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ARTICLE

Combination Therapy with Oral Sildenafil and Inhaled Iloprost for Severe Pulmonary Hypertension

Hossein Ardeschir Ghofrani, MD; Ralph Wiedemann, MD; Frank Rose, MD; Horst Olschewski, MD; Ralph Theo Schermuly, PhD; Norbert Weissmann, PhD; Werner Seeger, MD; and Friedrich Grimminger, MD

2 April 2002 | Volume 136 Issue 7 | Pages 515-522

Background: Inhalation of the stable prostacyclin analogue iloprost is being studied for treatment of pulmonary hypertension. The selective phosphodiesterase-5 inhibitor sildenafil has been reported to cause pulmonary vasodilatation.

Objective: To evaluate the safety and effectiveness of oral sildenafil, alone and in combination with inhaled iloprost, for treatment of pulmonary hypertension.

Design: Randomized, controlled, open-label trial.

Setting: Intensive care unit.

Patients: 30 patients with severe pulmonary arterial hypertension (n = 16), chronic thromboembolic pulmonary hypertension (n = 13), or pulmonary hypertension due to aplasia of the left pulmonary artery (n = 1), all classified as New York Heart Association class III or IV.

Intervention: All patients received inhaled nitric oxide and aerosolized iloprost (inhaled dose, 2.8 µg). They were then randomly assigned to receive 12.5 mg of oral sildenafil, 50 mg of sildenafil, 12.5 mg of sildenafil plus inhaled iloprost, or 50 mg of sildenafil plus inhaled iloprost.

Measurements: Systemic and pulmonary arterial pressure, pulmonary arterial occlusion pressure, cardiac output, central venous pressure, peripheral arterial oxygen saturation, and arterial and mixed venous blood gases were measured during right-heart catheterization by using a Swan–Ganz catheter.

Results: In rank order of pulmonary vasodilatory potency (maximum reduction of pulmonary vascular resistance and increase in cardiac index), 50 mg of sildenafil plus iloprost was most effective, followed by 12.5 mg of sildenafil plus iloprost. Iloprost alone and 50 mg of sildenafil were almost equally effective but were less potent than the combination regimens, and the least potent treatments were 12.5 mg of sildenafil and nitric oxide. In patients who received 50 mg of sildenafil plus iloprost, the maximum change in pulmonary vasodilatory potency was –44.2% (95% CI, –49.5% to –38.8%), compared with –14.1% (CI, –19.1% to –9.2%) in response to nitric oxide. With administration of 50 mg of sildenafil plus iloprost, the area under the curve for reduction in pulmonary vasodilatory resistance surpassed that of administration of 50 mg of sildenafil alone and iloprost alone combined, the vasodilatory effect lasted longer than 3 hours, and systemic arterial pressure and arterial oxygenation were maintained. No serious adverse events occurred.

Conclusion: Although limited by the small sample and lack of long-term observations, the study shows that oral sildenafil is a potent pulmonary vasodilator that acts synergistically with inhaled iloprost to cause strong pulmonary vasodilatation in both severe pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.

Editors' Notes Context Common therapies for pulmonary hypertension have disadvantages: Continuous intravenous epoprostenol may cause sepsis, hypotension, and tachyphylaxis; nitric oxide requires continuous inhalation; and inhaled iloprost requires up to 12 doses per day. Phosphodiesterase in lung tissue (PDE-5) inhibits the action of these therapies by inactivating the second messengers of prostacyclin and nitric oxide (cyclic adenosine monophosphate and cyclic guanosine monophosphate). Because sildenafil blocks the action of PDE-5, thereby causing vascular dilatation, it could be useful in treating pulmonary hypertension. Contribution This randomized, controlled trial of low- or high-dose sildenafil, with or without inhaled iloprost, showed dose-dependent improvement in mean pulmonary artery pressure and hemodynamics with sildenafil alone. Iloprost amplified the effects. Implications Sildenafil may enhance the management of pulmonary hypertension. –The Editors

 

Author and Article Information

From University Hospital, Justus-Liebig-University, Giessen, Germany.

Acknowledgments: The authors thank Dr. R.L. Snipes for linguistic editing of the manuscript and George Afram for technical assistance.

Grant Support: By the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich 547).

Requests for Single Reprints: Hossein Ardeschir Ghofrani, MD, Department of Internal Medicine, University Hospital, Justus-Liebig-University, Klinikstrasse 36, 35392 Giessen, Germany; e-mail, ardeschir.ghofrani{at}innere.med.uni-giessen.de.

Current Author Addresses: Drs. Ghofrani, Wiedemann, Rose, Olschewski, Schermuly, Weissmann, Seeger, and Grimminger: Department of Internal Medicine, University Hospital, Justus-Liebig-University, Klinikstrasse 36, 35392 Giessen, Germany.

Author Contributions: Conception and design: H.A. Ghofrani, R. Wiedemann, H. Olschewski, W. Seeger, F. Grimminger.

Analysis and interpretation of the data: H.A. Ghofrani, R. Wiedemann, F. Rose, H. Olschewski, R.T. Schermuly, N. Weissmann, W. Seeger, F. Grimminger.

Drafting of the article: H.A. Ghofrani, H. Olschewski, W. Seeger, F. Grimminger.

Critical revision of the article for important intellectual content: H.A. Ghofrani, R. Wiedemann, F. Rose, H. Olschewski, R.T. Schermuly, N. Weissmann, W. Seeger, F. Grimminger.

Final approval of the article: H.A. Ghofrani, R. Wiedemann, F. Rose, H. Olschewski, R.T. Schermuly, N. Weissmann, W. Seeger, F. Grimminger.

Provision of study materials or patients: H.A. Ghofrani, R. Wiedemann, F. Rose, H. Olschewski, R.T. Schermuly, W. Seeger, F. Grimminger.

Statistical expertise: H.A. Ghofrani, H. Olschewski, N. Weissmann, W. Seeger,

Obtaining of funding: H.A. Ghofrani, W. Seeger, F. Grimminger.

Administrative, technical, or logistic support: H.A. Ghofrani, R. Wiedemann, F. Rose, H. Olschewski, R.T. Schermuly, N. Weissmann, W. Seeger, F. Grimminger.

Collection and assembly of data: H.A. Ghofrani, R. Wiedemann, F. Rose, R.T. Schermuly, W. Seeger, F. Grimminger.

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