Perindopril May Improve Diastolic Heart Failure

BARCELONA — Treatment with the ACE inhibitor perindopril appeared to help elderly patients with left ventricular diastolic dysfunction in a study with about 850 patients.

The study was plagued by underenrollment and by many patients changing medications from their assigned study regimens, and this may explain why the results failed to show a statistically significant difference in favor of perindopril for the primary end point of all-cause death or unplanned hospitalization for heart failure. But post hoc and secondary analyses of the data suggested that treatment with the ACE inhibitor led to improved patient outcomes, including fewer hospitalizations for heart failure, fewer days in the hospital, improved heart failure status, and improved exercise capacity, Dr. John G.F. Cleland reported at a joint meeting of the European Society of Cardiology and the World Heart Federation.

“These data should not be wasted due to methodologic problems; we need to understand what the data are telling us,” commented Dr. Kenneth Dickstein, a cardiologist and professor of medicine at the University of Bergen in Stavanger, Norway. Agreeing with Dr. Cleland's interpretation, Dr. Dickstein concluded that the results “support a role for inhibition of the renin-angiotensin system in patients with heart failure and preserved systolic function.”

This finding is important because although blockade of the renin-angiotensin system with an ACE inhibitor or angiotensin-receptor blocker is standard treatment for LV systolic dysfunction, scant data exist to prove the treatment's value in patients with preserved LV function and diastolic dysfunction. The only study to address this until now was the Candesartan in Heart Failure—Assessment of Reduction in Mortality and Morbidity (CHARM) trial, specifically the CHARM-Preserved part of the study that assessed the efficacy of candesartan in patients with heart failure and a LV ejection fraction of at least 40% (Lancet 2003;362:777–81). The new findings are consistent with the CHARM-Preserved results, Dr. Dickstein said.

The Perindopril in Elderly People With Chronic Heart Failure (PEP-CHF) study enrolled patients aged 70 or older with evidence of diastolic dysfunction. The only background medication that patients had to receive was a diuretic. Patients were randomized to treatment with either 2 mg/day perindopril or placebo. The perindopril dosage was later raised to 4 mg/day if patients had no contraindication to the increased dosage.

The study was sponsored by Servier, which markets perindopril (Acenon). Dr. Cleland and his associates received payments from Servier for working on the study.

The initial statistical calculations called for enrolling about 1,000 patients into the trial, but only 852 entered the study because of slow recruitment. The average age of the enrolled patients was 75, and their average LV ejection fraction was about 65%. About three-quarters of patients had New York Heart Association class I or II heart failure.

Although 90% of patients remained on their assigned therapy after their first year in the study, after 18 months about 40% of patients had stopped their assigned regimen, which Dr. Cleland attributed to the difficulty of keeping older patients on a blinded regimen. Another problem was a much lower than anticipated event rate. The study design anticipated that 50% of patients would have the primary end point of death or heart-failure hospitalization each year. Instead, the actual rate for this end point was 12.7%. Patients were followed for an average of 2.2 years.

For the complete follow-up period, the incidence of the primary end point had a relative rate reduction of 8% in the patients treated with perindopril, a nonsignificant difference. Perindopril treatment also failed to produce a significant reduction in unplanned hospitalizations for heart failure.

But in a post-hoc analysis that focused only on outcomes during the first year of follow-up, when most patients remained on their assigned regimen, the incidence of the primary end point was 10.8% in the perindopril group and 15.3% in the placebo group, a 31% relative reduction that was statistically significant. Also at 1 year, the incidence of unplanned heart failure hospitalizations was reduced by 37% in the perindopril group, compared with the placebo group, also a significant difference.

The 1-year results “are probably the truth and what the study is trying to tell us,” Dr. Dickstein commented.

Additional analysis of data collected in PEP-CHF indicated that patients with a serum level of N-terminal pro-brain natriuretic peptide (NT-proBNP, a marker of cardiac stress) below the median of 400 pg/mL had event rates similar to those in the normal elderly population. In contrast, patients whose level was above the median had event rates that were similar to those in patients with systolic heart failure who benefited when they were treated with perindopril. This finding suggested that NT-proBNP might be a useful marker for predicting the efficacy of ACE inhibitor treatment in patients with diastolic heart failure, Dr. Cleland said in an interview.

BARCELONA — Treatment with the ACE inhibitor perindopril appeared to help elderly patients with left ventricular diastolic dysfunction in a study with about 850 patients.

The study was plagued by underenrollment and by many patients changing medications from their assigned study regimens, and this may explain why the results failed to show a statistically significant difference in favor of perindopril for the primary end point of all-cause death or unplanned hospitalization for heart failure. But post hoc and secondary analyses of the data suggested that treatment with the ACE inhibitor led to improved patient outcomes, including fewer hospitalizations for heart failure, fewer days in the hospital, improved heart failure status, and improved exercise capacity, Dr. John G.F. Cleland reported at a joint meeting of the European Society of Cardiology and the World Heart Federation.

“These data should not be wasted due to methodologic problems; we need to understand what the data are telling us,” commented Dr. Kenneth Dickstein, a cardiologist and professor of medicine at the University of Bergen in Stavanger, Norway. Agreeing with Dr. Cleland's interpretation, Dr. Dickstein concluded that the results “support a role for inhibition of the renin-angiotensin system in patients with heart failure and preserved systolic function.”

This finding is important because although blockade of the renin-angiotensin system with an ACE inhibitor or angiotensin-receptor blocker is standard treatment for LV systolic dysfunction, scant data exist to prove the treatment's value in patients with preserved LV function and diastolic dysfunction. The only study to address this until now was the Candesartan in Heart Failure—Assessment of Reduction in Mortality and Morbidity (CHARM) trial, specifically the CHARM-Preserved part of the study that assessed the efficacy of candesartan in patients with heart failure and a LV ejection fraction of at least 40% (Lancet 2003;362:777–81). The new findings are consistent with the CHARM-Preserved results, Dr. Dickstein said.

The Perindopril in Elderly People With Chronic Heart Failure (PEP-CHF) study enrolled patients aged 70 or older with evidence of diastolic dysfunction. The only background medication that patients had to receive was a diuretic. Patients were randomized to treatment with either 2 mg/day perindopril or placebo. The perindopril dosage was later raised to 4 mg/day if patients had no contraindication to the increased dosage.

The study was sponsored by Servier, which markets perindopril (Acenon). Dr. Cleland and his associates received payments from Servier for working on the study.

The initial statistical calculations called for enrolling about 1,000 patients into the trial, but only 852 entered the study because of slow recruitment. The average age of the enrolled patients was 75, and their average LV ejection fraction was about 65%. About three-quarters of patients had New York Heart Association class I or II heart failure.

Although 90% of patients remained on their assigned therapy after their first year in the study, after 18 months about 40% of patients had stopped their assigned regimen, which Dr. Cleland attributed to the difficulty of keeping older patients on a blinded regimen. Another problem was a much lower than anticipated event rate. The study design anticipated that 50% of patients would have the primary end point of death or heart-failure hospitalization each year. Instead, the actual rate for this end point was 12.7%. Patients were followed for an average of 2.2 years.

For the complete follow-up period, the incidence of the primary end point had a relative rate reduction of 8% in the patients treated with perindopril, a nonsignificant difference. Perindopril treatment also failed to produce a significant reduction in unplanned hospitalizations for heart failure.

But in a post-hoc analysis that focused only on outcomes during the first year of follow-up, when most patients remained on their assigned regimen, the incidence of the primary end point was 10.8% in the perindopril group and 15.3% in the placebo group, a 31% relative reduction that was statistically significant. Also at 1 year, the incidence of unplanned heart failure hospitalizations was reduced by 37% in the perindopril group, compared with the placebo group, also a significant difference.

The 1-year results “are probably the truth and what the study is trying to tell us,” Dr. Dickstein commented.

Additional analysis of data collected in PEP-CHF indicated that patients with a serum level of N-terminal pro-brain natriuretic peptide (NT-proBNP, a marker of cardiac stress) below the median of 400 pg/mL had event rates similar to those in the normal elderly population. In contrast, patients whose level was above the median had event rates that were similar to those in patients with systolic heart failure who benefited when they were treated with perindopril. This finding suggested that NT-proBNP might be a useful marker for predicting the efficacy of ACE inhibitor treatment in patients with diastolic heart failure, Dr. Cleland said in an interview.

BARCELONA — Treatment with the ACE inhibitor perindopril appeared to help elderly patients with left ventricular diastolic dysfunction in a study with about 850 patients.

The study was plagued by underenrollment and by many patients changing medications from their assigned study regimens, and this may explain why the results failed to show a statistically significant difference in favor of perindopril for the primary end point of all-cause death or unplanned hospitalization for heart failure. But post hoc and secondary analyses of the data suggested that treatment with the ACE inhibitor led to improved patient outcomes, including fewer hospitalizations for heart failure, fewer days in the hospital, improved heart failure status, and improved exercise capacity, Dr. John G.F. Cleland reported at a joint meeting of the European Society of Cardiology and the World Heart Federation.

“These data should not be wasted due to methodologic problems; we need to understand what the data are telling us,” commented Dr. Kenneth Dickstein, a cardiologist and professor of medicine at the University of Bergen in Stavanger, Norway. Agreeing with Dr. Cleland's interpretation, Dr. Dickstein concluded that the results “support a role for inhibition of the renin-angiotensin system in patients with heart failure and preserved systolic function.”

This finding is important because although blockade of the renin-angiotensin system with an ACE inhibitor or angiotensin-receptor blocker is standard treatment for LV systolic dysfunction, scant data exist to prove the treatment's value in patients with preserved LV function and diastolic dysfunction. The only study to address this until now was the Candesartan in Heart Failure—Assessment of Reduction in Mortality and Morbidity (CHARM) trial, specifically the CHARM-Preserved part of the study that assessed the efficacy of candesartan in patients with heart failure and a LV ejection fraction of at least 40% (Lancet 2003;362:777–81). The new findings are consistent with the CHARM-Preserved results, Dr. Dickstein said.

The Perindopril in Elderly People With Chronic Heart Failure (PEP-CHF) study enrolled patients aged 70 or older with evidence of diastolic dysfunction. The only background medication that patients had to receive was a diuretic. Patients were randomized to treatment with either 2 mg/day perindopril or placebo. The perindopril dosage was later raised to 4 mg/day if patients had no contraindication to the increased dosage.

The study was sponsored by Servier, which markets perindopril (Acenon). Dr. Cleland and his associates received payments from Servier for working on the study.

The initial statistical calculations called for enrolling about 1,000 patients into the trial, but only 852 entered the study because of slow recruitment. The average age of the enrolled patients was 75, and their average LV ejection fraction was about 65%. About three-quarters of patients had New York Heart Association class I or II heart failure.

Although 90% of patients remained on their assigned therapy after their first year in the study, after 18 months about 40% of patients had stopped their assigned regimen, which Dr. Cleland attributed to the difficulty of keeping older patients on a blinded regimen. Another problem was a much lower than anticipated event rate. The study design anticipated that 50% of patients would have the primary end point of death or heart-failure hospitalization each year. Instead, the actual rate for this end point was 12.7%. Patients were followed for an average of 2.2 years.

For the complete follow-up period, the incidence of the primary end point had a relative rate reduction of 8% in the patients treated with perindopril, a nonsignificant difference. Perindopril treatment also failed to produce a significant reduction in unplanned hospitalizations for heart failure.

But in a post-hoc analysis that focused only on outcomes during the first year of follow-up, when most patients remained on their assigned regimen, the incidence of the primary end point was 10.8% in the perindopril group and 15.3% in the placebo group, a 31% relative reduction that was statistically significant. Also at 1 year, the incidence of unplanned heart failure hospitalizations was reduced by 37% in the perindopril group, compared with the placebo group, also a significant difference.

The 1-year results “are probably the truth and what the study is trying to tell us,” Dr. Dickstein commented.

Additional analysis of data collected in PEP-CHF indicated that patients with a serum level of N-terminal pro-brain natriuretic peptide (NT-proBNP, a marker of cardiac stress) below the median of 400 pg/mL had event rates similar to those in the normal elderly population. In contrast, patients whose level was above the median had event rates that were similar to those in patients with systolic heart failure who benefited when they were treated with perindopril. This finding suggested that NT-proBNP might be a useful marker for predicting the efficacy of ACE inhibitor treatment in patients with diastolic heart failure, Dr. Cleland said in an interview.