Characteristics and long-term follow-up of participants with peripheral arterial disease during ALLHAT

Abstract

Background: Hypertension is a major risk factor for peripheral artery disease (PAD). Little is known about relative efficacy of antihypertensive treatments for preventing PAD.

Objectives: To compare, by randomized treatment groups, hospitalized or revascularized PAD rates and subsequent morbidity and mortality among participants in the Antihypertensive and Lipid-Lower Treatment to Prevent Heart Attack Trial (ALLHAT).

Design: Randomized, double-blind, active-control trial in high-risk hypertensive participants.

Participants: Eight hundred thirty participants with specified secondary outcome of lower extremity PAD events during the randomized phase of ALLHAT.

Interventions/events: In-trial PAD events were reported during ALLHAT (1994-2002). Post-trial mortality data through 2006 were obtained from administrative databases. Mean follow-up was 8.8 years.

Main measures: Baseline characteristics and intermediate outcomes in three treatment groups, using the Kaplan-Meier method to calculate cumulative event rates and post-PAD mortality rates, Cox proportional hazards regression model for hazard ratios and 95 % confidence intervals, and multivariate Cox regression models to examine risk differences among treatment groups.

Key results: Following adjustment for baseline characteristics, neither participants assigned to the calcium-channel antagonist amlodipine nor to the ACE-inhibitor lisinopril showed a difference in risk of clinically advanced PAD compared with those in the chlorthalidone arm (HR, 0.86; 95 % CI, 0.72-1.03 and HR, 0.98; 95 % CI, 0.83-1.17, respectively). Of the 830 participants with in-trial PAD events, 63 % died compared to 34 % of those without PAD; there were no significant treatment group differences for subsequent nonfatal myocardial infarction, coronary revascularizations, strokes, heart failure, or mortality.

Conclusions: Neither amlodipine nor lisinopril showed superiority over chlorthalidone in reducing clinically advanced PAD risk. These findings reinforce the compelling need for comparative outcome trials examining treatment of PAD in high-risk hypertensive patients. Once PAD develops, cardiovascular event and mortality risk is high, regardless of type of antihypertensive treatment.

Trial registration: ClinicalTrials.gov NCT00000542.

Figure 1

Consort diagram for participants who developed hospitalized or treated PAD (revascularization procedure or hospitalized) during the randomized phase of ALLHAT and were eligible for long-term mortality follow-up. ^*Wilcoxon test for the equality of survival function probability values are: amlodipine vs. chlorthalidone P = 0.099; lisinopril vs. chlorthalidone P = 0.915.

Figure 2

Years to peripheral arterial disease.

Figure 3

Peripheral arterial disease by treatment group comparisons and subgroups. No significant treatment × subgroup interactions were identified. Interaction P values are as follows: Amlodipine vs. chlorthalidone: age, P = 0.421; gender, P = 0.385; race, P = 0.737; history of CHD, P = 0.120; history of diabetes, P = 0.093. Lisinopril vs. chlorthalidone: age, P = 0.408; gender, P = 0.239; race, P = 0.603; history of CHD, P = 0.704; history of diabetes, P = 0.040. Peripheral arterial disease refers to in-trial hospitalization or lower extremity revascularization procedure.

Figure 4

Post-peripheral arterial disease all-cause mortality by treatment group.