Long-Term Effects of Flosequinan on the Morbidity and Mortality of Patients With Severe Chronic Heart Failure: Primary Results of the PROFILE Trial After 24 Years

Objectives The purpose of this clinical trial was to evaluate the long-term effects of flosequinan on the morbidity and mortality of patients with severe chronic heart failure. Background Flosequinan was the first oral vasodilator to be used in the clinic to augment the effects of digitalis, diuretics, and angiotensin-converting enzyme inhibitors in heart failure. However, the drug activated neurohormonal systems and exerted both positive inotropic and chronotropic effects, raising concerns about its safety during long-term use. Methods Following a run-in period designed to minimize the risk of tachycardia, we randomly assigned 2,354 patients in New York Heart Association functional class III to IV heart failure and with an ejection fraction ≤35% to receive long-term treatment with placebo or flosequinan (75 or 100 mg/day) in addition to their usual therapy. The primary outcome was all-cause mortality. Results The trial was terminated after a recommendation of the Data and Safety Monitoring Board, because during an average of 10 months of follow-up, 192 patients died in the placebo group and 255 patients died in the flosequinan group (hazard ratio: 1.39, 95% confidence interval: 1.15 to 1.67; p = 0.0006). Flosequinan also increased the risk of disease progression, which was paralleled by drug-related increases in heart rate and neurohormonal activation. However, during the first month, patients in the flosequinan group were more likely to report an improvement in well-being and less likely to experience worsening heart failure. Similarly, during the month following drug withdrawal at the end of the trial, patients withdrawn from flosequinan were more likely than those withdrawn from placebo to report symptoms of or to require treatment for worsening heart failure. Conclusions Although flosequinan produced meaningful symptomatic benefits during short- and long-term treatment, the drug increased the risk of death in patients with severe chronic heart failure.