The Divergent Cardiovascular Effects of Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers on Myocardial Infarction and Death

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Abstract

The renin angiotensin aldosterone system (RAAS) plays a central role in the pathophysiology of hypertension and vascular disease. Angiotensin converting enzyme inhibitors (ACEis) suppress angiotensin II (ANG II) concentrations, whereas angiotensin receptor blockers (ARBs) block the binding of ANG II to AT1 receptors. ACEis and ARBs are both effective anti-hypertensive agents and have similar risk reductions in stroke — a blood pressure dependent phenomenon. ACEis also reduce the risk of myocardial infarction (MI) and mortality in high risk hypertensive patients, as well as in diabetics, the elderly, those with vascular disease, and in congestive heart failure. ARBs, in contrast, do not reduce the risk of MI or death in clinical trials where the comparator has been another active therapy or even a placebo. Systematic reviews of ARBs that include meta-analyses or meta-regression analyses confirm that ARBs lack the cardiovascular protective effects of ACEis, which in part are “independent” of blood pressure lowering. Practice guidelines, especially those in high risk hypertensive patients, should reflect the evidence that ACEis and ARBs have divergent cardiovascular effects — ACEis reduce mortality, whereas ARBs do not. ACEis should be the preferred RAAS inhibitor in high risk patients.

Section snippets

BP and CV endpoints

The CV endpoints of greatest clinical importance in the treatment of hypertension are mortality, MI, and stroke (CVA) — the “hard endpoints”. The relationship of BP and mortality was assessed in a collaborative meta-analysis of prospective observational studies in 1,000,000 subjects with no known CV disease, thus evaluating the potential impact of BP reduction independent of any additional cardio-protective effects drugs might provide.12 For every 10 mmHg reduction in systolic BP (SBP), it was

The ARB MI paradox – the evidence is there from 2004

A 2004 editorial in the British Medical Journal15 (co-authored by one of us: MHS) was the first reference in the literature to suggest that ARBs may not provide similar CV protection as ACEis. Early ARB trials appeared not to reduce the risk of MI or death despite demonstrating good tolerability and effective BP lowering.15 It was noted in the VALUE16 trial that there was a statistically significant 19% excess of MI with the ARB valsartan as compared to the calcium channel blocker amlodipine in

Angiotensin II, bradykinin, AT1 and AT2 receptors – how is it all connected?

The unique BP “independent” effects of ACE inhibitors have biologic plausibility.4 ACEis suppress angiotensin II (ANG II) — ANG II not only plays a central role in the pathophysiology of HTN via vasoconstriction and fluid retention, but has direct tissue toxicity on the vasculature, heart, brain, and kidneys. ANG II induces CV damage by sustaining cell growth, inflammation, and fibrosis; has a direct effect on smooth muscle migration, vascular hypertrophy and formation of extracellular matrix

ACEis and ARBs as compared to placebo

There are distinct advantages to clinical trials where the comparator is a placebo rather than another active comparator. Placebo controlled trials provide the most rigorous measure of treatment efficacy and harm, allows for trial conditions that maximize “treatment separation” thus increasing the likelihood of detecting beneficial or harmful effects, and can be an “add on” to standard care.23 Three recent meta-analyses of ARB trials with placebo comparators provide insight into ARBs’

ACEi vs. ARB trials

The direct comparison of ACEis and ARBs in head to head trials – some would say – is the optimum way to evaluate their relative CV protective effects. There are 4 large such trials, and although each was negative for the hypothesis of statistical “superiority” of the ARBs, they do provide a unique perspective. The ELITE II25 trial in chronic HF (n = 3152, follow up 18 months) compared losartan 50 mg vs. captopril 50 mg 3 times daily; the losartan treated group had a 13% higher total mortality than

Hypertension – ACEis and ARBs – BP independent effects

A recent pooled meta-analysis of ACEi and ARB trials with any comparators included 20 trials with 158,998 patients (7 ACEis, n = 76,615 patients; 13 ARBs, n = 82,383 patients)14 and had a high prevalence of HTN. The trials were contemporary – all published since 200014 – and as such, patients had similar co-morbidities, background medications, etc. The average follow up was 4.3 years, initial mean SBP was 153 mmHg, and at least 2/3 of the patients had a diagnosis of HTN. All cause mortality had a

Diabetes mellitus

HTN is a common co-morbidity in DM, with ACEis and ARBs preferred therapies — in part, secondary to their unique nephroprotection.2 Practice guidelines in diabetes mellitus do not distinguish between ACEis and ARBs32 but the evidence does not support this conclusion. In a parallel meta-analysis of trials of ACEis and ARBs vs. any comparators (23 trials, n = 32,827; 13 trials, n = 23,867, respectively) in diabetes mellitus, ACEi significantly reduced all-cause mortality by 13% (RR 0.87; 95% CI

ACEis and ARBs in HF — placebo controlled trials

The head to head trials of ACEis vs. ARBs in HF have been reviewed – ELITE II,25 OPTIMAAL,26 and VALIANT3 – supporting the conclusion that ACEi is preferred — a conclusion that is supported in the placebo controlled trials. In the CONSENSUS-1 trial (n = 253, follow up 188 days), patients with severe HF (New York Heart Association/NYHA 4) were randomized to either the ACEi enalapril or a placebo — the 1 year mortality rate was reduced by 31% (36% vs. 52%, p = 0.001),39 thus began a paradigm shift for

ACEis and ARBs in vascular disease

There are three large placebo controlled trials of ACEis in high risk patients with essentially normal BP (133/78–139/79 mmHg) that had inclusion criteria of either vascular disease or DM, with no symptoms of HF or LV dysfunction: HOPE,44 EUROPA,45 and PEACE.46 In a meta-analysis of these three trials (n = 29,805, average follow up 4.5 years), ACEis reduced all-cause mortality (7.8 vs. 8.9%, p = 0.0004), cardiovascular mortality (4.3 vs. 5.2%, p = 0.0002), and non-fatal MI (5.3 vs. 6.4%, p = 0.0001),

ARB trial design

A trial design common amongst the ARB trials is the “Prospective Randomized Open-label Blinded Endpoint (PROBE)” trial — where both patients and physician are aware of their randomized treatment. Open label trials were introduced in 1992 as a potential alternative source of unbiased evidence.51 The statistical integrity of “open label trials” is based on the premise that all primary analyses are performed using strictly objective end-points, such as death from all causes. Consequently, it has

Conclusion

The parallel meta-analyses of ACEi and ARB trials vs. placebo or other active comparator, and the meta-regression analyses that adjust for BP within the trials, clearly and consistently demonstrate that ACEis reduce the risk of MI and death above and “independent” of BP lowering, whereas ARBs do not — the so called “ARB MI Paradox”. This is a consistent finding amongst the different high risk populations: HTN, DM, those with vascular disease, and HF. This truth has been obscured by the open

Statement of conflict of interest

There is no conflict of interest.

References (56)

  • B.B. Granger et al.

    Adherence to candesartan and placebo and outcomes in chronic heart failure in the CHARM programme: double-blind, randomised, controlled clinical trial

    Lancet

    (2005)
  • G.R. Dagenais et al.

    Angiotensin-converting-enzyme inhibitors in stable vascular disease without left ventricular systolic dysfunction or heart failure: a combined analysis of three trials

    Lancet

    (2006)
  • S. Kaul et al.

    Trial and error. How to avoid commonly encountered limitations of published clinical trials

    J Am Coll Cardiol

    (2010)
  • Blood pressure-dependent and independent effects of agents that inhibit the renin–angiotensin system

    J Hypertens

    (2007)
  • P.A. Sarafidis et al.

    Effects of renin–angiotensin system blockers on renal outcomes and all-cause mortality in patients with diabetic nephropathy: an updated meta-analysis

    Am J Hypertens

    (2008)
  • M.A. Pfeffer et al.

    Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both

    N Engl J Med

    (2003)
  • M.H. Strauss et al.

    Angiotensin receptor blockers may increase risk of myocardial infarction: unraveling the ARB-MI paradox

    Circulation

    (2006)
  • American Diabetes Association

    Standards of medical care — 2013

    Diabetes Care

    (2013)
  • G. Mancia et al.

    2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC)

    Eur Heart J

    (2013)
  • S. Bangalore et al.

    Angiotensin receptor blockers and risk of myocardial infarction: meta-analyses and trial sequential analyses of 147 020 patients from randomised trials

    BMJ

    (2011)
  • I.Y. Elgendy et al.

    Efficacy and safety of angiotensin receptor blockers in older patients: a meta-analysis of randomized trials

    Am J Hypertens

    (2015)
  • P. Verdecchia et al.

    Angiotensin-converting enzyme inhibitors and calcium channel blockers for coronary heart disease and stroke prevention

    Hypertension

    (2005)
  • S. Lewington et al.

    Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies

    Lancet

    (2002)
  • M.R. Law et al.

    Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies

    BMJ

    (2009)
  • L.C. van Vark et al.

    Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin–angiotensin–aldosterone system inhibitors involving 158 998 patients

    Eur Heart J

    (2012)
  • S. Verma et al.

    Angiotensin receptor blockers and myocardial infarction

    BMJ

    (2004)
  • P.S. Sever et al.

    Blood pressure reduction is not the only determinant of outcome

    Circulation

    (2006)
  • R.T. Tsuyuki et al.

    Angiotensin receptor blockers do not increase risk of myocardial infarction

    Circulation

    (2006)
  • Cited by (0)

    Statement of Conflict of Interest: see page 481.

    1

    Dr. Martin Strauss received speaker honorarium from Servier, Forest Laboratories. Boehringer, Bayer, Pfizer, Bristol Myer Squibb and has performed consultancy work for Forest Laboraties.

    2

    Tel.: + 44 113 3925402.

    3

    Dr. Alistar Hall has received speaker honorarium from Servier and has performed consultancy work for Astra Azeneca.

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