Treatment of hypertension in peripheral arterial disease

BACKGROUND: Peripheral arterial disease (PAD) causes considerable morbidity and mortality. Hypertension is a risk factor for PAD. Treatment for hypertension must be compatible with the symptoms of PAD. Controversy regarding the effects of beta-adrenoreceptor blockade for hypertension in patients with PAD has led many physicians to stop prescribing beta-adrenoreceptor blockers. Little is known about the effects of other classes of anti-hypertensive drugs in the presence of PAD. This is the second update of a Cochrane review first published in 2003.

OBJECTIVES: To determine the effects of anti-hypertensive drugs in patients with both raised blood pressure and symptomatic PAD in terms of the rate of cardiovascular events and death, symptoms of claudication and critical leg ischaemia, and progression of atherosclerotic PAD as measured by ankle brachial index (ABI) changes and the need for revascularisation (reconstructive surgery or angioplasty) or amputation.

SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Cochrane Peripheral Vascular Diseases Group Specialised Register (last searched March 2013) and CENTRAL (2013, Issue 2).

SELECTION CRITERIA: Randomised controlled trials (RCTs) of at least one anti-hypertensive treatment against placebo or two anti-hypertensive medications against each other, with interventions lasting at least one month. Trials had to include patients with symptomatic PAD.

DATA COLLECTION AND ANALYSIS: Data were extracted by one author (DAL) and checked by the other (GYHL). Potentially eligible studies were excluded when the results presentation prevented adequate extraction of data and enquiries to authors did not yield raw data.

MAIN RESULTS: Eight RCTs were included with a total of 3610 PAD patients. Four studies compared a recognised class of anti-hypertensive treatment with placebo and four studies compared two anti-hypertensive treatments with each other. Studies were not pooled due to the variation of the comparisons and the outcomes presented. Overall the quality of the available evidence was unclear, primarily as a result of a lack of detail in the study reports on the randomisation and blinding procedures and incomplete outcome data. Two studies compared angiotensin converting enzyme (ACE) inhibitors against placebo. In one study there was a significant reduction in the number of cardiovascular events in patients receiving ramipril (odds ratio (OR) 0.72, 95% confidence interval (CI) 0.58 to 0.91; n = 1725). In the second trial using perindopril (n = 52) there was a marginal increase in claudication distance but no change in ABI and a reduction in maximum walking distance. A trial comparing the calcium antagonist verapamil versus placebo in patients undergoing angioplasty (n = 96) suggested that verapamil reduced restenosis (per cent diameter stenosis (± SD) 48.0% ± 11.5 versus 69.6% ± 12.2; P < 0.01), although this was not reflected in the maintenance of a high ABI (0.76 ± 0.10 versus 0.72 ± 0.08 for verapamil versus placebo). Another study (n = 80) demonstrated no significant difference in arterial intima-media thickness (IMT) in men receiving the thiazide diuretic hydrochlorothiazide (HCTZ) compared to those receiving the alpha-adrenoreceptor blocker doxazosin (-0.12 ± 0.14 mm and -0.08 ± 0.13 mm, respectively; P = 0.66). A study (n = 36) comparing telmisartan to placebo found a significant improvement in maximum walking distance at 12 months with telmisartan (median (interquartile range (IQR)) 191 m (157 to 226) versus 103 m (76 to 164); P < 0.001) but no differences in ABI (median (IQR) 0.60 (0.60 to 0.77) versus 0.52 (0.48 to 0.67)) or arterial IMT (median (IQR) 0.08 cm (0.07 to 0.09) versus 0.09 cm (0.08 to 0.10)). Two studies compared the beta-adrenoreceptor blocker nebivolol with either the thiazide diuretic HCTZ or with metoprolol. Both studies found no significant differences in intermittent or absolute claudication distance, ABI, or all-cause mortality between the anti-hypertensives. A subgroup analysis of PAD patients (n = 2699) in a study which compared a calcium antagonist-based strategy (verapamil slow release (SR) ± trandolapril) to a beta-adrenoreceptor blocker-based strategy (atenolol ± hydrochlorothiazide) found no significant differences in the composite endpoints of death, non-fatal myocardial infarction or non-fatal stroke with or without revascularisation (OR 0.90, 95% CI 0.76 to 1.07 and OR 0.96, 95% CI 0.82 to 1.13, respectively).

AUTHORS' CONCLUSIONS: Evidence on the use of various anti-hypertensive drugs in people with PAD is poor so that it is unknown whether significant benefits or risks accrue. However, lack of data specifically examining outcomes in PAD patients should not detract from the overwhelming evidence on the benefit of treating hypertension and lowering blood pressure.