The efficacy of sildenafil citrate (Viagra®), an oral agent for the treatment of erectile dysfunction (ED), has been demonstrated in global studies. This 12-week randomized, double-blind, placebo-controlled, parallel-group, flexible-dose study assessed the efficacy and safety of sildenafil to treat ED in men in Egypt and South Africa. Men with ED of varied etiology were randomized to receive sildenafil 50 mg (n=128) or placebo (n=126); doses could be adjusted to 100 or 25 mg. Questions from the International Index of Erectile Function (IIEF) assessing the ability to achieve (Q3) and maintain (Q4) erections demonstrated a significant improvement with sildenafil compared with placebo (P<0.0001). Improved erections were reported by 74% of patients receiving sildenafil and 27% of those receiving placebo (P<0.0001). Headache, dyspepsia, and flushing were the most common adverse events in sildenafil-treated patients. These results are consistent with clinical trials in other countries. We conclude that sildenafil is an efficacious and well-tolerated treatment for men with ED in Egypt and South Africa.
Erectile dysfunction (ED), the consistent inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance,1 is estimated to affect over 152 million men worldwide.2 Based on estimated and projected male population distributions from the United Nations3 and prevalence rates of ED from the Massachusetts Male Aging Study,4 projections for 2025 indicate an expected 111% rise in worldwide prevalence, with the largest increases in developing countries that have expanding populations and increased life expectancies. In Africa, the prevalence of ED, currently estimated to exceed 12 million men, is projected to increase at a rate surpassing that of any other continent as a result of escalating risk factors and improved diagnosis.2
Sildenafil citrate (Viagra®), the first of a new class of orally effective treatments for ED of varied etiology, enables erection only after sexual stimulation.5 The use of sildenafil is more discreet than other options and generally preferred when patients are given a choice of treatment for ED.6 After extensive clinical trials and widespread use of sildenafil in the general population, the incidence of adverse events and treatment discontinuations is remarkably low.7,8
These favorable characteristics likely reflect the high selectivity of sildenafil for phosphodiesterase type 5 (PDE5) compared with other PDEs.9 In addition to its presence in the corpus cavernosum, PDE5 is found in lower concentrations in other tissues, including platelets, vascular and visceral smooth muscle, and skeletal muscle, but not cardiac myocytes.10 Because of its limited PDE activity in cardiovascular tissues, sildenafil is not associated with deleterious cardiovascular effects11 unless combined with an organic nitrate, which can cause a synergistic blood-pressure–lowering effect and is therefore contraindicated.
The efficacy, safety, and tolerability of sildenafil have been demonstrated in several global studies,5,12,13,14,15 including trials conducted in the Americas, Pan-Asia, and Europe, and in men with concomitant diseases, including diabetes16 and cardiovascular disease.17 This randomized, double-blind, placebo-controlled, parallel-group, flexible-dose study evaluated the efficacy, safety, and tolerability of sildenafil in men with ED in two African countries, Egypt and South Africa.
Materials and methods
From January to September 1998, 254 men with ED of more than 6 months' duration signed an informed consent agreement and enrolled in our study, which was conducted at 24 sites in Egypt (n=118) and South Africa (n=136) with the approval of local ethics committees. Male outpatients, 18 y of age or older, who had clinically diagnosed ED1 of varied etiology (except for spinal cord injury) and who were engaged in a stable relationship for at least the past 6 months were eligible for enrollment. Exclusion criteria were concomitant treatment with nitrates in any form; certain endocrine anomalies (prolactin level >3 times the upper limit of normal; free testosterone >20% below normal) or sexual disorders or genital abnormalities; major hematological, renal, or hepatic disease; significant cardiovascular disease during the previous 6 months; blood pressure <90/50 or >180/110 mmHg; poorly controlled diabetes mellitus; concomitant use of other ED therapies; a history of alcohol or substance abuse; or a major psychiatric disorder. All eligible patients underwent a physical examination, including sitting blood pressure and heart-rate measurements, a 12-lead electrocardiogram, and standard laboratory safety tests. After a 4-week run-in period, patients were randomized to receive sildenafil 50 mg or placebo, to be taken at least 1h before anticipated sexual activity, but not more than once daily. During the 12-week treatment period, clinic visits occurred at weeks 2, 4, 8, and 12, when study drug dose could be adjusted to 100 or 25 mg, based on efficacy and tolerability.
Efficacy was assessed by responses to the International Index of Erectile Function (IIEF) instrument. The assessment18 was completed at baseline and at the end of week 12 or at study withdrawal. The primary efficacy variables were question 3 (Q3, ability to achieve an erection) and question 4 (Q4, ability to maintain an erection) of the IIEF; these questions most closely address the National Institutes of Health's definition of ED.1 Responses to Q3 and Q4 were graded on a scale of 1 (‘almost never/never’) to 5 (‘almost always/always’), with 0 representing ‘no attempt at sexual intercourse.’ The responses to all 15 questions of the IIEF were combined into domain scores addressing five areas: erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction with sex life. After 12 weeks of treatment, subjects responded with yes or no to the global efficacy question (GEQ): ‘Has treatment improved your erections?’ Efficacy was also assessed at weeks 2, 4, 8, and 12 by determining the proportion of successful attempts at sexual intercourse from the patient event-log data and by responses to question 7 (Q7) of the IIEF (‘When you attempted sexual intercourse, how often was it satisfactory for you?’). All observed or volunteered adverse events, regardless of relation to study drug, were documented at each visit. Standard laboratory safety tests and heart-rate measurements were conducted at each visit, exclusive of body weight and sitting BP. Physical examinations and 12-lead ECG monitoring were performed at baseline and at week 12.
Efficacies were evaluated using the responses from the intent-to-treat (ITT) population, consisting of individuals who were randomized, took at least one dose of study medication, and had at least one on-treatment evaluation. Safety analyses included all men who received one or more doses of study drug. Responses to IIEF questions, including the primary efficacy variables, were analyzed using an analysis-of-covariance model, whereas responses to the GEQ were analyzed using logistic regression. The proportion of successful attempts at intercourse, derived from the patient event-log data, was analyzed using a generalized linear model. All statistical comparisons were made using two-sided tests and performed at the 5% significance level.
Of 279 men screened in Egypt and South Africa, 128 and 126 patients were randomized to sildenafll and placebo, respectively. Overall, the two treatment groups were comparable with respect to age, duration of ED, ED etiology, and proportion of current smokers (Table 1). Compared with the patients from Egypt, those from South Africa were older and had experienced ED longer, and fewer were current smokers. Psychogenic etiology was the predominant cause of ED in the Egyptian men (39.0%), whereas an organic etiology was the predominant cause in South African men (51.5%). Many patients had clinically significant comorbidities, including diabetes mellitus (27%), hypertension (24%), unspecified visual disorders (14%), and hypercholesterolemia (6%). The medications received by patients for concurrent illnesses included antihypertensives (24%), antidiabetic drugs (24%), anti-inflammatory agents (15%), antibiotics (11%), diuretics (10%), and drugs for hyperlipidemia (8%).
The median duration of treatment was 84 days in both treatment groups; median numbers of total doses taken were 41 and 33 for the sildenafil and placebo groups, respectively. At treatment end, the number of patients receiving sildenafil 25, 50, or 100 mg was 7, 32, and 86, respectively; three patients discontinued because of serious adverse events. For patients receiving the matching placebo, the corresponding numbers were 1, 5, and 114, respectively; six discontinued treatment.
The end-of-treatment mean scores for Q3 (ability to achieve an erection), Q4 (ability to maintain an erection), and Q7 (satisfaction with treatment) of the IIEF were significantly higher for the sildenafil group than for the placebo group (P<0.0001; Figure 1). Mean scores for the remaining IIEF questions demonstrated significant treatment effects for sildenafil compared with placebo in domains assessing erectile function, orgasmic function, intercourse satisfaction, overall satisfaction (P<0.0001), and sexual desire (P=0.01; Figure 2). The end-of-treatment GEQ responses showed that improved erections were reported by a greater proportion of men receiving sildenafil than those receiving placebo (74 vs 27%; P<0.0001; Figure 3a). According to event-log data, 69% of attempts at sexual intercourse were successful for patients receiving sildenafil, compared with 28% for those receiving placebo (P<0.0001; Figure 3b).
In all, 15 of 128 patients in the sildenafil group (11.7%) and 11 of 126 patients in the placebo group (11.9%) discontinued treatment. No patient in the sildenafil group—but four in the placebo group — withdrew because of an insufficient clinical response (Table 2). Three patients receiving sildenafil discontinued treatment because of a serious adverse event (myocardial infarction, accidental vertebral fracture, diverticulitis), none of which was considered treatment related. There were no deaths during the study.
Other than flushing, the overall incidence of cardiovascular events was low. In the sildenafil group, a patient who had a history of myocardial infarction experienced reinfarction, and three patients reported palpitations. In the placebo group, one patient had hypertension. None of these cardiovascular events was considered by the investigator to be related to treatment. Visual disturbances, reported by four patients taking placebo and 10 patients in the sildenafil group (including five who reported transient changes in perception of color hue or brightness), were judged as mild and related to treatment. Sildenafil was not associated with abnormal laboratory test results or clinically significant changes in blood pressure.
Our study demonstrated that sildenafil is highly effective in treating ED of psychogenic, organic, or mixed etiology in South African and Egyptian men. Sildenafil was associated with significant increases in the ability to achieve and maintain an erection. Both the percentage of patients reporting improved erections (74 vs 27%) and the proportion of successful attempts at sexual intercourse (69 vs 28%) were significantly increased with sildenafil treatment compared with placebo. At treatment end, nearly 75% of sildenafil-treated patients were receiving the 100-mg dose, suggesting increased efficacy with increasing dose. These results are of similar magnitude to those reported by previously published studies and database analyses in patients with ED of varied etiology,5,7,8,12 including a study that showed near normalization of erectile function in sildenafil-treated patients compared with age-matched healthy controls.19
This study also confirms that sildenafil is well tolerated. The low incidence of adverse events, including cardiovascular events, among sildenafil-treated patients is similar to that reported by other published studies and extensive analyses of clinical trials.5,7,8,12 The most common adverse events associated with sildenafil were predominantly transient, mild or moderate in severity, and consistent with its known pharmacologic effects.
Differences in the demographic characteristics of the study population may reflect recruitment variability. The Egyptian patients were predominantly recruited from private practices, whereas those in South Africa were largely drawn from hospitals and clinics. Many study sites in South Africa were located in metropolitan areas with predominantly white populations, which likely contributed to the low representation of blacks. Nonetheless, comparison of the demographic parameters suggests a potential relationship between age and both duration and etiology of ED.
Reports from Africa indicate that ED is highly prevalent among certain populations and associated with chronic diseases, including diabetes mellitus and hypertension.20,21 In this study, the use of sildenafil to treat ED in men from two African countries was shown to be effective and well tolerated. The levels of efficacy and incidence of adverse events were similar to those of previously published reports.
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This study was supported by a research grant from Pfizer Inc. Participants in the African Sildenafil Study Group included MAM Abdel Aal, MD; Said Abdel Azim, MD; Wael Abu Fad, MD; Luigi Aldera, MD; MS Bornman, MD; Gary Burgess, MD; Magdy A El Akkad, MD; Adel H El-Behairy, MD; M Hatem El-Bialy, MD; Moustafa El-Demiry, MD; Eman H El-Morsi, MD; Mohammad El-Gallad, MD; Ahmed M El-Taher, MD; MAH Habib, MD; AAL Hegazy, MD; Goolam M Hoosen, MD; Ismail M Khalaf, MD; Mohammad Koth, MD; Bernard Levinson, MD; Ivan P Levinson, MD; Irving Lissoos, MD; Kamal ZM Shaeer, MD; Bahgat A Metawea, MD; Sherif Mourad, MD; Johannes H Naude, MD; MAK Omar, MD; Simon Reif, MD; Mac Robertson, MD; A Carel Schmidt, MD; David O Smart, MD.
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Levinson, I., Khalaf, I., Shaeer, K. et al. Efficacy and safety of sildenafil citrate (Viagra®) for the treatment of erectile dysfunction in men in Egypt and South Africa. Int J Impot Res 15, S25–S29 (2003). https://doi.org/10.1038/sj.ijir.3900970
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