New agents may permit tailored therapy in PAH

PULMONARY HYPERTENSION

Montreal—New therapies for the treatment of pulmonary arterial hypertension (PAH) will allow clinicians to tailor therapy to the patient whose condition is not optimized with existing monotherapy, as well as the patient with newly diagnosed PAH, said presenters at CHEST, the 71st annual meeting of the American College of Chest Physicians.

Several pathogenetic mechanisms contribute to the development and progression of PAH. These include under- expression of vasodilating, antiproliferative substances, such as prostacyclin and nitric oxide, and overexpression of vasoconstricting, proproliferative substances, such as endothelin-1.

One method to attack these multiple targets is combination therapy. Current guidelines for the treatment of PAH do not address combination therapy because no studies had been published at the time the guidelines were written, said Richard N. Channick, MD, associate professor of medicine, University of California, San Diego.

“Adding inhaled iloprost (Ventavis) to bosentan (Tracleer) is a common practice in the US,” he said. “A recent [Food and Drug Administration] FDA labeling change allows combination therapy with inhaled iloprost.” Inhaled iloprost is a prostacyclin that was approved by the FDA in December 2004.

In a double-blind, randomized study, 65 patients with PAH who were being treated with bosentan monotherapy were randomly assigned to combination therapy or continued monotherapy. Patients had New York Heart Association (NYHA) functional class III or IV heart failure and had to be on a stable dose of bosentan for at least 16 weeks to be eligible. They were assigned to iloprost,

5 mg (titrated down to 2.5 mg if not tolerated), or placebo added to bosentan. Compliance with scheduled doses was more than 90% in each arm, with most patients taking six inhalations per day.

At week 12, 6-minute walk distance improved by 30 m in patients assigned to iloprost (P = .001 compared with baseline) and by 4 m in the patients assigned to placebo, reported Vallerie McLaughlin, MD, lead investigator of the study, and director of the pulmonary hypertension program at the University of Michigan, Ann Arbor. The improvement in 6-minute walk distance in the iloprost group relative to the placebo group was of marginal significance (P = .051). Furthermore, 34% of the iloprost recipients improved by at least one functional class compared with only 6% of placebo recipients (P = .002).

None of the iloprost patients experienced clinical worsening compared with 15% of the placebo group (P = .02). Clinical deterioration was defined as any one of the following: death owing to worsening PAH, receipt of lung transplant or atrial septostomy, hospitalization for worsening PAH, or any early discontinuation of the study drug owing to worsening PAH.

Headache and cough occurred significantly more often in the iloprost recipients, which is consistent with previous studies of iloprost.

According to Dr. McLaughlin, combination therapy may be considered for patients who remain in functional class III or IV despite bosentan monotherapy.

A potential alternative to bosentan is sitaxsentan (Thelin), a highly selective endothelin-A (ET-A) receptor antagonist that is currently under review by the FDA. “Sitaxsentan is 6,500 times more selective for the ET-A receptor than bosentan,” said David Langleben, MD, professor of medicine, McGill University, Montreal.

A total of 424 PAH patients with NYHA class II to IV heart failure were randomly assigned in two studies to receive placebo or 50, 100, or 300 mg of sitaxsentan once daily for 12 or 18 weeks. Overall, patients taking the 100-mg dose (n = 115) had significantly greater time to clinical worsening (P = .0345) than those taking placebo (n = 119). In addition, a 55-week extension study showed that 65% of the subset of patients with PAH owing to connective tissue disease showed improvement in functional heart failure class.

Interim results of a 1-year, phase 3 extension study randomizing 145 patients to 100 mg sitaxsentan once daily or 125 mg bosentan twice daily showed significantly fewer liver function ab-

normalities in the sitaxsentan group

(P = .014).