Results of Targeted Anti–Tumor Necrosis Factor Therapy With Etanercept (ENBREL) in Patients With Advanced Heart Failure
Background—Previously, we showed that tumor necrosis factor (TNF) antagonism with etanercept, a soluble TNF receptor, was well tolerated and that it suppressed circulating levels of biologically active TNF for 14 days in patients with moderate heart failure. However, the effects of sustained TNF antagonism in heart failure are not known.
Methods and Results—We conducted a randomized, double-blind, placebo-controlled, multidose trial of etanercept in 47 patients with NYHA class III to IV heart failure. Patients were treated with biweekly subcutaneous injections of etanercept 5 mg/m2 (n=16) or 12 mg/m2 (n=15) or with placebo (n=16) for 3 months. Doses of 5 and 12 mg/m2 etanercept were safe and well tolerated for 3 months. Treatment with etanercept led to a significant dose-dependent improvement in left ventricular (LV) ejection fraction and LV remodeling, and there was a trend toward an improvement in patient functional status, as determined by clinical composite score.
Conclusion—Treatment with etanercept for 3 months was safe and well-tolerated in patients with advanced heart failure, and it resulted in a significant dose-dependent improvement in LV structure and function and a trend toward improvement in patient functional status.
Recent experimental studies have shown that etanercept (ENBREL), a recombinant human tumor necrosis factor (TNF) receptor that binds to TNF and functionally inactivates this cytokine, is sufficient to reverse some of the deleterious effects of TNF in vitro and in vivo.1 2 3 Recently, we reported that a single intravenous infusion of etanercept was safe and well tolerated and led to a decrease in biologically active levels of TNF, as well as to an improvement in the functional status of heart failure patients.4 To extend these studies, we conducted a randomized, multidose study with etanercept to further characterize the safety and potential efficacy of TNF antagonism in patients with advanced heart failure.
We studied 47 patients with stable New York Heart Association (NYHA) functional class III to IV heart failure. Patients were eligible if their screening left ventricular (LV) ejection fraction was <35%; they were receiving stable doses of an angiotensin-converting enzyme (ACE) inhibitor, digoxin, and oral diuretics for 30 days before enrollment; and they were able to walk ≥100 meters during a 6-minute walk test. ACE-intolerant patients were on hydralazine/isosorbide or losartan. The use of β-blockers was permitted (but not required) as long as the patient was on stable doses of β-blockers for 3 months before enrollment. The study was conducted at Baylor College of Medicine (Methodist Hospital and the Houston Veterans Affairs Medical Center) and the University of Pittsburgh, and it was approved by the Institutional Review Boards at both centers.
Study Protocol and Objectives
This study was a randomized, double-blind, placebo-controlled, multidose trial of etanercept, a soluble TNF receptor. The primary objective was to evaluate the safety and tolerability of etanercept. The secondary objective was to assess the clinical and laboratory indices for evidence of improvement in (1) LV function and structure and (2) patient functional and clinical status, as measured by a clinical composite score. Patients were randomized to receive 5 mg/m2 or 12 mg/m2 etanercept SC twice weekly for 3 months. The etanercept doses were based on data from a previous dose escalation study with etanercept in heart failure and studies with etanercept in rheumatoid arthritis.4 Baseline evaluations consisted of a history and cardiopulmonary examination, echocardiography with Doppler, routine laboratory tests, and the assessment of patient functional status. Data were recorded at baseline and then on days 1, 30, 60, and 90 after study drug administration.
Safety and Tolerability of Etanercept
Patients were evaluated for adverse events throughout the study. In addition to serially monitoring heart rate and blood pressure, we also assessed hemoglobin/hematocrit, white blood cell count, platelet count, serum electrolytes, and serum creatinine. Assessment for antibodies to etanercept were performed as described previously4 at baseline and at the end of 3 months of blinded therapy.
Effect of Etanercept on LV Structure and Function
Two-dimensional and Doppler echocardiography were used to measure LV ejection fraction and LV end-diastolic and LV end-systolic volumes using the modified Simpson’s rule. LV mass was determined using the area-length method. All 2D and Doppler echocardiographic readings were performed at baseline and after 3 months of therapy, and they were interpreted by a single qualified reader who was blinded to the treatment protocol.
Effect of Etanercept on Clinical Status
To assess the effects of etanercept on clinical functional status, we employed a clinical composite score that classified patients as better, worse, or unchanged at the end of 3 months of blinded therapy (see Data Supplement for details).
Data are expressed as mean±SD. The likelihood ratio χ2 test was used to test for differences in baseline categorical and nominal variables, including the clinical composite score. Given the small sample sizes and because the data were generally not normally distributed, nonparametric tests were used to compare the groups on quantitative variables, including measures of LV function and structure. The Kruskal-Wallis test was used to test for differences among the 3 groups, and the Wilcoxon rank sum test was used to make pair-wise treatment comparisons for these variables. All statistical analyses were performed using the last observation carried forward in the presence of missing data. All probability values are 2-tailed.
Table 1⇓ shows the baseline characteristics of the study population. There was no significant difference in age, sex, race, NYHA class, LV ejection fraction, cause of heart failure (ischemic versus nonischemic), or circulating levels of TNF between the 3 groups of patients. All patients were on stable drug therapy, including digoxin, diuretics, and ACE inhibitors. An equal number of patients in each group were taking β -blockers. There was no significant difference in medication use between the treatment groups.
Of the 31 patients who received etanercept, 27 completed 3 months of therapy (75% in the 5 mg/m2 group and 100% in the 12 mg/m2 group); all of the patients in the placebo group finished 3 months of blinded therapy. The reasons for discontinuation from the study were as follows: 1 patient with a history of sustained ventricular tachycardia who refused an implantable cardiac defibrillator died, 1 patient requested to be withdrawn for worsening heart failure during the second week after enrollment, 1 patient declined to continue after developing pneumonia, and 1 patient was lost to follow-up.
Safety and Tolerability of Etanercept
Etanercept was safe and well tolerated when administered twice weekly using subcutaneous doses of 5 or 12 mg/m2. There were no dose-limiting toxicities observed in the etanercept groups. The adverse events were equally distributed among the 3 groups and were mild in intensity (Table 2⇓). The overall frequency of injection site reactions was ≈10%, and the reactions were considered mild or moderate in intensity; none required treatment. Abnormal laboratory results were infrequent and were not clinically significant (data not shown). There were no significant changes in heart rate or blood pressure (see Data Supplement), and there were no significant changes in hematological or serum chemical parameters between the placebo and etanercept groups during 3 months. Serological tests for antibodies against etanercept were negative at the end of 3 months of blinded therapy, as well as at the 30- and 90-day follow-up after the end of blinded therapy.
Effect of Etanercept on LV Structure and LV Function
Figure 1A⇓ shows that there was a dose-dependent increase in LV ejection fraction for the patients who received etanercept, whereas there was a small decrease in LV ejection fraction for the patients who received placebo. Figures 1B⇓ through 1D show, respectively, that the improvement in LV ejection performance in the etanercept treatment group was accompanied by a dose-dependent decrease in LV end-diastolic volume, LV end-systolic volume, and LV mass. The changes in LV ejection fraction and LV end-diastolic and end-systolic volumes were statistically significant (P=0.01, P=0.04, and P=0.02, respectively) when compared with placebo. However, the dose-dependent reduction in LV mass in the etanercept treatment groups did not reach statistical significance (P=0.3).
Effect of Etanercept on Functional Status
There was a trend (P=0.20) toward improvement in the clinical composite score after 3 months of therapy with 12 mg/m2 etanercept. At the end of 3 months of treatment, 44% of the placebo-treated patients, 56% of the 5 mg/m2 etanercept–treated patients, and 67% of the 12 mg/m2 etanercept–treated patients were scored as improved. Importantly, there was no significant difference (P=0.96) in the number of patients who were considered worse after 3 months of therapy with etanercept.
In the present study, twice-weekly subcutaneous injections of etanercept were safe and well tolerated when administered to patients with advanced heart failure for 3 months (Table 2⇑). Furthermore, treatment with etanercept led to a significant dose-dependent improvement in LV function and LV remodeling (Figures 1A⇑ through 1C), consistent with prior experimental studies, which showed that etanercept reversed the untoward biological effects of pathophysiologically relevant concentrations of TNF in vitro and in vivo.1 2 Finally, although this study was designed to assess safety and was therefore not sized to detect statistically significant changes in patient functional status, there was a trend toward improvement in the clinical composite score after 3 months of therapy with etanercept (Figure 2⇓), whereas there was no worsening of clinical status at the end of 3 months of therapy. Moreover, there was a consistent treatment effect in patients who were and who were not receiving β-blockers (data not shown).
This study is consistent with previous clinical studies which have suggested that cytokine antagonism may be beneficial in patients with heart failure.4 5 Although, this study must be regarded as provisional because of the modest numbers of patients and the modest duration of follow-up, the results do suggest that it is safe and potentially efficacious to use etanercept in conjunction with existing conventional therapies for heart failure. Indeed, the lack of untoward hemodynamic effects with etanercept allows physicians to add this biological response modifier to existing strategies of ACE inhibitors, β-blockers, and diuretics, without the untoward consequences that often occur when traditional vasoactive neurohormonal antagonists are used in combination. Whether the salutary effects that were observed with etanercept in the present study can be sustained over longer periods of time and in larger patient populations will be addressed in the following 3 ongoing multicenter trials: Randomized Etanercept North AmerIcan Strategy to Study AntagoNism of CytokinEs (RENAISSANCE), Research into Etanercept CytOkine antagonism in VEntriculaR dysfunction (RECOVER), and Randomized EtaNErcept Worldwide evALuation (RENEWAL).
This research was supported by the National Institutes of Health (P50 HL-O6H) and Immunex Corporation. We gratefully acknowledge the technical assistance of Carolyn Thibodeaux, B.J. Schneider, and Dorellyn Lee-Jackson, and we thank Dr Andrew I. Schafer for past and present support and guidance.
Dr Mann serves as an unpaid consultant to Immunex Corporation; Dr Feldman is an Immunex Corporation stockholder.
Guest Editor for this article was William W. Parmley, MD, University of California at San Francisco.
Supplementary material to this article can be found Online Only at www.circulationaha.org
- Received September 5, 2000.
- Revision received January 11, 2001.
- Accepted January 12, 2001.
- Copyright © 2001 by American Heart Association
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