Orlando, Fla.—Using a higher dose of the angiotensin-receptor blocker (ARB) losartan reduces death or hospital admission for heart failure, based on the findings of the HEAAL study, presented Tuesday at the American Heart Association conference.
Principal investigator Marvin A Konstam, MD, from Tufts Medical Center and Tufts University School of Medicine in Boston, and colleagues were the first to examine the relative impact of different ARB doses on clinical outcomes.
The investigators followed 3,834 heart failure patients in 30 countries, who were randomized to receive either 50 mg or 150 mg a day of the ARB losartan (Cozaar; Merck) between November 2001 and March 2005. They included heart failure patients (NYHA II-IV) with a left ventricular ejection fraction (LVEF) of 40 percent or less and intolerance for ACE inhibitors.
During the median follow up of 4.7 years, primary endpoint events (a composite of all-cause death or hospitalization for heart failure) occurred 828 times in the high-dose group versus 889 time in the low-dose group.
Konstam said that this means the higher dose was associated with a 10 percent risk reduction versus the lower dose, mostly due to a 13 percent reduction in the risk of heart failure hospitalizations.
In his commentary on the trial, Karl Swedberg, MD, from the Sahlgrenska University Hospital in Goteborg, Sweden, commended the HEAAL investigators for conducting appropriate dose range between the two study groups, and also for maintaining a “reasonable” retention rate out to almost five years.
The researchers found no significant difference in all-cause mortality between groups.
Konstam reported that 150 mg dose of ARBs was associated with higher rates of hypotension, hyperkalemia and renal impairment, although the overall rates of clinically adverse events were small.
In patients with heart failure, reduced LVEF and ACE inhibitor intolerance, the HEAAL investigators found that the incremental value is derived from up-titrating ARB doses to levels demonstrated to confer benefit on clinical outcomes.
Konstam said that “their findings confirm the stance that incremental inhibition of the rennin-angiotensin system, within the range explored in heart failure trials to date, achieves a progressively favorable impact on clinical outcomes.”
Swedberg said that based on these results, “all patients receiving losartan treatments need to be re-evaluated,” due to the findings that proved the “incremental benefit of a higher dose of losartan.” He also suggested that this up-titrating might need to be re-evaluated for all ARBs, including candesartan and valsartan.
However, Swedberg concluded by questioning whether this increased dose of losartan was more effective than an ACE inhibitor.
The HEAAL trial was simultaneously published in the Lancet, and the accompanying editorial, written by Henry Krum, MD, center of cardiovascular research and education in therapeutics at Monash University in Melbourne, Australia, wrote: "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."