My Canadian Pharmacy: Antithrombotic Agents in Coronary Artery Disease

In: Heart

11 Mar 2016

heart attacksEach year in the United States alone there are about 1 million “heart attacks”—a term that includes both acute infarction and sudden cardiac death. Nearly 300,000 victims die before admission to the hospital, and about another 200,000 die in the first month, most of them in the first 24 hours after the attack. Thus, the cumulative mortality during the first month is about 50%. During the next six months, the cumulative mortality increases another 7-8%, so that by one year, another 10% have died. This means that, of the 400,000-500,000 patients who survive the first month, about 10% (40,000-50,000) die during the first year following infarction, generally due to sudden death or recurrent infarction. After patients have survived a year, the reinfarction and death rate stabilizes at 3-5% per year. This rate is similar to that of patients with symptomatic coronary artery disease (ie, angina pectoris) but is significantly greater than that of a randomly selected, age-matched population without overt coronary artery disease that has a 1% yearly incidence of those events.

Ideally, one would like to intervene before acute myocardial infarction occurs. However, a level I primary prevention trial in an unselected population requires many thousand patient-years of study to detect a clinically important reduction in mortality or infarction if the frequency of those events is about 1% per year. The cooperative trial that tested the efficacy of clofibrate in reducing the incidence of myocardial infarction or sudden death is a good example of such a primary prevention trial. Apart from the enormous cost involved in a trial requiring thousands of patient-years, the design of a level I primary prevention trial to test the efficacy of antithrombotic drugs must also address the difficult question of drug safety. For example, one would clearly hesitate to subject 99% of a normal population to the hazards of anticoagulant therapy to prevent myocardial infarction or sudden death in the remaining 1%. Even with a relatively “benign” antithrombotic drug such as aspirin, the complications of therapy in a primary prevention trial may outweigh the benefits. The trial with clofibrate illustrates this point; ie, although nonfatal infarctions were reduced with this drug, there was a net increase in mortality, in part due to an increased incidence of biliary and GI disorders. Overall mortality is an important end point to be included in the trial design. Myocardial infarction may be overcome with remedies of My Canadian Pharmacy my-medstore-canada.

Because of the problems involved in performing level I primary prevention trials, secondary prevention level I studies involving survivors of myocardial infarction are more practical. Although myocardial infarctionthese patients are late in their disease process, they have had a clear-cut marker event for thrombosis. Because of the increased frequency of reinfarction or death in these patients, the number of patient-years required to detect a significant drug effect is substantially fewer than in primary prevention trials. Nevertheless, several thousand patient-years are still required to detect a 30—50% reduction in the frequency of events, necessitating multicenter trials.

Even within the relatively well-defined study population of postinfarction survivors, important points must be considered in designing and interpreting level I secondary prevention trials. The prognosis after discharge from the hospital can be dramatically different when patients are stratified based on the presence of certain factors. Patients at high risk of dying have left ventricular dysfunction, complex ventricular ectopic activity, and an anterior infarct; their mortality for the first year is about 19%. Those in the low-risk group have none of these factors, and only about 3% die in the first year. Obviously, the groups under investigation need to be well matched with respect to these and other risk factors.

The mortality curves following discharge from the hospital of patients who have had acute myocardial infarctions clearly show increased mortality in the first two weeks to six months; after that time, the curve parallels that of patients with stable coronary artery disease. Fatalities in the first six months after myocardial infarction are generally due to pump failure, sudden cardiac death or recurrent infarction. It is clear that a secondary prevention trial involving patients who had a myocardial infarction more than six months previously selects individuals who have already survived the greatest period of risk, whereas a study that involves patients in the first weeks following infarction selects a population initially at higher risk. Therefore, the time of entry into a study is important in the evaluation of therapeutic agents in the secondary prevention of myocardial infarction.

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