For decades doctors have prescribed two drugs, aspirin and warfarin, to heart disease patients to help prevent blood clots, and although both drugs are effective they have never been compared in a large clinical trial. An international study begun recently by researchers at the San Francisco Veterans Affairs Medical Center (SFVAMC) will match these two old drugs against each other, and against a newer drug called clopidogrel, to see which of them prevents more heart attacks, strokes, and deaths in patients with chronic heart failure.
Unlike most international clinical trials in recent years, the 4,500-patient study will not be predominantly funded by a pharmaceutical or biotech company, said the study's chairman Barry Massie, MD, UCSF professor of medicine, and chief of the cardiology division at the SFVAMC. All three drugs in the trial already are approved for patients with heart disease and several other conditions. But the VA, which is paying about half of the trial's cost through its cooperative study program, recognized that determining which drug is most effective could save patient lives and might also reduce costs.
"The results of this study have the potential to greatly affect practice," Massie said. "For instance, between 20 and 40 percent of heart failure patients now receive warfarin. That figure will either increase or decrease substantially depending on the results. Aspirin is widely used in patients with coronary heart disease, the leading cause of heart failure. However, there is some evidence that aspirin may have negative effects in heart failure patients under some circumstances. If this proves to be so, many of these patients will be switched to warfarin or clopidogrel."
When the study is completed, Massie said, doctors will be able to choose among the three medicines based on three important factors: efficacy, safety and cost.
One of the most interesting and important questions the trial will address is whether aspirin interferes with a standard group of heart failure drugs known as ACE inhibitors, as some earlier studies have suggested.
"ACE inhibitors work by several mechanisms, one of which involves increasing the levels of chemicals called prostaglandins. Aspirin reduces the production of prostaglandins and therefore may interfere with part of the benefit of ACE inhibitors. This vitally important issue can only be addressed in a large controlled study such as WATCH (Warfarin and Antiplatelet Therapy in Chronic Heart failure), where aspirin is being compared to clopidogrel, another agent that prevents clotting and thrombosis by a mechanism that does not involve prostaglandins," Massie said.
Patients entering the so-called WATCH trial will be recruited from roughly 150 hospitals in the US, Canada and the United Kingdom. Each patient will be randomly assigned to take one of the three drugs for at least two years. Because each drug has been shown in separate studies to save lives, it would be unethical to assign a group to take a placebo, Massie said. The researchers will keep track of the number of heart attacks, strokes, deaths and bleeding incidents in each group.
The three drugs work by different mechanisms, and each has potential drawbacks. Warfarin, a blood thinner, prevents blood coagulation by interfering with vitamin K, which the body needs to make clotting proteins. It also can cause excessive bleeding, so patients require close monitoring and frequent blood tests. Aspirin and clopidogrel both work against platelets, blood cells that stick together and encourage clotting. Aspirin helps prevent platelets from clumping together. Clopidogrel prevents platelets from being activated, and while some studies show it works better than aspirin, it is also more expensive.
Aspirin and warfarin have never been directly compared in a clinical trial of heart failure patients, although both have been available for decades, Massie said. Warfarin's potential for preventing heart attacks in heart failure patients was only discovered a few years ago, he explained, and in the United States is usually not used for this application.
The San Francisco VA Medical Center will coordinate many aspects of the trial in conjunction with the Perry Point Maryland VA Cooperative Studies Coordinating Center, which will be conducted at approximately 40 VA Medical Centers, 50 non-VA hospitals in the US, and 60 sites in Canada and the UK. WATCH is the first VA-sponsored trial to coordinate with research sites overseas.
Among the researchers working on the project are national study coordinator Susan Ammon, RN, SFVAMC cardiology research nurse; John Teerlink, MD, UCSF assistant professor of cardiology and SFVAMC staff physician; Kelly Givner, SFVAMC administrative assistant. The data collection and analysis is being conducted at Perry Point under the direction of Joseph Collins, DSc, MD, and the statistician, William Krol , PhD. John Cleland, MD, professor of medicine at the University of Hull, UK; Koon Teo, MD, professor of medicine at McMaster University in London, Ontario; and Paul Armstrong, MD, professor of medicine at the University of Edmonton are lead investigators in the UK and Canada.
In addition to funding from the Department of Veterans Affairs, support for the study comes from Sanofi-Synthelabo, Bristol-Myers Squibb Company, and DuPont.