Higher dosage of losartan needed for maximal benefit in patients with CHF and left ventricular dysfunction

Key Points

A dosage of losartan of 150 mg/day is superior to 50 mg/day for the treatment of patients with congestive heart failure (CHF). A randomized comparison of the 2 dosages found the higher dosage to be associated with a significant reduction on the combined endpoint of heart failure hospitalization and all-cause mortality, said Marvin A. Konstam, MD, at the 2009 scientific sessions of the American Heart Association in Orlando, Fla.

In CHF patients with left ventricular dysfunction and intolerance to ACE inhibition, "incremental value is derived from uptitrating doses of angiotensin receptor blockers to levels demonstrated to confer benefit on clinical outcome," he said.

In the study, 3,846 patients with New York Heart Association class II to IV heart failure, a left ventricular ejection fraction of 40% or less, and intolerance to ACE inhibitors were started on losartan, 12.5 to 25 mg/day for 2 weeks, which was uptitrated to 50 mg/day. After 1 more week, half the patients had further titration to 100 mg and then 150 mg/day over the course of 2 weeks while the other half remained on 50 mg/day. The median follow-up of the study was 4.7 years.

"For every 31 patients treated for 4 years with the high dose, there was one fewer death or heart failure-related hospitalization," said Dr Konstam, principal investigator of the study and professor of medicine, Tufts University School of Medicine, and director of Tuft Medical Center's Cardiovascular Center, Boston.

The main driver of the reduction in the risk of the primary composite endpoint with high-dose losartan was a reduction in the rate of heart failure hospitalizations, which was reduced by 13% in the high-dose group compared to the low-dose group (450 events vs 503 events; P=.025). There was no significant reduction in the risk of all-cause morality between the groups (635 deaths in patients assigned to 150 mg/day vs 665 deaths in patients assigned to 50 mg/day; P=.24).

Renal impairment occurred significantly more often in the high-dose group compared with the low-dose group (7.12% vs 4.73%; P<.001). The 150-mg dosage was also associated with higher rates of hypotension (2.92% vs 2.07%, respectively; P=.002) and hyperkalemia (2.79% vs 1.87%, respectively; P<.001). However, the frequency of discontinuation from study drug for any of these reasons was extremely low, supporting the conclusion that the benefit of the higher dose outweighed the risk.

Because of the number of discontinuations in the study, approximately 30% in both dosage groups, the study results reflect an underestimation of the true effect of the higher dosage on outcomes, said Karl Swedberg, MD, PhD, Sahlgrenska University Hospital, Goteborg, Sweden. "All patients on losartan today need to be re-evaluated and uptitrated to a higher level," he said.