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© 2002 American Society for Clinical Oncology Long-Term Enalapril Therapy for Left Ventricular Dysfunction in Doxorubicin-Treated Survivors of Childhood CancerByFrom the Division of Pediatric Cardiology, University of Rochester Medical Center and Golisano Children’s Hospital at Strong, James P. Wilmot Cancer Center, and Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY; Department of Biometry and Epidemiology, Medical University of South Carolina, Charleston, SC; and Departments of Pediatric Oncology and Biostatistics, Dana-Farber Cancer Institute, Division of Hematology/Oncology and Department of Cardiology, Children’s Hospital, Department of Pediatrics, Harvard Medical School, and Department of Biostatistics, Harvard School of Public Health, Boston, MA. Address reprint requests to Steven E. Lipshultz, MD, Division of Pediatric Cardiology, University of Rochester Medical Center, 601 Elmwood Ave, Box 631, Rochester, NY 14642; email: steve_lipshultz{at}urmc.rochester.edu
PURPOSE: A common late effect of doxorubicin therapy for childhood cancer is reduced left-ventricular (LV) wall thickness resulting in elevated LV afterload and depressed LV function. Many children are given angiotensin-converting enzyme inhibitors, which have been studied primarily in adults. We document the long-term effects of angiotensin-converting enzyme inhibitors in doxorubicin-treated survivors of childhood cancer. PATIENTS AND METHODS: In this retrospective study, we reviewed records of 18 children who had regular echocardiographic examinations during enalapril therapy (mean age at cancer diagnosis, 8 years; mean time between completion of doxorubicin therapy and start of enalapril, 7 years; median follow-up since the start of enalapril, 10 years). RESULTS: Over the first 6 years of enalapril therapy, there was progressive improvement toward normal values in LV dimension, afterload, fractional shortening, and mass, but all these parameters deteriorated between 6 and 10 years. LV wall thickness deteriorated throughout the study period, as did LV contractility and systolic blood pressure. Diastolic blood pressure fell slightly. By 6 years on enalapril, all six patients who had had congestive heart failure at the start of enalapril therapy had either died or undergone cardiac transplantation, compared with three of the 12 asymptomatic patients. CONCLUSION: In doxorubicin-treated long-term survivors of childhood cancer, enalapril-induced improvement in LV structure and function is transient. The primary defect, which is LV wall thinning, continues to deteriorate, and thus the short-term improvement was mostly related to lowered diastolic blood pressure.
AN ESTIMATED ONE in 570 young adults aged 20 to 34 years old in the United States is a survivor of childhood cancer, and the effectiveness of intensive chemotherapy means that there are currently more than 250,000 survivors of childhood cancer in the United States, with a 77% 5-year survival for children diagnosed with cancer from 0 to 14 years of age.1 This success brings a new challenge; many long-term survivors treated with doxorubicin have reduced left-ventricular (LV) wall thickness, which elevates LV afterload, leading to depressed LV performance.2-7 The abnormality in afterload is often progressive. Long-term problems may include impaired contractility, late congestive heart failure, high-grade ectopy, or sudden death.2-7 One study of 20,227 long-term survivors of childhood cancer found markedly increased cardiovascular mortality rates in survivors even after 25 years of follow-up.8 There has been no decrease in the late mortality rate by treatment era, and doxorubicin therapy is a risk factor for late mortality.9 It is common to treat these patients with afterload-reducing agents such as angiotensin-converting enzyme (ACE) inhibitors. The safety and effectiveness of ACE inhibitors have been established in adults, but their long-term effects in children have not been explored.10 Effects in children may be different from those in adults because ACE inhibition is known to counteract the hypertrophic processes that are integral to cardiac growth in growing children.11-13 The purpose of this retrospective study was to assess the long-term effects of afterload reduction therapy with enalapril on LV loading conditions and function, blood pressure, risk of congestive heart failure, need for cardiac transplantation, and risk of cardiac death in doxorubicin-treated long-term survivors of childhood cancer with LV dysfunction.
The study group consisted of all 18 patients at Boston Children’s Hospital diagnosed with childhood malignancy from 1984 through 1989 and treated with doxorubicin who had completed treatment at least 1 year before this study had begun and had received enalapril as of 1990. No patients were excluded. This retrospective review of medical records was approved by the Committee on Human Investigation at Boston Children’s Hospital. All the children had regular echocardiographic examinations of LV structure and function. In this study, we examined the echocardiograms at six points in time: time 1, the earliest echocardiogram performed at least 1 year after doxorubicin therapy was completed (mean time before enalapril started, 2.3 years); time 2, echocardiograms performed immediately before enalapril was started; time 3, the first follow-up study on enalapril (mean duration of enalapril therapy, 0.45 year); time 4, the latest follow-up study on enalapril before 1992 (mean duration of enalapril therapy, 2.4 years); time 5, the latest follow-up study before 1996 (mean duration of enalapril therapy, 6 years); and time 6, the latest follow-up study before April 2001 (mean duration of enalapril therapy, 10 years). All initial echocardiograms for each patient were obtained at Boston Children’s Hospital. Vital status and cardiac clinical status, including heart transplantation, were assessed at the time of enalapril treatment and at the most recent follow-up before April 2001. Heart failure was determined by clinical signs and symptoms as decided by a pediatric cardiologist and was not determined on the basis of LV fractional shortening or whether or not the patient was on anticongestive medication.
Echocardiography
Statistical Analysis
Patient Population Table 1 lists characteristics of the study group over the treatment period. No adverse enalapril reactions were noted (such as clinically significant hypotension or abnormalities of the complete blood count, electrolyte levels, or urinalysis results). The patients who had asymptomatic LV dysfunction when afterload reduction therapy began were not receiving other cardiac medications. In contrast, the patients with congestive heart failure when afterload reduction therapy was initiated were receiving digoxin and furosemide anticongestive therapy. There were no other concomitant medications at the time of initiation of afterload reduction therapy. At 6 years after starting enalapril, all six symptomatic patients and three of the 12 asymptomatic patients had a cardiac death or had undergone heart transplantation and were censored from further study follow-up. By 10 years after starting enalapril, four of the remaining nine patients had developed congestive heart failure, and five were asymptomatic.
Serial Cardiac Parameters Before enalapril therapy was started, patients had markedly abnormal values for all echocardiographic measurements (Table 2). Over the first 6 years of enalapril therapy, there was progressive improvement toward normal values in LV dimension, afterload, fractional shortening, and mass. However, all tended to become worse between 6 and 10 years, some significantly so.
In contrast, LV wall thickness, LV contractility, and systolic and diastolic blood pressures all tended to become more abnormal during the study period, some significantly so. Diastolic blood pressure deteriorated slightly as well. LV end-diastolic dimension. End-diastolic dimension z score was always markedly elevated, although it fluctuated significantly. Dilatation decreased significantly during the first 0.45 year after enalapril was started. It decreased significantly again by 6 years, possibly reflecting the loss of the sickest patients. Dimension was still significantly higher than normal at 10 years on enalapril therapy. LV wall thickness. The wall thickness z scores were significantly below normal throughout the study. Wall thickness z scores became progressively more negative during enalapril therapy, but the trend was not statistically significant. The thinning cannot be attributed to increasing LV dilation, and so may be the result of enalapril-induced regression of LV hypertrophy. LV afterload or end-systolic wall stress. Afterload remained elevated throughout the study. Afterload increased markedly during the interval before enalapril, although the difference was not statistically significant. Afterload dropped significantly after enalapril was initiated; it rose again at 10 years, but not statistically significantly. LV contractility (stress-velocity index). LV contractility fluctuated but remained depressed throughout the study. There was a significant decrease in LV contractility from 2.4 to 6 years on enalapril. LV fractional shortening. Fractional shortening fluctuated significantly during the study but remained significantly depressed throughout. Before enalapril was started, fractional shortening fell significantly. The start of enalapril therapy was associated with a significant improvement, but there was a significant decrease in fractional shortening between 6 and 10 years on enalapril, and at 10 years it was still significantly below normal. LV mass. LV mass fluctuated significantly during the study. Although initially significantly reduced, it significantly increased during the period before enalapril therapy as LV dilation also increased, but it fell significantly back to a reduced value by the end of the study. Systolic blood pressure. Systolic blood pressure began at a below-normal value and then fell significantly. In general, the systolic blood pressure was significantly lower during enalapril therapy than it was before enalapril was started. Diastolic blood pressure. Diastolic blood pressure did not change much; it began slightly below normal and then showed small decreases throughout most of the study period.
Changes Within Patient Subgroups
Symptomatic heart disease. Patients with symptomatic heart disease when they started enalapril were more likely to have been female (six of nine girls v zero of nine boys; P = .009). Symptomatic patients had more LV dilation and increased LV mass at the initiation of enalapril therapy (Table 3). After 2.4 years of enalapril, these patients were more likely to have had progressive LV dilation (Table 4). LV contractility improved more in patients who started therapy with symptomatic heart disease than it did in those who started enalapril without heart disease. Dropout. Children for whom enalapril therapy failed (and who therefore died or had heart transplantation) were more likely to have had dilated cardiomyopathy at baseline, more LV dilation, and more depressed LV contractility, and they were more likely to be female (Table 3). Time until dropout differed significantly by the following patient characteristics: age at enalapril initiation (older patients more likely to drop out; P = .01), age at diagnosis with cancer (older more likely to drop out; P = .006), duration between doxorubicin therapy and start of enalapril (shorter more likely to drop out; P = .003), and baseline LV dimension (abnormal more likely to drop out; P = .009). The difference in time until dropout was marginally significant by cardiac symptom status at baseline (symptomatic more likely to drop out; P = .07). Enalapril dose. Patients receiving higher doses of enalapril had less deterioration in fractional shortening over 2.4 years than those receiving lower doses (Table 4). Age at the initiation of enalapril. Younger children had higher LV afterload, less depression of LV contractility, and higher diastolic blood pressure than older children (Table 3). Over the first 2.4 years on therapy, younger children had more LV dilation, increases in LV afterload and LV mass, and more depression of fractional shortening than older children (Table 4). Length of follow-up from the completion of doxorubicin to the start of enalapril. The longer the duration between doxorubicin therapy and the start of enalapril, the higher the LV afterload, the thinner the LV wall, and the better the LV contractility at initiation of enalapril (Table 3). During the first 2.4 years of enalapril therapy, children with longer time between the completion of doxorubicin and the start of enalapril had a greater reduction in systolic and diastolic blood pressure than children with shorter intervals (Table 4). Sex. At the start of enalapril therapy, girls had more LV dilation and less wall thinning (Table 3). During the first 2.4 years on enalapril, girls had a larger decrease in contractility than boys (Table 4). Cumulative doxorubicin dose. Patients with lower cumulative doxorubicin doses had lower LV fractional shortening at the start of enalapril (Table 3). Cumulative doxorubicin dose was not related to the response to enalapril. Age at diagnosis with cancer. Patients who were younger at the diagnosis of malignancy had less depressed LV contractility when they started enalapril (Table 2).
Baseline Cardiac Parameters as Predictors of Cardiac Outcomes
The higher the systolic blood pressure at the start of enalapril, the lower the LV afterload 2.4 years later. This suggests that patients with higher systolic blood pressure may be more likely to respond to afterload reduction. The higher the diastolic blood pressure measured at the start of enalapril therapy, the lower the afterload while on enalapril. Higher diastolic pressure was also associated with lower subsequent LV dimension (less dilation), improved LV contractility and fractional shortening, and lower LV mass, all of which are consistent with improvement. This suggests that of all the cardiac parameters measured at baseline, diastolic blood pressure is most likely to predict benefit from enalapril therapy.
Enalapril therapy for LV dysfunction in doxorubicin-treated long-term survivors of childhood cancer resulted in early improvement in all cardiac parameters, with higher diastolic blood pressure predicting a better response to enalapril. Unfortunately, the beneficial enalapril effect was transient, producing 6 to 10 years of improvement followed by a return to or toward baseline. By 6 years of therapy, all patients who had started with congestive heart failure had progressed to cardiac transplantation or cardiac death. Progressive LV wall thinning on enalapril remains a concern for the future. Our study suggested that a higher diastolic blood pressure before enalapril therapy predicted the greatest improvement after 2.4 years on enalapril therapy. The primary problem in doxorubicin-treated patients is reduced LV wall thickness for body-surface area, which results in increased LV afterload, causing decreased LV fractional shortening. Our results suggest that enalapril does not address the primary defect in wall thickness but rather reduces afterload by reducing blood pressure and LV dilation. This study confirmed that our previously identified risk factors for late cardiotoxicity also predict outcome and response to therapy.2-7 Greater LV dilation and lower LV contractility at the start of enalapril therapy were associated with enalapril failure, leading to either death or heart transplantation. This study also supports previously established risk factors for the development of doxorubicin-induced cardiotoxicity, such as young age, female sex, higher cumulative doxorubicin dose, and longer follow-up period. Our study shows that doxorubicin-treated children have progressive asymptomatic LV dysfunction regardless of whether they receive enalapril. Our study suggests that enalapril shifts the LV dysfunction curve to the right by 6 to 10 years but does not prevent progression. In a multicenter randomized trial of enalapril versus placebo in adults with LV dysfunction, enalapril was associated with a 37% reduction in the risk of developing heart failure.19 Heart failure rates in the enalapril and placebo groups diverged early and continued to diverge over the 48-month study, suggesting that enalapril delays or prevents heart failure.19 Similar results were obtained in another study in which captopril was given to patients with some systolic dysfunction but without severe LV dilatation.20 Overall mortality in the captopril group was 19% lower than in the placebo group.20 ACE inhibition may retard progression of severe LV dysfunction to overt heart failure, suggesting that the prevention of congestive heart failure may actually be the result of delaying onset beyond the expected survival. By studying younger patients, who have a longer expected survival, we were able to address the question of whether heart failure in this nonadult population was prevented or merely delayed. We found that patients with LV dysfunction whose disease had already progressed to overt heart failure had a poor prognosis. Children with congestive heart failure in this study were more likely to show an initial response to therapy than were children with asymptomatic LV dysfunction. However, between 2.4 and 6 years, medical management had failed for all of the children with baseline congestive heart failure, and all had either received heart transplantation or died a cardiac death. This suggests that the course of congestive heart failure for these patients may be worse than in adults with congestive heart failure, who have a 50% mortality rate by 5 years after presentation.21,22 Pharmacotherapy for heart failure shifts the survival curve to the right, but patients continue to deteriorate over time. This study showed that the primary underlying abnormality, an inappropriately thin LV wall, worsened on enalapril therapy. It is well established that ACE inhibition causes regression of pathologic cardiac hypertrophy11-13 and also impairs physiologic cardiac hypertrophy,23-26 which is the mechanism by which the heart grows in humans after the age of 6 months. Although enalapril’s antihypertrophic effects may benefit patients with LV hypertrophy, it is unclear whether they are beneficial in children who already have LV wall thinning associated with anthracycline treatment. Limiting hypertrophic growth in a growing child may have negative consequences. This may partly explain why in this study the younger patients had worse outcomes than the older patients. Although this study supports ACE inhibition with enalapril in patients who received anthracyclines for childhood malignancy, there are several qualifications. Patients experienced only short-term improvements of LV function, and LV walls continued to thin. The enalapril therapy appears to balance short-term benefits of afterload reduction with long-term exacerbation of inadequate hypertrophy, and this balance may come out differently in those who start with inadequate hypertrophy, but we do not have data to address this. Quality-of-life assessment was not included in the study. The study had a small sample size and some dropout, and no multivariable modeling was performed. Our results are similar to those of a study of adults with epirubicin-associated LV dysfunction treated with an ACE inhibitor for a median of 2.2 years, which found improvement.27 There is still a need for a randomized controlled study.28 Such a study would be most beneficial if the duration of follow-up was long-term, especially for survivors of childhood cancer whose clinically significant cardiovascular outcomes occur over decades.8,9 In summary, the effectiveness of intensive chemotherapy for childhood cancer means that increasing numbers of young adults are cancer survivors. Many have received moderate to high doses of anthracyclines. The progressive deleterious effect of this treatment on the heart is thus an emerging public health problem. We conclude that enalapril treatment produces a 6- to 10- year benefit before asymptomatic LV dysfunction returns to baseline and a 2- to 6-year benefit before medical management fails for patients with congestive heart failure. Enalapril may be beneficial in the intermediate follow-up of asymptomatic LV dysfunction and in the short-term follow-up of heart failure but does not prevent progressive LV wall thinning. Medical management is most likely to fail for children with dilated cardiomyopathy. Children with higher diastolic blood pressure are more likely to have a beneficial response to enalapril.
Supported in part by National Institutes of Health grant nos. CA 68484, CA 55576, CA 06516, CA 79060, HL 59837, HL 53392, and HR 96041 and the David B. Perini, Jr, Quality-of-Life Program.
1. Office of Cancer Survivorship, National Cancer Institute Workshop on Long-Term Follow-Up Care Programs for Survivors of Pediatric Cancer, Niagara-on-the-Lake, Ontario, Canada, June 25, 2002 2. 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]
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. Grenier MA, Lipshultz SE: Epidemiology of anthracycline cardiotoxicity in children and adults. Semin Oncol 25: 72-85, 1998 (suppl 10)[Medline] 5. Giantris A, Abdurrahman L, Hinkle A, et al: Anthracycline-induced cardiotoxicity. Crit Rev Oncol Hematol 27: 53-68, 1998[Medline] 6. Nysom K, Colan SD, Lipshultz SE: Late cardiotoxicity following anthracycline therapy for childhood cancer. Prog Pediatr Cardiol 8: 121-138, 1998[CrossRef] 7. Lipshultz SE: Ventricular dysfunction clinical research in infants, children and adolescents. Prog Pediatr Cardiol 12: 1-28, 2000[CrossRef][Medline]
8. 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
9. 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 10. Grenier MA, Fioravanti J, Truesdell SC, et al: Angiotensin-converting enzyme inhibitor therapy for ventricular dysfunction in infants, children and adolescence: A review. Prog Pediatr Cardiol 12: 91-111, 2000[CrossRef][Medline] 11. Beinlich CJ, Rissinger CJ, Vitkauskas KJ, et al: Role of bradykinin in the antihypertrophic effects of enalapril in the newborn pig heart. Mol Cell Biochem 164: 77-83, 1996[CrossRef] 12. Wamboldt RB, Henning SL, English DR, et al: Regression of cardiac hypertrophy normalizes glucose metabolism and left ventricular function during reperfusion. J Mol Cell Cardiol 29: 939-948, 1997[CrossRef][Medline] 13. Cichoka E, Kawalec W, Januszewics P, et al: The effect of ACE inhibition on left ventricular function and structure in hypertensive adolescents. Pediatria Polska 70: 145-151, 1995[Medline] 14. Colan SD, Parness IA, Spevak PJ, et al: Developmental modulation of myocardial mechanics: Age and growth-related alterations in afterload and contractility. J Am Coll Cardiol 19: 619-629, 1992[Abstract] 15. Devereux RB, Alonso DR, Lutas EM, et al: Echocardiographic assessment of left ventricular hypertrophy: Comparison to necropsy findings. Am J Cardiol 57: 450-458, 1986[CrossRef][Medline]
16. Lipshultz SE, Easley K, Orav EJ, et al: The reliability of multicenter pediatric echocardiographic measurements of left ventricular structure and function. Circulation 104: 310-316, 2001
17. Gullestad LA, Aukrust P, Ueland T, et al: Effects of high- versus low-dose angiotensin converting enzyme inhibition on cytokine levels in chronic heart failure. J Am Coll Cardiol 34: 2061-2067, 1999 18. Simbre VC II, Adams MJ, Despande SS, et al: Cardiomyopathy caused by antineoplastic therapies. Curr Treat Options Cardiovasc Med 3: 493-505, 2001 19. 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] 20. Pfeffer MA, Braunwald E, Moye LA, et al: Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: Results of the survival and ventricular enlargement trial—The SAVE Investigators. N Engl J Med 327: 669-677, 1992[Abstract] 21. Cohn JN, Johnson G, Ziesche S, et al: A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 325: 303-310, 1991[Abstract] 22. The SOLVD Investigators: Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 325: 293-302, 1991[Abstract] 23. Dixon IMC, Reid NL, Ju H: Angiotensin II and TGF beta in the development of cardiac fibrosis, myocyte hypertrophy and heart failure. Heart Failure Rev 2: 107-116, 1997[Medline] 24. Kichuk MR, Zhang X, Oz M, et al: Angiotensin-converting enzyme inhibitors promote nitric oxide production in coronary microvessels from failing explanted human hearts. Am J Cardiol 70: 137A-142A, 1997 25. Loirat C, Azznot A, Pillion G, et al: Sequential echocardiographic study prior and during antihypertensive therapy in children with severe hypertension. Clin Exp Hypertens A8: 805-810, 1986 26. Liebermann E: Pediatric hypertension: Clinical perspective. Mayo Clin Proc 69: 1098-1107, 1994[Medline] 27. Jensen BV, Nielsen SL, Skovsgaard T: Treatment with angiotensin-converting-enzyme inhibitor for epirubicin-induced dilated cardiomyopathy. Lancet 347: 297-299, 1996[CrossRef][Medline] 28. 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] Submitted December 20, 2001; accepted August 8, 2002.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
