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Journal of Clinical Oncology, Vol 22, No 5 (March 1), 2004: pp. 769-773 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.12.937
Cardiovascular Trials in Long-Term Survivors of Childhood Cancer
1 Department of Pediatrics, University of Miami School of Medicine, Holtz Children's Hospital, University of Miami/Jackson Memorial Medical Center, and Sylvester Comprehensive Cancer Center, Miami, FL Late Cardiotoxicity in Long-Term Survivors of Childhood Cancer The problems of late cardiotoxicity in long-term survivors of childhood cancer are clinically devastating and likely to become more prevalent [1-17]. Premature cardiovascular morbidity and mortality are consistently found across multiple studies [1-17]. Progressive, asymptomatic left ventricular dysfunction, congestive heart failure, cardiac transplantation, and cardiac death from either pump failure or arrhythmias develop much more often in these patients than in children without a history of cancer treatment. Concerns about premature atherosclerosis in this population have also been raised [18-20]. These late cardiovascular effects are typically related to anthracycline use, although radiation to the heart and other oncologic therapies are also associated with late cardiotoxicity [2,5-7,15-17,20-25]. Clearly, we need to both prevent cardiotoxicity in newly diagnosed children with cancer and alter the course of progressive cardiotoxicity in long-term survivors of childhood cancer. Completing a randomized, placebo-controlled, clinical trial in long-term survivors of childhood cancer is an important achievement. The carefully performed longitudinal prospective study by Silber et al [26], the angiotensin converting enzyme inhibitor (ACEI) After Anthracycline (AAA) trial, is one of the first such trials to be completed. The primary purpose of the AAA study was to determine whether enalapril, an ACEI, could lower the rate of decline in cardiac function in survivors of childhood cancer who had been treated with anthracyclines [26,27]. The importance of this question is undisputed. Unfortunately, for the reasons below, the study did not answer this question, creating a dilemma as to whether another larger and potentially more expensive study should be initiated. Interpreting the Results of the AAA Study Although the AAA study did not find that ACEI prevented a decline in ventricular function in patients with anthracycline-associated cardiomyopathy (ACM), the follow-up time in the study was not long enough nor was the study population large enough to conclude that ACEI is not beneficial [26]. The progression of cardiac dysfunction and the appearance of new-onset symptoms is quite slow in ACM [14,28-31], and follow-up in the AAA study ranged from just 2 to 7 years [26]. In addition, the study was not powered to rule out a clinically relevant effect of ACEI, which requires a different study design than proving their clinical effectiveness [26]. Today, the wealth of data supporting the efficacy of ACEI therapy in ischemic, postinfectious, and idiopathic dilated cardiomyopathy (DCM) has led to its first-line use in most patients with symptomatic and asymptomatic left ventricular dysfunction [32,33]. During the AAA study, we also initiated a randomized trial of enalapril in treating long-term survivors of childhood cancer (POG 9480) but terminated the study because of inadequate enrollment. Many of the patients for this trial who met the ventricular dysfunction entrance criteria of the AAA study were either already being treated with an ACEI or had physicians who believed that a placebo-controlled trial of ACEI was unethical, given the clear benefits reported for other DCM populations [8]. The patient pool reviewed for the AAA study included 4,308 subjects, of whom 401 were eligible and 146 agreed to participate [26,27]. The reasons so few patients were eligible and only 36% of these agreed to participate are not stated, but the risk profile for ACEI is generally extremely favorable, so factors other than perceived risk probably account for the low recruitment rate. Substantial evidence about the benefits of ACEI in DCM now makes therapeutic equipoise difficult to claim unless there are documented, fundamental biologic differences between ischemic and idiopathic DCM and the cardiomyopathy that occurs long after anthracycline therapy (ACM), or the risk-benefit ratio is altered in this population as a result of a lower probability of a positive response to ACEI or of therapy-related risks that are markedly higher than those in other forms of DCM. Differences Between ACM and DCM Based on prior data and the observations in the AAA study, several characteristics of ACM distinguish it from other forms of DCM. The only statistically significant finding in the AAA study was a fall in end-systolic stress in the first year of therapy [26]. Given the predictable fall in blood pressure during ACEI therapy and the dependence of wall stress on blood pressure, this was therefore predictable. A notable finding was the absence of ventricular remodeling in response to the fall in wall stress [26]. In most forms of DCM, ACEIs induce reverse ventricular remodeling, with a reduction in ventricular volume and an improved mass-to-volume ratio, which further reduces wall stress and improves cardiac function. As in the AAA study, we also found that despite a marked fall in end-systolic stress after 2.4 years of enalapril therapy, ventricular size and thickness did not change [30]. The absence of reverse ventricular remodeling corroborates the observation that, in contrast to other forms of DCM, the natural history of ACM is characterized by minimal, nonprogressive dilation [14]. The natural history of the disease and the response to ACEI therapy is unlike that of DCM but is more characteristic of a restrictive cardiomyopathy, a disease class that does not benefit from ACEI therapy [31-35]. Further confounding the results, 38% of the AAA participants also received cardiac irradiation, [26,27] a therapy also associated with the development of late restrictive cardiomyopathy [20-25]. The risk-profile of ACEIs is so low that their use is often recommended, even when efficacy has not been proven [8]. There are several reasons to question the wisdom of this approach. Although the risk of ACEI therapy in patients with ACM has not been reported to exceed those in other forms of DCM, available data simply do not adequately address this issue. The time scale for the development of ACM is different from other forms of DCM. For example, the Studies of Left Ventricular Dysfunction prevention trial found the 4-year cumulative incidence of hospitalization to be 25% for new or worsening heart failure in the placebo group [36], but was only 1.8% in ACM patients [9]. Even if the benefit of ACEI treatment in ACM patients with asymptomatic left ventricular dysfunction was similar to that in DCM patients, their exposure to potentially toxic effects is more than 10 times as long as it is in DCM patients, rendering current risk-benefit data meaningless. Although no evidence of carcinogenesis was seen in studies of rats or mice receiving enalapril, an excess rate of gastrointestinal cancers relative to placebo has been observed in several large trials in patients receiving prolonged ACEI therapy [37-39]. A causal relationship to ACEIs has not been established, but cannot be excluded. The fact that malignancy rates may be increased in clinical trials of ACEI in nononcology adult patients [37-39] may be even more of a concern to younger cancer survivors who are already at increased risk for relapsed primary or secondary malignancies. In addition, the global risk for premature atherosclerotic heart disease is apparently increased in long-term survivors of childhood cancer [18,19,24], a risk that may also be affected by ACEI therapy [30,40,41]. Other concerns that are related to the use of enalapril in this population in the absence of proven efficacy include the unknown effects of chronic neurohormonal suppression or other side effects of long-term enalapril therapy in this population, the considerable cost of a therapy that may be required for life in a young patient population with large past medical expenses and lifetime insurance limits, the fact that this study did not demonstrate any beneficial effects of enalapril on reducing progression to congestive heart failure or death, the fact that this study did not find that the participants' quality of life was improved, an unknown understanding of other drug interactions with this therapy for this population, and the potential for healthy, asymptomatic survivors to feel or be treated differently from their peers for taking chronic medications, which may increase the likelihood of these children feeling like "cardiac cripples." Thus, the argument for using ACEI in patients with ACM has been based exclusively on trials of patients with DCM secondary to other causes, but the accumulating data from ACM patients, including the results of the AAA study, do not support this argument [8,26,28-33]. No data indicate a long-term benefit from ACEI therapy in patients with ACM, and the applicability of trials conducted in other patient groups is questionable. The clinical pattern of a dominantly restrictive cardiomyopathy predicts a reduced likelihood of benefit. Data are also inadequate to address the risk associated with ACEI therapy of asymptomatic left ventricular dysfunction in this population, but any adverse effects of long-term therapy clearly increase the risks for these patients, purely on the basis of markedly longer exposure. Further, these patients may be at increased risk for potential adverse events. Altogether, these findings argue against the routine use of ACEI therapy in patients with asymptomatic left ventricular dysfunction secondary to ACM. Implications for the Design of Future Studies Meaningful end points are essential in any clinical trial. Given the rarity with which new cases of congestive heart failure or death occur in the first decade after front-line, cumulative dose limited, anthracycline therapy in this population, surrogate end points must be used in clinical trials [8,30,31,42-44]. Unfortunately, there are currently no validated surrogate end points for survival in patients with ventricular dysfunction or congestive heart failure [45-47]. This problem is illustrated by the AAA study. The primary hypothesis of the AAA study was that ACEI would slow the decline in cardiac function, and the maximum exercise cardiac index (MCI) was the primary end point [26,27]. Although MCI may be directly relevant to quality of life, it is not a reliable surrogate for cardiac function. Extensive data indicate that the relationship between cardiac function and exercise performance is weak [1,48-57]. The results from the AAA study support this conclusion [26]. In the AAA study, seven patients (six from the control group) were removed from the study because of a fall in cardiac function (shortening fraction, ejection fraction, or both) [26]. Despite a decrement in cardiac function considered sufficiently severe to warrant removal from the trial, none had a fall in MCI; in fact, MCI increased in six of the seven patients, almost doubling in some cases [26]. A similar analysis of the relation between the change in cardiac function and the change in MCI for the whole group is not reported, but it is telling that the patients who had the largest deterioration in ventricular function still improved their exercise performance [26]. A surprisingly poor correlation has been noted between ventricular function, assessed as ejection fraction or shortening fraction, and various indices of exercise performance. As noted in standard textbooks of exercise testing, "the discrepancy between ventricular function and exercise capacity is now well known" [48]. For example, the Vasodilator Heart Failure Trial I and II studies reported a correlation of 0.16 and 0.19, respectively, between ejection fraction and peak exercise oxygen uptake [49]. Of particular interest to the AAA study, asymptomatic patients with severe left ventricular dysfunction may have a capacity for exercise that is not different from normal controls [50]. Change in peak oxygen uptake over time does not correlate with change in ventricular function [51]. Although both ejection fraction and peak oxygen uptake at baseline are independently predictive of survival, change in peak oxygen uptake predicted nontransplanted survival, whereas change in ejection fraction did not [52]. The failure of ventricular function to correlate closely with exercise capacity has been attributed to the multitude of independent factors that influence each [53]. For example, diastolic function correlates more closely to peak oxygen uptake than does systolic function [54,55]. The response of exercise capacity to interventions is also poorly predictive of the coincident change in ventricular function. For example, exercise training in heart failure patients improves exercise capacity that is in part related to vascular effects, whereas the impact on ventricular function is inconstant and generally negligible [56,57]. Fewer data are available from patients with ACM, but we have found that exercise capacity was generally diminished in childhood survivors of leukemia treated with doxorubicin, but it did not differ between those with or without abnormalities of ventricular contractility, afterload, or shortening fraction [1]. Exercise performance may be poorly correlated with cardiac function in long-term survivors of childhood cancer as a result of multiple other late-effects that may influence exercise performance, including deconditioning and a sedentary lifestyle, psychosocial issues, depression, abnormal body composition with increased fat and decreased skeletal muscle, mitochondrial mutations in skeletal muscle from anthracycline therapy, limiting mitochondrial energetics, decreased bone mineral density, increased prevalence of chronic fatigue, growth hormone and thyroid hormone deficiencies and other late endocrine effects, peripheral neuropathies from vincristine, abnormal pulmonary function from pulmonary fibrosis related to bleomycin or radiation therapy, scoliosis from radiotherapy, late CNS effects, and autonomic dysfunction. Therefore, exercise performance may be an especially unreliable surrogate for cardiac function and ultimate cardiac outcome in this population. In addition to the poor correlation between ventricular function and exercise performance, these surrogate exercise end points have been poor predictors of outcomes, such as congestive heart failure or death. Surrogate end points are usually chosen for their correlations with outcomes in untreated populations. For example, ventricular function and output, as well as exercise capacity, predict survival in patients with congestive heart failure. However, treatment-associated improvement in a surrogate end point is often not predictive of a treatment-associated improvement in clinical outcome. In a large study by Packer et al [58], improvements in cardiac output, cardiac function, or exercise tolerance did not reliably predict survival. Further, studies using these surrogate end points have indicated benefit in a population that was adversely affected. For example, long-term administration of inotropic agents improved hemodynamic profiles, cardiac output, and ejection fraction in patients with heart failure, but it also decreased survival [58]. The lack of effect of ACEI on cardiac function in the AAA trial is not surprising, in part because the study was not statistically powered for this end point. This finding should not be interpreted to mean that ACEI therapy may or may not beneficial in this population. More importantly, and less commonly appreciated, clinical trials designed to evaluate surrogate end points, such as exercise performance and wall stress, will not help us decide whether this therapy will impact on late cardiovascular morbidity and mortality in these patients. This situation creates an enormous problem for any future efforts to evaluate efficacy of ACEI in ACM. The low incidence of congestive heart failure, death, or cardiac transplantation in the first decade after front-line, cumulative dose limited, anthracycline therapy means that any study based on these end points would have to be prohibitively long, large, and expensive [8,30,31,42-44]. On the other hand, valid surrogate end points are currently unavailable. Perhaps circulating levels of brain natriuretic peptide (BNP) may predict outcome; therapeutic interventions that lower BNP also reduce morbidity [59,60]. We have found that BNP concentrations accurately reflect cardiomyopathy in long-term survivors of childhood cancer [18]. Although this end point needs to be validated, it is an example of the new and needed approaches to this problem. The efficacy of ACEI therapy in anthracycline-treated, long-term survivors of childhood cancer remains an unanswered, but important, question. The potential adverse effects of this therapy in patients with ACM argue against using this therapy, especially without convincing evidence of efficacy. It is unlikely that studies examining reductions in morbidity and mortality in this population can be conducted, and it is therefore likely that the question will remain open, unless a surrogate end point for morbidity and mortality can be found. In addition to studies evaluating primary and secondary prevention strategies, exploring the utility of potential surrogate cardiac end points should be a priority for physicians caring for anthracycline recipients. Authors' Disclosures of Potential Conflicts of Interest The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: Steven E. Lipshultz, Chiron, Boehringer Ingelheim. Received more than $2,000 a year from a company for either of the last 2 years: Steven E. Lipshultz, Chiron. REFERENCES 1. Lipshultz SE, Colan SD, Gelber RD, et al: Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med 324:808-815, 1991[Abstract]
2. Lipshultz SE, Sallan SE: Cardiovascular abnormalities in long-term survivors of childhood cancer. J Clin Oncol 11:1199-1203, 1993
3. Lipshultz SE, Lipsitz SR, Mone SM, et al: Female sex and higher drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N Engl J Med 332:1738-1743, 1995 4. Nysom K, Holm K, Lipsitz SR, et al: The relation between cumulative anthracycline dose and late cardiotoxicity in survivors of childhood leukemia. J Clin Oncol 16:545-550, 1998[Abstract] 5. Grenier MA, Lipshultz SE: Epidemiology of anthracycline cardiotoxicity in children and adults. Semin Oncol 25:72-85, 1998 (suppl 10)[Medline] 6. Giantris A, Abdurrahman L, Hinkle A, et al: Anthracycline-induced cardiotoxicity. Crit Rev Oncol Hematol 27:53-68, 1998[Medline] 7. Nysom K, Colan SD, Lipshultz SE: Late cardiotoxicity following anthracycline therapy for childhood cancer. Prog Pediatr Cardiol 8:121-138, 1998[CrossRef] 8. Lipshultz SE: Ventricular dysfunction clinical research in infants, children and adolescents. Prog Pediatr Cardiol 12:1-28, 2000[CrossRef][Medline]
9. Kremer LC, van Dallen EC, Offringa M, et al: Anthracycline-induced clinical heart failure in a cohort of 607 children: Long-term follow-up study. J Clin Oncol 19:191-196, 2001
10. Green DM, Grigoriev YA, Nan B, et al: Congestive heart failure after treatment for Wilms' tumor: A report from the National Wilms' Tumor Study group. J Clin Oncol 19:1926-1934, 2001
11. Mertens AC, Yasui Y, Neglia JP, et al: Late mortality experience in five-year survivors of childhood and adolescent cancer the Childhood Cancer Survivor Study. J Clin Oncol 19:3163-3172, 2001
12. Moller TR, Garwicz Barlow L, et al: Decreasing late mortality among five-year survivors of cancer in childhood and adolescence: A population-based study in the Nordic countries. J Clin Oncol 19:3173-3181, 2001
13. Green DM, Hyland A, Chung CS, et al: Cancer and cardiac mortality among 15-year survivors of cancer diagnosed during childhood or adolescence. J Clin Oncol 17:3207-3215, 1999 14. Lipshultz SE, Lipsitz SR, Sallan SE, et al: Chronic progressive LV systolic dysfunction and afterload excess years after doxorubicin therapy for childhood acute lymphoblastic leukemia. Circulation 100:I-530, 1999 15. Simbre VC II, Adams MJ, Deshpande SS, et al: Cardiomyopathy caused by antineoplastic therapies. Curr Treat Options Cardiovasc Med 3:493-505, 2001 16. Hinkle AS, Proukou CB, Deshpande SS, et al: Cardiovascular complications: Chemotherapy to include prevention strategies, in Wallace H, Green D (eds), Late Effects of Childhood Cancer. London, UK, Edward Arnold, 2003 17. Lipshultz SE. Cancer therapy-associated cardiovascular disease. In Pediatric Heart Failure (ed. Shaddy R, Wernovsky G) New York, NY: Marcel Decker, 2004 18. Lipshultz SE, Hinkle AS, French CA, et al: Accelerated atherosclerosis contributes to elevated global risk for premature symptomatic cardiovascular disease in survivors of childhood cancer. Proc Am Soc Clin Oncol 22:797, 2003 (abstr 3203). 19. Hinkle AS, Proukou C, French CA, et al: A clinic-based, comprehensive care model for studying late effects in long-term survivors of pediatric illness. Pediatrics: (in press) 20. Constine LS, Hinkle AS, French CA, et al: Radiation-associated risk factors for premature cardiovascular disease in childhood cancer survivors include accelerated atherosclerosis. Int J Radiat Oncol Biol Phys 57:S199–S200, 2003 (suppl 2)[CrossRef][Medline] 21. Adams MJ, Constine L, Lipshultz SE : Radiation effects on the heart, in Crawford MH, DiMarco JP (eds): Cardiology. Second Edition. London, Mosby International, 2003 22. Adams MJ, Hardenbergh PH, Constine LS, et al: Radiation-associated cardiovascular disease. Crit Rev Oncol Hematol 45:55-75, 2003[Medline] 23. Adams MJ, Lipsitz SR, Colan SD, et al: Late cardiotoxicity of mediastinal irradiation. Proc Am Soc Clin Oncol 22:797, 2003 (abstr 3202) 24. Adams MJ, Lipshultz SE, Schwartz C, et al: Radiation-associated cardiovascular disease: Manifestations and management. Semin Radiat Oncol 13:346-356, 2003[CrossRef][Medline] 25. Mone SM, Gillman MW, Miller TL, et al: Effects of environmental exposures on the cardiovascular system: Prenatal period through adolescence. Pediatrics: (in press)
26. Silber JH, Cnaan A, Clark BJ, et al: Enalapril to prevent cardiac function decline in long-term survivors of pediatric cancer exposed to anthracyclines. J Clin Oncol 22:820-828, 2004 27. Silber JH, Cnaan A, Clark BJ, et al: Design and baseline characteristics for the ACE Inhibitor After Anthracycline (AAA) study of cardiac dysfunction in long-term pediatric cancer survivors. Am Heart J 142:577-585, 2001[CrossRef][Medline] 28. Lipshultz SE, Colan SD, Mone SM, et al: Afterload reduction therapy in long-term survivors of childhood cancer treated with doxorubicin. Circulation 84:II-659, 1991 29. Lipshultz SE, Lipsitz SR, Sallan SE, et al: Is enalapril beneficial in doxorubicin-treated long-term survivors of childhood cancer? Circulation 96:I-436, 1997
30. Lipshultz SE, Lipsitz SR, Sallan SE, et al: Long-term enalapril therapy for left ventricular dysfunction in doxorubicin-treated survivors of childhood cancer. J Clin Oncol 20:4517-4522, 2002
31. Lipshultz SE, Lipsitz SR, Sallan SE, et al: Treatment for asymptomatic anthracycline-induced cardiac dysfunction in childhood cancer survivors: The need for evidence. J Clin Oncol 21:3377-3378, 2003
32. Hunt SA, Baker DW, Chin MH, et al: ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult: Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure): Developed in Collaboration With the International Society for Heart and Lung Transplantation; Endorsed by the Heart Failure Society of America. Circulation 104:2996-3007, 2001 33. Grenier MA, Fioravanti J, Truesdell SC, et al: Angiotensin-converting enzyme inhibitor therapy in infants, children and adolescents: A review. Prog Pediatr Cardiol 12:91-111, 2000[CrossRef][Medline]
34. Bengur AR, Beekman RH, Rocchini AP, et al: Acute hemodynamic effects of captopril in children with a congestive or restrictive cardiomyopathy Circulation 83:523-527, 1991
35. Henein MY, Amadi A, O'Sullivan C, et al: ACE inhibitors unmask incoordinate diastolic wall motion in restrictive left ventricular disease. Heart 76:326-331, 1996 36. The SOLVD Investigators: Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 327:685-691, 1992[Abstract] 37. Braunwald E: ACE inhibitors—a cornerstone of the treatment of heart failure. N Engl J Med 325:351-353, 1991[Medline] 38. McEvoy GK (ed): American Hospital Formulary Service—Drug Information 93. American Society of Hospital Pharmacists, Inc, Bethesda, MD, 1993, p 943
39. Enalapril (CASRN: 75847-73-3) Human Health Effects and Animal Toxicity Studies. National Library of Medicine Database HSDB. http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/
40. Teo KK, Burton JR, Buller CE, et al: Long-term effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis: The Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT). Circulation 102:1748-1754, 2000 41. Knowles JW, Reddick RL, Jennette JC, et al: Enhanced atherosclerosis and kidney dysfunction in eNOS(-/-)Apoe(-/-) mice are ameliorated by enalapril treatment. J Clin Invest 105:451-458, 2000[Medline] 42. Herman EH, Lipshultz SE, Ferrans VJ: The use of cardiac biomarkers to detect myocardial damage induced by chemotherapeutic agents, in Wu AHB (ed): Cardiac Markers (2nd ed). Totowa, NJ, Humana Press, 2003, pp. 87-110
43. Lipshultz SE, Sanders SP, Goorin AM, et al: Monitoring for anthracycline cardiotoxicity. Pediatrics 93:433-437, 1994
44. Lipshultz SE, Sanders SP, Goorin AM, et al: The anthracycline cardiotoxicity debate. Pediatrics 94:781-782, 1994 45. Fleming TR: Surrogate end points in cardiovascular disease trials. Am Heart J 139:S193–S196, 2000[CrossRef][Medline] 46. Gheorghiade M, Adams KF Jr, Gattis WA, et al: Surrogate end points in heart failure trials. Am Heart J 145:S67–S70, 2003 (suppl 2)[CrossRef][Medline]
47. Anand IS, Florea VG, Fisher L: Surrogate end points in heart failure. J Am Coll Cardiol 39:1414-1421, 2002 48. Interpretation of hemodynamic responses to exercise testing: Exercise capacity, heart rate, and blood pressure, in Froelicher VF, Myers J, Follansbee WP and Labovitz AJ (eds): Exercise and the heart. St. Louis, Mosby, 1993, pp 71-98 49. Cohn JN: Contribution of ACE inhibition to the management of heart failure. Introduction. Am Heart J 126: 755, 1993 (suppl)[CrossRef][Medline]
50. Harrington D, Anker SD, Coats AJ: Preservation of exercise capacity and lack of peripheral changes in asymptomatic patients with severely impaired left ventricular function. Eur Heart J 22:392-399, 2001 51. Florea VG, Henein MY, Anker SD, et al: Relation of changes over time in ventricular size and function to those in exercise capacity in patients with chronic heart failure. Am Heart J 139:913-917, 2000[Medline]
52. Florea VG, Henein MY, Anker SD, et al: Prognostic value of changes over time in exercise capacity and echocardiographic measurements in patients with chronic heart failure. Eur Heart J 21:146-153, 2000 53. Smith RF, Johnson G, Ziesche S, et al: Functional capacity in heart failure: Comparison of methods for assessment and their relation to other indexes of heart failure. The V-HeFT VA Cooperative Studies Group. Circulation 87: VI88-VI93, 1993 (suppl 6) 54. Eriksson SV, Caidahl K, de Faire U, et al: Diastolic and systolic function as predictors of exercise capacity after myocardial infarction in young men. Cardiology 90:8-12, 1998[CrossRef][Medline] 55. Lapu-Bula R, Robert A, De Kock M, et al: Relation of exercise capacity to left ventricular systolic function and diastolic filling in idiopathic or ischemic dilated cardiomyopathy. Am J Cardiol 83:728-734, 1999[CrossRef][Medline] 56. Parnell MM, Holst DP, Kaye DM: Exercise training increases arterial compliance in patients with congestive heart failure. Clin Sci (Lond) 102:1-7, 2002[Medline] 57. You Fang Z, Marwick TH: Mechanisms of exercise training in patients with heart failure. Am Heart J 145:904-911, 2003[CrossRef][Medline] 58. Packer M, Carver JR, Rodeheffer RJ, et al: Effect of oral milrinone on mortality in severe congestive heart failure. N Engl J Med 325:1468-1475, 1991[Abstract] 59. Troughton RW, Frampton CM, Yandle TG, et al: Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations. Lancet 355:1126-1130, 2000[CrossRef][Medline]
60. Cheng V, Kazanagra R, Garcia A, et al: A rapid bedside test for B-type peptide predicts treatment outcomes in patients admitted for decompensated heart failure: A pilot study. J Am Coll Cardiol 37:386-391, 2001
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