PEP-CHF hints at functional benefits but fails to show clinical gains for ACE inhibitor in "diastolic" HF

September 03, 2006

Barcelona, Spain - The addition of an ACE inhibitor to diuretics appeared to alleviate symptoms and boost exercise capacity but failed to show a significant effect on clinical outcomes in a randomized, controlled trial of patients with heart failure and preserved LV function presented at the World Congress of Cardiology 2006.

Although neither finding from the Perindopril in Elderly People with Chronic Heart Failure (PEP-CHF) study can be called conclusive, the study provides qualified support for ACE-inhibitor therapy in a population for which there is scant available data for guiding management decisions, according to Dr John GF Cleland (University of Hull, UK), who presented the results here today. Indeed, he told heart wire , PEP-CHF provides "more convincing evidence" for a benefit from drug therapy than has been demonstrated in the few other trials of patients with so-called "diastolic" HF. "This is the first study to show a clear effect of a treatment other than diuretics on symptoms in this patient group."

Cleland told heart wire that, based on PEP-CHF, ACE inhibitors are a "logical" choice for the typical patient with HF and preserved LV function. But he cautioned against making too much of the trial's findings, because it failed to show a significant perindopril effect on the primary end point, a composite of all-cause mortality or HF hospitalization and because of the trial's other limitations. Patient enrolment was slow and was ultimately stopped short of the planned target of 1000, he told reporters at a press conference. And the number of observed clinical events was "dramatically lower than anticipated," which also weakened the trial's statistical strength.

As presented at the meeting, the PEP-CHF trial randomized 850 HF patients who were at least 70 years of age and had an LVEF of >45% and echocardiographic features suggesting possible diastolic dysfunction to receive perindopril at 4 mg/day or placebo.

Perindopril-related reductions in the primary end point after one year fell short of significance overall (p=0.055) and were significant or nearly so in several subgroups, including patients aged 75 or younger (p=0.035), those with systolic hypertension (p=0.055), or those with a prior MI (p=0.004). Significant improvements were observed compared with the placebo group in some secondary end points, including the proportion of patients in NYHA functional class 1 (p<0.03) and change in six-minute-walk distance (p=0.02) over the total mean follow-up averaging 26 months.

One-year outcomes in PEP-CHF, perindopril vs placebo

End point Perindopril, n=424 (%) Placebo, n=426 (%) p
All-cause mortality or unplanned HF hospitalization 10.8 15.3 0.055
Unplanned HF hospitalization 8.0 12.4 0.033
All-cause mortality 4.0 4.5 NS

Hazard ratios for end points in the perindopril group compared with placebo controls

End point HR (95% CI) p
All-cause mortality or unplanned HF hospitalization (total follow-up) 0.92 (0.70-1.21) 0.545
All-cause mortality or unplanned HF hospitalization (1 year) 0.69 (0.47-1.01) 0.055
Unplanned HF hospitalization (1 year) 0.63 (0.41-0.97) 0.033

In an interview with heartwire , heart-failure expert Dr Kenneth Dickstein (University of Bergen, Stavanger, Norway) called the PEP-CHF data "impressive" despite the lack of a difference in the primary end point. The significant secondary outcomes, he said, very closely resembled trends seen in the CHARM-Preserved trial of candesartan in a similar patient population. Taken together, PEP-CHF and CHARM-Preserved strongly suggest that "these drugs," those that inhibit the renin-angiotensin system, "can improve the status of patients with heart failure and preserved left ventricular function." Dickstein observed, however, that it would be premature actually to recommend such therapy based on these trials.

Hazard ratio for all-cause mortality or unplanned HF hospitalization at 1 year by subgroups

Patient subgroups HR (95% CI) p
Age <75 years 0.53 (0.29-0.97) 0.035
Age >75 years 0.87 (0.53-1.42) 0.575
Systolic BP <140 0.79 (0.50-1.24) 0.303
Systolic BP >140 0.52 (0.26-1.03) 0.055
History of MI 0.38 (0.19-0.75) 0.004
No MI history 0.92 (0.58-1.46) 0.719
The PEP-CHF trial was funded by Servier Laboratories.


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