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Enalapril to Prevent Cardiac Function Decline in Long-Term Survivors of Pediatric Cancer Exposed to Anthracyclines

From the Divisions of Pediatric Oncology, Biostatistics and Epidemiology, Cardiology, Department of Pediatrics, and the Center for Outcomes Research, Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia and The University of Pennsylvania School of Medicine, Philadelphia, PA; The Divisions of Pediatric Cardiology, Hematology/Oncology, Children's Hospital Medical Center, Cincinnati, OH; Division of Pediatric Cardiology, New York University of Medicine; and Department of Pediatric Cardiology, Memorial Sloan-Kettering Medical Center, New York, NY

Address reprint requests to Jeffrey H. Silber, MD, PhD, Center for Outcomes Research, Children's Hospital of Philadelphia, 3535 Market St, Suite 1029, Philadelphia, PA, 19104; e-mail: Silber{at}.chop.edu

	ABSTRACT

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PURPOSE: To determine whether an angiotensin-converting enzyme (ACE) inhibitor, enalapril, prevents cardiac function deterioration (defined using maximal cardiac index [MCI] on exercise testing or increase in left ventricular end-systolic wall stress [LVESWS]) in long-term survivors of pediatric cancer.

PATIENTS AND METHODS: This was a randomized, double-blind, controlled clinical trial comparing enalapril to placebo in 135 long-term survivors of pediatric cancer who had at least one cardiac abnormality identified at any time after anthracycline exposure.

RESULTS: There was no difference in the rate of change in MCI per year between enalapril and placebo groups (0.30 v 0.18 L/min/m²; P = .55). However, during the first year of treatment, the rate of change in LVESWS was greater in the enalapril group than in the placebo group (-8.59 v 1.85 g/cm²; P = .033) and this difference was maintained over the study period, resulting in a 9% reduction in estimated LVESWS by year 5 in the enalapril group. Six of seven patients removed from random assignment to treatment because of cardiac deterioration were initially treated with placebo (P = .11), and one has died as a result of heart failure. Side effects from enalapril included dizziness or hypotension (22% v 3% in the placebo group; P = .0003) and fatigue (10% v 0%; P = .013).

CONCLUSION: Enalapril treatment did not influence exercise performance, but did reduce LVESWS in the first year; this reduction was maintained over the study period. Any theoretical benefits of LVESWS reduction in this anthracycline-exposed population must be weighed against potential side effects from ACE inhibitors when making treatment decisions.

	INTRODUCTION

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Nearly 70% of all children diagnosed with a malignancy become long-term survivors, and can reasonably be described as cured [1]. However, this impressive cure rate has been achieved at a significant cost in terms of side effects associated with the intense treatment needed to achieve these results. Consequently, there are now approximately 250,000 long-term survivors of pediatric cancer [1] at risk for a wide variety of medical late effects of therapy [2], with half of these patients having been exposed to anthracyclines. It is estimated that more than half of all patients exposed to anthracyclines (ie, more than 60,000 patients) will show cardiac abnormalities on two-dimensional echocardiography or gated nuclear angiography (GNA) testing at 10 to 20 years from diagnosis [3-5]. Of these, possibly 5% could develop congestive heart failure. Arrhythmias are also noted to occur in approximately 40% of patients by 20 years from diagnosis [3,6], and the incidence of cardiac abnormalities increases with time [3,7-10].

One of the more challenging aspects of the late cardiac dysfunction associated with anthracyclines is the early asymptomatic nature of the disease. It is not uncommon for patients to seem clinically well months or even days before developing acute congestive heart failure and pulmonary edema [11]. Given the silent nature of the underlying state, many have suggested screening programs to look for late cardiac effects from anthracyclines in patients treated during childhood [7]. The late manifestations of anthracycline toxicity on screening examinations are varied, but include increased left ventricular end-systolic wall stress (LVESWS) [8,9,12,13] and diminished contractile state (as measured by wall stress-velocity index [SVI] [8,9]), wall thickness [8,9,12,13], and left ventricular shortening fraction (SF) [3,4,8,14].

A central question in the care of patients exposed to anthracyclines is how to treat long-term survivors with mild abnormalities detected on routine screening examinations. There currently is no consensus about what (if anything) can be done to curtail the progression of the late consequences of anthracycline therapy.

A current hypothesis regarding the etiology of late anthracycline toxicity might suggest an intervention. It has been postulated that the imbalance of cardiac work to the myocardial mass of the thinned ventricle produces myocyte hypertrophy, with metabolic changes promoting apoptosis and progressive myocardial damage [11]. This can lead to congestive heart failure and arrhythmogenic fibrosis. Reduced cardiac output is thought to activate the renin-angiotensin system, elevating systemic vascular resistance and left ventricular wall stress, increasing cardiac work, and propagating an ongoing cycle of damage that ultimately leads to heart failure.

A related theory had been postulated for adults with congestive heart failure associated with etiologies not involving anthracycline therapy [15]. Several studies have reported that angiotensin-converting enzyme (ACE) inhibitors reduce the incidence of new episodes of congestive heart failure in asymptomatic adult patients [15-17].

The primary hypothesis of the ACE Inhibitor After Anthracycline (AAA) study was that a reduction of LVESWS through the use of an ACE inhibitor would lower the rate of decline in cardiac function associated with prior anthracycline exposure. We report on the results of a double-blind, placebo-controlled study of enalapril, an ACE inhibitor, in long-term survivors of pediatric cancer who were exposed to anthracyclines and who had developed specific abnormalities on cardiac screening tests any time after anthracycline exposure. Our goal was to determine whether a prevention regimen with an ACE inhibitor would slow the progression of cardiac dysfunction by decreasing LVESWS.

	PATIENTS AND METHODS

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Eligibility, Inclusion, and Exclusion Criteria
The AAA study design and baseline patient population have been described in detail elsewhere [18]. The target population consisted of patients age 8 years and older who developed cancer before the age of 20 years, had been treated with anthracyclines, and had been at least 4 years from diagnosis and 2 years from completing all cancer treatment. Patients must have shown, at some time after anthracycline exposure, one or more of the following measures of decline in cardiac systolic performance: an echocardiographic left ventricular SF of 29%, or a 10% decrease from an earlier test; a GNA resting left ventricular ejection fraction (EF) of 55%, decrease in EF with exercise, or a 10% decrease in resting EF over time; a maximal cardiac index (MCI) of 7.4 L/min/m² on cycle ergometry at peak exercise; or an ECG QTc interval of 440 milliseconds on resting ECG. Patients were excluded from entry if they previously had been treated with or currently were being treated with an ACE inhibitor; were receiving digoxin or other inotropic agents; had a history of congestive heart failure; had a history of congenital heart disease that study investigators believed could account for the abnormal cardiac findings or that would impair any potential benefit from enalapril; had documented renal artery stenosis; or were females planning to become pregnant during the study period (enalapril may cause damage to the fetal kidney) [19-21].

Organization and Randomization
The study design was approved by a Data and Safety Monitoring Board assembled by the National Heart, Lung, and Blood Institute, and approved by institutional review boards at the four participating study institutions. Investigators and patients were blinded to treatment assignment. Investigators reviewed individual patient's cardiac data as part of ongoing monitoring of patient safety. The study began enrollment in October 1994 and closed enrollment in March 1999. Patients remained in treatment and follow-up until March 2001, allowing the last patient enrolled in March 1999 to be observed for 2 years. The study was stratified on three variables: age at treatment ( 3 v > 3 years at diagnosis of cancer), total cumulative anthracycline dosage (< 300 v 300 mg/m²), and time from diagnosis: (< 10 v 10 years).

Determination of Sample Size
Analyses of the primary end point (the comparison of rate of change in MCI between the two treatment groups) and the secondary outcome (the rate of change in LVESWS) were based on an intent-to-treat approach. Following Beck's approach [22], we estimated a required sample size of 61 patients per group to detect a 50% difference in the MCI slope with 80% power, while controlling for a two-sided type I error of 0.05 and assuming a 5% dropout rate per year and median follow-up of 3 years. Calculations for LVESWS were similar and showed that a 30% difference is detectable with this sample size. The study was closed after random assignment of 135 patients with a mean follow-up of 34.6 months, of whom 118 patients had MCI evaluations beyond baseline.

Patient Recruitment, Screening, and Enrollment
Overall, 4,308 patient charts across four institutions were screened, of which 401 (9.3%) were found to be eligible. Of those, 146 (36.4%) agreed to participate, 112 (28%) refused, and the remaining patients did not make a definitive statement concerning participation. Of the 146 who agreed to participate, 135 were ultimately randomly assigned to receive treatment or placebo [18].

Scheduled Measurements and Dosing
Patients received cardiac performance testing every 6 months and physical examinations between 2 and 5 times per year. Once patients consented and were randomly assigned, they received 0.05 mg/kg/d of study drug, progressively escalated to 0.10 mg/kg/d, and finally received 0.15 mg/kg/d if no side effects were noted.

Description of Cardiac Evaluations
To determine MCI on cycle ergometry, all patients were exercised to maximum volition using a standard ramp cycle protocol with helium acetylene inert gas rebreathing [18,23,24]. LVESWS and the echocardiographic left ventricular contractile state (determined from the relationship between LVESWS and rate-adjusted velocity of fiber shortening) were determined [25,26]. Resting multigated equilibrium blood pool scintigraphy [27] or GNA was administered before entrance and at the end of the study to determine cardiac EF [18].

Adherence to Study Procedures and Discontinuation
Patient compliance with the study protocol was assessed by self-report history. Patients were considered to have adhered to the protocol if they reported missing less than 30% of the prescribed study medication. All patients were screened for cardiac declines over time. Patients with declining cardiac performance were discontinued from the randomized study as determined by the following criteria: documented acute congestive heart failure with pulmonary edema and S3 gallop without obvious correctable cause; SF decline by 20% from baseline for two consecutive measures, both below 28%; or MCI decline by 30% from baseline for two consecutive measures, both below 2 standard deviations from mean. Patients who were discontinued from the randomized study continued to be observed with cardiac evaluations in accordance with the AAA schedule.

Quality-of-Life Measures and Adverse Events
At each follow-up visit patients were given the Short Form-36 General Health Survey if older than the age of 14 years [28] or the Childhood Health Questionnaire-85 [29,30] if 14 years. Adverse events were collected according to a record that included, but was not limited to, adverse events associated with enalapril [18,31,32].

Statistical Analysis
To test for a treatment effect, we compared the rates of change over time in MCI and LVESWS between the two treatment groups. The main analyses were based on mixed-effects linear models [33]. This approach allows all available data to be used on all patients, and accounts for both a different number of evaluations on different patients and different times of those evaluations. This approach prevents the need to impute missing observations. The linear mixed-effects model is excellent for handling missing data under the standard assumption in longitudinal studies of ignorable missingness [34]. Ignorable missingness implies that the likelihood of the data does not depend on the actual values of the missing data. Although such an assumption can not be proved, we explored the data and found no patterns by treatment or other characteristics that correlated with missingness of the data, and hence concluded that the ignorable missingness assumption was reasonable in this study. We also fit a model with one change point to account for early versus later changes in LVESWS over time. In addition to MCI and LVESWS, the SVI or the residual deviation from the standard stress-velocity regression line as published by Colan et al [25] (computed as observed minus expected rate-adjusted velocity of fiber shortening for a specified LVESWS) and SF percentage also were analyzed using the mixed-effects approach.

Adverse events were summarized by the frequency and severity of each event type and compared between the two groups using Fisher's exact test or an exact Kruskal-Wallis test [35]. The number of declines was analyzed using a Fisher's exact test. Because of differential follow-up, we also calculated a log-rank test.

	RESULTS

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Characteristics of Randomly Assigned Patients by Treatment
Detailed baseline comparisons have been reported elsewhere [18]. Table 1 lists selected characteristics of patients in the enalapril and placebo groups. There were relatively more whites in the enalapril group and relatively more blacks in the placebo group. Distribution of initial cancer diagnoses showed no difference between groups. Table 2 lists baseline cardiac performance measures. There were no significant differences between treatment groups on these parameters, although patients randomly assigned to enalapril tended to display slightly higher initial LVESWS (P = .16). Of note, both groups showed markedly elevated LVESWS [26], with levels similar to those reported by Lipshultz et al [8]. Overall observed baseline LVESWS was 70.89 g/cm² ± 19.79, and the age-adjusted expected LVESWS on the basis of normals as referenced by Colon et al [26] was 50.10 ± 3.08 (P < .0001). At baseline, there were 111 patients with abnormalities on SF, EF, LVESWS, or SVI. Of the 24 patients without such abnormalities, seven had baseline abnormalities on MCI. The remaining 17 qualified for abnormalities noted before baseline according to the protocol (of note, nine were randomly assigned to receive enalapril and eight were randomly assigned to receive placebo).

LVESWS
Table 3 shows that there was no difference between enalapril and placebo groups in the rate of change of wall stress over the entire study period (P = .24). However, on inspection of the LVESWS data, it became apparent that wall stress in the enalapril group declined in the first year patients received therapy, and then leveled off, whereas there was no initial or subsequent decline in wall stress in the placebo group.

Table 4 lists the piecewise linear mixed-effects model of change in LVESWS over time showing a change point of slope at 1 year. In this model, there was a difference in slopes between groups (P = .036), with the enalapril-treated group showing a reduction in wall stress in the first year, and the placebo group displaying no change in LVESWS. The slopes of both the enalapril and placebo group LVESWS curves were nearly flat after 1 year. Estimated LVESWS at year 5 showed a 9% reduction from baseline in the enalapril group versus a 2% increase from baseline in the placebo group. Of note, the reduction in LVESWS associated with enalapril was largely due to a reduction in end-systolic pressure. When a model identical to that in Table 4 was used, the first-year reduction in end-systolic pressure in the enalapril group was -7.2 v +5.87 mmHg in the placebo group (P = .0006). Subsequent changes in end-systolic pressure were not significant. There also was no significant difference between treatment and placebo groups with respect to measurement of end systolic posterior wall thickness over the length of the study.

As expected, a strong inverse relationship between SF and LVESWS was observed at each observation period, and with the data overall for all time periods of follow-up. The Pearson correlation coefficients between SF and LVESWS were consistent over time periods, ranging only between -0.45 (P = .0001) at baseline to -0.67 (P = .003) at 60 months, with an overall correlation of -0.54 (P = .0001).

Clinically Significant Declines in Cardiac Performance
Patients were taken off randomly assigned medication and placed on enalapril (or other medications deemed necessary by their cardiologists) if they experienced two consecutive significant declines in cardiac performance below baseline levels (see Patients and Methods). Such declines occurred in seven of 135 patients and are listed in detail in Table 5. Of the seven individuals who experienced a decline in cardiac performance, six of seven had been randomly assigned to placebo, and one had been randomly assigned to enalapril (P = .059). The Kaplan-Meier [36] plot of time to discontinuance and results of the log-rank test (P = .11) are shown in Fig 1. Note that the one enalapril-treated patient who experienced a decline in cardiac performance also was receiving growth hormone. One patient randomly assigned to placebo died 8 months after the end of the study. This patient started to receive testosterone during the study. No other patients in the study were receiving either growth hormone or testosterone.

View larger version (12K): [in this window] [in a new window]   Fig 1. Kaplan-Meier plot of time to discontinuance from study as a result of significant repeated declines in cardiac function.

	DISCUSSION

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The lack of detection of a difference in the study's primary end point, MCI, also deserves some comment. MCI improved in both groups and may have reflected increased familiarity with the test, and possibly improved conditioning merely because of enrollment onto the trial. The effort-dependent nature of the test may have added variability to these results and possibly obscured differences between groups, especially because increased fatigue was noted more frequently in the enalapril group.

What should we conclude from this study? Enalapril can be tolerated reasonably well in this population, but dizziness and fatigue were common and required numerous dosage reductions. Enalapril can reduce LVESWS in this population, but the rate of change of other important cardiac outcomes that reflect exercise ability or contractile state was similar in both groups, suggesting that the trial results failed to establish that LVESWS reduction leads to improved contractile state. It is possible that the median follow-up time of 3 years was insufficient to allow the reduced wall stress associated with enalapril treatment to improve exercise performance as measured by MCI or contractile state as measured by the SVI. The future clinical impact of an isolated reduction of LVESWS remains to be determined [37]. Lipshultz et al [38] have suggested that the beneficial effect of enalapril may diminish after 6 years of treatment, in part because of progressive wall thinning. Although we did not see any difference in wall thickness between treated and control groups in our study, the observation that beneficial effects of enalapril may not last beyond 6 years is important and one that we could not address given the study follow-up time.

Therefore, we would conclude that clinicians, with their patients, will need to decide whether the theoretical (but yet unproven) benefits of wall stress reduction in this population is worth the potential risks of taking enalapril, including increased fatigue and dizziness, and, of course, the risk of fetal kidney damage if taken during pregnancy.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Acknowledgment

 
We thank Margaret Tartaglione, Patricia Timlin, Denise DePaul, Wendy Hobbie, Judith Gallagher, Victoria Vetter, Sidney Heyman, Charles Heise, Xiaoyun Li, Judy Correll, Rinske Niermans, and Anna Meadows; DSMB members Frederick James, William Evans, John Falletta, Norman Fost, Josephine Isabel-Jones, and Genell Knatterud; NHLBI staff Nancy Geller, Gail Pearson, George Sopko, and Constance Weinstein; and Merck and Co. for supplying the placebo.

	NOTES

 
Primarily funded by grant no. R01 HL-50424 from the National Heart, Lung, and Blood Institute. Other funding was obtained from the National Center for Research Resources, grant no. M01-RR-00240, and the National Cancer Institute, grant no. CA-16520.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

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Submitted June 5, 2003; accepted October 28, 2003.

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