ArticlesRandomised, double-blind, placebo-controlled trial of human recombinant growth hormone in patients with chronic heart failure due to dilated cardiomyopathy
Introduction
Dilated cardiomyopathy is the cause of chronic heart failure in a substantial proportion of patients and, despite advances in treatment, has a mean survival time of 5 years.1, 2 The only effective treatment for end-stage dilated cardiomyopathy is heart transplantation but, since there is a limited number of donor organs, other forms of therapy—such as left-ventricular-assist devices or partial left ventriculectomy—are being investigated.3, 4 Both of these procedures reduce left-ventricular wall stress and aid the recovery of myocardial fibres. Experience with these procedures is still limited and no survival data are available. Other forms of treatment are desirable.
Growth hormone given over short periods increases left-ventricular contractility in healthy men.5 Fazio and colleagues6 treated seven patients who had chronic heart failure due to dilated cardiomyopathy with recombinant human growth hormone (rhGH) and found substantial improvements in cardiac function and exercise capacity. Serum concentrations of insulin-like growth factor-I (IGF-I) increased greatly. However, this preliminary study was uncontrolled.
We did a randomised, double-blind, and placebocontrolled study of rhGH in 50 patients with chronic heart failure due to dilated cardiomyopathy. The primary endpoints were effects of rhGH on left-ventricular mass and left-ventricular systolic-wall stress. Secondary endpoints were the effects on left-ventricular size and function. Because growth hormone exerts most of its effects through IGF-I, we also investigated the relation between the change in serum IGF-I concentrations and the treatment effects.
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Patients and methods
Patients with dilated cardiomyopathy who met all of the inclusion criteria were eligible for the study. The inclusion criteria were: age 25–70 years, left-ventricular ejection fraction less than 45% by echocardiography or by left-ventricular angiography, exclusion of coronary artery disease by selective coronary angiography, optimum and stable medical therapy with inhibitors of angiotensin-converting enzyme (ACE), or angiotensin-II receptor antagonists if ACE inhibitors were not tolerated,
Protocol
After baseline measurements that included a physical examination, 12-lead electrocardiogram, three walking tests (6 min each), right-heart catheterisation, and cardiac MRI, patients were randomly allocated either placebo or rhGH (Genotropin, Pharmacia & Upjohn, Erlangen, Germany). The randomisation was balanced in groups of ten patients, and this, along with the labelling of the visually identical vials, was done by the pharmacy department of the community hospital Berlin-Buch. All patients
Cardiac function
After the patient had fasted overnight and before morning medication was taken, right-heart catheterisation was done between 0900 and 1100 h. Measurements were taken in a quiet room at 30 min, 90 min, and 150 min. At each time point the cardiac output was calculated three times by the thermodilution technique (Siemens Sirecust 1260). The variation of the cardiac-output measurements was less than 10%. There were no time-dependent haemodynamic changes and the last set of measurements was used as
Laboratory tests
Blood samples were taken after the haemodynamic measurements were done. Plasma epinephrine and norepinephrine were measured by high-performance liquid chromatography (Chromsystems, Munich, Germany); the reference ranges are 30–85 pg/mL and 185–275 pg/mL, respectively. At baseline and at the end of the study blood was taken on two consecutive mornings for serum growth hormone, IGF-I, and IGF binding protein-3 (IGFBP-3) measurements. The mean concentration of the 2 days was used in the analyses.
Statistics
Based on the data of Fazio and colleagues6 we calculated that a sample size of 20 was needed to detect a 50 g increase in left-ventricular mass with an estimated SD of 30 with 90% power and at significance level of 0·01. Data were analysed by intention to treat, with the carry-forward principle for missing data. The distribution of all continuous variables was assessed by the Kolmogorov-Smirnov test. Normally distributed data were compared by the independent-samples t test or paired t test.
Results
The trial profile of the 50 patients is shown in figure 1. The MRI data of three patients (two rhGH) could not be analysed because of poor-quality scans.
The mean age was 54 years (SD 10) and the mean left-ventricular ejection fraction was 26% (10). Because of randomisation there were no significant differences at baseline between the two groups (table 1). 19 patients were taking enalapril: the mean dose was 17 mg daily. The other patients received comparable doses of other ACE inhibitors or
Discussion
This is the first randomised, double-blind, and placebocontrolled trial of rhGH in patients with dilated cardiomyopathy. The principal finding is that although rhGH treatment increased left-ventricular myocardial mass, this change was not of clinical benefit. The increase in myocardial mass resulted from a small increase in wall thickness; left-ventricular end-diastolic volumes were unchanged.
Our patients were similar to those in an uncontrolled trial of rhGH in terms of severity of heart
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