Exercise treadmill testing is frequently used in clinical practice to

Preventive Cardiology FEATURE Case Report 55 Commentary 59 Exercise capacity on treadmill predicts future cardiac events Pamela N. Peterson, MD, MSPH 1-3 David J. Magid, MD, MPH 3 P. Michael Ho, MD, PhD 2-4 John S. Rumsfeld, MD, PhD 2-4 Frederick A. Masoudi, MD, MSPH 1-3 TIME-SAVER Reduced exercise capacity is associated with an increased risk of myocardial infarction, unstable angina, and coronary revascularization in patients referred for exercise treadmill testing for clinical indications. The prognostic importance of reduced exercise capacity for nonfatal coronary events is independent of demographic factors, clinical factors, and other exercise treadmill testing measures. Reduced exercise capacity may identify patients in whom aggressive risk-factor modifi cation, further diagnostic testing, and close follow-up is warranted. Disclosure The authors have no relationship with any commercial entity that might represent a confl ict of interest with the content of this article. Exercise treadmill testing is frequently used in clinical practice to obtain valuable diagnostic and prognostic information. Multiple measures acquired during this test, including exercise capacity, contribute to the overall interpretation of the test. The prognostic value of exercise capacity in predicting mortality has been well established. 1-6 Little is known, however, about the role of exercise capacity in predicting nonfatal cardiac events. Our objective was to evaluate the prognostic importance of exercise capacity for predicting nonfatal cardiac events, independent of other parameters measured during exercise treadmill testing among patients referred for this test for clinical reasons. The study was designed to clarify the significance of reduced exercise capacity for clinicians interpreting exercise treadmill test results in clinical practice. Methods We used a retrospective cohort study design, enrolling 9191 consecutive patients referred for exercise treadmill testing in a large managed care organization. Symptom-limited treadmill testing was performed according to standardized protocols. Exercise capacity was defined as the proportion of the age- and sex-predicted metabolic equivalents achieved 7,8 and was categorized as less than 85%, 85% to 100%, and greater than 100%. The primary outcomes of myocardial infarction (MI), unstable angina, and coronary revascularization procedures, defined as either coronary artery bypass graft surgery or percutaneous coronary intervention, were identified using primary discharge diagnosis ICD-9-CM (International Classification of Diseases, Ninth Revision, Clinical Modification) codes. All-cause mortality was evaluated as a secondary outcome. Outcomes across levels of exercise capacity were compared using the Kaplan-Meier method, and differences in event rates were evaluated with From the 1 Denver Health Medical Center; 2 University of Colorado at Denver and Health Sciences Center; 3 Clinical Research Unit, Kaiser Permanente of Colorado; and 4 Denver VA Medical Center, Denver, CO. 48 Cardiology Review Vol 25 No 12 December 2008 Preventive.indd 48 12/12/08 2:09:45 PM

the log-rank test. The independent prognostic importance of exercise capacity for nonfatal cardiac events was assessed using multivariable Cox proportional hazards regression. We adjusted for demographics, indication for treadmill testing, comorbidities, and several exercise treadmill testing measures, including heart rate recovery, chronotropic incompetence, ventricular ectopy in recovery, ST-segment deviation, and chest pain during exercise. Finally, the relationship between exercise capacity and nonfatal cardiac events was explored in prespecified patient subgroups. Results Patients with lower exercise capacity were more likely to be women, to smoke, and to have a higher body mass index and more comorbid conditions, such as diabetes and hypertension. With regard to other exercise treadmill test measures, patients with reduced exercise capacity were more likely to have chest pain upon exercising, ST-segment changes, abnormal heart rate recovery, and an abnormal chronotropic index. Over a mean of 2.7 years of follow-up, rates of MI, unstable angina, and coronary revascularization were greater among those with lower exercise capacity (log rank, P <.01 across levels of exercise capacity for each outcome; Figure 1). After accounting for demographic, clinical, and exercise treadmill test measures, lower exercise capacity remained strongly associated with A Proportion free from MI B Proportion free from unstable angina C Proportion free from revascularization 0.950 0.925 0.900 0.875 0.850 0.825 0.950 0.925 0.900 0.875 0.850 0.825 Freedom from myocardial Infarction (MI) to proportion of predicted METs achieved. 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 Freedom from unstable angina according to proportion of predicted METs achieved. 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 Freedom from revascularization according to proportion of predicted METs achieved. 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 Figure 1. Kaplan-Meier curve of freedom from nonfatal cardiac events according to proportion of age- and sex-predicted metabolic equivalents (METs) achieved. December 2008 Vol 25 No 12 Cardiology Review 49 Preventive.indd 49

Preventive Cardiology an increased risk of MI (hazard ratio [HR], 2.36; 95% confidence interval [CI], 1.55-3.60), unstable angina (HR, 2.39; 95% CI, 1.78-3.21), and coronary revascularization (HR, 1.75; 95% CI, 1.46-2.08) for those who achieved less than 85% of their predicted exercise capacity compared with those who achieved more than 100% (Table). Those achieving 85% to 100% of their predicted exercise capacity did not have a significant increase in risk of nonfatal outcomes compared with those who achieved more than 100%. Finally, the association between exercise capacity and each of the outcomes was consistent in all patient subgroups evaluated (Figure 2). Exercise capacity was also independently associated with an increased risk of all-cause mortality. This was true for those who achieved less than 85% (HR, 2.90; 95% CI, 1.88-4.47) of their predicted exercise capacity and for those achieving 85% to 100% (HR, 1.78; 95% CI, 1.13-2.81) compared with those who achieved greater than 100% (Table). Table. Prediction of outcomes by proportion of age- and sex-predicted metabolic equivalents achieved using Cox proportional hazard analysis. Patients with event (n) Discussion In this community-based population of patients referred for exercise treadmill testing for clinical indications, patients with a decreased exercise capacity had an increased risk of MI, unstable angina, and coronary revascularization; this finding was independent of patient characteristics and other exercise treadmill test parameters. Failure to reach 85% of age- and sexpredicted metabolic equivalents was associated with a 2.4-fold higher risk of MI, a 2.4-fold higher risk of unstable angina, a 1.8-fold higher risk of revascularization, and an almost 3-fold higher risk of death from all causes. Crude HR (95% CI) Adjusted HR (95% CI) Outcomes MI a Total 119 <85% 49 2.36 (1.60-3.49) 2.36 (1.55-3.60) 85%-100% 18 0.78 (0.46-1.34) 0.79 (0.46-1.36) >100% 52 Ref Ref Unstable angina b Total 259 <85% 101 2.69 (2.03-3.55) 2.39 (1.78-3.21) 85%-100% 61 1.46 (1.06-2.01) 1.31 (0.94-1.81) >100% 97 Ref Ref CABG or PCI c Total 749 <85% 228 1.72 (1.46-2.03) 1.75 (1.46-2.08) 85%-100% 172 1.15 (0.96-1.38) 1.08 (0.90-1.31) >100% 349 Ref Ref All-cause mortality d Total 132 <85% 52 2.72 (1.80-4.04) 2.90 (1.88-4.47) 85%-100% 33 1.57 (1.01-2.45) 1.78 (1.13-2.81) >100% 47 Ref Ref CABG = coronary artery bypass graft, CI = confi dence interval, HR = hazard ratio, MI = myocardial infarction, and PCI = percutaneous coronary intervention. a ectopy, age, sex, history of coronary artery disease (CAD), smoking, cancer, chronic obstructive pulmonary disease (COPD), and other vascular disease. b Adjusted for chest pain, ST-segment changes, heart rate recovery, chronotropic index, ventricular ectopy, age, sex, diabetes, history of CAD, lipid disorders, statin use, and beta blocker use. c ectopy, age, sex, diabetes, history of CAD, lipid disorders, statin use, beta blocker use, and angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker use. d ectopy, age, sex, diabetes, smoking status, cancer, and COPD. The primary finding of this analysis is that exercise capacity predicts future cardiac events. Prior studies have not focused specifically on the utility of exercise capacity for predicting future nonfatal cardiac events in patients referred for exercise treadmill test- 50 Cardiology Review Vol 25 No 12 December 2008 Preventive.indd 50

Case Report 55 Commentary 59 No ST changes ST changes No beta blocker Beta blocker Age < 65 Age > 65 Male Female No history of CAD History of CAD No chest pain on ETT Chest pain on ETT ing. While poor exercise capacity is generally considered a maker of a poor prognosis, this association is often attributed to other comorbidities. Various conditions can result in reduced exercise capacity, such as chronic lung disease, arthritis, and musculoskeletal disorders. Clinicians interpreting exercise treadmill tests might assume that future adverse outcomes are related to such conditions, thereby underestimating the risk of future cardiac morbidity, particularly in the absence of other treadmill indicators, such as chest pain or STsegment changes. We found that patients with reduced exercise capacity have an increased risk of subsequent nonfatal cardiac events, independent of other comorbidities and traditionally reported exercise treadmill test measures, such as 0 5 10 15 Hazard ratio Figure 2. The association between exercise capacity and hospitalization for MI among patient subgroups. CAD indicates coronary artery disease, ETT = excercise treadmill testing. ST-segment deviations and chest pain. Exercise capacity, therefore, is an important indicator of cardiovascular risk and not simply a less specific indicator of a greater burden of comorbidity. Because multiple exercise treadmill test measures have prognostic significance and should be incorporated in the assessment of prognosis, 9 it is important to understand the prognostic value of exercise capacity independent of the contribution of other measures. This study demonstrates the predictive value of exercise capacity for nonfatal cardiac events independent of other exercise testing measures, including chest pain, ST-segment changes, heart rate recovery, chronotropic index, and ventricular ectopy in recovery. Although other studies have shown that reduced exercise capacity is associated with higher mortality rates, 1-6 none of these adjusted for all exercise treadmill test parameters independently associated with survival, such as chronotropic index and heart rate recovery. Reduced exercise capacity may be useful in clinical practice to identify high-risk patients who may benefit from therapeutic interventions. Prospective studies are needed to determine the best approach for these patients; however, aggressive risk-factor modification and close follow-up should be considered to reduce the risk of future cardiac events. Given the magnitude of the association, further evaluation of the benefits of aggressive diagnostic and therapeutic strategies directed at preventing cardiac events in patients with reduced exercise tolerance is warranted. Physical activity is also known to improve exercise tolerance and reduce the risk of adverse outcomes. 10,11 Finding poor exercise tolerance on exercise treadmill testing may provide clinicians with an opportunity to discuss the benefits of physical activity and encourage sedentary patients to increase their level of physical activity. Our study had several limitations. First, exercise capacity was estimated on the basis of the speed and degree of incline of the treadmill and not directly measured using ventilatory gas exchange. 12 Achieved metabolic equivalents, however, are standardized and are an objective measure of exer- December 2008 Vol 25 No 12 Cardiology Review 51 Preventive.indd 51

Preventive Cardiology cise capacity in clinical practice. Second, the generalizability of the results may be limited because the study population came from a single managed care organization. Finally, the results may be affected by unmeasured confounding variables; however, a large number of covariates were included in the multivariable models, including comorbid conditions and extensive treadmill variables. Conclusions Exercise capacity was a strong and independent predictor of nonfatal cardiac events in a community cohort of patients referred for exercise treadmill testing. This study suggests that exercise capacity independently identifies patients at higher risk for cardiovascular events. While prospective studies are needed to determine the optimal diagnostic and therapeutic approaches for these patients, clinicians should consider aggressive risk-factor modification and close follow-up in those with impaired exercise capacity. References 1. Wei M, Gibbons LW, Kampert JB, Nichaman MZ, Blair SN. Low cardiorespiratory fitness and physical inactivity as predictors of mortality in men with type 2 diabetes. Ann Intern Med. 2000;132(8):605-611. 2. Church TS, Kampert JB, Gibbons LW, Barlow CE, Blair SN. Usefulness of cardiorespiratory fitness as a predictor of all-cause and cardiovascular disease mortality in men with systemic hypertension. Am J Cardiol. 2001;88(6): 651-656. 3. Domínguez H, Torp-Pedersen C, Koeber L, Rask-Madsen C. Prognostic value of exercise testing in a cohort of patients followed for 15 years after acute myocardial infarction. Eur Heart J. 2001;22(4):300-306. 4. Weiner DA, Ryan TJ, McCabe CH, et al. The role of exercise testing in identifying patients with improved survival after coronary artery bypass surgery. J Am Coll Cardiol. 1986;8(4):741-748. 5. Myers J, Prakash M, Froelicher V, Do D, Partington S, Atwood JE. Exercise capacity and mortality among men referred for exercise testing. N Engl J Med. 2002;346(11):793-801. 6. Gulati M, Pandey DK, Arnsdorf MF, et al. Exercise capacity and the risk of death in women: the St James Women Take Heart Project. Circulation. 2003;108(13):1554-1559. 7. Gulati M, Black HR, Shaw LJ, et al. The prognostic value of a nomogram for exercise capacity in women. N Engl J Med. 2005;353(5):468-475. 8. Morris CK, Myers J, Froelicher VF, Kawaguchi T, Ueshima K, Hideg A. Nomogram based on metabolic equivalents and age for assessing aerobic exercise capacity in men. J Am Coll Cardiol. 1993;22(1):175-182. 9. Kligfield P, Lauer MS. Exercise electrocardiogram testing: beyond the ST segment. Circulation. 2006;114(19): 2070-2082. 10. Mark DB, Lauer MS. Exercise capacity: the prognostic variable that doesn t get enough respect. Circulation. 2003; 108(13):1534-1536. 11. Warburton DE, Nicol CW, Bredin SS. Health benefits of physical activity: the evidence. CMAJ. 2006;174(6): 801-809. 12. Myers J, Buchanan N, Walsh D, et al. Comparison of the ramp versus standard exercise protocols. J Am Coll Cardiol. 1991;17(6):1334-1342. Do you have an interesting ECG you d like to share with Cardiology Review? If so, we d love to hear from you! ECG Rounds submissions should represent common but often not recognized conditions, offer striking example of less common but classically described conditions, or just be plain interesting. Use a question and answer format. Provide a high-resolution (300 dpi) diagnostic ECG, a brief description of the presenting condition, and a brief discussion of the condition that notes why the ECG revealed the diagnosis. Please be sure to remove all patient-identifying features from the ECG. ECG Rounds submissions will undergo peer-review, are subject to editing, and will be published in the journal or on its Website, www.cardiologyreviewonline.com, at the editors discretion. ECG Rounds submissions may be e-mailed to Christina Loguidice, Editor, Cardiology Review, at cloguidice@cardiology-review.com. 52 Cardiology Review Vol 25 No 12 December 2008 Preventive.indd 52 12/12/08 2:09:48 PM