European Heart Journal Advance Access originally published online on May 8, 2006
European Heart Journal 2006 27(12):1506-1507; doi:10.1093/eurheartj/ehi892
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Angiotensin II receptor blockers and coronary artery disease: ‘presumed innocents’
Chair and Division of Cardiology
II Faculty of Medicine
University of Rome ‘La Sapienza’
Sant'Andrea Hospital
Via di Grottarossa 1035-9
00189 Rome
Italy
Tel: +39 06 3377 5654
Fax: +39 06 3377 5061
E-mail address: massimo.volpe{at}uniroma1.it
IRCCS Neuromed
Pozzilli
Isernia
Italy
Chair and Division of Cardiology
II Faculty of Medicine
University of Rome ‘La Sapienza’
Sant'Andrea Hospital
Via di Grottarossa 1035-9
00189 Rome
Italy
Chair and Division of Cardiology
II Faculty of Medicine
University of Rome ‘La Sapienza’
Sant'Andrea Hospital
Via di Grottarossa 1035-9
00189 Rome
Italy
A ‘surrealistic’ debate has been progressively mounting on scientific journals on a potentially unfavourable influence of angiotensin II receptor blockers (ARBs) on the development of myocardial infarction (MI). The debate has now evolved in the opening of a ‘trial’ with a virtual jury. However, in any respectable trial, alligations must be proven beyond any reasonable doubt, and the ‘burden of the proof’ is a commitment for the prosecutors. Thus, until proofs are convincingly provided to a ‘jury’ (and possibly counterbalanced by the case of the defendant), the accused must be considered ‘presumably innocent’. This does not seem the case in the editorial recently appeared on this Journal, as an opinion-commentary by Strauss et al.1 to a meta-analysis,2 which produced evidence of no difference in MI between ARBs and angiotensin-converting enzyme-inhibitors (ACE-Is). Almost at the same time, in an independent meta-analysis,3 including all available randomized, controlled, international studies with ARBs, no detectable difference on the endpoint MI between ARBs and other active comparators was found; this included ACE-Is, which were tested in a sub-analysis derived from head-to-head studies.
We wish to comment on the positions and interpretations of the editorial by Strauss et al.1 The ‘personal war’ of Strauss et al., indeed, began in 2004 with a surprising narrative editorial,4 in which the use of ARBs was related to increased MI. The subtitle of this editorial was simply astonishing ‘These drugs may increase myocardial infarction and patients may need to be told’, and obviously generated disappointment among physicians and, most of all, among patients taking ARBs. Because their article was based, to say the least, on a partial analysis, taking into account only some arbitrarily selected trials, many criticisms were soon raised. Now, before the opinion of ‘popular jury’ is influenced by the ‘interim verdict’ that Strauss et al. anticipate, but mostly while waiting for ‘head-to-head’ studies that might eventually clarify whether ARBs and ACE-Is have different influence on development of MI, we propose to readers thoughts and criticisms on the new arguments of the ‘prosecution’.
First, Strauss et al. refer as the ‘most robust data to support’ and ‘the ultimate proof’ of the superiority of ACE-Is vs. ARBs on MI incidence, to a data presentation of the BPLTTC at the recent ESH Meeting.5 There are major problems in their interpretation: (i) the reference is not due to a written contribution by the BPLTTC Investigators, but rather to the transcription of a medical reporter; (ii) rather than ‘a highly statistically significant benefit of ACE-Is relative to ARBs in MI’, the conference coverage more soberly states that ‘unlike in the case of ACE-Is, there is no BP-independent effect on MI with ARBs’; (iii) as also stated in the conference report, ‘the power of the analysis is limited by the much smaller number of ARBs trials’ (five vs. 21 with ACE-Is). Moreover, the analysis does not consider any head-to-head comparison, thus data are extrapolated by studies where ACE-Is are compared with other treatments, often placebo, not to ARBs; (iv) the greater albeit small reductions in BP achieved with ACE-Is may explain the decrease of MI observed in high-risk patients. In support of this concept is another recent, large meta-analysis, which clearly showed that prevention of coronary artery disease by ACE-Is was unequivocally linked to systolic BP reduction.6 As shown in the BPLTTC analysis,7 the benefit provided by ACE-Is on MI could only be shown when ACE-Is were compared with placebo. In addition, the thesis of Strauss et al. does not clarify why ACE-Is should be more protective than ARBs in terms of MI in hypertension, and not in post-MI or in patients with heart or renal failure.2,3 Finally, the BPLTTC analysis is limited to studies in hypertensives, and it is confounding for the reader to conclude that ONTARGET/TRANSCEND study will provide the head-to-head counterproof to this issue, as this is not a hypertension trial.
Strauss et al. even attempted to explain the differences between ARBs and ACE-Is on coronary events by referring to putative deleterious effects of AT2 receptors on coronary circulation. To support this view, they keep quoting the only available reference that could support their hypothesis (the same article used 2 years ago).8 Although the pathophysiological role of AT2 receptors is not defined and any speculation on their effect in human coronary disease is under-warranted, more consistent evidence support a favourable role of AT2r in the cardiovascular system.9,10
It is recognized that ARBs may reduce stroke, development of heart failure, and prevent the progression of diabetic nephropathy and new onset of diabetes.11 Whether the beneficial effects of ARBs is partially independent of BP effects is unclear, and any conclusion is premature, due also to the heterogeneity of the trials examined. However, at this stage, there is no evidence of higher risk of MI in patients receiving ARBs, nor of a superiority of ACE-Is. Given the approach used by Strauss et al. in conceiving and supporting their hypothesis (arbitrary selection of studies not powered for the endpoint, indirect comparison of classes, and so on), the ‘unexplained’ risk of MI could be well justified by the play of chance. Therefore, the ‘jury’ should stay away from a ‘verdict’ and wait for further evidence. It is unfair to ‘prosecute’ ARBs now and they should be ‘presumed innocent’ until convincing, scientifically undisputable proofs are provided. This conclusion may make feel safer thousands of doctors using ARBs in their clinical practice, and mostly millions of patients currently taking ARBs.
References
- 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] - 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] - Volpe M, Trimarco B, Mancia G. (2005) Angiotensin II receptor blockers and myocardial infarction: deeds and misdeeds. J Hypertens 23:2113–2118.[Medline]
- Verma S and Strauss M. (2004) Angiotensin receptor blockers and myocardial infarction. Br Med J 329:1248–1249.
[Free Full Text] - Turnbull F. (2005) Blood pressure independent effects for agents inhibiting the renin–angiotensin system. Program and abstract from the Fifteenth European Meeting on Hypertension, 17–21 June 2005. (Plenary Session, Milan, Italy) http://www.medscape.com (4 January 2006).
- 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 artery disease and stroke prevention. Hypertension 46:386–392.
[Abstract/Free Full Text] - Turnbull F. for The Blood Pressure Lowering Treatment Trialists' Collaboration. (2005) Effects of different blood pressure lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus. Arch Intern Med 165:1410–1419.
[Abstract/Free Full Text] - Levy BI. (2004) Can angiotensin II type 2 receptors have deleterious effects in cardiovascular disease? Implications for therapeutic blockade of the renin–angiotensin system. Circulation 109:8–13.
[Free Full Text] - Steckelings UM, Kaschina E, Unger T. (2005) The AT2 receptor: a matter of love and hate. Peptides 26:1401–1409.[CrossRef][Web of Science][Medline]
- Volpe M, Musumeci B, De Paolis P, Savoia C, Morganti A. (2003) Angiotensin II AT2 receptor subtype: an uprising frontier in cardiovascular disease? J Hypertens 21:1429–1443.[CrossRef][Web of Science][Medline]
- Ruilope LM, Rosei EA, Bakris GL, Mancia G, Poulter NR, Taddei S, Unger T, Volpe M, Waeber B, Zannad F. (2005) Angiotensin receptor blockers: therapeutic targets and cardiovascular protection. Blood Press 14:196–209.[CrossRef][Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||