To print: Select File and then Print from your browser's menu --------------------------------------------------------------------------------------- Title: Clopidogrel Demonstrates Superior Benefit in Patients at Risk of Stroke URL: http://www.pslgroup.com/dg/DC1A.htm Doctor's Guide November 13, 1996
NEW ORLEANS, Nov. 13, 1996 -- The CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) study, the largest clinical trial ever conducted on any medicine in development, shows that a new antiplatelet agent, clopidogrel, is significantly more effective than aspirin at reducing the likelihood of ischemic stroke, heart attack or vascular death in at-risk patients. The results of CAPRIE also underscore that blood clots, or thrombi, in diseased blood vessels are a common link among some of the major fatal and disabling diseases of the industrialized world. The CAPRIE study showed statistically significant difference in efficacy between clopidogrel and aspirin: While aspirin prevents about a quarter of strokes, heart attacks (myocardial infarction or MI) or vascular death from occurring in at-risk patients with a previous stroke, heart attack or with peripheral arterial disease (claudication), clopidogrel prevents about one-third of these events. CAPRIE was a three-year, randomized, triple-blind international clinical study which enrolled 19,185 patients who had previously suffered an ischemic stroke, heart attack, or claudication. The study is unique because for the first time patients with three different prior conditions were included in the same single study. Patients in CAPRIE received either 75 mg once daily of clopidogrel or 325 mg per day of aspirin, the current gold standard of anti-platelet therapy. The study was conducted by investigators at almost 400 clinical centers in 16 countries around the world. All the patients entered into CAPRIE have the same underlying disease, atherosclerosis, a disease of the blood vessels that is caused by the build up of fatty plaque deposits in artery walls anywhere in the body. As these plaque deposits bulge up under the surface of the artery wall, they can cause cracks or fissures in the vessel wall. Blood platelets accumulate, or aggregate, around these fissures, and in turn, cause the formation of thrombi, or blood clots that can completely block, or occlude, arteries. This process called atherothrombosis, is the common link which results in ischemic strokes, heart attacks or vascular death. Both aspirin and clopidogrel prevent platelet aggregation that leads to atherothrombosis, but by different mechanisms of action. This study shows that clopidogrel was more effective than aspirin in the population studied. CAPRIE supports the conclusion that a person suffering from any one manifestation of atherothrombosis is at risk of future disabling or life-threatening events caused by the same underlying process. For instance, a patient who has had a myocardial infarction is at increased risk of a stroke as well as of a second heart attack. Clopidogrel More Effective Than Aspirin Previous studies with antiplatelet therapy, primarily aspirin, have demonstrated about a 27% risk reduction in cerebrovascular and cardiovascular events. The CAPRIE study demonstrated that treatment with clopidogrel provided an overall relative risk reduction in ischemic stroke, myocardial infarction or vascular death (the primary outcome cluster for CAPRIE) of 8.7% amongst the 9,599 patients treated with clopidogrel compared with the 9,586 patients treated with aspirin (p = 0.043). This benefit was over and above that achieved with aspirin, which until now has been considered to be the gold standard therapy for these patients. For ethical reasons, CAPRIE could not compare clopidogrel against placebo, since two meta-analyses conducted by the Antiplatelet Trialists' Collaboration have clearly demonstrated the clinical benefit of anti-platelet agents. The later meta-analysis (a comprehensive review of 142 existing studies in the field) showed that in patients who had atherothrombotic conditions such as MI, angina, ischemic stroke, transient ischemic attacks or symptomatic peripheral arterial disease, treatment with aspirin reduced the risk of a further ischemic event or death by 25%. Clopidogrel At Least As Safe As Aspirin The CAPRIE study showed no evidence of any adverse hematological effects with clopidogrel. Specifically, there was no difference in the incidence of neutropenia between the group treated with aspirin (0.17%) and that treated with clopidogrel (0.09%). There was an increase in some minor adverse events (diarrhea, rash and itching) in those patients receiving clopidogrel compared with aspirin, but the observed differences of about 0.1% are considered clinically unimportant. More importantly, CAPRIE showed that patients treated with clopidogrel were significantly less likely to suffer from severe gastrointestinal bleeding than those treated with aspirin. This finding is particularly striking since the study population had been rigorously selected to exclude those patients with a history of ulcers or gastrointestinal bleeding. The study showed no other clinically relevant differences in clinical or biological effects between the groups. CAPRIE Studied World's Leading Contributors to Disability and Death Up to one in ten people in the developed world have a history of either coronary artery disease (heart attack or angina pectoris), ischemic stroke or claudication. Anyone who has had a recent ischemic stroke or heart attack, or who has claudication is at much higher risk of disability or death from future strokes or heart attacks. Stroke is the leading cause of serious long-term disability in the developed world and most survivors have reduced activity and quality of life. About one in three people who suffer a heart attack or stroke die within a year. Moreover, over a period of five years, 25% to 30% of patients with claudication will also have suffered a heart attack, a stroke or vascular death, a fact that is consistent with the shared atherothrombotic pathophysiology of these conditions. Clopidogrel Fulfills a Clinical Need for More Effective, Safer and Better-Tolerated Antiplatelet Drugs Clopidogrel is a promising new antiplatelet agent which prevents blood clot formation inside an atherosclerotic artery by inhibiting platelet activation and aggregation. It inhibits platelet aggregation by specific and potent blockade of the platelet ADP receptor, specifically affecting ADP dependent activation of the GP IIb/IIIa complex, which is the major receptor of fibrinogen present on the platelet surface. The Clinical Trials Methodology Group at McMaster University, Hamilton, Ontario, Canada, served as the CAPRIE Co-ordinating and Methods Centre. The study was initiated and implemented jointly by Sanofi, the discoverer of clopidogrel, the Clinical Trials Methodology Group at McMaster University and the CAPRIE Steering Committee. The study sponsors are Sanofi along with Bristol-Myers Squibb. CAPRIE: Additional Quotes Professor Michael Gent "In the future it seems that heart attacks, ischemic strokes and peripheral arterial disease will increasingly be seen as symptomatic of one underlying disease," said Professor Michael Gent, Chairman of the CAPRIE Steering Committee. Professor Gent is also director of the Clinical Trials Methodology Group at Hamilton Civic Hospital Research Center and director of the Department of Clinical Epidemiology and Biostatistics at McMaster University in Hamilton, Ontario, Canada. "The findings of this study will help us to save more patients from fatal events and permanent disability. We have made a significant step forward in tackling one of the biggest medical challenges of the Western world," he added. "The impact of CAPRIE on medical practice in the future could be enormous. More people in the Western world are killed or permanently disabled by cardiovascular disease, including stroke, than by any other illness. For patients at risk, I believe that we have shown the most effective way yet discovered of preventing heart attacks. strokes and, indeed, vascular death." Professor J. Donald Easton "CAPRIE indicates that clopidogrel has a remarkably safe profile," said Professor J. Donald Easton, Vice Chairman of the CAPRIE Central Validation Committee and member of the study steering committee. Professor Easton is also physician-in-chief and chairman of the Department of Clinical Neurosciences, Brown University School of Medicine, Providence, RI, and physician-in-chief at the Department of Neurology at the Rhode Island Hospital. In the past, some doctors have held back antiplatelet therapy because of fear about adverse events. "Once it is approved by the regulatory authorities, clopidogrel will allow us to treat many more vulnerable patients," he added. Dr. James Chesebro "Clopidogrel has beaten the gold standard aspirin in reducing heart attack, stroke and death and is at least as safe as aspirin or safer than aspirin when it comes to bleeding from the stomach," said Dr. James Chesebro of the Cardiovascular Institute at Mount Sinai Medical Center in New York City. Dr. Chesebro is also a member of the CAPRIE Steering Committee. Professor Marc Verstraete "Clopidogrel is at least as beneficial as aspirin in reducing the chances of people who have had a heart attack, stroke or claudication (peripheral arterial obliterative disease) having another episode or vascular death, but with less side effects than aspirin. Clopidogrel is a remarkably safe medicine," said Professor Marc Verstraete of the Center for Molecular and Vascular Biology of the Katholeike University, Universiteit, Leuven, Belgium, and a member of the CAPRIE Steering Committee and Chairman of the Central Validation Committee. "The huge CAPRIE trial was conducted in an exemplary manner, almost like a military operation. Each reported outcome event was individually validated by a group of independent American and European cardiologists or neurologists: in total, 2,800 outcome events were validated by the Central Validation Committee. This cumbersome step is essential as the strength of a study is largely, but not only, based, on the validity of its endpoints," he added. Professor John Dormandy "People with claudication are at a risk of experiencing a heart attack or stroke. Their problems are not confined to their legs and in fact their life expectancy is about 10 years less than people without claudication," said Professor John Dormandy, Consultant Vascular Surgeon, Department of Vascular Surgery at St. George's Hospital in London. "In CAPRIE, which is considered the largest long term study of claudicants ever undertaken, clopidogrel substantially reduced the risk of heart attack, stroke and other vascular deaths by 23.8% in these patients compared to aspirin. That means that claudicants who were given clopidogrel, as compared with aspirin, were at less risk of a disabling or life threatening event. The CAPRIE Study found clopidogrel to be at least as safe as aspirin, if not more so, and I believe that clopidogrel is much more appropriate than any existing therapy to protect these patients from heart attacks, strokes and other vascular deaths. Clopidogrel is likely to become the aspirin of the next decade," he continued. "As for the future, aspirin is now given to claudicants undergoing angioplasty procedures because it improves their outcome. Though clopidogrel has not yet been studied specifically for this use, I would be surprised if it did not work as we11 or better than aspirin here, too," Professor Dormandy added. Professor John Hampton "CAPRIE is the first study to compare a new antiplatelet agent with aspirin in a large group of patients with different manifestations of vascular disease. In the total group of patients with strokes, myocardial infarctions or peripheral vascular disease, those who took clopidogrel had fewer further vascular events than those who took aspirin. Aspirin is no longer the gold standard of antiplatelet therapy," said Professor John R. Hampton, of the Division of Cardiovascular Medicine at Queen's Medical Centre, Nottingham, UK. Dr. Jay Coffman "CAPRIE, the first mega-trial to include heart attack, stroke and vascular disease patients in a single protocol, revealed clopidogrel to be superior to aspirin in preventing additional heart attacks or strokes and vascular death in people at-risk for these disabling and deadly events," said Dr. Jay Coffman of the Boston University Medical Center in Boston, MA, and a member of the CAPRIE Steering Committee. "Not only is clopidogrel significantly better than aspirin overall, but it is safer, too. Clopidogrel causes less gastrointestinal distress and bleeding than aspirin and does not lower white blood cell count, a problem with another popular antiplatelet agent," Dr. Coffman added. --------------------------------------------------------------------------------------------- Copyright © 1999 P\S\L Consulting Group Inc. All rights reserved. Republication or redistribution of P\S\L content is expressly prohibited without the prior written consent of P\S\L. 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