European Heart Journal Advance Access originally published online on May 3, 2006
European Heart Journal 2006 27(12):1507-1508; doi:10.1093/eurheartj/ehi893
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Angiotensin-II receptor blockers and coronary artery disease: ‘presumed innocents’: reply
Division of Cardiology
North York General Hospital
Toronto
Canada
Clinical Cardiology
McMaster University
Hamilton
Canada
Division of Cardiac Surgery
St Michael's Hospital
University of Toronto
14EN-215, 200 Elizabeth Street
Toronto M5G 2C4
Canada
Tel: +1 416 782 0092
Fax: +1 416 782 0096
E-mail address: subodh.verma{at}sympatico.ca
‘Is the jury out’ or ‘is the jury in’?
The commentary by Volpe et al.1 does not appear to recognize that two important issues in cardiology have recently gained new insight. First, the reduction of myocardial infarction and death with ACE-inhibitors in high-risk patients is greater than that derived from blood pressure lowering alone. A ‘blood pressure-independent’ effect of ACE-inhibitors is supported by two recent meta-analyses that applied meta-regression, a statistical principal that adjusts for blood pressure differences within trials. One of the analysis included 179 122 patients from trials with ACE-inhibitors or calcium channel blockers with comparators of diuretics, beta-blockers, or placebo.2 A 10 mmHg fall in systolic pressure translated into a 15% relative risk reduction in myocardial infarction and cardiovascular death, with the ACE-inhibitor having an additional 12% relative risk reduction above that achieved by blood pressure lowering.
A second meta-regression analysis from the Blood Pressure Lowering Treatment Trialists Collaboration (BPLTTC) of 137 356 high-risk patients also confirmed a ‘blood pressure-independent effect’ of ACE-inhibitors on myocardial infarction and cardiovascular death with a relative risk reduction of –9% (–14 to –3%) above that predicted by blood pressure lowering alone (unpublished data-presented ESH 2005).3 The meta-regression evaluated angiotensin-II receptor blockers trials (ARB) (IDNT, RENAAL, SCOPE, VALUE, LIFE) as well as ACE-inhibitors, thereby evaluating a recent observation by two of these authors (S.V. and M.H.S.) that major ARB trials in high-risk patients have shown almost a complete lack of reduction in myocardial infarction and mortality, despite significant blood pressure reductions in their favour, with MI actually increasing in some studies.4
The BPLTTC meta-regression demonstrated a clinically important 15% relative risk reduction (P=0.001) benefit of ACE-inhibitors relative to ARB on myocardial infarction and cardiovascular death. Whereas the benefit of ACE-inhibitor was significantly greater than blood pressure lowering alone (–9%) (–14 to –3%), ARB was not, with a trend for the benefit to be less than that predicted from blood lowering alone (+7%) (–7 to +24%).3 ACE-inhibitors and ARB were similar with respect to the outcomes of stroke and heart failure,3 and in a Cochrane meta-analysis of diabetic nephropathy, renal outcomes were also similar, despite a mortality reduction dramatically favouring ACE-inhibitors (20 vs. 0%).5
Three large meta-analyses of ARB6–8 have not found an increase in myocardial infarction with ARB, but blood pressure differentials in favour of ARB in some trials were not adjusted for by meta-regression. However, there was no decrease in myocardial infarction with ARB either, even compared with placebo or non-ACE-inhibitor therapy.6–8 The meta-analyses suggest that at best, ARB are ‘vascular neutral’, but this may be an overly optimistic conclusion as the trials were heterogeneous. Our recent editorial, ‘Is The Jury Out’,3 discusses this issue in detail with reference to one of the meta-analysis,8 but similar limitations are evident in others as well.
For example, in a large meta-analysis by Volpe7 (n=56 254, 11 trials), a potential 18% increase in myocardial infarction with ARB when compared with a placebo [relative risk (RR) 0.99, 95% CI 0.84–1.18], and a 12% increase when compared with other active therapy (RR 1.04, 95% CI 0.96–1.125), could not be excluded. Myocardial infarction overall tended to increase with ARB (RR 1.036, 95% CI 0.97–1.11) but unfortunately, the more important endpoint of cardiovascular mortality, which may differ significantly from MI, was omitted from the analysis. This is particularly relevant in OPTIMAAL,9 where losartan and captopril had similar myocardial infarction rates, but cardiovascular mortality was significantly greater with losartan when compared with captopril (RRR 1.17, 95% CI 1.01–1.34, P=0.032). In Volpe's meta-analysis, the myocardial infarction data for VALLIANT-favoured valsartan, but the number of patients with myocardial infarction is in fact greater with valsartan than captopril as reported by McMurray et al.10 (587 vs. 559, respectively). CHARM Added was appropriately excluded from the meta-analyses as background therapy included ACE-inhibitors but VALLIANT should also have been excluded, as 39% of patients received ACE-inhibitor prior to randomization.3
It cannot be emphasized enough, that an apparent lack of difference between ACE-inhibitors and ARB in these meta-analysis does not meet the ‘burden of proof’ that a difference does not exist. Even with out large trial data comparing ACE-inhibitors and ARB directly, the evidence from individual trials of ACE-inhibitors and ARB suggest that ACE-inhibitors have a unique vascular protective effect on blood pressure lowering,4 whereas the meta-analyses suggest ARB are at best, vascular neutral.6–8 The results from the two recent large meta-regression analyses that included over 310 000 patients are consistent with these conclusions.2,3
The distinct difference between ACE-inhibitors and ARB on coronary artery events may reflect their unique mechanisms of action. Despite both modulating the renin–angiotensin system, ACE-inhibitors decrease angiotensin II levels, whereas ARB block the AT1 receptor, which in turn inhibits a negative feed back loop resulting in angiotensin II levels that increase three to five-fold over baseline. ARB result in unopposed stimulation of both AT2 which shares many of the deleterious effects of AT1, as well as AT4, which promotes the release of prothrombotic PAI-1. ACE-inhibitors upregulate bradykinin levels which enhances vascular protection via endothelial function, ischaemic preconditioning, and fibrinolysis.11
‘Is the jury out’ or ‘Is the jury in?’ is simply a metaphor, which recognizes that ‘while knowledge will continue to evolve, therapeutic choices must be made today.’ ACE-inhibitors should be considered as first line therapy in preference to ARB for the high-risk patient.
References
- Massimo V, Tocci G, Savoia C. (2006) Angiotensin II receptor blockers and coronary artery disease: ‘presumed innocents’. Eur Heart J. in press.
- Verdecchia P, Reboldi G, Angeli F, Gattobigio R, Bentivoglio M, Thijs L, Staessen JA, Porcellati C. (2005) Angiotensin-converting enzyme inhibitors and calcium channel blockers for coronary heart disease and stroke prevention. Hypertension 46:386–392.
[Abstract/Free Full Text] - Strauss MH, Lonn EM, Verma S. (2005) Is the jury out? Class specific differences on coronary outcomes with ACE-inhibitors and ARBs: insight from meta-analysis and The Blood Pressure Lowering Treatment Trialists' Collaboration. Eur Heart J 26:2351–2353.
[Free Full Text] - Verma S and Strauss M. (2004) Angiotensin receptor blockers and myocardial infarction. BMJ 329:1248–1249.
[Free Full Text] - Strippoli GF, Craig M, Deeks JJ, Schena FP, Craig JC. (2004) Effects of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists on mortality and renal outcomes in diabetic nephropathy: systematic review. BMJ 329:828.
[Abstract/Free Full Text] - McDonald MA, Simpson SH, Ezekowitz JA, Gyenes G, Tsuyuki RT. (2005) Angiotensin receptor blockers and risk of myocardial infarction: systematic review. BMJ 331:873.
[Abstract/Free Full Text] - Volpe M, Mancia G, Trimarco B. (2005) Angiotensin II receptor blockers and myocardial infarction: deeds and misdeeds. J Hypertens 23:2113–2118.[Medline]
- Verdecchia P, Angeli F, Gattobigio R, Reboldi GP. (2005) Do angiotensin II receptor blockers increase the risk of myocardial infarction? Eur Heart J 26:2381–2386.
[Abstract/Free Full Text] - Dickstein K and Kjekshus J. (2002) Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan. Lancet 360:752–760.[CrossRef][Web of Science][Medline]
- McMurray J, Solomon S, Pieper K, Reed S, Rouleau J, Velazquez E, White H, Howlett J, Swedberg K, Maggioni A, Kober L, Van de WF, Califf R, Pfeffer M. (2006) The effect of valsartan, captopril, or both on atherosclerotic events after acute myocardial infarction: an analysis of the Valsartan in Acute Myocardial Infarction Trial (VALIANT). J Am Coll Cardiol 47:726–733.
[Abstract/Free Full Text] - Strauss MH and Verma S. (2005) Inhibition of the renin-angiotensin system in cardiovascular protection: is it important to watch your C'ARB' intake? Can J Cardiol 21:577–580.[Medline]
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