Can Preventive Therapy Alter the Initial Presentation of Coronary Heart Disease?

During the past 2 decades, a large body of evidence has accumulated about the effects of medical therapies given to reduce the risk for events associated with coronary heart disease (CHD). These studies and trials have usually focused on hard end points, such as total mortality rate, fatal and nonfatal myocardial infarction, and sudden death. Together, these interventions reduce the risk for a CHD event, especially when used in patients with known CHD (secondary prevention) and in high-risk patients with no history of CHD (primary prevention). In contrast, we know little about how these primary preventive therapies affect the way in which CHD initially presents (as the acute coronary syndrome or as stable angina pectoris). The article by Go and colleagues in this issue (1) attempts to determine whether the recent use of medication (statins, -blockers, and angiotensin-converting enzyme [ACE] inhibitors) or patient characteristics influence the manner of initial clinical presentation of CHD. The authors used observational data from patients who were enrolled in Kaiser Permanente of Northern California. All patients had no history of CHD. The authors divided the study sample into 2 groups: those who presented with myocardial infarction (men between 45 and 75 years of age and women between 55 and 75 years of age) and those who presented with stable exertional angina pectoris (men and women between 18 and 75 years of age). The authors compared the characteristics of these 2 groups. Patients who presented with acute myocardial infarction as the first manifestation of CHD were more likely to be men, smokers, physically inactive, and hypertensive but were less likely to have parental history of CHD. With regard to medical therapy, after correction for potential confounders, patients presenting with myocardial infarction were less likely to have taken recent statin therapy (adjusted odds ratio, 0.45 [95% CI, 0.32 to 0.62]) or -blocker therapy (adjusted odds ratio, 0.26 [CI, 0.19 to 0.35]). The 2 groups did not differ in the frequency of recent use of ACE inhibitors. These findings raise important questions about whether and how medical therapy might alter the presentation of CHD. Many of the findings are consistent with previous research or with common sense. The clinical findings relating sex and clinical presentation of CHD are consistent with those of the National Health and Nutrition Examination Study (NHANES) (2), in which the age-adjusted prevalence of angina was higher among women, while that of self-reported myocardial infarction was higher among men. Previous research has shown that cigarette smoking and hypertension are associated with a higher risk for acute myocardial infarction (3, 4). The higher incidence of exertional angina in Go and colleagues' study among those with a family history of CHD may be because of heightened awareness of the manifestations of CHD and, therefore, better recognition of the symptoms of CHD. The finding that those presenting with angina pectoris were more likely to engage in moderate to intense physical activity may reflect the need for a substantial workload to provoke exertional angina. Go and colleagues' most intriguing and potentially consequential finding is the suggestion that medical therapies might alter the clinical presentation of CHD. This finding may be important, and the authors are appropriately cautious about the interpretation of their findings. Because the study is observational, factors that are associated with taking statins or -blockers could be the real cause of the difference in clinical presentation of CHD (confounding). Go and colleagues acknowledge that because their study was not prospective, it lacked information on confounding factors, such as the use of aspirin therapy to prevent CHD. If aspirin therapy was strongly associated with the use of statins and -blockers, it could explain some of the effect of these 2 drugs. This mechanism is plausible because patients with the acute coronary syndrome who were taking long-term aspirin therapy have a lower likelihood of acute myocardial infarction compared with patients with unstable angina (5). Studies on aspirin as primary prevention therapy for CHD reveal greater benefit among men than women (6). Thus, the more frequent occurrence of myocardial infarction among men in Go and colleagues' study might be related to a lower use of aspirin in men. Of particular interest is the observation that statin therapy was associated with lower odds of presenting with acute myocardial infarction and, conversely, with higher odds of presenting with exertional angina pectoris. This finding agrees with previous research. The finding of statin use and reduced myocardial infarction rates is consistent with the West of Scotland Coronary Prevention Study (WOSCOPS) (7), which involved 6595 men between 45 and 64 years of age with low-density lipoprotein (LDL) cholesterol levels ranging from 4.01 mmol/L (155 mg/dL) to 6.00 mmol/L (232 mg/dL) and with no history of myocardial infarction (5% of patients had angina at baseline). In WOSCOPS, pravastatin reduced nonfatal myocardial infarction by 31% (P< 0.001). Another primary prevention study, the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) (8), tested lovastatin therapy among low-risk patients (5608 men between 45 and 73 years of age and 997 women between 55 and 73 years of age). Statins reduced fatal and nonfatal myocardial infarction by 40% (P= 0.002). Neither study reported whether statin therapy affected the incidence of exertional angina. Go and colleagues do not provide information on statin dosage or degree of lipid-lowering, both of which have been associated with greater reduction of clinical events in previous trials (9). The mechanism of the effect of statins in Go and colleagues' study is speculative. Is it due to the extent of LDL cholesterol reduction, or is it a pleiotropic effect of statins? In addition to reduction of LDL cholesterol levels, statins have been shown to improve endothelial function, increase nitric oxide availability, inhibit inflammation, and stabilize atherosclerotic plaques (10, 11). The mechanism by which statin therapy could tip the scales toward presenting initially with exertional angina rather than acute myocardial infarction could be due to pleiotropic effects in addition to the lowering of LDL cholesterol. The evidence about -blocker therapy for primary prevention of CHD is less extensive than that for statins. One randomized clinical trial evaluated low-dose (25 mg/d) metoprolol (controlled release/extended release) in 793 patients. Of these patients, only 4% had a history of cardiovascular disease and none had a history of angina or myocardial infarction in the preceding 3 months. The progression of intimamedia thickness in the carotid bulb at 18 months and 36 months was slower with metoprolol. The effect did not seem to be related to reduction in blood pressure. Metoprolol was associated with a trend toward reduction in nonfatal and fatal myocardial infarction and nonfatal stroke (P= 0.055) (12). In addition to better control of blood pressure, a stabilizing vascular effect resulting from -blocker therapy could contribute to the lower incidence of myocardial infarction in Go and colleagues' study. Go and colleagues suggest that the use of statin and -blocker therapy might favorably alter the initial clinical presentation of CHD. Randomized clinical trials are needed to confirm the study's results in appropriate patient groups and investigate their mechanisms. If confirmed by such trials, these findings could have a substantial effect on patient care.