An Externally Validated Model for Predicting Long-Term Survival after Exercise Treadmill Testing in Patients with Suspected Coronary Artery Disease and a Normal Electrocardiogram

Context How might we best stratify low-risk patients with normal electrocardiograms but suspected coronary artery disease? Contribution This large prospective study evaluated a posttreadmill test mortality prediction rule in adults with normal electrocardiograms and suspected coronary artery disease. A nomogram that included clinical variables (age, sex, smoking, and diabetes) and treadmill variables (exercise capacity, abnormal heart rate recovery, and ventricular ectopy during recovery) better identified patients with less than a 3% mortality rate over 3 years than did a standard Duke treadmill score. Implication The nomogram warrants additional validation to verify that it reliably identifies low-risk patients who need no further cardiac work-up after a treadmill test. The Editors Exercise treadmill testing is recommended for assessing prognosis in patients with symptoms suggestive of coronary artery disease and at least an intermediate probability for disease, as assessed by age, sex, and symptoms (1). Current guidelines focus on the Duke treadmill score, which incorporates functional capacity, electrocardiographic evidence of ischemia, and test-induced angina pectoris (24). However, this scheme of risk stratification based primarily on age, sex, symptom status, and the Duke treadmill score does not take into account other simple historical measures that have known diagnostic and prognostic value (5, 6), as well as more recently discovered exercise test predictors of risk (7), such as heart rate recovery (811) and stress-related ventricular ectopy (12). Because combining clinical and exercise variables improves prognostic accuracy (1315), we developed a practical prognostic model for all-cause mortality based on measures that are easily obtained at the time of stress testing and do not require blood testing. We then compared this model with the current standard Duke treadmill score and externally validated the model for its ability to accurately identify low-risk persons for whom conservative management would be appropriate. We focused on all-cause mortality as an end point because, unlike cardiac mortality, it is wholly unbiased, objective, and clinically relevant (16, 17). For ease of use, we present this model as a nomogram. Methods Patients Since September 1990, all patients undergoing any type of stress testing at our institution have had demographic, clinical, and stress data entered prospectively into a computerized database as part of routine clinical reporting (8, 9, 12). For our analysis, we focused on adult patients 30 years of age or older who were referred for symptom-limited exercise treadmill testing for evaluation of suspected coronary disease between 1 September 1990 and 31 December 2002. None had known coronary disease, heart failure, documented left ventricular systolic dysfunction, any type of cardiomyopathy, valvular or congenital heart disease, previous renal or cardiac transplantation, atrial fibrillation, digitalis use, pacemaker or defibrillator placement, or end-stage renal disease. Furthermore, none had any baseline electrocardiographic abnormalities, such as Q-wave myocardial infarction, right or left bundle-branch block, left ventricular hypertrophy with accompanying repolarization abnormalities, preexcitation syndrome, or resting ST-T wave changes precluding exercise interpretation (defined as 1 mm of horizontal or downsloping ST-segment depression 80 ms after the J point). We focused on patients with normal electrocardiograms to allow for ST-segment interpretation and to minimize the likelihood of undiagnosed left ventricular systolic dysfunction (18). Our institutional review board granted permission to use electronically obtained clinical data for research purposes and waived the requirement for informed consent. Clinical Data As described elsewhere, all patients underwent a routine structured chart review and interview with prospective data entry of demographic and clinical data before exercise testing (8, 9, 12, 19). For our analysis, we focused on age, sex, smoking history, diabetes mellitus, hypertension, and history of typical angina (5, 6)variables that can be easily obtained in a stress laboratory without blood tests or access to medical records and have been correlated elsewhere with severe angiographic coronary disease and death (5, 6). We considered patients who reported regular use of cigarettes any time within the past year to be recent or current smokers. We classified diabetes on the basis of whether it was being treated regularly with insulin or treated with oral agents only. If resting systolic blood pressure was at least 140 mm Hg, resting diastolic blood pressures was at least 90 mm Hg, or medications were regularly used for treating elevated blood pressure, we considered hypertension to be present. We considered typical angina present if, on reporting a history of chest pain or discomfort, patients answered affirmatively to all 3 of the following questions: Is the pain or discomfort substernal? Is the pain or discomfort brought on by physical or emotional stress? and Is the pain quickly relieved by rest and/or use of nitroglycerin? We did not consider other symptoms, such as atypical angina, dyspnea, or nonanginal chest pain, that were not routinely recorded before 1 January 1996 (20). Trained personnel prospectively recorded all clinical data online before exercise testing; they were blinded to both the hypothesis of this study and the patient outcomes. Exercise Testing We performed symptom-limited exercise testing mostly by using the Bruce and modified Bruce protocols; protocol selection was based on aiming for a test that would last 8 to 12 minutes. We estimated exercise capacity in metabolic equivalents, where 1 metabolic equivalent is an oxygen consumption of 3.5 mL per kg of body weight per minute, and calculated the age- and sex-adjusted proportion of predicted exercise capacity achieved by using previously published regression equations (21). We measured ST-segment deviation to the nearest 0.5 mm and considered it abnormal if horizontal or sloping away from the isoelectric line at least 80 ms after the J point in at least 2 contiguous leads for at least 3 consecutive beats was observed. We recorded exercise-induced angina as being test-limiting or nontest-limiting. The Duke treadmill score (2, 3) was calculated as follows: (Bruce equivalent number of minutes until test termination) (5the amount of ST-segment deviation in millimeters) (4the angina index). ST-segment deviation had to be horizontal or sloping away from the isoelectric baseline. The angina index had a value of 0 if no angina occurred during exercise, 1 if nontest-limiting angina occurred, and 2 if test-limiting angina occurred. A score of 5 or greater was considered low risk; between 5 and 10, intermediate risk; and less than 10, high risk. We calculated heart rate recovery as the difference between heart rate at peak exercise and that 1 minute later; we considered a heart rate recovery of 18 or fewer beats/min to be abnormal for patients undergoing stress echocardiography (10) and a heart rate recovery of 12 or fewer beats/min to be abnormal for patients undergoing other types of testing that used an upright cooldown (8, 9). If at least 7 premature ventricular beats/min, frequent ventricular couplets, any ventricular triplets, nonsustained or sustained ventricular tachycardia or torsade de pointes, or ventricular fibrillation occurred in the first 5 minutes of recovery, we considered frequent ventricular ectopy to be present (12). Outcomes The primary outcome was all-cause mortality as determined with the Social Security Death Index (22). Accuracy of this measure can be described in terms of specificity (death has occurred when the Index indicates that it has) and sensitivity (the Index indicates that death has occurred when in fact it has). Previous investigators have demonstrated specificity greater than 99% (22); we have shown that, among patients seen in our exercise laboratory, the sensitivity of the Index exceeds 95% (9). The final censoring date was 1 May 2004. Data on cardiac deaths were not available. External Validation Data In 2001, physicians from Kaiser Permanente Colorado, Denver, Colorado, visited the stress laboratory of the Cleveland Clinic, Cleveland, Ohio. They agreed to adopt the Cleveland Clinic database and definitions for their tests. After receiving local institutional review board approval in May 2006, they sent the Cleveland Clinic's deidentified data for analyses from consecutive patients who underwent testing in Denver and met the same inclusion and exclusion criteria as those of patients at the Cleveland Clinic. Statistical Analysis We used the KaplanMeier method to describe survival according to the Duke treadmill score and tested differences by using the log-rank chi-square statistic. We used Cox proportional hazards modeling (23) to predict mortality rate based on all the variables listed in Table 1 because they are easily measured, are routinely available, and have theoretical support. Any angina during testing was considered a composite variable (angina scores of 1 and 2 were combined) because relatively few patients had test-limiting angina (angina score of 2). To allow for nonlinear associations, we used restricted cubic splines for continuous or ordinal variables (24). We confirmed the proportional hazards assumption for all variables by calculating scaled Schoenfeld residuals and inspecting time-based hazard ratio plots. We constructed our nomogram on the basis of the results of the proportional hazards model. Table 1. Demographic, Clinical, and Exercise Test Characteristics in the Derivation and Validation Data Sets Prediction model accuracy was assessed in 2 different ways. First, we assessed model discrimination by measuring the concordance index (c-index) for censored data after 10-fold cross-validation (25). The c-index is analogous to the