Perindopril for Elderly People With Chronic Heart Failure - PEP-CHF

Description:

The goal of the trial was to evaluate perindopril compared with placebo in patients age ≥70 years with clinical congestive heart failure (CHF) and preserved left ventricular systolic function.

Hypothesis:

Perindopril therapy in patients age ≥70 years with CHF and preserved left ventricular systolic function will be associated with decreased mortality and fewer admissions for exacerbations of heart failure.

Study Design

Patients Enrolled: 850
Mean Follow Up: Median 2.1 years
Mean Patient Age: Mean age 76 years
Mean Ejection Fraction: Baseline 65%

Patient Populations:

Age ≥70 years; clinical diagnosis of CHF by history/symptoms/signs; treated with diuretics for at least 1 week; no major left ventricular systolic dysfunction; hospitalized for a cardiac disorder (e.g., myocardial infarction, arrhythmia, CHF) within the preceding 3 months; and ambulate without assistance

Exclusions:

Inadequate echocardiographic windows; hemodynamically significant aortic stenosis, mitral stenosis, or outflow tract obstruction; important aortic or mitral regurgitation as determined by the investigator; previous intolerance to ACE inhibitors; serum potassium >5.4 mmol/L or creatinine >200 µmol/L; sitting systolic blood pressure <100 mm Hg; uncontrolled hypertension; stroke within 30 days; unstable angina or hemodynamics; life expectancy <1 year; severe liver disease; intolerance to test dose of perindopril; or contraindication to drug therapy with ACE inhibitor

Primary Endpoints:

Death and unplanned hospitalizations for heart failure

Secondary Endpoints:

Quality of life

Drug/Procedures Used:

During a 24-hour open-label run-in phase, a single dose of perindopril 2 mg will be adminstered to all patients. Patients were randomized to receive perindopril 2 mg/d (n = 424) or matching placebo (n = 426) in a double-blind fashion. Systolic blood pressure, creatinine, and potassium were measured at follow-up. If tolerated, the medication was increased to target maintenance dose of 4 mg daily or withdrawn if there was intolerance to the initial dose.

Principal Findings:

At baseline, New York Heart Association (NYHA) class I or II was present in 75% of patients. Study drug compliance was 90% at 1 year, but dropped to 40% in the perindopril group and 36% in the placebo group by 18 months.

The primary endpoint of death or unplanned hospitalization for heart failure at the end of the study did not differ between treatment groups (hazard ratio [HR] 0.92, p = 0.55). At 1 year, the composite had occurred in fewer patients in the perindopril group compared with the placebo group (10.8% vs. 15.3%, HR 0.69, p = 0.055). Among the components of the primary composite endpoint at 1 year, unplanned hospitalization occurred less frequently in the perindopril group compared with the placebo group (8.0% vs. 12.4%, p = 0.033), but there was no difference in mortality at 1 year and no difference in either component at study end. The composite of cardiovascular death or unplanned HF hospitalization at 1 year, a post-hoc analysis, occurred less frequently in the perindopril group (9.4% vs. 14.8%, p = 0.018). NYHA class at 1 year was more frequently improved in the perindopril group than the placebo group (p < 0.03).

Interpretation:

Among patients age ≥70 years with clinical CHF and preserved left ventricular systolic function, treatment with perindopril did not differ from placebo in the primary endpoint of death or unplanned hospitalizations for HF at the end of study follow-up, but tended to be associated with a reduction in the composite at 1 year.

A major limitation of the trial was the high rate of discontinuation at 18 months (62%), the majority of whom went on open-label angiotensin-converting enzyme (ACE) inhibitors (~90%). Additionally, the event rate in the trial was lower than expected, further reducing the power of the trial. Perindopril appeared favorable at 1-year follow-up when the large majority of patients were on study drug, although these data should not be considered definitive given the post-hoc nature of the analysis.

References:

Cleland JGF, et al. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. European Heart Journal (2006) 27, 2338–2345.

Presented by J.G.F. Cleland, European Society of Cardiology Scientific Congress, September 2006.

Cleland JG, Tendera M, Adamus J, et al. Perindopril for elderly people with chronic heart failure: the PEP-CHF study. The PEP investigators. Eur J Heart Fail 1999;1:211-7.

Clinical Topics: Heart Failure and Cardiomyopathies, Statins, Acute Heart Failure

Keywords: Perindopril, Myocardial Infarction, Potassium, Follow-Up Studies, Diuretics, Heart Failure, Blood Pressure, Creatinine


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