MedWire - ESC (Munich, Germany), September 2, 2008: Two new analyses of data from the EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) were presented during the Clinical Trial Update II Session held today at the European Society of Cardiology (ESC) congress.
The first analysis showed that, in patients with stable coronary artery disease (CAD), a resting heart rate (RHR) of 75 beats per minute (bpm) or more is associated with increased total and cardiovascular mortality, and hospitalization for heart failure (HF), in comparison with a RHR under this threshold. The second analysis discussed the “ synergistic effect” of perindopril and calcium channel blockers (CCBs), which were used in the trial for the prevention of cardiac events and death.
Prognostic value of resting heart rate
Dr. Roberto Ferrari, University of Ferrara, Italy
“It is becoming evident that heart rate is an independent predictor of all-cause and of cardiovascular mortality in the general population, in patients with CAD and left ventricular dysfunction or hypertension, and in patients undergoing bypass surgery,” said Professor Ferrari, the ESC President-Elect. He commented that this was evident not only from the published data but also from data presented at the 2008 ESC meeting - referring specifically to the
BEAUTIFUL study.
“However, there are no data on the prognostic role of heart rate in CAD patients without HF on optimal preventative treatment,” he added. Thus, a re-analysis of the EUROPA data was performed to see what effect, if any, RHR would have on patient outcome.
EUROPA involved over 12,000 patients who had stable CAD without HF and who were optimally treated and followed-up for a mean time of 4.2 years. Professor Ferrari noted that the results of the study were originally reported at the ESC Congress in 2003 and subsequently published in
The Lancet. [1]
The aim of this prospective, randomised, double-blind, placebo-controlled, multicenter trial was to see if treatment with the angiotensin-converting enzyme (ACE)-inhibitor perindopril had benefits beyond its blood-pressure lowering capabilities. The key finding was that, in comparison with placebo, treatment with the ACE-inhibitor produced a relative risk reduction (RRR) of 20% in the primary, composite endpoint of cardiovascular death, nonfatal myocardial infarction (MI), and resuscitated cardiac arrest at 5 years (
p=0.0003).
For the current analysis, the baseline RHRs of patients enrolled in the EUROPA trial were obtained and used to see if there was any effect of RHR on patient outcomes at 5 years. Patients were divided into two groups: those with an RHR of <75 bpm (n=9071) and those with an RHR of ≥ 75 bpm (n=3134).
Professor Ferrari noted that there were some clear differences between the groups in terms of baseline characteristics and treatment. Patients with an RHR of ≥75 bpm were more likely to have hypercholesterolemia, high systolic and diastolic blood pressure, diabetes or smoke than those with an RHR of <75 bpm. However, those with the higher heart rate were less likely to be treated with antiplatelet, lipid-lowering, beta-blockers, and CCBs. The use of diuretics was more common in those with the higher heart rate.
After adjusting for age, sex, body mass index, and other baseline factors - including whether or not patients had been randomized to perindopril or placebo - an RHR ≥75 bpm was associated with a 21% significant increase in total mortality, a 24% increase in cardiovascular mortality, and a 51% increase in hospitalization for HF. There was no difference between the groups with regards to the effect of RHR on nonfatal MI, although patients with the higher RHR were more likely to have a fatal MI.
Professor Ferrari concluded that heart rate should “be considered in the risk stratification of CAD patients” and that “ the role of pure heart rate reduction should be tested.”
Discussing these data, Professor Nicolas Danchin (Hôpital Europé en Georges Pompidou, Paris, France) noted that heart rate “should be considered an important parameter and should be measured by clinicians.” However, these data “cannot establish whether elevated heart rate is a true impendent risk factor, or, above all, a marker for future cardiovascular events, possibly related to incipient left ventricular dysfunction.” Professor Danchin said that additional data were needed to see if reducing heart rate
per se would improve outcomes in this patient population.
Synergistic effect of perindopril and CCBs
Professor Michel E. Bertrand, Lille Heart Institute, France
Professor Bertrand presented data from a second new analysis of the EUROPA data, this time looking at the possible synergistic effects of perindopril and CCBs in the prevention of cardiac events and death in patients with CAD. He again noted that the originally published EUROPA data [1] had shown that perindopril confers a significant benefit versus placebo in reducing the risk of cardiovascular death, nonfatal MI, and resuscitated cardiac arrest by 20%.
Two years after the EUROPA data were published, the findings of the blood pressure-lowering arm (BPLA) of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) were made available. [2] These showed that a combination of a CCB, amlodipine, with perindopril was more effective than a beta-blocker plus diuretic combination in reducing cardiovascular mortality (24% RRR;
p=0.001). These results prompted the EUROPA investigators to take a second look at their data, Professor Bertrand explained.
There were two goals of the post-hoc analysis of the EUROPA data. The first was to compare the effect perindopril with placebo on the development of major cardiac events and death. The second was to see if there were any synergistic effects between perindopril and CCBs.
Approximately 17% of patients participating in EUROPA were treated with a CCB throughout the study; 1022 were in the perindopril arm and 1110 in the placebo arm. This meant that 3095 patients had received placebo but no CCBs, and that 3326 had been treated with perindopril but no CCBs. Looking again at the trial’s primary endpoint, it was revealed that the percentage of patients experiencing cardiovascular death, MI, or resuscitated cardiac arrest was lowest in those who were given perindopril plus CCBs (4.89% vs. 6.58% for perindopril with no CCBs; 7.45% for placebo plus CCBs; 7.98% for placebo with no CCBs;
p<0.05 for all comparisons with perindopril plus CCBs).
The combination of perindopril plus CCBs was associated with a 35% RRR in the primary endpoint and a 46% RRR in total mortality compared with placebo plus CCBs, Professor Bertrand reported. There were also less fatal and nonfatal MIs and fewer hospitalizations for HF in the perindopril- plus CCB-treated patients.
Professor Bertrand also reported statistical data showing that there was synergy between the combination of perindopril and CCBs in terms of effects on the various endpoints. “Clinical interaction between perindopril and CCBs suggests a synergistic effect, which deserves further investigation,” he concluded.
However, Professor Peter S. Sever, of Imperial College London, UK, said that the method used to calculate synergy was confusing, although he added that his own estimations brought him to the same conclusion. Although a chance finding cannot be excluded, the possible synergy between an ACE-inhibitor and CCBs is a novel finding and deserves further evaluation.
References- Fox KM; EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 2003;362:782-788.
- Dahlö f B, Sever PS, Poulter NR, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005;366:895-906.
