BENEFiT study shows Tracleer (bosentan) improves haemodynamics in CTEPH patients refused surgery

BENEFiT study shows Tracleer (bosentan) improves haemodynamics in CTEPH patients refused surgery

Patients suffering from chronic thromboembolic pulmonary hypertension (CTEPH) who miss out on potentially curative surgery may respond to medical treatment with the dual endothelin receptor antagonist bosentan (Tracleer) according to results of BENEFiT, a multicentre phase III trial presented at this year’s American Thoracic Society meeting. To date there has been no approved medical therapy for the condition.

The 157-patient phase III BENEFiT study is the first prospective double-blind randomised placebo-controlled trial to evaluate a medical treatment for CTEPH patients who are either inoperable or who experience persistent pulmonary hypertension despite surgery. The condition occurs in almost 4 per cent of patients surviving a pulmonary embolus. Whilst most non-fatal emboli resolve completely, in CTEPH pulmonary vessels become progressively occluded with persistent, organised thrombotic material, explained Professor Lewis Rubin of University of California. Without surgery the obstruction can extend down through the arterial tree into deeper smaller vessels, becoming incorporated into the vessel walls, promoting vascular remodelling, raising pulmonary artery pressure, and causing pulmonary arterial hypertension (PAH). Eventually this leads to right-sided heart failure.

Discussing the study itself, Professor Gerald Simonneau, Head of Pneumology at Hospital Antoine Beclere, France, the centre leading the BENEFiT study, said the trial’s rationale for investigating the endothelin antagonist bosentan in CTEPH followed from its efficacy in treating PAH arising from other causes. Endothelin, a potent and long-lasting endogenous vasoconstrictor plays a pathogenic role in PAH. In CTEPH, plasma concentrations of endothelin are increased as are pulmonary endothelin receptors on vascular smooth muscle cells.

Results from BENEFiT which randomised patients to bosentan or placebo for 16 weeks showed a highly significant 24% improvement in pulmonary vascular resistance (PVR), one of the study’s primary endpoints, and in other haemodynamic measures including cardiac index for bosentan-treated patients. Treatment also significantly decreased the biomarker NT-pro-BNP (-622mg/L p=0.0034) and there was a trend to improvement in quality of life and time to clinical worsening.

Six-minute walk test not significant by 16 weeks

Improvement on another primary endpoint, the 6-minute walk test, had not reached significance by 16 weeks although patients saw a beneficial treatment effect on dyspnoea, he observed. Other open-label studies of bosentan suggest haemodynamic improvement translates into a significant functional benefit as measured by the 6-minute test after six months or longer.

Professor Rubin commented: “The haemodynamic improvement observed with bosentan in BENEFiT holds real significance for CTEPH patients who don’t receive surgery. There has been no alternative approved treatment to offer them.” Patients left untreated have a poor prognosis, he noted. Among patients with a pulmonary artery pressure (PAP) >40mm Hg, five year mortality is 70 per cent. This rises to 90 per cent where PAP exceeds 50 mm Hg..

“Surgery to remove the clot is the preferred option and is potentially curable,” he stressed. However, eligibility criteria vary from centre to centre. Whilst some centres are aggressive in tackling most cases surgically, others often refuse surgery because patients’ disease is concentrated in distal, difficult-to-access vessels or because they have co-morbidities thought to jeopardise outcomes. Currently up to half of patients or more are considered unsuitable candidates for surgery by some centres.

A large number of patients, who present with dyspnoea initially and have no past history of pulmonary embolus, may not be diagnosed until their disease has progressed to right heart failure. “They present with progressive shortness of breath on exertion but in the absence of a history of pulmonary embolus this is often ascribed to asthma or obesity,” he suggested. “It’s only after progressive deterioration, when right heart failure is suspected and they are finally sent for echocardiography, that CTEPH is considered as a diagnosis.”

Patients in the BENEFiT study are currently continuing therapy in an open-label extension phase. Actelion, the manufacturer of bosentan, may submit a new licensing application for the CTEPH indication later this year, a company spokesman said.

Olwen Glynn Owen