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Exercise Tests in Heart Failure Patients
Journal of the American College of Cardiology © 2012 by the American College of Cardiology Foundation Published by Elsevier Inc.
EDITORIAL COMMENT
Exercise Tests in Heart Failure Patients Is Simple Better?* Stanley A. Rubin, MD Los Angeles, California
The most direct, and in a sense the most important, problem which our conscious knowledge of nature should enable us to solve is the anticipation of future events, so that we may arrange our present affairs in accordance with such anticipation. Heinrich Hertz (1)
My wife exits my wardrobe closet in despair of ever seeing me discard some old, infrequently worn, and out-of-fashion clothing. She then recites to me an aphorism from a media maven of homemaking: “Simplify.” She wants me to get rid of the obsolete, focus on essential needs, and thereby simplify my life. Can we apply this bit of domestic wisdom to the choice of selecting an exercise test for the “anticipation of future events” in heart failure patients? In a clinical research article in this issue of the Journal, Forman et al. (2) suggest that, perhaps, we can. This is 1 of See page 2653
myriad substudies from Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HFACTION), a randomized multicenter trial designed to test the effect of exercise training on major adverse events in over 2,000 patients with moderately severe heart failure (3,4). In this substudy, the authors assessed the value of baseline clinical data as well as that of 2 baseline exercise tests (1 simple, 1 complex) for predicting the mortality and morbidity (primary outcome) and mortality (secondary outcome) of patients enrolled in the study. The 6-minute walk (6MW) test served as the simple test, whereas the cardiopulmonary exercise (CPX) test served as the complex test. The former assesses functional capacity from the distance a patient walks over a measured course during a 6-minute period (5). The latter assesses functional capacity as well as cardiopulmonary performance, including peak oxygen consumption and anaerobic threshold,
*Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Department of Medicine, University of California, Los Angeles, California. The author has reported that he has no relationships relevant to the contents of this paper to disclose.
Vol. 60, No. 25, 2012 ISSN 0735-1097/$36.00 http://dx.doi.org/10.1016/j.jacc.2012.08.1012
during exercise on a treadmill or cycle ergometer with collection and analysis of expired gas (6). From what is known about the quality of data from these exercise tests, we would anticipate that the baseline complex CPX test performed better at predicting adverse events than the baseline simple 6MW test. Surprisingly, the authors found that the 6MW test performed about as well as the CPX test in estimating the major study outcomes at an average follow-up of 2.5 years (2). What are the takeaway messages from this study? Absence of a strong effect limits application of this study. As in most research, the study value rises and falls on the basis of its methods, its data analysis, its results and interpretation, and, from that point, to application. With respect to the methods and data analysis, Journal readers will recognize that the statistical test used in this kind of study is some type of correlation analysis between a variable obtained at baseline and the frequency of the endpoint of morbidity and mortality. In this study (2), the authors used the C statistic. Its range of values for a reasonable model is from 0.5 to 1.0. When a model provides no information, C ⫽ 0.5. When the authors used clinical variables alone (as indicated at the bottom of Table 5 in the paper) for predicting the primary study endpoint, the value of the C statistic was 0.60 (2). By adding the 6MW test data, the value of the C statistic barely increased to 0.62. The CPX fared little better, with the C statistic value increasing to only 0.63. Therefore, although the simple 6MW test performed about as well as the more complex CPX test in predicting outcome, neither added very much to the prediction of the primary endpoint beyond the clinical variables. In response to a suggestion from manuscript reviewers (disclosure: I did not review this manuscript), the authors were quite forthcoming in sections of the paper, when they stated, “[the data from the exercise studies added] only modest prognostic discrimination to models that included important demographic and clinical covariates. . .” (2). The demographic and clinical variables might have performed better (i.e., had greater predictive value) if they included the biomarker B-type natriuretic peptide, the left ventricular ejection fraction, and the New York Heart Association class. Indeed, all of these variables were obtained at baseline. I was surprised to find an HF-ACTION substudy that analyzed the correlation between B-type natriuretic peptide and performance of the 2 exercise tests (7). It is not clear why these data were not included in the analysis of the current study. So, where does that leave us with respect to exercise testing in heart failure research and clinical management? Potential benefit in the design of future heart failure research studies. One or the other of these exercise tests— or both, as in the HF-ACTION study—is routinely included in trials of drugs and devices in chronic heart failure studies, because it is recognized that baseline functional capacity is part of characterizing enrolled patients.
JACC Vol. 60, No. 25, 2012 December 25, 2012:2662–3
Furthermore, if measured at time points during the study and at the end of the study, change in functional capacity in response to treatment or management strategy is an important result. The 6MW test is technically less demanding and less expensive than a CPX test. Therefore, unless a heart failure study requires collection of a variable only available from the CPX test, such as oxygen consumption or anaerobic threshold, the 6MW test may suffice for the purpose of measuring functional capacity in future studies. The simple 6MW test could be of particular value in studies that include patients who are older, frail, physically deconditioned, or have advanced heart failure symptoms. Exercise testing is useful in heart failure management. Attributing patient symptoms of fatigue and dyspnea to heart failure in the presence of, for example, musculoskeletal disorders, pulmonary disorders, or chronic diseases, or even the level of physical conditioning or volition of a patient, is not always readily resolved by history, physical examination, and initial laboratory tests. Cardiology clinical guidelines state, in part, “. . . Symptoms of both systolic and diastolic heart failure may first manifest as dyspnea or fatigue during physical activity. Therefore, it is appropriate to assess the functional capacity of patients with confirmed or suspected heart failure to determine whether, in fact, such impairment exists. . .” (6). For this purpose, the 6MW test is practical and simple. In select patients, the value of the test may be increased by the use of rhythm and oximetry monitoring. The conduct of the test should follow published guidelines (5). Although the test is very safe for patients, both resuscitative equipment and qualified personnel must be on-hand and organized so as to manage a rare untoward event (8). At the other end of complexity, the CPX test, with measurement of peak oxygen consumption and other variables, is a class IIa guideline recommendation for identification of candidates for cardiac transplantation, determination of disability, and assistance in the formulation of an exercise prescription. Its role in the general management of patients with heart failure has not been defined (9). The 6MW test is valuable in the assessment of other cardiopulmonary disorders. Of particular value in determining functional capacity and response to therapy in pulmonary arterial hypertension (PAH), the 6MW test is the only exercise endpoint accepted by the U.S. Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products for use in studies evaluating treatment effects (10). In patients with PAH, serial determinations of functional class and exercise capacity assessed by using the 6MW test provide benchmarks for disease severity, response to therapy, and progression (11). Conclusions. So, is simple better? If the question is which exercise test—the simple 6MW or the complex CPX test—to include as part of a heart failure research study, then the answer is a qualified “yes” in favor of the 6MW test. In addition, the 6MW test is a useful adjunct for the
Rubin Exercise Tests in Heart Failure Patients: Is Simple Better?
2663
clinician who is trying to determine the cause of a patient’s dyspnea or fatigue, and is also likely useful in charting the progress of therapy or the clinical course of some patients who have heart failure or PAH. However, predicting adverse events in heart failure (Hertz’s admonition about “anticipation of future events”) largely rests on clinical and demographic variables. Forman et al. (2) demonstrate that prediction of prognosis was little enhanced by adding the results of either the 6MW or the CPX test. As for my personal problem of convincing my wife to leave my closet contents alone, I doubt that she’ll relent from her view of “simplify.” Reprint requests and correspondence: Dr. Stanley A. Rubin, UCLA School of Medicine, Department of Medicine, Westwood and LeConte Avenue, Los Angeles, California 90095-1736. E-mail: [email protected].
REFERENCES
1. Hertz HR. The Principles of Mechanics [Jones DE, Walley JT, English translators]. New York, NY: Dover Publications, 1956 [original work published in 1894]. 2. Forman DE, Fleg JL, Kitzman D, et al. 6-Minute walk test provides prognostic utility comparable to cardiopulmonary exercise testing in ambulatory outpatients with systolic heart failure. J Am Coll Cardiol 2012;60:2653– 61. 3. Whellan DJ, O’Connor CM, Lee KL, et al. Heart failure and a controlled trial investigating outcomes of exercise training (HFACTION): design and rationale. Am Heart J 2007;153:201–11. 4. O’Connor CM, Whellan DJ, Lee KL, et al. Efficacy and safety of exercise training in patients with chronic heart failure: HF-ACTION randomized controlled trial. JAMA 2009;301:1439 –50. 5. ATS Statement. Guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002;166:111–17. 6. Arena R, Myers J, Williams MA, et al. Assessment of functional capacity in clinical and research settings: a scientific statement from the American Heart Association Committee on Exercise, Rehabilitation, and Prevention of the Council on Clinical Cardiology and the Council on Cardiovascular Nursing. Circulation 2007;116:329 – 43. 7. Felker GM, Whellan D, Kraus WE, et al. N-terminal pro– brain natriuretic peptide and exercise capacity in chronic heart failure: data from the Heart Failure and a Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) study. Am Heart J 2009;158: S37– 44. 8. Myers J, Arena R, Franklin B, et al. Recommendations for clinical exercise laboratories. A scientific statement from the American Heart Association. Circulation 2009;119:3144 – 61. 9. Hunt SA, Abraham WT, Chin MH, et al. 2009 focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults. Circulation 2009;119: e391– 479. 10. Galiè N, Hoeper MM, Humbert M, et al. for the ESC Committee for Practice Guidelines (CPG). Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009;30:2493–537. 11. Badesch DB, Abman SH, Simonneau G, et al. Medical therapy for pulmonary arterial hypertension practice guidelines. Chest 2007;131: 1917–28. Key Words: cardiopulmonary exercise testing y heart failure y prognosis y walking test.
EDITORIAL COMMENT
Exercise Tests in Heart Failure Patients Is Simple Better?* Stanley A. Rubin, MD Los Angeles, California
The most direct, and in a sense the most important, problem which our conscious knowledge of nature should enable us to solve is the anticipation of future events, so that we may arrange our present affairs in accordance with such anticipation. Heinrich Hertz (1)
My wife exits my wardrobe closet in despair of ever seeing me discard some old, infrequently worn, and out-of-fashion clothing. She then recites to me an aphorism from a media maven of homemaking: “Simplify.” She wants me to get rid of the obsolete, focus on essential needs, and thereby simplify my life. Can we apply this bit of domestic wisdom to the choice of selecting an exercise test for the “anticipation of future events” in heart failure patients? In a clinical research article in this issue of the Journal, Forman et al. (2) suggest that, perhaps, we can. This is 1 of See page 2653
myriad substudies from Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HFACTION), a randomized multicenter trial designed to test the effect of exercise training on major adverse events in over 2,000 patients with moderately severe heart failure (3,4). In this substudy, the authors assessed the value of baseline clinical data as well as that of 2 baseline exercise tests (1 simple, 1 complex) for predicting the mortality and morbidity (primary outcome) and mortality (secondary outcome) of patients enrolled in the study. The 6-minute walk (6MW) test served as the simple test, whereas the cardiopulmonary exercise (CPX) test served as the complex test. The former assesses functional capacity from the distance a patient walks over a measured course during a 6-minute period (5). The latter assesses functional capacity as well as cardiopulmonary performance, including peak oxygen consumption and anaerobic threshold,
*Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Department of Medicine, University of California, Los Angeles, California. The author has reported that he has no relationships relevant to the contents of this paper to disclose.
Vol. 60, No. 25, 2012 ISSN 0735-1097/$36.00 http://dx.doi.org/10.1016/j.jacc.2012.08.1012
during exercise on a treadmill or cycle ergometer with collection and analysis of expired gas (6). From what is known about the quality of data from these exercise tests, we would anticipate that the baseline complex CPX test performed better at predicting adverse events than the baseline simple 6MW test. Surprisingly, the authors found that the 6MW test performed about as well as the CPX test in estimating the major study outcomes at an average follow-up of 2.5 years (2). What are the takeaway messages from this study? Absence of a strong effect limits application of this study. As in most research, the study value rises and falls on the basis of its methods, its data analysis, its results and interpretation, and, from that point, to application. With respect to the methods and data analysis, Journal readers will recognize that the statistical test used in this kind of study is some type of correlation analysis between a variable obtained at baseline and the frequency of the endpoint of morbidity and mortality. In this study (2), the authors used the C statistic. Its range of values for a reasonable model is from 0.5 to 1.0. When a model provides no information, C ⫽ 0.5. When the authors used clinical variables alone (as indicated at the bottom of Table 5 in the paper) for predicting the primary study endpoint, the value of the C statistic was 0.60 (2). By adding the 6MW test data, the value of the C statistic barely increased to 0.62. The CPX fared little better, with the C statistic value increasing to only 0.63. Therefore, although the simple 6MW test performed about as well as the more complex CPX test in predicting outcome, neither added very much to the prediction of the primary endpoint beyond the clinical variables. In response to a suggestion from manuscript reviewers (disclosure: I did not review this manuscript), the authors were quite forthcoming in sections of the paper, when they stated, “[the data from the exercise studies added] only modest prognostic discrimination to models that included important demographic and clinical covariates. . .” (2). The demographic and clinical variables might have performed better (i.e., had greater predictive value) if they included the biomarker B-type natriuretic peptide, the left ventricular ejection fraction, and the New York Heart Association class. Indeed, all of these variables were obtained at baseline. I was surprised to find an HF-ACTION substudy that analyzed the correlation between B-type natriuretic peptide and performance of the 2 exercise tests (7). It is not clear why these data were not included in the analysis of the current study. So, where does that leave us with respect to exercise testing in heart failure research and clinical management? Potential benefit in the design of future heart failure research studies. One or the other of these exercise tests— or both, as in the HF-ACTION study—is routinely included in trials of drugs and devices in chronic heart failure studies, because it is recognized that baseline functional capacity is part of characterizing enrolled patients.
JACC Vol. 60, No. 25, 2012 December 25, 2012:2662–3
Furthermore, if measured at time points during the study and at the end of the study, change in functional capacity in response to treatment or management strategy is an important result. The 6MW test is technically less demanding and less expensive than a CPX test. Therefore, unless a heart failure study requires collection of a variable only available from the CPX test, such as oxygen consumption or anaerobic threshold, the 6MW test may suffice for the purpose of measuring functional capacity in future studies. The simple 6MW test could be of particular value in studies that include patients who are older, frail, physically deconditioned, or have advanced heart failure symptoms. Exercise testing is useful in heart failure management. Attributing patient symptoms of fatigue and dyspnea to heart failure in the presence of, for example, musculoskeletal disorders, pulmonary disorders, or chronic diseases, or even the level of physical conditioning or volition of a patient, is not always readily resolved by history, physical examination, and initial laboratory tests. Cardiology clinical guidelines state, in part, “. . . Symptoms of both systolic and diastolic heart failure may first manifest as dyspnea or fatigue during physical activity. Therefore, it is appropriate to assess the functional capacity of patients with confirmed or suspected heart failure to determine whether, in fact, such impairment exists. . .” (6). For this purpose, the 6MW test is practical and simple. In select patients, the value of the test may be increased by the use of rhythm and oximetry monitoring. The conduct of the test should follow published guidelines (5). Although the test is very safe for patients, both resuscitative equipment and qualified personnel must be on-hand and organized so as to manage a rare untoward event (8). At the other end of complexity, the CPX test, with measurement of peak oxygen consumption and other variables, is a class IIa guideline recommendation for identification of candidates for cardiac transplantation, determination of disability, and assistance in the formulation of an exercise prescription. Its role in the general management of patients with heart failure has not been defined (9). The 6MW test is valuable in the assessment of other cardiopulmonary disorders. Of particular value in determining functional capacity and response to therapy in pulmonary arterial hypertension (PAH), the 6MW test is the only exercise endpoint accepted by the U.S. Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products for use in studies evaluating treatment effects (10). In patients with PAH, serial determinations of functional class and exercise capacity assessed by using the 6MW test provide benchmarks for disease severity, response to therapy, and progression (11). Conclusions. So, is simple better? If the question is which exercise test—the simple 6MW or the complex CPX test—to include as part of a heart failure research study, then the answer is a qualified “yes” in favor of the 6MW test. In addition, the 6MW test is a useful adjunct for the
Rubin Exercise Tests in Heart Failure Patients: Is Simple Better?
2663
clinician who is trying to determine the cause of a patient’s dyspnea or fatigue, and is also likely useful in charting the progress of therapy or the clinical course of some patients who have heart failure or PAH. However, predicting adverse events in heart failure (Hertz’s admonition about “anticipation of future events”) largely rests on clinical and demographic variables. Forman et al. (2) demonstrate that prediction of prognosis was little enhanced by adding the results of either the 6MW or the CPX test. As for my personal problem of convincing my wife to leave my closet contents alone, I doubt that she’ll relent from her view of “simplify.” Reprint requests and correspondence: Dr. Stanley A. Rubin, UCLA School of Medicine, Department of Medicine, Westwood and LeConte Avenue, Los Angeles, California 90095-1736. E-mail: [email protected].
REFERENCES
1. Hertz HR. The Principles of Mechanics [Jones DE, Walley JT, English translators]. New York, NY: Dover Publications, 1956 [original work published in 1894]. 2. Forman DE, Fleg JL, Kitzman D, et al. 6-Minute walk test provides prognostic utility comparable to cardiopulmonary exercise testing in ambulatory outpatients with systolic heart failure. J Am Coll Cardiol 2012;60:2653– 61. 3. Whellan DJ, O’Connor CM, Lee KL, et al. Heart failure and a controlled trial investigating outcomes of exercise training (HFACTION): design and rationale. Am Heart J 2007;153:201–11. 4. O’Connor CM, Whellan DJ, Lee KL, et al. Efficacy and safety of exercise training in patients with chronic heart failure: HF-ACTION randomized controlled trial. JAMA 2009;301:1439 –50. 5. ATS Statement. Guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002;166:111–17. 6. Arena R, Myers J, Williams MA, et al. Assessment of functional capacity in clinical and research settings: a scientific statement from the American Heart Association Committee on Exercise, Rehabilitation, and Prevention of the Council on Clinical Cardiology and the Council on Cardiovascular Nursing. Circulation 2007;116:329 – 43. 7. Felker GM, Whellan D, Kraus WE, et al. N-terminal pro– brain natriuretic peptide and exercise capacity in chronic heart failure: data from the Heart Failure and a Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) study. Am Heart J 2009;158: S37– 44. 8. Myers J, Arena R, Franklin B, et al. Recommendations for clinical exercise laboratories. A scientific statement from the American Heart Association. Circulation 2009;119:3144 – 61. 9. Hunt SA, Abraham WT, Chin MH, et al. 2009 focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults. Circulation 2009;119: e391– 479. 10. Galiè N, Hoeper MM, Humbert M, et al. for the ESC Committee for Practice Guidelines (CPG). Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009;30:2493–537. 11. Badesch DB, Abman SH, Simonneau G, et al. Medical therapy for pulmonary arterial hypertension practice guidelines. Chest 2007;131: 1917–28. Key Words: cardiopulmonary exercise testing y heart failure y prognosis y walking test.