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Endothelin receptor antagonism may not improve outcomes in severe chronic HF
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Patients with severe chronic HF treated with endothelin receptor antagonism did not experience improved outcomes, according to a study in JACC: Heart Failure.
The ENABLE trial consisted of two separate studies in Europe and Australia (ENABLE-1) and North America (ENABLE-2) from June 1999 to January 2002. Researchers analyzed data from 1,613 patients with NYHA class IIIb or IV HF symptoms for at least 2 months and left ventricular ejection fraction of less than 35%.
Study details
Patients were randomly assigned oral bosentan (Tracleer, Actelion Pharmaceuticals; n = 805) or placebo (n = 808), which were taken in addition to their medications. Those assigned bosentan started at 62.5 mg twice per day, which increased to 125 mg twice per day after 4 weeks. Signs of fluid retention, laboratory variables and clinical status were regularly monitored. The median follow-up was 1.5 years.
The primary endpoint for each trial was defined as clinical status improvement at 9 months. Risk for all-cause mortality or hospitalization for HF was a primary endpoint across both trials, and the secondary endpoint was all-cause mortality.
At 9 months, clinical status did not change in the bosentan and placebo groups in both the European and Australian trial (P = .928) and the North American trial (P = .263).
Death or hospitalization for HF occurred in 321 patients in the placebo group vs. 312 patients in the bosentan group (HR = 1.01; 95% CI, 0.86-1.18). At follow-up, 160 patients assigned bosentan and 173 patients assigned placebo died (HR = 0.94; 95% CI, 0.76-1.16). Pump failure (n = 128) and sudden death (n = 98) were the major causes of death.
Worsening of HF in the bosentan group was often associated with fluid retention at 2 to 4 weeks, the researchers wrote.
Increased risk
Patients in the bosentan group had higher risk for anemia, peripheral edema, decreased hemoglobin, abnormal liver function tests and headache compared with the placebo group. Patients who reported edema saw symptoms within the first 2 weeks, which continued throughout follow-up. Those assigned bosentan were less likely to experience renal failure or impairment.
Serum levels of hepatic transaminases increased more than three times the normal level in 9.7% of patients in the bosentan group and 3.4% of patients in the placebo group, although no patients developed chronic or acute liver disease.
“This pharmacological action is of established value in the treatment of patients who have pulmonary hypertension due to a primary pulmonary vascular disorder in the absence of left [HF] (pulmonary arterial hypertension),” Milton Packer, MD, distinguished scholar in cardiovascular science at Baylor University Medical Center in Dallas, and colleagues wrote. “Such patients show improved exercise tolerance and symptoms and a reduced risk of disease progression. Given these benefits, physicians should distinguish [PAH] from pulmonary hypertension associated with chronic [HF] before prescribing endothelin receptor antagonists for long-term use.”
In a related editorial, Stephen S. Gottlieb, MD, professor of medicine at the University of Maryland School of Medicine in Baltimore, wrote: “Careful studies may lead us to illuminate specific beneficial effects of antagonizing a powerful prognostic factor, but for now we can be confident that [endothelin] antagonists should be avoided in patients with [HF].” – by Darlene Dobkowski
Disclosure: The study was funded by Actelion. Gottlieb and Packer report no relevant financial disclosures. Please see the full study for a list of the other researchers’ relevant financial disclosures.
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