A Clinical Approach to Exercise Tolerance Testing in Coronary Artery Disease

Transcription

1 Clin. Cardiol. 6, Clinical Cardiology Publishing Co., Inc. A Clinical Approach to Exercise Tolerance Testing in Coronary Artery Disease R. M. MILLS, JR., M.D. and J. M. GREENBERG, M.D. University of Massachusetts Medical School and Worcester Memorial Hospital, Worcester, Massachusetts, USA Summary: Data from exercise tolerance testing should be incorporated into clinical decision making. A strategy for stratification of individual patients into high, indeterminate, and low-risk categories using Bruce protocol exercise testing is outlined. This approach will help to ensure further evaluation of high-risk individuals without excessive testing of patients having excellent long-term prognoses. Keywords: exercise testing, coronary artery disease Introduction In this essay, we will present an argument for the rational use of exercise tolerance testing (ETT) in the management of patients having, or seriously suspected of having, coronary disease. Our perspective is that of the clinician. We will make some references to game theory and to simple computer programming. We believe that clinical medicine is much more analogous to the formal mathematics of game theory than to statistics. The clinician plays on behalf of his patient against an Address for reprints: Roger M. Mills, Jr., M.D. Cardiac Catheterization Laboratory Worcester Memorial Hospital I19 Belmont Street Worcester, MA 01605, USA Received: December Accepted with revision: April 18, 1983 opponent, in this case coronary heart disease, who manifests unpredictable behavior. The clinician therefore needs a strategy for dealing with various events, not a tote-sheet on the odds. The physician confronted with an individual patient is not much aided by statistical data. As Rapoport ( 1 970) points out, We are so used to the word probability that we do not usually realize that the word has no demonstrable meaning when applied to a single event. Using the example of a fair coin, he continues, The single toss will, of course, yield either heads or tails. The outcome... certainly is not determined by a probability. In this situation, the intellectual discipline of planning a strategy with one s course at various branch points in a flow chart being determined by objective data provides an appropriate language in which to describe rational clinical medicine. In order to apply this approach to exercise testing, we will first review the current central dogma of coronary heart disease. Next, we will relate the results of the exercise tolerance test to the prognosis in coronary heart disease. Finally, we will try to put this approach into a practical format. We will say little about diagnosis. Diagnosis is always an hypothesis, sometimes firm, sometimes tentative. Fortunately, the most important question is usually, What do I do next? Management is the subject of this discussion, and as it develops, we hope the distinction will become clear. Review of Basic Principles Over the past three decades, a central dogma has evolved concerning coronary heart disease. Reviewing and referencing this process would require a textbook.

2 346 Clin. Cardiol. Vol. 6, July 1983 Simply stated, cardiologists now accept three fundamental principles, as follows: I. Coronary arterial disease leads to reversible or irreversible tissue hypoxia on the basis of oxygen supply/demand imbalance in an essentially aerobic system. 2. Coronary blood flow must be in proportion to myocardial oxygen need. There is no other mechanism to increase oxygen supply. Therefore, clinical manifestations of coronary heart disease may reflect either primary decreases in blood supply (progressive atherosclerosis, arterial occlusion, spasm, etc.) or increased myocardial oxygen demand precipitated by increases in the heart rate, intramyocardial tension, or inotropic state. 3. In any given individual, the clinical picture at a given time and the long-term prognosis depend upon both the extent and severity of coronary arterial disease and the adequacy of left ventricular function. From these principles, two basic approaches to clinical treatment of ischemic heart disease have evolved. The first is to reduce myocardial oxygen need to a minimum, and to attempt to prevent major increases in need. The second is to improve blood supply itself, thereby relieving pain and preventing extensive myocardial necrosis. These approaches are equivalent to medical and surgical therapy. The physician s need to make rational choices between therapeutic options constitutes the major management problem in coronary heart disease. The payoff in game theory terminology will consist of arriving at decisions which (I) do not expose individuals with relatively benign disease to excessive iatrogenic morbidity or mortality, and simultaneously, (2) ensure that individuals whose status might best be improved by surgical intervention receive it. How can we develop a strategy for management which will generate these decisions? Exercise Testing and Coronary Prognosis The first hint that an individual s response to exercise demonstrated important prognostic information came from the work of Robb and Marks (1967), and Mattingly (1962). These authors demonstrated that signifi-.cant ST depression after the double Master s two-step test defined a group of patients with markedly higher subsequent coronary death rates. (Actuarial analysis of coronary deaths per 1000 patient years observation.) Ellestadt (1975) has reviewed a large body of published data, and added his own data and observations on this subject. Several important points deserve emphasis. First, using a maximal treadmill exercise tolerance test, those individuals with no detectable abnormalities have a very low long-term risk (approximately 1% per year) of documented myocardial infarction (Fig. 1). Second, as shown by McNear and colleagues (1978), in patients with angiographically documented coronary artery disease, the ability to enter stage IV of a standard Bruce protocol treadmill exercise test and achieve a heart rate of 160 beats/min or more with an appropriate rise in blood pressure during exercise defines a low-risk group of patients with a 48-month survival >90%. Thus, the criteria of a normal maximal test, or at least ten minutes of Bruce protocol exercise with heart rate and blood pressure as above, define a group of patients with a benign long-term course regardless of the presence or absence of anatomic coronary arterial disease. On the other hand, many workers have defined criteria for high-risk groups. In general, using maximal treadmill tests, the extent and duration of ST-segment depression appears to correlate with the anatomic severity of arterial disease, while the blood pressure response more closely reflects left ventricular function. The heart rate-blood pressure product at peak exercise is relatively constant for a given individual, and may, in addition, give some insight as to symptomatic response to medical therapy. Specific criteria defining high-risk groups include: ( 1) The presence of ischemic ST depressions in patients with known coronary disease (McNeer et al., 1978; Fig. 2). (2) The depth of ST depression occurring at low-level exercise, approximately 4 METS* (Ellestad, 1975; Fig. 3). (3) Chronotropic incompetence (Ellestad, 1975) or inability to achieve heart rate greater than 120 beats/ min (McNeer et al., 1978; Figs. 4 and 5). (4) Ischemic cardiac pain during the exercise test (Cole and Ellestad, 1978; Fig. 6). (5) Fall in systolic blood pressure with exercise (Morris el al., 1978). Thus, reasonable working criteria for a high-risk group might be stated as ( I) inability to complete stage 11 of the standard Bruce protocol because of (a) ischemic pain, (b) falling blood pressure, or (c) fatigue associated with 2 mm or more of horizontal or downsloping STsegment depression; or (2) inability to appropriately raise heart rate and blood pressure with exercise. These two groups, high and low risk, represent the extremes of a spectrum of responses; any divisions of a continuum represent arbitrary judgments. Some investigators may disagree with the criteria outlined above; some patients will be difficult to classify. At any rate, a third category must be defined as those patients who fit * One MET is equivalent to the resting oxygen consumption, approximately 3.5 ml/kg/min. Tables indicating energy expenditure in METS during treadmill are available in Guidelinesfor Graded Exercise Testing and Exercise Prescription, Lea and Febiger, Philadelphia (1975). Bruce Stages and METS expenditures are as follows: Stage I, 4 METS; Stage 2, 6.6 METS; Stage 3, 10 METS; Stage 4, 14.2 METS.

3 R. M. Mills and J. M. Greenberg: Clinical exercise testing % li Q Years FIG. I Incidence of myocardial infarction only in negative (51, n=1013), equivocal (52, n=269), and positive (55, n=578) responders. 70t n (A) (B) Months FIG. 2 Comparison of survival with respect to positive or negative ST-segment interpretation. (A) All nonsurgical patients. (B) Patienis with significant narrowing of one or more coronary vessels. Nilmbers in parentheses represent the number of patients followed for 48 months. Survival rates calculated by life table method. The observed difference in survival in all nonsurgical patients persists when the diagnosis of coronary artery disease is known. Reprinted by permission of the American Heart Association, Inc. from a clinical approach to exercise tolerance testing in coronary artery disease, Circulation 57 ( I 978). somewhere in between the high-risk and low-risk categories. These individuals can enter stage 111, but not stage IV of the Bruce protocol. They may experience discomfort at fairly high heart rates, or ST-segment depression with high systolic blood pressures. Interpretation of such exercise responses with an arbitrary positive or negative for ischemia is fraught with hazard. We propose calling these tests indeterminate. This is clearly the arena in which nuclear methods might be helpful. Clinical Management Having now established that exercise testing can be used to differentiate three groups of individuals, i.e., those

4 348 Clin. Cardiol. Vol. 6, July 1983 T T T Years FIG. 3 Prognosis of angina, myocardial infarction, and death. When the onset of 2 mm ST-segment depression is at 3 minutes (2E3. n= I3 I ), the prognosis is significantly worse than when it is manifested first at 5 minutes (2E5. n=93). When manifested only at 7 minutes (2E7, n=42), which is near peak capacity, the prognosis is only slightly worse than a negative test. 100 % Neg. stress test (n = Yean FIG. 4 Those with bradycardia (pulse fell below the 95% confidence limits for age and sex) and normal ST segments have a high incidence of combined events (similar to those with ST-segment depression). with low- and high-risk prognosis, and an indeterminate group, let us turn now to the two major management problems the clinician faces. First is the patient with a chest pain syndrome suspected of being ischemic in origin. The first step, as always, is a careful history and physical examination. In addition, a reasonable preliminary laboratory examination should be obtained, including a hemoglobin or hematocrit, two-hour postprandial blood sugar, serum cholesterol, resting electrocardiogram, and a chest film (with cardiac fluoroscopy if easily available). At this point, the clinician must formulate a tentative diagnosis, either (A) the symptoms are due to coronary artery disease, or (B) the symptoms may be due to coronary disease, or (C) the symptoms are not due to coronary disease. If, on clinical grounds, the physician feels very confident of diagnosis C, the evaluation should end. An exercise tolerance test will not be diagnostically useful as a normal response is expected, and an abnormal response will most likely be false-positive. (i.e., Bayes theorem applies). However, if the patient falls in diagnostic category B,

5 R. M. Mills and J. M. Greenberg: Clinical exercise testing 349 L (A u (8) FIG. 5 Comparison of survival with respect to maximum heart rate achieved. (A) All nonsurgical patients, and (B) CAD patients. Numbers in parentheses indicate number of patients. The observed difference in survival is greater when the diagnosis of coronary artery disease is known. Reprinted by permission of the American Heart Association, Inc., Circulation 57 (1978). Months Yearly intervals FIG. 6 Bar graph demonstrating that the coronary events double at yearly intervals in all subjects with chest pain in addition of ST-segment depression during exercise testing. 0 no pain; U, pain. Reprinted with permission, from A clinical approach to exercise tolerance testing in coronary artery disease, Am J Curdiol41 (1978). the symptoms may be due to coronary artery disease, an exercise test is the next appropriate step. Three types of response are possible. If there is a low-risk response, the patient can be followed clinically unless a firm anatomic diagnosis is mandatory. On the other hand, if a high-risk response occurs, the symptoms are almost certainly due to coronary artery disease. The patient should then be considered for angiography (see below). In the indeterminate group, nuclear studies with either thallium perfusion imaging or an assessment of the ejection fraction with exercise should be considered to add further diagnostic data. If the diagnosis of coronary artery disease is supported by the nuclear methods, medical therapy should be monitored with serial exercise tests every 12 to 18 months, watching for conversion to a high-risk response. Patients falling into category A, the symptoms are due to coronary artery disease, should also undergo

6 350 Clin. Cardiol. Vol. 6, July 1983 exercise tolerance testing. Individuals able to perform at levels above 6 METS on no medication, with a peak heart rate greater than 140 beats/min and a peak systolic blood pressure greater than 160 mmhg, giving a peak double product of greater than 22,400, can be symptomatically improved with beta-blocking drugs. If such a patient does not show a fall in systolic blood pressure with exercise or greater than 2 mm ST depression, medical treatment may be started with careful follow up, on the basis of the clinical and laboratory data. Those patients unable to perform at 6 METS, those in whom blood pressure falls, or who are not able to achieve a heart rate greater than 135 beats/min should be advised to undergo angiography to search for life-threatening coronary pathoanatomy. The concept of predicting response to medical therapy from exercise tolerance testing has not, to our knowledge, been outlined in detail before. However, the theory is fairly simple. The heart rate-blood pressure product at which angina occurs is relatively constant for a given individual, unless some change in coronary pathoanatomy occurs. Thus, the peak double product can be viewed as the individual s physiologic limit. Patients adequately beta blocked usually achieve heart rate-blood pressure products in the range of 18,000 during late stage 11 of the standard Bruce protocol. (Heart rate approximately 120 beats/min, systolic blood pressure approximately 150 mmhg.) If the patient s physiologic limit is above 18,000, medical therapy will probably allow activities up to approximately 6 METS without symptoms. This level of activity is usually sufficient for most middle-aged adults to live an asymptomatic, reasonably active life. On the other hand, if the patient experiences angina pectoris, or shows other definite evidence of myocardial ischemia at low levels of heart rate-blood pressure product, he is (1) unlikley to respond to medical therapy, and (2) in a high-risk group. This approach is outlined in a flow chart (Fig. 6). A second clinical problem, where management again is crucial, is the evaluation of the patient who has sustained myocardial infarction. Diagnosis is essentially certain; these patients have atherosclerotic coronary heart disease in almost all instances. The clinical issue is, DO we proceed to catheterization, and if so, when? One reasonable approach is to eliminate from further consideration those patients whose age, mental status, left ventricular function, or associated medical problems would preclude surgical treatment. The remaining individuals should then be screened for a very high-risk group by early, low-level exercise tolerance testing. Various protocols exist from institution to institution, but all seem safe. Patients with ischemic pain, marked ST depression, or exercise-induced falls in blood pressure on early low-level testing should be studied angiographically prior to hospital discharge. Those remaining may be further subdivided into patients who have had anterior transmural infarcts, and all others. The extensive electrocardiographic changes of anterior infarction make interpretation of the exercise electrocardiogram extremely difficult (Castellanet et al., 1978). At the same time, left ventricular function is usually more impaired after anterior infarction. Thus we believe a rational case can be made for recommending elective coronary angiography to most patients who have!sustained anterior infarction. The remainder can then be handled by following the same steps as category A, the symptoms are due to coronary artery disease in the previous discussions (Fig. 7). Symptoms not coronary disease End A\ Symptoms may be coronary disease \ Lowrisk Indeterminate High-risk ETT response ETT V Follow clinically appro High-risk ETT Carheterization and surgery p r!e i if Repeat exercise with nuclear methods Decision to catheterize made on need to know criteria Symptoms are coronary disease / Indeterminate Low-ris k response Trial of medical therapy and reassess FIG. 7 Diagram for clinical evaluation of the patient. ETT = exercisi: tolerance test.

7 ~ exercise R. M. Mills and J. M. Greenberg: Clinical exercise testing 35 1 Not a surgical / candidate-by virtue of age, LV dysfunction, or associated systemic disease Y Medical therapy Management of the patient after mvocardial infarction Potential surgical All others Anterior transmural I infarction I Early "low-level" test 1 Low-r i s k High-risk - -, Catheterization with surgical response response intervention if appropriate Lima1 /" exercise test at 6-8 weeks Low-risk response V Medical therapy and repeat exercise test at months FIG. 8 Diagram for management of the patient after myocardial infarction. In conclusion, rational use of exercise tolerance testing in patient management requires an understanding of the basic pathophysiology of the disease and of the prognostic implications of various types of exercise responses. In addition, the physician must be willing to accept that certain subsets of patients will best be managed medically, while others will enjoy a better symptomatic result and perhaps a longer life with surgical intervention. If these conditions are met, then the exercise test will provide a relatively simple and useful discriminator in the management of patients with coronary artery disease. References Castellanet MJ, Greenberg PS, Ellestad MH: Comparison of S-T segment changes on exercise testing with angiographic findings in patients with prior myocardial infarction. Am J Cardiol 42, 29 ( 1978) Cole JP, Ellestad MH: Significance of chest pain during treadmill exercise: Correlation with coronary events. Am J Cardiol4 I, 227 (1 978) Ellestad MH: Stress Testing Principles and Practice. FA Davis Company, Philadelphia (1975) Mattingly TW: The postexercise electrocardiogram: Its value in the diagnosis and prognosis of coronary arterial disease. Am J Cardiol9, 395 (1 962) McNeer JF, Margolis JR, Lee KL, Kisslo JA, Peter RH, Kong Y, Behar VS, Wallace AG, McCants CB, Rosati RA: The role of the exercise lest in the evaluation of patients for ischemic heart disease. Circulation 57, 64 (1 978) Morris SN, Phillips JI, Jordan JW, McHenry PL: Incidence and significance of decreases in systolic blood pressure during graded treadmill exercise testing. Am J Cardiol4 I, 22 I ( 1978) Rapoport A: Fights, Games, and Debates. The University of Michigan Press, Ann Arbor ( 1970) Robb GP, Marks H H: Postexercise electrocardiogram in arteriosclerotic heart disease: Its value in diagnosis and prognosis. JAMA 200,9 18 ( 1967)