Fast track — ArticlesEffects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial
Introduction
Clinical trials have shown that angiotensin-receptor blockers (ARBs), given with or without an angiotensin-converting-enzyme (ACE) inhibitor, reduce morbidity or mortality in patients with heart failure and reduced left-ventricular ejection fraction (LVEF).1, 2, 3, 4, 5, 6 These trials investigated the effects of one high dose of an ARB and therefore do not provide guidance about optimum dosing or the relative risk–benefit profile of various dosing regimens.
Higher doses of ARBs than are typically used to treat hypertension could improve clinical outcomes in patients with heart failure. Trials establishing ARB efficacy have used valsartan 320 mg daily or candesartan 32 mg daily.1, 2, 3 However, losartan 50 mg daily did not improve clinical outcomes compared with captopril 150 mg daily.7 Incremental losartan doses of up to 150 mg in patients with heart failure result in progressive increases in plasma renin activity and in circulating concentrations of angiotensin II.8 Taken together, these observations lend support to the possibility that high ARB doses could achieve improved clinical benefits, through more complete inhibition of angiotensin effects at the AT1 receptor or increased stimulation of the AT2 receptor.9
The Heart failure Endpoint evaluation of Angiotensin II Antagonist Losartan (HEAAL) study compared clinical outcomes in patients with heart failure, reduced LVEF, and intolerance to ACE inhibitors who were randomly assigned to a high (150 mg) or low (50 mg) daily dose of losartan. We tested the hypothesis that incremental losartan dosing would reduce the risk of the primary combined endpoint of death or admission for heart failure.
Section snippets
Study design and participants
The design of the study has been previously described.10 HEAAL was an international, multicentre, double-blind, event-driven trial, comparing the effect of two doses of losartan (Merck, Whitehouse Station, NJ, USA), 150 mg daily and 50 mg daily, on death or admission for heart failure. Patients were enrolled in this study between November, 2001, and March, 2005, at 255 sites in 30 countries.
Eligibility criteria for patients were: age 18 years or older; symptomatic heart failure (New York Heart
Results
Figure 1 shows the trial profile. 1927 were randomly assigned to losartan 150 mg daily and 1919 to losartan 50 mg daily (figure 1). Six patients in each group were excluded from the analyses because of poor data quality. The two treatment groups were well balanced at baseline (table 1). At time of screening, ARBs had been prescribed to 1483 (77%) patients in the 150 mg group and to 1457 (76%) in the 50 mg group. Apart from ACE inhibitors, a high proportion of patients were receiving standard
Discussion
Our findings show that, for patients with heart failure and reduced LVEF who are ACE-inhibitor intolerant, losartan 150 mg daily is superior to 50 mg daily with respect to the composite outcome of death or admission for heart failure. Results for prespecified secondary outcomes and changes in NYHA class lend support to the greater efficacy of the 150 mg dose than of the 50 mg dose. Although more patients receiving the 150 mg dose than the 50 mg dose had hyperkalaemia, hypotension, and renal
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Prof H Drexler died September, 2009
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Prof P A Poole-Wilson died March, 2009
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Investigators listed at end of paper