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Bosentan for Inoperable Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Postpulmonary Endarterectomy Pulmonary Hypertension: Presented at ESC

By Chris Berrie

VIENNA, AUSTRIA -- September 14, 2007 -- The dual endothelin receptor antagonist bosentan provides significantly improved haemodynamics and decreased pulmonary vascular resistance (PVR) in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) and with postpulmonary endarterectomy (PEA) pulmonary hypertension (PH), according to a study presented here at the European Society of Cardiology (ESC) Congress.

The findings from a predefined subgroup analysis of the multicentre, prospective, randomised, double-blind, placebo-controlled Bosentan Effects in Inoperable Forms of Chronic Thromboembolic Pulmonary Hypertension (BENEFIT) trial were presented on September 5th.

Iris Lang, MD, Steering Committee Member and Professor in Vascular Biology, Division of Cardiology, Department of Internal Medicine 2, Medical University, Vienna, Austria, explained that CTEPH is an extraordinary subset within PH, and appears as an obstruction due to build-up of material in the pulmonary arteries, according to the 'Venice' clinical classification of pulmonary hypertension (PH).

If CTEPH is treated surgically, "it makes the patient healthy and happy again, and this actually means, to cure the disease," Dr. Lang said.

However, PEA depends on CTEPH being operable with an acceptable operative risk, which is not always the case, she added. Problems can also arise from small vessel disease, mismatch between haemodynamics and extent of occlusions, or recurrent PH. It is estimated that CTEPH is inoperable in as many as 50% of cases.

As an endothelin receptor antagonist, bosentan has emerged as a potential pharmacological treatment in such inoperable cases. Its effect has been linked to the upregulation of endothelin receptors distal to the ligation in pulmonary arteries in animal models of CTEPH.

The aim of the main BENEFIT trial was to examine the efficacy of bosentan, as well as its safety and tolerability, in patients with inoperable CTEPH and persistent/recurrent PH post-PEA. The present predefined subgroup analysis compared the treatment effects between patients with inoperable CTEPH (n = 113) and those with persistent/recurrent PH (n = 44).

The main study design had an initial 3-week screening period, followed by patient randomisation (week 0) to either placebo or bosentan 62.5 mg BID. After 4 weeks, bosentan was uptitrated to 125 mg BID, and the trial was terminated at week 16.

The key result of the main BENEFIT trial was that bosentan provided clinically relevant improvements in cardiac haemodynamics -- decreased PVR, increased cardiac output, and decreased N-terminal proB-type natriuretic peptide (NT-proBNP). This was accompanied by no effects on exercise capacity and an improvement in the Borg dyspnoea index. In addition, bosentan was shown to be safe and well tolerated by patients, consistent with previous controlled trials.

In Dr. Lang's subgroup analysis, treatment effect (TE) was expressed as a percentage of baseline PVR at week 16.

Bosentan was seen to significantly reduce PVR both for inoperable CTEPH (TE, -17.5%; 95% confidence interval [CI], -27.0, -6.7) and for persistent/recurrent PH (TE, -32.5%; 95% CI, -44.4, -18.1).

Borg dyspnoea index also showed a significant improvement in CTEPH (TE, -0.8; 95% CI, -1.6, -0.1). This effect was not seen with persistent/recurrent PH (TE, +0.1; 95% CI, -0.9, +1.2).

In contrast, the change in the 6-minute walk was not significant in either the inoperable CTEPH group (TE, +8.8 m; 95% CI, -22.5, +40.0) or the persistent/recurrent PH group (TE, -11.5 m; 95% CI, -39.6, +16.6).

Similar significant effects were observed within each patient group for cardiac index, mean pulmonary arterial pressure, and NT-proBNP.

Dr. Lang concluded that bosentan provided improved haemodynamics, decreased PVR and had positive effects on cardiac index, mean pulmonary arterial pressure and NT-proBNP. Therefore, she said, "I would like to propose that this drug will be a therapeutic option for patients without further hope in the inoperable form."

Funding for this study was provided by Actelion Ltd.


[Presentation title: Bosentan for Inoperable Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Post-Pulmonary Endarterectomy Pulmonary Hypertension. Abstract 4505]

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