Research Article

Originally Published 8 August 2016

Orthostatic Hypotension in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) Blood Pressure Trial: Prevalence, Incidence, and Prognostic Significance

Jerome L. Fleg, Gregory W. Evans, Karen L. Margolis, Joshua Barzilay, Jan N. Basile, J. Thomas Bigger, Jeffrey A. Cutler, … Show All … , Richard Grimm, Carolyn Pedley, Kevin Peterson, Rodica Pop-Busui, JoAnn Sperl-Hillen, and William C. CushmanAuthor Info & Affiliations

Hypertension

Volume 68, Number 4

https://doi.org/10.1161/HYPERTENSIONAHA.116.07474

PDF/EPUB

Abstract

Orthostatic hypotension (OH) is associated with hypertension and diabetes mellitus. However, in populations with both hypertension and diabetes mellitus, its prevalence, the effect of intensive versus standard systolic blood pressure (BP) targets on incident OH, and its prognostic significance are unclear. In 4266 participants in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) BP trial, seated BP was measured 3×, followed by readings every minute for 3 minutes after standing. Orthostatic BP change, calculated as the minimum standing minus the mean seated systolic BP and diastolic BP, was assessed at baseline, 12 months, and 48 months. The relationship between OH and clinical outcomes (total and cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, heart failure hospitalization or death and the primary composite outcome of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) was assessed using proportional hazards analysis. Consensus OH, defined by orthostatic decline in systolic BP ≥20 mm Hg or diastolic BP ≥10 mm Hg, occurred at ≥1 time point in 20% of participants. Neither age nor systolic BP treatment target (intensive, <120 mm Hg versus standard, <140 mm Hg) was related to OH incidence. Over a median follow-up of 46.9 months, OH was associated with increased risk of total death (hazard ratio, 1.61; 95% confidence interval, 1.11–2.36) and heart failure death/hospitalization (hazard ratio, 1.85, 95% confidence interval, 1.17–2.93), but not with the primary outcome or other prespecified outcomes. In patients with type 2 diabetes mellitus and hypertension, OH was common, not associated with intensive versus standard BP treatment goals, and predicted increased mortality and heart failure events.

Introduction

See Editorial Commentary, pp 851–852

After assumption of upright posture from supine or seated positions, arterial blood pressure (BP) is typically maintained by increased sympathetic activity leading to vasoconstriction and increased heart rate. Orthostatic hypotension (OH) occurs when these normal compensatory mechanisms are deficient. The most widely accepted definition of OH is a decline of systolic BP (SBP) ≥20 mm Hg or a decline of diastolic BP (DBP) ≥10 mm Hg within 3 minutes of standing.¹ Risk factors associated with OH include advanced age, hypertension, antihypertensive drugs, and diabetes mellitus.^2,3 OH may lead to postural instability, falls, and syncope⁴ and is predictive of increased risk for stroke,⁵ coronary events,^6,7 and total mortality^7–9 in community-based populations.

Although hypertension occurs in >50% of adults with diabetes mellitus, there is surprisingly little information on the incidence or prognostic significance of OH in this setting. Participants in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) BP trial were at high risk for OH because of their diabetes mellitus, hypertension, and treatment with antihypertensive drugs.¹⁰ It was anticipated that those individuals randomized to the intensive SBP treatment goal of <120 mm Hg might be at particularly high risk for OH because of their greater number and doses of antihypertensive medications and their lower SBP goal. The present study, therefore, seeks to answer 2 important questions: (1) What is the incidence of OH in adults with diabetes mellitus and hypertension randomized to intensive (SBP <120 mm Hg) versus standard (SBP <140 mm Hg) BP goals? (2) Does OH have independent prognostic significance for the combined primary end point of the trial (nonfatal myocardial infarction (MI), nonfatal stroke, and cardiovascular death) in this population? The large size and design of ACCORD presented an excellent opportunity to answer these questions.

Methods

Study Design

ACCORD was a double 2-by-2 factorial design randomized trial conducted at 77 clinical sites organized into 7 networks in the United States and Canada.¹¹ The trial enrolled 10 251 high-risk participants with type 2 diabetes mellitus (T2DM). Participants were eligible if they had T2DM and a glycohemoglobin level of ≥7.5% and were between the ages of 40 and 79 years with cardiovascular disease or 55 to 79 years with anatomic evidence of subclinical atherosclerosis, albuminuria, left ventricular hypertrophy, or ≥2 additional risk factors for cardiovascular disease (dyslipidemia, hypertension, smoking, or obesity). Study exclusions included a body mass index of >45 and a serum creatinine of >1.5 mg/dL. All participants were randomly assigned to either intensive or standard glycemic control (the ACCORD Glycemia trial).¹² In addition, 5518 of these participants were randomly assigned to either simvastatin plus fenofibrate or simvastatin plus placebo (the ACCORD Lipid trial)¹³; the remaining 4733 participants were randomly assigned to either intensive or standard BP control (the ACCORD BP trial),¹⁰ on which the current report is based.

ACCORD BP was a nonblinded trial in which participants were randomly assigned to intensive therapy that targeted SBP of <120 mm Hg or to standard therapy that targeted SBP of <140 mm Hg. Individuals with SBP between 130 and 180 mm Hg who were taking ≤3 antihypertensive medications and who had the equivalent of a 24-hour urinary protein excretion of <1.0 g were eligible for the BP trial. The ACCORD BP trial tested a treatment strategy to achieve specific SBP goals rather than an evaluation of any specific drug regimen. Therefore, all available classes of antihypertensive medications were used to lower BP as previously described.¹⁰ The average difference in BP achieved in the in the intensive treatment group compared with the standard treatment group was 14.2 mm Hg for SBP and 6.1 mm Hg for DBP. The mean number of antihypertensive medications used was 2.1 for the standard group and 3.4 for the intensive group. The primary composite end point of cardiovascular death, nonfatal MI, or nonfatal stroke did not differ significantly between treatment arms although the risk for stroke, a prespecified secondary outcome, was significantly lower in the intensive treatment arm.¹⁰ Serious adverse events related to the intervention, including most commonly hypotension and syncope, were observed in 3.3% of the intensive group compared with 1.3% in the standard group (P<0.001).¹⁰

All participants in the ACCORD BP trial were eligible for participation in the OH measurements, which began in October 2004. Standing BP was measured at baseline and at the 12-month and 48-month follow-up visits using the same automated oscillometric device (Omron HEM-907) that was used to measure seated BP. After at least 5 minutes of seated rest, BP was determined 3× at 1-minute intervals; participants were then asked to stand. Starting when their feet touched the ground, BP was taken every minute for 3 minutes in the same arm used for the seated measurements. Blood pressure change was calculated using the minimum standing measurement minus the mean of the seated measurements¹ The person recording the standing measurements also recorded whether the participant experienced dizziness or felt lightheaded on standing for this assessment.

The occurrence of consensus OH was defined by a decline in SBP ≥20 mm Hg or a decline in DBP ≥10 mm Hg from sitting to standing.¹ The detection of OH unaccompanied by orthostatic symptoms of dizziness, presyncope, or syncope was not to influence treatment, according to the antihypertensive drug treatment algorithm. Medication adjustments were allowed for the management of symptomatic OH.

For participants in the intensive therapy group, clinic visits to assess BP were scheduled once a month for 4 months and every 2 months thereafter; for participants in the standard therapy group, visits were scheduled at months 1 and 4 and every 4 months thereafter. Additional visits were scheduled as needed in both groups to monitor and ensure appropriate implementation of the study intervention strategies. Telephone follow-up was used for those unable to visit the clinic. The occurrence of a coronary event, stroke, or cardiovascular death was reported by the clinic staff and adjudicated by a Clinical Events Committee, blinded to treatment group assignment.

Statistical Analysis

Differences in baseline characteristics, including the prevalence of OH symptoms, between the group ever demonstrating consensus OH and the group that did not were compared by 2-sample t test or χ² analysis. The baseline characteristics examined included age, sex race, body mass index, duration of diabetes mellitus, smoking status, glycohemoglobin, hematocrit, treatment with antihypertensive drugs, and history of coronary heart disease, stroke, heart failure, or carotid/peripheral artery disease.

Prevalence of OH at a specific visit was defined based on the occurrence of consensus OH at that visit, regardless of whether OH had been identified at previous visits. Incidence of OH at a specific follow-up visit was defined as the occurrence of consensus OH at that visit among participants who had been examined previously but had not demonstrated OH. Resolution of OH at a specific follow-up visit is defined as the absence of consensus OH at that visit among participants who had consensus OH at their last assessment. Visit-specific differences in OH prevalence, incidence, and resolution by assigned treatment group were evaluated using χ² analyses. Because the cohorts of participants examined differed among visits, we also performed a similar analysis restricted to participants examined at all 3 visits (baseline and 12 and 48 months post randomization).

The associations between baseline characteristics and the occurrence of consensus OH at baseline or during follow-up were examined using generalized linear mixed model assuming a binary distribution and a logit link, with the presence of consensus OH as the response variable and after adjusting for subject and all variables shown in Table 4. Visit month was treated as a time-dependent variable in these analyses. By treating each assessment as a separate observation while accounting for the within-in subject correlation, this model assigns more weight to participants with multiple assessments than to those assessed only a single time point. Similar analyses based on general linear models for repeated measurements with delta SBP (standing SBP−seated SBP) and delta DBP (standing DBP−seated DBP) as dependent variables are presented in the Appendix in the online-only Data Supplement.

The associations between consensus OH and subsequent cardiovascular events were evaluated using proportional hazards models accounting for left truncation, with follow-up for each participant beginning at the time of the first standing BP assessment and OH status treated as a time-dependent covariate based on the occurrence of consensus OH at the most recent assessment for each participant. All models included covariates controlling for BP treatment group assignment, glycemia treatment group assignment, and history of cardiovascular disease at baseline. We also tested for interactions between BP treatment group assignment and consensus OH. In sensitivity analyses, we also examined systolic OH alone, time-dependent definitions of OH based on any occurrence (ever OH) or based on an updated value defined as the number of visits with OH divided by the number of assessments completed at or before the most recent visit. In all cases, results were qualitatively similar to the model with OH based solely on the last visit; the results for the systolic OH analyses are included in the Appendix in the online-only Data Supplement, as are analyses of delta SBP and delta DBP as predictors in place of OH. For all analyses, a 2-tailed P<0.05 was required to reject the null hypothesis.

Results

In total, 4266 ACCORD BP participants had orthostatic BP measurements on at least 1 visit, including 1321 at baseline, 2625 at 12 months, and 3702 at 48 months, with 926 having measurements at all 3 time points (Figure 1). The smaller number of orthostatic BP measurements at baseline and 12 months was because the OH measurements did not commence until 44 months after ACCORD BP began. Consensus OH occurred on at least 1 time point in 852 individuals (20.0%). Individuals with OH were more likely to be women, non-Hispanic white, have had previous MI, and use β-blockers and insulin. They also had higher seated SBP and DPB at baseline. Those with OH were less likely to use sulfonylureas (Table 1).

Table 1. Participant Characteristics by Orthostatic Hypotension Status

Baseline Characteristic	Ever Consensus OH		Never Consensus OH		P Value
Baseline Characteristic	n	Value*	n	Value*	P Value
Age, y	852	62.1 (6.8)	3414	62.1 (6.8)	0.94
Sex, % male	852	50.2 (428)	3414	54.2 (1849)	0.04
Ethnicity, %
Non-Hispanic white	852	68.3 (582)	3414	60.5 (2065)	<0.0001
Hispanic	852	6.5 (55)	3414	6.6 (225)	0.94
Black	852	19.1 (163)	3414	23.5 (803)	0.006
Previous cardiovascular event, %	852	35.1 (299)	3414	32.7 (1115)	0.18
Previous myocardial Infarction, %	852	16.7 (142)	3414	12.9 (439)	0.004
Previous stroke, %	852	6.8 (58)	3414	5.9 (201)	0.34
Previous heart failure, %	843	4.9 (41)	3381	3.9 (130)	0.20
Previous coronary revascularization, %	852	0.12¹	3414	0.15⁵	1
Diabetes mellitus duration, median, y	843	10¹¹	3380	10¹⁰	0.076
Peripheral neuropathy, %	851	42.1 (358)	3410	38.9 (1326)	0.092
Left ventricular hypertrophy, %	851	5.3 (45)	3395	5.2 (175)	0.86
Body mass index, kg/m²	852	32.3 (5.3)	3414	32.1 (5.6)	0.44
Systolic blood pressure, mm Hg	852	141.6 (17.5)	3414	138.5 (15.2)	<0.0001
Diastolic blood pressure, mm Hg	852	76.9 (11.09)	3414	75.7 (10.1)	0.003
LDL-cholesterol, mg/dL	850	109.6 (37.0)	3393	109.5 (36.5)	0.93
HDL-cholesterol, mg/dL	850	46.7 (13.3)	3393	46.0 (13.6)	0.21
Triglycerides, median, mg/dL	850	151 (129)	3393	147 (130)	0.39
Former smokers, %	850	44.0 (374)	3412	42.4 (1448)	0.20
Current smokers, %	850	14.0 (119)	3412	12.4 (424)	0.20
Antihypertensives, %	852	87.4 (745)	3414	87.3 (2981)	0.95
RAS inhibitors, %	852	67.1 (572)	3414	68.5 (2339)	0.46
Diuretics, %	852	34.7 (296)	3414	34.5 (1177)	0.90
β-Blockers, %	852	30.1 (256)	3414	24.7 (843)	0.0016
Calcium channel blockers, %	852	18.4 (157)	3414	18.3 (624)	0.92
α-Blockers, %	852	2.2 (19)	3414	1.7 (58)	0.31
Statins, %	852	67.0 (571)	3414	65.3 (2229)	0.35
Fibrates, %	852	8.2 (70)	3414	6.7 (227)	0.11
Insulin, %	852	41.9 (357)	3414	35.5 (1211)	0.0005
Metformin, %	852	55.1 (469)	3414	58.0 (1981)	0.12
Sulfonylureas, %	852	44.7 (381)	3414	48.6 (1658)	0.046
Thiazolidinediones, %	852	22.1 (188)	3414	21.2 (722)	0.57

HDL indicates high-density lipoprotein; LDL, low-density lipoprotein; OH, orthostatic hypotension; and RAS, renin–angiotensin system.

Values represent mean (SD) for continuous variables and % (n) for discrete variables.

Figure 1. Consort diagram showing the number of participants undergoing orthostatic blood pressure measurements at baseline and at 12 and 48 mo after randomization.

Table 2 compares the prevalence, incidence, and resolution of OH in the intensive versus standard BP treatment groups. The most noteworthy finding is the lack of significant difference in OH prevalence, incidence, or resolution between the treatment groups at all time points. A similar lack of treatment group difference in OH occurrence was observed in the subset with standing BP measurements at all 3 points. Although OH prevalence at baseline averaged 17.8% in the total sample with baseline measurements, prevalence at 12 and 48 months declined to 10.4% and 12.8%, respectively, with resolution rates between 70% and 82%. Similar time trends were seen in the subset assessed at all 3 points.

Table 2. Prevalence and Incidence of Consensus Orthostatic Hypotension by Visit and Treatment Group

Participants Analyzed	Intensive Group % (n/n)	Standard Group % (n/n)	P Value
All participants
Prevalence
Baseline	19.3 (127/658)	16.1 (107/663)	0.15
12 mo	9.5 (126/1324)	11.4 (148/1301)	0.13
48 mo	12.2 (223/1830)	13.5 (252/1872)	0.26
Incidence
12 mo*	8.0 (36/453)	9.9 (47/473)	0.30
48 mo†	9.9 (95/958)	11.0 (104/942)	0.45
Resolution
12 mo‡	81.7 (89/109)	78.2 (68/ 87)	0.54
48 mo§	70.5 (74/105)	71.2 (89/125)	0.90
Participants with data at all 3 visits
Prevalence
Baseline	18.7 (86/461)	16.8 (78/465)	0.49
12 mo	10.2 (47/461)	11.6 (54/465)	0.53
48 mo	12.2 (56/461)	12.9 (60/465)	0.77
Incidence
12 mo*	7.7 (29/375)	9.8 (38/387)	0.31
48 mo†	9.8 (34/346)	8.6 (30/349)	0.58
Resolution
12 mo‡	79.1 (68/ 86)	79.5 (62/ 78)	0.95
48 mo§	70.2 (33/ 47)	75.9 (41/ 54)	0.52

OH indicates orthostatic hypotension.

Restricted to participants assessed and free from OH at baseline.

^†

Restricted to participants assessed at baseline or 12 mo and free from OH.

^‡

Restricted to participants with OH at baseline.

^§

Restricted to participants with OH at previous visit.

At the baseline examination, 31 of 676 (4.6%) intensive group participants and 35 of 679 (5.2%) standard group participants reported feeling dizzy on standing for the BP measurement (P=0.71). During follow-up, these numbers were 71 of 1337 (5.3%) intensive group participants and 65 of 1308 (5.0%) standard group participants (P=0.72) for the 12-month examination and 106 of 1860 (5.7%) intensive group participants and 77 of 1896 (4.1%) standard group participants (P=0.02) at the 48-month examination. Thus, symptomatic dizziness on standing was modestly but significantly higher in the intensive than in the standard group only during the at 48-month examination.

Although <10% of participants with consensus OH at any time point reported dizziness on standing during the examination, at the 12- and 48-month visits, participants with consensus OH were about twice as likely to report symptoms of dizziness on standing during the BP examination compared with those without OH (Table 3). Of participants reporting dizziness when standing for the BP examination at baseline, only 11 of 66 (16.7%) had consensus OH. These numbers were 25 of 136 (18.4%) at 12-month follow-up and 39 of 183 (21.3%) at 48-month follow-up. Figure 2 displays histograms of the orthostatic change in SBP and DBP at the baseline visit, showing a normal distribution for both variables centered around 0 to −5 mm Hg, with a similar proportion of individuals demonstrating reductions in SBP ≥20 mm Hg and reductions in DBP ≥10 mm Hg.

Table 3. Dizziness on Standing as a Function of Measured Orthostatic Hypotension and Treatment Arm

Time Point	Consensus OH			No Consensus OH
Time Point	Overall	Intensive Therapy	Standard Therapy	Overall	Intensive Therapy	Standard Therapy
Baseline examination	11/242 (4.6)	6/132 (4.6)	5/110 (4.6)	55/1113 (4.9)	25/544 (4.6)	30/569 (5.3)
12-mo Examination	25/276 (9.1)*	12/128 (9.4)	13/148 (8.8)	111/2369 (4.7)*	59/1209 (4.9)	52/1160 (4.5)
48-mo Examination	39/487 (8.0)*	22/230 (9.6)†	17/257 (6.6)†	144/3269 (4.4)*	84/1630 (5.2)†	60/1639 (3.7)†

Entries are number with event/number assessed (% with event). OH indicates orthostatic hypotension.

P<0.05 comparing overall percent with dizziness among participants with consensus OH to the overall percent with dizziness among participants without consensus OH using Fisher exact test.

^†

P<0.05 comparing percent with dizziness among intensive therapy participants to the percent with dizziness among standard therapy participants after stratifying on Consensus OH status using Cochran–Mantel–Hanzel statistics.

Figure 2. Histograms showing distribution of orthostatic change in systolic (A) and diastolic (B) blood pressure (SBP and DBP, respectively) at baseline.

Table 4 shows the baseline characteristics independently associated with consensus OH on fully adjusted regression analysis. Female sex, higher SBP and hemoglobin A1c, current smoking, and use of β-blockers, α-blockers, and insulin were associated with greater likelihood of OH, whereas black race was associated with a lesser likelihood of OH. Of note, the assigned BP treatment group was not associated with OH. In addition, individuals were less likely to show OH at the 12- and 48-month visits than at baseline. In Tables S3 and S4 in the online-only Data Supplement, the baseline characteristics associated with delta SBP and delta DBP as continuous variables are generally similar to those for consensus OH.

Table 4. Factors Associated With Orthostatic Hypotension After Adjustment for Other Variables Shown

Baseline Characteristic	Odds Ratio	95% Confidence Interval	P Value
BP intervention: intensive vs standard	0.925	0.798–1.074	0.31
Glycemia intervention: intensive vs standard	0.947	0.816–1.098	0.47
12-mo visit vs baseline	0.554	0.459–0.668	<0.0001
48-mo visit vs baseline	0.702	0.591–0.835	<0.0001
Age, y	1.003	0.991–1.016	0.61
Female vs male	1.251	1.054–1.485	0.01
Hispanic vs non-Hispanic white	0.863	0.634–1.174	0.34
Black vs non-Hispanic white	0.667	0.544–0.819	0.0001
Cardiovascular disease history	0.902	0.719–1.131	0.37
Previous myocardial infarction	1.261	0.968–1.644	0.09
Previous stroke	1.120	0.804–1.560	0.50
Previous heart failure	1.026	0.713–1.478	0.89
Previous coronary revascularization	1.499	0.159–14.122	0.72
Diabetes mellitus duration, y	1.006	0.996–1.017	0.24
Peripheral neuropathy	1.076	0.920–1.257	0.36
Left ventricular hypertrophy	0.989	0.703–1.393	0.95
Hemoglobin A1c, %	1.088	1.014–1.167	0.02
Body mass index, kg/m²	0.997	0.982–1.012	0.68
Systolic BP, mm Hg	1.013	1.007–1.018	<0.0001
Diastolic BP, mm Hg	1.007	0.998–1.016	0.13
LDL-cholesterol, mg/dL	1.000	0.998–1.002	0.88
HDL-cholesterol, mg/dL	1.003	0.996–1.010	0.39
Triglycerides, mg/dL	1.000	0.999–1.000	0.58
Current vs never smokers	1.382	1.095–1.743	0.006
Former vs never smokers	1.164	0.984–1.377	0.08
Renin–angiotensin system inhibitors	0.956	0.811–1.126	0.59
Diuretics	0.993	0.841–1172	0.93
β-Blockers	1.240	1.033–1.288	0.02
Calcium channel blockers	1.035	0.850–1.260	0.73
α-Blockers	1.701	1.018–2.843	0.04
Statins	1.033	0.872–1.223	0.71
Fibrates	1.146	0.862–1.523	0.35
Insulin	1.242	1.030–1.497	0.02
Metformin	0.938	0.800–1.101	0.43
Sulfonylureas	0.994	0.840–1.176	0.95
Thiazolidinediones	1.098	0.915–1.318	0.32

BP indicates blood pressure; HDL, high-density lipoprotein; and LDL, low-density lipoprotein.

Table 5 examines the relationship between consensus OH at the most recent visit and the primary combined outcome and its components and with other secondary outcomes after controlling for treatment assignment for both the blood pressure and glycemia interventions, cardiovascular disease history at baseline, and clinical network (primary outcome only). No significant relationship was observed between OH and the combined primary outcome of nonfatal MI, nonfatal stroke, cardiovascular death, or its components. However, compared with individuals without OH, those with OH had 85% higher risk for heart failure deaths or hospitalizations (P=0.01) and 62% higher risk for total mortality (P=0.02). Similar findings were observed for the subset of individuals with systolic OH (Tables S1 and S2) except that only the higher hazard for mortality was significant (hazard ratio, 1.80; P<0.01). There was no evidence of an interaction between the effect of treatment group and the effect of consensus OH for any of the reported outcomes (P>0.13 in all cases).

Table 5. Relationship Between Consensus Orthostatic Hypotension at Most Recent Visit and Cardiovascular Outcomes

End Point	OH		No OH		OH (Yes/No)
End Point	No. of Events	%/y	No. of Events	%/yr	Hazard Ratio	95% Confidence Interval	P Value
Primary outcome	35	2.19	219	1.87	1.13	0.81–1.59	0.47
Nonfatal MI	25	1.56	140	1.19	1.31	0.87–1.98	0.21
Nonfatal stroke	4	0.24	46	0.38	0.71	0.28–1.79	0.45
CVD mortality	8	0.48	50	0.41	1.19	0.62–2.27	0.60
Total mortality	28	1.67	125	1.03	1.62	1.10–2.36	0.02
Total stroke	4	0.24	51	0.43	0.64	0.26–1.61	0.32
HF death or hospitalization	21	1.30	77	0.65	1.85	1.17–2.93	0.01

CVD indicates cardiovascular disease; HF, heart failure; MI, myocardial infarction; and OH, orthostatic hypotension.

Discussion

In the ACCORD BP trial, consensus OH, defined by a decline in systolic BP ≥20 mm Hg or a decline in diastolic BP ≥10 mm Hg, occurred at ≥1 of the 3 time points in 20% of participants. Independent factors associated with OH were female sex, white race, current smoking, higher baseline systolic BP and hemoglobin A1c, and use of α blockers, β-blockers, and insulin. Of note, neither age nor assignment to intensive versus standard BP treatment goals was associated with OH although dizziness on standing during the examination was slightly more common in the intensive than in the standard group at the 48-month examination. Individuals were less likely to experience OH at 12 or 48 months of follow-up than at baseline. OH based on standing BP measurements was poorly correlated with orthostatic symptoms—only 17% to 20% of those reporting lightheadedness or dizziness on standing at the time of the examination had consensus OH and <10% of those with consensus OH reported dizziness on standing during the examination. Although no significant relationship was found between OH and the combined primary end point of nonfatal MI, nonfatal stroke, cardiovascular death, or its components, OH was associated with higher total mortality and higher rates of heart failure hospitalization and death.

The current findings in a large cohort with T2DM and hypertension share both similarities and noteworthy differences from previous studies examining the epidemiology of OH. Higher rates of OH have been associated with higher systolic BP,^5,7,14,15 which may reflect both exaggerated baroreflex changes and regression to the mean of repeated BP measurements. Alpha adrenergic-blocking drugs reduce BP by arterial vasodilation, which is exacerbated by venodilation on standing; their ability to cause OH is widely recognized.¹⁶ β-blockers have also been associated with OH, likely related to blunting of the compensatory cardioacceleration that occurs on standing.¹⁶ Association of OH with higher hemoglobin A1c and insulin use may reflect more advanced diabetes mellitus, with higher prevalence of later stages of cardiovascular autonomic neuropathy when OH is more likely to occur.¹⁷ In addition, insulin-induced vasodilatation, possibly mediated via endothelium-dependent mechanisms, may also contribute.^18,19 This explanation is further supported by trends for longer duration of diabetes mellitus and higher prevalence of peripheral neuropathy in patients with OH on univariate analysis although both were nonsignificant on multivariable analysis. Higher rates of OH occurrence in women than in men and in whites versus blacks have been previously observed.^20,21

A noteworthy difference between the current findings and previous studies was the lack of increase in OH with age in ACCORD. In epidemiological studies, OH prevalence is generally low in younger patients and increases substantially with age,^5,8,9,14 probably secondary to age-associated autonomic dysfunction. The likely higher prevalence of autonomic dysfunction in the ACCORD cohort with longstanding T2DM plus the upper age cutoff of 80 years for trial eligibility may partially explain the absence of a relationship of OH with age in this study.

The observation that OH incidence was unrelated to assigned BP treatment group intensity and the lower rates of OH on follow-up than at baseline are important and reassuring findings. Although assignment to intensive BP control did not significantly affect the composite primary end point in ACCORD BP, there was a substantial reduction in the annual stroke rate in this group, 0.32% versus 0.52% per year, P=0.01.¹⁰ The current data are, therefore, reassuring that a decision to treat individuals with diabetes mellitus who are at high stroke risk to a lower BP target would not increase the risk of OH. Furthermore, a similar lack of increased OH incidence in nondiabetic individuals at high cardiovascular risk treated to a systolic BP target of 120 mm Hg was shown in SPRINT (Systolic Blood Pressure Intervention Trial), in which mortality and major cardiovascular events were reduced by 25% in patients assigned to this BP target.²²

Our findings that OH was independently associated with increased risk of total mortality and heart failure deaths or hospitalizations have also been observed in previous studies.^7–9,17,18 Increased total mortality in patients with OH was seen in men 71 to 93 years old in the Honolulu Heart Program,⁸ in a general population in Malmo, Sweden,⁷ and in the Hypertension Detection and Follow-up Program.⁹ In the latter study, the association of OH with accelerated mortality was particularly strong in the diabetic subset. A higher rate of heart failure was observed in patients with OH in the predominantly middle-aged ARIC (Atherosclerosis Risk in Communities) cohort²³ and the Cardiovascular Health Study participants of mean age 74 years.²⁴ In contrast with ARIC,⁵ we did not observe an increased stroke risk in patients with OH despite the high-risk profile of ACCORD participants. Although OH was associated with a higher rate of coronary events in previous epidemiological studies,^7–9 the rate of MI was not significantly increased with OH in ACCORD.

The current findings should be interpreted in light of the study’s strengths and limitations. To our knowledge, the ACCORD cohort represents the largest sample of individuals with diabetes mellitus in whom the prevalence and incidence of OH have been reported. The standardized protocol using multiple measurements of seated and standing BP and the detailed participant follow-up and adjudication of cardiovascular events and cause of death are additional study attributes. However, the use of seated BP may have resulted in lower rates of OH than had supine BP been used before standing. Nevertheless, seated BP is more representative of clinical practice. A second limitation was the implementation of standing BP measurements well after the trial began, resulting in a smaller sample with orthostatic BP determination at all 3 time points. Finally, the absence of individuals aged ≥80 years was based on the parent ACCORD Glycemia Trial exclusion criteria, thus eliminating the age group with the highest expected rate of OH.

Perspectives

The prevalence and incidence of consensus OH in this ACCORD cohort with both hypertension and T2DM were relatively high. However, incident OH rate decreased over time and was not related to aggressive versus standard BP target assignment. Factors associated with OH in this setting were white race, female sex, current smoking, higher seated systolic BP and hemoglobin A1c, and use of α blockers, β-blockers, and insulin. Occurrence of OH was an independent marker for total mortality and heart failure death or hospitalization but not for nonfatal MI, stroke, cardiovascular death, or their composite. The current findings are reassuring that a decision to treat high-risk individuals with diabetes mellitus to a lower BP target should not increase the risk of OH.

Novelty and Significance

What Is New?

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In patients 40 to 79 years old with T2DM and hypertension,

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incident OH is not related to age or to intensive versus standard SBP targets.

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In patients 40 to 79 years old with T2DM and hypertension, OH independently predicts total mortality and heart failure death/hospitalization.

What Is Relevant?

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Treatment of elevated SBP to an intensive target of 120 mm Hg does not increase OH.

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However, OH remains a marker for adverse prognosis in this population.

Summary

In patients with T2DM and hypertension, OH was common, not associated with intensive versus standard BP treatment goals, and predicted increased mortality and heart failure events.

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References

Consensus Statement. The definition of orthostatic hypotension, pure autonomic failure and multiple system atrophy. Clin Autonomic Res. 1996;6:125–126.

Abstract

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