NEW YORK — As an increasing number of medical therapies become available for the treatment of pulmonary arterial hypertension and clinical experience accrues, questions have begun to arise as to how to initiate and optimize treatment, and how best to assess response, according to Dr. Harold I. Palevsky.

“There was a time when the treatment of pulmonary hypertension was very simple. All we had to decide was whether or not a patient was capable of managing intravenous prostacyclin,” Dr. Palevsky said at a meeting sponsored by the Pulmonary Hypertension Association and the University of Michigan.

Now clinicians can choose from six Food and Drug Administration-approved therapies from three therapeutic classes, in addition to supportive therapies such as supplemental oxygen, digoxin, diuretics, and anticoagulants.

The three available prostacyclin derivatives are intravenous epoprostenol, inhaled iloprost, and subcutaneous or intravenous treprostinil. The two approved endothelin receptor antagonists are oral bosentan and oral ambrisentan, and the phosphodiesterase type 5 inhibitor is oral sildenafil.

Initial therapy is based primarily on an assessment of the patient's current and future risk, said Dr. Palevsky, professor of medicine, University of Pennsylvania, and director, pulmonary vascular disease program, University of Pennsylvania Health System, Philadelphia. A global risk assessment for the individual patient includes evaluation of WHO (World Health Organization) functional class, 6-minute walk test, serum B type natriuretic peptide (BNP) level, and echocardiography of right heart function. In addition, catheterization measures of pulmonary and cardiac pressures and cardiac output must be considered.

Accordingly, a patient with PAH and mildly impaired functional status, a 400-m 6-minute walk test, minimally elevated BNP, normal right heart function, and normal or near normal cardiac index would be considered low risk and a likely candidate for oral therapy, Dr. Palevsky said.

In contrast, the patient in WHO class IV, with a 6-minute walk test distance of less than 300 m, elevated BNP, and significant right ventricular dysfunction may require a more complex regimen involving inhaled or infused therapy.

Once therapy is initiated, periodic assessments are needed to identify progress. The goals of therapy are to improve cardiac output, because that will lead to improvement in the patient's functional capacity and quality of life, and to decrease vascular resistance, which is the determinant of right ventricular performance, he said.

For patients who do not improve on monotherapy, an option increasingly being explored is combination therapy.

“A fundamental question today is what model we should use,” said Dr. Palevsky, who is also chief of pulmonary, allergy, and critical care at Penn Presbyterian Medical Center, Philadelphia.

“One model is the one used for systemic hypertension, where you give one therapy, assess the response, and if that's not doing what you want, add a second drug, and if that's not enough add a third drug. The alternative is a cancer chemotherapy model, where you give the patient the best therapy up front aiming for remission, and then down-titrate to maintenance therapy,” he said.

Preliminary data from a U.S. trial comparing inhaled iloprost plus oral bosentan with bosentan alone suggest that the current stepwise approach might be problematic, he said.

The multicenter, double-blinded trial randomized 67 adults with PAH to 12 weeks of treatment with the endothelin receptor antagonist alone or in combination with the inhaled prostacyclin derivative.

Although this was primarily a safety study, the trial found that the combination group had an improvement in the 6-minute walk by a placebo-corrected 26 m (Am. J. Respir. Crit. Care Med. 2006;174:1257–63).

Moreover, one-third of the patients who had the combination improved by one functional class, Dr. Palevsky said.

In the open-label extension phase of the trial, 60 patients received the combination and were followed for 12 months. “What was concerning about this was that after the patients previously receiving monotherapy began also receiving iloprost they didn't catch up, raising the question of whether we need to be more aggressive in early treatment,” he said.

A similar study undertaken in Europe showed contrasting results. A total of 40 patients were randomized to receive bosentan alone or in combination with iloprost for 12 weeks, but an interim analysis found that the primary end point, the 6-minute walk test, was not met, and the trial was terminated (Eur. Respir. J. 2006;28:691–4).

Several other studies are underway investigating other combinations and addressing other questions, such as whether patients with early PAH can benefit from treatment. Newer agents also are being evaluated. “Whether any of the alternatives under investigation will supplant our current therapies is not yet known, but it's our dream. I'd love to be able to see the CADD pump in the Smithsonian before I retire,” Dr. Palevsky said, referring to the continuous infusion pump used with epoprostenol.

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'I'd love to be able to see the CADD pump in the Smithsonian before I retire.' DR. PALEVSKY

Treatment of Pulmonary Arterial Hypertension Is Evolving