Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension - BENEFiT

Dec 15, 2008
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Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Actelion Pharmaceuticals Ltd.
Date Published:
01/01/2008
Date Updated:
12/15/2008
Original Posted Date:
12/15/2008
References

Description:

The goal of the trial was to evaluate the oral endothelin receptor antagonist bosentan in patients with chronic thromboembolic pulmonary hypertension (CTEPH).

Hypothesis:

Bosentan would be more effective in improving pulmonary hemodynamics and exercise capacity in patients with CTEPH.

Study Design

  • Placebo Controlled
  • Randomized
  • Blinded
  • Parallel

Patients Enrolled: 157
Mean Follow Up: 16 weeks
Mean Patient Age: 63 years
Female: 71%

Patient Populations:

  • Symptomatic patients (World Health Organization functional class II, III, or IV) with inoperable CTEPH or persistent pulmonary hypertension after pulmonary endarterectomy
  • Age 18-80 years
  • 6-minute walk distance <450 m
  • Mean pulmonary artery pressure ≥25 mm Hg
  • Pulmonary artery wedge pressure <15 mm Hg
  • Pulmonary vascular resistance ≥300 dyn·sec·cm-5
  • Anticoagulation therapy for at least 3 months

Exclusions:

  • Other cause for pulmonary hypertension such as HIV or sickle cell disease
  • Patients with severe obstructive or restrictive lung disease
  • Pulmonary endarterectomy or pulmonary embolism within 6 months of randomization

Primary Endpoints:

  • Change in pulmonary vascular resistance after 16 weeks of treatment
  • Change in 6-minute walk distance after 16 weeks of treatment

Secondary Endpoints:

  • Change from baseline in World Health Organization functional class
  • Change in cardiac index
  • Change in total pulmonary resistance
  • Change in mean right atrial pressure
  • Change in mean pulmonary arterial pressure
  • Change in mixed venous oxygen saturation at rest
  • Time to clinical worsening, defined as death, lung transplantation, or hospitalization related to pulmonary hypertension

Drug/Procedures Used:

Patients with inoperable CTEPH or persistent pulmonary hypertension after pulmonary endarterectomy were randomized to bosentan (n = 77) or placebo (n = 80). Patients received bosentan 62.5 mg twice daily for 4 weeks, which was then increased to 125 mg twice daily.

Concomitant Medications:

The concomitant use of ximelagatran, sirolimus, fluconazole, glyburide, and calcineurin inhibitors was forbidden. Calcium channel blockers were permitted if they were started at least 1 month prior to randomization.

Principal Findings:

Overall, 157 patients were randomized. The mean age was 63 years, 71% of participants were women, 29% had prior pulmonary endarterectomy, and the mean cardiac index was 2.2 L·min-1·m-2.

The co-primary endpoint, pulmonary vascular resistance, decreased 146 dyn·sec·cm-5 in the bosentan group and increased 30 dyn·sec·cm-5 in the placebo group (p < 0.0001 for comparison of mean change between groups). The 6-minute walk distance was increased 2.9 m in the bosentan group and 0.8 m in the placebo group (p = 0.54 for comparison of mean change between groups).

For secondary endpoints, functional class improved 14.5% vs. 11.3% (p = 0.63), and the proportion of patients that clinically worsened was 2.6% vs. 8.8% (p = 0.17), respectively, for bosentan vs. placebo.

There was no difference in serious adverse events; worsened right ventricular failure was 2.6% vs. 3.8% and pulmonary hypertension was 2.6% vs. 1.3%. For general adverse events: peripheral edema was 13.0% vs. 7.5%, abnormal liver test was 7.8% vs. 1.3%, headache was 6.5% vs. 1.3%, vertigo was 5.2% vs. 1.3%, and palpitations were 5.2% vs. 0%, respectively, for bosentan versus placebo.

Interpretation:

Among patients with inoperable CTEPH or persistent pulmonary hypertension after pulmonary endarterectomy, the use of bosentan for 16 weeks improved the mean change in pulmonary vascular resistance compared with placebo. The improvement in pulmonary vascular resistance did not translate into a beneficial effect on 6-minute walk distance. There were no important safety concerns; however, peripheral edema, abnormal liver tests, headache, vertigo, and palpitations were numerically higher in the bosentan group.

Inoperable CTEPH remains a difficult disease to treat. Further studies are needed to determine if the improvement in pulmonary vascular resistance with bosentan will translate into improved clinical outcomes.

References:

Jais X, D’Armini AM, Jansa P, et al., on behalf of the BENEFiT Study Group. Bosentan for treatment of inoperable chronic thromboembolic pulmonary hypertension: BENEFiT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension), a randomized, placebo-controlled trial. J Am Coll Cardiol 2008;52:2127-34.

Keywords: Endarterectomy, Pulmonary Wedge Pressure, Receptors, Endothelin, Pulmonary Embolism, Hypertension, Pulmonary, Edema, Vascular Resistance, Headache, Vertigo, Sulfonamides


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