The approved maximal dose of sildenafil is only 50 mg in Japan, but the impact of dose regulation on treatment outcomes has not been established. Moreover, the contributors to the efficacy in patients having an intact peripheral nervous system have not been fully elucidated. We assessed in Japanese patients the treatment outcomes of sildenafil for erectile dysfunction (ED) under regulation of the approved dose and identified factors contributing to its efficacy among those with various etiologies other than pelvic surgery. We retrospectively reviewed 196 ED patients treated with sildenafil. The overall efficacy was 70.9% (139/196), and patients with psychological problems and concomitant cardiovascular disease showed high response rates (82.4 and 87.0%, respectively). Of the 139 responders, 89.9% achieved efficacy with a dose of 25 or 50 mg. Logistic regression analysis revealed concomitant cardiovascular disease and a favorable nocturnal penile tumescence result to be independent contributors to the efficacy.
Sildenafil citrate (sildenafil), a selective phosphodiesterase type-5 (PDE5) inhibitor, was the first oral agent for the treatment of erectile dysfunction (ED). In Japan, it was launched over 5 years ago. The drug has been well accepted internationally and its efficacy is as high as 60–70%.1, 2 However, the response rate differs, depending on the etiology of ED. For example, post-radical pelvic surgery and severe diabetes respond poorly to sildenafil.3 Additionally, the efficacy is dose-dependent; 100 mg was more effective than 50 mg.1 In Japan, the officially approved dose is up to 50 mg, which is in contrast to other Asian countries, where 100 mg is available.
In this study, we evaluated the outcome of sildenafil treatment for ED in Japanese patients, and identified the clinic-based factors related to the efficacy of the drug.
Materials and methods
We retrospectively reviewed the medical records of patients with ED who were treated with sildenafil between April 1999 and March 2003 at the Sapporo Medical University Hospital. We evaluated 196 of 251 patients for whom we could confirm efficacy of the drug.
The patients underwent routine laboratory investigation plus total testosterone and free testosterone assessment. Total testosterone was measured by enzyme immunoassay and free testosterone by radioimmunoassay. The evaluation consisted of a comprehensive history taking, physical examination, and nocturnal penile circumferential change measured with an erectometer.4 In this study, the current smokers were defined as ‘smokers’, and the patients with moderate or severe alcohol abuse, as suffering from ‘alcoholism’.5 The definition of the National Institutes of Health (NIH) Consensus on ED, which defined impotence as the consistent inability to attain and maintain a penile erection sufficient to permit satisfactory sexual intercourse, was used in this study.6
Sildenafil was administered with doses from 25 to 50 mg. If the patient hoped for a larger dose, we tried 75 or 100 mg of the drug after obtaining written informed consent in a research setting. The clinical efficacy was assessed subjectively in terms of improved erection and satisfaction in sexual intercourse. We did not use a validated sexual inventory for the assessment of the clinical outcomes in the current study.
Logistic regression analysis was carried out to determine the significant contributors to the efficacy among the variables other than peripheral nerve damage caused by pelvic surgery; that is, age, smoking, alcoholism, concomitant cardiovascular disease, concomitant diabetes mellitus, nocturnal penile circumferential change (nocturnal penile tumescence; NPT), and hypogonadism. As the baseline erectile function, we evaluated the nocturnal penile circumferential change with an erectometer. We defined favorable erectile function as a circumferential change of more than 30 mm.4 Hypogonadism was defined by the level of serum testosterone with 2 standard deviations below the mean level for young men (313.7 ng/dl total testosterone or 8.8 pg/ml free testosterone).7, 8, 9 In logistic regression analysis, ‘pelvic surgery’ was excluded because we attempted to evaluate the predictive factors of efficacy without traumatic peripheral nerve damage. Statistical analysis was performed using commercial software (StatView 5.0-J, windows edition). P<0.05 was considered to be significant.
Patients' characteristics are shown in Table 1. The median age of this study group was 51 years (range: 22–79 years). Patients in their 60s accounted for 30.6% of the total, followed by 17.3% for those in their 70s and 16.8% for those in their 50s.
The overall efficacy of sildenafil was 70.9% (Table 2). Comorbid conditions were stratified as follows: (1) vasculogenic problems including hypertension, ischemic heart disease, and cerebral infarction, (2) diabetes mellitus, (3) psychogenic problem (including no clinically manifested organic causes of ED in young patients) or depression, (4) spinal cord injury, and (5) radical pelvic surgery for rectal cancer, prostate cancer, or bladder cancer with or without nerve sparing). Patients having concomitant cardiovascular disease and psychological problems showed a higher response rate (87.0 and 82.4%). On the other hand, ED after radical pelvic surgery showed the lowest response rate (29.0%).
Of the 139 responders, 90% achieved the efficacy with a dose of 25 or 50 mg. Only a small proportion of responders need dose escalation up to 75 or 100 mg for a satisfactory response (Table 2).
The results of logistic regression analysis for the predictive factor for the efficacy are shown in Table 3. In 155 of 196 patients, detailed data for the multivariate analysis were available. It revealed concomitant cardiovascular disease and NPT to be independent factors related to the efficacy of sildenafil.
Adverse events were found in nine patients (4.6%), including four with hot flushes, two with headaches, two with blurred vision, and one with dizziness. There were no severe adverse events. No patients discontinued the medication because of adverse events.
The number of Japanese patients with ED is estimated to be over 9.8 million.10 ED is more prevalent in Japanese men than in American men. However, most elderly men do not complain about dissatisfaction despite declining sexual function.11 This discrepancy between the sexuality and satisfaction among Japanese men might influence the treatment outcome. In addition, there is a difference in the approved dose of sildenafil between Japan and other countries. Thus, we set out to analyze the outcome of sildenafil use for ED in Japanese patients, and assessed the factors predicting the effectiveness of this drug, based on the clinical information prior to prescription.
Successful treatment of ED with sildenafil after radical prostatectomy depends on the presence of the intact cavernous nerve. It is suggested that the efficacy of sildenafil requires sparing of the neuronal nitric oxide (nNO)–cyclic guanylate monophosphate (cGMP) pathway.12, 13 In this study, we excluded the factor of radical pelvic surgery from the multivariate analysis in order to clarify more relevant contributors to the efficacy in patients with intact nNO–cGMP pathway.
The baseline erectile function and etiological diagnosis of ED were suggested to be predictive factors for the efficacy of sildenafil. In this study, we used an erectometer for the assessment of baseline erectile function. This modality may have lower reliability or reproducibility for diagnosis of organic ED than RigiScan. However, our previous study indicated that it was clinically useful for screening purposes.4 The current results suggested that favorable NPT was an independent factor related to efficacy. This is similar to a previous report,5 because high NPT results imply that baseline erectile function is favorable. Moreover, favorable NPT might be related to the possibility of a psychogenic cause for ED, for which the efficacy of sildenafil was also high in the current study group.
The systemic cardiovascular disease has also been suggested to be a risk factor for ED. The incidence of ED in patients with hypertension was about 70%,14 which was also suggested in the Japanese population.15, 16 Furthermore, most ED patients (86%) with cardiovascular disease responded to sildenafil,17 which is similar to the current results. In the current study, concomitant cardiovascular disease was revealed to be a predictive factor for the efficacy of sildenafil in multivariate analysis. Thus, we believe that all ED patients with stable cardiovascular disease and without nitrate administration are good candidates for PDE5 inhibitors.
It is widely accepted that the efficacy of sildenafil is dose-dependent.1, 3 Many East Asian countries, excluding Japan, have officially approved doses of sildenafil of up to 100 mg. The dose in Japan has been regulated by the result of a clinical trial for the efficacy of sildenafil, which failed to demonstrate the superiority of 100 to 50 mg.18 In addition, in our current study, 90% of responders achieved efficacy with 25 or 50 mg of sildenafil. As for other Asian countries, 65% of the patients were satisfied with 100 mg sildenafil in Korea,19 and 47% in Singapore.20 In all, 100 mg Sildenafil leads to an increase of adverse events such as blurred vision in 11.1%, compared with 2.2% for the dose of 50 mg.21 Moreover, 40% of sildenafil nonresponders responded to the same dose after the re-education by ED specialists, including the timing of taking the drug or prevention of interaction with food.22 Thus, 50 mg sildenafil administration with thorough education before prescription remains the mainstay for most Asian men to avoid undesirable complications. Although the definitive reason why Japanese men were satisfied with a lower dose is still unclear, the dose regulation of this country and the detailed information given about the administration of this drug might have affected the efficacy. However, severe ED caused by uncontrolled diabetes or radical pelvic surgery needs a higher dose of sildenafil.20 Moreover, the tachyphylaxis effect from long-term use of sildenafil might need a dose escalation.23, 24 In the future, we might have to consider approval of the use of 100 mg sildenafil in Japan, too.
It has been suggested that the PDE5 inhibitor for ED improved the partner's sexual function.25 We previously reported that the prevalence of female sexual function in Japanese females was age-related, and that erectile function of the male partner contributed to the frequency of sexual intercourse.26 Thus, it is crucial to investigate the relationship between the efficacy of sildenafil and the alteration of female sexual function in the Japanese population in a future study.
The clinical efficacy was assessed in terms of the patients' satisfaction in this study. The perception of sexual function and its impact on the health-related quality of life among elderly males may differ by physique, race, site, and country.11 Therefore, this variation may influence the different clinical outcomes of sildenafil in Japanese patients from those of other populations.
There were some limitations in the current study. The study population included only the patients in whom we could assess the treatment outcome at the second presentation because of retrospective analysis. The assessment of clinical efficacy did not include evaluation using a validated questionnaire such as the International Index of Erectile Function. In some previous studies, the clinical outcomes were assessed by global efficacy questions that asked patients about the effect of sildenafil on sexual function and about their satisfaction with treatment.1, 2, 5, 19, 20 Therefore, in terms of patients' satisfaction with the drug, a validated questionnaire might not always be necessary. Nevertheless, we will assess the definite erectile function with a validated questionnaire in a future study. To eliminate these limitations, a prospective randomized trial will be needed. However, we believe that the current results will be informative for patients in the light of the prevention of clinically meaningless dose escalation and the prediction of efficacy prior to drug administration.
The overall efficacy rate of sildenafil was 70.9%, and about 90% of Japanese responders had been satisfied with doses up to 50 mg in Japan. The predictive factors for efficacy were revealed to be concomitant cardiovascular disease and baseline erectile function. Therefore, ED patients with a stable cardiovascular disease without nitrate administration are good candidates for sildenafil.
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Kobayashi, K., Hisasue, S., Kato, R. et al. Outcome analysis of sildenafil citrate for erectile dysfunction of Japanese patients. Int J Impot Res 18, 302–305 (2006). https://doi.org/10.1038/sj.ijir.3901400
- multivariate analysis