Predicting Prognosis in Advanced Heart Failure
1996; Elsevier BV; Volume: 110; Issue: 2 Linguagem: Inglês
10.1378/chest.110.2.310
ISSN1931-3543
AutoresMandeep R. Mehra, Carl J. Lavie, Richard V. Milani,
Tópico(s)Cardiovascular Function and Risk Factors
ResumoSeveral investigators have searched for methods for predicting clinical outcome in patients with advanced heart failure, including various parameters of exercise capacity for prognostic risk stratification.1Mehra MR Ventura HO. Advanced heart failure.in: Civetta JM Taylor RW Kirby RR 3rd ed. Critical care. J.B. Lippincott Company, Philadelphia1996Google Scholar These exercise indices include subjective parameters such as functional capacity (New York Heart Association [NYHA] classification) and objective parameters obtained by maximal and submaximal exercise stress testing. Functional class assessment is rather subjective and therefore often inaccurate, leading to substantially poor prognosis discriminating ability at mild to moderate levels of functional limitation.Maximal exercise testing has thus far been the time-honored form of objective exercise assessment. An important advance in exercise testing in heart failure accrued from the work by Weber et al,2Weber KT Kinasewitz GT Janicki JS et al.Oxygen utilization and ventilation during exercise in patients with chronic cardiac failure.Circulation. 1982; 65: 1213-1223Crossref PubMed Scopus (721) Google Scholar wherein the investigators demonstrated that concomitant measurements of respiratory gas exchange and air flow with assessment of maximal oxygen consumption ( V˙o2 max) and anaerobic threshold could allow demarcation of the causes of exercise intolerance into cardiocirculatory, pulmonary, and physical deconditioning. Soon thereafter, Szlachcic and colleagues3Szlachcic J Massie BM Kramer BL et al.Correlates and prognostic implication of exercise capacity in chronic congestive heart failure.Am J Cardiol. 1985; 55: 1037-1042Abstract Full Text PDF PubMed Scopus (430) Google Scholar investigated the prognostic importance of maximal oxygen consumption measured during upright bicycle ergometry in a cohort of 27 heart failure patients (21/27 NYHA III/IV; 6/27 NYHA II). At 1-year follow-up, heart failure patients with a V˙o2 max <10 mL/kg/min were found to have a mortality of 77% compared with a 21% mortality in the group with higher V˙o2 max (p 14 mL/kg/min and that V˙o2 max was the best discriminant of 2-year survival. Data such as these have led to the widespread use of metabolic exercise assessment to determine need for and timing of heart transplantation. While most investigators agree that a V˙o2 max 18 to 20 mL/kg/min predicts clinical stability and good outcome, controversy abounds in patients with a V˙o2 max between 10 and 18 mL/kg/min, a range most frequently encountered in patients with left ventricular dysfunction.5Pina IL. Optimal candidates for heart transplantation: is 14 the magic number?.J Am Coll Cardiol. 1995; 26: 436-437Abstract Full Text PDF PubMed Scopus (27) Google Scholar Investigators have searched for ways to refine the discriminant function of this "gray area," by assessing measurements of percent predicted values of V˙o2 max adjusted for age and gender, as well as the additive prognostic impact of echocardiographic diastolic indices.6Di Salvo TG Mathier M Semigran MJ. Preserved right ventricular ejection fraction predicts exercise capacity and survival in advanced heart failure.J Am Coll Cardiol. 1995; 25: 1143-1153Abstract Full Text PDF PubMed Scopus (586) Google Scholar, 7Richards D Mehra MR Ventura HO et al.The discriminatory role of cardiopulmonary exercise parameters and diastolic indices in assessing prognosis in advanced heart failure.J Heart Lung Transplant. 1996; 15 (in press)Google Scholar In a recent study7Richards D Mehra MR Ventura HO et al.The discriminatory role of cardiopulmonary exercise parameters and diastolic indices in assessing prognosis in advanced heart failure.J Heart Lung Transplant. 1996; 15 (in press)Google Scholar of 123 patients with advanced heart failure and a mean V˙o2 max of 16.9 mL/kg/min, it has been demonstrated that percent predicted values of V˙o2 max were a better predictor of clinical events than weight adjusted V˙o2 max. This investigation also found that, although the presence of restrictive physiology was significantly correlated with V˙o2 max, it added little in the way of prognostic information in the intermediate range V˙o2 max. A separate investigation from our group has shed light on the presence of a gender mismatch in the predictive ability of V˙o2 max, demonstrating that in women, percent predicted values of V˙o2 max are more closely indicative of clinical outcome than weight adjusted V˙o2 max.8Richards DR Mehra MR Ventura HO et al.Can maximal oxygen consumption predict outcome of heart failure in women as well as in men? Evidence for a gender mismatch.Circulation. 1995; 92: I-402Google ScholarTraditional maximal exercise testing can be difficult in some patients who are limited by severe cardiac dysfunction or peripheral vascular disease. In such patients, submaximal exercise testing, with or without gas exchange data, is required to evaluate metabolic performance. When gas exchange data is available, our laboratory has used successfully the ventilation/carbon dioxide production ratio assessed at submaximal exercise, to reliably predict V˙o2 max and prognosis.9Milani RV Mehra MR Reddy TR et al.Ventilation/carbon dioxide production ratio in early exercise predicts poor functional capacity in congestive heart failure.Br Heart J. 1996; (in press)Google Scholar When cardiopulmonary testing is not available, however, submaximal tests, such as the 6-min walk test, offer the advantage of a safe and reproducible test that better approximates the usual daily activity levels of patients. Guyatt and associates10Guyatt GH Sullivan MJ Thompson PJ et al.The 6-minute walk: a new measure of exercise capacity in patients with chronic heart failure.Can Med Assoc J. 1985; 132: 919-923PubMed Google Scholar performed the first study of the clinical utility of the 6-min walk test in heart failure patients and showed a significant correlation with functional class but failed to define a close association with results of cycle ergometer testing. This poor correlation with maximal exercise suggested that the 6-min walk test, in fact, might be a measure of a patient's ability to perform usual day to day activity, whereas the maximal exercise test may be a more artificial estimate of laboratory exercise capacity. Another important attribute of the 6-min walk test, demonstrated in serial studies, relates to the incremental improvement in test performance that occurs with concurrent encouragement and the training effect resulting from serial tests. These factors must be kept in mind when critically assessing the value of information derived from the 6-min walk test.The first investigation to convincingly link the 6-min walk test and morbidity and mortality prediction in heart failure was accomplished by Bittner et al11Bittner V Weiner DH Yusuf S et al.Prediction of mortality and morbidity with a 6-minute walk test in patients with left ventricular dysfunction.JAMA. 1993; 270: 1702-1707Crossref PubMed Scopus (716) Google Scholar on behalf of the Studies of Left Ventricular Dysfunction (SOLVD) group. These investigators reported that the test independently and strongly predicted long-term mortality and hospitalization rates for heart failure beyond that of traditional indices such as left ventricular ejection fraction and NYHA functional class. It should be emphasized that the patient cohort studied was predominantly that of mild to moderate heart failure, with only 15% of the population suffering from severe heart failure.In this issue of CHEST, Cahalin and colleagues (see page 325) attempt to define the prognostic utility of the 6-min walk test in 45 patients with severe heart failure (mean NYHA class 3.3±0.6) who were referred for heart transplantation. These researchers concluded that the 6-min walk test was useful in predicting V˙o2 max and short-term survival but did not prognosticate long-term outcome. The concept of the study is an important one, since the availability of a safe, noninvasive, reproducible, and easily performable prognostic discriminator in patients with severe heart failure is clearly desirable. Several aspects of this investigation, however, merit discussion. For one, the study population was not quite representative of the commonly prevailing etiologic entities of advanced heart failure, and it displayed a predominance of nonischemic dilated cardiomyopathy (78%). Second, the majority of patients were men and therefore the findings of this study might not be generalized to women.Although these investigators concluded that the 6-min walk test "accurately" predicted V˙o2 max, the overall correlation was only modest (r=0.64). Based on the data presented by Cahalin and associates, we have analyzed the ability of using a cut point of 350 meters on the 6-min walk test to predict a V˙o2 max of ≤14 mL/kg/min, a threshold at which heart transplantation becomes a considered option. The sensitivity is 71% and specificity 60%, with a positive and negative predictive value of 86% and 50%, respectively. One can, therefore, hypothesize that the 6-min walk test might serve as a reasonable preliminary screening test for stratifying patients into a "high risk" group who may require early referral for further maximal exercise testing if they fail to walk a distance in excess of 350 meters. Furthermore, as alluded to earlier, it is not surprising that the correlation of maximal exercise with the submaximal walk test was not very strong, since the two tests probably measure different aspects of exercise capacity.The most important observation by Cahalin and colleagues relates to the relationship between short-and long-term event free survival prediction in relation to the 6-min walk test. The investigators found that while 6-month survival was predicted by the 6-min walk test, long-term survival was better discriminated by maximal exercise parameters, particularly percent of predicted V˙o2 max. This finding is intriguing and again emphasizes the fact that the 6-min walk test and maximal exercise provide complementary information. It is reasonable to assume that because laboratory conditions of maximal exercise call on ordinarily unused circulatory reserves, cardiopulmonary stress testing might be a better predictor of late outcome. Conversely, the 6-min walk test tends to define cardiac limitations during day-to-day activities; and therefore, failure to walk a distance of 300 to 350 meters might denote a state of exhaustion of cardiac reserves and thereby be predictive of short-term survival.Why are exercise indices important in the prognostic assessment of advanced heart failure? First and foremost, risk stratification allows prediction of longevity and impending need for hospitalization. Second, accurate prognostication can allow appropriate selection of advanced treatment options in heart failure, particularly as it relates to committing scarce resources such as cardiac transplantation. Lastly, measures of exercise capacity can be serially followed to assess benefits of medical therapy. These reasons underscore the importance for the development and standardization of simple, noninvasive, safe, and inexpensive objective exercise indices. In summary, the 6-min walk test fulfills most of these criteria, and it can be used routinely in the ambulatory setting to assess short-term prognosis, particularly in centers where cardiopulmonary exercise assessment may not be readily available. Moreover, if future studies confirm the clinical utility of the 6-min walk test in advanced heart failure, the usefulness of this test might evolve to allow delineation of patients with severe heart failure who may benefit from closer surveillance and earlier clinical therapeutic intervention. Several investigators have searched for methods for predicting clinical outcome in patients with advanced heart failure, including various parameters of exercise capacity for prognostic risk stratification.1Mehra MR Ventura HO. Advanced heart failure.in: Civetta JM Taylor RW Kirby RR 3rd ed. Critical care. J.B. Lippincott Company, Philadelphia1996Google Scholar These exercise indices include subjective parameters such as functional capacity (New York Heart Association [NYHA] classification) and objective parameters obtained by maximal and submaximal exercise stress testing. Functional class assessment is rather subjective and therefore often inaccurate, leading to substantially poor prognosis discriminating ability at mild to moderate levels of functional limitation. Maximal exercise testing has thus far been the time-honored form of objective exercise assessment. An important advance in exercise testing in heart failure accrued from the work by Weber et al,2Weber KT Kinasewitz GT Janicki JS et al.Oxygen utilization and ventilation during exercise in patients with chronic cardiac failure.Circulation. 1982; 65: 1213-1223Crossref PubMed Scopus (721) Google Scholar wherein the investigators demonstrated that concomitant measurements of respiratory gas exchange and air flow with assessment of maximal oxygen consumption ( V˙o2 max) and anaerobic threshold could allow demarcation of the causes of exercise intolerance into cardiocirculatory, pulmonary, and physical deconditioning. Soon thereafter, Szlachcic and colleagues3Szlachcic J Massie BM Kramer BL et al.Correlates and prognostic implication of exercise capacity in chronic congestive heart failure.Am J Cardiol. 1985; 55: 1037-1042Abstract Full Text PDF PubMed Scopus (430) Google Scholar investigated the prognostic importance of maximal oxygen consumption measured during upright bicycle ergometry in a cohort of 27 heart failure patients (21/27 NYHA III/IV; 6/27 NYHA II). At 1-year follow-up, heart failure patients with a V˙o2 max <10 mL/kg/min were found to have a mortality of 77% compared with a 21% mortality in the group with higher V˙o2 max (p 14 mL/kg/min and that V˙o2 max was the best discriminant of 2-year survival. Data such as these have led to the widespread use of metabolic exercise assessment to determine need for and timing of heart transplantation. While most investigators agree that a V˙o2 max 18 to 20 mL/kg/min predicts clinical stability and good outcome, controversy abounds in patients with a V˙o2 max between 10 and 18 mL/kg/min, a range most frequently encountered in patients with left ventricular dysfunction.5Pina IL. Optimal candidates for heart transplantation: is 14 the magic number?.J Am Coll Cardiol. 1995; 26: 436-437Abstract Full Text PDF PubMed Scopus (27) Google Scholar Investigators have searched for ways to refine the discriminant function of this "gray area," by assessing measurements of percent predicted values of V˙o2 max adjusted for age and gender, as well as the additive prognostic impact of echocardiographic diastolic indices.6Di Salvo TG Mathier M Semigran MJ. Preserved right ventricular ejection fraction predicts exercise capacity and survival in advanced heart failure.J Am Coll Cardiol. 1995; 25: 1143-1153Abstract Full Text PDF PubMed Scopus (586) Google Scholar, 7Richards D Mehra MR Ventura HO et al.The discriminatory role of cardiopulmonary exercise parameters and diastolic indices in assessing prognosis in advanced heart failure.J Heart Lung Transplant. 1996; 15 (in press)Google Scholar In a recent study7Richards D Mehra MR Ventura HO et al.The discriminatory role of cardiopulmonary exercise parameters and diastolic indices in assessing prognosis in advanced heart failure.J Heart Lung Transplant. 1996; 15 (in press)Google Scholar of 123 patients with advanced heart failure and a mean V˙o2 max of 16.9 mL/kg/min, it has been demonstrated that percent predicted values of V˙o2 max were a better predictor of clinical events than weight adjusted V˙o2 max. This investigation also found that, although the presence of restrictive physiology was significantly correlated with V˙o2 max, it added little in the way of prognostic information in the intermediate range V˙o2 max. A separate investigation from our group has shed light on the presence of a gender mismatch in the predictive ability of V˙o2 max, demonstrating that in women, percent predicted values of V˙o2 max are more closely indicative of clinical outcome than weight adjusted V˙o2 max.8Richards DR Mehra MR Ventura HO et al.Can maximal oxygen consumption predict outcome of heart failure in women as well as in men? Evidence for a gender mismatch.Circulation. 1995; 92: I-402Google Scholar Traditional maximal exercise testing can be difficult in some patients who are limited by severe cardiac dysfunction or peripheral vascular disease. In such patients, submaximal exercise testing, with or without gas exchange data, is required to evaluate metabolic performance. When gas exchange data is available, our laboratory has used successfully the ventilation/carbon dioxide production ratio assessed at submaximal exercise, to reliably predict V˙o2 max and prognosis.9Milani RV Mehra MR Reddy TR et al.Ventilation/carbon dioxide production ratio in early exercise predicts poor functional capacity in congestive heart failure.Br Heart J. 1996; (in press)Google Scholar When cardiopulmonary testing is not available, however, submaximal tests, such as the 6-min walk test, offer the advantage of a safe and reproducible test that better approximates the usual daily activity levels of patients. Guyatt and associates10Guyatt GH Sullivan MJ Thompson PJ et al.The 6-minute walk: a new measure of exercise capacity in patients with chronic heart failure.Can Med Assoc J. 1985; 132: 919-923PubMed Google Scholar performed the first study of the clinical utility of the 6-min walk test in heart failure patients and showed a significant correlation with functional class but failed to define a close association with results of cycle ergometer testing. This poor correlation with maximal exercise suggested that the 6-min walk test, in fact, might be a measure of a patient's ability to perform usual day to day activity, whereas the maximal exercise test may be a more artificial estimate of laboratory exercise capacity. Another important attribute of the 6-min walk test, demonstrated in serial studies, relates to the incremental improvement in test performance that occurs with concurrent encouragement and the training effect resulting from serial tests. These factors must be kept in mind when critically assessing the value of information derived from the 6-min walk test. The first investigation to convincingly link the 6-min walk test and morbidity and mortality prediction in heart failure was accomplished by Bittner et al11Bittner V Weiner DH Yusuf S et al.Prediction of mortality and morbidity with a 6-minute walk test in patients with left ventricular dysfunction.JAMA. 1993; 270: 1702-1707Crossref PubMed Scopus (716) Google Scholar on behalf of the Studies of Left Ventricular Dysfunction (SOLVD) group. These investigators reported that the test independently and strongly predicted long-term mortality and hospitalization rates for heart failure beyond that of traditional indices such as left ventricular ejection fraction and NYHA functional class. It should be emphasized that the patient cohort studied was predominantly that of mild to moderate heart failure, with only 15% of the population suffering from severe heart failure. In this issue of CHEST, Cahalin and colleagues (see page 325) attempt to define the prognostic utility of the 6-min walk test in 45 patients with severe heart failure (mean NYHA class 3.3±0.6) who were referred for heart transplantation. These researchers concluded that the 6-min walk test was useful in predicting V˙o2 max and short-term survival but did not prognosticate long-term outcome. The concept of the study is an important one, since the availability of a safe, noninvasive, reproducible, and easily performable prognostic discriminator in patients with severe heart failure is clearly desirable. Several aspects of this investigation, however, merit discussion. For one, the study population was not quite representative of the commonly prevailing etiologic entities of advanced heart failure, and it displayed a predominance of nonischemic dilated cardiomyopathy (78%). Second, the majority of patients were men and therefore the findings of this study might not be generalized to women. Although these investigators concluded that the 6-min walk test "accurately" predicted V˙o2 max, the overall correlation was only modest (r=0.64). Based on the data presented by Cahalin and associates, we have analyzed the ability of using a cut point of 350 meters on the 6-min walk test to predict a V˙o2 max of ≤14 mL/kg/min, a threshold at which heart transplantation becomes a considered option. The sensitivity is 71% and specificity 60%, with a positive and negative predictive value of 86% and 50%, respectively. One can, therefore, hypothesize that the 6-min walk test might serve as a reasonable preliminary screening test for stratifying patients into a "high risk" group who may require early referral for further maximal exercise testing if they fail to walk a distance in excess of 350 meters. Furthermore, as alluded to earlier, it is not surprising that the correlation of maximal exercise with the submaximal walk test was not very strong, since the two tests probably measure different aspects of exercise capacity. The most important observation by Cahalin and colleagues relates to the relationship between short-and long-term event free survival prediction in relation to the 6-min walk test. The investigators found that while 6-month survival was predicted by the 6-min walk test, long-term survival was better discriminated by maximal exercise parameters, particularly percent of predicted V˙o2 max. This finding is intriguing and again emphasizes the fact that the 6-min walk test and maximal exercise provide complementary information. It is reasonable to assume that because laboratory conditions of maximal exercise call on ordinarily unused circulatory reserves, cardiopulmonary stress testing might be a better predictor of late outcome. Conversely, the 6-min walk test tends to define cardiac limitations during day-to-day activities; and therefore, failure to walk a distance of 300 to 350 meters might denote a state of exhaustion of cardiac reserves and thereby be predictive of short-term survival. Why are exercise indices important in the prognostic assessment of advanced heart failure? First and foremost, risk stratification allows prediction of longevity and impending need for hospitalization. Second, accurate prognostication can allow appropriate selection of advanced treatment options in heart failure, particularly as it relates to committing scarce resources such as cardiac transplantation. Lastly, measures of exercise capacity can be serially followed to assess benefits of medical therapy. These reasons underscore the importance for the development and standardization of simple, noninvasive, safe, and inexpensive objective exercise indices. In summary, the 6-min walk test fulfills most of these criteria, and it can be used routinely in the ambulatory setting to assess short-term prognosis, particularly in centers where cardiopulmonary exercise assessment may not be readily available. Moreover, if future studies confirm the clinical utility of the 6-min walk test in advanced heart failure, the usefulness of this test might evolve to allow delineation of patients with severe heart failure who may benefit from closer surveillance and earlier clinical therapeutic intervention.
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