PATHOPHYSIOLOGY AND NATURAL HISTORY EXERCISE TESTING Predictive value of the exercise tolerance test for mortality in North American men: The Lipid Research Clinics Mortality Follow-up Study*

More than 3600 white men, from 30 to 79 years old and without a history of myocardial infarction, underwent submaximal treadmill exercise tolerance tests as part of their baseline evaluation for the Lipid Research Clinics Mortality Follow-Up Study. The exercise test was conducted according to a common protocol and coded centrally; depression of the ST segment by at least 1 mm (visual coding) and/or 10 ,V-sec (ST integral, computer coding) signified a positive test. Concurrent measurements of age, blood pressure, history of cigarette smoking, and plasma levels of lipids, lipoproteins, and glucose, as well as other coronary risk factors, were obtained. Cumulative mortality from cardiovascular disease was 11.9% (22/185) over 8.1 years mean follow-up among men with a positive exercise test vs 1.2% (36/2993) over 8.6 years mean follow-up among men with a negative test. Threequarters (43) of these deaths were due to coronary heart disease. The relative risk for cardiovascular mortality associated with a positive exercise test was 9.3 before and 4.6 after age adjustment. Cardiovascular mortality rates were especially elevated (relative risk 15.6 before and 5.1 after age adjustment) among the 82 men whose exercise tests were adjudged "strongly" positive based on degree and timing of the ischemic electrocardiographic response. A positive exercise test was also moderately associated with noncardiovascular mortality; the relative risk for all-cause mortality was 7.2 before and 3.4 after age adjustment. The relative risk for cardiovascular mortality associated with a positive exercise test was not appreciably altered by covariance adjustment for known coronary risk factors other than age. A positive exercise test was a stronger predictor of cardiovascular death than were high plasma levels of low-density lipoprotein cholesterol, low plasma levels of high-density lipoprotein cholesterol, smoking, hyperglycemia, or hypertension. Its impact on risk of cardiovascular death was equivalent to that of a 17.4 year increment in age. Circulation 74, No. 2, 252-261, 1986. EXERCISE tolerance tests are widely used in the evaluation of patients in whom coronary heart disease (CHD) is suspected.1 Subjecting an individual to a series of increasing workloads so as to gradually inFrom the Lipid Metabolism-Atherogenesis Branch, DHVD, NHLBI, and the Division of Epidemiology and Clinical Applications, NIH, Bethesda; the School of Public Health and LRC Program, University of North Carolina, Chapel Hill; the Centers for Disease Control (Chamblee), Atlanta; the Lipid Research Clinic, Oklahoma Medical Research Foundation, Oklahoma City; and the Central Electrocardiographic Laboratory, Birmingham, AL. Supported by National Heart, Lung, and Blood Institute contracts NOI-HV12159, N01-HV12156, NOI-HV12160, NOI-HV22914, YOIHV30010, NOI-HV22913, NOI-HV12158, NOI-HV12161, NOIHV22915, NOI-HV22932, NO1-HV22917, NO1-HV12157, NOIHV12243, NOI-HV32961, and NO1-HV62941. Address for correspondence: Basil M. Rifkind, M.D., Chief, Lipid Metabolism-Atherogenesis Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892. Received March 7, 1986; revision accepted May 1, 1986. *Members of committees involved in this study are listed before the references. crease his or -her heart rate is a safe and noninvasive method of eliciting electrocardiographic signs of ischemia that are inapparent at rest. In this way one may corroborate objectively a patient's subjective symptoms. Exercise-induced electrocardiographic changes correlate well (although imperfectly) with the angiographic demonstration of coronary lesions24 and are highly prognostic of subsequent mortality in such patients.5'6 The predictive value of a positive exercise test for subsequent cardiovascular events in predominantly asymptomatic populations and how it might be influenced by known CHD risk factors such as smoking, blood pressure, and plasma lipids is more controversial.7-17 Since the prevalence of positive exercise tests and that of CHD are small in such populations,'8 only a large study with several years of follow-up can address this issue adequately. CIRCULATION 252 by gest on A ril 4, 2017 http://ciajournals.org/ D ow nladed from PATHOPHYSIOLOGY AND NATURAL HISTORY-EXERCISE TESTING In one such study, involving more than 11,000 Italian workers followed for 5 to 10 years, the incidence rate of CHD events (coronary death, nonfatal myocardial infarction, and/or angina pectoris) in 135 asymptomatic normotensive subjects with reproducibly abnormal submaximal exercise tests (horizontal or downsloping ST segment depression of 1 mm or more) was 5.5 times higher than that in 379 matched controls.17 Since cases and controls were matched with respect to their "coronary risk index" (a linear combination of smoking, blood pressure, age, and serum cholesterol at baseline), the prognostic value of a positive exercise test appeared to be independent of these other risk factors. The authors did not report whether the risk ratio differed significantly between upper and lower strata of these risk factors. In another large study, a 10 year follow-up of 3611 men and 547 women initially free of clinical CHD, a positive exercise test was predictive of an increased incidence of manifestations of CHD only among participants with at least one other CHD risk factor (smoking, hypertension, hypercholesterolemia, diabetes, family history, angina pectoris) at baseline.'6 The present report concerns the ability of a single submaximal exercise test to predict death from CHD and from other cardiovascular and noncardiovascular causes in 1870 normolipidemic and 1770 hyperlipidemic 30to 79-year-old white male participants in the Lipid Research Clinics (LRC) Prevalence Study.1921 The constancy of the predictive value of the exercise test among various CHD risk factor strata, as well as its persistence after adjusting statistically for these risk factors, is examined.