Tadalafil for Pulmonary Arterial Hypertension
Abstract & Commentary
By Jonathan Abrams, MD, Professor of Medicine, Division of Cardiology, University of New Mexico. Dr. Abrams serves on the speaker's bureau for Merck, Pfizer, and Parke-Davis.
Source: Galie G, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 119:2894-2903.
Pulmonary arterial hypertension (PAH) is a dreaded multifactorial disease that is usually fatal. PAH can be a result of a number of conditions, including chronic thromboembolic hypertension, HIV, and congenital cardiac lessons, such as a large ASD with pulmonary shunting resulting in decreased nitric oxide (NO) expression. Treatment for the various causes of PAH has been problematic, as this disorder is usually lethal. Therapy has included prostanoids. In recent years, PDE-5 inhibitors, such as sildenafil, and, more recently, bosentan, an endothelin-receptor antagonists.
The PHIRST study examines the benefits of tadalafil, an oral PDE inhibitor, given once daily for 16 weeks in stable PAH subjects. Half of the 405 subjects were on placebo and half on one of five blinded treatment arms over a two-year period (2005 to 2007). Efficacy and tolerability of tadalafil or placebo over 16 weeks, with/without background bosentan therapy, was assessed. Patients with various causes of PAH were selected from 84 centers in the United States, Canada, Europe, and Japan. Patients were randomized to placebo, 0. 2.5, 10, 20, or 40 mg of tadalafil, and were stratified by baseline walking distance of < 325 meters or > 325 meters.
A long-term extension study was also included, utilizing 20 mg or 40 mg of tadalafil or placebo; 334 subjects entered this study. The primary endpoint was the placebo-corrected change from baseline to week 16 in patients who underwent a placebo-corrected, six-minute walk test. Secondary efficacy scores included functional class, worsening symptoms, death or lung transplant, dyspnea score, and WHO quality of life. Repeat walk test and Borg dyspnea score were measured at 4, 8, 12, and 16 weeks. Patients who had no significant change in functional class were censored at the completion of 16 weeks.
Results: At baseline, patients were well-balanced (mostly WHO class II-III), and most had idiopathic/heritable PAH.
Exercise capacity in the tadalafil subjects improved at all but the lowest dose (2.5mg). Tadalafil 40 mg was the only dose that was effective vs. placebo, reaching the prespecified level of significance. Functional class improvement occurred in patients on bosentan, but was better with tadalafil alone or both together (NS). Time to clinical worsening improved with tadalafil 40 mg; rehospitalization and worsening of WHO functional class were lower in this group. Borg dyspnea score was not different among the groups. QOL was better with tadalafil vs. placebo.
Right heart catheterization data on 93 patients demonstrated improvement with decreased right heart pressures and increased cardiac index. Improvement was greatest with 20 mg and 40 mg of tadalafil, with best results in naïve-treated patients.
All doses of tadalafil were generally well tolerated; headache and flushing were adverse events, which were generally mild. The extension study of at least 10 months duration showed a significant increase in six-minute walk time with tadalafil vs. placebo. Galie et al concluded that tadalafil 40 mg improved exercise capacity, decreased the incidence of clinical worsening, and improved functional status in PAH subjects, even if they were on bosentan.
Commentary
While little to no evidence suggests increased survival in PAH with tadalafil, the PHIRST trial and others utilizing intravenous PDE inhibitor therapy or inhaled prostacyclin delivery systems, have been in use for over five years. Improved six-minute walk test ability and a modest lowering of pulmonary artery pressure, indicate benefit with PDE-5 inhibitors such as sildenafil. This trial used tadalafil, an oral PDE inhibitor, and demonstrates a potentially positive role for long-term Tadalafil once-daily therapy.
It is well known that a diagnosis of PAH is very serious. Over the past few years, there has been considerable interest in lowering pulmonary arterial pressure with phosphodiesterase inhibitors. This surprising class of drugs is known to improve sexual dysfunction in men. The potent penile vasodilator effect of these agents has been widely utilized. Thus, enhanced nitric oxide availability, used in improving male sexual function, has been utilized effectively in approaches to PAH. Tadalafil, and presumably, as yet untested, PDE inhibitors, provide benefit in PAH. This study demonstrates the safety and efficacy of an oral treatment for patients with symptomatic PAH. The favorable efficacy profile of once-daily therapy offers a clinically meaningful addition to the currently approved treatment options.
The role of enhancing nitric oxide in PAH is yet another outcome of the remarkable discoveries of Robert Furchgott (recently deceased), Louis Ignarro, and others, relating to nitric oxide. An oral tablet taken once daily should be greatly beneficial to PAH subjects. PDE inhibitors have been tested and found to be safe in millions of men with erectile dysfunction. This study provides assurance that the rare PAH patient should be able to function better and longer, as documented in the PHIRST trial report. The FDA has recently approved Tadalafil for this use.
Pulmonary arterial hypertension (PAH) is a dreaded multifactorial disease that is usually fatal. PAH can be a result of a number of conditions, including chronic thromboembolic hypertension, HIV, and congenital cardiac lessons, such as a large ASD with pulmonary shunting resulting in decreased nitric oxide (NO) expression.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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