Aims: Many individuals diagnosed with heart failure do not present with reduced left ventricular ejection fraction or significant valve disease. In this patient group, robust randomized controlled trials are scarce. Notably, no trials have specifically targeted patients with documented diastolic dysfunction, and none have demonstrated unequivocal benefits in terms of symptom alleviation, reduced morbidity, or improved survival rates.
Methods and Results: The Perindopril for Elderly People with Chronic Heart Failure (PEP-CHF) trial was a randomized, double-blind study designed to evaluate the effects of perindopril against placebo. The study enrolled patients aged 70 years or older with a heart failure diagnosis, who were already receiving diuretic therapy. Echocardiographic evidence of diastolic dysfunction was required for inclusion, while patients with significant left ventricular systolic dysfunction or valve disease were excluded. Participants were randomized to receive either perindopril at a dose of 4 mg/day or placebo. The primary endpoint was a composite outcome of all-cause mortality and unplanned hospitalization related to heart failure, assessed over a minimum follow-up period of one year.
A total of 850 patients were included in the randomization. The average age of participants was 76 years (SD 5), and 55% were female. The median follow-up duration was 2.1 years (interquartile range 1.5-2.8 years). Patient recruitment and event rates were lower than initially projected, which reduced the study’s statistical power to detect a difference in the primary endpoint to 35%. A significant proportion of patients discontinued their assigned treatment regimen after one year, with 28% in the perindopril group and 26% in the placebo group transitioning to open-label ACE-inhibitors. Over the entire study duration, 107 patients in the placebo group and 100 patients in the perindopril group reached the primary endpoint (Hazard Ratio [HR] 0.919; 95% Confidence Interval [CI] 0.700-1.208; P = 0.545). However, at the one-year mark, a trend towards reduction in the primary outcome (HR 0.692; 95% CI 0.474-1.010; P = 0.055) and a statistically significant reduction in hospitalization for heart failure (HR 0.628; 95% CI 0.408-0.966; P = 0.033) were observed in the perindopril group. Furthermore, improvements in functional class (P<0.001), New York Heart Association (NYHA) class (P=0.022), and exercise tolerance as measured by the six-minute walk test (6MWT) (P=0.029) were also noted in the perindopril group at one year.
Conclusion: Due to the limited statistical power of this study concerning its primary endpoint, uncertainties persist regarding the long-term effects of perindopril on morbidity and mortality in this specific clinical context of elderly patients with heart failure and diastolic dysfunction. Nevertheless, the observed improvements in symptoms and exercise capacity, along with the reduced incidence of heart failure-related hospitalizations during the first year of treatment with perindopril – the period when most patients adhered to their assigned therapy – suggest that perindopril may offer clinical benefits for this patient population in the management of diastolic heart failure, particularly in the early stages of treatment.
