© 2007 European Society of Cardiology
RAS blockers: Does sex matter/ Re: Sex differences in the effectiveness of ARB and ACEI in patients with congestive heart failure — A population study: Marie Hudson et al. European Journal of Heart Failure 9 (2007) 602–609
a Scientist, Division of Cardiovascular Surgery, Saint Michael's Hospital and Cardiologist, Division of Cardiology, North York General Hospital Toronto, Canada
b Clinical Cardiology, C-NET Research Group, LIGHT (Leeds Institute for Genetics Health and Therapeutics), Faculty of Medicine, University of Leeds UK E-mail address: A.S.Hall{at}leeds.ac.uk.
* Corresponding author. Tel.: +16 730 0938. E-mail address: Dr.Marty{at}bellnet.ca.
Received May 31, 2007; The retrospective analysis by Hudson et al. [1] suggests that the global mortality of male patients discharged post hospitalization for CHF with a prescription for ARB was no different than for an ACEI, with a survival advantage for females prescribed ARB. Randomized prospective trials would suggest otherwise.
A meta-analysis of trials that randomized ARB vs. ACEI (ELITE I, ELITE II, OPTIMAAL, VALIANT, DETAIL; n=19,419, 99% with CHF) [2] found a greater global mortality with ARB than ACEI (OR 1.06 .99-1.14, p=.1). The majority of patients were post an acute MI. In OPTIMAAL[3] (n=5477), cardiovascular mortality was significantly increased with losartan as compared to captopril (OR 1.17 CI 1.01-1.34) despite a mean follow up of just 2.7 years. The mortality rate in VALIANT (n=9818) [4] was not statistically different for valsartan and captopril (19.9% vs.19.5% respectively). Although VALIANT was event driven, one could argue that the follow-up of 24.7 months was just simply too short to differentiate drug efficacy considering the cardiovascular benefits of ACEI in SAVE and SOLVD, both placebo controlled trials, took 3.5 years to achieved significance. VALIANT was a negative "superiority" trial and as such, the "apparent" absence of a difference in mortality does not rule out that a clinically important difference exists, nor can it prove statistical equivalence.
In Hudson's [1] retrospective analysis, 13% of patients were prescribed ARB over ACEI despite guidelines recommending otherwise. Bias on the part of physicians is the likely explanation and statistical models can not adjust for this. Follow-up of only 2-3 years with relatively small numbers prescribed ARB (n=2587) as compared to ACEI (n=17,111) may accentuate any bias and contribute to conclusions that are erroneous. This may account for the apparent survival advantage in females with ARB, but not in males, with the inference being that ACEI have reduced efficacy in females. This appears not to be so, as a meta-analysis of placebo controlled CHF trials with ACEI demonstrated a similar survival advantage in women (n=2373, HR 0.80, 95% CI 0.76-.85) [5] as in men.
ACEI are well established as the preferential therapy over ARB for CHF, regardless of gender. A multiplicity of meta-analyses supports a similar conclusion for all "high risk patients". In a meta-analysis of 150,943 patients[2], ACEI reduced the risk of MI by 14% (p<.00001) and CV death by 12% (p<.0005). Four separate meta-analyses of ARB (n=56,254-68,711)[2,6-8] failed to demonstrate any reduction in either MI or CV death. Two meta-regression analyses (n=136,838 and 179,122) [9,10] suggest that the benefits of ACEI on the combined endpoint of MI and CV death was significantly greater than could be predicted by blood pressure lowering alone (9% and 12% respectively). "Blood pressure independent" effects are unique to ACEI [9,10] and are not evident with ARB [9].
A retrospective analysis can at best generate plausible hypotheses — with the emphasis on the word "plausible". Further division into sub-groups adds little, as one sub-group will tend to do better, and the other worse, than the overall sample. Although a retrospective analysis may reflect real life medical practice, it is not necessarily how medicine should be practiced in real life. The latter is perhaps best left to the clinical trials!
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- Hudson M., Rahme E., Behlouli H., Sheppard R., Pilote L. Sex differences in the effectiveness of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in patients with congestive heart failure — a population study. Eur J Heart Fail (June 2007) 9(6-7):602–609.
[Abstract/Free Full Text] - Strauss M.H., Hall A.S. Angiotensin receptor blockers may increase risk of myocardial infarction: unraveling the ARB-MI paradox. Circulation (August 22 2006) 114(8):838–854.[CrossRef]
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[Abstract/Free Full Text] - Volpe M., Mancia G., Trimarco B. Angiotensin II receptor blockers and myocardial infarction: deeds and misdeeds. J Hypertens (December 2005) 23(12):2113–2118.[Web of Science][Medline]
- Blood pressure-dependent and independent effects of agents that inhibit the renin-angiotensin system. J Hypertens (2007) 25(5):951–8. May.[Web of Science][Medline]
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