{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T00:06:04Z","timestamp":1792368364486,"version":"4.4.0"},"reference-count":42,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"22","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2009,6,9]]},"abstract":"<jats:p>\n                    <jats:bold>\n                      <jats:italic>Background\u2014<\/jats:italic>\n                    <\/jats:bold>\n                    Treatment options for pulmonary arterial hypertension target the prostacyclin, endothelin, or nitric oxide pathways. Tadalafil, a phosphodiesterase type-5 inhibitor, increases cGMP, the final mediator in the nitric oxide pathway.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>\n                      <jats:italic>Methods and Results\u2014<\/jats:italic>\n                    <\/jats:bold>\n                    In this 16-week, double-blind, placebo-controlled study, 405 patients with pulmonary arterial hypertension (idiopathic or associated), either treatment-naive or on background therapy with the endothelin receptor antagonist bosentan, were randomized to placebo or tadalafil 2.5, 10, 20, or 40 mg orally once daily. The primary end point was the change from baseline to week 16 in the distance walked in 6 minutes. Changes in World Health Organization functional class, clinical worsening, and health-related quality of life were also assessed. Patients completing the 16-week study could enter a long-term extension study. Tadalafil increased the distance walked in 6 minutes in a dose-dependent manner; only the 40-mg dose met the prespecified level of statistical significance (\n                    <jats:italic>P<\/jats:italic>\n                    &lt;0.01). Overall, the mean placebo-corrected treatment effect was 33 m (95% confidence interval, 15 to 50 m). In the bosentan-naive group, the treatment effect was 44 m (95% confidence interval, 20 to 69 m) compared with 23 m (95% confidence interval, \u22122 to 48 m) in patients on background bosentan therapy. Tadalafil 40 mg improved the time to clinical worsening (\n                    <jats:italic>P<\/jats:italic>\n                    =0.041), incidence of clinical worsening (68% relative risk reduction;\n                    <jats:italic>P<\/jats:italic>\n                    =0.038), and health-related quality of life. The changes in World Health Organization functional class were not statistically significant. The most common treatment-related adverse events reported with tadalafil were headache, myalgia, and flushing.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>\n                      <jats:italic>Conclusions\u2014<\/jats:italic>\n                    <\/jats:bold>\n                    In patients with pulmonary arterial hypertension, tadalafil 40 mg was well tolerated and improved exercise capacity and quality of life measures and reduced clinical worsening.\n                  <\/jats:p>","DOI":"10.1161\/circulationaha.108.839274","type":"journal-article","created":{"date-parts":[[2009,5,26]],"date-time":"2009-05-26T22:24:15Z","timestamp":1243376655000},"page":"2894-2903","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":923,"title":["Tadalafil Therapy for Pulmonary Arterial Hypertension"],"prefix":"10.1161","volume":"119","author":[{"given":"Nazzareno","family":"Galie\u0300","sequence":"first","affiliation":[{"name":"From the Institute of Cardiology, Universita\u0300 di Bologna, Bologna, Italy (N.G.); Heart Institute of the Cascades, Bend, Ore (B.H.B.); University Hospital, Justus-Liebig University, Giessen, Germany (H.A.G.); Los Angeles Biomedical Research Institute at Harbor\u2013University of California at Los Angeles, Torrance, Calif (R.J.O.); Antoine Be\u0301cle\u0300re University Hospital, Clamart, France (G.S.); Division of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, Tex (Z.S.); Greater Los..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce H.","family":"Brundage","sequence":"additional","affiliation":[{"name":"From the Institute of Cardiology, Universita\u0300 di Bologna, Bologna, Italy (N.G.); Heart Institute of the Cascades, Bend, Ore (B.H.B.); University Hospital, Justus-Liebig University, Giessen, Germany (H.A.G.); Los Angeles Biomedical Research Institute at Harbor\u2013University of California at Los Angeles, Torrance, Calif (R.J.O.); Antoine Be\u0301cle\u0300re University Hospital, Clamart, France (G.S.); Division of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, Tex (Z.S.); Greater Los..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hossein A.","family":"Ghofrani","sequence":"additional","affiliation":[{"name":"From the Institute of Cardiology, Universita\u0300 di Bologna, Bologna, Italy (N.G.); Heart Institute of the Cascades, Bend, Ore (B.H.B.); University Hospital, Justus-Liebig University, Giessen, Germany (H.A.G.); Los Angeles Biomedical Research Institute at Harbor\u2013University of California at Los Angeles, Torrance, Calif (R.J.O.); Antoine Be\u0301cle\u0300re University Hospital, Clamart, France (G.S.); Division of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, Tex (Z.S.); Greater Los..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald J.","family":"Oudiz","sequence":"additional","affiliation":[{"name":"From the Institute of Cardiology, Universita\u0300 di Bologna, Bologna, Italy (N.G.); Heart Institute of the Cascades, Bend, Ore (B.H.B.); University Hospital, Justus-Liebig University, Giessen, Germany (H.A.G.); Los Angeles Biomedical Research Institute at Harbor\u2013University of California at Los Angeles, Torrance, Calif (R.J.O.); Antoine Be\u0301cle\u0300re University Hospital, Clamart, France (G.S.); Division of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, Tex (Z.S.); Greater Los..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald","family":"Simonneau","sequence":"additional","affiliation":[{"name":"From the Institute of Cardiology, Universita\u0300 di Bologna, Bologna, Italy (N.G.); Heart Institute of the Cascades, Bend, Ore (B.H.B.); University Hospital, Justus-Liebig University, Giessen, Germany (H.A.G.); Los Angeles Biomedical Research Institute at Harbor\u2013University of California at Los Angeles, Torrance, Calif (R.J.O.); Antoine Be\u0301cle\u0300re University Hospital, Clamart, France (G.S.); Division of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, Tex (Z.S.); Greater Los..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeenat","family":"Safdar","sequence":"additional","affiliation":[{"name":"From the Institute of Cardiology, Universita\u0300 di Bologna, Bologna, Italy (N.G.); Heart Institute of the Cascades, Bend, Ore (B.H.B.); University Hospital, Justus-Liebig University, Giessen, Germany (H.A.G.); Los Angeles Biomedical Research Institute at Harbor\u2013University of California at Los Angeles, Torrance, Calif (R.J.O.); Antoine Be\u0301cle\u0300re University Hospital, Clamart, France (G.S.); Division of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, Tex (Z.S.); Greater Los..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shelley","family":"Shapiro","sequence":"additional","affiliation":[{"name":"From the Institute of Cardiology, Universita\u0300 di Bologna, Bologna, Italy (N.G.); Heart Institute of the Cascades, Bend, Ore (B.H.B.); University Hospital, Justus-Liebig University, Giessen, Germany (H.A.G.); Los Angeles Biomedical Research Institute at Harbor\u2013University of California at Los Angeles, Torrance, Calif (R.J.O.); Antoine Be\u0301cle\u0300re University Hospital, Clamart, France (G.S.); Division of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, Tex (Z.S.); Greater Los..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. James","family":"White","sequence":"additional","affiliation":[{"name":"From the Institute of Cardiology, Universita\u0300 di Bologna, Bologna, Italy (N.G.); Heart Institute of the Cascades, Bend, Ore (B.H.B.); University Hospital, Justus-Liebig University, Giessen, Germany (H.A.G.); Los Angeles Biomedical Research Institute at Harbor\u2013University of California at Los Angeles, Torrance, Calif (R.J.O.); Antoine Be\u0301cle\u0300re University Hospital, Clamart, France (G.S.); Division of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, Tex (Z.S.); Greater Los..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Chan","sequence":"additional","affiliation":[{"name":"From the Institute of Cardiology, Universita\u0300 di Bologna, Bologna, Italy (N.G.); Heart Institute of the Cascades, Bend, Ore (B.H.B.); University Hospital, Justus-Liebig University, Giessen, Germany (H.A.G.); Los Angeles Biomedical Research Institute at Harbor\u2013University of California at Los Angeles, Torrance, Calif (R.J.O.); Antoine Be\u0301cle\u0300re University Hospital, Clamart, France (G.S.); Division of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, Tex (Z.S.); Greater Los..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Beardsworth","sequence":"additional","affiliation":[{"name":"From the Institute of Cardiology, Universita\u0300 di Bologna, Bologna, Italy (N.G.); Heart Institute of the Cascades, Bend, Ore (B.H.B.); University Hospital, Justus-Liebig University, Giessen, Germany (H.A.G.); Los Angeles Biomedical Research Institute at Harbor\u2013University of California at Los Angeles, Torrance, Calif (R.J.O.); Antoine Be\u0301cle\u0300re University Hospital, Clamart, France (G.S.); Division of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, Tex (Z.S.); Greater Los..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyn","family":"Frumkin","sequence":"additional","affiliation":[{"name":"From the Institute of Cardiology, Universita\u0300 di Bologna, Bologna, Italy (N.G.); Heart Institute of the Cascades, Bend, Ore (B.H.B.); University Hospital, Justus-Liebig University, Giessen, Germany (H.A.G.); Los Angeles Biomedical Research Institute at Harbor\u2013University of California at Los Angeles, Torrance, Calif (R.J.O.); Antoine Be\u0301cle\u0300re University Hospital, Clamart, France (G.S.); Division of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, Tex (Z.S.); Greater Los..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robyn J.","family":"Barst","sequence":"additional","affiliation":[{"name":"From the Institute of Cardiology, Universita\u0300 di Bologna, Bologna, Italy (N.G.); Heart Institute of the Cascades, Bend, Ore (B.H.B.); University Hospital, Justus-Liebig University, Giessen, Germany (H.A.G.); Los Angeles Biomedical Research Institute at Harbor\u2013University of California at Los Angeles, Torrance, Calif (R.J.O.); Antoine Be\u0301cle\u0300re University Hospital, Clamart, France (G.S.); Division of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, Tex (Z.S.); Greater Los..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199701093360207"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2003.06.020"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra035488"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2004.02.033"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2004.02.029"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra040291"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1378\/chest.06-2674"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.158.4.9802113"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199507273330403"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200411-1587OC"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2005.06.183"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00395-004-0504-5"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.0000016641.12984.dc"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2003.10.056"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa050010"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ahj.2005.09.006"},{"key":"e_1_3_2_17_2","unstructured":"Cialis (tadalafil) product label. 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