Abstract
BackgroundAngiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs) efficaciously reduce systolic blood pressure (BP), a well-established risk factor for myocardial infarction (MI). Both inhibit the renin-angiotensin system, albeit through different mechanisms, and produce similar reductions in BP. However, in parallel meta-analyses of ACEi and ARB trials, ACEis reduce risk of MI whereas ARBs do not—a phenomenon described as the ‘ARB-MI paradox’. In addition, ACEis reduce all-cause mortality, whereas ARBs do not, which appears to be independent of BP lowering. The divergent cardiovascular effects of ACE inhibitors and ARBs, despite similar BP reductions, are counter-intuitive. This systematic review aims to ascertain the extent to which clinical outcomes in randomised trials of ACEi and ARBs are attributable to reductions in systolic BP.MethodsA comprehensive search of bibliographic databases will be performed to identify all randomised studies of agents of the ACEi and ARB class. Placebo and active comparator-controlled studies that report clinical outcomes, with greater than 500 person-years of follow-up in each study arm, will be included. Two independent reviewers will screen study records against a priori-defined eligibility criteria and perform data extraction. The Cochrane Risk of Bias Tool will be applied to all included studies. Studies retracted subsequent to initial publication will be excluded. Primary outcomes of interest include MI and all-cause mortality; secondary outcomes include stroke, heart failure, revascularisation and cardiovascular mortality. Meta-regression will be performed, evaluating the relationship between attained reduction in systolic BP and relative risk of each outcome, stratified by drug class. Where a BP-dependent effect exists (two-tailed p value < 0.05), relative risks, standardised per 10 mmHg difference in BP, will be reported for each study outcome. Publication bias will be examined using Funnel plots, and calculation of Egger’s statistic.DiscussionThis systematic review will provide a detailed synthesis of evidence regarding the relationship between BP reduction and clinical outcomes with ACEi and ARBs. Greater understanding of the dependency of the effect of each class on BP reduction will advance insight into the nature of the ARB-MI paradox and guide the future usage of these agents.Systematic review registrationPROSPERO CRD42017072988
Highlights
Elevated systolic blood pressure (BP) is a well-established risk factor for myocardial infarction (MI), stroke, heart failure, and death [1,2,3,4]. This risk may be ameliorated with antihypertensive treatment: a reduction in systolic BP of 10 mmHg translates into a 17% reduction in the incidence of coronary artery disease, a 27% reduction in stroke, a 28% reduction in heart failure, and a 13% reduction in all-cause mortality [5]
Controversy persists over the comparative safety and efficacy of angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs), with regard to myocardial infarction (MI) [8, 9]
Despite robust evidence that ARBs reduce BP, stroke and heart failure, no study has demonstrated a significant, protective impact of ARBs for MI, cardiovascular or all-cause mortality—endpoints reduced by ACEis in multiple trials [7, 10]
Summary
Elevated systolic blood pressure (BP) is a well-established risk factor for myocardial infarction (MI), stroke, heart failure, and death [1,2,3,4]. Controversy persists over the comparative safety and efficacy of angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs), with regard to myocardial infarction (MI) [8, 9]. Angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs) efficaciously reduce systolic blood pressure (BP), a well-established risk factor for myocardial infarction (MI). Both inhibit the renin-angiotensin system, albeit through different mechanisms, and produce similar reductions in BP.
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