Recent Clinical Trial Updates
BERLIN, Germany—One year into the Trial of Medical Therapy versus Invasive in the Elderly (TIME), improvements in angina and measures of quality of life previously seen in older patients who had been randomized to receive either optimal anti-ischemic drug therapy or revascularization by either percutaneous intervention or coronary artery bypass graft continued. However, larger benefits noted at 6 months in the revascularized group disappeared at 12 months.
The reason, however, according to Dr Matthias Pfisterer of the University Hospital in Basel, Switzerland, was that 46% of patients in the medical group underwent a revascularization period in that later period. The remaining patients, he said, had more angina and lower quality-of-life scores than those in the original revascularized group. (Eleven percent of the invasively treated group also underwent a further revascularization.)
The study involved 301 patients who had been randomized to either the medical treatment or angiography and revascularization if needed. In that group, 70% of patients underwent PCI and 30% coronary artery bypass grafting. In the earlier analysis, patients who had revascularization had higher mortality rates (although they were not statistically significant), said Dr Pfisterer. However, the 1-year mortality rates were essentially the same. “The overall benefits outweighed the early risks of revascularization,” he said. He said patients aged >75 years should probably be offered an evaluation for revascularization treatment just as younger ones are.
In the Prevention of Atrial Fibrillation After Cardioversion (PAFAC) trial, Thomas Fetsch, MD, of the University of Münster in Germany, said the intent was to find a safer therapy. The finding that a combination of quinidine and verapamil was safer than sotalol continued >2 years into the study’s follow-up. “The most important thing for the future is to compare quinidine and verapamil to amiodarone,” he said.
Results from two studies of omapatrilat, a vasopeptidase inhibitor, gave scant positive information about the drug which an advisory committee of the US Food and Drug Administration refused to approve for the treatment of hypertension in July 2002, citing high numbers of side effects. The Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril (OCTAVE) trial, first presented at the Atlanta meeting of the American College of Cardiology in March 2002, demonstrated that the drug was more effective at reducing blood pressure than enalapril, but that the side effects from the drug appeared to outweigh this benefit. In subgroup analyses of the drug’s effects, presented at the European Society of Cardiology meetings in Berlin, Michael A. Weber, MD, of Downstate Medical College at State University of New York, found that the drug was significantly more effective in patients with severe atherosclerosis. “Even in people getting 3 medications in addition to study medications, there was still a large difference in efficacy between the two groups,” he said during the Recent Clinical Trials Update II portion of the meeting on September 4, 2002. Omapatrilat also had a distinct advantage in patients with diabetes, he said.
However, Dr Weber and others involved in the study are concerned about angioedema, which is roughly 3 times higher than that seen in the enalapril or ACE inhibitor group. Juerg Nussberger, MD, of the Hypertension Division, University Hospital Lausanne, Switzerland, however, did not feel that there were sufficient enrollees in the subgroups. “I was not aware you could draw conclusions from 9% of the population. Omapatrilat decreases blood pressure more than enalapril, but it induces 3 times more angioedema than enalapril.”
The risk of angioedema could be even higher in the omapatrilat population because the people enrolled in the OCTAVE trial were selected because they could take ACE inhibitors safely, he said. “If you take ACE or NEP/ACE inhibitors, angioedemas have to be expected.” Dr Weber agreed that concerns about angioedema are valid.
“It would be delightful to identify those people most likely to have an episode of angioedema on an ACE or vasopeptidase inhibitor,” he said. However, he pointed out that only 2 individuals in the entire OCTAVE study suffered life-threatening angioedemas. “To this date, there have been zero deaths.”
In the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE), researchers demonstrated omapatrilat’s “noninferiority” to enalapril, said Milton Packer, MD, Professor of Medicine at Columbia University College of Physicians and Surgeons in New York and director of the study. “It would have been better than placebo, if that had been included in the study. This study did not confirm our hope that the combination of ACE/NEP inhibition would be better than ACE inhibition alone.”
In explaining why the primary hypothesis was not achieved, Dr Packer said there were 4 possible reasons:
Omapatrilat is not better than enalapril.
There was a problem with the end point selected for the trial.
There was a problem with the way in which omapatrilat was given.
There was a problem with patient selection.
Because his study dealt with heart-failure patients, he said the problems with angioedema were not severe, perhaps because “people in heart failure are resistant to this.”
Later, during a press conference, he described the results of OCTAVE as “tantalizing.” Dr Packer went on to say, “I’ve learned humility from this. It is the heartbreak of clinical trials. It highlights the enormous continuing challenge of how to design clinical trials.”
The original results of the Perindopril pROtection aGainst REcurrent Stroke Study (PROGRESS) showed that 1 in every 11 stroke sufferers given perindopril together with another drug, indapamide, avoided death, heart attack, or further stroke over 5 years of treatment. In a new analysis of the results, investigators also found a statistically significant 26% reduction in the risk of cardiac events such as myocardial infarction or death by coronary heart effect.
The drug combination also reduced heart failure significantly, according to Anushka Patel, MD, of the University of Sydney in Australia. Peter Sleight, MD, of the Department of Cardiovascular Medicine at John Radcliffe Hospital, University of Oxford, United Kingdom, said the major benefit of the PROGRESS trial is that it gives good evidence that blood pressure should be lowered after stroke. “Some people feared it would cause cerebral ischemia,” he said.
“PROGRESS shows the value of lowering normal levels of risk factors in high risk patients,” said Dr Sleight. “This reduces all vascular events, not just the presenting one. However, we still do not know what to do about blood pressure in the acute phase of stroke.”
He said he would like to see some information on the effect of the diuretic alone and how much it contributed to the effect seen.
In what was a tour de force for the entire session, Philip Jong, PhD, of the University of Toronto, and Salim Yusuf, MD, Professor of Medicine at McMaster University in Hamilton, Ontario, Canada, described the 12-year results of the Studies of Left Ventricular Dysfunction (SOLVD)—the so-called extended or XSOLVD studies.
SOLVD evaluated enalapril use for ≈3 to 4 years and compared it with placebo. The study consisted of 2 components. The treatment trial, which included patients with heart failure, found that enalapril reduced mortality. The second, or prevention part of the study, involved patients with asymptomatic left ventricular dysfunction. In this trial, enalapril reduced the rates of new hospitalizations and MI, but did not have a significant reduction in mortality.
After the trial was completed, patients would be treated similarly, and scientists anticipated new benefits. For that reason, patients were all monitored for an average of 12 years. In the prevention trial, 50.9% of the enalapril group and 56.4% of the placebo group patients died. In the treatment trial, the benefits in terms of reduced mortality were sustained for ≈5 years after the end of the study. After that time, the rates of mortality began to converge. After 12 years, 79.8% of patients in the enalapril group had died, compared with 80.8% in the placebo group, according to the investigators.
Enalapril extended the median survival by 9.2 months in the prevention trial and by 8.6 months in the treatment trial. The researchers concluded: “These data suggest trials of 3- to 4-year intervention are probably too short to fully evaluate the long-term benefits of ACE-Inhibitors. In particular in less symptomatic patients, the full benefits of treatment may only emerge after several years of follow-up. Moreover, even the SOLVD extended follow-up study may be underestimating the true long-term benefits of 10-12 years of treatment because after the end of the study, patients were most probably treated similarly in the active and placebo group.”
Dr Yusuf pointed out that the original benefits seen in the SOLVD trials were sustained in the treatment portion and amplified in the prevention trial for a further decade.
Karl Swedberg, MD, of Sahlgrenska Univerity in Göteborg, Sweden, in his commentary on the trial noted, “SOLVD had a major impact on the acceptance of ACE inhibitors in the treatment of chronic failure.” He said the 12 years had proved the importance of such treatment and recommended that plans for long-term follow-up should be discussed during the designing of randomized trials.
“These are lifelong therapies. Translating treatment effects seen in short-term trial to long-term effects is difficult,” said Dr Swedberg.
This Week in Circulation
Wine Reduces Risk of Cardiovascular Complications in Patients Who Have Had Myocardial Infarctions
Individuals who drank wine in moderation after suffering a heart attack had significant reductions in heart disease complications in the 4 years after their initial event, compared with people who did not drink, according to French researchers in a report in this week’s issue of Circulation (Circulation. 2002;106:1465–1469).
In the study led by Michel de Lorgeril, MD, of the Laboratoire du Stress Cardiovaculaire et Pathologies Associees, Universite Joseph Fourier de Grenoble, France, the researchers evaluated the drinking and dietary habits of 437 patients who had had a recent myocardial infarction and monitored them for an average of 4 years. There were 104 cardiovascular complications.
Patients whose average ethanol intake was 7.7% of the average total energy intake (about 2 drinks per day) had a 59% percent reduction in cardiovascular complications and those who drank about 4 drinks per day (16% of their total energy intake) had a 52% reduction in cardiovascular complications.
The authors concluded: “Despite a small sample size, this investigation suggests that in a very homogeneous population of patients with established CHD [coronary heart disease], after controlling for many potential confounders, wine drinking is associated with a reduced risk of CVD [cardiovascular disease] complications after a recent AMI [acute myocardial infarction]. Further studies are required to confirm the data, however, and to examine whether the relations found are due to ethanol or to other wine ingredients.”