Clamart, France - The medical treatment of inoperable chronic thromboembolic pulmonary hypertension (CTEPH) looks set to be confined to off-label therapy for the foreseeable future, because the only rigorously conducted trial of any drug in this specific indication has failed to show a clear benefit [1].

That trial—Bosentan Effects in Inoperable Forms of Chronic Thromboembolic Pulmonary Hypertension (BENEFIT)—conducted with the dual endothelin antagonist bosentan (Tracleer, Actelion Pharmaceuticals), produced mixed results, with a positive treatment effect of bosentan on hemodynamics but no improvement in exercise capacity. The BENEFIT results were first reported at the European Society of Cardiology (ESC) meeting in Vienna in 2007 and appear in the December 16, 2008 issue of the Journal of the American College of Cardiology, by Dr Xavier Jais (Antoine Beclere Hospital, Clamart, France) and colleagues.

Coauthor Dr Irene M Lang (Medical University of Vienna, Austria), told heartwire that the published results do not differ from those she presented at the ESC meeting, but she believes they could be sufficient for bosentan to be approved for CTEPH. However, the drug's manufacturer told heartwire it has no plans to pursue an approval for this indication.

CTEPH is a form of pulmonary hypertension (PH); PH affects more than 2.5 million people worldwide and is characterized by hypertension in the pulmonary artery, vein, or capillaries, leading to shortness of breath, dizziness, fainting, and other symptoms, all of which are worsened by exertion and can lead to markedly decreased exercise tolerance, heart failure, and death. The only approved therapies currently available are for a different form of PH, pulmonary arterial hypertension, which comprises only a small proportion of PH cases, so the majority of patients are without approved treatment.

Some people think there is a signal there and that [bosentan] should be approved for inoperable CTEPH because there is a bad need for medical treatments for this indication.

When the BENEFIT results were reported at the ESC meeting, the discussant, Dr Nazzareno Galie (University of Bologna, Italy), said this was the first time a randomized controlled study has shown favorable hemodynamic effects of a targeted therapy in this group of patients (inoperable CTEPH), but he noted the obvious discrepancy: a clear decrease in pulmonary vascular resistance was demonstrated, but there was no change in six-minute walking distance.

Lang told heartwire: "Some people think there is a signal there and that [bosentan] should be approved for inoperable CTEPH because there is a bad need for medical treatments for this indication. This is a chronic, very devastating disease that hits elderly people, and it's an important problem."

There are a couple of possible explanations for the discrepancies in BENEFIT, Galie said in Vienna. First, CTEPH patients are older and have more comorbidities than patients with PAH, in whom bosentan is already approved. In addition, the short duration of the study—just three months of follow-up—may have played a role, he said, explaining that improvements in exercise capacity can sometimes take as long as a year to manifest.

Lang takes this up, explaining to heartwire that there is to be a "statistical look" at the open-label phase of the BENEFIT trial, but that she does not yet know the results of this phase. She added that she was not sure whether Actelion Pharmaceuticals would file for approval of bosentan for inoperable CTEPH on the basis of BENEFIT, stating that this is a matter "of some debate."

However company spokesperson Roland Haefeli, vice president for investor relations and public affairs, told heartwire: "In terms of [inoperable] CTEPH, we currently have no plans for regulatory proceedings [with bosentan]."

Lang told heartwire that whether or not bosentan is actually approved for inoperable CTEPH, the drug would still be used for this indication. "I estimate that around 60% of patients with inoperable CTEPH are treated medically off-label, mainly with sildenafil and bosentan, which is a very bad situation," she said.

In many countries, sildenafil is the preferred option, she added, because it is available generically and therefore considerably cheaper than bosentan. Sildenafil, a phosphodiesterase inhibitor best known as the erectile-dysfunction therapy Viagra, is approved for PAH as Revatio (Pfizer). Lang added that there has never been an appropriately powered trial to assess sildenafil for the CTEPH indication, "but it appears to do something."

Another new drug is also being investigated for inoperable CTEPH as well as other forms of PH, she adds. Bayer's riociguat, a soluble guanylate cyclase stimulator, is about to begin two phase 3 trials: one in CTEPH and the other in PAH [2]. And phase 2 studies of riociguat are under way in patients suffering from other forms of PH.