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Sildenafil Citrate (Viagra®) in the Treatment of Men with Erectile Dysfunction in Southern Latin America: a Double-Blind, Rando

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Sildenafil Citrate (Viagra®) in the Treatment of Men with Erectile Dysfunction in Southern Latin America: a Double-Blind, Rando International Journal of Impotence Research (2002) 14, Suppl 2, S33–S41 ß 2002 Nature Publishing Group All rights reserved 0955-9930/02 $25.00 DOI: 0955-9930Nature Publishing Group www.nature.com/ijir Sildenafil citrate (Viagra1) in the treatment of men with erectile dysfunction in southern Latin America: a double-blind, randomized, placebo-controlled, parallel-group, multicenter, flexible-dose escalation study E Becher1*, A Tejada Noriega2, R Gomez3 and R Decia4 on behalf of the Southern Latin America Sildenafil Study Group, Buenos Aires, Argentina 1Centro de Diagno´stico Urolo´gico, Buenos Aires, Argentina; 2Servicio de Urologı´a, ANDROMED, Instituto de Andrologı´a, Urologı´a y Sexologı´a, Lima, Peru; 3Servicio de Urologı´a, INTEGRAMEDICA, Santiago de Chile, Chile; and 4Servicio de Urologı´a, Hospital Italiano de Montevideo, Montevideo, Uruguay Our objectives were: (1) to determine the efficacy, safety, and tolerability of sildenafil citrate (Viagra1) administered to men with broad-spectrum erectile dysfunction (ED) in southern Latin America; and (2) to correlate Rigiscan1 measurements assessing ED etiology with the investigator’s assessment. A total of 141 men with broad-spectrum ED (mean age 57) were enrolled in a randomized, 12-week, double-blind, placebo-controlled, flexible-dose escalation study of sildenafil. After the 12-week treatment period, the mean score for the primary efficacy variables had risen significantly: for the sildenafil group, 66.2% from baseline for question 3 of the International Index of Erectile Function and 77.6% for question 4, vs 15.1% and 21.2% for the placebo group, respectively (P < 0.0001). Rigiscan1 data confirmed investigator assessments of etiology. Headache and flushing, usually mild and transient, were the most common adverse events. Sildenafil was an effective, well-tolerated treatment for men in southern Latin America with broad-spectrum ED. International Journal of Impotence Research (2002) 14, Suppl 2, S33–S41. doi:10.1038=sj.ijir.3900896 Keywords: sildenafil; erectile dysfunction; Latin American; safety; efficacy; intercourse success rates Introduction the opening of potassium channels and hyperpolar- ization of the muscle cell membrane, sequestration of intracellular calcium by the endoplasmic reticu- Erectile dysfunction (ED) is defined as the persistent lum, and blocking of calcium influx by the inhibi- inability to achieve or maintain an erection suffi- tion of calcium channels.4 The consequence is a 1 cient to permit satisfactory sexual intercourse. It drop in cytosolic calcium concentrations and has been estimated to affect up to 30 million men in relaxation of the smooth muscle. During the return 2,3 the USA. ED may result from psychological, to the flaccid state, cGMP is hydrolyzed to GMP by neurologic, hormonal, vascular, or cavernosal phosphodiesterase type 5 (PDE5).4 Other phospho- impairment or from a combination of these fac- diesterases are also found in the corpus cavernosum, 4,5 2–5 tors. The disorder is age-associated, with but they do not appear to have an important role in estimated prevalence rates of roughly 39% among the erection process. Sildenafil citrate (Viagra1, men 40-y-old and 67% among those 70-y-old. Pfizer Inc, New York, NY, USA) is a selective Normal penile erection depends on the relaxation inhibitor of cGMP-specific PDE5.6–8 of smooth muscles in the corpora cavernosa. In By selectively inhibiting cGMP catabolism in response to sexual stimuli, cavernous nerves and cavernosal smooth muscle cells, sildenafil enables endothelial cells release nitric oxide (NO), which the natural erection response to sexual stimulation, stimulates the formation of cyclic guanosine mono- but does not cause erections in the absence of such 4 phosphate (cGMP) by guanylate cyclase. Cyclic stimulation. GMP in turn activates a specific protein kinase, In a number of randomized, placebo-controlled, which phosphorylates certain proteins, resulting in double-blind, and open-label studies, sildenafil has been shown to be an effective oral treatment for male ED and to have an adequate safety profile.9–14 *Correspondence: E Becher, Centro de Diagno´stico Urolo´gico (CDU), Av. Cordoba 2424, Ciudad de Buenos Aires, Whether the results of these initial double-blind Argentina 1120. and open-label randomized trials can be extrapo- E-mail: [email protected] lated to a population-based sample of men with ED Sildenafil citrate in the treatment of ED in Latin America E Becher et al S34 in Latin America remains to be determined. There- prior to sexual activity, as alcohol may impair the fore, the objectives of the present study were to ability to have erections, and thus potentially cause determine the efficacy, safety, and tolerability of the treatment to be less effective. A total of six study sildenafil over a 12-week period, taken as required, visits were conducted to provide assessments of prior to anticipated sexual activity in male out- efficacy, safety, and tolerability. Following rando- patients with objectively determined broad- mization, patients returned to the clinic for follow- spectrum etiology. The patients were all from up visits after 2, 4, 8, and 12 weeks of treatment. southern Latin America (Argentina, Chile, Peru, Other concomitant medications, which could and Uruguay). This was also the first study to have an effect on erectile function, remained objectively classify ED etiology through Rigiscan1 constant during the study, unless changes were (Timm Medical Technologies, Eden Prairie, MN) required for patient safety. measurements and to correlate it with the investi- Patients who experienced no adverse events (AEs) gator’s clinical assessment. with the 50-mg dose of sildenafil (or corresponding placebo), but whose ED was insufficiently improved at this dose, could increase their dose to 100 mg at Methods the subsequent visit. Patients who responded well at a particular dose were not allowed to receive higher doses. Patients who were receiving the 50- or 100-mg This was a double-blind, randomized, placebo- dose were allowed to decrease the dose to the next controlled, multicenter, parallel-group, flexible-dose lowest level only if they were experiencing intoler- escalation study. Each man had to be in a stable able or severe AEs. Any dose adjustments between relationship with a female partner of at least 6 regularly scheduled visits were done for safety months’ duration. The cause and etiology of the ED purposes only. Sildenafil was provided as 25-, 50-, were determined from the medical history, physical and 100-mg tablets in bottles (14 tablets=bottle). examination, and other diagnostic procedures, in- At weeks 0 (baseline) and 12, each participant cluding a Rigiscan test (nocturnal penile tumescence completed the International Index of Erectile Func- [NPT] testing). The penile tumescence and rigidity tion (IIEF), a 15-question validated, multidimen- measure was performed at the base and=or tip of the sional, self-administered questionnaire used for the penis at the prescreening evaluation. This monitor- clinical assessment of ED and treatment outcomes in ing of nocturnal erections was performed at home for clinical studies.15,16 The global efficacy assessment two nights, with a monitoring period of at least 5 h question (GEAQ) (‘Did treatment improve your per night, in order to distinguish between psycho- erections?’) was asked at week 12. Event logs (patient genic and organic ED, and to enable the investigators diaries) were completed after each attempt at sexual to perform a subanalysis according to the established intercourse and reviewed at each study visit. etiology. The results of this NPT testing were The primary efficacy measures in this study were expressed as the mean average rigidity reached by the responses to questions 3 (Q3, ability to achieve the patients during the monitoring period. an erection) and 4 (Q4, ability to maintain an Men were excluded if they had penile anatomical erection) of the IIEF. IIEF responses were rated on defects, a primary diagnosis of another sexual a scale of 1 (‘almost never=never’) to 5 (‘almost disorder (for example, premature ejaculation), spinal always=always’). A score of 0 indicated no attempt cord injury, any major psychiatric disorder not well at sexual intercourse. The secondary efficacy mea- controlled with treatment, poorly controlled diabetes sures in the study were the responses to the GEAQ mellitus, a history of alcohol or substance abuse, and the responses on the event log, including the major hematological, renal, or hepatic abnormalities, proportion of successful attempts at intercourse. hypotension (sitting blood pressure < 90=50 mm Hg) In addition, the responses to the IIEF were used to or malignant hypertension, a recent (occurring with- evaluate the effect of sildenafil or placebo on five in the previous 6 months) stroke or myocardial domains of male sexual erectile function (questions infarction, or if they were receiving nitrates. 1 – 5, and question 15 of the IIEF; possible total score The institutional review board at each center 1 – 30), orgasmic function (questions 9 and 10 of the approved the protocol, and all the men gave written IIEF; possible total score 0 – 10), sexual desire informed consent to participate. (questions 11 and 12 of the IIEF, possible total score To confirm the diagnosis of male ED after the 2 – 10), intercourse satisfaction (questions 6, 7, and 8 preliminary evaluation and following a 4-week run- of the IIEF; possible total score 0 – 15), and overall in period with no treatment, during which baseline satisfaction (questions 13 and 14 of the IIEF; data on sexual function were collected, patients possible total score 2 – 10). The domain scores were entered a 12-week double-blind treatment period. computed by adding the scores for the individual The men were instructed to take a dose of the study questions in each domain. drug approximately 1 h before planned sexual All observed or volunteered AEs, regardless of activity but no more than once daily. Patients were treatment group or suspected causal relationship to only allowed to drink up to two units of alcohol study drug, were recorded by the investigators.
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