© 2004 American Thoracic Society
Sildenafil in Pulmonary Arterial HypertensionTo the Editor:The recent editorial of Humbert and Simonneau (1) claimed an evolution of the therapy from vasodilators to antiproliferative agents; but in patients with pulmonary arterial hypertension (PAH) who belong to New York Heart Association (NYHA) Class I to II, the vasodilator challenge response remains the first step of the algorithm currently used for their management (2). Humbert and Simonneau (1) rightly pointed out strong expectations toward sildenafil therapy for PAH because of its double effect on pulmonary vasoconstriction and remodeling of distal pulmonary vasculature. In awaiting confirming clinical results on the effectiveness of sildenafil in PAH, other available therapies for PAH (Ca2+ channel blockers, epoprostenol, bosentan) have limited efficacy or are expensive and are associated with significant complications. So, in "the real world," the absence of definitive evidence-based data from randomized trials comparing different treatments makes the choice of therapy for individual patients complex and empirical, depending on the physician's experience, patient preferences, and costs (3). We were pushed to test sildenafil in a patient with primary PAH and NYHA Class II who demonstrated to be unresponsive to nifedipine and iloprost during an acute vasodilator challenge. The patient also had chronic virus B hepatitis and initially refused to take bosentan because of a possible increase of liver enzymes. Hemodynamic evaluation was made by a Swan-Ganz thermodilution catheter during oxygen supplementation via a Venturi mask (0.5 FIO2). The vasodilators were challenged every 1.5 hours and after hemodynamic variables returned to preintervention (4 µm inhaled iloprost, 10 mg sublingual nifedipine, 75 mg oral sildenafil). Only sildenafil obtained a significant reduction of mean pulmonary arterial pressure from 71.4 to 57 mm Hg (–20%) and pulmonary vascular resistance from 1,333 to 843 dynes/second per m2/cm5, whereas iloprost and nifedipine did not significantly affect mean pulmonary arterial pressure (64 and 70 mm Hg, respectively). Cardiac index was increased by sildenafil (from 2.7 to 3.7 L/min/m2), but not by iloprost (2.6 L/min/m2) and nifedipine (2.8 L/min/m2). Arterial oxygenation remained good either during oxygen supplementation alone or with the three vasodilators. On the basis of this acute challenge response, we gave to the patient 75 mg sildenafil orally twice daily. After 2 months of sildenafil therapy without adverse effects, the 6-minute walking test and the Borg dyspnea index improved compared with baseline (480 versus 260 mt; Borg score 7 versus 4). We suggest that sildenafil also could be tested during an acute vasodilator challenge for patients with PAH who are unresponsive to usual vasodilators to address an alternative patient-tailored treatment.
a Ospedali Riuniti di Trieste Trieste, Italy FOOTNOTES Conflict of Interest Statement: M.C., V.A., U.L., and A.G. do not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
From the Authors: We thank Dr. Confalonieri and colleagues for commenting our editorial on sildenafil in pulmonary arterial hypertension (1). Indeed, patients displaying pulmonary arterial hypertension with a better outcome can be identified by an acute vasodilator challenge performed during right heart catheterization (2–4). However, we disagree that vasodilator challenge should be restricted to the less severe patients, as there is no clinical predictor for acute vasodilator response (3). Currently, the drugs of choice for testing vasoreactivity are short-acting agents such as intravenous prostacyclin, intravenous adenosine, or inhaled nitric oxide (3). During vasodilator challenge, acute responders have a substantial reduction in mean pulmonary artery pressure (decrease exceeding 10 mm Hg to reach a mean pulmonary artery pressure less than 40 mm Hg) with a normal or high cardiac output (4). Acute responders respond favorably to chronic oral therapy with calcium channel blockers and have an excellent long-term prognosis and survival (2, 3). The occurrence of severe life-threatening hemodynamic compromise during acute vasodilator challenge with calcium channel blockers such as nifedipine in nonresponders is an important risk indicating that these agents should not be used as first-line vasodilators for acute testing (3). We are still waiting for well designed studies analyzing the meaning of acute testing with nebulized iloprost and oral sildenafil in the management of patients with pulmonary arterial hypertension. Short-term application of sildenafil during right heart catheterization may reduce pulmonary vascular resistance in a dose-dependent manner (5). In combination with inhaled iloprost, augmentation of the pulmonary vasodilatory effect of each single agent was noted (5). The meaning of this information remains unclear, and there is currently no information supporting the use of inhaled iloprost or oral sildenafil as a screening agent for patient-tailored treatment in pulmonary arterial hypertension. Several treatments of pulmonary arterial hypertension are now approved in North America (epoprostenol, treprostinil, bosentan) and Europe (epoprostenol, iloprost, bosentan). With the exception of recent data from patients receiving prolonged epoprostenol therapy, the long-term effects of novel treatments are still unknown (6). As head-to-head comparisons of currently approved therapies are not available and are unlikely to be performed, the choice of optimal treatment will be dictated by clinical experience and drug availability, as well as patient preference. We would like to highlight that only approved drugs should be used in the management of these severely compromised patients. Currently, we are still waiting for evidence regarding long-term sildenafil therapy in pulmonary arterial hypertension.
Hôpital Antoine-Béclère, Université Paris-Sud Clamart, France FOOTNOTES Conflict of Interest Statement: M.H. was supported by grants from Université Paris-Sud, INSERM, and AFM, and has also relationships with drug companies including Actelion, Aventis, Astrazeneca, GlaxoSmithKline, Myogen, Pfizer, Schering, and United Therapeutics. In addition to being investigators in trials involving these companies, relationships include consultancy services and membership of scientific advisory boards. None exceeded $10,000 per company per year in any one of the 3 years preceding submission of this letter. G.S. was supported by grants from Université Paris-Sud, INSERM, and AFM, and also has relationships with drug companies including Actelion, Aventis, Encysive, GlaxoSmithKline, Myogen, Sanofi-Synthélabo, Schering, Pfizer, and United Therapeutics. In addition to being investigators in trials involving these companies, relationships include consultancy services and membership of scientific advisory boards. None exceeded $10,000 per company per year in any one of the 3 years preceding submission of this letter. REFERENCES
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