Comparative Effects of Low and High Doses of the Angiotensin-Converting Enzyme Inhibitor, Lisinopril, on Morbidity and Mortality in Chronic Heart Failure

TLDR

ACE inhibitors are commonly prescribed at lower doses than those proven to reduce morbidity and mortality in heart failure patients. The study aims to determine whether low and high doses of ACE inhibitors provide comparable benefits in heart failure. 3164 heart failure patients were randomized to low (2.5–5 mg) or high (32.5–35 mg) daily lisinopril for 39–58 months, with standard background therapy maintained. High‑dose lisinopril lowered death or hospitalization risk by 12% and heart‑failure hospitalizations by 24% versus low dose, with no significant mortality difference and higher adverse events but similar discontinuation rates, indicating very low doses should be avoided when tolerated and efficacy differences between intermediate and high doses are small.

Abstract

Background —Angiotensin-converting enzyme (ACE) inhibitors are generally prescribed by physicians in doses lower than the large doses that have been shown to reduce morbidity and mortality in patients with heart failure. It is unclear, however, if low doses and high doses of ACE inhibitors have similar benefits. Methods and Results —We randomly assigned 3164 patients with New York Heart Association class II to IV heart failure and an ejection fraction ≤30% to double-blind treatment with either low doses (2.5 to 5.0 mg daily, n=1596) or high doses (32.5 to 35 mg daily, n=1568) of the ACE inhibitor, lisinopril, for 39 to 58 months, while background therapy for heart failure was continued. When compared with the low-dose group, patients in the high-dose group had a nonsignificant 8% lower risk of death ( P =0.128) but a significant 12% lower risk of death or hospitalization for any reason ( P =0.002) and 24% fewer hospitalizations for heart failure ( P =0.002). Dizziness and renal insufficiency was observed more frequently in the high-dose group, but the 2 groups were similar in the number of patients requiring discontinuation of the study medication. Conclusions —These findings indicate that patients with heart failure should not generally be maintained on very low doses of an ACE inhibitor (unless these are the only doses that can be tolerated) and suggest that the difference in efficacy between intermediate and high doses of an ACE inhibitor (if any) is likely to be very small.