Comparison of the Efficacy and Safety of Sildenafil Citrate (Viagra®) And

Home , Sildenafil

Comparison of the efﬁcacy and safety of sildenaﬁl citrate (Viagra1) and oral phentolamine for the treatment of erectile dysfunction

F Ugarte1* and A Hurtado-Coll2 for the Sildenaﬁl Study Group

1Hospital Angeles del Pedegral, Consultorio 827, Mexico, DF; and 2Centro Medico Nacional 20 de Noviembre, ISSSTE, Mexico DF

This open-label, multi-center study from Mexico compared the efficacy and safety of oral sildenafil and phentolamine in men with erectile dysfunction. Patients received sildenafil (25 – 100 mg; n ¼ 123) or phentolamine (40 mg; n ¼ 119) for 8 weeks, and efficacy was assessed using the International Index of Erectile Function (IIEF) as well as two global efficacy questions. Mean scores for the erectile function domain of the IIEF were significantly higher for sildenafil (27.23 0.62; P ¼ 0.0001) than for phentolamine (19.35 0.66). Approximately twice as many men receiving sildenafil had successful attempts at sexual intercourse (88% vs 42%), improved erections (95% vs 51.1%), and improved ability to have sexual intercourse (94.4% vs 46.4%) compared with phentolamine. The most common adverse events included rhinitis, headache, tachycardia, and nausea, with a higher frequency reported in patients receiving phentolamine than sildenafil (41% vs 33%), with the exception of headache, which was reported more frequently in sildenafil users. Overall, sildenafil was more effective and appeared to be better tolerated than phentolamine for the treatment of erectile dysfunction. International Journal of Impotence Research (2002) 14, Suppl 2, S48–S53. doi:10.1038=sj.ijir.3900898

Keywords: sildenaﬁl; phentolamine; erectile dysfunction; Hispanic

Introduction directly antagonizing a-adrenergic agonists at the receptor level, thereby reducing intracellular cal-

1 cium release and inhibiting contractility; and (2) by Sildenafil citrate (Viagra ) is a potent and selective indirectly enhancing nitric oxide synthase activity, inhibitor of cGMP-dependent phosphodiesterase 5, thereby increasing cGMP levels and promoting which is the predominant phosphodiesterase of relaxation. Both mechanisms contribute to its relax- 1 human corpus cavernosum. It thus enhances ing effect on corpus cavernosum erectile tissue and relaxation of the penile corpus cavernosum induced facilitation of erection.11,12 Because of inherent by nitric oxide-mediated neurotransmission and problems with self-injection, there has recently been 2 improves penile erectile function. Sildenafil is the renewed interest in an oral administration of first orally active therapy for erectile dysfunction phentolamine. The first demonstration of the effec- 3 (ED) of varying etiologies. After more than 11 000 tiveness of oral phentolamine for the treatment of patient-years of observation in clinical trials, silde- ED was in 1988, when a placebo-controlled cross- nafil has been shown to be effective and well over study showed that eight of 16 men responded tolerated in patients with a wide range of comorbid- to phentolamine 50 mg and not to placebo.13 Since ities, including diabetes, stable cardiovascular dis- that time, another small study in which patients ease, treated prostate cancer, spinal cord injury, were initially screened for their ability to tolerate end-stage renal disease, minor depression, multiple the hypotensive effects of phentolamine showed 4–9 sclerosis, and Parkinson’s disease. that oral doses of 20 – 60 mg were effective but in Phentolamine has been used since 1984 for the less than half of the men who received the drug.14 10 intracavernosal treatment of ED. It is believed to Although not formally reported, preliminary results elicit smooth muscle relaxation in the corpus of phase III clinical studies conducted in more than cavernosum by a dual mechanism of action: (1) by 3800 patients suggest improved erectile function in 53% and 63% of men taking oral phentolamine 40 mg and 80 mg, respectively, compared with 28% *Correspondence: F Ugarte, Hospital Angeles del Pedegral, 12 Periferico Sur No. 3697, Torre Angeles Consultorio 827, taking placebo. At the time of this writing, oral Col. Heroes de Padierna, Codigo Postal 10700 Mexico DF. phentolamine is approved for the treatment of ED E-mail: [email protected] only in Mexico and Brazil. Comparison of the efficacy and safety of sildenafil with phentolamine E Ugarte and A Hurtado-Coll S49 This study was conducted to compare the efficacy hypersensitivity or previous intolerance to sildenafil, and safety of sildenafil citrate and phentolamine phentolamine, or other components of the tablets as mesylate in men with ED of organic, psychogenic, or well as those currently taking contraindicated medi- mixed etiology. cations (nitrates or nitric oxide donors for sildenafil and alpha blockers for phentolamine) were ineligible for the study. Materials and methods After the 4-week run-in period, during which baseline data on sexual function were collected, patients were randomized to receive sildenafil or This was an open-label, randomized, multicenter, phentolamine for 8 weeks on an outpatient basis. parallel-group study conducted between 8 January Patients were to take one tablet approximately 30 min 1999, and 22 June 1999, at 17 centers in Mexico in (phentolamine) or 1 h (sildenafil) before anticipated compliance with ethical committee and informed sexual activity but were not to take more than one consent regulations. The study was conducted over tablet daily. Patients receiving sildenafil were started a 12-week period and consisted of a 4-week at a dose of 50 mg. At the investigator’s discretion, no-treatment run-in period followed by an 8-week this could be increased to 100 mg if ED was not open-label treatment period. sufficiently improved, provided the 50-mg dose had Eligible patients were 18 y or older, had at least a 6- been well tolerated. Dose reductions were allowed if month history of ED, and were in a stable sexual patients experienced intolerable adverse effects. For relationship with a female partner. They had mild to patients receiving 50 mg, the dose could be reduced moderate ED as determined by investigator rating of to 25 mg; for patients receiving 100 mg, the dose the erectile function domain of the International could be reduced to 50 mg. Patients randomized to Index of Erectile Function (IIEF) questionnaire phentolamine received a dose of 40 mg with no (questions 1 – 5 and 15) (Q1 – Q5, Q15).15 These adjustment in dose. questions assessed the ability to get an erection Efficacy was assessed on the basis of patient (Q1), the frequency of erections that were hard responses to the IIEF questionnaire, which was enough for penetration (Q2), the frequency of pene- administered at baseline and at the end of the 8- tration (Q3), the frequency of maintained erection week treatment period (or at the time of disconti- (Q4), the chance of maintaining erection until nuation for subjects who discontinued early). The completion (Q5), and the self-confidence to get and primary efficacy measure was the erectile function maintain an erection (Q15). Each was scored on a domain (Q1 – Q5, Q15) of the IIEF, rated as pre- scale of 1 – 5, with 1 representing the worst response viously described. Other domains, including orgas- and 5 the best. A score between 11 and 25 was mic function (frequency of ejaculation and orgasm= required for study entry. The investigators classified climax; Q9 and Q10), sexual desire (frequency of the etiology of ED as organic, psychogenic, or mixed, feelings and rating of sexual desire; Q11 and Q12), based on medical history and physical examination. intercourse satisfaction (attempts at and satisfaction Patients were to be otherwise healthy (determined by and enjoyment of sexual intercourse; Q6 – Q8), and clinical laboratory tests and physical examination overall satisfaction (with sex life and sexual rela- performed at screening) and free of clinically tionship with partner; Q13 and Q14), and individual significant diseases, psychological conditions, or questions of the IIEF were also analyzed. Responses social circumstances that would impair their ability ranged from 1 (almost never=never or very low) to 5 to participate in the study or put themselves or others (almost always=always or very high), with a score of at risk by participating. They were also to be free of 0 indicating no attempt at sexual intercourse. During any other factors that could interfere with the the entire 12-week study period, patients also evaluation of the study results or affect patient safety. completed an event log each time they engaged in Such factors included genital anatomic deformities sexual activity and=or took study medication. The that impair erection, ED due to another primary event log recorded whether or not study medication sexual disorder, history of spinal cord injury or was taken, whether or not sexual intercourse was radical prostatectomy, marked liver function abnorm- successful, whether the erection was hard enough or alities, history of gastroduodenal ulceration, or lasted long enough to complete the sexual activity, known history of retinitis pigmentosa. Patients were and the latency between dosing and successful not to have used any investigational drugs within 6 sexual intercourse. At the end of the 8-week weeks of study entry and were not to be taking treatment period, patients also responded ‘yes’ or medications causally associated with ED unless these ‘no’ to two global efficacy assessment questions, were prescribed more than 2 weeks before entry and which asked whether they experienced an improve- dose adjustments were not anticipated during the ment in the quality of their erection and in their study. Patients were required to discontinue all other overall sexual ability. therapies for ED for the duration of the study and were Safety was assessed by changes in vital signs and not to donate blood or blood products during the adverse events that occurred during treatment and study and 1 month thereafter. Patients with known up to 7 days after the last dose of study medication.

International Journal of Impotence Research Comparison of the efficacy and safety of sildenafil with phentolamine E Ugarte and A Hurtado-Coll S50 The treatment groups were checked for similarity were 16.0 6.7 (n ¼ 123) and 10.7 6.6 (n ¼ 119) for with respect to demographic and event log variables sildenafil and phentolamine, respectively. using descriptive statistics. Intention-to-treat ana- Baseline mean scores for the erectile function lyses were performed on all efficacy variables and domain of the IIEF were similar for patients included all patients with at least one assessment randomized to sildenafil or phentolamine (16.26 vs after baseline and who had taken at least one dose of 15.36, respectively). After treatment with sildenafil, study medication; safety analyses were based on all the least squares mean score for this domain was patients who took at least one dose of study 27.23 (maximum, 30), which was statistically sig- medication. The primary efficacy variable (erectile nificantly (P < 0.0001) greater than the score of 19.35 function domain score) as well as other domain after treatment with phentolamine (Table 2). Like- scores and responses to individual questions of the wise, baseline mean scores for orgasmic function IIEF were analyzed using analysis of covariance, (6.57 vs 6.00), sexual desire (6.81 vs 6.78), inter- including terms for treatment, center, and baseline course satisfaction (8.21 vs 7.85), and overall satis- value of the efficacy variables. Responses to the faction (4.82 vs 4.59) were similar for the two groups global efficacy assessment questions and the propor- but were statistically significantly (P < 0.0001) tion of successful intercourse events derived from higher after treatment with sildenafil than after the event logs were analyzed for a difference treatment with phentolamine (Table 2). Scores for between the treatment groups using logistic regres- each individual question of the IIEF were also sion. The Cochran-Mantel-Haenszel statistic was statistically significantly (P < 0.0001) higher for used to analyze differences between treatments in patients receiving sildenafil, ranging between 3.89 the latency between dosing and successful inter- and 4.70 (maximum, 5) compared with 2.73 and course. Covariates modeled in all analyses included 3.98 for patients receiving phentolamine. age, duration of disease, history of smoking, and Data from the event log of erectile function etiology of disease. All tests of hypotheses were indicated that the mean number of successful performed at the 5% significance level using two- attempts at sexual intercourse per week was 3.11 sided tests of significance. in the sildenafil group. This was significantly higher than the 1.17 successful attempts per week in the phentolamine group (P ¼ 0.0001). The per cent of successful attempts at sexual intercourse is shown in Figure 1, along with the per cent of at least one Results successful attempt at sexual intercourse and the per cent of men responding ‘yes’ to the global efficacy assessment questions, which indicated improved A total of 249 patients were screened. Of these, 242 erections and overall sexual ability. Significantly were randomized (123 to sildenafil and 119 to more men receiving sildenafil than placebo had at phentolamine) and took at least one dose of study least one successful attempt at intercourse (94.8% medication. Treatment groups were similar with vs 65.2%), improved erections (95.1% vs 51.1%) regard to demographic characteristics and etiology and improved sexual ability (94.4% vs 46.4%; of ED, with patients ranging in age from 25 to 80 y P ¼ 0.0001) (Figure 1). and duration of ED ranging from 6 months to 34 y; most patients had ED of mixed etiology (Table 1). At ¼ the end of the study, the majority of patients (n 67) Table 2 Least squares mean scores ( s.d.) for individual in the sildenafil group were taking the 50-mg dose; domains of the International Index of Erectile Function only two were taking 25 mg, and the others (n ¼ 51) were taking 100 mg. All patients in the phentola- International Sildenafil Phentolamine Index of Erectile 25 – 100 mg 40 mg mine group received 40-mg doses throughout the Function Domaina (n ¼ 120) (n ¼ 110) study. The median number of doses taken per month Erectile function 27.23 0.62 19.35 0.66b (Q1 – Q5, Q15) b Table 1 Characteristics of the study groups Orgasmic function 9.25 0.21 7.52 0.23 (Q9, Q10) b Sildenafil Phentolamine Sexual desire 7.98 0.13 7.04 0.14 (n ¼ 123) (n ¼ 119) (Q11, Q12) Intercourse satisfaction 13.70 0.26 10.33 0.27b Mean age, y (range) 53.6 (25 – 75) 55.2 (28 – 80) (Q6 – Q8) Mean weight, kg (range) 79.9 (43 – 115) 77.1 (51 – 155) Overall satisfaction 8.49 0.19 5.72 0.20b Mean time since 3.4 (0.5 – 34.0) 3.1 (0.5 – 25.1) (Q13, Q14) ED diagnosis, y (range) a ED etiology, n (%) Each question of the International Index of Erectile Function was Mixed 62 (50.4) 61 (51.3) scored on a scale of 0 (or 1) to 5; maximum score was 30 for Organic 42 (34.1) 41 (34.5) erectile function, 15 for intercourse satisfaction, and 10 for Psychogenic 19 (15.4) 17 (14.3) orgasmic function, sexual desire, and overall satisfaction. bStatistically significantly lower (P < 0.0001) than sildenafil.

International Journal of Impotence Research Comparison of the efficacy and safety of sildenafil with phentolamine E Ugarte and A Hurtado-Coll S51 serious adverse events, none of which were considered related to study drug; two were in patients receiving phentolamine (cerebrovascular accident, worsening of existing pterygium) and one in a patient receiving sildenafil (ruptured Achilles tendon). There were no significant changes in vital signs during the study.

Discussion

This study was designed to reflect clinical practice, with patients taking study medication according to the instructions in the respective package inserts for the drugs. Those randomized to sildenafil were started at a dose of 50 mg with allowance for increases (to 100 mg) or decreases (to 25 mg) in dose depending on efficacy and tolerability. Those randomized to phentolamine were given a fixed dose of 40 mg. Both drugs were given as required for 8 Figure 1 Per cent of patients with successful attempts at sexual intercourse and at least one successful attempt at sexual weeks. Under these conditions, the overall results of intercourse (derived from the event log of sexual function) and this open-label, parallel-group study indicate that per cent of patients reporting improved erections and improved oral sildenafil is better tolerated and more effective sexual ability (derived from the global efficacy assessment than oral phentolamine in the treatment of ED in questions) after treatment with sildenafil (25 – 100 mg) or phento- men with disease of psychogenic, organic, or mixed lamine (40 mg). etiology. The erectile function domain of the IIEF (the primary efficacy variable) was more improved by 8 A total of 29 patients discontinued from the weeks of treatment with sildenafil compared with study, nine for reasons unrelated to the study drug. phentolamine. Indeed, the erectile function score Of the 20 discontinuations related to study drug, 19 approached the maximum score of 30 after treat- were from the phentolamine group: 15 discontinued ment with sildenafil (27.23) and was significantly due to lack of efficacy, three due to adverse events higher than the score after treatment with phento- (dyspnea and tachycardia, epistaxis, cephalea), and lamine (19.35) (P < 0.0001). Consistent with this one due to a serious adverse event (flushing, chest result, nearly twice as many men receiving silde- pain, shortness of breath, and tachycardia). The nafil than phentolamine reported improved erec- other treatment-related discontinuation was due to tions (95.1% vs 51.1%, respectively) (P ¼ 0.0001). adverse events (dizziness and tachycardia) in a The results with phentolamine are generally com- patient receiving sildenafil. parable with rates of improved erections reported Overall, adverse events were experienced by 49 in other studies, ranging from 20% to 63% for patients (41.2%) in the phentolamine group and 41 doses between 20 and 80 mg.12 – 14 On the other (33.3%) in the sildenafil group. Cardiovascular hand, rates of improved erections for sildenafil in adverse events (such as palpitations and tachycar- this study were somewhat higher than those dia) were observed more frequently in patients previously reported, which were generally between receiving phentolamine than in patients receiving 65% and 88%.16 sildenafil (1.7% and 5.9% vs 0% and 0.8%, respectively). Respiratory (17.6% vs 8.9%) and Table 3 Most common treatment-related adverse events with digestive (12.6% vs 9.8%) complaints were also sildenafil or phentolamine more frequent in patients receiving phentolamine Number (%) of patients compared with patients receiving sildenafil. Adverse events occurring in 3% or more patients Sildenafil Phentolamine in either group are shown in Table 3. The most 25 – 100 mg 40 mg common adverse events occurring during the study Adverse eventa (n ¼ 123) (n ¼ 119) were headache (for patients receiving sildenafil) Headache 14 (11.4) 6 (5.0) and rhinitis (for patients receiving phentolamine) Rhinitis 6 (4.9) 15 (12.6) (Table 3). Most adverse events (95%) were mild or Flushing 5 (4.1) 3 (2.5) moderate in nature. Besides the serious adverse Tachycardia 1 (0.8) 7 (5.9) event that led to discontinuation in a patient Nausea 1 (0.8) 6 (5.0) receiving phentolamine, there were three other aAdverse event occurring in 3% of patients in either group.

International Journal of Impotence Research Comparison of the efficacy and safety of sildenafil with phentolamine E Ugarte and A Hurtado-Coll S52 Reflective of the improved erections, sildenafil of 12.6%, was the most common adverse event also improved other aspects of sexual intercourse to observed in patients receiving phentolamine; this a greater extent than phentolamine. This included was also reported most frequently in other trials.12 other domains as well as individual items of the Headache, tachycardia, and nausea also occurred at IIEF. As for erectile function, other domain scores a frequency of 5% or more in patients receiving approached maximum after treatment with sildena- phentolamine. Overall, sildenafil appeared to be fil. Thus, scores for intercourse satisfaction (13.69= better tolerated than phentolamine in this study 15), orgasmic function (9.25=10), sexual desire population. (7.98=10), and overall satisfaction (8.49=10) as well as the individual items contributing to these scores were all significantly higher after treatment with Conclusions sildenafil than treatment with phentolamine (P < 0.0001). Sildenafil also significantly improved the proportion of attempts at sexual intercourse that The treatment of ED is moving out of the arena of were successful. Indeed, twice as many attempts specialist care as alternatives to invasive therapies were successful after treatment with sildenafil than become available and more men request oral medica- after treatment with phentolamine (88.3% vs 42.2%, tions for treatment of this disorder. The results of this respectively) (P ¼ 0.0001), and there were almost study provide important information for clinicians three times as many successes per week after managing patients with ED. In a population in which treatment with sildenafil than after treatment with both sildenafil and phentolamine are available as oral phentolamine (3.11 vs 1.17, respectively) (P < medications, more patients experience improve- 0.0001). Overall, these data indicate that more ments in erectile function and intercourse satisfac- patients receiving sildenafil than phentolamine tion with sildenafil. The overall results of this study who attempted sexual intercourse were successful. indicate that oral sildenafil is better tolerated than Again, these results were reflected in the patients’ oral phentolamine in men, and its efficacy in the overall rating of sexual ability. More than twice as treatment of ED is also superior in this population. many patients receiving sildenafil than phentolamine reported that the study medication had improved their sexual ability (94.4% vs 46.4%, respectively) (P ¼ 0.0001). Acknowledgements More patients receiving sildenafil than phentolamine had at least one successful attempt at sexual Members of the Sildenafil Study Group: R Andrade, intercourse (95% vs 65.2%, respectively). D Calvo, J CastroBusso, J Jaspersen, L Guzmań, Overall, patients receiving sildenafil had E Len˜ ero, J Marina, JA Medina, A Mendoza, improved erections that resulted in more frequent A Moncada, F Orozco, C Pacheco, C PerezToriz, successful sexual intercourse than patients receiv- R Quibrera, A Rish, A Rodriguez, R Salgueiro, ing phentolamine. This is reflected by the fact that A Sedano, M Sotomayor, M Telich, E Zonana. 12.6% of patients in the phentolamine group This study was supported by Pfizer Inc. discontinued because of lack of efficacy. By contrast, none of the patients receiving sildenafil discontinued for this reason. The overall incidence of treatment-related References adverse events was lower for sildenafil than for phentolamine (33.3% vs 41.2%, respectively). 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International Journal of Impotence Research