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European Journal of Heart Failure 2008 10(9):817-818; doi:10.1016/j.ejheart.2008.06.017
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© 2008 European Society of Cardiology

All clinical trials are not created equal: The dilemma of HEAAL

Paul J. Hauptman*

Division of Cardiology, Saint Louis University School of Medicine United States

Key Words: Randomised clinical trial • Losartan • Dose

Received June 3, 2008; Accepted June 26, 2008

"All animals are created equal but some are more equal than others"—George Orwell, Animal Farm [1]

Many of the core advances in clinical therapeutics in heart failure have come about through randomised clinical trials (RCTs). Over the last twenty years, trials have increased in sophistication and the results of these trials have directly impacted patient care and outcomes. Landmark studies have the weight of history behind them: from CONSENSUS [2] and V-HeFT [3] to SOLVD [4] and COPERNICUS [5], these are but a few of the names that carry gravitas and elicit respect by junior faculty and professor emeriti alike. And with good reason: were it not for these trials, we would be practicing today like we were in the era of digoxin and diuretics. It is not a time that can be looked upon with nostalgia.

Of course, not all trials have had such a large impact but instead have provided crucial incremental knowledge: trials like CHARM [6], EPHESUS [7] and EUROPA [8] which fine tuned our thinking and helped to answer important, if not absolutely crucial, questions.

It is also true that RCTs have their drawbacks. We know about the limitations in enrollment; for example, chronic under-representation of women and the elderly [9,10]. We know about the difficulty our profession has had in some cases translating findings of efficacy in the RCT into the so-called real world of practice. We also know that there are precious few trials that compare drugs within a class: COMET [11] came to us as comets often do: alone but full of valuable data. Still, we have seen ‘softer’ variants, as in CIBIS-III [12] when we asked if it mattered whether bisoprolol or enalapril were started first or in ATLAS [13] when we asked if high dose lisinopril was better than low dose lisinopril. We have also learned as much from the negative trials as from the positive: from PROMISE [14] to RENEWAL [15], we know a lot about what not to do.

In that context, the Heart Failure Endpoint Evaluation of AII-Antagonist Losartan study or HEAAL study should theoretically advance our knowledge about dosing of angiotensin receptor blockers in heart failure; in effect, it replicates the ATLAS trial performed in the ACE inhibitor family. As demonstrated in this issue of the European Journal of Heart Failure, Konstam and colleagues have designed a multi-national study [16] that should help to answer the question about whether high dose losartan (150 mg daily) is better than low dose losartan (50 mg daily) in patients with New York Heart Association Classes II to IV, ejection fraction ≤40% and "known or recently diagnosed intolerance to ACE inhibitors".

Of course, there is a problem here: losartan failed to demonstrate superiority over captopril in two heart failure trials: the pilot ELITE and the larger more definitive ELITE-II [17,18]. Further, there were non-significant trends favouring captopril in the OPTIMAAL study [19]. More definitive proof of efficacy, predominantly in the ACE inhibitor intolerant patient, is available for two other ARBs, candesartan and valsartan, based on placebo-controlled trials [6,20]. The potential reasons for the failure of losartan are many; Konstam et al. [16] and others [21] suggest that it may have been the result of under dosing of losartan. In addition, ELITE-II was not designed as a non-inferiority trial. In the current trial, there is one other issue; the power calculation has been based on the unlikely assumption that the rates of all cause mortality and HF hospitalisation would be the same as those observed in ELITE-II.

At this stage, it is reasonable to ask several questions. First, are there enough data from the earlier trials to justify HEAAL? Second, can a class effect be assumed among the ARBs? If the answers are "yes", HEAAL may contribute meaningfully. Of course, it is highly likely that drugs within a class are not all the same [22,23]. Indeed it is quite reasonable to assume that the finding of differential outcomes between two active study drugs in the one comparator trial, COMET, was in fact not an outlier result but a real reflection of the fact that when drugs differ by chemical structure, pharmacokinetics and pharmacodynamics, they are likely to differ in clinical efficacy.

For now, we should take a "wait and see" approach and then critically analyze the results from HEAAL. Perhaps we can anticipate the publication of the data by assuming that the trial will generate at least one hypothesis. Specifically, we will learn more about how to frame the question about the importance of dose. We will almost certainly learn less about whether we should use losartan in heart failure. After all, imagine a trial in the heart failure cohort that showed high dose atenolol performed better than low dose atenolol; to what degree would it change our prescribing practice with beta blockers?

Not all trials can be landmarks; not all trials can rule the farm. But some trials are more equal than others, a message with connotations that George Orwell would almost certainly understand.


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* Saint Louis University Hospital, 3635 Vista Avenue, St. Louis MO 63110, United States. Tel.: +1 314 577 8896; fax: +1 314 268 5172. E-mail address: hauptmpj{at}slu.edu. Back


   References
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 Notes
 References
 

  1. Orwell G. Animal Farm (1983) New York: Harcourt Brace edition/First Plume printing. 123.
  2. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group. N Engl J Med (1987) 316(23):1429–1435.[Abstract]
  3. Cohn J.N., Archibald D.G., Ziesche S., et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med (1986) 314:1547–1552.[Abstract]
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  17. Pitt B., Segal R., Martinez F.A., et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet (1997) 349:747–752.[CrossRef][Web of Science][Medline]
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