Using a high dose of the angiotensin-receptor blocker (ARB) losartan reduces death or hospital admission for heart failure. This is the conclusion of the HEAAL study, findings from which are reported in an Article Online First and in an upcoming edition of The Lancet, written by Prof Marvin A Konstam, Tufts Medical Center and Tufts University School of Medicine, Boston, MA, USA, and colleagues. The study findings are to be presented at the American Heart Association (AHA) Meeting in Orlando, Florida, USA.
ARBs are effective treatments for patients with heart failure, but the relation between dose and clinical outcomes has not been explored. In this study, the authors compared the effects of high-dose (150 mg) versus low-dose (50 mg) losartan on clinical outcomes in patients with heart failure. This randomised trial was done in 255 sites in 30 countries. 3846 patients with heart failure, a left-ventricular ejection fraction 40% or less, and intolerance to angiotensin-converting-enzyme (ACE) inhibitors were randomly assigned to losartan 150 mg (n=1927) or 50 mg daily (n=1919). The primary endpoint was death or admission to hospital for heart failure.
With 4•7-year median follow-up in each group, 828 (43%) patients in the 150 mg group versus 889 (46%) in the 50 mg group died or were admitted for heart failure; the higher dose reduced the risk of death or admission for heart failure by 10% compared with the lower dose. When the two endpoints were looked at separately, 635 patients in the 150 mg group versus 665 in the 50 mg group died—a hazard reduction of 6% for the higher dose group—but this finding was not statistically significant. For admission to hospital for heart failure, the numbers were 450 (high dose) versus 503 (low dose)—a hazard reduction of 13% for the high dose group, and this result was statistically significant. Kidney impairment (n=454 vs 317), low blood pressure (203 vs 145), and hyperkalaemia* (195 vs 131) were more common in the 150 mg group than in the 50 mg group, but these adverse events did not lead to significantly more treatment discontinuations in the 150 mg group.
Professor Konstam says**: "Beyond demonstrating superiority of a higher dose of an ARB in patients with heart failure and reduced cardiac function, HEAAL is one of the first studies to examine relative dose effects on clinical outcomes for any cardiovascular medication, Our findings confirm the view that incremental inhibition of the renin-angiotensin system, within the range explored in heart failure trials to date, achieves an incremental benefit. But they also emphasise the importance, across clinical practice, of targeting drug doses that have demonstrated favourable impact on clinical outcomes."
The authors conclude: "These findings suggest that increased doses of an ARB are needed to achieve the maximum benefit for clinical outcomes and symptoms related to heart failure in this population."
In an accompanying Comment, Dr Henry Krum, Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, VIC, Australia, says: "In the absence of efficacious novel agents, we clearly need to focus on improving the therapeutic use of existing drugs. HEAAL reminds us that much still needs to be learned in this area, specifically a renewed focus on seeking the optimum dose of such agents in patients with chronic heart failure."
Prof Marvin A Konstam, Tufts Medical Center, Boston, MA, USA. T) +1-617-636-6293 E) mkonstam@tuftsmedicalcenter.org
Dr Henry Krum, Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, VIC, Australia. T) +61 417325834 E) henry.krum@med.monash.edu
For full Article and Comment, see: http://press.thelancet.com/heall.pdf
Note to editors: *hyperkalaemia=high levels of blood potassium, which can cause abnormal heart rhythms and is potentially fatal.
**Quote direct from Professor Konstam and cannot be found in text of Article
Journal
The Lancet