THERAPEUTIC CONTROVERSIES Edited by Dennis F. Thompson and Marsha A. Raebel
ASPmIN FORTHEPREVENTION OF VASCULAR DEATH IN WOMEN Laura Engles McAnally, Carolyn R. Corn, and Stephen F. Hamilton
OBJECTIVE: To review current information relevant to the use of aspirin for preventing vascular death in women, and to provide recommendations based on this information. DATA SOURCES: References from pertinent articles are identified throughout the text. DATA SYNTHEStS: Based on current information, low-dose aspirin is not recommended as primary prevention for cardiovascular death in women; efforts are better focused at promoting risk-factor reduction. Low-dose aspirin is recommended for reducing further cardiovascular morbidity and mortality in women with known cardiovascular disease. Women presenting with unstable angina or myocardial infarction should receive aspirin 325 mg as soon as the diagnosis is confirmed, and this dosage should be continued on a chronic basis. Women who have experienced transient ischemic attacks or ischemic stroke should receive aspirin 1000 mg/d, with a subsequent dosage reduction to 325 mg/d in patients who do not tolerate the higher dose. CONCLUStONS: Current recommendations are based on the results of studies that involved few women. Further investigation of antiplatelet agents for primary and secondary prevention of vascular death in women is needed.
Ann Pharmacother 1992;26:1530-4. THE USE OF DRUGS should be a process of balancing risks and benefits based on individualized considerations made
LAURA ENGLES MCANALLY, Phann.D., is a Postdoctoral Fellow inCardiovascular Pharmacotherapy, College of Pharmacy, Department of Pharmacy Practice; CAROLYN R. CORN, M.D., is an Associate Professor of Medicine, and theDirector of Nuclear Cardiology, College of Medicine, Section of Cardiology; and STEPHEN F. HAMILTON, Phann.D., FCCP, is an Associate Professor of Pharmacy Practice and an Associate Professor of Medicine, College of Pharmacy, Department of Pharmacy Practice, University ofOklahoma-Health Sciences Center, P.O. Box 2690 I, Oklahoma City, OK 73190. Reprints: Stephen F. Hamilton, Pharm.D., FCCP. DENNIS F.THOMPSON, Pharm.D., isthe Assistant Dean for Clinical Programs, an Associate Professor, and the Head, Department ofPharmacy Practice, School ofPharrnacy, Southwestern Oklahoma State University, Weatherford, OK 73096; and MARSHA A.RAEBEL, Phann.D., istheCoordinator of Drug Information and Clinical Pharmacy, Scott and White Memorial Hospital, a Clinical Associate Professor, College of Pharmacy, University of Texas at Austin, andan Assistant Professor of Medicine, Texas A&M University, College ofMedicine, Temple, TX76508.
1530
•
The Annals ofPharmacotherapy
•
in the best interest of the patient. The considerations must involve an understanding of the pathophysiologic process, established pharmacotherapeutic alternatives, and published experience with the drug. The published data should show clinically and statistically significant results in relieving suffering and prolonging an acceptable quality of life, and ideally should be developed specifically in the patient population under consideration. In reality, most clinical decisions involve less than complete information, as when aspirin is considered for primary and/or secondary prevention of vascular morbidity and mortality in women. Developments over recent years have led to a better understanding of ischemic heart disease and the causes of vascular death. For example, it is now clear that ischemic syndromes correlate with the morphology of the atheroma involved; specifically, stable angina pectoris proceeds to unstable angina, acute myocardial infarction, or both when a stable atheroma fissures or ruptures and becomes a complicated plaque. It is also clear that platelet activation resulting from the complicated plaque plays an important role in the progression of stable angina to the more unstable syndromes. The beneficial effects of aspirin on the survival of patients, presumably as a result of limiting platelet plugging and arterial spasm, are well-known and important. This effect assessment, however, is based on the results of studies that have involved few women. Coronary artery disease, a leading cause of death in the US, has decreased among men in the last decade but evidence suggests that it is becoming increasingly prevalent in women.' The American Heart Association has dedicated its efforts to a better understanding of the specific factors that influence cardiovascular disease in women, and some early information is now available. The incidence of coronary artery disease peaks about a decade later in women than in men. After age 40, it is the leading cause of death in women and, by age 70, the incidence is equivalent to that in men.' Women have a worse prognosis after myocardial infarction than do men, with both a higher incidence of early and late mortality and a higher incidence of reinfarction.' In
1992 December, Volume 26
addition, women have twice the risk of operative mortality as men after coronary artery bypass grafting and are more likely to have recurrent angina, myocardial infarction, or coronary death following the procedure.v Similar results have been reported after coronary angioplasty in women: they have lower angiographic and clinical success rates and a higher incidence of complications and in-hospital mortality related to the procedure than do men," The ultimate explanation for these observations is uncertain, and it is clearly naive to presume that estrogen withdrawal and the increased age of women at peak incidence of heart disease are the only major factors. We are left with the problem of how to provide optimal care for women until more complete and specific information is available. In this article we offer some specific recommendations based on the current body of information. Primary Prevention ofCardiovascular Morbidity and Mortality
There have been two large studies of aspirin for the primary prevention of cardiovascular events.P Combined, the populations of these studies comprise 27210 physiciansall men, no women. The study of aspirin in American physicians was stopped early because there was obvious reduction in the incidence of fatal and nonfatal myocardial infarctions. This was a randomized, double-blind, placebocontrolled study in a select group of healthy male physicians and it evaluated two primary prevention outcomes. The study involved the use of aspirin 325 mg taken every other day and beta carotene 50 mg taken on alternate days for the prevention of cardiovascular disease and cancer, respectively. A 47 percent reduction in the incidence of fatal and nonfatal myocardial infarction was observed. However, there were only 83 deaths in the placebo group and 81 deaths in the aspirin group, compared with the expected 733 for the general white male population," and this made extrapolation to the female or multiracial male population difficult. The study's early termination potentially overestimates the short-term benefit and underestimates the longterm risks of therapy. The second study, designed without placebo-control, involved 5139 British male physicians and compared aspirin therapy (500 mg/d) with no treatment. There were more events than in the American study: 121 nonfatal myocardial infarctions and 137 cardiovascular deaths. There was no reduction in the incidence of myocardial infarction or death with aspirin treatment, but aspirin did reduce the incidence of transient ischemic attacks (p
ASPmIN FORTHEPREVENTION OF VASCULAR DEATH IN WOMEN Laura Engles McAnally, Carolyn R. Corn, and Stephen F. Hamilton
OBJECTIVE: To review current information relevant to the use of aspirin for preventing vascular death in women, and to provide recommendations based on this information. DATA SOURCES: References from pertinent articles are identified throughout the text. DATA SYNTHEStS: Based on current information, low-dose aspirin is not recommended as primary prevention for cardiovascular death in women; efforts are better focused at promoting risk-factor reduction. Low-dose aspirin is recommended for reducing further cardiovascular morbidity and mortality in women with known cardiovascular disease. Women presenting with unstable angina or myocardial infarction should receive aspirin 325 mg as soon as the diagnosis is confirmed, and this dosage should be continued on a chronic basis. Women who have experienced transient ischemic attacks or ischemic stroke should receive aspirin 1000 mg/d, with a subsequent dosage reduction to 325 mg/d in patients who do not tolerate the higher dose. CONCLUStONS: Current recommendations are based on the results of studies that involved few women. Further investigation of antiplatelet agents for primary and secondary prevention of vascular death in women is needed.
Ann Pharmacother 1992;26:1530-4. THE USE OF DRUGS should be a process of balancing risks and benefits based on individualized considerations made
LAURA ENGLES MCANALLY, Phann.D., is a Postdoctoral Fellow inCardiovascular Pharmacotherapy, College of Pharmacy, Department of Pharmacy Practice; CAROLYN R. CORN, M.D., is an Associate Professor of Medicine, and theDirector of Nuclear Cardiology, College of Medicine, Section of Cardiology; and STEPHEN F. HAMILTON, Phann.D., FCCP, is an Associate Professor of Pharmacy Practice and an Associate Professor of Medicine, College of Pharmacy, Department of Pharmacy Practice, University ofOklahoma-Health Sciences Center, P.O. Box 2690 I, Oklahoma City, OK 73190. Reprints: Stephen F. Hamilton, Pharm.D., FCCP. DENNIS F.THOMPSON, Pharm.D., isthe Assistant Dean for Clinical Programs, an Associate Professor, and the Head, Department ofPharmacy Practice, School ofPharrnacy, Southwestern Oklahoma State University, Weatherford, OK 73096; and MARSHA A.RAEBEL, Phann.D., istheCoordinator of Drug Information and Clinical Pharmacy, Scott and White Memorial Hospital, a Clinical Associate Professor, College of Pharmacy, University of Texas at Austin, andan Assistant Professor of Medicine, Texas A&M University, College ofMedicine, Temple, TX76508.
1530
•
The Annals ofPharmacotherapy
•
in the best interest of the patient. The considerations must involve an understanding of the pathophysiologic process, established pharmacotherapeutic alternatives, and published experience with the drug. The published data should show clinically and statistically significant results in relieving suffering and prolonging an acceptable quality of life, and ideally should be developed specifically in the patient population under consideration. In reality, most clinical decisions involve less than complete information, as when aspirin is considered for primary and/or secondary prevention of vascular morbidity and mortality in women. Developments over recent years have led to a better understanding of ischemic heart disease and the causes of vascular death. For example, it is now clear that ischemic syndromes correlate with the morphology of the atheroma involved; specifically, stable angina pectoris proceeds to unstable angina, acute myocardial infarction, or both when a stable atheroma fissures or ruptures and becomes a complicated plaque. It is also clear that platelet activation resulting from the complicated plaque plays an important role in the progression of stable angina to the more unstable syndromes. The beneficial effects of aspirin on the survival of patients, presumably as a result of limiting platelet plugging and arterial spasm, are well-known and important. This effect assessment, however, is based on the results of studies that have involved few women. Coronary artery disease, a leading cause of death in the US, has decreased among men in the last decade but evidence suggests that it is becoming increasingly prevalent in women.' The American Heart Association has dedicated its efforts to a better understanding of the specific factors that influence cardiovascular disease in women, and some early information is now available. The incidence of coronary artery disease peaks about a decade later in women than in men. After age 40, it is the leading cause of death in women and, by age 70, the incidence is equivalent to that in men.' Women have a worse prognosis after myocardial infarction than do men, with both a higher incidence of early and late mortality and a higher incidence of reinfarction.' In
1992 December, Volume 26
addition, women have twice the risk of operative mortality as men after coronary artery bypass grafting and are more likely to have recurrent angina, myocardial infarction, or coronary death following the procedure.v Similar results have been reported after coronary angioplasty in women: they have lower angiographic and clinical success rates and a higher incidence of complications and in-hospital mortality related to the procedure than do men," The ultimate explanation for these observations is uncertain, and it is clearly naive to presume that estrogen withdrawal and the increased age of women at peak incidence of heart disease are the only major factors. We are left with the problem of how to provide optimal care for women until more complete and specific information is available. In this article we offer some specific recommendations based on the current body of information. Primary Prevention ofCardiovascular Morbidity and Mortality
There have been two large studies of aspirin for the primary prevention of cardiovascular events.P Combined, the populations of these studies comprise 27210 physiciansall men, no women. The study of aspirin in American physicians was stopped early because there was obvious reduction in the incidence of fatal and nonfatal myocardial infarctions. This was a randomized, double-blind, placebocontrolled study in a select group of healthy male physicians and it evaluated two primary prevention outcomes. The study involved the use of aspirin 325 mg taken every other day and beta carotene 50 mg taken on alternate days for the prevention of cardiovascular disease and cancer, respectively. A 47 percent reduction in the incidence of fatal and nonfatal myocardial infarction was observed. However, there were only 83 deaths in the placebo group and 81 deaths in the aspirin group, compared with the expected 733 for the general white male population," and this made extrapolation to the female or multiracial male population difficult. The study's early termination potentially overestimates the short-term benefit and underestimates the longterm risks of therapy. The second study, designed without placebo-control, involved 5139 British male physicians and compared aspirin therapy (500 mg/d) with no treatment. There were more events than in the American study: 121 nonfatal myocardial infarctions and 137 cardiovascular deaths. There was no reduction in the incidence of myocardial infarction or death with aspirin treatment, but aspirin did reduce the incidence of transient ischemic attacks (p
