulses; and neurological assessment.

Data from epidemiological studies and clinical trials have demonstrated that elevations in resting heart rate and reduced heart rate variability are associated with higher cardiovascular risk. In the Framingham Heart Study, an average resting heart rate of 83 beats per minute was associated with a substantially higher risk of death from a CV event than those at lower heart rate levels.64 Moreover, reduced heart rate variability was also associated with an increase in CV mortality.65 No clinical trials have prospectively evaluated the impact of reducing heart rate on CV outcomes.

Laboratory Tests and Other Diagnostic Procedures

Routine laboratory tests recommended before initiating therapy include a 12-lead ECG; urinalysis; blood glucose and hematocrit; serum potassium, creatinine (or the corresponding estimated glomerular filtration rate [eGFR]), and calcium66; and a lipoprotein profile (after 9- to 12-hour fast) that includes HDL and LDL cholesterol (HDL-C and LDL-C) and triglycerides (TGs). Optional tests include measurement of urinary albumin excretion or albumin/creatinine ratio (ACR), except for those with diabetes or kidney disease, for whom annual measurements should be made. More extensive testing for identifiable causes is not indicated generally unless BP control is not achieved or the clinical and routine laboratory evaluation strongly suggests an identifiable secondary cause (ie, vascular bruits, symptoms of catecholamine excess, unprovoked hypokalemia). See the section Identifiable Causes of Hypertension for a more thorough discussion.

The presence of decreased GFR or albuminuria has prognostic implications as well. Studies reveal a strong relationship between decreases in GFR and increases in cardiovascular morbidity and mortality.67,68 Even small decreases in GFR increase cardiovascular risk.67 Serum creatinine may overestimate glomerular filtration. The optimal tests to determine GFR are debated, but calculating GFR from the recent modifications of the Cockcroft and Gault equations is useful.69

The presence of albuminuria, including microalbuminuria, even in the setting of normal GFR, is also associated with an increase in cardiovascular risk.70–72 Urinary albumin excretion should be quantitated and monitored on an annual basis in high-risk groups, such as those with diabetes or renal disease.

Additionally, three emerging risk factors—(1) high-sensitivity C-reactive protein (HS-CRP), a marker of inflammation; (2) homocysteine; and (3) elevated heart rate—may be considered in some individuals, particularly those with CVD but without other risk factor abnormalities. Results of an analysis of the Framingham Heart Study cohort demonstrated that those with an LDL value within the range associated with low CV risk, who also had an elevated HS-CRP value, had a higher CV event rate as compared with those with low CRP and high LDL-C.73 Other studies also have shown that elevated CRP is associated with a higher CV event rate, especially in women.74 Elevations in homocysteine have also been described as associated with higher CV risk; however, the results with this marker are not as robust as those with high HS-CRP.75,76

Identifiable Causes of Hypertension

Additional diagnostic procedures may be indicated to identify causes of hypertension, particularly in patients whose (1) age, history, physical examination, severity of hypertension, or initial laboratory findings suggest such causes; (2) BP responds poorly to drug therapy; (3) BP begins to increase for uncertain reason after being well controlled; and (4) onset of hypertension is sudden. Screening tests for particular forms of identifiable hypertension are shown in Table 8.

TABLE 8. Screening Tests for Identifiable Hypertension

DiagnosisDiagnostic Test
GFR indicates glomerular filtration rate; CT, computed tomography; TSH, thyroid stimulating hormone; PTH, parathyroid hormone.
Chronic kidney diseaseEstimated GFR
Coarctation of the aortaCT angiography
Cushing syndrome and other glucocorticoid excess states including chronic steroid therapyHistory/dexamethasone suppression test
Drug-induced/related (see Table 18)History; drug screening
Pheochromocytoma24-hour urinary metanephrine and normetanephrine
Primary aldosteronism and other mineralocorticoid excess states24-hour urinary aldosterone level or specific measurements of other mineralocorticoids
Renovascular hypertensionDoppler flow study; magnetic resonance angiography
Sleep apneaSleep study with O2 saturation
Thyroid/parathyroid diseaseTSH; serum PTH

Pheochromocytoma should be suspected in patients with labile hypertension or with paroxysms of hypertension accompanied by headache, palpitations, pallor, and perspiration.77 Decreased pressure in the lower extremities or delayed or absent femoral arterial pulses may indicate aortic coarctation; truncal obesity, glucose intolerance, and purple striae suggest Cushing syndrome. Examples of clues from the laboratory tests include unprovoked hypokalemia (primary aldosteronism), hypercalcemia (hyperparathyroidism), and elevated creatinine or abnormal urinalysis (renal parenchymal disease). Appropriate investigations should be conducted when there is a high index of suspicion of an identifiable cause.78–81

The most common parenchymal kidney diseases associated with hypertension are chronic glomerulonephritis, polycystic kidney disease, and hypertensive nephrosclerosis. These can generally be distinguished by the clinical setting and additional testing. For example, a renal ultrasound is useful in diagnosing polycystic kidney disease. Renal artery stenosis and subsequent renovascular hypertension should be suspected in a number of circumstances, including (1) onset of hypertension before 30 years of age, especially in the absence of family history, or onset of significant hypertension after age 55; (2) an abdominal bruit, especially if a diastolic component is present; (3) accelerated hypertension; (4) hypertension that had been easy to control but is now resistant; (5) recurrent flash pulmonary edema; (6) renal failure of uncertain etiology, especially in the absence of proteinuria or an abnormal urine sediment; and (7) acute renal failure precipitated by therapy with an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) under conditions of occult bilateral renal artery stenosis or moderate to severe volume depletion.

In patients with suspected renovascular hypertension, noninvasive screening tests include the ACEI-enhanced renal scan, duplex Doppler flow studies, and magnetic resonance angiography. While renal artery angiography remains the gold standard for identifying the anatomy of the renal artery, it is not recommended for diagnosis alone because of the risk associated with the procedure. At the time of intervention, an arteriogram will be performed using limited contrast to confirm the stenosis and identify the anatomy of the renal artery.

Genetics of Hypertension

The investigation of rare genetic disorders affecting BP has led to the identification of genetic abnormalities associated with several rare forms of hypertension, including mineralocorticoid-remediable aldosteronism, 11-β-hydroxylase and 17α-hydroxylase deficiencies, Liddle syndrome, the syndrome of apparent mineralocorticoid excess, and pseudohypoaldosteronism type II.82 The individual and joint contributions of these genetic mutations to BP levels in the general population, however, are very small. Genetic association studies have identified polymorphisms in several candidate genes (eg, angiotensinogen, α-adducin, β- and DA-adrenergic receptors, β-3 subunit of G proteins), and genetic linkage studies have focused attention on several genomic sites that may harbor other genes contributing to primary hypertension.83–85 However, none of these various genetic abnormalities has been shown, either alone or in joint combination, to be responsible for any applicable portion of hypertension in the general population.


Blood Pressure Control Rates

Hypertension is the most common primary diagnosis in America (35 million office visits as the primary diagnosis).5 Current control rates (SBP <140 mm Hg and DBP <90 mm Hg), though improved, are still far below the Healthy People goal of 50% (originally set as the year 2000 goal and since extended to 2010; Table 1). In the majority of patients, reducing SBP has been considerably more difficult than lowering DBP. Although effective BP control can be achieved in most patients who are hypertensive, the majority will require 2 or more antihypertensive drugs.28,29,86 Failure to prescribe lifestyle modifications, adequate antihypertensive drug doses, or appropriate drug combinations may result in inadequate BP control.

Goals of Therapy

The ultimate public health goal of antihypertensive therapy is to reduce cardiovascular and renal morbidity and mortality. Since most persons with hypertension, especially those >50 years old, will reach the DBP goal once the SBP goal is achieved, the primary focus should be on attaining the SBP goal. Treating SBP and DBP to targets that are <140/90 mm Hg is associated with a decrease in CVD complications.87 In patients with hypertension and diabetes or renal disease, the BP goal is <130/80 mm Hg.88,89

Benefits of Lowering Blood Pressure

In clinical trials, antihypertensive therapy has been associated with reductions in stroke incidence averaging 35% to 40%; myocardial infarction, 20% to 25%; and HF, >50%.90 It is estimated that in patients with stage 1 hypertension (SBP 140 to 159 mm Hg and/or DBP 90 to 99 mm Hg) and additional cardiovascular risk factors, achieving a sustained 12 mm Hg reduction in SBP over 10 years will prevent 1 death for every 11 patients treated. In the added presence of CVD or target organ damage, only 9 patients would require such BP reduction to prevent 1 death.91

Lifestyle Modifications

Adoption of healthy lifestyles by all persons is critical for the prevention of high BP and is an indispensable part of the management of those with hypertension.10 Weight loss of as little as 10 lbs (4.5 kg) reduces BP and/or prevents hypertension in a large proportion of overweight persons, although the ideal is to maintain normal body weight.92,93 BP is also benefited by adoption of the Dietary Approaches to Stop Hypertension (DASH) eating plan,94 which is a diet rich in fruits, vegetables, and lowfat dairy products with a reduced content of dietary cholesterol as well as saturated and total fat (modification of whole diet). It is rich in potassium and calcium content.95 Dietary sodium should be reduced to no more than 100 mmol per day (2.4 g of sodium).94–96 Everyone who is able should engage in regular aerobic physical activity such as brisk walking at least 30 minutes per day most days of the week.97,98 Alcohol intake should be limited to no more than 1 oz (30 mL) of ethanol, the equivalent of two drinks, per day in most men and no more than 0.5 oz of ethanol (one drink) per day in women and lighter weight persons. A drink is 12 oz of beer, 5 oz of wine, and 1.5 oz of 80-proof liquor (Table 9).99 Lifestyle modifications reduce BP, prevent or delay the incidence of hypertension, enhance antihypertensive drug efficacy, and decrease cardiovascular risk. For example, in some individuals, a 1600 mg sodium DASH eating plan has BP effects similar to single drug therapy.94 Combinations of 2 (or more) lifestyle modifications can achieve even better results.100 For overall cardiovascular risk reduction, patients should be strongly counseled to quit smoking.

TABLE 9. Lifestyle Modifications To Prevent and Manage Hypertension*

ModificationRecommendationApproximate SBP Reduction (Range)
DASH indicates Dietary Approaches to Stop Hypertension.
*For overall cardiovascular risk reduction, stop smoking.
†The effects of implementing these modifications are dose- and time-dependent and could be greater for some individuals.
Weight reductionMaintain normal body weight (body mass index 18.5–24.9 kg/m2).5–20 mm Hg/10 kg92,93
Adopt DASH eating planConsume a diet rich in fruits, vegetables, and low-fat dairy products with a reduced content of saturated and total fat.8–14 mm Hg94,95
Dietary sodium reductionReduce dietary sodium intake to no more than 100 mmol per day (2.4 g sodium or 6 g sodium chloride).2–8 mm Hg94–96
Physical activityEngage in regular aerobic physical activity such as brisk walking (at least 30 minutes per day, most days of the week).4–9 mm Hg97,98
Moderation of alcohol consumptionLimit consumption to no more than 2 drinks (eg, 24 oz beer, 10 oz wine, or 3 oz 80-proof whiskey) per day in most men and to no more than 1 drink per day in women and lighter-weight persons.2–4 mm Hg99

Pharmacological Treatment

A large number of drugs are currently available for reducing BP. Tables 10 and 11 provide a list of the commonly used antihypertensive agents and their usual dose range and frequency of administration.

TABLE 10. Oral Antihypertensive Drugs

ClassDrug (Trade Name)Usual Dose Range, mg/dUsual Daily Frequency*
Thiazide diuretics
Chlorothiazide (Diuril)125–5001–2
Chlorthalidone (generic)12.5–251
Hydrochlorothiazide (Microzide, HydroDIURIL)12.5–501
Polythiazide (Renese)2–41
Indapamide (Lozol)1.25–2.51
Metolazone (Mykrox)0.5–1.01
Metolazone (Zaroxolyn)2.5–51
Loop diuretics
Bumetanide (Bumex)0.5–22
Furosemide (Lasix)20–802
Torsemide (Demadex)2.5–101
Potassium-sparing diuretics
Amiloride (Midamor)5–101–2
Triamterene (Dyrenium)50–1001–2
Aldosterone receptor blockers
Eplerenone (Inspra)50–1001
Spironolactone (Aldactone)25–501
Atenolol (Tenormin)25–1001
Betaxolol (Kerlone)5–201
Bisoprolol (Zebeta)2.5–101
Metoprolol (Lopressor)50–1001–2
Metoprolol extended release (Toprol XL)50–1001
Nadolol (Corgard)40–1201
Propranolol (Inderal)40–1602
Propranolol long-acting (Inderal LA)60–1801
Timolol (Blocadren)20–402
BBs with intrinsic sympathomimetic activity
Acebutolol (Sectral)200–8002
Penbutolol (Levatol)10–401
Pindolol (generic)10–402
Combined α-blockers and BBs
Carvedilol (Coreg)12.5–502
Labetalol (Normodyne, Trandate)200–8002
Benazepril (Lotensin)10–401
Captopril (Capoten)25–1002
Enalapril (Vasotec)5–401–2
Fosinopril (Monopril)10–401
Lisinopril (Prinivil, Zestril)10–401
Moexipril (Univasc)7.5–301
Perindopril (Aceon)4–81
Quinapril (Accupril)10–801
Ramipril (Altace)2.5–201
Trandolapril (Mavik)1–41
Angiotensin II antagonists
Candesartan (Atacand)8–321
Eprosartan (Teveten)400–8001–2
Irbesartan (Avapro)150–3001
Losartan (Cozaar)25–1001–2
Olmesartan (Benicar)20–401
Telmisartan (Micardis)20–801
Valsartan (Diovan)80–3201–2

TABLE 10. Oral Antihypertensive Drugs (continued)

ClassDrug (Trade Name)Usual Dose Range, mg/dUsual Daily Frequency*
Source: Physicians’ Desk Reference. 57th ed. Montvale, NJ: Thomson PDR; 2003.
*In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval (trough effect). BP should be measured just prior to dosing to determine if satisfactory BP control is obtained. Accordingly, an increase in dosage or frequency may need to be considered. These dosages may vary from those listed in the Physician’s Desk Reference, 57th ed.
†Available now or soon to become available in generic preparations.
Diltiazem extended release (Cardizem CD, Dilacor XR, Tiazac)180–4201
Diltiazem extended release (Cardizem LA)120–5401
Verapamil immediate release (Calan, Isoptin)80–3202
Verapamil long acting (Calan SR, Isoptin SR)120–4801–2
Verapamil (Coer, Covera HS, Verelan PM)120–3601
Amlodipine (Norvasc)2.5–101
Felodipine (Plendil)2.5–201
Isradipine (Dynacirc CR)2.5–102
Nicardipine sustained release (Cardene SR)60–1202
Nifedipine long-acting (Adalat CC, Procardia XL)30–601
Nisoldipine (Sular)10–401
α1 blockers
Doxazosin (Cardura)1–161
Prazosin (Minipress)2–202–3
Terazosin (Hytrin)1–201–2
Central α2 agonists and other centrally acting drugs
Clonidine (Catapres)0.1–0.82
Clonidine patch (Catapres-TTS)0.1–0.31 weekly
Methyldopa (Aldomet)250–1 0002
Reserpine (generic)0.1–0.251
Guanfacine (Tenex)0.5–21
Direct vasodilators
Hydralazine (Apresoline)25–1002
Minoxidil (Loniten)2.5–801–2

TABLE 11. Combination Drugs for Hypertension

Combination TypeFixed-Dose Combination, mg*Trade Name
BB indicates β-blocker; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CCB, calcium channel blocker.
*Some drug combinations are available in multiple fixed doses. Each drug dose is reported in milligrams.
ACEIs and CCBs
Amlodipine-benazepril hydrochloride (2.5/10, 5/10, 5/20, 10/20)Lotrel
Enalapril-felodipine (5/5)Lexxel
Trandolapril-verapamil (2/180, 1/240, 2/240, 4/240)Tarka
ACEIs and diuretics
Benazepril-hydrochlorothiazide (5/6.25, 10/12.5, 20/12.5, 20/25)Lotensin HCT
Captopril-hydrochlorothiazide (25/15, 25/25, 50/15, 50/25)Capozide
Enalapril-hydrochlorothiazide (5/12.5, 10/25)Vaseretic
Fosinopril-hydrochlorothiazide (10/12.5, 20/12.5)Monopril/HCT
Lisinopril-hydrochlorothiazide (10/12.5, 20/12.5, 20/25)Prinzide, Zestoretic
Moexipril-hydrochlorothiazide (7.5/12.5, 15/25)Uniretic
Quinapril-hydrochlorothiazide (10/12.5, 20/12.5, 20/25)Accuretic
ARBs and diuretics
Candesartan-hydrochlorothiazide (16/12.5, 32/12.5)Atacand HCT
Eprosartan-hydrochlorothiazide (600/12.5, 600/25)Teveten-HCT
Irbesartan-hydrochlorothiazide (150/12.5, 300/12.5)Avalide
Losartan-hydrochlorothiazide (50/12.5, 100/25)Hyzaar
Olmesartan medoxomil-hydrochlorothiazide (20/12.5, 40/12.5, 40/25)Benicar HCT
Telmisartan-hydrochlorothiazide (40/12.5, 80/12.5)Micardis-HCT
Valsartan-hydrochlorothiazide (80/12.5, 160/12.5, 160/25)Diovan-HCT
BBs and diuretics
Atenolol-chlorthalidone (50/25, 100/25)Tenoretic
Bisoprolol-hydrochlorothiazide (2.5/6.25, 5/6.25, 10/6.25)Ziac
Metoprolol-hydrochlorothiazide (50/25, 100/25)Lopressor HCT
Nadolol-bendroflumethiazide (40/5, 80/5)Corzide
Propranolol LA-hydrochlorothiazide (40/25, 80/25)Inderide LA
Timolol-hydrochlorothiazide (10/25)Timolide
Centrally acting drug and diuretic
Methyldopa-hydrochlorothiazide (250/15, 250/25, 500/30, 500/50)Aldoril
Reserpine-chlorthalidone (0.125/25, 0.25/50)Demi-Regroton, Regroton
Reserpine-chlorothiazide (0.125/250, 0.25/500)Diupres
Reserpine-hydrochlorothiazide (0.125/25, 0.125/50)Hydropres
Diuretic and diuretic
Amiloride-hydrochlorothiazide (5/50)Moduretic
Spironolactone-hydrochlorothiazide (25/25, 50/50)Aldactazide
Triamterene-hydrochlorothiazide (37.5/25, 75/50)Dyazide, Maxzide

More than two-thirds of hypertensive individuals cannot be controlled on one drug and will require two or more antihypertensive agents selected from different drug classes.28,87,101–103 For example, in ALLHAT, 60% of those whose BP was controlled to <140/90 mm Hg received two or more agents, and only 30% overall were controlled on one drug.28 In hypertensive patients with lower BP goals or with substantially elevated BP, 3 or more antihypertensive drugs may be required.

Since the first VA Cooperative trial published in 1967, thiazide-type diuretics have been the basis of antihypertensive therapy in the majority of placebo-controlled outcome trials in which CVD events, including strokes, CHD, and HF, have been reduced by BP lowering.104–108 However, there are also excellent clinical trial data proving that lowering BP with other classes of drugs, including ACEIs, ARBs, β-blockers (BBs), and calcium channel blockers (CCBs), also reduces the complications of hypertension.90,101,102,107,109–112 Several randomized controlled trials have demonstrated reduction in CVD with BBs, but the benefits are less consistent than with diuretics.107,108 The European Trial on Systolic Hypertension in the Elderly (Syst-EUR) study showed significant reductions in stroke and all CVD with the dihydropyridine CCB, nitrendipine, compared with placebo.113 The Heart Outcomes Prevention Evaluation (HOPE) trial, which was not restricted to hypertensive individuals but which included a sizable hypertensive subgroup, showed reductions in a variety of CVD events with the ACEI ramipril compared with placebo in individuals with prior CVD or diabetes mellitus combined with other risk factor(s).110 The European trial on reduction of cardiac events with perindopril in stable coronary artery disease (EUROPA), in which the ACEI perindopril was added to existent therapy in patients with stable coronary disease and without HF, also demonstrated reduction in CVD events with ACEIs.114

Since 1998, several large trials comparing newer classes of agents, including CCBs, ACEIs, an α1 receptor blocker, and an ARB, with the older diuretics and/or BBs have been completed.101,102,109,112,115–118 Most of these studies showed the newer classes were neither superior nor inferior to the older ones. One exception was the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study, in which CVD events were 13% lower (because of differences in stroke but not CHD rates) with the ARB losartan than with the BB atenolol.102 There has not been a large outcome trial completed as yet comparing an ARB with a diuretic. All of these trials taken together suggest broadly similar cardiovascular protection from BP-lowering with ACEIs, CCBs, and ARBs, as with thiazide-type diuretics and BBs, although some specific outcomes may differ between the classes. There do not appear to be systematic outcome differences between dihydropyridine and nondihydropyridine CCBs in hypertension morbidity trials. On the basis of other data, short-acting CCBs are not recommended in the management of hypertension.

Rationale for Recommendation of Thiazide-Type Diuretics as Preferred Initial Agent

In trials comparing diuretics with other classes of antihypertensive agents, diuretics have been virtually unsurpassed in preventing the cardiovascular complications of hypertension. In the ALLHAT study, which involved more than 40 000 hypertensive individuals,109 there were no differences in the primary CHD outcome or mortality between the thiazide-type diuretic chlorthalidone, the ACEI lisinopril, or the CCB amlodipine. Stroke incidence was greater with lisinopril than chlorthalidone therapy, but these differences were present primarily in blacks, who also had less BP lowering with lisinopril than diuretics. The incidence of HF was greater in CCB-treated and ACEI-treated individuals compared with those receiving the diuretic in both blacks and whites. In the Second Australian National Blood Pressure (ANBP2) study, which compared the effects of an ACEI-based regimen against diuretics-based therapy in 6000 white hypertensive individuals, cardiovascular outcomes were less in the ACEI group, with the favorable effect apparent only in men.112 CVD outcome data comparing ARB with other agents are limited.

Clinical trial data indicate that diuretics are generally well tolerated.103,109 The doses of thiazide-type diuretics used in successful morbidity trials of low-dose diuretics were generally the equivalent of 25 to 50 mg of hydrochlorothiazide or 12.5 to 25 mg of chlorthalidone, although therapy may be initiated at lower doses and titrated to these doses if tolerated. Higher doses have been shown to add little additional antihypertensive efficacy but are associated with more hypokalemia and other adverse effects.119–122

Uric acid will increase in many patients receiving a diuretic, but the occurrence of gout is uncommon with dosages ≤50 mg/d of hydrochlorothiazide or ≤25 mg of chlorthalidone. Some reports have described an increased degree of sexual dysfunction when thiazide diuretics, particularly at high doses, are used. In the Treatment of Mild Hypertension Study (TOMHS), participants randomized to chlorthalidone reported a significantly higher incidence of erection problems through 24 months of the study; however, the incidence rate at 48 months was similar to placebo.123 The VA Cooperative study did not document a significant difference in the occurrence of sexual dysfunction using diuretics compared with other antihypertensive medications103 (see the section Erectile Dysfunction). Adverse metabolic effects may occur with diuretics. In ALLHAT, diabetes incidence after 4 years of therapy was 11.8% with chlorthalidone therapy, 9.6% with amlodipine, and 8.1% with lisinopril. However, those differences did not translate to fewer CV events for the ACEI or CCB groups.109 Those who were already diabetic had fewer CV events in the diuretic group than with ACEI treatment. Trials longer than 1 year duration using modest doses of diuretics generally have not shown an increase in serum cholesterol in diuretic-treated patients.124,125 In ALLHAT, serum cholesterol did not increase from baseline in any group, but it was 1.6 mg/dL lower in the CCB group and 2.2 mg/dL lower in the ACEI group than in diuretic-treated patients.109 Thiazide-induced hypokalemia could contribute to increased ventricular ectopy and possible sudden death, particularly with high doses of thiazides in the absence of a potassium-sparing agent.121 In the Systolic Hypertension in the Elderly Program (SHEP) trial, the positive benefits of diuretic therapy were not apparent when serum potassium levels were below 3.5 mmol/L.126 However, other studies have not demonstrated increased ventricular ectopy as a result of diuretic therapy.127 Despite potential adverse metabolic effects of diuretics, with laboratory monitoring, thiazide-type diuretics are effective and relatively safe for the management of hypertension.

Thiazide diuretics are less expensive than other antihypertensive drugs, although as members of other classes of drugs have become available in generic form, their cost has been reduced. Despite the various benefits of diuretics, they remain underutilized.128

Achieving Blood Pressure Control in Individual Patients

The algorithm for the treatment of hypertensive patients is shown in Figure 16. Therapy begins with lifestyle modification, and if the BP goal is not achieved, thiazide-type diuretics should be used as initial therapy for most patients, either alone or in combination with one of the other classes (ACEIs, ARBs, BBs, CCBs) that have also been shown to reduce one or more hypertensive complications in randomized controlled outcome trials. Selection of one of these other agents as initial therapy is recommended when a diuretic cannot be used or when a compelling indication is present that requires the use of a specific drug, as listed in Table 12. If the initial drug selected is not tolerated or is contraindicated, then a drug from one of the other classes proven to reduce cardiovascular events should be substituted.

Figure 16. Algorithm for treatment of hypertension.

TABLE 12. Clinical Trial and Guideline Basis for Compelling Indications for Individual Drug Classes

Compelling Indication*Recommended DrugsClinical Trial Basis
BB indicates β-blocker; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; Aldo ANT, aldosterone antagonist.
*Compelling indications for antihypertensive drugs are based on benefits from outcome studies or existing clinical guidelines; the compelling indication is managed in parallel with the BP.
†Conditions for which clinical trials demonstrate benefit of specific classes of antihypertensive drugs used as part of an antihypertensive regimen to achieve BP goal to test outcomes.
Heart failureACC/AHA Heart Failure Guideline,132 MERIT-HF,133 COPERNICUS,134 CIBIS,135 SOLVD,136 AIRE,137 TRACE,138 ValHEFT,139 RALES,140 CHARM141
Post-myocardial infarctionACC/AHA Post-MI Guideline,142 BHAT,143 SAVE,144 Capricorn,145 EPHESUS146
High coronary disease riskALLHAT,109 HOPE,110 ANBP2,112 LIFE,102 CONVINCE,101 EUROPA,114 INVEST147
DiabetesNKF-ADA Guideline,88,89 UKPDS,148 ALLHAT109
Chronic kidney diseaseNKF Guideline,89 Captopril Trial,149 RENAAL,150 IDNT,151 REIN,152 AASK153
Recurrent stroke preventionPROGRESS111

Since most hypertensive patients will require 2 or more antihypertensive medications to achieve their BP goals, addition of a second drug from a different class should be initiated when use of a single agent in adequate doses fails to achieve the goal. When BP is more than 20 mm Hg above systolic goal or 10 mm Hg above diastolic goal, consideration should be given to initiate therapy with 2 drugs, either as separate prescriptions or in fixed-dose combinations (Figure 16).129

The initiation of therapy with more than one drug increases the likelihood of achieving BP goal in a more timely fashion. The use of multidrug combinations often produces greater BP reduction at lower doses of the component agents, resulting in fewer side effects.129,130

The use of fixed-dose combinations may be more convenient and simplify the treatment regimen and may cost less than the individual components prescribed separately. Use of generic drugs should be considered to reduce prescription costs, and the cost of separate prescription of multiple drugs available generically may be less than nongeneric, fixed-dose combinations. The starting dose of most fixed-dose combinations is usually below the doses used in clinical outcome trials, and the doses of these agents should be titrated upward to achieve the BP goal before adding other drugs. However, caution is advised in initiating therapy with multiple agents, particularly in some older persons and in those at risk for orthostatic hypotension, such as diabetics with autonomic dysfunction.

Follow-Up and Monitoring

Once antihypertensive drug therapy is initiated, most patients should return for follow-up and adjustment of medications at monthly intervals or less until the BP goal is reached. More frequent visits will be necessary for patients with stage 2 hypertension or with complicating comorbid conditions. Serum potassium and creatinine should be monitored at least 1 to 2 times/year. After BP is at goal and stable, follow-up visits can usually be at 3- to 6-month intervals. Comorbidities such as HF, associated diseases such as diabetes, and the need for laboratory tests influence the frequency of visits. Other cardiovascular risk factors should be monitored and treated to their respective goals, and tobacco avoidance must be promoted vigorously. Low-dose aspirin therapy should be considered only when BP is controlled because of the increased risk of hemorrhagic stroke when the hypertension is not controlled.131

Special Situations in Hypertension Management

Compelling Indications

Hypertension may exist in association with other conditions in which there are compelling indications for use of a particular treatment based on clinical trial data demonstrating benefits of such therapy on the natural history of the associated condition (Table 12). Compelling indications for specific therapy involve high-risk conditions that can be direct sequelae of hypertension (HF, ischemic heart disease, chronic kidney disease, recurrent stroke) or commonly associated with hypertension (diabetes, high coronary disease risk). Therapeutic decisions in such individuals should be directed at both the compelling indication and BP lowering.

The absence of a positive indication can signify a lack of information for a particular drug class. For example, in recurrent stroke, there is no study employing CCBs or ARBs. Different stages of the conditions may dictate different strategies. In HF management, thiazide-type diuretics are recommended for reducing the incidence of HF but not in lengthening survival in individuals who already have the condition. Furthermore, widespread use of combination therapy in clinical trials confounds interpretation of the effects of single drugs. In the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial, recurrent stroke rate was reduced only when a thiazide-type diuretic was added to ACEI background therapy.

Ischemic Heart Disease

Hypertensive patients are at increased risk for myocardial infarction (MI) or other major coronary event and may be at higher risk of death following an acute MI. Myocardial oxygen supply in hypertensives may be limited by coronary artery disease (CAD) while myocardial oxygen demand is often greater because of the increased impedance to left ventricular ejection and the frequent presence of left ventricular hypertrophy (LVH).154 Lowering both SBP and DBP reduces ischemia and prevents CVD events in patients with CAD, in part by reducing myocardial oxygen demand. One caveat with respect to antihypertensive treatment in patients with CAD is the finding in some studies of an apparent increase in coronary risk at low levels of DBP. For example, in the SHEP study, lowering DBP to <55 or 60 mm Hg was associated with an increase in cardiovascular events, including MI.155 No similar increase in coronary events (a J-shaped curve) has been observed with SBP. Patients with occlusive CAD and/or LVH are put at risk of coronary events if DBP is low. Overall, however, many more events are prevented than caused if BP is aggressively treated.

Stable Angina and Silent Ischemia

Therapy is directed toward preventing MI and death and reducing symptoms of angina and the occurrence of ischemia. Unless contraindicated, pharmacological therapy should be initiated with a BB.142,156 BBs will lower BP, reduce symptoms of angina, improve mortality, and reduce cardiac output, heart rate, and AV conduction. The reduced inotropy and heart rate decrease myocardial oxygen demand. Treatment should also include smoking cessation, management of diabetes, lipid lowering, antiplatelet agents, exercise training, and weight reduction in obese patients.

If angina and BP are not controlled by BB therapy alone, or if BBs are contraindicated, as in the presence of severe reactive airway disease, severe peripheral arterial disease, high-degree AV block, or the sick sinus syndrome, either long-acting, dihydropyridine or nondihydropyridine-type CCBs may be used. CCBs decrease total peripheral resistance, which leads to reduction in BP and in wall tension. CCBs also decrease coronary resistance and enhance poststenotic coronary perfusion. Nondihydropyridine CCBs also can decrease heart rate, but when in combination with a BB, they may cause severe bradycardia or high degrees of heart block. Therefore, long-acting dihydropyridine CCBs are preferred for combination therapy with BBs. If angina or BP is still not controlled on this two-drug regimen, nitrates can be added, but these should be used with caution in patients taking phosphodiesterase-5 inhibitors such as sildenafil. Short-acting dihydropyridine CCBs should not be used because of their potential to increase mortality, particularly in the setting of acute MI.

Heart Failure

The HF syndrome occurs when the heart is incapable of maintaining sufficient flow to accommodate tissue perfusion and metabolic requirements. Forty to 50% of patients with symptoms of HF may have preserved systolic function. These patients are more likely to have hypertension, LVH, and isolated diastolic dysfunction and are more likely to be women.141,157 A variety of neurohormonal systems, especially the renin-angiotensin-aldosterone and sympathetic nervous systems may be activated in response to the LV dysfunction, but such activation may lead to abnormal ventricular remodeling, further LV enlargement, and reduced cardiac contractility. The inexorable progression to more severe stages of LV dysfunction can be significantly reduced by effective therapy with ACEIs, BBs, and diuretics.

Hypertension precedes the development of HF in approximately 90% of patients and increases risk for HF by 2- to 3-fold. Hypertension is especially important in HF affecting African Americans and the elderly. CAD is the cause of HF in approximately two-thirds of HF patients in the United States. The true incidence of HF has been unchanged in men and has declined among women during the past 50 years.158 However, HF hospitalization rates have more than doubled in the past 20 years159 because of the improved therapy resulting in increased life expectancy. HF will probably become even more prevalent in the future as our population ages.

Optimal therapy for HF may require the use of specialized HF disease management programs and utilization of a variety of health professionals to reinforce treatment recommendations. American College of Cardiology/American Heart Association (ACC/AHA) guidelines are available to manage HF.132 In the stage A group (New York Heart Association [NYHA] class I), those at high risk for HF but no demonstrable clinical symptoms or LV dysfunction, treatment should include fastidious risk factor management to control BP, hypercholesterolemia, and hyperglycemia. ACEIs may be appropriate because of their beneficial effects on mortality in patients at high risk for CVD.110,114 The ALLHAT study also has suggested that thiazide-diuretic therapy is useful in preventing disease progression.109 In stage B HF (NYHA class I) as defined by the presence of reduced LV function (ejection fraction [EF] ≤40%) in otherwise asymptomatic individuals, ACEIs and BBs are recommended. Stage C patients (NYHA class II–III) manifest LV dysfunction and overt symptoms, and in these individuals, ACEIs and BBs are again indicated. Aldosterone antagonists also may be of value in this situation.140 Loop diuretics are often necessary to control volume retention. However, there is no evidence that diuretics prevent progression of disease, and diuretics can also increase serum creatinine levels when used in excess. Patients with stage D (NYHA class IV) HF may require advanced care, such as inotropic drugs, implantable defibrillators, biventricular pacemakers, mechanical-assist devices, or transplantation, in addition to the treatment described above for stage C patients.

HF is a “compelling indication” for the use of ACEIs. Abundant evidence exists to justify their use with all stages of HF (Table 12). In patients intolerant of ACEIs, ARBs may be used. BBs are also recommended in HF because of clinical studies demonstrating decreased morbidity and mortality and improvement in HF symptoms (Table 12).

Aldosterone antagonists may provide additional benefit in patients with severe LV dysfunction, usually late stage C (NYHA class III–IV). In the Randomized Aldactone Evaluation Study (RALES), low-dose spironolactone (12.5 to 25 mg daily), when added to standard therapy, decreased mortality by 34%.140 In the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), eplerenone reduced mortality by 15% in patients following a recent MI with LVEF ≤40%, 90% of whom had HF symptoms.140 Hyperkalemia is a risk with aldosterone antagonists, even at low doses (especially since most patients also are taking ACEIs or ARBs), but its incidence can be reduced by limiting therapy to patients with serum creatinine <2.5 mg/dL and monitoring serum potassium carefully.

BP targets in HF have not been firmly established, but lowering SBP is almost uniformly beneficial. In most successful trials, systolic blood pressures were lowered to the range of 110 to 130 mm Hg. One trial demonstrated benefits of β-blockade in patients with SBP >85 mm Hg,134 suggesting that very low BPs (eg, SBP <100 mm Hg) may be desirable in some HF patients.

Digoxin continues to be used in HF despite inconsistent clinical results. In the Digitalis Investigation Group (DIG) trial, it did not reduce mortality in NYHA class II–III patients taking ACEIs and diuretics but did reduce HF symptoms and hospitalizations.160

Diabetes and Hypertension

The combined unadjusted prevalence of total diabetes and impaired fasting glucose in those over 20 years old is 14.4% and is the leading cause of blindness, ESRD, and nontraumatic amputations.161–165 Type 2 diabetes constitutes over 90% of diabetes in the United States and is associated with a 70% to 80% chance of premature death from CVD and stroke.166–170 The concordance of hypertension and diabetes is increased in the population; hypertension is disproportionately higher in diabetics,171 while persons with elevated BP are 2.5 times more likely to develop diabetes within 5 years.172,173 The common absence of normal nocturnal “dipping” of BP in diabetics is linked to other CVD surrogates such as LVH and microalbuminuria.171

The coexistence of hypertension in diabetes is particularly pernicious because of the strong linkage of the 2 conditions with all CVD,168,169 stroke,87,109,110,168,169,174–176 progression of renal disease,165,175,177,178 and diabetic retinopathy.179 The United Kingdom Prospective Diabetes Study (UKPDS)174 demonstrated that each 10 mm Hg decrease in SBP was associated with average reductions in rates of diabetes-related mortality of 15%; myocardial infarction, 11%; and the microvascular complications of retinopathy or nephropathy, 13%. Randomized controlled trials that have included large diabetic populations, including UKPDS, Hypertension Optimal Treatment (HOT) Trial, SHEP, Syst-EUR,67 HOPE Study,110 Losartan Intervention For Endpoint Reduction in Hypertension Study (LIFE), and ALLHAT, have demonstrated that adequate BP control improves CVD outcomes, especially stroke, when aggressive BP targets are achieved.87,88,109,164,175,180

Microalbuminuria (30 to 300 mg/d) is associated with increased CVD risk in diabetics and other high-risk patients.67,181 Overt albuminuria (>300 mg/d or >200 mg/g creatinine on spot urine) or renal insufficiency (estimated GFR <60 mL/min, corresponding to serum creatinine >1.5 in men or >1.3 mg/dL in women) defines the presence of chronic kidney disease (CKD) in diabetic patients. SBP correlates better than DBP with renal disease progression in diabetics.171,177,178,182,183 The rate of decline in renal function among patients with diabetic nephropathy has been reported to be a continuous function of arterial pressure down to approximately 125 to 130 mm Hg SBP and 70 to 75 mm Hg DBP.177,178,182,183

The JNC 7 recommendations are consistent with guidelines from the American Diabetes Association (ADA),88,164 which has also recommended that BP in diabetics be controlled to levels of 130/80 mm Hg or lower (although available data are somewhat sparse to justify the low target level of 130/80 mm Hg). Whatever the goal level, rigorous control of BP is paramount for reducing the progression of diabetic nephropathy to ESRD.88,164,177,178,181–183

Regarding the selection of medications, clinical trials with diuretics, ACEIs, BBs, ARBs, and calcium antagonists have demonstrated benefit in the treatment of hypertension in both type 1 and type 2 diabetics.87,88,109,164,175,180 The question of which agent class is superior for lowering BP is somewhat moot because the majority of diabetic patients will require 2 or more drugs to achieve BP control.164,171,184

Thiazide-type diuretics are beneficial in diabetics, either alone or as part of a combined regimen. In the prespecified diabetic subgroup of ALLHAT, therapy that began with chlorthalidone reduced the primary end point of fatal CHD and MI to the same degree as therapy based on lisinopril or amlodipine. Of potential concern is the tendency for thiazide-type diuretics to worsen hyperglycemia, but this effect tended to be small and did not produce more CV events compared with the other drug classes.185

Therapy with an ACEI also is an important component of most regimens to control BP in diabetic patients.67,172,173,178,179 ACEIs may be used alone for BP lowering but are much more effective when combined with a thiazide-type diuretic or other antihypertensive drugs. The ADA has recommended ACEIs for diabetic patients over 55 years old at high risk for CVD and BBs for those with known CAD.88 In the Micro-Hope subanalysis of the HOPE Study, which included both hypertensive and normotensive individuals,186 high-risk diabetic patients treated with ACEI added to conventional therapy showed a reduction in combined MI, stroke, and CVD death of about 25% and reduction in stroke by about 33% compared with placebo plus conventional therapy. With respect to microvascular complications, the ADA has recommended both ACEIs and ARBs for use in Type 2 diabetic patients with CKD because these agents delay the deterioration in GFR and the worsening of albuminuria.88,164,171,181

BBs, especially β1-selective agents, are beneficial in diabetics as part of multidrug therapy, but their value as monotherapy is less clear. A BB is indicated in a diabetic with ischemic heart disease but may be less effective in preventing stroke than an ARB, as was found in the LIFE study.187 Although BBs can cause adverse effects on glucose homeostasis in diabetics, including worsening of insulin sensitivity and potential masking of the epinephrine-mediated symptoms of hypoglycemia, these problems are usually easily managed and are not absolute contraindications for BB use.

Calcium channel blockers may be useful in diabetics, particularly as part of combination therapy to control BP. They were shown to reduce CVD events in diabetics compared with placebo in several clinical outcome trials.87,101,113,118 In the diabetic cohort of ALLHAT, amlodipine was as effective as chlorthalidone in all categories except HF, where it was significantly inferior.109 The Appropriate Blood Pressure Control in Diabetes (ABCD) study in diabetics was stopped prematurely when it was found that the dihydropyridine nitrendipine was inferior to lisinopril in reducing the incidence of ischemic cardiac events.188 However, in normotensive diabetics in the Second ABCD (ABCD2) study, nitrendipine was equivalent to lisinopril in stroke prevention and in retardation of the development of albuminuria.189

Chronic Kidney Disease
Age and Kidney Function

Renal excretory function, as represented by GFR, deteriorates with age beginning in the third or fourth decade of life. By the sixth decade, GFR commonly declines by 1 to 2 mL/min per year. This age-related loss of renal function is proportional to BP level, and the rate of GFR deterioration can accelerate to 4 to 8 mL/min per year if SBP remains uncontrolled.165 Such rates of deterioration may lead to the development of ESRD and the need for dialysis or transplantation, especially in those with other coexistent renal disease.

CKD is defined as either (1) reduced excretory function with an eGFR <60 mL/min/1.73 m2 (approximately corresponding to a creatinine of >1.5 mg/dL in men or >1.3 mg/dL in women) or (2) the presence of albuminuria (>300 mg/d or 200 mg/g creatinine). In a number of laboratories, serum creatinine is being replaced as an index of renal function by eGFR, the values of which are derived from newer algorithms that include adjustments for gender, race, and age. These algorithms are available on web sites.66 The measurements appear to be of greater value than 24-hour urine collections for creatinine clearance.

Urinary albumin excretion has diagnostic and prognostic value equivalent to reduced eGFR. To avoid inaccuracies associated with 24-hour urine collections, spot urine samples may be used and the ACR determined. Microalbuminuria is present when the spot urine ACR is between 30 and 200 mg albumin/g creatinine. ACR values >200 mg albumin/g creatinine signify the presence of CKD.

CVD Risk in CKD

CVD is the most common cause of death in individuals with CKD, and CKD is itself an independent risk factor for CVD. Individuals with eGFR <60 mL/min have an approximate 16% increase in CVD mortality, and individuals with eGFR <30 mL/min, a 30% increase.190 CVD risk also exhibits a continuous relationship with albuminuria; the presence of microalbuminuria confers a 50% increase in risk and the presence of macroalbuminuria, a 350% increase.191


NHANES III data indicated that about 3% (5.6 million people) of adults in the United States had elevated serum creatinine values and 70% of these had hypertension.192 While 75% of individuals received treatment, only 11% with hypertension and elevated serum creatinine had BP <130/85 mm Hg and only 27% had BP <140/90 mm Hg.193 In the prevention of CKD, the value of vigorous antihypertensive therapy is most pronounced in those individuals with the greatest degrees of albuminuria. In the Modification of Diet and Renal Disease (MDRD) study, individuals with proteinuria had slower rates of progression to ESRD if their SBP values were <130 mm Hg. A meta-analysis of individuals with CKD and albuminuria found that positive predictors of outcome were lower SBP levels (110 to 129 mm Hg), lower albumin excretion ratio (AER) (<1.0 g/d), and the presence of ACEI therapy.194,195 However, in the African American Study of Kidney Disease and Hypertension (AASK) study of African American individuals with hypertensive CKD, those achieving a mean BP of 128/78 mm Hg experienced renal deterioration at the same rate as those achieving a mean of 141/85 mm Hg.196 Many studies demonstrate that antihypertensive regimens that include an ACEI or ARB are more effective in slowing progression of CKD than other antihypertensive regimens.149–152,196

The joint recommendations of the American Society of Nephrology and the National Kidney Foundation (NKF) provide useful guidelines for management of hypertensive patients with CKD. They recommend a goal BP for all CKD patients of <130/80 mm Hg and a need for more than 1 antihypertensive drug to achieve this goal. The guidelines indicate that most patients with CKD should receive an ACEI or an ARB in combination with a diuretic and that many will require a loop diuretic rather than a thiazide. In addition, if there is a conflict between the goals of slowing progression of CKD and CVD risk reduction, individual decision-making is recommended, based on risk stratification.

Patients with Cerebrovascular Disease

The risk of clinical complications of cerebrovascular disease including ischemic stroke, hemorrhagic stroke, and dementia increases as a function of BP levels. Given the population distribution of BP, most ischemic strokes occur in individuals with prehypertension or stage 1 hypertension. The incidence of ischemic or hemorrhagic stroke is reduced substantially by treatment of hypertension. No specific agent has proven to be clearly superior to all others for stroke protection. In the LIFE study, there were fewer strokes in the losartan-treated group than in the group treated with atenolol.102 In the ALLHAT study, the stroke incidence was 15% greater with ACEI than with thiazide-type diuretic or dihydropyridine CCB, but the BP reduction in the lisinopril group was also less than with chlorthalidone or amlodipine.109

With respect to the prevention of recurrent stroke, PROGRESS demonstrated that addition of the diuretic indapamide to the ACEI perindopril caused a 43% reduction in stroke occurrence.111 The reduced incidence of stroke appeared related to the BP reduction obtained by the combination therapy even though many patients on entry into the study were not hypertensive.197 No significant reduction was present in those on perindopril alone whose BP was only 5/3 mm Hg lower than in the control group.

The management of BP during an acute stroke remains controversial. BP is often elevated in the immediate post-stroke period and is thought by some to be a compensatory physiological response to improve cerebral perfusion to ischemic brain tissue. As a result, it has been common practice after acute cerebral infarction to reduce or withhold BP treatment until the clinical condition has stabilized. There still are no large clinical studies on which to base definitive recommendations. Nevertheless, the American Stroke Association has provided the following guidelines: In patients with recent ischemic stroke whose SBP is >220 mm Hg or DBP 120 to 140 mm Hg, cautious reduction of BP by about 10% to 15% is suggested, while carefully monitoring the patient for neurological deterioration related to the lower pressure. If the DBP is >140 mm Hg, carefully monitored infusion of sodium nitroprusside should be used to reduce the BP by 10 to 15%.198

BP control affects the use of thrombolytic agents in ischemic stroke. SBP >185 mm Hg or diastolic pressures >110 mm Hg are contraindications to the use of tissue plasminogen activator (t-PA) within the first 3 hours of an ischemic stroke. Once a thrombolytic agent has been initiated, BP should be monitored closely, especially in the first 24 hours after initiation of treatment. SBP ≥180 mm Hg or DBP ≥105 mm Hg usually necessitates therapy with intravenous agents to prevent intracerebral bleeding.199

Other Special Situations


The prevalence, impact, and control of hypertension differ across racial and ethnic subgroups of the US population. In African Americans, hypertension is more common, more severe, develops at an earlier age, and leads to more clinical sequelae than in age-matched non-Hispanic whites.200 Mexican Americans and Native Americans have lower control rates than non-Hispanic whites and African Americans.201,202 The pathogenesis of hypertension in different racial subgroups may differ with respect to the contributions of such factors as salt, potassium, stress, cardiovascular reactivity, body weight, nephron number, sodium handling, or hormonal systems, but in all subgroups, the pathogenesis is multifactorial.200,203 African Americans have a greater prevalence of other cardiovascular risk factors, especially obesity.200,203 Much of the variance in hypertension-related sequelae across racial or ethnic groups may be attributable to differences in socioeconomic conditions, access to healthcare services, or attitudes, beliefs, and deficits in accurate health-related information.200,203 For example, when medications and provider services were provided free of charge as in the Hypertension Detection and Follow-up Program, African American men treated with the intensive “Stepped-Care Approach” actually benefited more than whites.204

Weight reduction and sodium reduction are recommended for all prehypertensive and hypertensive patients but may be particularly effective in minorities. The salt content of some traditional diets in minorities may be very high.205 The low-sodium DASH eating plan was associated with greater reductions in BP in African Americans than other demographic subgroups.94 In clinical trials, lowering BP prevents sequelae of hypertension in all racial or ethnic groups.200,203 Nonetheless, monotherapy with BBs, ACEIs, or ARBs lowers BP to a somewhat lesser degree in African Americans than whites.109,206–208 In the ALLHAT trial with more than 15 000 blacks, the ACEIs were less effective in lowering blood pressure than either the thiazide-type diuretic or the CCBs. This was associated with a 40% greater risk of stroke, 32% greater risk of HF, and 19% greater risk of CVD in those randomized to the ACEI versus the diuretic.109 The interracial differences in BP-lowering observed with these drugs are abolished when they are combined with a diuretic.109,203,208

Racial differences in incidence of antihypertensive drug side effects may occur; African Americans and Asians have a 3- to 4-fold higher risk of angioedema109,209,210 and have more cough attributed to ACEIs than whites.211

Several other benefits of treatment have been demonstrated in minority populations. A 28% reduction in mortality was observed in African Americans who received BB therapy after acute myocardial infarction compared with those not receiving a BB.212 A greater degree of preservation of renal function occurred in African Americans with hypertensive nephrosclerosis treated with a regimen containing an ACEI compared with BB or a calcium antagonist.196 No large outcome studies have been carried out with ARBs in African American and other minority patients. Unfortunately, sufficient numbers of Mexican Americans, other Hispanic Americans, Native Americans, or Asian/Pacific Islanders have not been included in most of the major clinical trials to allow reaching strong conclusions about their responses to individual antihypertensive therapies.

Irrespective of whether race or ethnicity should be a significant consideration in the choice of individual antihypertensive drugs, the use of combination or multiple antihypertensive drug therapy, which usually includes a thiazide-type diuretic, in minority groups will lower BP and reduce the burden of hypertension-related cardiovascular and renal disease.

Metabolic Syndrome
Definition and Associations

The term “metabolic syndrome” describes a constellation of cardiovascular risk factors related to hypertension, abdominal obesity, dyslipidemia, and insulin resistance. The definition adopted by the National Cholesterol Education Program (Adult Treatment Panel [ATP] III) guidelines in 200121 is the presence of 3 or more of the 5 risk factors (Table 13). The World Health Organization has a somewhat different definition of the metabolic syndrome, but for consistency JNC 7 has adopted the ATP III definition.

TABLE 13. Clinical Criteria Defining the Metabolic Syndrome in ATP III

Source: Executive Summary of the Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486–2497.
Waist circumference
    >102 cm (>40 inches) for men
    >88 cm (>35 inches) for women
Blood pressure
    ≥130 mm Hg systolic and/or
    ≥85 mm Hg diastolic
Fasting glucose
    ≥110 mg/dL or 6.1 mmol/L
    ≥150 mg/dL or 1.69 mmol/L
HDL cholesterol
    <40 mg/dL (1.04 mmol/L) in men
    <50 mg/dL (1.29 mmol/L) in women

Several other associated features have been reported, including hyperinsulinemia, insulin resistance, and higher density of LDL-C particles.213 The metabolic syndrome has also been associated with high levels of inflammatory risk markers,214 reduced fibrinolysis (including elevated plasminogen activator inhibitor-1),215 heightened magnitude of oxidative stress,216,217 microalbuminuria,218 abnormalities in autonomic regulation,219 and activation of the renin-angiotensin-aldosterone axis.220


When the ATP III criteria were applied to the data from the NHANES III survey (1988–1994), the prevalence of the metabolic syndrome in adults in the United States was estimated at 23.7% or about 47 million individuals.221 BMI (kg/m2) is related to the metabolic syndrome in both men and women (Table 14).222 In addition, because abdominal obesity is also correlated with the metabolic syndrome, ATP III uses it rather than BMI. This becomes important in overweight individuals with a BMI 25 to 29.9 kg/m2 and large waist circumference (>40 inches in men, >35 inches in women) who may have metabolic syndrome despite not being obese.

TABLE 14. Estimated Prevalence of the Metabolic Syndrome Using the ATP III Definition Among Normal Weight, Overweight, and Obese Men and Women in NHANES III222

CategoryBMI, kg/m2Metabolic Syndrome Prevalence, %
Normal weight<25.04.6%6.2%

The metabolic syndrome will likely increase further in the next several years, primarily because of the rapid increase in obesity. The health problems related to the metabolic syndrome will likely escalate dramatically.

Age Trends

The prevalence of the metabolic syndrome is highly age-dependent. A prevalence of 7% among adults aged 20 to 29 years rises to 40% or more among Americans over 60 years old.

Clinical Impact

The metabolic syndrome is associated in men with a 4-fold increase in risk for fatal CHD and a 2-fold greater risk of CVD and all-cause mortality, even after adjustment for age, LDL-C, smoking, and family history of CHD.223 The metabolic syndrome is associated with increased CHD risk in women.224 Patients with the metabolic syndrome have a 5- to 9-fold increased risk of developing diabetes.225,226

Clinical Management of the Metabolic Syndrome

The cornerstone for clinical management in adults is appropriate lifestyle changes.

Overweight and Obesity.

Treatment of overweight and obesity is summarized in the next section using key principles in the Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults.227

Physical Activity.

The metabolic syndrome can improve with increased physical activity.228 (See the section Prevention and Lifestyle Modifications for Overweight and Obesity.)

Prehypertension and Hypertension.

The vast majority of individuals with the metabolic syndrome will fall into the categories of prehypertension or stage 1 hypertension. Lifestyle modification is the cornerstone of management in all patients with prehypertension or with the metabolic syndrome, but if BP exceeds 140/90 mm Hg, pharmacological therapy is indicated as described in the hypertension treatment algorithm (Figure 16).


Elevated TG and reduced HDL are typical lipid abnormalities in metabolic syndrome. Elevated LDL is not a prime feature of metabolic syndrome but is important in clinical management.21

Impaired Glucose Tolerance and Diabetes.

Modest lifestyle change including healthful nutrition and increased physical activity can reduce the development of diabetes by nearly 60% in high-risk individuals.229 Management guidelines published by the American Diabetes Association are appropriate for individuals with impaired fasting glucose and diabetes.230


All patients with lipid abnormalities for LDL, HDL, or TG should be treated according to the ATP III recommendations.21

Overweight and Obesity
Prevalence and Epidemiology

Using the NHANES databases for the periods 1988 to 1994 versus 1999 to 2000, the age-adjusted prevalence of obesity (BMI ≥30 kg/m2) among US adults increased from 22.9% to 30.5%,33 while the prevalence of overweight (BMI ≥25 kg/m2) increased from 55.9% to 64.5%. Obese subjects, especially men, with no other risk factors have increased relative risk for CVD (Table 15).231

TABLE 15. Relative 10-Year Risk for Diabetes, Hypertension, Heart Disease, and Stroke Over the Next Decade Among Men Initially Free of Disease Stratified by Baseline BMI231

BMIDiabetesHypertensionHeart DiseaseCVA

Obesity occurs more often among Hispanics, Native Americans, and African Americans than whites in the United States. These demographic differences extend to children, in whom obesity and related health problems are increasing at nearly double the rate in ethnic minorities compared with whites.232,233 The rapid increase in the population of ethnic minorities in the United States is another factor that will lead to a rise in the prevalence of obesity and its complications unless effective, culturally diverse, population-based health promotion strategies are promoted.

Prevention and Lifestyle Modifications for Overweight and Obesity

The major goal of management of both the metabolic syndrome and overweight and obesity is to reduce the age-related rate of weight gain. This challenging task will require a complex combination of healthy behaviors, including decrease in sedentary activities, increase in physical activity, and reduction in calorie intake (Table 16). Simple yet practical suggestions include reducing time spent watching television or being online and increasing time spent walking or in activities that raise heart rate. The emphasis for weight management should be on avoidance of excess total energy intake and a regular pattern of physical activity. Reducing food portion sizes and limiting fat intake can assist in reducing overall calorie intake. High-sodium diets may be especially deleterious in obese subjects.234

TABLE 16. Lifestyle Changes Beneficial in Reducing Weight*

*For more detailed information refer to the Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. Obes Res. 1998;6(suppl):51S–209S.
Decrease time in sedentary behaviors such as television watching, video game play, or spending time online
Increase physical activity such as walking, biking, aerobic dancing, tennis, soccer, basketball, etc.
Decrease portion sizes for meals, snacks
Reduce portion sizes or frequency of consumption of calorie-containing beverages

Specific nutrient intakes for individuals should be based on lipoprotein levels, BP, and the presence of coexisting heart disease, diabetes, and other risk factors. For example, adoption of the well-studied low-sodium DASH eating plan94 provides heart-healthy foods that can be used to promote weight loss, reduce BP in both hypertensive and prehypertensive individuals, and reduce LDL. The benefits of modest lifestyle changes on cardiovascular risk factors are well documented. In the Framingham Heart Study, weight loss of 5 pounds or greater was associated with reductions in cardiovascular risk of about 40%.235 A 10% reduction in body weight can reduce disease risk factors.227

Physical activity is a key feature of treatment. Increased physical activity, when combined with a reduction in calories, is essential to weight loss success. Based on the available evidence, the recommendation is to engage in regular physical activity at least 30 minutes per day, most days of the week (see Table 9). In addition, physical activity is critical to the maintenance of weight loss and is important for overall reduction in cardiovascular risk; 60 to 90 minutes per week of walking can reduce CHD mortality by about 50%.236 The CVD benefits of slow walking appear to be comparable to those of walking more quickly, suggesting that the most important predictor of benefit was walking time, not speed. Exercise programs appear beneficial at any age and are associated with overall reductions in CVD outcomes by about 50%.237 Although aerobic fitness may negate much of the cardiovascular risk associated with obesity,238 studies report that individuals with obesity have much lower levels of physical activity and poorer aerobic fitness than leaner individuals.239

Left Ventricular Hypertrophy

The common feature of all forms of LVH is increased left ventricular mass, although there are many different presentations and subtypes, each with different prognosis and therapy.240 LVH subclasses can be characterized generally by the relative wall thickness, the presence or absence of reduced contractility, and the end-diastolic chamber size. LVH can occur in endurance athletes with normal or supranormal systolic function, large end-diastolic volumes, and elongation of myofibrils (eccentric hypertrophy). LVH due to hypertension is usually characterized by concentric hypertrophy with circumferential hypertrophy of myofibrils, normal or increased contractility, increased relative wall thickness, normal or low end-diastolic volumes, and at times impaired relaxation (diastolic dysfunction). In population-based samples, 30% to 50% of individuals with stage 1 and 2 hypertension have impaired LV relaxation, and in more severe forms of hypertension, about two-thirds have abnormal LV relaxation. In untreated or poorly treated individuals, LVH becomes a major risk factor for dilated cardiomyopathy and HF.241

Detection and Risk

Echocardiography is much more sensitive than electrocardiography (ECG) for detection of LVH, although ECG-LVH is a highly specific indicator for the condition. Individuals with LVH are more than twice as likely to suffer premature cardiovascular events or death. Current ECG algorithms defining LVH produce a high false-positive rate in African Americans and overestimate the prevalence of LVH in this population.242,243 The attributable risk of LVH for all-cause mortality is greater than that of single or multivessel coronary artery disease or low EF.


Several studies suggest that LVH regression is associated with a lower overall CVD risk. Weight loss, salt restriction, and BP lowering with most antihypertensive agents produce LVH regression. Selection of individual drugs appears to be less important, but certain trends have emerged. Fifty studies of LVH regression conducted before 1996 were subjected to meta-analysis.244 In these studies, predictors of LV mass reduction during treatment were higher pretreatment LV mass, greater fall in SBP or DBP, and longer duration of treatment. The most consistent reduction in LV mass was achieved with ACEIs, the least reduction occurred with BBs, and intermediate benefits occurred for diuretics and calcium antagonists. However, in both the Treatment of Mild Hypertension Study and the VA Cooperative Monotherapy trial, diuretic therapy achieved the greatest benefit in LV mass reduction.245,246 The LIFE study found that LVH, defined by electrocardiography, was reduced significantly more by a losartan-based than atenolol-based regimen despite equivalent BP lowering.102

Peripheral Arterial Disease

Major risk factors for peripheral arterial disease (PAD) are hypertension, diabetes, and smoking. Symptomatic peripheral arterial disease is associated with a greatly increased risk of death from CVD, in part because diffuse atherosclerosis, CAD, and renovascular disease frequently coexist in these patients. Therefore, more intensive screening for these related cardiovascular disorders is appropriate in persons with PAD. Renovascular hypertension should be strongly considered in this population if BP is uncontrolled and if ACEI or ARB treatment is being considered.

Antihypertensive drug treatment is ineffective in relieving the symptoms of PAD, and vasodilator agents such as ACEIs, CCBs, α-adrenergic blockers, and direct vasodilators do not improve walking distance or symptoms of claudication.247–249 This lack of efficacy may be due to inability of maximally dilated diseased vessels to dilate further during exercise, redistribution of flow caused by the creation of a “steal” phenomenon where blood flow increases in nondiseased vascular beds at the expense of diseased beds, or alteration of pressure-flow relationships distal to the occluded areas by BP reduction. BBs may cause peripheral vasoconstriction and have the potential to increase the frequency of intermittent claudication in individuals with PAD. However, recent studies have shown that BBs have little effect on walking distance or calf blood flow in patients with intermittent claudication.250 Thus, BBs can be used in PAD patients, especially if needed for treatment of CAD or HF.

No selective outcome benefit has been demonstrated for any individual class of antihypertensive medication in patients with PAD.109 Therefore, antihypertensive drug choices should be made on the basis of the presence or absence of compelling indications. If Raynaud’s phenomenon is present, CCBs can be used.251 LDL lowering will reduce the risk for CVD events in people with PAD.252


Treating hypertension in PAD patients reduces the risk of MI, stroke, HF, and death.253 A structured walking program has been shown to increase the pain-free and maximum walking distances in patients with intermittent claudication.254 Smoking cessation may be the most important factor in whether PAD progresses. Patients should be encouraged and assisted to stop smoking. Lipid abnormalities should be controlled using lifestyle modification or drugs as appropriate. Coexisting glucose intolerance or insulin resistance calls for increased exercise and weight reduction, and aggressive management of diabetes is indicated. Table 17 outlines medical therapies of PAD.

TABLE 17. Medical Therapy of Peripheral Arterial Disease

Stop smoking
Achieve ideal body weight
Structure exercise program
Achieve goal blood pressure
Control lipids (goal LDL <100 mg/dL)
Prevent or control diabetes
Administer antiplatelet therapy (aspirin, clopidogrel, or both)
Consider use of Cilostazol for symptoms of claudication if exercise alone is ineffective

Hypertension in Older People

The number of Americans aged 65 years or older has increased from 24.2 million to 32.6 million from 1980 to 2000 and is expected to continue to rise.255 SBP increases almost linearly with age in industrialized societies (Figure 12), as does the overall prevalence of hypertension and the proportion of hypertensives with isolated SBP elevation (ISH) (Figure 17).192 In contrast, DBP increases in parallel with SBP until about age 55, after which it declines as a manifestation of age-related increases in central arterial stiffness. By age 60, about two-thirds of those with hypertension have ISH, and by age 75, almost all hypertensives have systolic hypertension and about three-fourths of hypertensives have ISH.

Figure 17. Frequency distribution of untreated hypertensive individuals by age and hypertension subtype. Frequency distribution of untreated hypertensive individuals by age and hypertension subtype. Numbers at the tops of bars represent the overall percentage distribution of untreated hypertension in that age group. ▪, ISH (SBP≥140 mm Hg and DBP <90 mm Hg); , SDH (SBP ≥140 mm Hg and DBP ≥90 mm Hg); □, IDH (SBP <140 mm Hg and DBP ≥90 mm Hg). Source: Franklin SS et al. Hypertension 2001;37:869–874.

Individuals over age 60 represent the most rapidly growing segment of the US population, and even in those who remain normotensive between 55 and 65 years old, there remains a lifetime risk of developing hypertension that exceeds 90%.16 At the same time, there is a 3- to 4-fold increase in CVD risk in older compared with younger individuals. These facts prompted the NHBPEP to issue a Clinical Advisory statement in May, 2000, stating that SBP should be the primary target for the diagnosis and management of older people with hypertension.256 Currently, BP control rates (systolic <140 mm Hg and diastolic <90 mm Hg) are only about 20% in older hypertensives, largely due to poor control of SBP.257

Treatment Benefits

In the SHEP study involving hypertensives over 60 years old with pretreatment SBP >160 and DBP <90 mm Hg, individuals treated with chlorthalidone (with or without BB) had reductions in the primary end point of stroke (36%), as well as HF events (54%), myocardial infarctions (27%), and overall CVD (32%)24 as compared with the placebo group. Using a similar design and sample size, the Syst-EUR study compared a regimen based on nitrendipine to placebo and found a significant reduction in stroke (41%) as well as overall CVD events (31%).113 A meta-analysis of 8 placebo-controlled trials in 15 693 elderly patients followed for 4 years found that active antihypertensive treatment reduced coronary events (23%), strokes (30%), cardiovascular deaths (18%), and total deaths (13%), with the benefit particularly great in those older than 70 years.258 Benefits of therapy have been demonstrated even in individuals over 80 years old.116,259 Analyses of treatment trials in the elderly by the Hypertension Trialists group have suggested that the choice of initial agent is less important than the degree of BP reduction achieved.90

Accurate and representative BP measurement can pose special problems in some older individuals (see the section Accurate Blood Pressure Measurement in the Office). BP is more variable in the older patient, often due to stiff large arteries and age-related decreases in baroreflex buffering. Exaggerated BP drops may occur in the elderly during postural change (see the section Orthostatic Hypotension), after meals,260 and after exercise.97 Pseudohypertension, where cuff BP overestimates the actual intra-arterial pressure due to relative inability of the BP cuff to compress a thickened, stiff, or calcified brachial artery, is an uncommon condition in older persons. But this condition should be strongly considered if usual treatment does not reduce BP, especially in those patients who complain of symptoms consistent with postural hypotension.261 A relatively small percentage of elderly patients have a reversible form of hypertension, most commonly due to renovascular disease, which is seen most often in smokers.262

SBP provides more appropriate classification and risk stratification than DBP in the elderly. In the Framingham Heart Study, SBP alone correctly classified the BP stage in 94% of adults over 60 years old, while DBP alone correctly classified 66%.192 Pulse pressure (PP) (SBP − DBP) is only marginally stronger than SBP for risk stratification in individuals over age 60, but under age 60, PP is not useful as a CVD risk predictor.18 PP generally decreases as a result of SBP lowering,24,263 but no prospective clinical trial has used PP as the primary clinical end point. Thus, on balance, SBP is superior to PP and DBP as a way to stratify patients and as a target for treatment in older persons.

Although there is no randomized prospective clinical trial that has conclusively proven the benefits of treatment in individuals with Stage 1 systolic hypertension (140 to 159 mm Hg), hypertension therapy should not be withheld in these patients, and therapy should not be withheld on the basis of age. There is no definitive evidence of an increase in risk of aggressive treatment (a J-curve) unless DBP is lowered to <55 or 60 mm Hg by treatment.155


Weight loss and reduced sodium intake are particularly beneficial in older people. In Trial of nonpharmacologic Interventions in the Elderly (TONE), reducing sodium to 80 mmol (2 g) per day reduced BP over 30 months, and about 40% of those on the low-salt diet were able to discontinue their antihypertensive medications.264 When weight loss was combined with salt reduction, an additional BP decrease was seen. Older persons should also be encouraged to avoid excessive alcohol intake and remain as physically active as feasible.

Use of specific drug classes in older people is largely similar to that recommended in the general algorithm and for individual compelling indications. Combination therapy with two or more drugs is generally needed to achieve optimal BP control. In routine practice, if the systolic goal is achieved, the diastolic goal will almost always be reached as well.

A significant number of elderly individuals have widely variable BP with exaggerated high and low extremes. Such individuals deserve consideration for a slow titration approach, as do individuals with a history of medication side effects and those with orthostatic hypotension. Unfortunately, the misperception that many elderly have “brittle hypertension” has contributed to widespread inadequacy of drug titration and to poor BP control.

Orthostatic Hypotension

BP measurements are typically recorded in the sitting position. This practice, while convenient for the practitioner, limits the ability to diagnose orthostatic hypotension (OH). Normally, standing is accompanied by a small increase in DBP and a small decrease in SBP when compared with supine values. OH is present when there is a supine-to-standing BP decrease >20 mm Hg systolic or >10 mm Hg diastolic. There is more OH in diabetics. OH occurred in about 7% of men over 70 years old in the Honolulu Heart Study, was highly age-dependent, and carried with it a 64% increase in age-adjusted mortality compared with a control population.265 There is a strong correlation between the severity of OH and premature death as well as increased numbers of falls and fractures.265–267 The causes of OH include severe volume depletion, baroreflex dysfunction, autonomic insufficiency, and certain venodilator antihypertensive drugs, especially α-blockers and α-β-blockers. Diuretics and nitrates may further aggravate OH.

In treating older hypertensive patients, clinicians should be alert to potential OH symptoms such as postural unsteadiness, dizziness, or even fainting. Lying and standing BPs should be obtained periodically in all hypertensive individuals over 50 years old. OH is a common barrier to intensive BP control that should be clearly documented; if present, drug therapy should be adjusted accordingly and appropriate warnings given to patients.

Resistant Hypertension

Resistant hypertension is defined as the failure to achieve goal BP in patients who are adhering to full doses of an appropriate 3-drug regimen that includes a diuretic. Several causes of resistant hypertension may be present.

Improper BP measurement can lead to overestimation of intra-arterial pressure. (See section on BP measurement.) Falsely high readings may also be observed in those whose brachial arteries are heavily calcified or arteriosclerotic and cannot be fully compressed.268 Clinic or white-coat hypertension may also lead to transient high readings that are not experienced throughout the day. This can be documented by home BP or ambulatory BP readings.

Inadequate diuretic therapy is common in resistant hypertension. Volume overload, once recognized, can be managed by use of appropriate diuretics. While a thiazide-type diuretic is recommended for the majority of hypertensive patients, a loop diuretic is often required for patients who have a decreased GFR or HF.

Failure to receive adequate medications can be the result of reluctance on the part of the patient or practitioner to use effective doses of medications. Causes and approaches to nonadherence are discussed in subsequent sections of this review.

Drug interactions that induce resistance may be difficult to detect unless the patient is asked open-ended questions regarding what they take when experiencing pain and what food supplements, health food preparations, and over-the-counter and Internet-purchased medications and supplements they use. Nonsteroidal anti-inflammatory drugs and pressor agents in cold remedies, nasal vasodilators, and some nontraditional remedies may counter the antihypertensive effects of prescribed medications.

If resistant hypertension persists after remediable causes are identified and corrected, then a concerted search for a cause of secondary hypertension should be conducted (Table 7). If resistance still persists, consultation with a hypertension specialist is a logical next step.

Specific causes of resistant hypertension are listed in Table 18. They usually can be identified by appropriate evaluation, and, once identified, can almost always be treated effectively. The prevalence of truly resistant hypertension is small.

TABLE 18. Causes of Resistant Hypertension

Improper BP measurement
Volume overload
    Excess sodium intake
    Volume retention from kidney disease
    Inadequate diuretic therapy
Drug-induced or other causes
    Inadequate doses
    Inappropriate combinations
    Nonsteroidal anti-inflammatory drugs; cyclooxygenase 2 inhibitors
    Cocaine, amphetamines, other illicit drugs
    Sympathomimetics (decongestants, anorectics)
    Oral contraceptive hormones
    Adrenal steroid hormones
    Cyclosporine and tacrolimus
    Licorice (including some chewing tobacco)
    Selected over-the-counter dietary supplements and medicines (eg,  ephedra, ma haung, bitter orange)
Associated conditions
    Excess alcohol intake
Identifiable causes of hypertension (See Table 7.)

Cognitive Function and Dementia

Dementia and cognitive impairment occur more commonly in people with hypertension. Reduced progression of cognitive impairment may occur with effective antihypertensive therapy.269,270 Narrowing and sclerosis of small penetrating arteries in the subcortical regions of the brain are common findings on autopsy in chronic hypertension.271–274 These changes are believed to contribute to hypoperfusion, loss of autoregulation, compromise of the blood-brain barrier, and ultimately to subcortical white matter demyelination, microinfarction, and cognitive decline. MRI studies in persons with chronic hypertension have revealed greater numbers of subcortical white matter lesions and microinfarcts, astrogliosis, ventricular enlargement, and extracellular fluid accumulation than in age-matched controls.275–285

Mild cognitive impairment (MCI) is a diagnostic category that represents a transitional state between normal aging and mild dementia in which patients exhibit signs of poor recent memory but can still perform daily tasks such as managing finances, driving, shopping, and preparing meals.286 Hypertension and hypercholesterolemia are risk factors for MCI and for other signs of cognitive decline, such as impaired attention, reaction time, verbal fluency, or executive function.275,276,278,287–289

Effective antihypertensive therapy strongly reduces the risk of developing significant white matter changes on MRI.290 However, existing white matter changes, once established, do not appear to be reversible.291,292 The optimal SBP/DBP to prevent cognitive decline in older individuals is thought by some to be in the SBP 135 to 150 mm Hg and DBP 70 to 79 mm Hg range.287,288 In the SystEUR trial, CCB therapy was superior to placebo in slowing the decline in cognitive function,293 but no comparative data are available regarding whether certain classes of antihypertensive drugs are superior to others in preventing cognitive decline.

Hypertension in Women
Nonpregnant Women
Sexual Dimorphism of BP and Hypertension Prevalence in Women.

There is a sexual dimorphism in BP, such that women have lower SBP levels than men during early adulthood, while the opposite is true after the sixth decade of life. DBP tends to be just marginally lower in women than men regardless of age.294 Similarly, in early adulthood, hypertension is less common among women than men. However, after the fifth decade of life, the incidence of hypertension increases more rapidly in women than men, and the prevalence of hypertension in women is equal to or exceeds that in men during the sixth decade of life. The highest prevalence rates of hypertension are observed in elderly black women, with hypertension occurring in more than 75% of women older than 75 years.295

Awareness, Treatment, and Control of High BP in Women.

Women are more likely than men to know that they have hypertension, to have it treated, and to have it controlled.1 In NHANES III, approximately 75% of hypertensive black and white women were aware of their high BP in contrast to just 65% of hypertensive men in these ethnic groups. Overall, 61% of hypertensive women, but only 44% of men, were being treated with antihypertensive medications. The higher treatment rates in women have been attributed to increased numbers of physician contacts.

Menopause and Blood Pressure.

The effect of menopause on BP is controversial. Longitudinal studies have not documented a rise in BP with menopause, while cross-sectional studies have found significantly higher SBP and DBP in postmenopausal versus premenopausal women.294 In NHANES III, the rate of rise in SBP tended to be steeper in postmenopausal compared with premenopausal women until the sixth decade, when the rate of increase tended to slow. Staessen et al296 reported that even after adjustment for age and BMI, postmenopausal women are more than twice as likely to have hypertension as premenopausal women. In a prospective study of conventional and ambulatory BP levels, postmenopausal women had higher SBP (4 to 5 mm Hg) than pre- and perimenopausal controls.297 The increase in SBP per decade was 5 mm Hg greater in the peri- and postmenopausal women than in the premenopausal group. Thus, there is evidence that at least part of the rise in BP (particularly SBP) seen later in life in women is due to menopause. A menopause-related increase in BP has been attributed to a variety of factors, including estrogen withdrawal, overproduction of pituitary hormones, weight gain, or a combination of these and other yet undefined neurohumoral influences.298

Postmenopausal Hormone Therapy and BP.

Results of studies evaluating the effects of hormone replacement therapy (HRT) on BP have been inconsistent. The Women’s Health Initiative (WHI), the largest longitudinal study to address this question, found an average 1 mm Hg increase in SBP over 5.6 years of follow-up among 8506 postmenopausal women randomized to conjugated equine estrogen and medroxyprogesterone acetate as compared with a placebo group.299 There was no difference in DBP between the hormone treatment groups. Further, in the WHI cross-sectional analysis of almost 100 000 women aged 50 to 79 years, current hormone use was associated with a 25% greater likelihood of having hypertension compared with past use or no prior use.300

Smaller observational and interventional studies have found different results. In the Baltimore Longitudinal Study on Aging (BLSA), women receiving HRT had a significantly smaller increase in SBP over time than nonusers, but DBP was not affected. The Postmenopausal Estrogen/Progestin Intervention trial showed no effect of HRT on SBP or DBP.301 In small studies that have used 24-hour ambulatory monitoring to evaluate the effects of HRT on BP, while overall results are inconsistent, several of the studies suggest that HRT improves or restores the normal nighttime reduction (“dipping”) in BP that may be diminished in postmenopausal women. Such an effect would tend to reduce total BP load and thereby reduce target organ damage.298

Overall, HRT-related change in BP is likely to be modest and should not preclude hormone use in normotensive or hypertensive women. All hypertensive women treated with HRT should have their BP monitored closely at first and then at 6-month intervals.

Oral Contraceptives and BP.

Many women taking oral contraceptives experience a small but detectable increase in BP; a small percentage experience the onset of frank hypertension. This is true even with modern preparations that contain only 30 μg estrogen. The Nurses’ Health Study found that current users of oral contraceptives had a significantly increased (relative risk [RR]=1.8; 95% confidence interval [CI]=1.5 to 2.3) risk of hypertension compared with never users.302 Absolute risk was small: only 41.5 cases of hypertension per 10 000 person-years could be attributed to oral contraceptive use. Controlled prospective studies have demonstrated a return of BP to pretreatment levels within 3 months of discontinuing oral contraceptives, indicating that their BP effect is readily reversible.

Oral contraceptives occasionally may precipitate accelerated or malignant hypertension. Family history of hypertension, including preexisting pregnancy-induced hypertension, occult renal disease, obesity, middle age (>35 years), and duration of oral contraceptive use increase susceptibility to hypertension. Contraceptive-induced hypertension appears to be related to the progestogenic, not the estrogenic, potency of the preparation.

Regular monitoring of BP throughout contraceptive therapy is recommended, and it has been suggested that contraceptive prescriptions be limited to 6 months to ensure at least semiannual reevaluations. Withdrawal of the offending contraceptive agent is generally desirable in cases of contraceptive-induced hypertension, but such therapy may have to be continued in some women (eg, if other contraceptive methods are not suitable) and combined with antihypertensive therapy.

Outcomes of Antihypertensive Trials in Women.

Relative benefits of antihypertensive therapy do not appear to differ between the sexes.303 Absolute risk reduction for stroke was also similar in men and women, but for coronary events, it was greater in men. Similarly, a placebo-controlled trial of CCB treatment showed treatment benefits for both sexes.113,304 More recent outcome trials comparing ACEIs, ARBs, or CCBs with diuretics and BBs in older, high-risk patients have generally shown similar benefits for women and men.101,102,109 The current evidence indicates that the sex of the patient should not play a role in decisions about whether or not to treat high BP.

Choice of Antihypertensive Drugs for Women.

While women generally respond to antihypertensive drugs similarly to men, some special considerations may dictate treatment choices for women. ACEIs and ARBs are contraindicated for women who are or intend to become pregnant because of the risk of fetal developmental abnormalities. Diuretics are particularly useful in elderly individuals because of a decreased risk of hip fracture. Some antihypertensive drugs have gender-specific adverse effect profiles. For example, in the TOMHS study, women reported twice as many adverse effects as men.305 Women are more likely to develop diuretic-induced hyponatremia, and men more likely to develop gout. Hypokalemia is more common in women taking a diuretic. ACEI-induced cough is twice as common in women as in men, and women are more likely to complain of CCB-related peripheral edema and minoxidil-induced hirsutism.

Pregnant Women

Hypertensive disorders in pregnancy are a major cause of maternal, fetal, and neonatal morbidity and mortality. Hypertension in pregnancy is classified into 1 of 5 categories (Table 19), and it is critical to differentiate preeclampsia, a pregnancy-specific syndrome of exaggerated vasoconstriction and reduced organ perfusion, from pre-existing chronic hypertension.7,306

TABLE 19. Classification of Hypertension in Pregnancy

ALT indicates alanine aminotransferase; AST, aspartate aminotransaminase; BP, blood pressure.
Chronic hypertensionBP ≥140 mm Hg systolic or 90 mm Hg diastolic prior to pregnancy or before 20 weeks gestation
Persists >12 weeks postpartum
PreeclampsiaBP ≥140 mm Hg systolic or 90 mm Hg diastolic with proteinuria (>300 mg/24 h) after 20 weeks gestation
Can progress to eclampsia (seizures)
More common in nulliparous women, multiple gestation, women with hypertension for ≥4 years, family history of preeclampsia, hypertension in previous pregnancy, renal disease
Chronic hypertension with superimposed preeclampsiaNew onset proteinuria after 20 weeks in a woman with hypertension
In a woman with hypertension and proteinuria prior to 20 weeks gestation:
    Sudden 2- to 3-fold increase in proteinuria
    Sudden increase in BP
    Elevated AST or ALT
Gestational hypertensionHypertension without proteinuria occurring after 20 weeks gestation
Temporary diagnosis
May represent preproteinuric phase of preeclampsia or recurrence of chronic hypertension abated in midpregnancy
May evolve to preeclampsia
If severe, may result in higher rates of premature delivery and growth retardation than mild preeclampsia
Transient hypertensionRetrospective diagnosis
BP normal by 12 weeks postpartum
May recur in subsequent pregnancies
Predictive of future primary hypertension

Prepregnancy Assessment.

Women should be evaluated prior to conception to define their BP status, and, if hypertensive, to assess its severity, possible secondary causes, and presence of target organ damage and to plan treatment strategies. Many hypertensive women who plan to become pregnant should be screened for pheochromocytoma because of the high morbidity and mortality of this condition if not diagnosed antepartum. In hypertensive women planning to become pregnant, it may be prudent prior to conception to change to antihypertensive medications known to be safe during pregnancy, such as methyldopa or BBs. ACEIs and ARBs should be discontinued prior to attempts at conception or as soon as pregnancy is confirmed. Those with progressive renal diseases should be encouraged to complete their childbearing while their renal function is relatively well preserved. Mild renal disease (serum creatinine <1.4 mg/dL) has a minimal effect on fetal survival, and the underlying renal disease does not generally worsen during pregnancy. However, moderate or severe renal insufficiency in pregnancy may accelerate both hypertension and the underlying disease and markedly reduce fetal survival.

Treatment of Chronic Hypertension During Pregnancy.

Women with Stage 1 hypertension are at low risk for cardiovascular complications during pregnancy and are candidates for lifestyle modification therapy only, as there is no evidence that pharmacological treatment improves neonatal outcomes. Further, BP usually falls during the first half of pregnancy; therefore, hypertension may be easier to control with reduced or no medications. With lifestyle modification, aerobic exercise should be restricted on the basis of theoretical concerns that inadequate placental blood flow may increase the risk of preeclampsia, and weight reduction should not be attempted, even in obese pregnant women. Although the data on pregnant women are sparse, many experts recommend restriction of sodium intake to the same 2.4 g sodium intake recommended for those with primary hypertension.7 Use of alcohol and tobacco must be strongly discouraged.

Use of antihypertensive drugs in pregnant women with chronic hypertension varies greatly among centers. Some clinicians prefer to stop antihypertensive medications while maintaining close observation, including use of home BP monitoring. This approach reflects concern about the safety of antihypertensive drug treatment in pregnancy. A meta-analysis of 45 randomized controlled studies of treatment with several classes of antihypertensive drugs in Stage 1 and 2 hypertension in pregnancy showed a direct linear relationship between treatment-induced fall in mean arterial pressure and the proportion of small-for-gestational-age infants.307 This relationship was independent of type of hypertension, type of antihypertensive agent, and duration of therapy.

However, for pregnant women with target organ damage or a prior requirement for multiple antihypertensive agents for BP control, antihypertensive medication should be continued as needed to control BP. In all cases, treatment should be reinstituted once BP reaches 150 to 160 mm Hg systolic or 100 to 110 mm Hg diastolic, in order to prevent increases in BP to very high levels during pregnancy. Aggressive treatment of severe chronic hypertension in the first trimester is critical, since fetal loss rates of 50% and significant maternal mortality have been reported in these patients.308 Most of the poor outcomes are related to superimposed preeclampsia (Table 19). Further, women with chronic hypertension are also at higher risk for adverse neonatal outcomes if proteinuria is present early in pregnancy. Fetal loss and acceleration of maternal renal disease increase at serum creatinine levels >1.4 mg/dL at conception.

Antihypertensive Drug Selection.

The primary goal of treating chronic hypertension in pregnancy is to reduce maternal risk, but the choice of antihypertensive agent(s) is largely driven by the safety of the fetus. Methyldopa is preferred by many as first-line therapy, based on reports of stable uteroplacental blood flow and fetal hemodynamics and the absence of long-term (7.5-year follow-up) adverse effects on development of children exposed to methyldopa in utero.309,310 Other treatment options are summarized in Table 20.

TABLE 20. Treatment of Chronic Hypertension in Pregnancy

ACEIs indicate angiotensin-converting enzyme inhibitor; BBs, beta blockers.
MethyldopaPreferred on the basis of long-term follow-up studies supporting safety
BBsReports of intrauterine growth retardation (atenolol)
Generally safe
LabetalolIncreasingly preferred to methyldopa because of reduced side effects
ClonidineLimited data
Calcium antagonistsLimited data
No increase in major teratogenicity with exposure
DiureticsNot first-line agents
Probably safe
ACEIs, angiotensin II receptor antagonistsContraindicated
Reported fetal toxicity and death


Preeclampsia is more common in women with chronic hypertension, with an incidence of approximately 25%. Risk factors for superimposed preeclampsia include renal insufficiency, a history of hypertension for 4 years or longer, and hypertension in a previous pregnancy. Prevention of preeclampsia relies on identification of high-risk women and close clinical and laboratory monitoring aimed at its early recognition, and institution of intensive monitoring or delivery when indicated. Treatment of preeclampsia includes hospitalization for bed rest, control of BP, seizure prophylaxis in the presence of signs of impending eclampsia, and timely delivery. Importantly, many women with preeclampsia have previously been normotensive, so acute BP elevations even to modest levels (ie, 150/100 mm Hg) may cause significant symptomatology and require treatment. Treatment does not alter the underlying pathophysiology of the disease, but it may slow its progression and provide time for fetal maturation. Preeclampsia rarely remits spontaneously and in most cases worsens with time.

While delivery may be appropriate therapy for the mother, it may compromise a fetus of less than 32 weeks gestation. Regardless of gestational age, delivery should be strongly considered when there are signs of fetal distress or intrauterine growth retardation or signs of maternal problems, including severe hypertension, hemolysis, elevated liver enzymes, low platelet count, deteriorating renal function, visual disturbance, headache, or epigastric pain. Vaginal delivery is preferable to cesarean delivery to avoid the added stress of surgery.

Antihypertensive Drug Therapy.

Antihypertensive therapy should be prescribed only for maternal safety; it does not improve perinatal outcomes and may adversely affect uteroplacental blood flow. Selection of antihypertensive agents and route of administration depends on anticipated timing of delivery. If delivery is likely more than 48 hours off, oral methyldopa is preferred because of its safety record. Oral labetalol is an alternative, and other BBs and calcium antagonists are also acceptable on the basis of limited data (Table 20). If delivery is imminent, parenteral agents are practical and effective (Table 21). Antihypertensives are administered before induction of labor for persistent DBPs of 105 to 110 mm Hg or higher, aiming for levels of 95 to 105 mm Hg.

TABLE 21. Treatment of Acute Severe Hypertension in Preeclampsia

Hydralazine5 mg IV bolus, then 10 mg every 20 to 30 minutes to a maximum of 25 mg, repeat in several hours as necessary
Labetalol (second-line)20 mg IV bolus, then 40 mg 10 minutes later, 80 mg every 10 minutes for 2 additional doses to a maximum of 220 mg
Nifedipine (controversial)10 mg PO, repeat every 20 minutes to a maximum of 30 mg
Caution when using nifedipine with magnesium sulfate, can see precipitous BP drop
Short-acting nifedipine is not approved by US Food and Drug Administration for managing hypertension
Sodium nitroprusside (rarely when others fail)0.25 μg/kg/min to a maximum of 5 μg/kg/min
Fetal cyanide poisoning may occur if used for more than 4 hours

Treating Hypertension During Lactation.

Hypertensive mothers can usually breast-feed safely. However, all antihypertensive drugs that have been studied are excreted into human breast milk. Therefore, in mothers with stage 1 hypertension who wish to breast-feed for a few months, it might be prudent to withhold antihypertensive medication, with close monitoring of BP, and reinstitute antihypertensive therapy following discontinuation of nursing. No short-term adverse effects have been reported from exposure to methyldopa or hydralazine. Propanolol and labetalol are preferred if a BB is indicated. ACEIs and ARBs should be avoided on the basis of reports of adverse fetal and neonatal renal effects. Diuretics may reduce milk volume and thereby suppress lactation. Breast-fed infants of mothers taking antihypertensive agents should be closely monitored for potential adverse effects.

Recurrence of Hypertension.

Hypertension recurs in a large proportion (20% to 50%) of subsequent pregnancies. Risk factors for recurrence include early onset of hypertension in the first pregnancy, a history of chronic hypertension, persistent hypertension beyond 5 weeks postpartum, and elevated BP early in pregnancy. Women with preeclampsia have a greater tendency to develop hypertension than those with normotensive pregnancies.

Hypertension in Children and Adolescents

In children and adolescents, hypertension is defined as elevated BP that persists on repeated measurement at the 95th percentile or greater for age, height, and gender (Table 22). As with adults, the fifth Korotkoff sound is used to define DBP.311

TABLE 22. 95th Percentile of Blood Pressure by Selected Ages, by the 50th and 75th Height Percentiles, and by Gender in Children and Adolescents

AgeGirls’ SBP/DBPBoys’ SBP/DBP
50th Percentile for Height75th Percentile for Height50th Percentile for Height75th Percentile for Height
Source: Adapted from Update on the 1987 Task Force Report on High Blood Pressure in Children and Adolescents: A working group report from the National High Blood Pressure Education Program. Pediatrics. 1996;98:649–658.

Clinicians should be alert to the possibility of identifiable causes of hypertension in younger children. Secondary forms of hypertension are more common in children and in individuals with severe hypertension (>20 mm Hg above the 95th percentile). Chronic hypertension is becoming increasingly common in adolescence and is generally associated with obesity, sedentary lifestyle, and a positive family history of hypertension and other CVDs. Like adults, children and adolescents with established hypertension develop target organ damage, including LVH. Appropriate assessment for LVH, including echocardiography, should be considered in children who have significant and persisting hypertension.

Lifestyle interventions should be recommended for all children with hypertension, with pharmacological therapy instituted for higher levels of BP or if insufficient response to lifestyle modifications occurs. Teenage children with BP below but near the 95th percentile should adopt healthy lifestyles similar to adults with prehypertension. Although the recommendations for drug choices are generally similar in children and adults, dosages of antihypertensive medication for children should be smaller and adjusted very carefully. ACEIs and ARBs should not be used if the patient is pregnant. These agents should be used with extreme caution in sexually active teenage girls and only when careful counseling and effective pregnancy precautions are established.

The presence of uncomplicated hypertension should not be a reason to restrict children from participating in physical activities, particularly because exercise may lower BP. Use of anabolic steroid hormones for the purpose of bodybuilding should be strongly discouraged. Efforts should be made to identify other modifiable risk factors in children (eg, obesity, lack of physical activity, smoking), and vigorous interventions should be made when present. Detailed recommendations regarding hypertension in children and adolescents can be found in the 1996 NHBPEP Working Group Report on Hypertension Control in Children and Adolescents.311

Hypertensive Crises: Emergencies and Urgencies

Hypertensive emergencies are characterized by severe elevations in BP (>180/120 mm Hg) complicated by evidence of impending or progressive target organ dysfunction. They require immediate BP reduction (not necessarily to normal) to prevent or limit target organ damage.312,313 Examples include hypertensive encephalopathy, intracerebral hemorrhage, acute myocardial infarction, acute left ventricular failure with pulmonary edema, unstable angina pectoris, dissecting aortic aneurysm, or eclampsia. Hypertensive urgencies are those situations associated with severe elevations in BP without progressive target organ dysfunction. Examples include upper levels of stage II hypertension associated with severe headache, shortness of breath, epistaxis, or severe anxiety. The majority of these patients present as noncompliant or inadequately treated hypertensives, often with little or no evidence of target organ damage.

Early triage to establish the appropriate therapeutic strategies for these patients is critical to limiting morbidity and mortality.314 Patients presenting with severe hypertension may represent as much as 25% of all patient visits to busy urban emergency rooms.315

Patients with a hypertensive emergency should be admitted to an Intensive Care Unit for continuous monitoring of BP and parenteral administration of an appropriate agent (Table 23). The initial goal of therapy in hypertensive emergencies is to reduce mean arterial BP by no more than 25% (within minutes to 1 hour), then, if stable, to 160/100 to 110 mm Hg within the next 2 to 6 hours. Excessive falls in pressure that may precipitate renal, cerebral, or coronary ischemia should be avoided. For this reason, short-acting nifedipine is no longer considered acceptable in the initial treatment of hypertensive emergencies or urgencies. If this level of BP is well tolerated and the patient is clinically stable, further gradual reductions toward a normal BP can be implemented in the next 24 to 48 hours. There are exceptions to the above recommendation—patients with an ischemic stroke in which there is no clear evidence from clinical trials to support the use of immediate antihypertensive treatment, patients with aortic dissection who should have their SBP lowered to <100 mm Hg if tolerated, and patients in whom BP is lowered to enable the use of thrombolytic agents (see the section on stroke).

TABLE 23. Parenteral Drugs for Treatment of Hypertensive Emergencies*

DrugDoseOnset of ActionDuration of ActionAdverse EffectsSpecial Indications
*These doses may vary from those in the Physicians’ Desk Reference (51st edition).
†Hypotension may occur with all agents.
‡Requires special delivery system.
    Sodium nitroprusside0.25–10 μg/kg/min as IV infusionImmediate1–2 minNausea, vomiting, muscle twitching, sweating, thiocynate and cyanide intoxicationMost hypertensive emergencies; caution with high intracranial pressure or azotemia
    Nicardipine hydrochloride5–15 mg/h IV5–10 min15–30 min, may exceed 4 hTachycardia, headache, flushing, local phlebitisMost hypertensive emergencies except acute heart failure; caution with coronary ischemia
    Fenoldopam mesylate0.1–0.3 μg/kg per min IV infusion<5 min30 minTachycardia, headache, nausea, flushingMost hypertensive emergencies; caution with glaucoma
    Nitroglycerin5–100 μg/min as IV infusion§2–5 min5–10 minHeadache, vomiting, methemoglobinemia, tolerance with prolonged useCoronary ischemia
    Enalaprilat1.25–5 mg every 6 h IV15–30 min6–12 hPrecipitous fall in pressure in high-renin states; variable responseAcute left ventricular failure; avoid in acute myocardial infarction
    Hydralazine hydrochloride10–20 mg IV10–20 min IV1–4 h IVTachycardia, flushing, headache, vomiting, aggravation of anginaEclampsia
10–40 mg IM20–30 min IM4–6 h IM
Adrenergic inhibitors
    Labetalol hydrochloride20–80 mg IV bolus every 10 min5–10 min3–6 hVomiting, scalp tingling, bronchoconstriction, dizziness, nausea, heart block, orthostatic hypotensionMost hypertensive emergencies except acute heart failure
0.5–2.0 mg/min IV infusion
    Esmolol hydrochloride250–500 μg/kg/min IV bolus, then 50–100 μg/kg/min by infusion; may repeat bolus after 5 min or increase infusion to 300 μg/min1–2 min10–30 minHypotension, nausea, asthma, first-degree heart block, HFAortic dissection, perioperative
    Phentolamine5–15 mg IV bolus1–2 min10–30 minTachycardia, flushing, headacheCatecholamine excess

Some patients with hypertensive urgencies may benefit from treatment with an oral, short-acting agent such as captopril, labetalol, or clonidine followed by several hours of observation. However, there is no evidence to suggest that failure to aggressively lower BP in the emergency room is associated with any increased short-term risk to the patient who presents with severe hypertension. Such a patient may also benefit from adjustment in their antihypertensive therapy, particularly the use of combination drugs, or reinstitution of medications if noncompliance is a problem. Most importantly, patients should not leave the emergency room without a confirmed follow-up visit within 1 to a few days.

Unfortunately, the term “urgency” has led to overly aggressive management of many patients with severe, uncomplicated hypertension. Aggressive dosing with intravenous drugs or even oral agents to rapidly lower BP is not without risk. Oral loading doses of antihypertensive agents can lead to cumulative effects causing hypotension, sometimes following discharge from the emergency room. Patients who continue to be noncompliant will often return to the emergency room within weeks.

Erectile Dysfunction and Hypertension

Erectile dysfunction (ED), defined as the inability to have and maintain an erection adequate for intercourse, becomes increasingly common in men over 50 years old and is even more common if they are hypertensive.316 In a survey of over 3000 health professionals, the frequency of ED was 4% in men under age 50, 26% in those 50 to 59, and 40% in those 60 to 69.316 The frequency was significantly higher if they were hypertensive, diabetic, obese, or smokers or were taking antidepressants or BBs.

Whereas hypertension per se may be associated with ED,317 the use of various antihypertensive medications may increase the incidence, in part because BP lowering itself may cause reduction of perfusion of genital organs. Available data regarding individual effects of antihypertensive drug therapy are confounded by age, vascular disease, and hormonal status. In the TOMHS study involving antihypertensive drugs from five different classes (excluding ARBs), participants randomized to chlorthalidone reported a significantly higher incidence of erection problems at 24 months of the study than participants randomized to placebo. Incidence rates through 48 months were more similar among treatment groups than at 24 months, with nonsignificant differences between chlorthalidone and placebo groups.123 In the VA Cooperative trial, no difference in incidence of sexual dysfunction was noted between a CCB, ACEI, hydrochlorothiazide, or BB compared with placebo.103 In other studies, centrally acting α-agonists have been associated with ED, while ACEIs, ARBs, and CCBs have not been observed to increase its incidence.317,318

A lower risk of ED was reported among men who were physically active, not obese, and nonsmokers.316 Therefore, lifestyle modifications should be encouraged to forestall ED. If ED appears after institution of antihypertensive drug therapy, the offending agent should be discontinued and treatment restarted with another agent. Sildenafil or other phosphodiesterase-5 inhibitors may be prescribed without a significant likelihood of adverse reactions in those with concomitant antihypertensive therapy so long as nitrates are avoided.319

There are no definitive data on a relation between sexual dysfunction and hypertension in women. Regardless of gender, clinicians should be willing to discuss sexual dysfunction problems and offer counseling to improve the patient’s quality of life.

Urinary Outflow Obstruction

Symptoms of urinary outflow obstruction or a known history of obstruction should be elicited as part of the hypertension workup. When a normal bladder is distended beyond approximately 300 mL, sympathetic nervous system stimulation may cause a substantial increase in BP. Patients with high spinal cord injuries in particular may exhibit large acute BP increases similar to individuals with autonomic dysfunction. BP control can be improved by keeping the bladder volume below 300 mL and by the use of sympatholytic drugs. Nonsurgical treatment of patients with urinary outflow obstruction includes the use of α1-blockers such as terazosin, doxazosin, or prazosin, which indirectly dilate prostatic and urinary sphincter smooth muscle and also lower BP.320

Patients Undergoing Surgery

Uncontrolled hypertension is associated with wider fluctuations of BP during induction of anesthesia and intubation and may increase the risk for perioperative ischemic events. BP levels of 180/110 mm Hg or greater should be controlled prior to surgery.321 For elective surgery, effective BP control can be achieved over several days to weeks of outpatient treatment. In urgent situations, rapidly acting parenteral agents such as sodium nitroprusside, nicardipine, and labetalol can be utilized to attain effective control very rapidly.

Surgical candidates with controlled hypertension should maintain their medications until the time of surgery, and therapy should be reinstated as soon as possible post-operatively. Adequate potassium supplementation should be provided, if needed, to correct hypokalemia well in advance of surgery. Older patients may gain particular benefit from treatment with β1-selective BBs before and during the perioperative period.322

Sudden intraoperative hypertension is managed by many of the same parenteral antihypertensive agents that are utilized in the management of hypertensive emergencies (see the section on emergencies and urgencies).323 Intravenous infusions of sodium nitroprusside, nicardipine, and labetalol can be effective. Nitroglycerin is often an agent of choice in patients with coronary ischemia, while the very short-acting BB esmolol may be of benefit in managing intraoperative tachycardia.

Hypertension is very common in the early postoperative period, related to increased sympathetic tone and vascular resistance.324 Contributing factors include pain and increased intravascular volume, which may require parenteral dosing with a loop diuretic such as furosemide. If resumption of oral treatment must be interrupted postoperatively, periodic dosing with intravenous enalaprilat or transdermal clonidine hydrochloride may be useful.

Dental Issues in the Hypertensive Subjects

A concern in dental care is the use of epinephrine in local anesthetic solutions. Many dental providers do not use catecholamine-containing local anesthetic formulations for any patient with elevated BP, as they are concerned with an adverse cardiovascular response. A systematic review of this topic325 concluded that although adverse events may occur in uncontrolled hypertensive patients during dental procedures, the use of epinephrine had a minimal effect. BP should be monitored closely in the dental office if general anesthesia is administered to hypertensives because of potential wide fluctuations in BP and the risk of hypotension in those receiving antihypertensive drugs. CCBs and other vasodilators may cause hypertrophy of the gums.

Obstructive Sleep Apnea

Obstructive sleep apnea (OSA) occurs in 2% to 4% of the adult population, and over 50% of individuals with OSA have hypertension.263,326–333 Obesity is so common in OSA that the index of suspicion for OSA should be high in any hypertensive patient whose BMI is above 27 kg/m2.331 These individuals should be questioned thoroughly for symptoms of OSA, including snoring, witnessed apnea, irregular breathing during sleep, restless sleeping, and chronic morning fatigue. Frequently it is the sleep partner who provides the most reliable history, especially regarding snoring, because the affected individual may deny or be unaware of the problem. If the diagnosis is suspected clinically, confirmation by a formal sleep study is indicated. The impact of sleep apnea on CVD is probably related in large part to its association with elevated BP. However, OSA may act through a number of mechanisms to elicit myocardial and vascular damage, including increase in catecholamine release,333,334 activation of inflammatory mechanisms,335 insulin resistance,336,337 and endothelial dysfunction.338 Other cardiovascular conditions associated with OSA include arrhythmias, HF, myocardial infarction, and stroke.331,332,339–344

Previous debate about whether OSA is an etiologic factor in hypertension has focused largely around the strong association of OSA with obesity. While obesity is known to contribute in large part to OSA,345–348 patients with OSA may also be at increased risk for weight gain,349 and treatment of OSA may reduce visceral fat.350 It now appears that the potential causal association between OSA and hypertension involves both the obesity-hypertension link and an independent role of OSA in chronic BP elevation. Episodes of apnea with repeated oxygen desaturation in OSA have been shown to stimulate strong sympathetic nervous system discharges that directly elevate BP.333,334 Poorer quality of sleep and shorter sleep periods may play a reinforcing role in the fatigue and daytime somnolence. Sleep deprivation alone may raise BP351 and impair glucose tolerance.352 There is also a direct relationship between the severity of sleep apnea and the level of BP. Finally, sustained and effective treatment of OSA with continuous positive airway pressure (CPAP) has been reported to lower nighttime and daytime BP in hypertensives with OSA.353–355

In addition to weight loss, improvements in the quality of sleep in OSA patients can occur as a result of a variety of positioning measures during sleep, particularly sleeping on one’s side. Treatment with CPAP can be useful in overall BP lowering and may also improve cardiac ischemia356,357 and HF symptoms.331,332 The role of oral prostheses and surgical approaches remains to be fully defined.354 No specific class of antihypertensive drugs has yet been demonstrated to be superior for BP lowering in OSA patients.354

Hypertension and the Eye

Hypertension can effect the retina, choroid, and optic nerve of the eye, particularly with stage 2 hypertension. These changes can be appreciated with inspection of the retinal vessels by direct ophthalmoscopy, photography, or angiography.

Hypertensive retinopathy is most commonly manifested by generalized or focal narrowing of retinal arterioles. In acute or advanced hypertension, the retinal vasculature may be injured sufficiently to cause occlusion or leakage. These changes may be manifested as nerve fiber layer infarcts (soft exudates or cotton-wool patches), extravascular edema (hard exudates), intraretinal hemorrhages, and retinal arterial macroaneurysms.

Hypertensive choroidopathy is most frequently seen in young patients with acute hypertension, including cases of eclampsia or pheochromocytoma. Findings include Elschnig spots (nonperfused areas of the choriocapillaris) and Siegrist streaks (linear hyperpigmentation over choroidal arteries).

Hypertensive optic neuropathy occurring with severe hypertension may present with flame hemorrhages, optic disc edema, venous congestion, and macular exudates.358–360

Renal Transplantation

Hypertension is a relatively common occurrence in patients receiving organ transplants; in those receiving kidney allografts, the prevalence of hypertension probably exceeds 65%.361 Nocturnal hypertension, a reversal of diurnal BP rhythm, may be present in these individuals who may need ABPM to evaluate overall BP control. Hypertension is less common in other forms of transplantation. The mechanisms of hypertension in transplant patients are multifactorial, but vasoconstriction and long-term vascular structural changes caused by chronic immunosuppressive drugs that are calcineurin inhibitors (cyclosporine and tacrolimus) and corticosteroids are among the most important.362 Impaired renal function is another exacerbating factor; despite successful renal transplantation, most patients have enough impairment in renal function to cause relative salt and water retention. Transplant renal artery stenosis may also be a factor.

Observational studies suggest that hypertension correlates with deterioration in graft function. Large-scale, controlled clinical trials on the effects of BP control on GFR decline or on CVD incidence are lacking in this population. The high risk of graft occlusion and cardiovascular events has suggested that BP should be lowered to 130/80 mm Hg or less. Because of the absence of compelling data, no particular class of antihypertensives can be considered to be superior to any other. The difficulty of lowering BP in this group makes combination drugs necessary in almost all patients. As with other renal diseases, serum creatinine and potassium should be monitored 1 to 2 weeks following initiation or escalation in therapy with ACEIs or ARBs. A greater than 1 mg/dL increase in serum creatinine should raise the question of renal artery stenosis.

Patients with Renovascular Disease

Hemodynamically significant renal artery stenosis may be associated with all stages of hypertension, but it is more commonly recognized in patients with stage 2 or resistant hypertension, since these are the individuals in whom special evaluation for the problem is carried out. If present bilaterally, renal artery stenosis can lead to reduced kidney function (ischemic nephropathy).363

Clinical clues to renovascular disease include (1) onset of hypertension before age 30 (especially without a family history) or recent onset of significant hypertension after age 55; (2) an abdominal bruit, particularly if it continues into diastole and is lateralized; (3) accelerated or resistant hypertension; (4) recurrent (flash) pulmonary edema; (5) renal failure of uncertain etiology, especially with a normal urinary sediment; (6) coexisting diffuse atherosclerotic vascular disease, especially in heavy smokers; or (7) acute renal failure precipitated by antihypertensive therapy, particularly ACEIs or ARBs.78,79,81

In patients with indications of renovascular disease, captopril-enhanced radionuclide renal scan, duplex Doppler flow studies, and magnetic resonance angiography may be used as noninvasive screening tests. Three-dimensional images can be obtained by spiral computed tomography, a technique that necessitates the use of intravenous contrast.81 Definitive diagnosis of renovascular disease requires renal angiography, which carries some risk, particularly of radiocontrast-induced acute renal failure or atheroembolism.364

In patients, usually women, with fibromuscular dysplasia, results of percutaneous transluminal renal angioplasty (PTRA) have been excellent and comparable to surgical revascularization.365 Patients with normal renal function and atherosclerotic renal artery stenosis that is focal, unilateral, and nonostial also may be managed by angioplasty.365 Renal artery stenting has become an important adjunct to PTRA, being used to counteract elastic recoil and to abolish the residual stenosis often observed after PTRA.366

Even though many patients with high-grade renal artery stenosis remain stable for prolonged periods if BP is well controlled,367 surgical revascularization or PTRA with renal artery stenting may be needed to preserve renal function.81

Drugs and Other Agents Affecting Blood Pressure

Many prescription drugs and some over-the-counter agents and herbal supplements may affect BP and complicate BP control in treated hypertensives. Consequently, searching for the presence of these agents in the medical history can identify a secondary component contributing to BP elevation. Such recognition may negate the need to employ unnecessary and potentially hazardous testing.

Use of agents that can affect BP in a given patient should be suspected in the following situations: (1) loss of control of previously well-controlled hypertension, (2) presence of comorbidities (particularly osteoarthritis), (3) biochemical evidence of intercurrent drug usage (such as an increase in serum potassium or creatinine concentrations with nonsteroidal anti-inflammatory drugs), and (4) atypical hypertension (such as severe but transient hypertension in a young patient presenting with chest pain and ECG changes accompanying possible cocaine usage).

Table 24 provides a list of those agents that may alter BP. They may affect BP in several ways. They may affect sodium balance; increase adrenergic or suppress parasympathetic neural activity; alter the production, release, or effectiveness of vasoactive hormones; or exert direct effects on the endothelium or vascular smooth muscle.

TABLE 24. Common Substances Associated With Hypertension in Humans

Boldfaced items within the list represent the substances of more current clinical importance.
Prescription Drugs
    Cortisone and other steroids (both cortico- and mineralo-), ACTH
    Estrogens (usually just oral contraceptive agents with high estrogenic activity)
    Nonsteroidal anti-inflammatory drugs
    Phenylpropanolamines and analogues
    Cyclosporine and tacrolimus
    Antidepressants (especially venlafaxine)
    Clonidine, BB combination
    Pheochromocytoma: BB without α-blocker first; glucagon
Street drugs and other “natural products”
    Cocaine and cocaine withdrawal
    Ma huang, “herbal ecstasy,” and other phenylpropanolamine analogs
    Nicotine and withdrawal
    Anabolic steroids
    Narcotic withdrawal
    Ergotamine and other ergot-containing herbal preparations
    St. John’s wort
Food substances
    Sodium chloride
    Tyramine-containing foods (with MAO-I)
Chemical elements and other industrial chemicals
    Thallium and other heavy metals
    Lithium salts, especially the chloride


Modest consumption of alcohol (eg, <30 g of ethanol a day or approximately two drinks daily) is not generally associated with BP increases. Larger amounts of alcohol ingestion have a dose-related effect on BP, both in hypertensive and normotensive subjects.10 The use of ambulatory BP monitoring has highlighted the biphasic effects of alcohol on BP, underscoring the importance of the timing of BP measurement. A large intake of alcohol (>30 g) may lower BP in the first 4 hours after ingestion. Approximately 10 to 15 hours later (perhaps at the time a patient is seen for an office visit or in the emergency room during withdrawal), BP increase may be noted. This accounts for some of the discrepancies reported in the literature about alcohol’s effect on BP. The mechanism(s) of alcohol’s effect on BP are unclear but appear to result predominantly from sympathetic neural activation, although changes in cortisol and cellular calcium concentrations also may play a role.

Nonaspirin Nonsteroidal Anti-Inflammatory Drugs (NANSAIDs)

NANSAIDs represent one of the most common medication classes consumed by hypertensive patients. Among the NANSAIDs, older agents like indomethacin are the most extensively studied. BP responses vary within the class of the NANSAIDs; however, increases in pressure are often accompanied by peripheral edema and weight gain, supporting a salt-retention mechanism of hypertension associated with the loss of natriuretic prostaglandins such as PGE2.368,369 Reduction in the well-described vasodilatory effects of some prostaglandins is another mechanism. COX-2 inhibitors also may cause elevation in BP.370–372 Recently, a double-blind randomized trial was conducted evaluating the effects of celecoxib, rofecoxib, and naproxen on 24-hour BP in type 2 diabetic patients with osteoarthritis whose hypertension was treated with ACEIs or ARBs. At equally efficacious doses for the management of osteoarthritis, treatment with rofecoxib, but not celecoxib or naproxen, induced a significant increase in average 24-hour SBP in type 2 diabetic patients receiving ACEIs or angiotensin II receptor blockers.373 Thus, current data suggest that certain NSAIDs and COX 2 inhibitors may have destabilizing effects on BP control in diabetic hypertensive patients. This is a major concern, as diabetic patients are often older and obese, and both obesity and aging predispose to osteoarthritis as well as diabetes.

Improving Hypertension Control

Issues Dealing with Adherence to Regimens

Behavioral models suggest that the most effective therapy prescribed by the most careful clinician will control hypertension only if the patient is motivated to take the medication as directed and to establish and maintain a health-promoting lifestyle. Motivation improves when patients have positive experiences with, and trust in, their clinicians. Better communication improves outcomes. Empathy builds trust and is a potent motivator (Table 25).374

TABLE 25. Provide Empathetic Reinforcement

Adopt an attitude of concern coupled with hope and interest in the patient’s future
Provide positive feedback for BP and behavioral improvement
If BP is not at goal, ask about behaviors to achieve BP control
Hold exit interviews to clarify regimen. A patient may tell you that they understand but tell the exit interviewer that they do not.
Schedule more frequent appointments and health care personnel contact with patients who are not achieving goal BP

What Can the Clinician Do?

Clinician-patient partnerships that are based on trust, respect, and a holistic knowledge of the patient correlate with positive outcomes of care: adherence, satisfaction, and improved health status. Patients often evaluate a clinician’s competence by their customer service skills, not their clinical skills.375 Customer service includes ease of access, minimal waiting time, and a positive regard from the office staff; all are known to influence provider satisfaction and patient adherence. Clinicians are the role model and should train staff by providing a positive, interactive, empathetic environment. This will increase patient comfort and willingness to participate in their own care.

Clinical Inertia

There is a broad range of clinician commitment to optimal hypertension therapy (Table 26). Failure to titrate or combine medications and to reinforce lifestyle modifications despite knowing that the patient is not at goal BP represents clinical inertia that must be overcome. This may be due in part to clinician focus on relieving symptoms, a lack of familiarity with clinical guidelines, or discomfort in titrating to a goal.376

TABLE 26. Clinician Awareness and Monitoring

Anticipate adherence problems for young men
Consider nonadherence as a cause of
    Failure to reach goal BP
    Resistant hypertension
    Sudden loss of control
Encourage patients to bring in all medications from all physicians and other sources, whether prescription, complementary, or over-the-counter, to each visit for review and to rule out iatrogenic causes of elevated blood pressure
Ask what the patient takes for pain
Recognize depression and other psychiatric illnesses, including panic attacks, and manage appropriately
Be willing to change unsuccessful regimens and search for those more likely to succeed

A number of approaches are available to overcome clinical inertia. One of the most effective is to use decision support systems that prompt the clinician to advance therapy when a goal has not been achieved (Table 27). Such systems can be electronic (computer- or PDA-based) or paper-based (flow charts, algorithms, guidelines). Feedback reminders from any source (computer-based, automated telephone-based, nurse care managers, outside auditors) can be very effective in not only helping to achieve BP goals but to alert clinicians to missed patient appointments, necessary prescription refills, and laboratory abnormalities.377

TABLE 27. Organize Care Delivery Systems

Schedule next appointment before patient leaves office
Use appointment reminders, preferably computer-based, and contact patients to confirm appointments
Follow up patients who missed appointments
Use an office-based systems approach for monitoring and follow-up (eg, educate staff to provide patient encouragement, computer or chart reminders, disease management aids)

Patient-centered behavioral interventions such as counseling improve BP control (Table 28).378 Nurse clinicians and pharmacists have proven their effectiveness in helping to achieve goal BP.379 Commercial health plans may provide resources for chart auditing or other assistance to improve BP control.380 Clinicians should periodically audit their own patient files to assess their degree of compliance and success with established goals and treatment interventions.

TABLE 28. Patient Education About Treatment

Assess patient’s understanding and acceptance of the diagnosis of hypertension
Discuss patient’s concerns and clarify misunderstandings
Tell patient the BP reading and provide a written copy
Come to agreement with the patient on goal BP
Ask patient to rate (1 to 10) his or her chance of staying on treatment
Inform patient about recommended treatment and provide specific written information about the role of lifestyle including diet, physical activity, dietary supplements, and alcohol intake. Use standard brochures when available.
Elicit concerns and questions and provide opportunities for the patient to state specific behaviors to carry out treatment recommendations
    Need to continue treatment
    Control does not mean cure
    One cannot tell if BP is elevated by feeling or symptoms; BP must be  measured

The National Committee for Quality Assurance (NCQA) has established the Health Plan Employer Data and Information Set (HEDIS), a set of standardized performance measures designed to ensure that purchasers and consumers have the information they need to reliably assess quality of health care ( Enforcement of HEDIS guidelines by managed care organizations has successfully increased the appropriate use of ACEIs in HF and BBs in patients who have suffered a myocardial infarction. NCQA now monitors physician records for the percent of patients whose BP is less than 140/90 mm Hg.381 BP control rates by physicians so monitored have increased to as high as 59%. Patients should be told their BP on each visit and be encouraged not only to ask for those numbers but to inquire as to why BP is above the goal, if that is the case. They also should be given a written record to keep as their part of this commitment.

Role of Other Healthcare Professionals

Clinicians must work with other healthcare professionals (eg, nurse case managers and other nurses, physician assistants, pharmacists, dentists, registered dietitians, licensed nutritionists, nutrition educators, optometrists, and podiatrists) to influence or reinforce instructions to improve patient lifestyles and BP control (Table 29). Nurse-managed hypertension clinics, worksite Occupational Health departments, managed care organizations, pharmacists, and lay community workers have all contributed to better hypertension control. Public health nurses and community outreach workers in high-risk communities also are helpful through their efforts to screen, identify cases, refer and track follow-up appointments, and educate patients. All health care professionals must be committed to enhancing BP control through reinforcing messages about the risks of hypertension, the importance of managing both SBP and DBP and achieving goal BP, education about effective lifestyle interventions, pharmacological therapies, and adherence to treatment.

TABLE 29. Collaborate With Other Health Professionals

Use complimentary skills and knowledge of nurses, physician assistants, pharmacists, registered dietitians, optometrists, dentists, and podiatrists
Refer selected patients for more intensive counseling

Patient Factors

Patient attitudes are greatly influenced by cultural differences, beliefs, and previous experiences with the health system.382 These attitudes must be understood and respected if the clinician is to build trust and increase communication with patients and families (Table 30). Clinicians should explain to patients that the terms “hypertension” and “high BP” are used interchangeably and that neither indicates an anxiety state. In addition to motivation, patients need specific education designed to help them modify their lifestyle and to take medications as prescribed to feel better and to reduce risks.

TABLE 30. Individualize the Regimen

Include patient in decision-making
Simplify the regimen to once-daily dosing, if possible
Incorporate treatment into patient’s daily lifestyle; eg, take medications just before or after brushing teeth
Agree with the patient on realistic short-term objectives for specific components of the medication and lifestyle modification plan
Encourage discussion of diet and physical activity
Encourage discussion of adverse drug effects and concerns
Encourage self-monitoring with validated BP devices
Minimize the cost of therapy. Recognize financial issues and enlist local community and national programs to assist in affording medications.
Indicate that adherence to the regimen will be a subject of discussion at each visit
Encourage gradual sustained weight loss

Characterization of Patients Leading to Tailored Therapy

There is a broad range of patient involvement in, and commitment to, hypertension therapy. Management strategies need to be focused on the patient’s goals when providing advice and encouraging adherence. Optimal management strategies are likely to differ for patient types. Healthy lifestyles influence adherence to medication as well as patient’s beliefs and involvement with behaviors including food, beverages, physical activity, healthy weight, salt and alcohol consumption, and smoking. A cluster analysis of 727 hypertensive patients found that the individuals fell into 4 categories.383 The largest group (39%) was health-oriented, informed about hypertension, and took their medication. A second group (16%) tended to rely on medication rather than lifestyle to control their BP. The third group (22%) had the highest BMI, did not practice health-promoting lifestyle except for low rates of alcohol consumption and tobacco abuse, often forgot to take their medication, and had a lower BP control rate. These patients may benefit most from clinical counseling and help in achieving lifestyle modifications and will likely require more frequent office visits or contact with nurses or other providers. The last group (23%) was more likely to be male and young, knew less about hypertension, was least afraid of consequences of hypertension or failure to take their medication, and was most likely to consume alcohol, abuse tobacco, and stop medication without informing their physician. They probably require persistent reinforcement, information on the hazards of lack of BP control, and small incremental goal-setting by allied health care personnel. Involvement of family members or other social supports also may be useful (Table 31).

TABLE 31. Promote Social Support Systems

With full permission of the patient, involve caring family members or other social support (ie, faith-based or community organizations) in the treatment process
Suggest common interest group activities (eg, a walking group) to enhance mutual support and motivation

Goal Setting and Behavioral Change

The clinician and patient must agree on BP goals and estimated time to reach them, and those goals should be clearly recorded in the chart. With the support of the clinician, the patient must be empowered with the understanding that making behavioral changes is ultimately his or her responsibility. As people make behavior change, they progress through a series of stages (precontemplation, contemplation, preparation, action, and maintenance). Behavior change is more successfully facilitated using this approach along with motivational interviewing rather than assigning the same intervention to every patient.384,385

Patients can be asked, using a 1 to 10 ranking, how likely they are to follow the plan. If not likely, the clinician can use motivational interviewing to identify the barriers to adherence. At visits where BP is above goal, alterations in the treatment plan should be made and documented accordingly. Home BP devices can be very useful in involving many patients in their own care. Devices must be calibrated by the clinician (see the section Self Measurement). This should be done, in part, by having the patient determine their BP with the device in the presence of the clinician. Home-determined BP tends to be approximately 5 mm Hg lower than office BP, and this information should be considered when assessing progress toward goal. But office BP should still be used to determine that a patient is at goal.

Patient satisfaction with their health care providers predicts compliance with treatment. All clinicians need to provide positive, patient-centered care to satisfy and enable their patients to follow treatment. Some patient-centered behavioral interventions, like counseling, have been shown to improve BP control, while the evidence for structured training or self-monitoring is less clear.

Economic Barriers

The cost of medications may be a barrier to effective treatment. Patients often perceive that lifestyle modifications such as following the DASH eating plan are expensive, but following these plans can be accomplished even on modest budgets. Nutrition educators offer classes in schools, communities, and worksites on food budgeting and meal planning. Clinicians should refer their patients to these classes. Medical nutrition therapy by registered dietitians improves the health of patients who have high cholesterol, diabetes, obesity, or other chronic disease risk factors.386 Patients should be advised that most lifestyle modifications may be cost-free or may even save money (eg, smoking cessation and reduction of alcohol consumption). Further, the beneficial effects of lifestyle modification may include reduction in the amount and cost of prescribed medications and the cost of insurance. A patient adhering to the DASH eating plan may require less medication and save money. Patients need to understand the important difference between the price of a medication and the cost of nonadherence. The price of medication is the amount of money needed for purchase, and the cost is the outcome or consequences of not adhering to this treatment advice, which may include impaired quality of life, CVD, kidney failure, stroke, and even premature death. The identification of persons who can assist the patient with insurance concerns and social services may be important to overall adherence. Most pharmaceutical companies have special needs programs that are often handled through their marketing departments.

Additional Sources of Information

Additional information is available at the NHLBI web site:

Scheme Used for Classification of the Evidence

The studies that provided evidence supporting the recommendations of this report were classified and reviewed by the staff and the executive committee. The classification scheme is from the JNC 6 report and other NHBPEP Working Group Reports.3,4,6,9

These symbols are appended to the citations in the reference list:

M: Meta-analysis; use of statistical methods to combine the results from clinical trials.

RA: Randomized controlled trials; also known as experimental studies.

RE: Retrospective analyses; also known as case-control studies.

F: Prospective study; also known as cohort studies, including historical or prospective follow-up studies.

X: Cross-sectional survey; also known as prevalence studies.

PR: Previous review or position statements.

C: Clinical interventions (nonrandomized).


National High Blood Pressure Education Program Coordinating Committee Participants

Claude Lenfant, MD (National Heart, Lung, and Blood Institute, Bethesda, Md); George L. Bakris, MD (Rush University Medical Center, Chicago, Ill); Henry R. Black, MD (Rush University Medical Center, Chicago, Ill); Vicki Burt, ScM, RN (National Center for Health Statistics, Hyattsville, Md); Barry L. Carter, PharmD, FCCP (University of Iowa, Iowa City, Iowa); Francis D. Chesley, Jr., MD (Agency for Healthcare Research and Quality, Rockville, Md); Jerome D. Cohen, MD (Saint Louis University School of Medicine, St. Louis, Mo); Pamela J. Colman, DPM (American Podiatric Medical Association, Bethesda, Md); William C. Cushman, MD (Veterans Affairs Medical Center, Memphis, Tenn); Mark J. Cziraky, PharmD, FAHA (Health Core, Inc., Newark, Del); John J. Davis, PAC (American Academy of Physician Assistants, Memphis, Tenn); Keith Copelin Ferdinand, MD, FACC (Heartbeats Life Center, New Orleans, La); Ray W. Gifford, Jr., MD, MS (Cleveland Clinic Foundation, Fountain Hills, Ariz); Michael Glick, DMD (New Jersey Dental School, Newark, NJ); Lee A. Green, MD, MPH (University of Michigan, Ann Arbor, Mich); Stephen Havas, MD, MPH, MS (University of Maryland School of Medicine, Baltimore, Md); Thomas H. Hostetter, MD (National Institutes of Diabetes and Digestive and Kidney Diseases, Bethesda, Md); Joseph L. Izzo, Jr., MD (State University of New York at Buffalo School of Medicine, Buffalo, NY); Daniel W. Jones, MD (University of Mississippi Medical Center, Jackson, Miss); Lynn Kirby, RN, NP, COHN (Sanofi-Synthelabo Research, Malvern, Pa); Kathryn M. Kolasa, PhD, RD, LDN (Brody School of Medicine at East Carolina University, Greenville, NC); Stuart Linas, MD (University of Colorado Health Sciences Center, Denver, Colo); William M. Manger, MD, PhD (New York University Medical Center, New York, NY); Edwin C. Marshall, OD, MS, MPH (Indiana University School of Optometry, Bloomington, Ind); Barry J. Materson, MD, MBA (University of Miami, Miami, Fla); Jay Merchant, MHA (Centers for Medicare & Medicaid Services, Washington, DC); Nancy Houston Miller, RN, BSN (Stanford University School of Medicine, Palo Alto, Calif); Marvin Moser, MD (Yale University School of Medicine, Scarsdale, NY); William A. Nickey, DO (Philadelphia College of Osteopathic Medicine, Philadelphia, Pa); Suzanne Oparil, MD (University of Alabama at Birmingham, Birmingham, Ala); Otelio S. Randall, MD, FACC (Howard University Hospital, Washington, DC); James W. Reed, MD, FACP, FACE (Morehouse School of Medicine, Atlanta, Ga); Edward J. Roccella, PhD, MPH (National Heart, Lung, and Blood Institute, Bethesda, Md); Lee Shaughnessy (National Stroke Association, Englewood, Colo); Sheldon G. Sheps, MD (Mayo Clinic, Rochester, Minn); David B. Snyder, RPh, DDS (Health Resources and Services Administration, Rockville, Md); James R. Sowers, MD, FACP, FACE (SUNY Health Science Center at Brooklyn, Brooklyn, NY); Leonard M. Steiner, MS, OD (Eye Group, Oakhurst, NJ); Ronald Stout, MD, MPH (Procter and Gamble, Mason, Ohio); Rita D. Strickland, EdD, RN (New York Institute of Technology, Springfield Gardens, NY); Carlos Vallbona, MD (Baylor College of Medicine, Houston, TX); Howard S. Weiss, MD, MPH (Georgetown University Medical Center, Washington Hospital Center, Walter Reed Army Medical Center, Washington, DC); Jack P. Whisnant, MD (Mayo Clinic and Mayo Medical School, Rochester, Minn); Laurie Willshire, MPH, RN (American Red Cross, Falls Church, Va); Gerald J. Wilson, MA, MBA (Citizens for Public Action on Blood Pressure and Cholesterol, Inc., Potomac, Md); Mary Winston, EdD, RD (American Heart Association, Dallas, Tex); Jackson T. Wright, Jr., MD, PhD (Case Western Reserve University, Cleveland, Ohio)

Additional Contributors

Jan N. Basile, MD, FACP (Veterans Administration Hospital, Charleston, SC); James I. Cleeman, MD (National Heart, Lung, and Blood Institute, Bethesda, Md); Darla E. Danford, MPH, DSc (National Heart, Lung, and Blood Institute, Bethesda, Md); Richard A. Dart, MD, FACP, FCCP, FAHA (Marshfield Clinic, Marshfield, Wis); Karen A. Donato, SM, RD (National Heart, Lung, and Blood Institute, Bethesda, Md); Mark E. Dunlap, MD (Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio); Brent M. Egan, MD (Medical University of South Carolina, Charleston, SC); William J. Elliott, MD, PhD (Rush University Medical Center, Chicago, Ill); Bonita E. Falkner, MD (Thomas Jefferson University, Philadelphia, Pa); John M. Flack, MD, MPH (Wayne State University School of Medicine, Detroit, Mich); David Lee Gordon, MD (University of Miami School of Medicine, Miami, Fla); Philip B. Gorelik, MD, MPH, FACP (Rush Medical College, Chicago, Ill); Mary M. Hand, MSPH, RN (National Heart, Lung, and Blood Institute, Bethesda, Md); Linda A. Hershey, MD, PhD (VA WNY Healthcare System, Buffalo, NY); Norman M. Kaplan, MD (University of Texas Southwestern Medical School at Dallas, Dallas, Tex); Daniel Levy, MD (National Heart, Lung, and Blood Institute, Framingham, Mass); James W. Lohr, MD (VA WNY Healthcare System and SUNY Buffalo, Buffalo, NY); Vasilios Papademetriou, MD, FACP, FACC (Veterans Affairs Medical Center, Washington, DC); Thomas G. Pickering, MD, DPhil (Mount Sinai Medical Center, New York, NY); Ileana L. Piña, MD, FACC (University Hospitals of Cleveland, Cleveland, Ohio); L. Michael Prisant, MD, FACC, FACP (Medical College of Georgia, Augusta, Ga); Clive Rosendorff, MD, PhD, FRCP (Veterans Affairs Medical Center, Bronx, NY); Virend K. Somers, MD, PhD (Mayo Clinic and Mayo Foundation, Rochester, Minn); Ray Townsend, MD (University of Pennsylvania School of Medicine, Philadelphia, Pa); Humberto Vidaillet, MD (Marshfield Clinic, Marshfield, Wis); Donald G. Vidt, MD (Cleveland Clinic Foundation, Cleveland, Ohio); William White, MD (The University of Connecticut Health Center, Farmington, Conn)


Joanne Karimbakas, MS, RD (American Institutes for Research Health Program, Silver Spring, Md).

The National High Blood Pressure Education Program (NHBPEP) Coordinating Committee Member Organizations

American Academy of Family Physicians; American Academy of Neurology; American Academy of Ophthalmology; American Academy of Physician Assistants; American Association of Occupational Health Nurses; American College of Cardiology; American College of Chest Physicians; American College of Occupational and Environmental Medicine; American College of Physicians-American Society of Internal Medicine; American College of Preventive Medicine; American Dental Association; American Diabetes Association; American Dietetic Association; American Heart Association; American Hospital Association; American Medical Association; American Nurses Association; American Optometric Association; American Osteopathic Association; American Pharmaceutical Association; American Podiatric Medical Association; American Public Health Association; American Red Cross; American Society of Health-System Pharmacists; American Society of Hypertension; American Society of Nephrology; Association of Black Cardiologists; Citizens for Public Action on High Blood Pressure and Cholesterol, Inc.; Hypertension Education Foundation, Inc.; International Society on Hypertension in Blacks; National Black Nurses Association, Inc.; National Hypertension Association, Inc.; National Kidney Foundation, Inc.; National Medical Association; National Optometric Association; National Stroke Association; NHLBI Ad Hoc Committee on Minority Populations; Society for Nutrition Education; The Society of Geriatric Cardiology. Federal Agencies: Agency for Health Care Research and Quality; Centers for Medicare and Medicaid Services; Department of Veterans Affairs; Health Resources and Services Administration; National Center for Health Statistics; National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases.

The executive committee, writing teams, and reviewers served as volunteers without remuneration.

Members of the National High Blood Pressure Education Program Coordinating Committee are listed in the Appendix.

This work was supported entirely by the National Heart, Lung, and Blood Institute. We appreciate the assistance by Carol Creech, MILS, and Gabrielle Gessner (American Institutes for Research Health Program, Silver Spring, Md).


Correspondence to Edward J. Roccella, PhD, Coordinator, National High Blood Pressure Education Program, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 31, Room 4A10, 31 Center Drive MSC 2480, Bethesda, MD 20892. E-mail


  • 1 Burt VL, Whelton P, Roccella EJ, Brown C, Cutler JA, Higgins M, et al. Prevalence of hypertension in the US adult population. Results from the Third National Health and Nutrition Examination Survey, 1988–1991. Hypertension. 1995; 25: 305–313.XCrossrefMedlineGoogle Scholar
  • 2 Hajjar I, Kotchen TA. Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988–2000. JAMA. 2003; 290: 199–206.XCrossrefMedlineGoogle Scholar
  • 3 World Health Report 2002: Reducing risks, promoting healthy life. Geneva, Switzerland: World Health Organization, 2002. Scholar
  • 4 JNC 6. National High Blood Pressure Education Program. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1997; 157: 2413–2446. PRCrossrefMedlineGoogle Scholar
  • 5 Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 Report. JAMA. 2003; 289: 2560–2572. PRCrossrefMedlineGoogle Scholar
  • 6 U. S. Department of Health and Human Services, National Heart, Lung, and Blood Institute. National High Blood Pressure Education Program. Available at: Accessed November, 2003.Google Scholar
  • 7 National High Blood Pressure Education Program. Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol. 2000; 183: S1–S22. PRCrossrefMedlineGoogle Scholar
  • 8 Roccella E, Kaplan N. Interpretation and evaluation of clinical guidelines. In: Izzo JL Jr, Black HR (eds). Hypertension Primer: The Essentials of High Blood Pressure: Basic Science, Population Science, and Clinical Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2003. pp. 126–127. PRGoogle Scholar
  • 9 Sheps SG, Roccella EJ. Reflections on the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Curr Hypertens Rep. 1999; 1: 342–345. PRCrossrefMedlineGoogle Scholar
  • 10 Whelton PK, He J, Appel LJ, Cutler JA, Havas S, Kotchen TA, et al. Primary prevention of hypertension: Clinical and public health advisory from The National High Blood Pressure Education Program. JAMA. 2002; 288: 1882–1888. PRCrossrefMedlineGoogle Scholar
  • 11 Last JM, Abramson JH. A Dictionary of Epidemiology. 3rd ed. New York, NY: Oxford University Press; 1995.Google Scholar
  • 12 Shaughnessy AF, Slawson DC, Bennett JH. Becoming an information master: a guidebook to the medical information jungle. J Fam Pract. 1994; 39: 489–499. PRMedlineGoogle Scholar
  • 13 Slawson DC, Shaughnessy AF. Obtaining useful information from expert based sources. BMJ. 1997; 314: 947–949. PRCrossrefMedlineGoogle Scholar
  • 14 Delbecq A, Van de Ven A, Gustafson D. Group Techniques for Program Planning: A Guide to Nominal Group and Delphi Process. Glenview, IL: Scott, Foresman; 1975. PRGoogle Scholar
  • 15 Franklin SS, Gustin W, Wong ND, Larson MG, Weber MA, Kannel WB, et al. Hemodynamic patterns of age-related changes in blood pressure. The Framingham Heart Study. Circulation. 1997; 96: 308–315.XCrossrefMedlineGoogle Scholar
  • 16 Vasan RS, Beiser A, Seshadri S, Larson MG, Kannel WB, D’Agostino RB, et al. Residual lifetime risk for developing hypertension in middle-aged women and men: The Framingham Heart Study. JAMA. 2002; 287: 1003–1010.FCrossrefMedlineGoogle Scholar
  • 17 Vasan RS, Larson MG, Leip EP, Kannel WB, Levy D. Assessment of frequency of progression to hypertension in nonhypertensive participants in the Framingham Heart Study: A cohort study. Lancet. 2001; 358: 1682–1686.FCrossrefMedlineGoogle Scholar
  • 18 Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual blood pressure to vascular mortality: A meta-analysis of individual data for one million adults in 61 prospective studies. Prospective Studies Collaboration. Lancet. 2002; 360: 1903–1913.MCrossrefMedlineGoogle Scholar
  • 19 Vasan RS, Larson MG, Leip EP, Evans JC, O’Donnell CJ, Kannel WB, et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl J Med. 2001; 345: 1291–1297.FCrossrefMedlineGoogle Scholar
  • 20 Anderson KM, Wilson PWF, Odell PM, Kannel WB. An updated coronary risk profile. A statement for health professionals. Circulation. 1991; 83: 356–362.CrossrefMedlineGoogle Scholar
  • 21 Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III): final report. Circulation. 2002; 106: 3143–3421. PRLinkGoogle Scholar
  • 22 Franklin SS, Larson MG, Khan SA, Wong ND, Leip EP, Kannel WB, et al. Does the relation of blood pressure to coronary heart disease risk change with aging? The Framingham Heart Study. Circulation. 2001; 103: 1245–1249.FCrossrefMedlineGoogle Scholar
  • 23 Kostis JB, Davis BR, Cutler J, Grimm RH Jr, Berge KG, Cohen JD, et al. Prevention of heart failure by antihypertensive drug treatment in older persons with isolated systolic hypertension. SHEP Cooperative Research Group. JAMA. 1997; 278: 212–216.RACrossrefMedlineGoogle Scholar
  • 24 SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA. 1991; 265: 3255–3264.RACrossrefMedlineGoogle Scholar
  • 25 Staessen JA, Thijs L, Fagard R, O’Brien ET, Clement D, de Leeuw PW, et al. Predicting cardiovascular risk using conventional vs ambulatory blood pressure in older patients with systolic hypertension. Systolic Hypertension in Europe Trial Investigators. JAMA. 1999; 282: 539–546.RACrossrefMedlineGoogle Scholar
  • 26 Hyman DJ, Pavlik VN. Characteristics of patients with uncontrolled hypertension in the United States. N Engl J Med. 2001; 345: 479–486.XCrossrefMedlineGoogle Scholar
  • 27 Lloyd-Jones DM, Evans JC, Larson MG, O’Donnell CJ, Roccella EJ, Levy D. Differential control of systolic and diastolic blood pressure: factors associated with lack of blood pressure control in the community. Hypertension. 2000; 36: 594–599.FCrossrefMedlineGoogle Scholar
  • 28 Cushman WC, Ford CE, Cutler JA, Margolis KL, Davis BR, Grimm RH, et al. Success and predictors of blood pressure control in diverse North American settings: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Clin Hypertens (Greenwich). 2002; 4: 393–404.RACrossrefMedlineGoogle Scholar
  • 29 Black HR, Elliott WJ, Neaton JD, Grandits G, Grambsch P, Grimm R, et al. Baseline characteristics and early blood pressure control in the CONVINCE trial. Hypertension. 2001; 37: 12–18.RALinkGoogle Scholar
  • 30 Hyman DJ, Pavlik VN, Vallbona C. Physician role in lack of awareness and control of hypertension. J Clin Hypertens (Greenwich). 2000; 2: 324–330.XMedlineGoogle Scholar
  • 31 Berlowitz DR, Ash AS, Hickey EC, Friedman RH, Glickman M, Kader B, et al. Inadequate management of blood pressure in a hypertensive population. N Engl J Med. 1998; 339: 1957–1963.CrossrefMedlineGoogle Scholar
  • 32 Stamler J, Stamler R, Neaton JD, Wentworth D, Daviglus ML, Garside D, et al. Low risk-factor profile and long-term cardiovascular and noncardiovascular mortality and life expectancy: findings for 5 large cohorts of young adult and middle-aged men and women. JAMA. 1999; 282: 2012–2018.FCrossrefMedlineGoogle Scholar
  • 33 Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among US adults, 1999–2000. JAMA. 2002; 288: 1723–1727.XCrossrefMedlineGoogle Scholar
  • 34 Cleveland LE, Goldman JD, Borrud LG. Data tables: results from USDA’s 1994 continuing survey of food intakes by individuals and 1994 diet and health knowledge survey. Riverdale, MD: Agricultural Research Service, US Department of Agriculture. 1996. Scholar
  • 35 James WP, Ralph A, Sanchez-Castillo CP. The dominance of salt in manufactured food in the sodium intake of affluent societies. Lancet. 1987; 1: 426–429.MedlineGoogle Scholar
  • 36 U S Department of Health and Human Services. Physical activity and health: a report of the Surgeon General. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion. 1996. PRGoogle Scholar
  • 37 Division of Adult and Community Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention. 5 a day surveillance: behavioral risk factor surveillance system online prevalence data, 1995–2000. Available at: Accessed November, 2003.Google Scholar
  • 38 Stamler R. Implications of the INTERSALT study. Hypertension. 1991; 17: I16–I20.LinkGoogle Scholar
  • 39 American Public Health Association. 2002–4 Reducing sodium content in the American diet. Association News. 2002;5–6.Google Scholar
  • 40 National High Blood Pressure Education Program. Summary report: the National High Blood Pressure Education Program Coordinating Committee meeting. Bethesda, MD: National High Blood Pressure Education Program, National Heart, Lung, and Blood Institute; 2002. pp. 1–37. Scholar
  • 41 Office of Disease Prevention and Health Promotion, US Department of Health and Human Services. Healthy People 2010. Available at: Accessed November, 2003.Google Scholar
  • 42 US Department of Health and Human Services, National Institutes of Health, National Heart, Lung, and Blood Institute. Facts about the DASH eating plan. Available at Accessed November, 2003.Google Scholar
  • 43 National Heart, Lung, and Blood Institute. Your guide to lowering high blood pressure. Available at Accessed November, 2003.Google Scholar
  • 44 US Department of Health and Human Services, National Institutes of Health, National Heart, Lung, and Blood Institute, National High Blood Pressure Education Program. National High Blood Pressure Education Month. Available at: Accessed November, 2003.Google Scholar
  • 45 US Department of Health and Human Services, National Institutes of Health, National Heart, Lung, and Blood Institute. The heart truth: a national awareness campaign for women about heart disease. Available at: Accessed November, 2003.Google Scholar
  • 46 National Institutes of Health, National Heart, Lung, and Blood Institute, Office of Prevention, Education, and Control. Mobilizing African American communities to address disparities in cardiovascular health: The Baltimore City Health Partnership Strategy Development Workshop. Summary report. Available at: Accessed November, 2003.Google Scholar
  • 47 US Department of Health and Human Services, National Institutes of Health, National Heart, Lung, and Blood Institute. NHLBI Healthy People 2010 Gateway. Available at: Accessed November, 2003.Google Scholar
  • 48 National Heart, Lung, and Blood Institute. Cardiovascular disease enhanced dissemination and utilization centers (EDUCs) awardees. Available at: Accessed November, 2003.Google Scholar
  • 49 National Institutes of Health, National Heart, Lung, and Blood Institute. Hearts N’ Parks. Available at: Accessed November, 2003.Google Scholar
  • 50 National Institutes of Health. Healthbeat radio network. Available at: Accessed November, 2003.Google Scholar
  • 51 National Heart, Lung, and Blood Institute. Salud para su Corazón (For the Health of Your Heart). Available at: Accessed November, 2003.Google Scholar
  • 52 National Institutes of Health. Mad as a hatter? Join our campaign for a mercury free NIH. Available at: Accessed November, 2003.Google Scholar
  • 53 Jones DW, Appel LJ, Sheps SG, Roccella EJ, Lenfant C. Measuring blood pressure accurately: new and persistent challenges. JAMA. 2003; 289: 1027–1030. PRCrossrefMedlineGoogle Scholar
  • 54 Working Meeting on Blood Pressure Measurement: Summary Report. Available at: Accessed November, 2003.Google Scholar
  • 55 Canzanello VJ, Jensen PL, Schwartz GL. Are aneroid sphygmomanometers accurate in hospital and clinic settings? Arch Intern Med. 2001; 161: 729–731. PRCrossrefMedlineGoogle Scholar
  • 56 Perloff D, Grim C, Flack J, Frohlich ED, Hill M, McDonald M, et al. Human blood pressure determination by sphygmomanometry. Circulation. 1993; 88: 2460–2470. PRCrossrefMedlineGoogle Scholar
  • 57 Gerin W, Schwartz AR, Schwartz JE, Pickering TG, Davidson KW, Bress J, et al. Limitations of current validation protocols for home blood pressure monitors for individual patients. Blood Press Monit. 2002; 7: 313–318.CrossrefMedlineGoogle Scholar
  • 58 World Hypertension League. Measuring your blood pressure. Available at: Accessed November, 2003.Google Scholar
  • 59 Pickering T. Recommendations for the use of home (self) and ambulatory blood pressure monitoring. American Society of Hypertension Ad Hoc Panel. Am J Hypertens. 1996; 9: 1–11. PRCrossrefMedlineGoogle Scholar
  • 60 Kario K, Pickering TG, Umeda Y, Hoshide S, Hoshide Y, Morinari M, et al. Morning surge in blood pressure as a predictor of silent and clinical cerebrovascular disease in elderly hypertensives: a prospective study. Circulation. 2003; 107: 1401–1406. FLinkGoogle Scholar
  • 61 Pickering TG, Coats A, Mallion JM, Mancia G, Verdecchia P. Blood Pressure Monitoring. Task force V: White-coat hypertension. Blood Press Monit. 1999; 4: 333–341. PRMedlineGoogle Scholar
  • 62 Verdecchia P. Prognostic value of ambulatory blood pressure: current evidence and clinical implications. Hypertension. 2000; 35: 844–851. PRCrossrefMedlineGoogle Scholar
  • 63 Clement DL, De Buyzere ML, De Bacquer DA, de Leeuw PW, Duprez DA, Fagard RH, et al. Prognostic value of ambulatory blood-pressure recordings in patients with treated hypertension. N Engl J Med. 2003; 348: 2407–2415. FCrossrefMedlineGoogle Scholar
  • 64 Gillman MW, Kannel WB, Belanger A, D’Agostino RB. Influence of heart rate on mortality among persons with hypertension: the Framingham Study. Am Heart J. 1993; 125: 1148–1154. FCrossrefMedlineGoogle Scholar
  • 65 Tsuji H, Venditti FJ Jr, Manders ES, Evans JC, Larson MG, Feldman CL, et al. Reduced heart rate variability and mortality risk in an elderly cohort. The Framingham Heart Study. Circulation. 1994; 90: 878–883. FCrossrefMedlineGoogle Scholar
  • 66 GFR /1.73 M2 by MDRD (± SUN and SAlb) Calculator. Available at: Accessed November, 2003.Google Scholar
  • 67 Mann JF, Gerstein HC, Pogue J, Bosch J, Yusuf S. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial. Ann Intern Med. 2001; 134: 629–636. RACrossrefMedlineGoogle Scholar
  • 68 Beddhu S, Allen-Brady K, Cheung AK, Horne BD, Bair T, Muhlestein JB, et al. Impact of renal failure on the risk of myocardial infarction and death. Kidney Int. 2002; 62: 1776–1783. RECrossrefMedlineGoogle Scholar
  • 69 Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999; 130: 461–470. XCrossrefMedlineGoogle Scholar
  • 70 Jensen JS, Feldt-Rasmussen B, Strandgaard S, Schroll M, Borch-Johnsen K. Arterial hypertension, microalbuminuria, and risk of ischemic heart disease. Hypertension. 2000; 35: 898–903. XCrossrefMedlineGoogle Scholar
  • 71 Gerstein HC, Mann JF, Yi Q, Zinman B, Dinneen SF, Hoogwerf B, et al. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA. 2001; 286: 421–426. FCrossrefMedlineGoogle Scholar
  • 72 Garg JP, Bakris GL. Microalbuminuria: marker of vascular dysfunction, risk factor for cardiovascular disease. Vasc Med. 2002; 7: 35–43. PRCrossrefMedlineGoogle Scholar
  • 73 Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002; 347: 1557–1565. FCrossrefMedlineGoogle Scholar
  • 74 Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000; 342: 836–843. FCrossrefMedlineGoogle Scholar
  • 75 Boden-Albala B, Sacco RL. Lifestyle factors and stroke risk: exercise, alcohol, diet, obesity, smoking, drug use, and stress. Curr Atheroscler Rep. 2000; 2: 160–166. PRCrossrefMedlineGoogle Scholar
  • 76 Parsons DS, Reaveley DA, Pavitt DV, Brown EA. Relationship of renal function to homocysteine and lipoprotein(a) levels: the frequency of the combination of both risk factors in chronic renal impairment. Am J Kidney Dis. 2002; 40: 916–923. CCrossrefMedlineGoogle Scholar
  • 77 Manger WM, Gifford RW. Pheochromocytoma. J Clin Hypertens (Greenwich). 2002; 4: 62–72.CrossrefMedlineGoogle Scholar
  • 78 Textor SC. Revascularization in atherosclerotic renal artery disease. Kidney Int. 1998; 53: 799–811.CrossrefMedlineGoogle Scholar
  • 79 Pohl MA. Renovascular hypertension and ischemic nephropathy. In: Wilcox CS (ed): Atlas of Diseases of the Kidney. Philadelphia, PA: Developed by Current Medicine, Inc.; 1999.Google Scholar
  • 80 Biglieri EG. Primary aldosteronism. Curr Ther Endocrinol Metab. 1997; 6: 170–172.MedlineGoogle Scholar
  • 81 National High Blood Pressure Education Program Working Group. 1995 update of the working group reports on chronic renal failure and renovascular hypertension. Arch Intern Med. 1996; 156: 1938–1947. PRCrossrefMedlineGoogle Scholar
  • 82 Lifton RP, Gharavi AG, Geller DS. Molecular mechanisms of human hypertension. Cell. 2001; 104: 545–556. PRCrossrefMedlineGoogle Scholar
  • 83 Bray MS, Li L, Turner ST, Kardia SL, Boerwinkle E. Association and linkage analysis of the alpha-adducin gene and blood pressure. Am J Hypertens. 2000; 13: 699–703. FCrossrefMedlineGoogle Scholar
  • 84 Beeks E, Janssen RG, Kroon AA, Keulen ET, Geurts JM, de Leeuw PW, et al. Association between the alpha-adducin Gly460Trp polymorphism and systolic blood pressure in familial combined hyperlipidemia. Am J Hypertens. 2001; 14: 1185–1190. CCrossrefMedlineGoogle Scholar
  • 85 Psaty BM, Smith NL, Heckbert SR, Vos HL, Lemaitre RN, Reiner AP, et al. Diuretic therapy, the alpha-adducin gene variant, and the risk of myocardial infarction or stroke in persons with treated hypertension. JAMA. 2002; 287: 1680–1689. RECrossrefMedlineGoogle Scholar
  • 86 Cooper-DeHoff RM, Bristol HA, Pepine CJ. Ethnic differences in systolic blood pressure control in hypertensive patients with coronary artery disease. Am J Hypertens. 2003; 16: 27A.Google Scholar
  • 87 Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet. 1998; 351: 1755–1762. RACrossrefMedlineGoogle Scholar
  • 88 American Diabetes Association. Treatment of hypertension in adults with diabetes. Diabetes Care. 2003; 26: S80–S82. PRCrossrefMedlineGoogle Scholar
  • 89 National Kidney Foundation Guideline. K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Kidney Disease Outcome Quality Initiative. Am J Kidney Dis. 2002; 39: S1–S246. PRCrossrefMedlineGoogle Scholar
  • 90 Neal B, MacMahon S, Chapman N. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Blood Pressure Lowering Treatment Trialists’ Collaboration. Lancet. 2000; 356: 1955–1964. MCrossrefMedlineGoogle Scholar
  • 91 Ogden LG, He J, Lydick E, Whelton PK. Long-term absolute benefit of lowering blood pressure in hypertensive patients according to the JNC VI risk stratification. Hypertension. 2000; 35: 539–543. XCrossrefMedlineGoogle Scholar
  • 92 The Trials of Hypertension Prevention Collaborative Research Group. Effects of weight loss and sodium reduction intervention on blood pressure and hypertension incidence in overweight people with high-normal blood pressure. The Trials of Hypertension Prevention, phase II. Arch Intern Med. 1997; 157: 657–667. RACrossrefMedlineGoogle Scholar
  • 93 He J, Whelton PK, Appel LJ, Charleston J, Klag MJ. Long-term effects of weight loss and dietary sodium reduction on incidence of hypertension. Hypertension. 2000; 35: 544–549. FCrossrefMedlineGoogle Scholar
  • 94 Sacks FM, Svetkey LP, Vollmer WM, Appel LJ, Bray GA, Harsha D, et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group. N Engl J Med. 2001; 344: 3–10. RACrossrefMedlineGoogle Scholar
  • 95 Vollmer WM, Sacks FM, Ard J, Appel LJ, Bray GA, Simons-Morton DG, et al. Effects of diet and sodium intake on blood pressure: subgroup analysis of the DASH-sodium trial. Ann Intern Med. 2001; 135: 1019–1028. RACrossrefMedlineGoogle Scholar
  • 96 Chobanian AV, Hill M. National Heart, Lung, and Blood Institute Workshop on Sodium and Blood Pressure: a critical review of current scientific evidence. Hypertension. 2000; 35: 858–863. PRCrossrefMedlineGoogle Scholar
  • 97 Kelley GA, Kelley KS. Progressive resistance exercise and resting blood pressure: a meta-analysis of randomized controlled trials. Hypertension. 2000; 35: 838–843. MCrossrefMedlineGoogle Scholar
  • 98 Whelton SP, Chin A, Xin X, He J. Effect of aerobic exercise on blood pressure: a meta-analysis of randomized, controlled trials. Ann Intern Med. 2002; 136: 493–503. MCrossrefMedlineGoogle Scholar
  • 99 Xin X, He J, Frontini MG, Ogden LG, Motsamai OI, Whelton PK. Effects of alcohol reduction on blood pressure: a meta-analysis of randomized controlled trials. Hypertension. 2001; 38: 1112–1117. MCrossrefMedlineGoogle Scholar
  • 100 Appel LJ, Champagne CM, Harsha DW, Cooper LS, Obarzanek E, Elmer PJ, et al. Effects of comprehensive lifestyle modification on blood pressure control: main results of the PREMIER clinical trial. Writing Group of the PREMIER Collaborative Research Group. JAMA. 2003; 289: 2083–2093. RAMedlineGoogle Scholar
  • 101 Black HR, Elliott WJ, Grandits G, Grambsch P, Lucente T, White WB, et al. Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial. JAMA. 2003; 289: 2073–2082. RACrossrefMedlineGoogle Scholar
  • 102 Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, Faire U, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): A randomised trial against atenolol. Lancet. 2002; 359: 995–1003. RACrossrefMedlineGoogle Scholar
  • 103 Materson BJ, Reda DJ, Cushman WC, Massie BM, Freis ED, Kochar MS, et al. Single-drug therapy for hypertension in men: a comparison of six antihypertensive agents with placebo. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. N Engl J Med. 1993; 328: 914–921. RACrossrefMedlineGoogle Scholar
  • 104 Cutler JA, MacMahon SW, Furberg CD. Controlled clinical trials of drug treatment for hypertension: a review. Hypertension. 1989; 13: I36–I44. PRLinkGoogle Scholar
  • 105 Collins R, Peto R, Godwin J, MacMahon S. Blood pressure and coronary heart disease. Lancet. 1990; 336: 370–371.CrossrefMedlineGoogle Scholar
  • 106 Chalmers J, Zanchetti A. The 1996 report of a World Health Organization expert committee on hypertension control. J Hypertens. 1996; 14: 929–933. PRMedlineGoogle Scholar
  • 107 Psaty BM, Smith NL, Siscovick DS, Koepsell TD, Weiss NS, Heckbert SR, et al. Health outcomes associated with antihypertensive therapies used as first-line agents: a systematic review and meta-analysis. JAMA. 1997; 277: 739–745. MCrossrefMedlineGoogle Scholar
  • 108 Psaty BM, Lumley T, Furberg CD, Schellenbaum G, Pahor M, Alderman MH, et al. Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysis. JAMA. 2003; 289: 2534–2544. MCrossrefMedlineGoogle Scholar
  • 109 The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002; 288: 2981–2997. RACrossrefMedlineGoogle Scholar
  • 110 Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000; 342: 145–153. RACrossrefMedlineGoogle Scholar
  • 111 PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001; 358: 1033–1041. RACrossrefMedlineGoogle Scholar
  • 112 Wing LM, Reid CM, Ryan P, Beilin LJ, Brown MA, Jennings GL, et al. A comparison of outcomes with angiotensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med. 2003; 348: 583–592. RACrossrefMedlineGoogle Scholar
  • 113 Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhager WH, et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet. 1997; 350: 757–764. RACrossrefMedlineGoogle Scholar
  • 114 The European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003; 362: 782–788. RACrossrefMedlineGoogle Scholar
  • 115 Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason A, et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet. 1999; 353: 611–616. RACrossrefMedlineGoogle Scholar
  • 116 Hansson L, Lindholm LH, Ekbom T, Dahlof B, Lanke J, Schersten B, et al. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity: the Swedish Trial in Old Patients with Hypertension-2 study. Lancet. 1999; 354: 1751–1756. RACrossrefMedlineGoogle Scholar
  • 117 Hansson L, Hedner T, Lund-Johansen P, Kjeldsen SE, Lindholm LH, Syvertsen JO, et al. Randomised trial of effects of calcium antagonists compared with diuretics and beta-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study. Lancet. 2000; 356: 359–365. RACrossrefMedlineGoogle Scholar
  • 118 Brown MJ, Palmer CR, Castaigne A, de Leeuw PW, Mancia G, Rosenthal T, et al. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet. 2000; 356: 366–372. RACrossrefMedlineGoogle Scholar
  • 119 Black HR. The evolution of low-dose diuretic therapy: the lessons from clinical trials. Am J Med. 1996; 101: 47S–52S. PRCrossrefGoogle Scholar
  • 120 Materson BJ, Cushman WC, Goldstein G, Reda DJ, Freis ED, Ramirez EA, et al. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents: Treatment of hypertension in the elderly, I: blood pressure and clinical changes. Results of a Department of Veterans Affairs Cooperative Study. Hypertension. 1990; 15: 348–360.LinkGoogle Scholar
  • 121 Siscovick DS, Raghunathan TE, Psaty BM, Koepsell TD, Wicklund KG, Lin X, et al. Diuretic therapy for hypertension and the risk of primary cardiac arrest. N Engl J Med. 1994; 330: 1852–1857. RECrossrefMedlineGoogle Scholar
  • 122 Flack JM, Cushman WC. Evidence for the efficacy of low-dose diuretic monotherapy. Am J Med. 1996; 101: 53S–60S. PRGoogle Scholar
  • 123 Grimm RH Jr, Grandits GA, Prineas RJ, McDonald RH, Lewis CE, Flack JM, et al. Long-term effects on sexual function of five antihypertensive drugs and nutritional hygienic treatment in hypertensive men and women. Treatment of Mild Hypertension Study (TOMHS). Hypertension. 1997; 29: 8–14. RALinkGoogle Scholar
  • 124 Moser M. Why are physicians not prescribing diuretics more frequently in the management of hypertension? JAMA. 1998; 279: 1813–1816.CrossrefMedlineGoogle Scholar
  • 125 Lakshman MR, Reda DJ, Materson BJ, Cushman WC, Freis ED. Diuretics and beta-blockers do not have adverse effects at 1 year on plasma lipid and lipoprotein profiles in men with hypertension. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Arch Intern Med. 1999; 159: 551–558. RACrossrefMedlineGoogle Scholar
  • 126 Franse LV, Pahor M, Di Bari M, Somes GW, Cushman WC, Applegate WB. Hypokalemia associated with diuretic use and cardiovascular events in the Systolic Hypertension in the Elderly program. Hypertension. 2000; 35: 1025–1030. RACrossrefMedlineGoogle Scholar
  • 127 Papademetriou V, Burris JF, Notargiacomo A, Fletcher RD, Freis ED. Thiazide therapy is not a cause of arrhythmia in patients with systemic hypertension. Arch Intern Med. 1988; 148: 1272–1276. CCrossrefMedlineGoogle Scholar
  • 128 Psaty BM, Manolio TA, Smith NL, Heckbert SR, Gottdiener JS, Burke GL, et al. Time trends in high blood pressure control and the use of antihypertensive medications in older adults: The Cardiovascular Health Study. Arch Intern Med. 2002; 162: 2325–2332. XCrossrefMedlineGoogle Scholar
  • 129 Sica DA. Rationale for fixed-dose combinations in the treatment of hypertension: the cycle repeats. Drugs. 2002; 62: 443–462. PRCrossrefMedlineGoogle Scholar
  • 130 Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ. 2003; 326: 1427–1434. MCrossrefMedlineGoogle Scholar
  • 131 Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002; 324: 71–86. RACrossrefMedlineGoogle Scholar
  • 132 Hunt SA, Baker DW, Chin MH, Cinquegrani MP, Feldman AM, Francis GS, et al. ACC/AHA Guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the International Society for Heart and Lung Transplantation;endorsed by the Heart Failure Society of America. Circulation. 2001; 104: 2996–3007. PRCrossrefMedlineGoogle Scholar
  • 133 Tepper D. Frontiers in congestive heart failure: effect of Metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). MERIT-HF Study Group. Congest Heart Fail. 1999; 5: 184–185. RAMedlineGoogle Scholar
  • 134 Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001; 344: 1651–1658. RACrossrefMedlineGoogle Scholar
  • 135 CIBIS Investigators and Committees. A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). Circulation. 1994; 90: 1765–1773. RACrossrefMedlineGoogle Scholar
  • 136 The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991; 325: 293–302. RACrossrefMedlineGoogle Scholar
  • 137 The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet. 1993; 342: 821–828. RAMedlineGoogle Scholar
  • 138 Kober L, Torp-Pedersen C, Carlsen JE, Bagger H, Eliasen P, Lyngborg K, et al. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. N Engl J Med. 1995; 333: 1670–1676. RACrossrefMedlineGoogle Scholar
  • 139 Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. The Valsartan Heart Failure Trial Investigators. N Engl J Med. 2001; 345: 1667–1675. RACrossrefMedlineGoogle Scholar
  • 140 Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999; 341: 709–717. RACrossrefMedlineGoogle Scholar
  • 141 McMurray J, Ostergren J, Pfeffer M, Swedberg K, Granger C, Yusuf S, et al. Clinical features and contemporary management of patients with low and preserved ejection fraction heart failure: baseline characteristics of patients in the Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) programme. Eur J Heart Fail. 2003; 5: 261–270.CrossrefMedlineGoogle Scholar
  • 142 Gibbons RJ, Abrams J, Chatterjee K, Daley J, Deedwania PC, Douglas JS, et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina-summary article: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on the Management of Patients With Chronic Stable Angina). J Am Coll Cardiol. 2003; 41: 159–168. PRCrossrefMedlineGoogle Scholar
  • 143 β-Blocker Heart Attack Trial Research Group. A randomized trial of propranolol in patients with acute myocardial infarction, I: mortality results. JAMA. 1982; 247: 1707–1714. RACrossrefMedlineGoogle Scholar
  • 144 Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ Jr, Cuddy TE, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the Survival and Ventricular Enlargement trial. The SAVE Investigators. N Engl J Med. 1992; 327: 669–677. RACrossrefMedlineGoogle Scholar
  • 145 The Capricorn Investigators. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: The CAPRICORN randomised trial. Lancet. 2001; 357: 1385–1390. RACrossrefMedlineGoogle Scholar
  • 146 Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003; 348: 1309–1321.CrossrefMedlineGoogle Scholar
  • 147 Pepine CJ, Handberg EM, Cooper-DeHoff RM, Marks RG, Kowey P, Messerli F, et al. for the INVEST Investigators. A calcium antagonist versus a noncalcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial. JAMA. 2003; 290: 2805–2816.CrossrefMedlineGoogle Scholar
  • 148 UKPDS 39. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group. BMJ. 1998; 317: 713–720. RACrossrefMedlineGoogle Scholar
  • 149 Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993; 329: 1456–1462. RACrossrefMedlineGoogle Scholar
  • 150 Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001; 345: 861–869. RACrossrefMedlineGoogle Scholar
  • 151 Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001; 345: 851–860. RACrossrefMedlineGoogle Scholar
  • 152 The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet. 1997; 349: 1857–1863. RACrossrefMedlineGoogle Scholar
  • 153 Wright JT Jr, Agodoa L, Contreras G, Greene T, Douglas JG, Lash J, et al. Successful blood pressure control in the African American Study of Kidney Disease and Hypertension. Arch Intern Med. 2002; 162: 1636–1643. RACrossrefMedlineGoogle Scholar
  • 154 Rosendorff C. Treatment of hypertension patients with ischemic heart disease. In: Izzo JL Jr, Black HR (eds): Hypertension Primer: The Essentials of High Blood Pressure: Basic Science, Population Science, and Clinical Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2003. pp. 456–459. PRGoogle Scholar
  • 155 Somes GW, Pahor M, Shorr RI, Cushman WC, Applegate WB. The role of diastolic blood pressure when treating isolated systolic hypertension. Arch Intern Med. 1999; 159: 2004–2009. RACrossrefMedlineGoogle Scholar
  • 156 Chrysant GS, Oparil S. Treatment of hypertension in the patient with cardiovascular disease. In: Antman EM (ed): Cardiovascular Therapeutics: A Companion to Braunwald’s Heart Disease. Philadelphia, PA: WB Saunders; 2001. pp. 768–795. PRGoogle Scholar
  • 157 Senni M, Redfield MM. Heart failure with preserved systolic function. A different natural history? J Am Coll Cardiol. 2001; 38: 1277–1282. PRCrossrefMedlineGoogle Scholar
  • 158 Levy D, Kenchaiah S, Larson MG, Benjamin EJ, Kupka MJ, Ho KK, et al. Long-term trends in the incidence of and survival with heart failure. N Engl J Med. 2002; 347: 1397–1402. FCrossrefMedlineGoogle Scholar
  • 159 American Heart Association. Heart disease and stroke statistics-2003 update. Dallas, TX: American Heart Association; 2002.Google Scholar
  • 160 The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997; 336: 525–533. RACrossrefMedlineGoogle Scholar
  • 161 Mokdad AH, Ford ES, Bowman BA, Nelson DE, Engelgau MM, Vinicor F, et al. Diabetes trends in the U S: 1990–1998. Diabetes Care. 2000; 23: 1278–1283. XCrossrefMedlineGoogle Scholar
  • 162 Prevalence of Diabetes and Impaired Fasting Glucose in Adults-United States, 1999–2000. Morbidity and Mortality Weekly Report. 2003; 52: 833–837.MedlineGoogle Scholar
  • 163 Collins AJ, Kasiske B, Herzog C, Chen S-C, Everson S, Constantini E, et al. Excerpts from the United States Renal Data System 2001 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Am J Kidney Dis. 2001; 38: S7–S247.Google Scholar
  • 164 American Diabetes Association. Diabetic nephropathy. Diabetes Care. 2002; 25: S85–S89. PRCrossrefGoogle Scholar
  • 165 Bakris GL, Williams M, Dworkin L, Elliott WJ, Epstein M, Toto R, et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis. 2000; 36: 646–661. PRCrossrefMedlineGoogle Scholar
  • 166 Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998; 339: 229–234. FCrossrefMedlineGoogle Scholar
  • 167 Assman G, Cullen P, Schulte H. The Munster Heart Study (PROCAM): results of follow-up at 8 years. Eur Heart J. 1998; 19: A2–A11. FMedlineGoogle Scholar
  • 168 Fagan TC, Sowers J. Type 2 diabetes mellitus: greater cardiovascular risks and greater benefits of therapy. Arch Intern Med. 1999; 159: 1033–1034.CrossrefMedlineGoogle Scholar
  • 169 Davis TM, Millns H, Stratton IM, Holman RR, Turner RC. Risk factors for stroke in type 2 diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS) 29. Arch Intern Med. 1999; 159: 1097–1103. RACrossrefMedlineGoogle Scholar
  • 170 Grundy SM, Benjamin IJ, Burke GL, Chait A, Eckel RH, Howard BV, et al. Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation. 1999; 100: 1134–1146. PRCrossrefMedlineGoogle Scholar
  • 171 Sowers JR, Haffner S. Treatment of cardiovascular and renal risk factors in the diabetic hypertensive. Hypertension. 2002; 40: 781–788.LinkGoogle Scholar
  • 172 Gress TW, Nieto FJ, Shahar E, Wofford MR, Brancati FL. Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus. Atherosclerosis Risk in Communities Study. N Engl J Med. 2000; 342: 905–912. FCrossrefMedlineGoogle Scholar
  • 173 Sowers JR, Bakris GL. Antihypertensive therapy and the risk of type 2 diabetes mellitus. N Engl J Med. 2000; 342: 969–970.CrossrefMedlineGoogle Scholar
  • 174 Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ. 2000; 321: 412–419. RACrossrefMedlineGoogle Scholar
  • 175 UKPDS 38. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ. 1998; 317: 703–713. RACrossrefMedlineGoogle Scholar
  • 176 Goldstein LB, Adams R, Becker K, Furberg CD, Gorelick PB, Hademenos G, et al. Primary prevention of ischemic stroke: a statement for healthcare professionals from the Stroke Council of the American Heart Association. Circulation. 2001; 103: 163–182. PRCrossrefMedlineGoogle Scholar
  • 177 Maki DD, Ma JZ, Louis TA, Kasiske BL. Long-term effects of antihypertensive agents on proteinuria and renal function. Arch Intern Med. 1995; 155: 1073–1080. MCrossrefMedlineGoogle Scholar
  • 178 Nelson RG, Bennett PH, Beck GJ, Tan M, Knowler WC, Mitch WE, et al. Development and progression of renal disease in Pima Indians with non-insulin-dependent diabetes mellitus. Diabetic Renal Disease Study Group. N Engl J Med. 1996; 335: 1636–1642. CCrossrefMedlineGoogle Scholar
  • 179 Kohner EM, Aldington SJ, Stratton IM, Manley SE, Holman RR, Matthews DR, et al. United Kingdom Prospective Diabetes Study, 30: diabetic retinopathy at diagnosis of non-insulin-dependent diabetes mellitus and associated risk factors. Arch Ophthalmol. 1998; 116: 297–303. RACrossrefMedlineGoogle Scholar
  • 180 Tuomilehto J, Rastenyte D, Birkenhager WH, Thijs L, Antikainen R, Bulpitt CJ, et al. Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. Systolic Hypertension in Europe Trial Investigators. N Engl J Med. 1999; 340: 677–684. RACrossrefMedlineGoogle Scholar
  • 181 Remuzzi G, Schieppati A, Ruggenenti P. Clinical practice: nephropathy in patients with type 2 diabetes. N Engl J Med. 2002; 346: 1145–1151.CrossrefMedlineGoogle Scholar
  • 182 Parving HH, Andersen AR, Smidt UM, Hommel E, Mathiesen ER, Svendsen PA. Effect of antihypertensive treatment on kidney function in diabetic nephropathy. BMJ (Clin Res Ed). 1987; 294: 1443–1447. FCrossrefMedlineGoogle Scholar
  • 183 Mogensen CE, Keane WF, Bennett PH, Jerums G, Parving HH, Passa P, et al. Prevention of diabetic renal disease with special reference to microalbuminuria. Lancet. 1995; 346: 1080–1084. PRCrossrefMedlineGoogle Scholar
  • 184 Sowers JR, Reed J. 1999 clinical advisory: treatment of hypertension and diabetes. J Clin Hypertens (Greenwich). 2000; 2: 132–133. PRMedlineGoogle Scholar
  • 185 Weinberger MH. Blood pressure and metabolic responses to hydrochlorothiazide, captopril, and the combination in black and white mild-to-moderate hypertensive patients. J Cardiovasc Pharmacol. 1985; 7: S52–S55. RACrossrefGoogle Scholar
  • 186 Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet. 2000; 355: 253–259. RACrossrefMedlineGoogle Scholar
  • 187 Lindholm LH, Ibsen H, Dahlof B, Devereux RB, Beevers G, de Faire U, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002; 359: 1004–1010. RACrossrefMedlineGoogle Scholar
  • 188 Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med. 1998; 338: 645–652. RACrossrefMedlineGoogle Scholar
  • 189 Schrier RW, Estacio RO, Esler A, Mehler P. Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Kidney Int. 2002; 61: 1086–1097. RACrossrefMedlineGoogle Scholar
  • 190 Manjunath G, Tighiouart H, Ibrahim H, MacLeod B, Salem DN, Griffith JL, et al. Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community. J Am Coll Cardiol. 2003; 41: 47–55. FCrossrefMedlineGoogle Scholar
  • 191 Hillege HL, Fidler V, Diercks GF, van Gilst WH, de Zeeuw D, van Veldhuisen DJ, et al. Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. Circulation. 2002; 106: 1777–1782. FLinkGoogle Scholar
  • 192 Franklin SS, Jacobs MJ, Wong ND, L’Italien GJ, Lapuerta P. Predominance of isolated systolic hypertension among middle-aged and elderly US hypertensives: analysis based on National Health and Nutrition Examination Survey (NHANES) III. Hypertension. 2001; 37: 869–874. XCrossrefMedlineGoogle Scholar
  • 193 Coresh J, Wei GL, McQuillan G, Brancati FL, Levey AS, Jones C, et al. Prevalence of high blood pressure and elevated serum creatinine level in the United States: findings from the third National Health and Nutrition Examination Survey (1988–1994). Arch Intern Med. 2001; 161: 1207–1216. XCrossrefMedlineGoogle Scholar
  • 194 Jafar TH, Schmid CH, Landa M, Giatras I, Toto R, Remuzzi G, et al. Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease: a meta-analysis of patient-level data. Ann Intern Med. 2001; 135: 73–87. MCrossrefMedlineGoogle Scholar
  • 195 Jafar TH, Stark PC, Schmid CH, Landa M, Maschio G, de Jong PE, et al. Progression of chronic kidney disease: the role of blood pressure control, proteinuria, and angiotensin-converting enzyme inhibition: a patient-level meta-analysis. Ann Intern Med. 2003; 139: 244–252. MCrossrefMedlineGoogle Scholar
  • 196 Wright JT Jr, Bakris G, Greene T, Agodoa LY, Appel LJ, Charleston J, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA. 2002; 288: 2421–2431. RACrossrefMedlineGoogle Scholar
  • 197 Tzourio C, Anderson C, Chapman N, Woodward M, Neal B, MacMahon S, et al. Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Arch Intern Med. 2003; 163: 1069–1075. RACrossrefMedlineGoogle Scholar
  • 198 Adams HP Jr, Adams RJ, Brott T, del Zoppo GJ, Furlan A, Goldstein LB, et al. Guidelines for the early management of patients with ischemic stroke: a scientific statement from the Stroke Council of the American Stroke Association. Stroke. 2003; 34: 1056–1083. PRLinkGoogle Scholar
  • 199 The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995; 333: 1581–1587. RACrossrefMedlineGoogle Scholar
  • 200 Cooper R, Rotimi C. Hypertension in blacks. Am J Hypertens. 1997; 10: 804–812. PRCrossrefMedlineGoogle Scholar
  • 201 National Heart, Lung, and Blood Institute. Strong Heart Study Data Book: A Report to American Indians Communities. Bethesda, MD: National Institutes of Health, National Heart, Lung, and Blood Institute. NIH Publication No. 01–3285, 2001. pp. 19. Scholar
  • 202 Crespo CJ, Loria CM, Burt VL. Hypertension and other cardiovascular disease risk factors among Mexican Americans, Cuban Americans, and Puerto Ricans from the Hispanic Health and Nutrition Examination Survey. Public Health Rep. 1996; 111: 7–10.MedlineGoogle Scholar
  • 203 Douglas JG, Bakris GL, Epstein M, Ferdinand KC, Ferrario C, Flack JM, et al. Management of high blood pressure in African Americans: consensus statement of the Hypertension in African Americans Working Group of the International Society on Hypertension in Blacks. Arch Intern Med. 2003; 163: 525–541. PRCrossrefMedlineGoogle Scholar
  • 204 Hypertension Detection and Follow-up Program Cooperative Group. Persistence of reduction in blood pressure and mortality of participants in the Hypertension Detection and Follow-up Program. JAMA. 1988; 259: 2113–2122. FCrossrefMedlineGoogle Scholar
  • 205 U S Department of Health and Human Services. Understanding and improving health and objectives for improving health. Healthy People 2010. Washington, DC: United States Government Printing Office; 2000. pp. 19–31.Google Scholar
  • 206 Jamerson K, DeQuattro V. The impact of ethnicity on response to antihypertensive therapy. Am J Med. 1996; 101: 22S–32S. PRCrossrefMedlineGoogle Scholar
  • 207 Saunders E, Weir MR, Kong BW, Hollifield J, Gray J, Vertes V, et al. A comparison of the efficacy and safety of a beta-blocker, a calcium channel blocker, and a converting enzyme inhibitor in hypertensive blacks. Arch Intern Med. 1990; 150: 1707–1713. RACrossrefMedlineGoogle Scholar
  • 208 Cushman WC, Reda DJ, Perry HM, Williams D, Abdellatif M, Materson BJ. Regional and racial differences in response to antihypertensive medication use in a randomized controlled trial of men with hypertension in the United States. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Arch Intern Med. 2000; 160: 825–831. RACrossrefMedlineGoogle Scholar
  • 209 Brown NJ, Ray WA, Snowden M, Griffin MR. Black Americans have an increased rate of angiotensin converting enzyme inhibitor-associated angioedema. Clin Pharmacol Ther. 1996; 60: 8–13. RECrossrefMedlineGoogle Scholar
  • 210 Lawrence J, Stockbridge N, Hung HMJ, Chi G. Joint statistical-clinical review: NDA resubmission dated 14 December 2001, including the results of the OCTAVE study. FDA, Center for Drug Evaluation and Research, Division of Cardio-Renal Drug Products. NDA: 21–188 (omapatrilat for hypertension), June 2002. pp. 1–31. Scholar
  • 211 Elliott WJ. Higher incidence of discontinuation of angiotensin converting enzyme inhibitors due to cough in black subjects. Clin Pharmacol Ther. 1996; 60: 582–588. XCrossrefMedlineGoogle Scholar
  • 212 Gottlieb SS, McCarter RJ, Vogel RA. Effect of beta-blockade on mortality among high-risk and low-risk patients after myocardial infarction. N Engl J Med. 1998; 339: 489–497. RECrossrefMedlineGoogle Scholar
  • 213 Reaven GM. Pathophysiology of insulin resistance in human disease. Physiol Rev. 1995; 75: 473–486. PRCrossrefMedlineGoogle Scholar
  • 214 Esposito K, Pontillo A, Di Palo C, Giugliano G, Masella M, Marfella R, et al. Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial. JAMA. 2003; 289: 1799–1804. RACrossrefMedlineGoogle Scholar
  • 215 Bastard JP, Pieroni L, Hainque B. Relationship between plasma plasminogen activator inhibitor 1 and insulin resistance. Diabetes Metab Res Rev. 2000; 16: 192–201. PRCrossrefMedlineGoogle Scholar
  • 216 Kunsch C, Medford RM. Oxidative stress as a regulator of gene expression in the vasculature. Circ Res. 1999; 85: 753–766. PRCrossrefMedlineGoogle Scholar
  • 217 Facchini FS, Hua NW, Reaven GM, Stoohs RA. Hyperinsulinemia: the missing link among oxidative stress and age-related diseases? Free Radic Biol Med. 2000; 29: 1302–1306.CrossrefMedlineGoogle Scholar
  • 218 Rowley K, O’Dea K, Best JD. Association of albuminuria and the metabolic syndrome. Curr Diab Rep. 2003; 3: 80–86. PRCrossrefMedlineGoogle Scholar
  • 219 Egan BM. Insulin resistance and the sympathetic nervous system. Curr Hypertens Rep. 2003; 5: 247–254. PRCrossrefMedlineGoogle Scholar
  • 220 Licata G, Scaglione R, Corrao S, Ganguzza A, Mazzola G, Arnone S, et al. Heredity and obesity-associated hypertension: impact of hormonal characteristics and left ventricular mass. J Hypertens. 1995; 13: 611–618. CCrossrefMedlineGoogle Scholar
  • 221 Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA. 2002; 287: 356–359. XCrossrefMedlineGoogle Scholar
  • 222 Park YW, Zhu S, Palaniappan L, Heshka S, Carnethon MR, Heymsfield SB. The metabolic syndrome: prevalence and associated risk factor findings in the US population from the Third National Health and Nutrition Examination Survey, 1988–1994. Arch Intern Med. 2003; 163: 427–436. XCrossrefMedlineGoogle Scholar
  • 223 Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA. 2002; 288: 2709–2716. FCrossrefMedlineGoogle Scholar
  • 224 Hsia J, Bittner V, Tripputi M, Howard BV. Metabolic syndrome and coronary angiographic disease progression: the Women’s Angiographic Vitamin & Estrogen trial. Am Heart J. 2003; 146: 439–445.CrossrefMedlineGoogle Scholar
  • 225 Laaksonen DE, Lakka HM, Niskanen LK, Kaplan GA, Salonen JT, Lakka TA. Metabolic syndrome and development of diabetes mellitus: application and validation of recently suggested definitions of the metabolic syndrome in a prospective cohort study. Am J Epidemiol. 2002; 156: 1070–1077. FCrossrefMedlineGoogle Scholar
  • 226 Wilson PWF, D’Agostino RB, Parise H, Meigs JB. The metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Diabetes. 2002; 51: A242. FGoogle Scholar
  • 227 National Institutes of Health. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: the evidence report. Obes Res. 1998; 6: (suppl 2): 51S–209S. PRCrossrefMedlineGoogle Scholar
  • 228 Laaksonen DE, Lakka HM, Salonen JT, Niskanen LK, Rauramaa R, Lakka TA. Low levels of leisure-time physical activity and cardiorespiratory fitness predict development of the metabolic syndrome. Diabetes Care. 2002; 25: 1612–1618.CrossrefMedlineGoogle Scholar
  • 229 Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. Diabetes Prevention Program Research Group. N Engl J Med. 2002; 346: 393–403. RACrossrefMedlineGoogle Scholar
  • 230 American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care. 2002; 25: S33–S49. PRCrossrefGoogle Scholar
  • 231 Field AE, Coakley EH, Must A, Spadano JL, Laird N, Dietz WH, et al. Impact of overweight on the risk of developing common chronic diseases during a 10-year period. Arch Intern Med. 2001; 161: 1581–1586. FCrossrefMedlineGoogle Scholar
  • 232 Gidding SS, Falkner B. Are we losing the game? Cardiovascular health in minority children. Ethn Dis. 2002; 12: 171–173.MedlineGoogle Scholar
  • 233 Strauss RS, Pollack HA. Epidemic increase in childhood overweight, 1986–1998. JAMA. 2001; 286: 2845–2848. XCrossrefMedlineGoogle Scholar
  • 234 He J, Ogden LG, Vupputuri S, Bazzano LA, Loria C, Whelton PK. Dietary sodium intake and subsequent risk of cardiovascular disease in overweight adults. JAMA. 1999; 282: 2027–2034. FCrossrefMedlineGoogle Scholar
  • 235 Wilson PW, Kannel WB, Silbershatz H, D’Agostino RB. Clustering of metabolic factors and coronary heart disease. Arch Intern Med. 1999; 159: 1104–1109. FCrossrefMedlineGoogle Scholar
  • 236 Lee IM, Rexrode KM, Cook NR, Manson JE, Buring JE. Physical activity and coronary heart disease in women: is “no pain, no gain” passe? JAMA. 2001; 285: 1447–1454. FCrossrefMedlineGoogle Scholar
  • 237 Gregg EW, Cauley JA, Stone K, Thompson TJ, Bauer DC, Cummings SR, et al. Relationship of changes in physical activity and mortality among older women. JAMA. 2003; 289: 2379–2386. FCrossrefMedlineGoogle Scholar
  • 238 Stevens J, Cai J, Evenson KR, Thomas R. Fitness and fatness as predictors of mortality from all causes and from cardiovascular disease in men and women in the lipid research clinics study. Am J Epidemiol. 2002; 156: 832–841. FCrossrefMedlineGoogle Scholar
  • 239 Simons-Morton DG, Hogan P, Dunn AL, Pruitt L, King AC, Levine BD, et al. Characteristics of inactive primary care patients: baseline data from the activity counseling trial. For the Activity Counseling Trial Research Group. Prev Med. 2000; 31: 513–521.CrossrefMedlineGoogle Scholar
  • 240 Devereux R. Management of hypertensive patients with left ventricular hypertrophy and diastolic dysfunction. In: Izzo J Jr, Black H (eds): Hypertension Primer: The Essentials of High Blood Pressure: Basic Science, Population Science, and Clinical Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2003. pp. 460–463.Google Scholar
  • 241 Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med. 1990; 322: 1561–1566. FCrossrefMedlineGoogle Scholar
  • 242 Okin PM, Wright JT, Nieminen MS, Jern S, Taylor AL, Phillips R, et al. Ethnic differences in electrocardiographic criteria for left ventricular hypertrophy: the LIFE study. For the LIFE Study Investigators. Am J Hypertens. 2002; 15: 663–671.CrossrefMedlineGoogle Scholar
  • 243 Koren MJ, Mensah GA, Blake J, Laragh JH, Devereux RB. Comparison of left ventricular mass and geometry in black and white patients with essential hypertension. Am J Hypertens. 1993; 6: 815–823.CrossrefMedlineGoogle Scholar
  • 244 Schmieder RE, Schlaich MP, Klingbeil AU, Martus P. Update on reversal of left ventricular hypertrophy in essential hypertension (a meta-analysis of all randomized double-blind studies until December 1996). Nephrol Dial Transplant. 1998; 13: 564–569. MCrossrefMedlineGoogle Scholar
  • 245 Liebson PR, Grandits GA, Dianzumba S, Prineas RJ, Grimm RH Jr, Neaton JD, et al. Comparison of five antihypertensive monotherapies and placebo for change in left ventricular mass in patients receiving nutritional-hygienic therapy in the Treatment of Mild Hypertension Study (TOMHS). Circulation. 1995; 91: 698–706. RACrossrefMedlineGoogle Scholar
  • 246 Gottdiener JS, Reda DJ, Massie BM, Materson BJ, Williams DW, Anderson RJ. Effect of single-drug therapy on reduction of left ventricular mass in mild to moderate hypertension: comparison of six antihypertensive agents. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Circulation. 1997; 95: 2007–2014. RACrossrefMedlineGoogle Scholar
  • 247 Coffman JD. Drug therapy: vasodilator drugs in peripheral vascular disease. N Engl J Med. 1979; 300: 713–717. PRCrossrefMedlineGoogle Scholar
  • 248 Roberts DH, Tsao Y, McLoughlin GA, Breckenridge A. Placebo-controlled comparison of captopril, atenolol, labetalol, and pindolol in hypertension complicated by intermittent claudication. Lancet. 1987; 2: 650–653. RACrossrefMedlineGoogle Scholar
  • 249 Solomon SA, Ramsay LE, Yeo WW, Parnell L, Morris-Jones W. Beta blockade and intermittent claudication: placebo controlled trial of atenolol and nifedipine and their combination. BMJ. 1991; 303: 1100–1104. RACrossrefMedlineGoogle Scholar
  • 250 Radack K, Deck C. Beta-adrenergic blocker therapy does not worsen intermittent claudication in subjects with peripheral arterial disease. A meta-analysis of randomized controlled trials. Arch Intern Med. 1991; 151: 1769–1776. MCrossrefMedlineGoogle Scholar
  • 251 Haynes WG, Lopez JAG, Mark AL. Treatment of hypertension combined with cardiovascular disease. In: Smith TW (ed): Cardiovascular Therapeutics: A Companion to Braunwald’s Heart Disease. Philadelphia, PA: WB Saunders; 1996. pp. 503–504. PRGoogle Scholar
  • 252 Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002; 360: 7–22.CrossrefMedlineGoogle Scholar
  • 253 Olin JW. Treatment of hypertensive patients with peripheral arterial disease. In: Izzo JL Jr, Black HR (eds): Hypertension Primer: The Essentials of High Blood Pressure: Basic Science, Population Science, and Clinical Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2003. pp. 467–469.Google Scholar
  • 254 Hiatt WR, Regensteiner JG, Hargarten ME, Wolfel EE, Brass EP. Benefit of exercise conditioning for patients with peripheral arterial disease. Circulation. 1990; 81: 602–609.CrossrefMedlineGoogle Scholar
  • 255 U S. Census Bureau. Persons 65 Years Old and Over-Characteristics by Sex: 1980 to 2000. Statistical Abstracts of the United States: 2002. Washington, DC: U S Census Bureau; 2001. pp. 43.Google Scholar
  • 256 Izzo JL Jr, Levy D, Black HR. Clinical Advisory Statement. Importance of systolic blood pressure in older Americans. Hypertension. 2000; 35: 1021–1024. PRCrossrefMedlineGoogle Scholar
  • 257 Burt VL, Cutler JA, Higgins M, Horan MJ, Labarthe D, Whelton P, et al. Trends in the prevalence, awareness, treatment, and control of hypertension in the adult US population: data from the health examination surveys, 1960 to 1991. Erratum in: Hypertension. 1996 May;27:1192. Hypertension. 1995; 26: 60–69. XCrossrefMedlineGoogle Scholar
  • 258 Staessen JA, Gasowski J, Wang JG, Thijs L, Den Hond E, Boissel JP, et al. Risks of untreated and treated isolated systolic hypertension in the elderly: meta-analysis of outcome trials. Lancet. 2000; 355: 865–872. MCrossrefMedlineGoogle Scholar
  • 259 Gueyffier F, Bulpitt C, Boissel JP, Schron E, Ekbom T, Fagard R, et al. Antihypertensive drugs in very old people: a subgroup meta-analysis of randomised controlled trials. INDANA Group. Lancet. 1999; 353: 793–796. MCrossrefMedlineGoogle Scholar
  • 260 Jonsson PV, Lipsitz LA, Kelley M, Koestner J. Hypotensive responses to common daily activities in institutionalized elderly. A potential risk for recurrent falls. Arch Intern Med. 1990; 150: 1518–1524. CCrossrefMedlineGoogle Scholar
  • 261 Spence JD, Sibbald WJ, Cape RD. Pseudohypertension in the elderly. Clin Sci Mol Med Suppl. 1978; 55: 399s–402s. CGoogle Scholar
  • 262 Nally J Jr. Management of renovascular hypertension. In: Izzo J Jr, Black H (eds): Hypertension Primer: The Essentials of High Blood Pressure: Basic Science, Population Science, and Clinical Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2003. pp. 500–502.Google Scholar
  • 263 Koch-Weser J. The therapeutic challenge of systolic hypertension. N Engl J Med. 1973; 289: 481–483.CrossrefMedlineGoogle Scholar
  • 264 Appel LJ, Espeland MA, Easter L, Wilson AC, Folmar S, Lacy CR. Effects of reduced sodium intake on hypertension control in older individuals: results from the Trial of Nonpharmacologic Interventions in the Elderly (TONE). Arch Intern Med. 2001; 161: 685–693.CrossrefMedlineGoogle Scholar
  • 265 Masaki KH, Schatz IJ, Burchfiel CM, Sharp DS, Chiu D, Foley D, et al. Orthostatic hypotension predicts mortality in elderly men: the Honolulu Heart Program. Circulation. 1998; 98: 2290–2295. FCrossrefMedlineGoogle Scholar
  • 266 Mukai S, Lipsitz LA. Orthostatic hypotension. Clin Geriatr Med. 2002; 18: 253–268.CrossrefMedlineGoogle Scholar
  • 267 Ooi WL, Hossain M, Lipsitz LA. The association between orthostatic hypotension and recurrent falls in nursing home residents. Am J Med. 2000; 108: 106–111.CrossrefMedlineGoogle Scholar
  • 268 Oster JR, Materson BJ. Pseudohypertension: a diagnostic dilemma. J Clin Hypertens. 1986; 4: 307–313.Google Scholar
  • 269 Staessen JA, Wang J. Blood-pressure lowering for the secondary prevention of stroke. Lancet. 2001; 358: 1026–1027.CrossrefMedlineGoogle Scholar
  • 270 Di Bari M, Pahor M, Franse LV, Shorr RI, Wan JY, Ferrucci L, et al. Dementia and disability outcomes in large hypertension trials: lessons learned from the Systolic Hypertension in the Elderly Program (SHEP) trial. Am J Epidemiol. 2001; 153: 72–78.CrossrefMedlineGoogle Scholar
  • 271 Reed DM, Resch JA, Hayashi T, MacLean C, Yano K. A prospective study of cerebral artery atherosclerosis. Stroke. 1988; 19: 820–825. FCrossrefMedlineGoogle Scholar
  • 272 Furuta A, Ishii N, Nishihara Y, Horie A. Medullary arteries in aging and dementia. Stroke. 1991; 22: 442–446. CCrossrefMedlineGoogle Scholar
  • 273 Dozono K, Ishii N, Nishihara Y, Horie A. An autopsy study of the incidence of lacunes in relation to age, hypertension, and arteriosclerosis. Stroke. 1991; 22: 993–996. RECrossrefMedlineGoogle Scholar
  • 274 Leung SY, Ng TH, Yuen ST, Lauder IJ, Ho FC. Pattern of cerebral atherosclerosis in Hong Kong Chinese: severity in intracranial and extracranial vessels. Stroke. 1993; 24: 779–786. PRCrossrefMedlineGoogle Scholar
  • 275 Schmidt R, Fazekas F, Koch M, Kapeller P, Augustin M, Offenbacher H, et al. Magnetic resonance imaging cerebral abnormalities and neuropsychologic test performance in elderly hypertensive subjects: a case-control study. Arch Neurol. 1995; 52: 905–910. RECrossrefMedlineGoogle Scholar
  • 276 Longstreth WT Jr, Manolio TA, Arnold A, Burke GL, Bryan N, Jungreis CA, et al. Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people. The Cardiovascular Health Study Collaborative Research Group. Stroke. 1996; 27: 1274–1282. FCrossrefMedlineGoogle Scholar
  • 277 Awada A, Omojola MF. Leuko-araiosis and stroke: a case-control study. Acta Neurol Scand. 1996; 94: 415–418. RECrossrefMedlineGoogle Scholar
  • 278 Swan GE, DeCarli C, Miller BL, Reed T, Wolf PA, Jack LM, et al. Association of midlife blood pressure to late-life cognitive decline and brain morphology. Neurology. 1998; 51: 986–993. FCrossrefMedlineGoogle Scholar
  • 279 Koga H, Yuzuriha T, Yao H, Endo K, Hiejima S, Takashima Y, et al. Quantitative MRI findings and cognitive impairment among community dwelling elderly subjects. J Neurol Neurosurg Psychiatry. 2002; 72: 737–741. CCrossrefMedlineGoogle Scholar
  • 280 Del Bigio MR, Yan HJ, Kozlowski P, Sutherland GR, Peeling J. Serial magnetic resonance imaging of rat brain after induction of renal hypertension. Stroke. 1999; 30: 2440–2447.CrossrefMedlineGoogle Scholar
  • 281 Awad IA, Johnson PC, Spetzler RF, Hodak JA. Incidental subcortical lesions identified on magnetic resonance imaging in the elderly, II: postmortem pathological correlations. Stroke. 1986; 17: 1090–1097.CrossrefMedlineGoogle Scholar
  • 282 Marshall VG, Bradley WG Jr, Marshall CE, Bhoopat T, Rhodes RH. Deep white matter infarction: correlation of MR imaging and histopathologic findings. Radiology. 1988; 167: 517–522. FCrossrefMedlineGoogle Scholar
  • 283 Estes ML, Chimowitz MI, Awad IA, McMahon JT, Furlan AJ, Ratliff NB. Sclerosing vasculopathy of the central nervous system in nonelderly demented patients. Arch Neurol. 1991; 48: 631–636. RECrossrefMedlineGoogle Scholar
  • 284 Chimowitz MI, Estes ML, Furlan AJ, Awad IA. Further observations on the pathology of subcortical lesions identified on magnetic resonance imaging. Arch Neurol. 1992; 49: 747–752. RECrossrefMedlineGoogle Scholar
  • 285 Baloh RW, Vinters HV. White matter lesions and disequilibrium in older people, II: clinicopathologic correlation. Arch Neurol. 1995; 52: 975–981. FCrossrefMedlineGoogle Scholar
  • 286 Petersen RC, Doody R, Kurz A, Mohs RC, Morris JC, Rabins PV, et al. Current concepts in mild cognitive impairment. Arch Neurol. 2001; 58: 1985–1992. PRCrossrefMedlineGoogle Scholar
  • 287 Glynn RJ, Beckett LA, Hebert LE, Morris MC, Scherr PA, Evans DA. Current and remote blood pressure and cognitive decline. JAMA. 1999; 281: 438–445. FCrossrefMedlineGoogle Scholar
  • 288 Sacktor N, Gray S, Kawas C, Herbst J, Costa P, Fleg J. Systolic blood pressure within an intermediate range may reduce memory loss in an elderly hypertensive cohort. J Geriatr Psychiatry Neurol. 1999; 12: 1–6. FCrossrefMedlineGoogle Scholar
  • 289 Kivipelto M, Helkala EL, Hanninen T, Laakso MP, Hallikainen M, Alhainen K, et al. Midlife vascular risk factors and late-life mild cognitive impairment: a population-based study. Neurology. 2001; 56: 1683–1689. RECrossrefMedlineGoogle Scholar
  • 290 Dufouil C, de Kersaint-Gilly A, Besancon V, Levy C, Auffray E, Brunnereau L, et al. Longitudinal study of blood pressure and white matter hyperintensities: the EVA MRI Cohort. Neurology. 2001; 56: 921–926. FCrossrefMedlineGoogle Scholar
  • 291 Yamaguchi S, Kobayashi S, Okada K, Koide H, Bokura H, Tsuchiya H, et al. Cognitive decline associated with worsening of white matter lesions: a 6-year follow-up study. J Stroke Cerebrovasc Dis. 1996; 6: 106–109. FCrossrefGoogle Scholar
  • 292 Schmidt R, Fazekas F, Kapeller P, Schmidt H, Hartung HP. MRI white matter hyperintensities: three-year follow-up of the Austrian Stroke Prevention Study. Neurology. 1999; 53: 132–139. FCrossrefMedlineGoogle Scholar
  • 293 Forette F, Seux ML, Staessen JA, Thijs L, Birkenhager WH, Babarskiene MR, et al. Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. Lancet. 1998; 352: 1347–1351. RACrossrefMedlineGoogle Scholar
  • 294 Rosenthal T, Oparil S. Hypertension in women. J Hum Hypertens. 2000; 14: 691–704. PRCrossrefMedlineGoogle Scholar
  • 295 Wolz M, Cutler J, Roccella EJ, Rohde F, Thom T, Burt V. Statement from the National High Blood Pressure Education Program: prevalence of hypertension. Am J Hypertens. 2000; 13: 103–104. XCrossrefMedlineGoogle Scholar
  • 296 Staessen J, Bulpitt CJ, Fagard R, Lijnen P, Amery A. The influence of menopause on blood pressure. J Hum Hypertens. 1989; 3: 427–433. RAMedlineGoogle Scholar
  • 297 Staessen JA, Ginocchio G, Thijs L, Fagard R. Conventional and ambulatory blood pressure and menopause in a prospective population study. J Hum Hypertens. 1997; 11: 507–514. FCrossrefMedlineGoogle Scholar
  • 298 Calhoun DA, Oparil S. Gender and blood pressure. In: Izzo JL Jr, Black HR (eds): Hypertension Primer: The Essentials of High Blood Pressure: Basic Science, Population Science, and Clinical Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2003. pp. 253–257. PRGoogle Scholar
  • 299 Manson JE, Hsia J, Johnson KC, Rossouw JE, Assaf AR, Lasser NL, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003; 349: 523–534. RACrossrefMedlineGoogle Scholar
  • 300 Wassertheil-Smoller S, Anderson G, Psaty BM, Black HR, Manson J, Wong N, et al. Hypertension and its treatment in postmenopausal women: baseline data from the Women’s Health Initiative. Hypertension. 2000; 36: 780–789.CrossrefMedlineGoogle Scholar
  • 301 The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA. 1995; 273: 199–208. RACrossrefMedlineGoogle Scholar
  • 302 Chasan-Taber L, Willett WC, Manson JE, Spiegelman D, Hunter DJ, Curhan G, et al. Prospective study of oral contraceptives and hypertension among women in the United States. Circulation. 1996; 94: 483–489. FCrossrefMedlineGoogle Scholar
  • 303 Gueyffier F, Boutitie F, Boissel JP, Pocock S, Coope J, Cutler J, et al. Effect of antihypertensive drug treatment on cardiovascular outcomes in women and men: a meta-analysis of individual patient data from randomized, controlled trials. The INDANA Investigators. Ann Intern Med. 1997; 126: 761–767. MCrossrefMedlineGoogle Scholar
  • 304 Staessen JA, Fagard R, Thijs L, Celis H, Birkenhager WH, Bulpitt CJ, et al. Subgroup and per-protocol analysis of the randomized European Trial on Isolated Systolic Hypertension in the Elderly. Arch Intern Med. 1998; 158: 1681–1691. RACrossrefMedlineGoogle Scholar
  • 305 Lewis CE, Grandits A, Flack J, McDonald R, Elmer PJ. Efficacy and tolerance of antihypertensive treatment in men and women with stage 1 diastolic hypertension: results of the Treatment of Mild Hypertension Study. Arch Intern Med. 1996; 156: 377–385. RACrossrefMedlineGoogle Scholar
  • 306 Taler SJ. Treatment of pregnant hypertensive patients. In: Izzo JL Jr, Black HR (eds): Hypertension Primer: The Essentials of High Blood Pressure: Basic Science, Population Science, and Clinical Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2003. pp. 491–493. PRGoogle Scholar
  • 307 von Dadelszen P, Ornstein MP, Bull SB, Logan AG, Koren G, Magee LA. Fall in mean arterial pressure and fetal growth restriction in pregnancy hypertension: a meta-analysis. Lancet. 2000; 355: 87–92. MCrossrefMedlineGoogle Scholar
  • 308 Buchbinder A, Sibai BM, Caritis S, Macpherson C, Hauth J, Lindheimer MD, et al. Adverse perinatal outcomes are significantly higher in severe gestational hypertension than in mild preeclampsia. Am J Obstet Gynecol. 2002; 186: 66–71. RECrossrefMedlineGoogle Scholar
  • 309 ACOG Practice Bulletin. Chronic hypertension in pregnancy. ACOG Committee on Practice Bulletins. Obstet Gynecol. 2001; 98: 177–185. PRGoogle Scholar
  • 310 Sibai BM. Treatment of hypertension in pregnant women. N Engl J Med. 1996; 335: 257–265. PRCrossrefMedlineGoogle Scholar
  • 311 National High Blood Pressure Education Program. Update on the 1987 Task Force Report on High Blood Pressure in Children and Adolescents: A working group report from the National High Blood Pressure Education Program. National High Blood Pressure Education Program Working Group on Hypertension Control in Children and Adolescents. Pediatrics. 1996; 98: 649–658. PRCrossrefMedlineGoogle Scholar
  • 312 Calhoun DA. Hypertensive crisis. In: Oparil S, Weber MA (eds): Hypertension: A Companion to Brenner and Recot’s The Kidney. Philadelphia, PA: WB Saunders Co.; 2000. pp. 715–718. PRGoogle Scholar
  • 313 Vidt DG. Management of hypertensive urgencies and emergencies. In: Izzo JL Jr, Black HR (eds): Hypertension Primer: The Essentials of High Blood Pressure. Dallas, TX: American Heart Association; 1999. pp. 437–440. PRGoogle Scholar
  • 314 Vidt DG. Emergency room management of hypertensive urgencies and emergencies. J Clin Hypertens (Greenwich). 2001; 3: 158–164. PRCrossrefMedlineGoogle Scholar
  • 315 Zampaglione B, Pascale C, Marchisio M, Cavallo-Perin P. Hypertensive urgencies and emergencies: prevalence and clinical presentation. Hypertension. 1996; 27: 144–147. XCrossrefMedlineGoogle Scholar
  • 316 Bacon CG, Mittleman MA, Kawachi I, Giovannucci E, Glasser DB, Rimm EB. Sexual function in men older than 50 years of age: results from the Health Professionals Follow-Up Study. Ann Intern Med. 2003; 139: 161–168. FCrossrefMedlineGoogle Scholar
  • 317 Della Chiesa A, Pfiffner D, Meier B, Hess OM. Sexual activity in hypertensive men. J Hum Hypertens. 2003; 17: 515–521. RACrossrefMedlineGoogle Scholar
  • 318 Fogari R, Zoppi A, Poletti L, Marasi G, Mugellini A, Corradi L. Sexual activity in hypertensive men treated with valsartan or carvedilol: a crossover study. Am J Hypertens. 2001; 14: 27–31. RACrossrefMedlineGoogle Scholar
  • 319 Kloner RA, Brown M, Prisant LM, Collins M. Effect of sildenafil in patients with erectile dysfunction taking antihypertensive therapy. Sildenafil Study Group. Am J Hypertens. 2001; 14: 70–73. RACrossrefMedlineGoogle Scholar
  • 320 Kirby RS. Doxazosin in benign prostatic hyperplasia: effects on blood pressure and urinary flow in normotensive and hypertensive men. Urology. 1995; 46: 182–186. RACrossrefMedlineGoogle Scholar
  • 321 Eagle KA, Berger PB, Calkins H, Chaitman BR, Ewy GA, Fleischmann KE, et al. ACC/AHA guideline update for perioperative cardiovascular evaluation for noncardiac surgery: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). Circulation. 2002; 105: 1257–1267. PRLinkGoogle Scholar
  • 322 Mangano DT, Layug EL, Wallace A, Tateo I. Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. Multicenter Study of Perioperative Ischemia Research Group. N Engl J Med. 1996; 335: 1713–1720. RACrossrefMedlineGoogle Scholar
  • 323 Vidt DG. Treatment of hypertensive emergencies and urgencies. In: Izzo JL Jr, Black HR, Goodfriend TL (eds): Hypertension Primer: The Essentials of High Blood Pressure: Basic Science, Population Science, and Clinical Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2003. pp. 452–459. PRGoogle Scholar
  • 324 Alper A, Calhoun D. Hypertensive emergencies. In: Antman EM (ed): Cardiovascular Therapeutics: A Companion to Braunwald’s Heart Disease. Philadelphia, PA: WB Saunders Co; 2002. pp. 817–831. PRGoogle Scholar
  • 325 Bader JD, Bonito AJ, Shugars DA. A systematic review of cardiovascular effects of epinephrine on hypertensive dental patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2002; 93: 647–653. PRCrossrefMedlineGoogle Scholar
  • 326 Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med. 1993; 328: 1230–1235. XCrossrefMedlineGoogle Scholar
  • 327 Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med. 2000; 342: 1378–1384. FCrossrefMedlineGoogle Scholar
  • 328 Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S, et al. Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study. JAMA. 2000; 283: 1829–1836. XCrossrefMedlineGoogle Scholar
  • 329 Young T, Peppard P, Palta M, Hla KM, Finn L, Morgan B, et al. Population-based study of sleep-disordered breathing as a risk factor for hypertension. Arch Intern Med. 1997; 157: 1746–1752. FCrossrefMedlineGoogle Scholar
  • 330 Bradley TD, Floras JS. Sleep apnea and heart failure, part I: obstructive sleep apnea. Circulation. 2003; 107: 1671–1678. PRLinkGoogle Scholar
  • 331 Dart RA, Gregoire JR, Gutterman DD, Woolf SH. The association of hypertension and secondary cardiovascular disease with sleep-disordered breathing. Chest. 2003; 123: 244–260. MCrossrefMedlineGoogle Scholar
  • 332 Wolk R, Kara T, Somers VK. Sleep-disordered breathing and cardiovascular disease. Circulation. 2003; 108: 9–12.LinkGoogle Scholar
  • 333 Morgan BJ. Pathophysiology of sleep apnea. In: Izzo JL Jr, Black H (eds): Hypertension Primer: The Essentials of High Blood Pressure: Basic Science, Population Science, and Clinical Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2003. pp. 156–158. PRGoogle Scholar
  • 334 Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest. 1995; 96: 1897–1904.CrossrefMedlineGoogle Scholar
  • 335 Shamsuzzaman AS, Winnicki M, Lanfranchi P, Wolk R, Kara T, Accurso V, et al. Elevated C-reactive protein in patients with obstructive sleep apnea. Circulation. 2002; 105: 2462–2464. CLinkGoogle Scholar
  • 336 Vgontzas AN, Papanicolaou DA, Bixler EO, Hopper K, Lotsikas A, Lin HM, et al. Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia. J Clin Endocrinol Metab. 2000; 85: 1151–1158. CCrossrefMedlineGoogle Scholar
  • 337 Punjabi NM, Sorkin JD, Katzel LI, Goldberg AP, Schwartz AR, Smith PL. Sleep-disordered breathing and insulin resistance in middle-aged and overweight men. Am J Respir Crit Care Med. 2002; 165: 677–682. CCrossrefMedlineGoogle Scholar
  • 338 Kato M, Roberts-Thomson P, Phillips BG, Haynes WG, Winnicki M, Accurso V, et al. Impairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnea. Circulation. 2000; 102: 2607–2610. CCrossrefMedlineGoogle Scholar
  • 339 Javaheri S, Parker TJ, Liming JD, Corbett WS, Nishiyama H, Wexler L, et al. Sleep apnea in 81 ambulatory male patients with stable heart failure: types and their prevalences, consequences, and presentations. Circulation. 1998; 97: 2154–2159. FCrossrefMedlineGoogle Scholar
  • 340 Kaneko Y, Floras JS, Usui K, Plante J, Tkacova R, Kubo T, et al. Cardiovascular effects of continuous positive airway pressure in patients with heart failure and obstructive sleep apnea. N Engl J Med. 2003; 348: 1233–1241. RACrossrefMedlineGoogle Scholar
  • 341 Leung RS, Bradley TD. Sleep apnea and cardiovascular disease. Am J Respir Crit Care Med. 2001; 164: 2147–2165. PRCrossrefMedlineGoogle Scholar
  • 342 Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Nieto FJ, et al. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med. 2001; 163: 19–25. XCrossrefMedlineGoogle Scholar
  • 343 Kanagala R, Murali NS, Friedman PA, Ammash NM, Gersh BJ, Ballman KV, et al. Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation. 2003; 107: 2589–2594. FLinkGoogle Scholar
  • 344 Dyken ME, Somers VK, Yamada T, Ren ZY, Zimmerman MB. Investigating the relationship between stroke and obstructive sleep apnea. Stroke. 1996; 27: 401–407. FCrossrefMedlineGoogle Scholar
  • 345 Levinson PD, McGarvey ST, Carlisle CC, Eveloff SE, Herbert PN, Millman RP. Adiposity and cardiovascular risk factors in men with obstructive sleep apnea. Chest. 1993; 103: 1336–1342. CCrossrefMedlineGoogle Scholar
  • 346 Millman RP, Carlisle CC, McGarvey ST, Eveloff SE, Levinson PD. Body fat distribution and sleep apnea severity in women. Chest. 1995; 107: 362–366. CCrossrefMedlineGoogle Scholar
  • 347 Newman AB, Nieto FJ, Guidry U, Lind BK, Redline S, Shahar E, et al. Relation of sleep-disordered breathing to cardiovascular disease risk factors: the Sleep Heart Health Study. Am J Epidemiol. 2001; 154: 50–59. XCrossrefMedlineGoogle Scholar
  • 348 Peppard PE, Young T, Palta M, Dempsey J, Skatrud J. Longitudinal study of moderate weight change and sleep-disordered breathing. JAMA. 2000; 284: 3015–3021. FCrossrefMedlineGoogle Scholar
  • 349 Phillips BG, Kato M, Narkiewicz K, Choe I, Somers VK. Increases in leptin levels, sympathetic drive, and weight gain in obstructive sleep apnea. Am J Physiol Heart Circ Physiol. 2000; 279: H234–H237. CCrossrefMedlineGoogle Scholar
  • 350 Chin K, Shimizu K, Nakamura T, Narai N, Masuzaki H, Ogawa Y, et al. Changes in intra-abdominal visceral fat and serum leptin levels in patients with obstructive sleep apnea syndrome following nasal continuous positive airway pressure therapy. Circulation. 1999; 100: 706–712. CCrossrefMedlineGoogle Scholar
  • 351 Kato M, Phillips BG, Sigurdsson G, Narkiewicz K, Pesek CA, Somers VK. Effects of sleep deprivation on neural circulatory control. Hypertension. 2000; 35: 1173–1175. CCrossrefMedlineGoogle Scholar
  • 352 Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet. 1999; 354: 1435–1439. CCrossrefMedlineGoogle Scholar
  • 353 Faccenda JF, Mackay TW, Boon NA, Douglas NJ. Randomized placebo-controlled trial of continuous positive airway pressure on blood pressure in the sleep apnea-hypopnea syndrome. Am J Respir Crit Care Med. 2001; 163: 344–348. RACrossrefMedlineGoogle Scholar
  • 354 Somers VK. Management of sleep apnea. In: Izzo JL Jr, Black HR (eds): Hypertension Primer: The Essentials of High Blood Pressure: Basic Science, Population Science, and Clinical Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2003. pp. 512–516. PRGoogle Scholar
  • 355 Becker HF, Jerrentrup A, Ploch T, Grote L, Penzel T, Sullivan CE, et al. Effect of nasal continuous positive airway pressure treatment on blood pressure in patients with obstructive sleep apnea. Circulation. 2003; 107: 68–73. RALinkGoogle Scholar
  • 356 Franklin KA, Nilsson JB, Sahlin C, Naslund U. Sleep apnoea and nocturnal angina. Lancet. 1995; 345: 1085–1087. CCrossrefMedlineGoogle Scholar
  • 357 Peled N, Abinader EG, Pillar G, Sharif D, Lavie P. Nocturnal ischemic events in patients with obstructive sleep apnea syndrome and ischemic heart disease: effects of continuous positive air pressure treatment. J Am Coll Cardiol. 1999; 34: 1744–1749. CCrossrefMedlineGoogle Scholar
  • 358 Wang JJ, Mitchell P, Leung H, Rochtchina E, Wong TY, Klein R. Hypertensive retinal vessel wall signs in a general older population: the Blue Mountains Eye Study. Hypertension. 2003; 42: 534–541.LinkGoogle Scholar
  • 359 Wong TY, Klein R, Sharrett AR, Manolio TA, Hubbard LD, Marino EK, et al. The prevalence and risk factors of retinal microvascular abnormalities in older persons: The Cardiovascular Health Study. Ophthalmology. 2003; 110: 658–666.CrossrefMedlineGoogle Scholar
  • 360 American Academy of Ophthalmology. Basic and Clinical Science Course, Section 12, 1999–2000. San Francisco, CA: American Academy of Ophthalmology; 1999. pp. 68–70.Google Scholar
  • 361 Textor SC. Hypertension and transplantation. In: Izzo JL Jr, Black HR (eds): Hypertension Primer: The Essentials of High Blood Pressure: Basic Science, Population Science, and Clinical Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2003. pp. 163–165. PRGoogle Scholar
  • 362 Canzanello VJ. Management of posttransplant hypertension. In: Izzo JL Jr, Black HR (eds): Hypertension Primer: The Essentials of High Blood Pressure: Basic Science, Population Science, and Clinical Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2003. pp. 519–522. PRGoogle Scholar
  • 363 Textor SC. Renal failure related to angiotensin-converting enzyme inhibitors. Semin Nephrol. 1997; 17: 67–76. PRMedlineGoogle Scholar
  • 364 Appel RG, Bleyer AJ, Reavis S, Hansen KJ. Renovascular disease in older patients beginning renal replacement therapy. Kidney Int. 1995; 48: 171–176.CrossrefMedlineGoogle Scholar
  • 365 Bonelli FS, McKusick MA, Textor SC, Kos PB, Stanson AW, Johnson CM, et al. Renal artery angioplasty: technical results and clinical outcome in 320 patients. Mayo Clin Proc. 1995; 70: 1041–1052. RECrossrefMedlineGoogle Scholar
  • 366 Sos TA. Angioplasty for the treatment of azotemia and renovascular hypertension in atherosclerotic renal artery disease. Circulation. 1991; 83 (Suppl I): I-162–I-166. FMedlineGoogle Scholar
  • 367 Harden PN, MacLeod MJ, Rodger RS, Baxter GM, Connell JM, Dominiczak AF, et al. Effect of renal-artery stenting on progression of renovascular renal failure. Lancet. 1997; 349: 1133–1136. CCrossrefMedlineGoogle Scholar
  • 368 Johnson AG, Nguyen TV, Day RO. Do nonsteroidal anti-inflammatory drugs affect blood pressure? A meta-analysis. Ann Intern Med. 1994; 121: 289–300. MCrossrefMedlineGoogle Scholar
  • 369 Whelton A. Nephrotoxicity of nonsteroidal anti-inflammatory drugs: physiologic foundations and clinical implications. Am J Med. 1999; 106: 13S–24S. PRCrossrefMedlineGoogle Scholar
  • 370 Whelton A, White WB, Bello AE, Puma JA, Fort JG. Effects of celecoxib and rofecoxib on blood pressure and edema in patients > or =65 years of age with systemic hypertension and osteoarthritis. Am J Cardiol. 2002; 90: 959–963. RACrossrefMedlineGoogle Scholar
  • 371 White WB, Kent J, Taylor A, Verburg KM, Lefkowith JB, Whelton A. Effects of celecoxib on ambulatory blood pressure in hypertensive patients on ACE inhibitors. Hypertension. 2002; 39: 929–934. RALinkGoogle Scholar
  • 372 Whelton A, Fort JG, Puma JA, Normandin D, Bello AE, Verburg KM. Cyclooxygenase-2–specific inhibitors and cardiorenal function: a randomized, controlled trial of celecoxib and rofecoxib in older hypertensive osteoarthritis patients. Am J Ther. 2001; 8: 85–95. RACrossrefMedlineGoogle Scholar
  • 373 Sowers JR, White WB, Pitt B, Whelton A, Simon L, van Ingen H, et al. Rofecoxib, but not celecoxib or naproxen, increases mean 24-hour systolic blood pressure in treated hypertensive patients with osteoarthritis and type 2 diabetes mellitus. J Am Coll Cardiol. 2003; 41: 320A. RAGoogle Scholar
  • 374 Barrier PA, Li JT, Jensen NM. Two words to improve physician-patient communication: What else? Mayo Clin Proc. 2003; 78: 211–214. PRCrossrefMedlineGoogle Scholar
  • 375 Herzlinger RE. Market-Driven Health Care: Who Wins, Who Loses in the Transformation of America’s Largest Service Industry. Reading, MA: Addison-Wesley Publishing Co; 1997. pp. 65–75, 231.Google Scholar
  • 376 Phillips LS, Branch WT, Cook CB, Doyle JP, El-Kebbi IM, Gallina DL, et al. Clinical inertia. Ann Intern Med. 2001; 135: 825–834.CrossrefMedlineGoogle Scholar
  • 377 Balas EA, Weingarten S, Garb CT, Blumenthal D, Boren SA, Brown GD. Improving preventive care by prompting physicians. Arch Intern Med. 2000; 160: 301–308. CCrossrefMedlineGoogle Scholar
  • 378 Boulware LE, Daumit GL, Frick KD, Minkovitz CS, Lawrence RS, Powe NR. An evidence-based review of patient-centered behavioral interventions for hypertension. Am J Prev Med. 2001; 21: 221–232. PR, MCrossrefMedlineGoogle Scholar
  • 379 Hill MN, Miller NH. Compliance enhancement: a call for multidisciplinary team approaches. Circulation. 1996; 93: 4–6.CrossrefMedlineGoogle Scholar
  • 380 Maue SK, Rivo ML, Weiss B, Farrelly EW, Brower-Stenger S. Effect of a primary care physician-focused, population-based approach to blood pressure control. Fam Med. 2002; 34: 508–513. FMedlineGoogle Scholar
  • 381 Shih SC, Bost JE, Pawlson LG. Standardized health plan reporting in four areas of preventive health care. Am J Prev Med. 2003; 24: 293–300.CrossrefMedlineGoogle Scholar
  • 382 Betancourt JR, Carrillo JE, Green AR. Hypertension in multicultural and minority populations: linking communication to compliance. Curr Hypertens Rep. 1999; 1: 482–488.CrossrefMedlineGoogle Scholar
  • 383 Weir MR, Maibach EW, Bakris GL, Black HR, Chawla P, Messerli FH, et al. Implications of a health lifestyle and medication analysis for improving hypertension control. Arch Intern Med. 2000; 160: 481–490. XCrossrefMedlineGoogle Scholar
  • 384 Emmons KM, Rollnick S. Motivational interviewing in health care settings: opportunities and limitations. Am J Prev Med. 2001; 20: 68–74.CrossrefMedlineGoogle Scholar
  • 385 Bandura A. Social Learning Theory. Englewood Cliffs, NJ: Prentice Hall; 1977.Google Scholar
  • 386 Pignone MP, Ammerman A, Fernandez L, Orleans CT, Pender N, Woolf S, et al. Counseling to promote a healthy diet in adults: a summary of the evidence for the U. S. Preventive Services Task Force. Am J Prev Med. 2003; 24: 75–92. PRCrossrefMedlineGoogle Scholar


eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.

Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.