GUSTO IV-ACS Lacks Vigor; COPERNICUS Affirmed
Hotline sessions at the 22nd Annual Congress of the European Society of Cardiology in Amsterdam were meant to be topical, but the results of two studies released August 27 and 28, 2000, made the biggest news for totally opposite reasons. The GUSTO IV-ACS (Global Use of Strategies to Open Occluded Arteries in Acute Coronary Syndromes) Phase III trial designed to evaluate the safety and efficacy of abciximab (a glycoprotein IIb/IIIa inhibitor) in patients with acute coronary syndromes showed that the drug—one of a fairly new class of drugs—did not show a statistically significant benefit over the placebo. By contrast, the COPERNICUS (CarvedilOl ProspEctive RaNdomIsed CUmulative Survival) trial demonstrated that patients with heart failure receiving the β-blocker carvedilol had a 35% lower risk of dying than patients treated with placebo. This confirmed the decision of the study’s data safety and monitoring board in March 2000 to halt the study because the treatment arm showed significant survival advantage.
Maarten Simoons, MD, professor of cardiology at the University of Rotterdam in the Netherlands and a principle investigator of the GUSTO trial expressed surprise at the results. He stated that the drug presented no greater risk than placebo and no greater benefit. When asked about the implications, he said, “Well, in the Netherlands, this saves millions.” He stated that the cost of the drug—as much as $1000 per treatment in the Netherlands and between $1200 and $1500 in the United States—had threatened to increase health budgets around the world.
Dr. Simoons hastened to add that the study does not suggest that abciximab or the class of drugs is useless. At least 9 studies have confirmed that the drug is valuable when patients receive percutaneous transluminal coronary angioplasty—either with stents or balloon alone. However, he said, the study seems to show that the drug is not valuable when used as a stand-alone treatment in this group. Researchers had hoped that the drug would help patients avoid surgery or angioplasty. All the data seemed to point that way, said Dr. Simoons; however, this study demonstrated the value of doing such clinical research.
A total of 7800 subjects were enrolled in the trial. All had chest pain, which indicated myocardial ischemia with either ST-segment depression or elevated Troponin T or I levels.
The study was international in scope with 458 sites worldwide including Western and Eastern Europe, North America, South Africa, Australia, and New Zealand. Patients were randomly assigned to 3 groups: placebo, abciximab bolus and 24-h infusion, and abciximab and 48-h infusion. At 30 days, the combined endpoint of death or myocardial infarction was 8% in the placebo group, 8.2% in abciximab patients who received treatment for 24 h, and 9.1% in those who received the drug for 48 h.
Dr. Simoons said that the study group plans a multi-variant analysis of the patients to determine the results according to the risks faced by the patients. However, he doubted that the drug would be used in patients in the absence of other interventions. Abciximab currently is approved for patients undergoing angioplasty and for patients with unstable angina not responding to conventional medical therapy when angioplasty is planned within 24 h. “The surprising findings from this trial are likely to generate considerable debate among cardiologists about the benefits of this class of agents when (percutaneous) coronary intervention is not planned,” said Dr. Simoons.
By contrast, the results of the COPERNICUS trials should impel physicians to change treatment of patients with heart failure, said Milton Packer, MD, from Columbia University College of Physicians and Surgeons in New York and the trial’s principle investigator. “These results adds considerably to the existing mandate that patients with heart failure should receive a β-blocker to improve symptoms and to prolong life “The COPERNICUS trial (together with the results of the US Carvedilol Program) shows that carvedilol is effective and well tolerated across the entire spectrum of patients with heart failure. We expect that this study will motivate physicians to take action to address the tremendous underutilization of this drug in appropriate patients with impaired cardiac function.”
The study enrolled 2289 patients at 334 centers. All patients received the conventional therapy of diuretics, ACE inhibitors, and usually digitalis. One group of patients received carvedilol in addition to these treatments; a second group received placebo. All patients had symptoms at rest or on minimal exertion and had a left ventricular ejection fraction <25%. All patients received treatment for as long as 29 months. The trial was stopped in March 2000 because of evidence that the treatment arm had a survival benefit. All patients in the study were offered open-label treatment with carvedilol.
Patients who received the β-blocker had an annual mortality rate of 11.4%. Those receiving placebo had an annual mortality of 18.5%. Dr. Packer said the difference was statistically significant and clinically important. He said there was benefit in all subgroups of patients, including women and the elderly.
Dr. Packer believes the study was important because it proved the benefit of the drug for patients with severe heart failure. It previously had been shown to provide benefit in mild to moderate disease in the US Carvedilol Trials program.
Polio Vaccine-AIDS Link Appears Questionable
Tests of 1950s-era polio vaccine performed by three independent laboratories failed to find traces of HIV type 1 or the related simian immunodeficiency virus (SIV), according to information released by Claudio Basilico, MD, Chairman of Microbiology at New York University Medical Center. The tests also failed to find DNA that would indicate that cells from chimpanzees were used to prepare the vaccine.
The tests came about because of a theory that the AIDS epidemic in Africa could have stemmed from an oral polio vaccine administered to people in the Belgian Congo in the late 1950s. The hypothesis first surfaced in an article in Rolling Stone magazine, and it has been proposed again by Edward Hooper in his book The River (Little, Brown and Co., 1999). Mr. Hooper states that cells from chimpanzees had been used in the preparation of the vaccine. However, according to a press release from the Wistar Institute in Philadelphia, where the vaccine was first made, the laboratory results identified only cells from the Asian macaque monkey. This confirmed information from Hilary Koprowski, MD, and Stanley Plotkin, MD, the two former Wistar scientists who developed the vaccine. “There is nothing in the results from these tests to support the theory that HIV entered the human population during the late 1950s poliovirus clinical trials in Africa,” said Dr. Basilico.
Three laboratories agreed to test the samples: Dr. Shirley Kwok, Roche Molecular Systems, Pleasanton, CA; Dr. Svante Paabo, Max Planck Institute, Leipzig, Germany; and Dr. Simon Wain-Hobson, Institut Pasteur, Paris, France. The results were presented at a seminar on the origin of AIDS at London’s Royal Society on September 11, 2000.
The World Health Organization (WHO) released a statement that genetic sequencing data suggest that HIV first entered the human population around 1930, at least 2 decades before the polio vaccine trials were performed. In addition, production of the experimental polio vaccine in question included treatment with the enzyme trypsin, as well as freezing, thawing, and filtration. Any of those procedures would have destroyed either HIV or SIV.
- Copyright © 2000 by American Heart Association