Abstract
Background
Current guidelines recommend treating hypertension in patients with peripheral arterial disease (PAD) to reduce the risk of cardiac events and stroke, but the effect of reducing blood pressure on lower extremity PAD events is largely unknown. We investigated the association of blood pressure with lower extremity PAD events using data from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
Methods
ALLHAT investigated the effect of different antihypertensive medication classes (chlorthalidone, amlodipine, lisinopril, or doxazosin) on cardiovascular events. Using these data, the primary outcome in our analysis was time to first lower extremity PAD event, defined as PAD-related hospitalization, procedures, medical treatment, or PAD-related death. Given the availability of longitudinal standardized blood pressure measurements, we analyzed systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP) as time-varying categorical variables (reference categories 120–129 mm Hg for SBP, 70–79 mm Hg for DBP, and 45–54 mm Hg for PP) in separate models. We used extended Cox regression with death as a competing risk to calculate the association of each BP component with PAD events, and report the results as sub-distribution hazard ratios (HR) and 95% confidence intervals (CI).
Results
The present analysis included 33,357 patients with an average age of 67.4 years, 53.1% men, 59.7% white race, and 36.2% with diabetes mellitus. The median baseline blood pressure was 146/84 mm Hg. Participants were followed for a median of 4.3 (IQR 3.6–5.3) years, during which time 1,489 (4.5%) had a lower extremity PAD event, and 4,148 (12.4%) died. In models adjusted for demographic and clinical characteristics, SBP <120 mm Hg was associated with a 26% (CI 5–52%, P=0.015) higher hazard and SBP≥160 mm Hg was associated with a 21% (CI 0–48%, P=0.050) higher hazard for a PAD event, compared with SBP 120–129 mm Hg. In contrast, lower, but not higher, DBP was associated with higher hazard of PAD events: for DBP <60 mm Hg HR = 1.72 (CI 1.38 – 2.16). PP had a U-shaped association with PAD events.
Conclusion
In this re-analysis of data from ALLHAT, we found a higher rate of lower extremity PAD events with higher and lower SBP and PP, and with lower DBP. Given the recent revised blood pressure guidelines advocating lower SBP targets for overall cardiovascular risk reduction, further refinement of optimal blood pressure targets specific to PAD is needed.
Clinical Trial Registration
URL: www.clinicaltrials.gov Unique identifier: NCT00000542
Keywords: Peripheral artery disease, hypertension, low blood pressure
INTRODUCTION
Guidelines recommend treating hypertension in patients with PAD to reduce cardiac events and stroke.1 However, lowering blood pressure (BP) could theoretically decrease perfusion to the distal extremities and exacerbate PAD symptoms such as claudication, rest pain, or even promoting in situ thrombosis.2,3 To date, no randomized clinical trial of blood pressure (BP) targets focused specifically on lower extremity PAD events as the primary outcome of interest, and optimal BP targets for PAD events are unknown.4
Current evidence on this topic comes largely from observational studies. For example, a recent analysis of 4.2 million relatively healthy adults showed a higher risk for incident PAD with each 20-mm Hg increase in systolic blood pressure (SBP) and 10-mm Hg increase in usual diastolic blood pressure (DBP).5 However, among patients of older age in that study, these linear associations were flattened and attenuated. In a separate analysis of men at high risk for cardiovascular disease, SBP had no significant association with incident PAD, and higher DBP was associated with a lower risk of incident PAD.6 That study, as well as other observational studies in high-cardiovascular risk cohorts, was limited by relatively few PAD events.7,8
We sought to investigate the association of SBP, DBP and pulse pressure (PP) with lower extremity PAD events in a large cohort of patients with hypertension and an elevated risk of cardiovascular disease. We conducted an analysis using data from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) to address our objectives.
METHODS
Study Cohort
The data for this study is publicly available from the National Heart, Lung, and Blood Institute. ALLHAT was a randomized, double-blind, multicenter clinical trial designed to investigate the effect of different antihypertensive medication classes (chlorthalidone, amlodipine, lisinopril, or doxazosin) on cardiovascular events.9 From February 1994 to March 2002, ALLHAT recruited patients aged 55 years old or older with baseline hypertension (SBP>140 mm Hg or DBP >90 mm Hg) and at least one other coronary artery disease risk factor (i.e., history of myocardial infarction or stroke, history of coronary artery bypass grafting / angioplasty, diabetes mellitus, high density lipoprotein [HDL] <35 mg/dL, left ventricular hypertrophy or current cigarette smoking). The target SBP was set at <140/90 mm Hg for all participants during the trial. Patients with a history of heart failure, left ventricular ejection fraction < 35%, and/or serum creatinine >2 mg/dL were excluded from recruitment. Because the doxazosin arm was terminated early by the data safety monitoring committee due to an excess of heart failure events,9 we excluded patients randomized to this arm (N=9,067) from the present analysis.
Blood Pressure Measurements
Trained study coordinators measured BP using a mercury sphygmomanometer, after allowing the patient to sit comfortably with feet flat on the floor for five minutes. We calculated the baseline BP by taking an average of all available pre-randomization BP measurements. At each study visit, two BP measurements were taken and averaged, and the averaged BP was recorded as the study visit BP. Study visits were scheduled at 1-, 3-, 6-, 9-, and 12-months after randomization, and thereafter every 4 months for the duration of follow-up. We calculated PP by taking the difference between the average SBP and DBP at each study visit.
Lower Extremity Peripheral Arterial Disease Events
The primary outcome for the present analysis was a lower extremity PAD event, defined as a PAD related hospitalization (with or without a revascularization procedure; documented by hospital discharge summary, procedure sheet or face sheet), PAD related procedures (lower extremity bypass, angioplasty, revascularization, or amputation), outpatient PAD medical treatment (as per the attending physician’s usual care regimen; documented by check box on endpoint questionnaire), or PAD-related death (as documented by hospital discharge summaries and death certificates). For patients with multiple events during the study period, the first event was analyzed as the event of interest. Each PAD event was based on clinic investigator reports, and 99% of inpatient events had documentation in the form of a death certificate or hospital discharge summary. We conducted a sensitivity analysis limiting the PAD event definition to PAD-related hospitalization or PAD-related procedures only, to align with the secondary outcome definition in the original ALLHAT report.
Statistical Analysis
We used three separate regression models for SBP, DBP and PP, respectively, as the independent variable. Because we hypothesized a priori that there may be non-linear associations with outcomes, we categorized SBP into the following six categories (in mm Hg): <120, 120–129 (reference category), 130–139, 140–149, 150–159, ≥160. Similarly, we categorized DBP into the following six categories (in mm Hg): <60, 60–69, 70–79 (reference category), 80–89, 90–99, ≥100. We categorized PP into the following five categories (in mm Hg): <45, 45–54 (reference category), 55–64, 65–74, ≥75.
We used all available BP values recorded prior to the PAD event, and analyzed the BP component as a time-varying variable. We used extended Cox proportional hazards regression to calculate the sub-distribution hazard ratios for PAD events, with robust standard errors accounting for clustering of BP measurements within subjects, and modeling death as a competing risk. Multivariable models were adjusted for age, sex, race, ethnicity, body mass index, smoking status, history of coronary heart disease, history of myocardial infarction or stroke, history of coronary revascularization, history of atherosclerosis (defined as intermittent claudication, gangrene, ischemic ulcers, carotid stenosis, Ankle-arm index <0.9, abdominal aortic aneurysm, or carotid or femoral bruits), history of major electrocardiogram changes, type 2 diabetes mellitus, presence of high density lipoprotein < 35 mg/dL, aspirin use, number of antihypertensive medications at enrollment, and study randomization group. Of note, baseline PAD status, which was part of the definition of a history of atherosclerosis, was not documented as a separate condition in the ALLHAT dataset. We tested the proportionality assumption using log-log plots and regressing Schoenfeld residuals against time for all covariates and did not note any significant violations. We present results as hazard ratios (HR) and 95% confidence intervals (CI).
We evaluated whether age, smoking status and diabetes mellitus modified the association of the BP component with PAD events by including a multiplicative interaction term in each of the relevant models.
Because different SBP and DBP values can generate similar PP, we conducted an exploratory analysis to create a visual representation of the association of SBP and DBP simultaneously with PAD events. The HR for PAD events were calculated in comparison to a reference value reflecting the median hazard of patients with SBP 120–129 mmHg and DBP 70–79 mmHg. A density plot of the individual hazard ratios in relation to BP recordings from the trial period was then constructed. We overlaid a similar density plot of the frequency with which individual BP values were observed during the trial (Supplemental Figure 1).
Stata version 15 (Stata Corp, College Station, TX) was used for statistical analyses. Findings were considered significant if a P-value was < 0.05. The study was reviewed by a Stanford University Institutional Review Board and determined that it did not require further review or informed consent due to the de-identified nature of publicly available dataset.
RESULTS
A total of 33,357 patients with hypertension at high-risk for cardiovascular disease were included in the analysis. At baseline, the median SBP was 146 mm Hg (interquartile range [IQR] 137 – 155 mm Hg), median DBP was 84 mm Hg (IQR 78–90 mm Hg), and median PP was 61.5 mm Hg (53.5–70 mm Hg; Figure 1). The mean age at baseline was 67.4 years and 53.1% were men. After a median follow-up of 4.3 years (IQR 3.6–5.3 years) representing 140,418 patient-years, 1489 patients (4.5%) had a lower extremity PAD event and there were 4,148 (12.4%) non-PAD related deaths.
Figure 1. Blood pressure measurements from baseline through follow-up.
Box and whisker plot of systolic blood pressure (top), diastolic blood pressure (middle), and pulse pressure (bottom) from year 0 (randomization) through follow-up. Line within the box represents the median value while length of the box represents the interquartile range. Whiskers extend to 1.5 x the interquartile range.
Systolic Blood Pressure
Patients with lower baseline SBP were more often men and had a higher prevalence of smoking and coronary heart disease than patients with higher baseline SBP (Table 1). We found a higher hazard of lower extremity PAD events with lower and higher categories of SBP (Figure 2). For example, SBP <120 mm Hg was associated with a 26% (CI 5% to 52%, P=0.015) higher adjusted hazard and SBP ≥160 mm Hg was associated with a 21% (CI 0% to 48%, P=0.050) higher adjusted hazard of a lower extremity PAD event, compared with the reference category of SBP 120–129 mm Hg. Having a history of cardiovascular disease or diabetes mellitus was associated with higher rates of PAD events, while the randomized treatment group (chlorthalidone, amlodipine or lisinopril) had no association with PAD events (Supplemental Table 1). We found no evidence of significant interaction on the association of SBP with PAD events by patient age, smoking status, or diabetes mellitus (P for interaction = 0.65, 0.58, 0.42 respectively).
Table 1. Baseline demographics and clinical risk factors by baseline systolic blood pressure.
SBP: systolic blood pressure; MI: myocardial infarction; ECG: electrocardiogram
| BASELINE SBP (MM HG) | ||||||
|---|---|---|---|---|---|---|
| <120 (n=1036) | 120–129 (n=2988) | 130–139 (n=6,298) | 140–149 (n=9,591) | 150–159 (n=8,793) | ≥160 (n=4,651) | |
| AGE, YEARS, MEAN (SD) | 65.7 (7.3) | 66.0 (7.5) | 66.9 (7.5) | 67.2 (7.6) | 68.1 (7.8) | 68.1 (7.9) |
| MALE SEX | 631 (60.9) | 1,727 (57.8) | 3,427 (54.4) | 5,073 (52.9) | 4,522 (51.4) | 2,339 (50.3) |
| RACE | ||||||
| WHITE | 594 (57.4) | 1,776 (59.4) | 3,715 (59.0) | 5,814 (60.6) | 5,332 (60.6) | 2,693 (57.9) |
| BLACK | 392 (37.8) | 1,068 (35.7) | 2,252 (35.8) | 3,311 (34.5) | 3,038 (34.6) | 1,729 (37.2) |
| OTHER | 50 (4.8) | 144 (4.8) | 331 ( 5.3) | 466 (4.9) | 423 (4.8) | 229 (4.9) |
| BMI, KG/M2, MEAN (SD) | 29.3 (5.9) | 29.7 (5.9) | 29.6 (5.8) | 29.7 (5.9) | 29.5 (5.9) | 29.2 (6.0) |
| SMOKER | ||||||
| NEVER | 331 (32.0) | 1,027 (34.4) | 2,366 (37.6) | 3,644 (38.0) | 3,428 (39.0) | 1,809 (38.9) |
| CURRENT | 252 (24.3) | 698 (23.4) | 1,307 (20.8) | 2,092 (21.8) | 1,856 (21.1) | 1,098 (23.6) |
| PAST | 453 (43.7) | 1,263 (42.3) | 2,625 (41.7) | 3,855 (40.2) | 3,509 (39.9) | 1,743 (37.5) |
| HISTORY OF: | ||||||
| CORONARY HEART DISEASE | 329 (32.3) | 805 (27.4) | 1,615 (26.0) | 2,369 (25.0) | 2,150 (24.7) | 1,135 (24.6) |
| MI OR STROKE | 312 (30.1) | 723 (24.2) | 1,520 (24.1) | 2,192 (22.9) | 1,998 (22.7) | 995 (21.4) |
| CORONARY REVASCULARIZATION | 195 (18.8) | 434 (14.5) | 852 (13.5) | 1,208 (12.6) | 1,145 (13.0) | 476 (10.2) |
| OTHER ATHEROSCLEROSIS | 270 (26.1) | 716 (24.0) | 1,517 (24.1) | 2,258 (23.5) | 2,046 (23.3) | 1,094 (23.5) |
| MAJOR ECG CHANGES | 94 (9.2) | 307 (10.4) | 620 (10.0) | 969 (10.2) | 876 (10.1) | 554 (12.0) |
| TYPE 2 DIABETES MELLITUS | 350 (33.8) | 1,025 (34.3) | 2,315 (36.8) | 3,493 (36.4) | 3,255 (37.0) | 1,625 (34.9) |
| HDL<35 MG/DL | 151 (14.6) | 424 (14.2) | 862 (13.7) | 1,155 (12.0) | 941 (10.7) | 344 (7.4) |
| ASPIRIN USE | 453 (43.7) | 1,145 (38.3) | 2,344 (37.2) | 3,389 (35.3) | 3,101 (35.3) | 1,520 (32.7) |
| ON ANTIHYPERTENSIVE MEDICATION AT BASELINE | 1,016 (98.1) | 2,927 (98.0) | 6,125 (97.3) | 8,788 (91.6) | 7,579 (86.2) | 3,312 (71.2) |
| SBP, MEAN (SD) | 123.9 (8.9) | 129.8 (8.3) | 134.6 (8.4) | 139.0 (8.9) | 143.7 (9.8) | 149.5 (11.7) |
| DBP, MEAN (SD) | 75.6 (6.6) | 77.5 (6.6) | 78.8 (6.7) | 79.8 (7.0) | 80.5 (7.5) | 82.1 (8.2) |
| PP, MEAN (SD) | 48.4 (8.6) | 52.3 (8.4) | 55.8 (8.9) | 59.2 (9.2) | 63.2 (10.0) | 67.4 (10.9) |
| RANDOMIZATION GROUP | ||||||
| CHLORTHALIDONE | 458 (44.2) | 1,382 (46.3) | 2,917 (46.3) | 4,373 (45.6) | 4,043 (46.0) | 2,082 (44.8) |
| AMLODIPINE | 296 (28.6) | 792 (26.5) | 1,723 (27.4) | 2,592 (27.0) | 2,385 (27.1) | 1,260 (27.1) |
| LISINOPRIL | 282 (27.2) | 814 (27.2) | 1,658 (26.3) | 2,626 (27.4) | 2,365 (26.9) | 1,309 (28.1) |
Figure 2. PAD event hazard ratios of individual blood pressure categories.
Association of categories of systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) with lower extremity peripheral arterial disease events. Results reported as hazard ratios (HR) with 95% confidence interval (CI) with death as a competing risk. Models adjusted for age, sex, race, BMI, smoking status, ECG changes, prior MI/stroke/revascularization/atherosclerosis, diabetes mellitus, HDL < 35 mg/dL, aspirin use, number of anti-hypertensive medications, and randomization group. Co-variates are shown in Supplemental Tables 1–3.
Diastolic Blood Pressure
Patients with lower baseline DBP were older and had a higher prevalence of smoking and coronary heart disease than patients with higher baseline DBP (Table 2). In contrast to the U-shaped association of SBP with lower extremity PAD events, lower DBP was associated with higher hazard of PAD events (Figure 2, Supplemental Table 2). For example, DBP <60 mm Hg was associated with a 72% (CI 38% to 116%, P<0.001) higher hazard of a lower extremity PAD event, while higher DBP had point estimates suggesting lower hazards, although these estimates did not always meet statistical significance. We found no evidence of significant interaction by patient age, smoking status, or diabetes mellitus (P for interaction = 0.19, 0.16, 0.20 respectively).
Table 2. Baseline demographics and clinical risk factors by baseline diastolic blood pressure.
DBP: diastolic blood pressure; MI: myocardial infarction; ECG: electrocardiogram
| BASELINE DBP (MM HG) | ||||||
|---|---|---|---|---|---|---|
| <60 (n=226) | 60–69 (n=2,015) | 70–79 (n=8,109) | 80–89 (n=13,841) | 90–99 (n=8,146) | ≥100 (n=1,020) | |
| AGE, YEARS, MEAN (SD) | 72.1 (7.8) | 72.1 (7.8) | 68.9 (7.7) | 67.3 (7.5) | 65.4 (7.3) | 63.7 (6.9) |
| MALE SEX | 127 (56.2) | 1,038 (51.5) | 4,195 (51.7) | 7,370 (53.3) | 4,418 (54.2) | 571 (56.0) |
| RACE | ||||||
| WHITE | 147 (65.0) | 1,291 (64.1) | 5,081 (62.7) | 8,351 (60.3) | 4,552 (55.9) | 502 (49.2) |
| BLACK | 70 (30.1) | 605 (30.0) | 2,615 (32.3) | 4,839 (35.0) | 3,183 (39.1) | 478 (46.9) |
| OTHER | 9 (4.0) | 119 (5.9) | 413 (5.1) | 651 (4.7) | 411 (5.0) | 40 (3.9) |
| BMI, KG/M2, MEAN (SD) | 28.8 (5.5) | 28.8 (5.5) | 29.1 (5.7) | 29.7 (5.9) | 29.9 (6.0) | 30.2 (6.0) |
| SMOKER | ||||||
| NEVER | 58 (25.6) | 721 (35.8) | 3,001 (37.0) | 5,328 (38.5) | 3,114 (38.2) | 383 (37.6) |
| CURRENT | 44 (19.5) | 371 (18.4) | 1,589 (19,6) | 2,917 (21.1) | 2,079 (25.5) | 303 (29.7) |
| PAST | 124 (54.9) | 923 (45.8) | 3,519 (43.4) | 5,595 (40.4) | 2,953 (36.3) | 334 (32.8) |
| HISTORY OF: | ||||||
| CORONARY HEART DISEASE | 70 (31.8) | 659 (33.3) | 2,317 (29.0) | 3,449 (25.2) | 1,698 (21.0) | 210 (20.8) |
| MI OR STROKE | 48 (21.2) | 560 (27.8) | 2,035 (25.1) | 3,270 (23.6) | 1,640 (20.1) | 187 (18.3) |
| CORONARY REVASCULARIZATION | 54 (23.9) | 405 (20.1) | 1,347 (16.6) | 1,752 (12.7) | 677 (8.3) | 75 (7.4) |
| OTHER ATHEROSCLEROSIS | 81 (35.8) | 601 (29.8) | 2,089 (25.8) | 3,194 (23.1) | 1,741 (21.4) | 195 (19.1) |
| MAJOR ECG CHANGES | 23 (10.5) | 196 (9.9) | 799 (10.0) | 1,400 (10.2) | 867 (10.7) | 135 (13.4) |
| TYPE 2 DIABETES MELLITUS | 98 (43.4) | 911 (45.2) | 3,257 (40.2) | 5,080 (36.7) | 8,146 (30.3) | 250 (24.5) |
| HDL<35 MG/DL | 25 (11.1) | 223 (11.1) | 1,007 (12.4) | 1,664 (12.0) | 880 (10.8) | 78 (7.7) |
| ASPIRIN USE | 104 (46.0) | 935 (46.4) | 3,259 (40.2) | 4,961 (35.8) | 2,463 (30.2) | 230 (22.6) |
| ON ANTIHYPERTENSIVE MEDICATION AT BASELINE | 220 (97.3) | 1,937 (96.1) | 7,658 (94.4) | 12,720 (91.9) | 6,588 (80.9) | 624 (61.2) |
| SBP, MEAN (SD) | 137.9 (13.7) | 136.9 (12.1) | 137.7 (11.4) | 139.2 (10.8) | 141.7 (10.9) | 147.0 (12.6) |
| DBP, MEAN (SD) | 64.4 (6.7) | 69.6 (5.6) | 75.2 (5.3) | 80.3 (5.3) | 85.0 (6.0) | 90.2 (7.1) |
| PP, MEAN (SD) | 73.5 (15.1) | 67.4 (12.4) | 62.5 (11.1) | 58.9 (10.0) | 56.7 (9.1) | 56.7 (9.2) |
| RANDOMIZATION GROUP | ||||||
| CHLORTHALIDONE | 106 (46.9) | 899 (44.6) | 3,721 (45.9) | 6,366 (46.0) | 3,706 (45.5) | 457 (44.8) |
| AMLODIPINE | 65 (28.8) | 585 (29.0) | 2,189 (27.0) | 3,720 (26.9) | 2,208 (27.1) | 281 (27.6) |
| LISINOPRIL | 55 (24.3) | 531 (26.4) | 2,199 (27.1) | 3,755 (27.1) | 2,232 (27.4) | 282 (27.6) |
Pulse Pressure
Patients with higher baseline PP were older, less often men, and had a higher prevalence of diabetes mellitus (Table 3). We observed higher hazards for lower extremity PAD events at lower and higher PP (Figure 2, Supplemental Table 3). We found no evidence of significant interaction by patient age, or smoking status (P for interaction = 0.46, 0.81, respectively), but did find a marginally significant interaction by diabetes mellitus (P for interaction = 0.04). The association of PP with PAD events was significant for patients without diabetes mellitus, but attenuated for patients with diabetes mellitus (Supplemental Table 4).
Table 3. Baseline demographics and clinical risk factors by baseline pulse pressure.
PP: pulse pressure; MI: myocardial infarction; ECG: electrocardiogram
| VARIABLE | |||||
|---|---|---|---|---|---|
| Baseline PP (mm Hg) | |||||
| <45 (n=2,445) | 45–54 (n=6,880) | 55–64 (n=10,666) | 65–74 (n=8,494) | ≥75 (n=4,872) | |
| AGE, YEARS, MEAN (SD) | 63.9 (6.7) | 65.3 (7.2) | 66.9 (7.5) | 68.6 (7.6) | 70.9 (7.7) |
| MALE SEX | 1526 (62.4) | 3844 (55.9) | 5611 (52.6) | 4373 (51.5) | 2365 (48.5) |
| RACE | |||||
| WHITE | 1332 (54.5) | 3954 (57.5) | 6305 (59.1) | 5233 (61.6) | 3100 (63.6) |
| BLACK | 1002 (41.0) | 2601 (37.8) | 3829 (35.9) | 2832 (33.3) | 1526 (31.3) |
| OTHER | 111 (4.5) | 325 (4.7) | 532 (4.99) | 429 (5.1) | 246 (5.1) |
| BMI, KG/M2, MEAN (SD) | 29.9 (6.0) | 29.9 (5.9) | 29.7 (5.9) | 29.4 (5.9) | 28.7 (5.8) |
| SMOKER | |||||
| NEVER | 818 (33.5) | 2481 (36.1) | 4200 (39.4) | 3247 (38.2) | 1858 (38.1) |
| CURRENT | 644 (26.3) | 1668 (24.2) | 2299 (21.6) | 1748 (20.6) | 944 (19.4) |
| PAST | 983 (40.2) | 2731 (36.7) | 4166 (39.1) | 3499 (41.2) | 2069 (42.5) |
| HISTORY OF: | |||||
| CORONARY HEART DISEASE | 595 (24.7) | 1619 (23.9) | 2610 (24.7) | 2236 (26.6) | 1343 (27.9) |
| MI OR STROKE | 570 (23.3) | 1570 (22.8) | 2476 (23.2) | 1980 (23.3) | 1144 (23.5) |
| CORONARY REVASCULARIZATION | 294 (12.0) | 810 (11.8) | 1249 (11.7) | 1165 (13.7) | 792 (16.3) |
| OTHER ATHEROSCLEROSIS | 531 (21.7) | 1539 (22.4) | 2530 (23.7) | 2002 (23.6) | 1299 (26.7) |
| MAJOR ECG CHANGES | 240 (10.0) | 680 (10.0) | 1101 (10.4) | 894 (10.6) | 505 (10.5) |
| TYPE 2 DIABETES MELLITUS | 675 (27.6) | 2237 (32.5) | 3835 (36.0) | 3308 (39.0) | 2008 (41.2) |
| HDL<35 MG/DL | 369 (15.1) | 927 (13.5) | 1259 (11.8) | 884 (10.4) | 438 (9.0) |
| ASPIRIN USE | 883 (36.1) | 2358 (34.3) | 3679 (34.5) | 3095 (36.4) | 1937 (39.8) |
| ON HYPERTENSIVE MEDICATION AT BASELINE | 2,445 (95.6) | 6,880 (93.3) | 9,684 (90.8) | 7,335 (86.4) | 3,973 (81.5) |
| SBP, MEAN (SD) | 128.5 (9.3) | 134.2 (9.1) | 139.0 (9.8) | 143.2 (10.4) | 147.7 (11.3) |
| DBP, MEAN (SD) | 82.0 (6.4) | 81.5 (6.7) | 80.9 (7.1) | 79.1 (7.3) | 75.1 (7.6) |
| PP, MEAN (SD) | 46.5 (7.0) | 52.7 (6.7) | 58.1 (7.2) | 64.2 (8.2) | 72.6 (10.1) |
| RANDOMIZATION GROUP | |||||
| CHLORTHALIDONE | 1,096 (44.8) | 3,160 (45.9) | 4,898 (45.9) | 3,918 (46.1) | 2,183 (44.8) |
| AMLODIPINE | 654 (26.8) | 1,871 (27.2) | 2,894 (27.1) | 2,301 (27.1) | 1,328 (27.3) |
| LISINOPRIL | 695 (28.4) | 1,849 (26.9) | 2,874 (27.0) | 2,275 (26.8) | 1,361 (27.9) |
Sensitivity Analyses
Results were not materially changed when we repeated our analyses using the more restrictive ALLHAT secondary outcome definition for PAD events (PAD related hospitalization or procedures) (Supplemental Figure 2).
Simultaneous Evaluation of Systolic and Diastolic Blood Pressure
We evaluated the association of SBP and DBP simultaneously with lower extremity PAD events using 120–129/70–79 mm Hg as the reference (Figure 3A). For any given SBP, lower DBP was associated with higher hazards for a PAD event (Figure 3B, rows), while for any given DBP, higher and lower SBPs correspond with higher hazards for a PAD event (Figure 3B, columns).
Figure 3. PAD event hazard ratios of simultaneous systolic and diastolic blood pressure measurements.
(A) Models evaluating the association of systolic and diastolic blood pressure simultaneously with the risk of a lower extremity PAD event, reported as hazard ratios (HR). The reference category is set at 120–129/70–79 mm Hg (hazard ratio = 0.9 to 1.1) and is shown in white, with higher hazards (> 1.1) shown in red and lower hazard (<0.9) shown in blue. The figure is overlaid with density plot of blood pressure measurement frequency, with darker areas indicating less frequent readings and brighter areas indicating more frequent readings. (B) Examples of blood pressure measurements with corresponding HR for a lower extremity PAD event.
DISCUSSION
In patients with hypertension at high risk for cardiovascular events enrolled in ALLHAT, we found a U-shaped association of SBP with PAD events. Specifically, SBP <120 mm Hg was associated with a 26% higher rate of lower extremity PAD, while SBP ≥ 160 mm Hg was associated with a 21% higher rate of lower extremity PAD events (compared with SBP 120–129 mm Hg). We also found that lower DBP (<70 mm Hg), but not higher DBP, was associated with higher rates of lower extremity PAD events. Correspondingly, lower and higher PP was also associated with higher rates of PAD events.
Our results contrast with two large cohort studies that showed a linear increase in the risk of incident PAD with higher SBP and DBP, without a higher risk with lower SBP or DBP.5,10 Differences in our findings likely stem from the fact that those studies were conducted in relatively healthy cohorts of patients without a history of cardiovascular disease, whereas ALLHAT specifically recruited patients with known hypertension and at least one additional cardiovascular risk factor, including prevalent PAD. Additionally, the lowest range of DBP investigated in those studies was 65–70 mm Hg, whereas our study investigated DBP < 60 mm Hg.
Similar to our results showing higher rates of PAD with lower DBP, in a study of 7529 men at high risk for cardiovascular disease enrolled in the Multiple Risk Factor Intervention Trial (MRFIT)6, higher DBP was associated with a lower risk of incident PAD (OR 0.99, P=0.003). Lowering DBP below a certain threshold in patients with cardiovascular risk factors may increase the risk of coronary events and with mortality in older patients, described as a “U” or “J-curve” association.11–18 Our results extend these findings to also include PAD events.
The mixed results depending on the relative health of the cohorts may reflect the fact that lower DBP, and the resultant higher PP, may be a marker for vascular stiffness. Commonly seen in patients at higher risk for cardiovascular events (e.g. older patients, patients with hypertension, diabetes or chronic kidney disease), vascular stiffness is associated with numerous adverse events, including PAD events.19–23 The study by Rapsomaniki et al confirms the association between PAD and elevated PP, where higher PP was associated with higher risk of PAD compared to eleven other cardiovascular outcomes (HR per 10 mm Hg 1.23 [CI 1.20–1.27]).10
Another possible explanation for our observed association between lower DBP and higher rates of PAD events may be due to the relative importance of lower extremity perfusion during diastole. In healthy individuals, SBP increases by 50–70 mm Hg during exercise, while the DBP shows only minor changes; however, in patients with hypertension, DBP increases during exercise to a greater degree due to the inability to adequately reduce peripheral resistance.24 Therefore, in the setting of PAD, where systolic flows are dampened by atherosclerotic disease in the lower extremities, perfusion becomes more dependent on DBP during exercise. In support of this theory, one study showed PAD being the only cardiovascular event that had a lower associated risk at higher mean arterial pressure (HR per 10 mm Hg 0.90 [CI 0.86, 0.94]), which is largely determined by DBP.10 Finally, because coronary perfusion occurs during diastole, patients with lower DBP may experience exertional angina that limits their exercise capacity, which may in turn increase the risk for a lower extremity PAD event.
It is also possible that intentionally lowering SBP and DBP to reduce the risk of cardiac and stroke events reduces lower extremity perfusion, leading to more PAD events. In the Systolic Blood Pressure Intervention Trial (SPRINT)25, participants randomized to an intensive SBP target of <120 mm Hg (versus a standard SBP target of <140 mm Hg) had a 25% lower rate of fatal and non-fatal cardiovascular events, including PAD events; moreover, intensive SBP control was as effective among patients in the lowest quintile of baseline DBP (<68 mm Hg) as in the highest quintile.26 However, in SPRINT there were too few PAD events to analyze the effect of intensive SBP control on these outcomes separately. To date, no randomized clinical trial of different BP targets has been powered to examine PAD events specifically.
Some recent studies have demonstrated a higher risk for lower extremity amputation with one of the sodium-glucose cotransporter 2 (SGLT-2) inhibitors27,28, canagliflozin, and although this association requires further confirmation, one potential concern is the risk of volume depletion on subsequent PAD events. In the original ALLHAT report, randomization to chlorthalidone, amlodipine or lisinopril had no significant effect on the occurrence of PAD events.9 Similarly, in our analysis we showed no association of randomized treatment group with PAD events when including the various BP components of interest. Piller et al29 in a separate post hoc analysis using ALLHAT data, also found no differences in PAD events when comparing chlorthalidone to amlodipine or lisinopril. Future studies are needed to elucidate the most appropriate pharmacotherapy, along with optimal BP levels to reduce PAD events in high risk patients.
Our analysis has several strengths. First, in ALLHAT, BP was carefully measured in duplicate according to guideline-recommended protocols. We were also able to leverage longitudinal BP measurements throughout the duration of follow-up. Second, PAD events in ALLHAT were defined by the treating clinician with hospital discharge summaries and/or death certificates in 99% of inpatient cases. Finally, given the large size of our relatively high-risk cohort with over 140,000 patient-years of follow-up, we were able to capture over one thousand PAD events, significantly more than many prior studies9.
However, there are also some limitations to our study. First, ALLHAT did not ascertain baseline PAD as a separate comorbid condition, including it instead as part of the “other atherosclerosis” definition. Although we included this variable in our adjusted models, we could not examine incident vs. recurrent PAD events separately. Second, ALLHAT did not capture asymptomatic PAD or the reasons for lower extremity revascularization (e.g. claudication vs. critical limb ischemia, and we were thus unable to examine the association of BP components with a more granular stratification of lower extremity PAD events. Third, as PAD events were a secondary outcome, the trial did not rigorously confirm these findings in the same manner as the primary outcome of cardiac events. Given the heterogeneity in PAD event definition among different studies, future investigations should include standardized protocols for PAD event ascertainment.30–32 Finally, as with any observational study, the associations observed among SBP, DBP and PP and lower extremity PAD event are not necessarily causal and could still be affected by residual confounding.
Conclusions
In this re-analysis of ALLHAT, we show a higher rate of lower extremity PAD events with higher and lower SBP and PP, and with lower DBP. The 2017 ACC/AHA blood pressure guidelines advocate a target BP of <130/80 mm Hg for nearly all patients with hypertension for overall cardiovascular risk reduction,33 and our results suggest that this BP target may not be optimal with regard to lower extremity PAD events. Future studies are needed to refine BP targets for prevention of lower extremity PAD events.
Supplementary Material
Clinical Perspective.
What is new?
In this re-analysis of data from ALLHAT, systolic blood pressure <120 mm Hg and ≥160 mm Hg were associated with significantly higher rates of peripheral arterial disease (PAD) events, defined as revascularization, hospitalization, or medical treatment for PAD.
Diastolic blood pressure <70 mm Hg and pulse pressure ≥65 mm Hg were also associated with increased rates of PAD events
What are the clinical implications?
Given lower blood pressure targets in recent guidelines, further studies are needed to evaluate optimal blood pressure targets with specific regard to lower extremity PAD events
In particular, further investigation is needed to evaluate patients with lower systolic and diastolic blood pressure to reduce PAD events.
Acknowledgments
This Manuscript was prepared using ALLHAT Research Materials obtained from the NHLBI Biologic Specimen and Data Repository Information Coordinating Center and does not necessarily reflect the opinions or views of the ALLHAT or the NHLBI.
Sources of Funding: The project was conducted with support from the TL1 component of the Stanford Clinical and Translational Science Award to Spectrum (NIH TL1 TR 001084). Dr. Chang is supported by grants from the NIH/National Institute of Diabetes and Digestive Kidney Diseases (K23DK095914, R03DK113341).
Footnotes
Disclosures:
None
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