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Prevalence and Prognostic Significance of Apparent Treatment Resistant Hypertension in Chronic Kidney Disease

Report From the Chronic Renal Insufficiency Cohort Study
and CRIC Study Investigators
Originally publishedhttps://doi.org/10.1161/HYPERTENSIONAHA.115.06487Hypertension. 2016;67:387–396

Abstract

The association between apparent treatment resistant hypertension (ATRH) and clinical outcomes is not well studied in chronic kidney disease. We analyzed data on 3367 hypertensive participants in the Chronic Renal Insufficiency Cohort (CRIC) to determine prevalence, associations, and clinical outcomes of ATRH in nondialysis chronic kidney disease patients. ATRH was defined as blood pressure ≥140/90 mm Hg on ≥3 antihypertensives, or use of ≥4 antihypertensives with blood pressure at goal at baseline visit. Prevalence of ATRH was 40.4%. Older age, male sex, black race, diabetes mellitus, and higher body mass index were independently associated with higher odds of having ATRH. Participants with ATRH had a higher risk of clinical events than participants without ATRH—composite of myocardial infarction, stroke, peripheral arterial disease, congestive heart failure (CHF), and all-cause mortality (hazard ratio [95% confidence interval], 1.38 [1.22–1.56]); renal events (1.28 [1.11–1.46]); CHF (1.66 [1.38–2.00]); and all-cause mortality (1.24 [1.06–1.45]). The subset of participants with ATRH and blood pressure at goal on ≥4 medications also had higher risk for composite of myocardial infarction, stroke, peripheral arterial disease, CHF, and all-cause mortality (hazard ratio [95% confidence interval], (1.30 [1.12–1.51]) and CHF (1.59 [1.28–1.99]) than those without ATRH. ATRH was associated with significantly higher risk for CHF and renal events only among those with estimated glomerular filtration rate ≥30 mL/min per 1.73 m2. Our findings show that ATRH is common and associated with high risk of adverse outcomes in a cohort of patients with chronic kidney disease. This underscores the need for early identification and management of patients with ATRH and chronic kidney disease.

Introduction

See Editorial Commentary, pp 275–277

The American Heart Association, in a Scientific Committee Statement in 2008, defined treatment resistant hypertension as blood pressure (BP) that remains above goal despite the concurrent use of 3 different antihypertensive medication classes, or controlled BP while being treated with ≥4 antihypertensive medication classes.1 The reported prevalence of treatment resistant hypertension in the literature has varied from 3% to 30% of patients with hypertension,24 with an increase in prevalence noted in analysis of data from the 1998 to 2008 US National Health and Nutrition Examination Survey.2 The term apparent treatment resistant hypertension (ATRH) is commonly used in epidemiologic studies to estimate prevalence and assess outcomes, as individuals with pseudoresistance (including white coat effect, measurement errors, or medication noncompliance) cannot be definitively identified and excluded.58 Recent evidence suggests that the presence of ATRH is associated with a higher risk of adverse renal and cardiovascular outcomes.3,610

Resistant hypertension is an especially important clinical problem in patients with chronic kidney disease (CKD). Good control of BP is important in lowering the high risk of cardiovascular disease in this population.1116 Although the prevalence of hypertension has been consistently reported to be high in patients with CKD,1719 ATRH is not well studied in this population. In addition, most studies evaluating the long-term prognosis of ATRH are in the general population or in populations with established cardiovascular disease, with a relatively low prevalence of patients with CKD.3,6,9

We analyzed data from the Chronic Renal Insufficiency Cohort (CRIC) study, which is an observational study cohort of patients with CKD. Previous analyses from CRIC have reported that the prevalence of hypertension was 85%, and despite high rates of hypertension awareness and treatment among CRIC participants, the rates of hypertension control were suboptimal.20 We sought to determine the prevalence and factors associated with ATRH in a large cohort of nondialysis CKD patients, and to evaluate the association of ATRH with long-term clinical outcomes. We hypothesized that ATRH is associated with various clinical and demographic characteristics of patients with CKD, and that the presence of ATRH is associated with a higher risk of renal and cardiovascular outcomes and mortality in this population.

Methods

Patient Population

The CRIC study is a multicenter, prospective, observational study of risk factors for progression of CKD. The design, rationale, and baseline patient characteristics of CRIC have been described in detail previously.21,22 In brief, the CRIC study includes a racially diverse group of adults aged 21 to 74 years with estimated glomerular filtration rates (eGFRs) of 20 to 70 mL/min per 1.73 m2. The CRIC study recruited 3939 patients between June 2003 and December 2008 from 13 sites in 7 centers in the United States (Baltimore, MD; Philadelphia, PA; Cleveland, OH; Detroit, MI; Chicago, IL; New Orleans, LA; and Oakland, CA). After exclusion of patients without BP information, medication information, or a diagnosis of hypertension (systolic BP [SBP] <140 mm Hg and diastolic BP [DBP] <90 mm Hg and not taking antihypertensive medications at baseline), 3367 patients were included in these analyses (Figure 1). The study protocol was approved by the institutional review boards of all participating centers and conducted in accordance with the Declaration of Helsinki. All participants provided written informed consent.

Figure 1.

Figure 1. Flow diagram of exclusion criteria applied to determine study population for final analysis. CRIC indicates Chronic Renal Insufficiency Cohort; DBP, diastolic blood pressure; and SBP, systolic blood pressure.

Data Collection

During the baseline study visit, all CRIC data were collected by trained study staff using questionnaires, anthropometric measures, collection of blood specimens, and a 24-hour urine sample. Current cigarette smoking was defined as currently smoking cigarettes and having smoked at least 100 cigarettes during an individual’s lifetime. Alcohol drinking was defined as the consumption of ≥1 beverages containing alcohol over the previous year. Body weight and height were each measured twice and averaged for analysis. Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. Waist circumference was measured at the uppermost lateral border of the iliac crest with a Gulick II tape and repeated until 2 measures agreed within 1 cm. Participants reporting a previous diagnosis of hypertension were asked whether they were using lifestyle modifications (ie, salt reduction, weight loss, exercise, or alcohol reduction) to lower BP.

BP Measurements

BP measurements in the CRIC study followed a standardized protocol: 3 BP measurements were obtained in the sitting position after at least 5 minutes of quiet rest by trained staff according to the protocol. An aneroid sphygmomanometer was used with 1 of 4 cuff sizes (pediatric, regular adult, large adult, or thigh) based on the participant’s arm circumference. Participants were advised to refrain from coffee, tea, or alcohol intake, cigarette smoking, and vigorous exercise for at least 30 minutes before their examination. All BP observers successfully completed training sessions on the use of the BP measurement protocol. Requirements for certification as a CRIC BP observer consisted of satisfactory performance on a written test assessing knowledge of preparation of study participants for BP measurement, selection of an appropriate cuff size, standard BP measurement techniques, a standardized videotape examination, and concordant live BP measurements with an instructor using a Y-tube stethoscope. On the basis of average of all 3 BP measurements in participants, we defined hypertension as SBP ≥140 mm Hg, DBP ≥90 mm Hg, or current antihypertensive medication use if they responded affirmatively to the question "Do you currently take prescribed medication for your hypertension or high BP?" on the baseline study questionnaire.

Definition of ATRH

We defined ATRH as mean SBP ≥140 mm Hg or mean DBP ≥90 mm Hg while taking ≥3 antihypertensive medications or taking ≥4 antihypertensive medications with mean SBP <140 mm Hg and mean DBP <90 mm Hg.1 We did not specify the use of a diuretic as a requirement for our primary analysis, but used an alternative definition specifying the use of a diuretic in sensitivity analysis. The BP goal of <140/90 mm Hg used for this analysis is consistent with the recommended BP goal for patients with CKD in recent guidelines.23,24

Outcome Measures

The following incident outcomes were defined a priori for this analysis: (1) composite of myocardial infarction (MI), stroke, and peripheral arterial disease (PAD), which comprised atherosclerotic cardiovascular events; (2) composite of MI, stroke, PAD, and congestive heart failure (CHF); (3) composite of MI, stroke, PAD, CHF, and all-cause mortality; (4) CHF; (5) stroke; (6) renal events; and (7) all-cause mortality. Renal events were defined as a 50% decline in eGFR or end-stage renal disease (start of long-term dialysis or renal transplantation). Cardiovascular events were adjudicated by blinded reviewers using predefined criteria. Deaths were ascertained from reports by next of kin, death certificates, hospital records, and linkage with the Social Security Death Master File. Details of the process of event ascertainment and adjudication in the CRIC study have been previously published.21 Participants were followed up until the occurrence of death, withdrawal from the study, or when the database was locked for analysis.

Statistical Methods

Summary statistics by ATRH status were performed for basic demographic and clinical characteristics. The χ2 test was used to compare categorical variables and t test or Wilcoxon rank-sum test were used for continuous variables. We then explored the factors associated with ATRH with logistic regression models. This was done in 2 steps: step 1, unadjusted associations between ATRH and each of the factors including age, sex, race, eGFR, 24-hour urine protein, BMI, and diabetes mellitus were modeled. Step 2, all these factors entered a multivariable model. Because of nonnormal distribution, 24-hour urine protein was log transformed. For the relationship between ATRH and outcomes, the outcomes were first analyzed by ATRH status using the Kaplan–Meier method. Cox regression models were then used. For each outcome, we fit four models in a tiered fashion. The first model only included ATRH as the predictor (ie, the unadjusted model); model A adjusted for age, sex, race, and clinical center; model B further adjusted for diabetes mellitus, smoking status, history of cardiovascular disease, BMI, hemoglobin, and low-density lipoprotein cholesterol; model C further adjusted for eGFR and 24-hour urine protein. To find whether the associations were consistent across subgroups, we also did stratified analyses in subgroups, which were defined by age (below or above mean), sex, race, eGFR (<30, 30–60, and >60 mL/min per 1.73 m2), and 24-hour urine protein (below or above median). As a sensitivity analysis, we modeled ATRH using 3 more definitions: (1) mean SBP ≥140 mm Hg or mean DBP ≥90 mm Hg while taking ≥3 antihypertensive medications; (2) mean SBP ≥140 mm Hg or mean DBP ≥90 mm Hg while taking ≥3 antihypertensive medications including a diuretic; and (3) taking ≥4 antihypertensive medications with mean SBP <140 mm Hg and mean DBP <90 mm Hg. In the sensitivity analyses for (1) and (3) above, the no-ATRH comparison group stays the same, which includes patients who are adequately treated and at goal on ≤3 medications, and also those with BP not at goal but on <3 medications. In sensitivity analysis for (2), the no-ATRH comparison group includes patients who are adequately treated and at goal on ≤3 medications and those with BP not at goal but on <3 medications or not on a diuretic. Additional sensitivity analysis was done defining ATRH as mean SBP ≥140 mm Hg or DBP ≥90 mm Hg while taking ≥3 antihypertensive medications or taking ≥4 antihypertensive medications with mean SBP <140 mm Hg and mean DBP <90 mm Hg at baseline enrollment and at 1 year of follow-up. All analyses were conducted using SAS version 9.4 (Cary, NC). All P values were 2 sided, and statistical significance was defined as P<0.05.

Results

Of the 3939 CRIC participants, 3367 were hypertensive, had baseline BP and medication information, and are included in these analyses. The prevalence of ATRH in the hypertensive participants in this cohort was 40.4% (n=1359), of which 52.5% (n=713) had BP that was not at goal on ≥3 medications, and 47.5% (n=646) had BP that was at goal on ≥4 medications. The baseline characteristics of patients with and without ATRH are detailed in Table 1. Those with ATRH were older, male, black, more likely to have an annual household income of ≤$20 000, and have history of cardiovascular disease (MI, stroke, CHF, and PAD), and diabetes mellitus. On average, patients with ATRH had higher BMI and larger waist circumference, higher SBP, and lower total and low-density lipoprotein cholesterol levels than those without ATRH. Patients with ATRH were more likely to be under the care of a nephrologist and to report at least 1 lifestyle modification for hypertension. Table S1 in the online-only Data Supplement shows baseline characteristics of patients with ATRH separated by component definitions (BP not at goal on ≥3 medications and BP at goal on ≥4 medications). Renin–angiotensin system blockers and diuretics were the most commonly used antihypertensive medications in all groups. There were no major differences in baseline characteristics of patients within the no-ATRH group (BP at goal on ≤3 medications and BP not at goal on <3 medications; Table S2).

Table 1. Characteristics of CRIC Participants by ATRH Status at Baseline Visit

CharacteristicsOverall Population (n=3367)
No ATRH* (n=2008)ATRH* (n=1359)P Value
Age, y (mean±SD)57.9±11.260.6±9.2<0.0001
Women, n (%)926 (46.1)561 (41.3)0.0056
Race, n (%)<0.0001
 Non-Hispanic white896 (44.6)388 (28.6)
 Non-Hispanic black776 (38.6)747 (55)
 Hispanic266 (13.2)173 (12.7)
 Other70 (3.5)51 (3.8)
Education, n (%)<0.0001
 Less than high school411 (20.5)362 (26.6)
 High school graduate381 (19)293 (21.6)
 Some college571 (28.4)418 (30.8)
 College graduate or higher645 (32.1)286 (21)
Household income, n (%)<0.0001
 ≤$20 000603 (30)520 (38.3)
 $20 001–$50 000492 (24.5)351 (25.8)
 $50 001–$100 000394 (19.6)190 (14)
 >$100 000200 (10)88 (6.5)
 Do not wish to answer319 (15.9)210 (15.5)
Health insurance, n (%)<0.0001
 None156 (8.6)91 (7.8)
 Medicaid/public aid271 (14.9)198 (17)
 Any Medicare604 (33.2)482 (41.4)
 VA/military/champus100 (5.5)73 (6.3)
 Private/commercial306 (16.8)126 (10.8)
 Unknown/incomplete information383 (21)195 (16.7)
Nephrology care, n (%)1292 (64.3)984 (72.4)<0.0001
Myocardial infarction, n (%)313 (15.6)467 (34.4)<0.0001
Stroke, n (%)156 (7.8)206 (15.2)<0.0001
Congestive heart failure, n (%)110 (5.5)235 (17.3)<0.0001
Peripheral arterial disease, n (%)107 (5.3)135 (9.9)<0.0001
Diabetes mellitus, n (%)863 (43)889 (65.4)<0.0001
BMI, kg/m2 (mean±SD)31.6±7.733.9±7.9<0.0001
Waist circumference, cm (mean±SD)104.5±17.2110.4±17.2<0.0001
Smoking status, n (%)0.0142
 Never911 (45.4)567 (41.7)
 Past819 (40.8)623 (45.8)
 Current278 (13.8)169 (12.4)
Any lifestyle modification, n (%)1949 (97.1)1345 (99)0.0002
Weight loss, n (%)1449 (72.5)1043 (76.9)0.0044
Exercise, n (%)1273 (63.7)835 (61.6)0.2160
Alcohol reduction, n (%)1191 (59.6)880 (64.9)0.0019
Salt reduction, n (%)1653 (82.7)1245 (91.8)<0.0001
Alcohol use, n (%)1323 (65.9)731 (53.8)<0.0001
NSAID use, n (%)1000 (49.8)785 (57.8)<0.0001
eGFR, mL/min per 1.73 m2 (mean±SD)45.8±15.638.9±13.7<0.0001
eGFR category, mL/min per 1.73 m2, n (%)<0.0001
 <30341 (17)404 (29.7)
 30–601311 (65.3)853 (62.8)
 >60356 (17.7)102 (7.5)
24-h urine protein, g/24 h, median (q1, q3)0.14 (0.07–0.70)0.41 (0.10–1.66)<0.0001
Total cholesterol, mg/dL (mean±SD)185.8±45.9178.9±45.9<0.0001
LDL, mg/dL (mean±SD)104±34.998.7±35.8<0.0001
HDL, mg/dL (mean±SD)48.3±15.945.3±14.2<0.0001
24-hour urine sodium, mmol/24 h (mean±SD)161.7±77.6165±77.80.2344
Systolic blood pressure, mm Hg (mean±SD)125.3±18.7139.5±24.0<0.0001
Diastolic blood pressure, mm Hg (mean±SD)71.9±12.172.4±14.50.2927
β-Blockers, n (%)720 (35.9)1114 (82)<0.0001
Calcium channel blockers, n (%)618 (30.8)939 (69.1)<0.0001
ACE inhibitors, n (%)978 (48.7)814 (59.9)<0.0001
Angiotensin receptor blockers, n (%)447 (22.3)493 (36.3)<0.0001
Renin–angiotensin system blockers, n (%)1361 (67.8)1153 (84.8)<0.0001
Vasodilators, n (%)77 (3.8)435 (32.0)<0.0001
α-Blockers, n (%)115 (5.7)405 (29.8)<0.0001
α-2 agonists, n (%)50 (2.5)291 (21.4)<0.0001
Potassium sparing diuretics, n (%)198 (9.9)165 (12.1)0.0363
Thiazide diuretics, n (%)585 (29.1)481 (35.4)0.0001
Loop diuretics, n (%)531 (26.4)865 (63.6)<0.0001
Diuretics, n (%)994 (49.5)1215 (89.4)<0.0001
Not on any diuretics or calcium channel blockers, n (%)681 (33.9)27 (2)<0.0001

ACE indicates angiotensin-converting enzyme; ATRH, apparent treatment resistant hypertension; BMI, body mass index; CRIC, Chronic Renal Insufficiency Cohort; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; LDL, low-density lipoprotein; and NSAID, nonsteroidal anti-inflammatory drug.

*ATRH defined as: mean systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg while taking ≥3 antihypertensive medications or taking ≥4 antihypertensive medications with mean systolic blood pressure <140 mm Hg and mean diastolic blood pressure <90 mm Hg.

For continuous variables, the P values are generated using the Student’s t test or the Wilcoxon rank-sum test; for categorical variables, the P values are generated using the χ2 test.

ATRH was more common in patients with lower eGFR; the prevalence was 22.3% in those with eGFR>60 mL/min per 1.73 m2, 39.4% in those with eGFR between 30 and 60 mL/min per 1.73 m2, and 54.2 % in those with eGFR<30 mL/min per 1.73 m2 (Figure 2). The association between clinical and demographic factors and ATRH is shown in Table 2. Older age, male sex, black race, presence of diabetes mellitus, and higher BMI were independently associated with significantly higher odds of having ATRH. In addition, every 5 mL/min per 1.73 m2 decrease in GFR was associated with a 14% higher odds of ATRH (adjusted odds ratio [95% confidence interval {CI}], 1.14 [1.10–1.17]), and doubling of proteinuria was associated with a higher odds of ATRH (adjusted odds ratio [95% CI], 1.28 [1.16–1.42]).

Table 2. Factors Associated With Apparent Treatment Resistant Hypertension*

VariableOdds Ratio (95% CI)
UnadjustedAdjusted
Age (per 5-y increase)1.14 (1.10–1.18)1.18 (1.13–1.23)
Male (ref=women)1.22 (1.06–1.40)1.61 (1.36–1.91)
Race (ref=non-Hispanic white)
 Non-Hispanic black2.22 (1.90–2.60)2.18 (1.83–2.59)
 Hispanic1.50 (1.20–1.88)1.08 (0.83–1.40)
 Other1.68 (1.15–2.46)2.20 (1.44–3.37)
eGFR (per 5 mL/min per 1.73 m2 decrease)1.17 (1.14–1.20)1.14 (1.10–1.17)
24-h urine protein (g/24 h; doubling)§1.45 (1.34–1.57)1.28 (1.16–1.42)
BMI categories (ref=18.5 to <25 kg/m2)
 <18.5 kg/m21.50 (0.62–3.67)1.47 (0.55–3.93)
 25 to <30 kg/m21.44 (1.13–1.85)1.23 (0.94–1.62)
 30 to <35 kg/m21.83 (1.43–2.34)1.53 (1.16–2.01)
 35 to <40 kg/m22.47 (1.89–3.21)2.03 (1.51–2.73)
 ≥40 kg/m22.73 (2.08–3.58)2.26 (1.66–3.08)
Diabetes mellitus (ref=no)2.51 (2.18–2.89)1.84 (1.56–2.17)

ATRH indicates apparent treatment resistant hypertension; BMI, body mass index; CI, confidence interval; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; ref, reference; and SBP, systolic blood pressure.

*ATRH defined as: mean SBP ≥140 mm Hg or DBP ≥90 mm Hg while taking ≥3 antihypertensive medications or taking ≥4 antihypertensive medications with mean SBP <140 mm Hg and mean DBP <90 mm Hg.

Logistic regression with ATRH (yes/no) as the outcome variable and each one of the variables as the predictor variable.

Logistic regression with ATRH (yes/no) as the outcome variable and all of the variables as the predictor variables.

§Twenty-four–hour urine protein has a non-normal distribution, and thus log-transformation is applied on it.

Figure 2.

Figure 2. Prevalence of apparent treatment resistant hypertension by estimated glomerular filtration rate (eGFR) status.

The incidence rate of all clinical outcomes studied was higher in participants with ATRH than in those without ATRH (Figure 3A and 3B shows cardiovascular and renal outcomes, other outcomes are shown in Figures S6–S10). Median follow-up for the various outcomes are as indicated in Tables 3 and 4. The presence of ATRH was associated with higher risk of all outcomes in unadjusted models, and also when adjusted for demographic and cardiovascular risk factors (Table 3). Although attenuated after full multivariable adjustment, the hazard ratio (HR) for each outcome except stroke remained statistically significant in ATRH: HR (95% CI) 1.26 (1.05–1.53) for composite of MI, stroke, and PAD; 1.48 (1.28–1.72) for composite of MI, stroke, PAD, and CHF; 1.38 (1.22–1.56) for composite of MI, stroke, PAD, CHF, and all-cause mortality; 1.66 (1.38–2.00) for CHF; 1.40 (0.97–2.02) for stroke; 1.28 (1.11–1.46) for renal events; and 1.24 (1.06–1.45) for all-cause mortality (Table 3).

Table 3. HRs for Outcomes Comparing Individuals With and Without ATRH*

OutcomeHR (95% CI)
Unadjusted (n=3367)Model A (n=3367)Model B (n=3332)Model C (n=3166)
Composite of MI, stroke, and PAD
 n: No ATRH=248, ATRH=296; median follow-up: 6.8 y2.03 (1.72–2.41)1.84 (1.54–2.18)1.41 (1.17–1.70)1.26 (1.05–1.53)
Composite of MI, stroke, PAD, and CHF
 n: No ATRH=380, ATRH=518; median follow-up: 6.5 y2.50 (2.19–2.85)2.25 (1.96–2.58)1.65 (1.43–1.90)1.48 (1.28–1.72)
Composite of MI, stroke, PAD, CHF, and all-cause mortality
 n: No ATRH=581, ATRH=719; median follow-up: 6.5 y2.31 (2.07–2.58)2.01 (1.80–2.25)1.56 (1.38–1.75)1.38 (1.22–1.56)
CHF
 n: No ATRH=222, ATRH=375; median follow-up: 6.8 y3.01 (2.55–3.55)2.73 (2.30–3.23)1.92 (1.60–2.29)1.66 (1.38–2.00)
Stroke
 n: No ATRH=68, ATRH=89; median follow-up: 7.1 y2.14 (1.56–2.93)1.85 (1.33–2.55)1.53 (1.08–2.17)1.40 (0.97–2.02)
Renal: 50% decrease in eGFR or end-stage renal disease defined as renal transplantation or start of long-term renal dialysis
 n: No ATRH=522, ATRH=601; median follow-up: 5.0 y2.19 (1.95–2.47)2.11 (1.87–2.38)1.84 (1.61–2.09)1.28 (1.11–1.46)
All-cause mortality
 n: No ATRH=345, ATRH=440; median follow-up: 7.4 y2.10 (1.82–2.41)1.79 (1.55–2.07)1.44 (1.23–1.68)1.24 (1.06–1.45)

Model A: adjusted for age (years), sex (men/women), race (non-Hispanic white, non-Hispanic black, Hispanic, and other), and center (7 categories). Model B: adjusted for model A plus diabetes mellitus (yes/no), smoking status (never/past/current), cardiovascular disease (yes/not yes), body mass index (kg/m2), hemoglobin (g/dL), and low-density lipoprotein (mg/dL). Model C: adjusted for model B plus eGFR (mL/min per 1.73 m2) and 24-hour urine protein (g/24 hours; 24-hour urine protein has a non-normal distribution, and thus log transformation is applied on it.). ATRH indicates apparent treatment resistant hypertension; CHF, congestive heart failure; CI, confidence interval; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HR, hazard ratio; MI, myocardial infarction; n, number of events; PAD, peripheral arterial disease; and SBP, systolic blood pressure.

*ATRH defined as: mean SBP ≥140 mm Hg or DBP ≥90 mm Hg while taking ≥3 antihypertensive medications or taking ≥4 antihypertensive medications with mean SBP <140 mm Hg and mean DBP <90 mm Hg.

Cox regression model for each outcome variable with ATRH (yes/no) as the main predictor variable.

Table 4. Hazard Ratios for Clinical Outcomes Comparing Participants With and Without ATRH by Definitions Based on BP Control Status and Use of Diuretic

OutcomeAdjusted HR (95% CI) in Those With BP Not at Goal on ≥3 Medications*Adjusted HR (95% CI) in Those With BP Not at Goal on ≥3 Medications Including a DiureticAdjusted HR (95% CI) in Those With BP at Goal on ≥4 Medications*
Composite of MI, stroke, and PAD1.29 (1.02–1.62)n: No ATRH=248, ATRH=160; median follow-up: 6.9 y1.26 (0.99–1.59)n: No ATRH=272, ATRH=136; median follow-up: 6.9 y1.18 (0.93–1.48)n: No ATRH=248, ATRH=136; median follow-up: 7 y
Composite of MI, stroke, PAD, and CHF1.49 (1.25–1.79)n: No ATRH=380, ATRH=275; median follow-up: 6.7 y1.50 (1.25–1.80)n: No ATRH=415, ATRH=240; median follow-up: 6.7 y1.42 (1.18–1.70)n: No ATRH=380, ATRH=243; median follow-up: 6.8 y
Composite of MI, stroke, PAD, CHF, and all-cause mortality1.41 (1.21–1.63)n: No ATRH=581, ATRH=391; median follow-up: 6.7 y1.45 (1.24–1.68)n: No ATRH=628, ATRH=344; median follow-up: 6.7 y1.30 (1.12–1.51)n: No ATRH=581, ATRH=328; median follow-up: 6.8 y
CHF1.62 (1.29–2.02)n: No ATRH=222, ATRH=194; median follow-up: 6.9 y1.65 (1.32–2.06)n: No ATRH=241, ATRH=175; median follow-up: 6.9 y1.59 (1.28–1.99)n: No ATRH=222, ATRH=181; median follow-up: 7 y
Stroke1.45 (0.95–2.23)n: No ATRH=68, ATRH=53;median follow-up: 7.1 y1.23 (0.80–1.90)n: No ATRH=80, ATRH=41; median follow-up: 7.1 y1.11 (0.70–1.75)n: No ATRH=68, ATRH=36; median follow-up: 7.3 y
Renal: 50% decrease in eGFR or end-stage renal disease defined as renal transplantation or start of long-term renal dialysis1.46 (1.25–1.71)n: No ATRH=522, ATRH=372; median follow-up: 5 y1.49 (1.27–1.75)n: No ATRH=565, ATRH=329; median follow-up: 5 y1.05 (0.88–1.25)n: No ATRH=522, ATRH=229; median follow-up: 5.7 y
All-cause mortality1.24 (1.02–1.50)n: No ATRH=345, ATRH=244; median follow-up: 7.5 y1.32 (1.09–1.60)n: No ATRH=371, ATRH=218; median follow-up: 7.5 y1.11 (0.91–1.36)n: No ATRH=345, ATRH=196; median follow-up: 7.5 y

Adjusted for age (years), sex (male/female), race (non-Hispanic white, non-Hispanic black, Hispanic, and other), center (7 categories), diabetes mellitus (yes/no), smoking status (never/past/current), cardiovascular disease (yes/not yes), body mass index (kg/m2), hemoglobin (g/dL), low-density lipoprotein (mg/dL), estimated glomerular filtration rate (mL/min per 1.73 m2), and 24-hour urine protein (g/24 h; 24-hour urine protein has a non-normal distribution, and thus log transformation is applied on it.). ATRH indicates apparent treatment resistant hypertension; BP, blood pressure; CHF, congestive heart failure; CI, confidence interval; eGFR, estimated glomerular filtration rate; HR, hazard ratio; MI, myocardial infarction; n, number of events; and PAD, peripheral arterial disease.

*Compared with ATRH, no ATRH defined as patients who are adequately treated and at goal on ≤3 medications, and also those with BP not at goal but on <3 medications.

Compared with ATRH, no ATRH defined as patients who are adequately treated and at goal on ≤3 medications and those with BP not at goal but on <3 medications or not on a diuretic.

Figure 3.

Figure 3. A, Cumulative incidence of composite cardiovascular outcomes (composite of myocardial infarction [MI], stroke, peripheral arterial disease [PAD], and congestive heart failure [CHF]) between patients with and without apparent treatment resistant hypertension. B, Cumulative incidence of renal outcomes between patients with and without apparent treatment resistant hypertension (ATRH). A and B, Top line, No ATRH; bottom line, ATRH.

The association between ATRH and clinical outcomes was consistent when stratified by subgroups of age, sex, race/ethnicity, and proteinuria (Figures S1–S5). However, there was significant interaction in the differences between ATRH and no-ATRH groups for CHF (interaction P=0.0001) and renal (interaction P=0.02) events when stratified by baseline eGFR (Figure 4A and 4B). ATRH was significantly associated with CHF in individuals with eGFR >60 mL/min per 1.73 m2 (HR [95% CI], 2.28 [1.13–4.58]) and 30 to 60 mL/min per 1.73 m2 (HR [95% CI], 2.18 [1.72–2.75]), but not in participants with eGFR <30 mL/min per 1.73 m2 (HR [95% CI], 1.00 [0.74–1.35]). Similarly ATRH was significantly associated with renal events in individuals with eGFR >60 mL/min per 1.73 m2 (HR [95% CI], 2.29 [1.15–4.57]) and 30 to 60 mL/min per 1.73 m2 (HR [95% CI], 1.47 [1.23–1.75]), but not in participants with eGFR <30 mL/min per 1.73 m2 (HR [95% CI], 1.09 [0.89–1.33]).

Figure 4.

Figure 4. A, Hazard ratios (confidence intervals) for congestive heart failure in participants with or without apparent treatment resistant hypertension (ATRH) in subgroups. B, Hazard ratios (confidence intervals) for renal outcomes in participants with or without ATRH in subgroups. eGFR indicates estimated glomerular filtration rate.

Additional analyses explored the components of the definition of ATRH. Individuals with ATRH and whose BP was at goal on ≥4 medications had significantly increased HR for composite of MI, stroke, PAD, CHF, and all-cause mortality (HR [95% CI], 1.30 [1.12–1.51]), composite of MI, stroke, PAD, and CHF (HR [95% CI], 1.42 [1.18–1.70]), and CHF (HR [95% CI], 1.59 [1.28–1.99]), but not if CHF was excluded from the composite outcomes, or for individual components of the composite outcomes other than CHF—composite of MI, stroke, and PAD (HR [95% CI], 1.18 [0.93–1.48]); all-cause mortality (HR [95% CI], 1.11 [0.91–1.36]); stroke (HR [95% CI], 1.11 [0.70–1.75]); and renal events (HR [95% CI], 1.05 [0.88–1.25]; Table 4). The point estimates of the HRs of risk were lower in participants with controlled BP on ≥4 medications than in participants whose BP was not at goal on ≥3 medications (Table 4).

In sensitivity analysis, the outcomes were similar in those with ATRH whose BP was not at goal on ≥3 medications with or without use of diuretics than in those with no ATRH (Table 4). Additional sensitivity analysis defining ATRH at baseline and at 1 year of follow-up showed similar results (Table S3).

Discussion

This is the largest cohort of patients to study the prognostic significance of ATRH in CKD. In this cohort of patients with CKD, the prevalence of ATRH was high, and patients with lower levels of eGFR were more likely to have ATRH. As in non-CKD populations, older age, male sex, black race, proteinuria, diabetes mellitus, and higher BMI were independently associated with ATRH. The presence of ATRH independently predicted a higher risk of mortality and adverse cardiovascular and renal outcomes. The increased risk for these outcomes was consistent in subgroups defined by age, sex, race, and urine protein excretion. ATRH was associated with higher risk of renal outcomes and CHF in participants with earlier stages (eGFR≥30 mL/min per 1.73 m2), but not in those with more advanced stages of CKD (eGFR<30 mL/min per 1.73 m2).

Population-based studies show high rates of hypertension in patients with CKD.1719 A previous analysis of the CRIC cohort noted high rates of awareness and treatment of hypertension in adult patients with CKD, but showed that control rates were suboptimal.20 The prevalence rates of ATRH in the literature have varied, related in part to the differences in definitions used for ATRH. The 40% prevalence of ATRH in this cohort is higher than other studies, which report prevalence of 12.7% to 21.7% in the general population3,7,10 and 11.1% to 22.9% in patients with established cardiovascular disease.6,9 Although 1 clinic-based study, which was limited to patients with CKD, reported an ATRH prevalence of 23%, this was a small study that was limited to a white population.8 The high prevalence of ATRH in the CRIC cohort may be because of the presence of CKD, and the inclusion of a large proportion of blacks, both predictors of resistant hypertension.1,25

Our finding of increasing ATRH prevalence with decreasing eGFR confirms a similar trend noted in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study analysis.25 There was a 14% higher risk of ATRH with every 5 mL/min per 1.73 m2 decrease in eGFR in our study. Although the mechanisms that contribute to resistant hypertension in CKD are not well defined, it may be speculated that increased salt and water retention, excessive activation of the renin–angiotensin–aldosterone system, and higher levels of sympathetic activation with decreasing eGFR would contribute to uncontrolled BP.26 Decreased eGFR and both moderately and severely increased albuminuria have been shown to be independently associated with lesser longitudinal SBP and DBP reductions in hypertensive patients, strongly inferring that these variables are physiological mediators of resistance to pharmacologic BP lowering.27

The association between ATRH and adverse cardiovascular and renal outcomes has been reported mostly in patients without CKD.3,6,9 We demonstrate that ATRH is an independent predictor of adverse cardiovascular and renal outcomes in patients with CKD. Although the magnitude of risk for outcomes is different, our results are similar to other studies in that there is a clear increased risk for most adverse cardiovascular and renal outcomes with the presence of ATRH (38% increase in risk for composite of MI, stroke, PAD, CHF, and all-cause mortality and 28% increase in risk for 50% decrease in eGFR or incident end-stage renal disease). The risk of stroke was not statistically significant in the fully adjusted model in this analysis—the number of stroke events, however, was low in this cohort. Importantly, ATRH was associated with a 66% increased risk for CHF. Given the increasing recognition of heart failure as a major cause of morbidity in patients with CKD,2830 our findings point toward a potential reversible factor contributing to the risk of heart failure. The findings were consistent in subgroups of age, race, sex, and proteinuria. Coupled with the high prevalence of ATRH shown in this cohort, our data highlight the importance of recognition of ATRH in patients with CKD. Whether a targeted intervention to lower BP in patients with ATRH results in improved cardiovascular and renal outcomes needs to be established in prospective studies and should be a high priority for future research.

The definition of resistant hypertension has been the subject of some debate in this field.31 Although the traditional definition has been uncontrolled BP on at least 3 antihypertensive medications classes,32 the American Heart Association definition also added a new group of patients, those with controlled BP on ≥4 antihypertensive medication classes.1 To our knowledge, the prognostic implication of this new component of the definition of resistant hypertension has not been previously studied in patients with CKD. A recent study of hypertensive patients followed in a large healthcare system showed that the risk of end-stage renal disease and stroke was significantly higher in patients whose BP was not at goal on ≥3 medications than in those whose controlled BP requires ≥4 medications, whereas the risks for ischemic heart events, CHF, and mortality were similar.33 We demonstrate that although the magnitude of risk for most clinical outcomes was lower in patients with CKD with controlled BP on ≥4 medications than those with uncontrolled hypertension on ≥3 medications, the risk (especially for CHF and composite outcomes that included CHF) was still higher than those without ATRH. This supports the inclusion of this group of patients in the ATRH definition because it does help in risk stratification. These data also suggest that optimization of drug therapy and achievement of BP goal may lower the risk of outcomes. Our sensitivity analyses showed increased risk of adverse outcomes regardless of whether a diuretic was a part of the antihypertensive regimen.

The association between ATRH and clinical outcomes differed based on level of eGFR; ATRH was associated with higher risk of renal outcomes and CHF in patients with eGFR>60 mL/min per 1.73 m2 and eGFR 30 to 60 mL/min per 1.73 m2, but not eGFR<30 mL/min per 1.73 m2. This underscores the importance of early recognition and systematic evaluation of underlying factors that may be contributing to ATRH in patients with relatively preserved renal function. It is also consistent with the concept that some risk factors can be detected in early, but not in late CKD, for example, fibroblast growth factor 23 was associated with progression of kidney disease only in patients with eGFR>30 mL/min per 1.73 m2, but not in those with eGFR<30 mL/min per 1.73 m2.34 It is also known that lower eGFR and higher albuminuria are associated with higher risk of all-cause mortality and cardiovascular mortality, independent of traditional cardiovascular risk factors including hypertension.35

Our study has many strengths; these include the large sample size (including subgroups to allow robust subgroup analyses), long duration of follow-up, and careful ascertainment and adjudication of clinical outcomes. In addition, sensitivity analyses with alternate definitions are consistent with the overall results reported. However, important limitations of this study need to be considered; this is an observational study, and the reported associations do not prove causation. A comprehensive evaluation of resistant hypertension was not done in the CRIC study; therefore, pseudoresistance is not excluded. Heart rate variability was not examined in our analysis, but this has previously been shown to be a predictor of mortality in the CRIC cohort.36 The no-ATRH comparison group in this study includes patients who are adequately treated and at goal on ≤3 medications, and also those with BP not at goal but on <3 medications—the latter could potentially be because of not only physician or patient inertia but also inability to tolerate more medications caused by side effects. Studies in the resistant hypertension literature have addressed this issue in different ways. Most studies have compared ATRH with no ATRH as in our analyses.3,6,9 Other studies7,10 excluded patients who were uncontrolled on <3 medications in primary analysis or included them in a secondary analysis. We examined the baseline characteristics of patients within the no-ATRH group (BP at goal on ≤3 medications and BP not at goal on <3 medications) and did not find major differences. In addition, defining ATRH at 2 time points—baseline and at 1-year follow-up—did not change results.

Perspectives

The association of ATRH with adverse cardiovascular and renal outcomes is compelling and has important clinical implications for patients with CKD. Our findings underscore the need for early identification, and systematic evaluation and management of patients with ATRH and CKD. In addition, these data support the need for novel therapeutic strategies to improve BP control in patients with CKD.

Acknowledgments

Lawrence J. Appel, MD, MPH, Harold I. Feldman, MD, MSCE, Alan S. Go, MD, Jiang He, MD, PhD, John W. Kusek, PhD, James P. Lash, MD, Akinlolu Ojo, MD, PhD, Mahboob Rahman, MD, and Raymond R. Townsend, MD are the Chronic Renal Insufficiency Cohort (CRIC) Study Investigators

Footnotes

Parts of this study were presented as an oral presentation at the annual American Society of Nephrology meeting on November 5, 2015 in San Diego, CA.

The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.115.06487/-/DC1.

Correspondence to Mahboob Rahman, Department of Medicine, Case Western University School of Medicine, University Hospitals Case Medical Center, 11100 Euclid Ave, Cleveland, OH 44106. E-mail

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Novelty and Significance

What Is New?

  • Apparent treatment resistant hypertension is associated with an increased risk of adverse cardiovascular and renal outcomes in patients with chronic kidney disease (CKD).

  • Individuals with apparent treatment resistant hypertension who have blood pressure at goal but on ≥4 medications have significantly increased risk for many adverse cardiovascular outcomes.

  • The increased risk for heart failure and adverse renal outcomes was present in subgroups defined by estimated glomerular filtration rate (eGFR) >60 mL/min per 1.73 m2 and estimated glomerular filtration rate 30 to 60 mL/min per 1.73 m2, but not estimated glomerular filtration rate <30 mL/min per 1.73 m2.

What Is Relevant?

  • Varying prevalence of apparent treatment resistant hypertension in the general population and in patients with established cardiovascular disease.

  • Few studies have investigated the prevalence and prognostic significance of apparent treatment resistant hypertension in patients with CKD.

Summary

There is a strong association between apparent treatment resistant hypertension and adverse cardiovascular and renal outcomes in patients with CKD. The current study underscores the need for early identification and systematic evaluation and management of patients with apparent treatment resistant hypertension and CKD. These data support the need for novel therapeutic strategies to improve blood pressure control in patients with CKD.