Effect of Blood Pressure Lowering Medications on Leg Ischemia in Peripheral Artery Disease Patients: A Meta-Analysis of Randomized Controlled Trials

PAD has increased 25% in less than 20 years and about 4%/year of patients with PAD will die from cardiovascular events. Treatment of hypertension in patients decreases the risk of cardiovascular events by 20 to 30%. Whether blood pressure treatment impacts leg ischemia is somewhat debated. The authors undertook this systematic review/meta-analysis to assess if antihypertensive medications worsen leg ischemia in PAD patients. The meta-analysis follows the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines and the protocol developed was published. A systematic search was performed to identify placebo controlled randomized trials evaluating the effects of antihypertensive medications on three recognized measures of the severity of leg ischemia including ankle brachial pressure index (ABPI), maximum walking distance (MWD) and pain free walking distance (PFWD) in patients with intermittent claudication. The study quality was determined by using the validated CONSORT checklist and the Cochrane collaboration tool. A meta-regression evaluated whether the effect of the antihypertensive medications on mean arterial pressure (MAP) was associated with changes in ABPI, MWD or PFWD. Search of Cochrane sources, Web of Science, PubMed, Scopus and Science direct found 11,434. Thirty-nine full-text articles were assessed for eligibility with five randomized controlled trials found available with the data required for analysis. The quality of four studies was high and one moderate. Eggers test and funnel plots suggested no publication bias. Heterogeneity across studies was high. The follow-up period was generally short with three studies having a follow-up period of ≤ 6 weeks. Meta-analysis suggested that antihypertensive had no significant effect on ABPI [standardized mean difference (SMD) = −0.151 (95% confidence interval [CI], −0.425 ± 0.123)], MWD [SMD = −0.155 (95% CI, −0.617 ± 0.306)] or PFWD [d = −0.013 (95% CI, −0.342 ± 0.316)]. The findings were similar in sub-group analyses that assessed treatment periods of > 1 or < 1 month. A subgroup analysis to determine whether ACE inhibitors had an effect on leg ischemia demonstrated no significant effect on either MWD (SMD = −0.164; 95% CI, −0.642 ± 0.314) or PFWD (SMD = −0.214; 95% CI −0.663 ± 0.236). In contrast, meta-regression analysis showed that the reduction in MAP due to the antihypertensive drugs was positively correlated with increased MWD during follow-up (β regression coefficient = 8.371; P = .035) but not PFWD or ABPI (PFWD, β = 4.276; P = .195; ABPI, β = −0.004; P = .035). Several challenges regarding analysis were noted by the authors: a cross-over study had no wash out period, to determine an effect in patients with claudication should have at least 6 months of follow-up, only two studies attained blood pressure goals, and the studies were performed in differing risk populations using various antihypertensive medications.