Inhaled Iloprost for Severe Pulmonary Hypertension
Horst Olschewski, M.D., Gerald Simonneau, M.D., Nazzareno Galiè, M.D., Timothy Higenbottam, M.D., Robert Naeije, M.D., Lewis J. Rubin, M.D., Sylvia Nikkho, M.D., Rudolf Speich, M.D., Marius M. Hoeper, M.D., Jürgen Behr, M.D., Jörg Winkler, M.D., Olivier Sitbon, M.D., Wladimir Popov, M.D., H. Ardeschir Ghofrani, M.D., Alessandra Manes, M.D., David G. Kiely, M.D., Ralph Ewert, M.D., Andreas Meyer, M.D., Paul A. Corris, F.R.C.P., Marion Delcroix, M.D., Miguel Gomez-Sanchez, M.D., Harald Siedentop, Dipl.Stat., Werner Seeger, M.D., for the Aerosolized Iloprost Randomized Study Group
Background Uncontrolled studies suggested that aerosolized iloprost,a stable analogue of prostacyclin, causes selective pulmonaryvasodilatation and improves hemodynamics and exercise capacityin patients with pulmonary hypertension.
Methods We compared repeated daily inhalations of 2.5 or 5.0µg of iloprost (six or nine times per day; median inhaleddose, 30 µg per day) with inhalation of placebo. A totalof 203 patients with selected forms of severe pulmonary arterialhypertension and chronic thromboembolic pulmonary hypertension(New York Heart Association [NYHA] functional class III or IV)were included. The primary end point was met if, after week12, the NYHA class and distance walked in six minutes were improvedby at least one class and at least 10 percent, respectively,in the absence of clinical deterioration according to predefinedcriteria and death.
Results The combined clinical end point was met by 16.8 percentof the patients receiving iloprost, as compared with 4.9 percentof the patients receiving placebo (P=0.007). There were increasesin the distance walked in six minutes of 36.4 m in the iloprostgroup as a whole (P=0.004) and of 58.8 m in the subgroup ofpatients with primary pulmonary hypertension. Overall, 4.0 percentof patients in the iloprost group (including one who died) and13.7 percent of those in the placebo group (including four whodied) did not complete the study (P=0.024); the most commonreason for withdrawal was clinical deterioration. As comparedwith base-line values, hemodynamic values were significantlyimproved at 12 weeks when measured after iloprost inhalation(P<0.001), were largely unchanged when measured before iloprostinhalation, and were significantly worse in the placebo group.Further significant beneficial effects of iloprost treatmentincluded an improvement in the NYHA class (P=0.03), dyspnea(P=0.015), and quality of life (P=0.026). Syncope occurred withsimilar frequency in the two groups but was more frequentlyrated as serious in the iloprost group, although this adverseeffect was not associated with clinical deterioration.
Conclusions Inhaled iloprost is an effective therapy for patientswith severe pulmonary hypertension.
Source Information
From the Department of Internal Medicine II, University Clinic, Giessen, Germany (H.O., H.A.G., W.S.); Service de Pneumologie, Hôpital Antoine Béclère, Clamart, France (G.S., O.S.); Istituto di Cardiologia, Università di Bologna, Bologna, Italy (N.G., A.M.); Royal Hallamshire Hospital, Sheffield, United Kingdom (T.H., D.G.K.); Department of Cardiology, Erasme University Hospital, Brussels, Belgium (R.N.); University of California at San Diego Medical Center, La Jolla (L.J.R.); Schering, Berlin, Germany (S.N., H.S.); Department of Internal Medicine, University Hospital, Zurich, Switzerland (R.S., W.P.); Department of Pneumology, Hannover Medical School, Hannover, Germany (M.M.H.); the Division of Pulmonary Diseases, University of MunichGroßhadern, Munich, Germany (J.B.); Department of Pneumology, University Clinic, Leipzig, Germany (J.W.); Department of Pneumology and Infectious Diseases, Ernst Moritz Arndt University, Greisswald, Germany (R.E.); Bereich Pneumologie, Medizinische Kernklinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany (A.M.); Freeman Hospital, High Heaton, Newcastle-upon-Tyne, United Kingdom (P.A.C.); Department of Pneumology, Gasthuisberg University Clinic, Leuven, Belgium (M.D.); and Pulmonary Hypertension Unit, Hospital 12 de Octubre, Madrid (M.G.-S.).
Address reprint requests to Dr. Seeger at the Department of Internal Medicine II, University Clinic, Klinikstr. 36, D-35392 Giessen, Germany, or at werner.seeger{at}innere.med.uni-giessen.de.
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