Original Articles EFFICACY AND SAFETY OF TADALAFIL FOR THE TREATMENT OF ERECTILE DYSFUNCTION: RESULTS OF INTEGRATED ANALYSES GERALD B. BROCK,* , † CHRIS G. MCMAHON,‡ K.K. CHEN,§ TIMOTHY COSTIGAN,§ WEI SHEN,§ VISH WATKINS,§ GREG ANGLIN§ AND STEVE WHITAKER From the Department of Surgery, Division of Urology, Faculty of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada, the Australian Centre for Sexual Health, St. Luke’s Hospital Complex, Sydney, New South Wales, Australia, Taipei Veterans General Hospital, Taipei, Taiwan, Eli Lilly and Company, Indianapolis, Indiana, and ICOS Corporation, Bothell, Washington ABSTRACT Purpose: We conducted integrated analyses of the efficacy and safety of tadalafil, a potent, selective phosphodiesterase 5 inhibitor, for the treatment of erectile dysfunction. Materials and Methods: A total of 1,112 men with a mean age of 59 years (range 22 to 82) and mild to severe erectile dysfunction of various etiologies were randomized to placebo or tadalafil, taken as needed without food or alcohol restrictions, at fixed daily doses of 2.5 mg., 5 mg., 10 mg., or 20 mg. in 5 randomized, double-blind, placebo controlled trials lasting 12 weeks. The 3 co-primary outcomes were changes from baseline in the erectile function domain of the International Index of Erectile Function and the proportion of “yes” responses to questions 2 and 3 of the Sexual Encounter Profile. Additional efficacy instruments included a Global Assessment Question. Results: Compared with placebo, tadalafil significantly enhanced all efficacy outcomes. Pa- tients receiving 20 mg. tadalafil experienced a significant mean improvement of 7.9 in Interna- tional Index of Erectile Function erectile function domain score from baseline (p 0.001 versus placebo), 75% of intercourse attempts (Sexual Encounter Profile question 3, a secondary efficacy outcome) were successfully completed (p 0.001 versus placebo) and 81% reported improved erections at end point compared with 35% in the control group (p 0.001). Tadalafil was consistently efficacious across disease severities and etiologies, as well as in patients of all ages. Tadalafil was well tolerated, and headache and dyspepsia were the most frequent adverse events. Conclusions: Tadalafil was effective and well tolerated in this patient population. KEY WORDS: penis, penile erection; impotence, drug therapy Approximately 150 million men worldwide are unable to achieve and maintain an erection adequate for satisfactory sexual performance. 1 Consistent with increasing life expect- ancies and the age related nature of erectile dysfunction, 2 this population is projected to more than double in the next 25 years. 1 In an epidemiological review focusing on the United States the prevalence of erectile dysfunction has been estimated to be as high as 30 million cases. 3 The introduction of sildenafil, a phosphodiesterase type 5 inhibitor, transformed the clinical landscape of erectile dys- function, empowering many men to seek treatment. 4, 5 Phos- phodiesterase type 5 inhibitors slow metabolism of 3',5'- cyclic guanosine monophosphate, a second messenger for the smooth muscle relaxing effects of nitric oxide. 6, 7 With sexual stimulation, endothelial cells and nonadrenergic, noncholin- ergic neurons release nitric oxide, which facilitates relax- ation of trabecular erectile tissues and dilatation of the he- licine artery of the penis through stimulation of cyclic guanosine monophosphate synthesis. 3, 8 The resultant in- crease in flow causes the engorgement of the sinusoidal spaces of the corpora cavernosa with blood. This engorge- ment causes the tunica albuginea to compress the subtunical venules that drain the corpora and diminish venous outflow from the penis. The penile blood pressure consequently in- creases, resulting in a physiological erection. 3 Tadalafil, a potent selective phosphodiesterase type 5 in- hibitor, is in development as an oral treatment for erectile dysfunction. 9 We evaluated its efficacy and safety with inte- grated analyses of findings from 5 randomized, double-blind placebo controlled trials involving men with erectile dysfunc- tion of varying severities and etiologies (table 1). MATERIALS AND METHODS Study design. Five randomized, double-blind, placebo con- trolled, parallel group trials were conducted at 74 centers from April 1999 to April 2001. Following a screening visit Accepted for publication April 26, 2002. Supported by Lilly ICOS LLC. * Requests for reprints: Division of Urology, Faculty of Medicine and Dentistry, University of Western Ontario, 1151 Richmond St., London, Ontario, Canada N6A 5B8. † Financial interest and/or other relationship with Lilly-ICOS, Pfizer, Bayer and Tap. ‡ Financial interest and/or other relationship with Lilly/ICOS. § Financial interest and/or other relationship with Eli Lilly and Company.  Financial interest and/or other relationship with ICOS Corporation. Editor’s Note: This article is the first of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the ques- tions on pages 1546 and 1547. 0022-5347/02/1684-1332/0 Vol. 168, 1332–1336, October 2002 THE JOURNAL OF UROLOGY ® Printed in U.S.A. Copyright © 2002 by AMERICAN UROLOGICAL ASSOCIATION,INC. ® DOI: 10.1097/01.ju.0000028041.27703.da 1332