Efficacy of Oral Sildenafil in Hemodialysis Patients with Erectile Dysfunction

Abstract

ABSTRACT. The aim of this study was to evaluate the efficacy and safety of oral sildenafil to treat erectile dysfunction (ED) in chronic renal failure in patients on hemodialysis (HD). A double-blind, randomized, placebo-controlled study of oral sildenafil (50 mg) administered as required in HD patients with ED was designed. Patients on HD for at least 6 mo and who had a stable relationship with a female sexual partner were included. Patients older than 70 yr with penile anatomic abnormalities, cirrhosis, diabetes, angina, severe anemia, and those who were on nitrate treatment or with a recent history of stroke or myocardial infarction were not included. The International Index of Erectile Dysfunction (IIEF) was employed to evaluate ED and treatment response. Forty-one patients were evaluated (21 received placebo, and 20 sildenafil). Baseline clinical and demographic parameters were similar in both groups. Sildenafil was associated with improvement in the score of all questions and domains of the IIEF, except those related to sexual desire. Using the erectile function domain to evaluate primary efficacy, improvement was observed in 85% of the sildenafil patients compared with 9.5% of placebo patients. Sildenafil use resulted in normal EF scores in 35% of sildenafil patients. Sildenafil was well tolerated. Headaches and flushing occurred in both groups. Dyspepsia was reported by two patients in the sildenafil group. In conclusion, oral sildenafil seems to be an effective and safe treatment for ED in selected patients with chronic renal failure on hemodialysis.

Erectile dysfunction (ED) is the persistent inability to achieve or maintain an erection sufficient to permit satisfactory sexual performance, and the resulting stress often impacts interaction with others (¹). End-stage renal failure patients on hemodialysis (HD) are frequently affected by ED. The prevalence of ED in these patients has been estimated to be between 71 and 82% (^2,3). This prevalence is positively associated with increasing age and diabetes and inversely associated with use of angiotensin-converting enzyme (ACE) inhibitors, even among patients with good functional status (³). In the state of Rio Grande do Sul (Brazil), we have estimated the prevalence of ED in HD patients to be 75% (unpublished observation).

There are several management guidelines for ED. The UK guidelines (⁴) suggest that a detailed history is the most important aspect in the assessment of patients with ED. Treatment options for men with ED include psychosexual therapy, drug therapy, transurethral or intracavernosal therapy, treatment with vacuum-constriction devices, and surgical treatment (⁵). Recently, sildenafil, a selective inhibitor of phosphodiesterase type-5, which is the predominant isozyme inactivating cyclic guanosine monophosphate (cGMP) in the corpus cavernosum, has been shown to be an effective, well-tolerated treatment for non-uremic men with ED (⁶). Its use results in increased smooth muscle relaxation and improved erection when nitric oxide is released in the presence of sexual stimulation.

There are few studies on the use of sildenafil in HD patients; most have only been published in abstract format and are open-label uncontrolled trials aimed at evaluating the drug’s safety and efficacy. As far as we know, there have been no double-blind, placebo-controlled studies with sildenafil in HD patients. Therefore, the present randomized, double-blind, placebo-controlled study was designed to investigate the use of oral sildenafil in HD patients with ED.

Materials and Methods

The study was designed as a randomized, double-blind, placebo-controlled study of oral sildenafil (50 mg), administered as needed in HD patients with erectile dysfunction, with a follow-up of 1 mo.

The target sample included patients on chronic HD who had received treatment for at least 6 mo in six dialysis units in the state of Rio Grande do Sul (southern Brazil). The inclusion criterion was having a stable relationship with a female sexual partner. We did not include patients older than 70 yr and those presenting penile anatomic abnormalities, cirrhosis, diabetes, angina (history of precordial pain), severe anemia (hematocrit lower that 21%), patients on nitrate treatment or with a history of recent (previous 6 mo) stroke or myocardial infarction. In addition, we did not include illiterate patients and those being treated for ED. Diabetes was diagnosed on the basis of previous history of diabetes, use of insulin or oral antidiabetes drugs, or blood glucose above 116 mg/dl. All patients included in the study underwent a mean of 12 dialysis hours per week with polysulphone membranes.

Initial evaluation was carried out in accordance with the United Kingdom management guidelines for ED (⁴) and consisted of a detailed history and limited physical examination. The 48 patients suspected of having ED on the basis of this initial evaluation were invited to complete the 15-question International Index of Erectile Dysfunction (IIEF), a self-administered, multidimensional questionnaire, which has been validated in several languages (⁷), including Brazilian Portuguese (⁸).

The IIEF is an instrument used for the clinical assessment of ED and treatment outcomes in clinical studies. It evaluates several aspects of sexual performance, rating each answer from 0 to 5, 0 meaning no sexual activity/no attempt at sexual intercourse. The total score ranges from 5 to 75. Treatment efficacy can be assessed through the answers to question 3 (frequency of penetration) and question 4 (maintenance of erection after penetration). Efficacy can also be evaluated through the scores for the five separate response domains of male sexual function of the IIEF: erectile function (questions 1 to 5 and 15, total score 1 to 30), overall satisfaction (questions 13 and 14, total score 2 to 10), intercourse satisfaction (questions 6 to 8, total score 0 to 15), orgasmic function (questions 9 and 10, total score 0 to 10), and sexual desire (questions 11 and 12, total score 2 to 10). The final score for each domain is the sum of the scores for the individual questions in that domain.

Patients with a score of 26 or higher on the erectile function domain were considered as not having ED and were excluded before final analysis. The erectile function domain scores (⁹) were also used to classify patients according to ED severity levels: absence of ED (score 26 or higher), mild (score 22 to 25), mild to moderate (score 17 to 21), moderate (score 11 to 16), or severe (score 6 to 10).

Both the placebo and sildenafil (50 mg; Viagra) were placed inside capsules of identical aspect prepared at the School of Pharmacy, Pontifi[Combining Acute Accent]cia Universidade Cato[Combining Acute Accent]lica do Rio Grande do Sul (PUCRS). They also prepared a randomization list, and 24 patients in each group received a sealed box containing the capsules. None of the authors or patients had access to the drug codes until all patient evaluations were finished. Patients received a diary for registering events related to their sexual life and ten capsules containing either placebo or sildenafil. Patients were instructed to take only one capsule per day as needed 1 h before sexual intercourse. They were also instructed not to take the medication on dialysis days. One month after the first evaluation, the patients completed a new IIEF questionnaire and reported the number of capsules that were used.

Medical and demographic data were obtained for each subject from the monthly dialysis records and included age (yr), time on dialysis (mo), hemoglobin (g/dl), hematocrit (%), creatinine (mg/dl), urea (mg/dl), Kt/V, and alanine aminotransferase (ALT, IU/L).

Statistical Analyses

Means and SD were calculated for each IIEF question or domain. Variables were tested if they presented normal distribution using the Kolmogorov-Smirnov test. The results of the placebo and sildenafil groups were compared using the t test or Mann-Whitney U test for parametric and nonparametric data, respectively. Comparison of basal and final results in each group was performed with paired t test or Wilcoxon test for parametric and nonparametric data, respectively. ANOVA was also employed. To simplify the presentation of results, only mean (SD) and paired and unpaired t test results will be shown. Results were similar using parametric or nonparametric tests. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated to examine the odds of improving ED with sildenafil. Clinical and demographic data were shown as mean (± SD) or as frequency distribution. t test, Fisher, and χ² tests were employed.

Ethics and Conflict of Interest

This study was approved by the Scientific Committee and Ethics Committee at PUCRS, and all patients signed a written informed consent form. The present clinical study was carried out at an academic institution and was entirely financed by the authors. Sildenafil tablets were provided free of charge by Pfizer, but the authors received no other type of support from the drug manufacturer to avoid conflict of interest, and there was no agreement whatsoever established between the research group and the manufacturers of sildenafil.

Results

The total number of patients in the six dialysis units was 438 (226 male adults, 210 female adults, 2 children). Ninety patients were considered eligible for the study. Using the methods described, 48 patients were invited and agreed to participate in the study. In the placebo group, one patient asked to be excluded when his wife became ill on the second study day and two patients died (one case of lung cancer, one case of sudden death). Neither death was associated with placebo ingestion or sexual intercourse. In the sildenafil group, one patient withdrew his consent, and three patients were excluded because they had initial IIEF scores higher than 26.

There were 21 and 20 patients analyzed in the placebo and sildenafil groups, respectively. The characteristics of each group are shown in Table 1. No difference was found between the groups regarding age, time on dialysis, hematocrit, hemoglobin, urea, Kt/V, and ALT. There were no significant differences in terms of hematocrit, hemoglobin, urea, Kt/V, and ALT before and after treatment in both groups. The mean number of tablets used was 2.95 (SD ± 1.1) and 3.5 (SD ± 1.2) for placebo and sildenafil, respectively (not significantly different). Mean systolic BP was 143 ± 23 and 151 ± 19 mmHg (P = 0.352) for placebo and sildenafil, respectively. Diastolic BP was 88 ± 19 and 93 ± 12 mmHg (P = 0.244) for placebo and sildenafil, respectively. Mean weekly dose of erythropoietin was 5514 ± 2704 and 5200 ± 2931 units (P = 0.562) for placebo and sildenafil, respectively.

Table 1: . Baseline parameters and final IIEF scores in the placebo and sildenafil groups (mean ± SD)

Table 2 depicts the scores for each of the 15 IIEF questions. Initial data shows no significant difference between the scores for the placebo and sildenafil groups before treatment in 14 questions. The score in the sildenafil group was significantly higher than in the placebo group only in question 14 (“How satisfied have you been with your sexual relationship with your partner?”).

Table 2: . International Index of Erectile Function (IIEF) question scores in patients on placebo and sildenafil^a before and after treatment

After treatment, patients receiving sildenafil had better scores in 12 out of 15 questions in comparison with the placebo group. The only questions for which the difference was NS were questions 6 (frequency of intercourse), 11 (frequency of sexual desire), and 12 (level of sexual desire).

In the intragroup longitudinal analysis, the placebo group showed an improved score in only two questions (8 and 12), regarding sexual intercourse pleasure and level of sexual desire. There was significant improvement in the scores of all questions in the sildenafil group, except in question 12 regarding the level of sexual desire.

The five IIEF domains are shown in Table 3.

No significant differences between scores in the placebo and sildenafil groups were detected in any of the domains before treatment. Patients treated with sildenafil had better scores in four domains in comparison with placebo patients, but no difference was observed in the sexual desire domain.

Table 3: . International Index of Erectile Function (IIEF) domain scores in patients on placebo and sildenafil before and after treatment^a

In the intragroup longitudinal analysis, a significant improvement was observed after treatment with sildenafil in the scores of all domains except sexual desire, whereas treatment with placebo had no significant impact on the scores.

ED was categorized in accordance with severity (Table 4). After sildenafil treatment, seven patients (35%) had scores above 26, thus achieving drug-induced resolution of the ED. This was not observed in any of the placebo patients. There was improvement in erectile function in 85% of the sildenafil patients against 9.5% of the placebo patients. The OR for improving ED with sildenafil was 53.8 (95% CI, 6.4 to 658.9; P < 0.001).

Table 4: . Severity of erectile dysfunction (ED) and change in severity categories after treatment with placebo or sildenafil

Side effects were reported in both groups. Two patients reported moderate and severe headaches, and one patient reported mild facial flushing in the placebo group. In the sildenafil group, moderate flushing and dyspepsia were reported by one patient, mild headache and dyspepsia by one patient, and mild headache by one patient.

Discussion

This study shows that sildenafil is effective and safe for the treatment of selected chronic renal failure patients on HD. It improved erectile function, although it did not improve sexual desire. These results are comparable to previous results with non-uremic patients —sildenafil improves erectile response to sexual stimulation, but it does not have an effect in the absence of such stimulation (⁶).

There have been few studies focusing on the use of sildenafil in HD patients, and most of them have not been published as full articles. In addition, we are not aware of any randomized, double-blind, placebo-controlled studies with this population. Paul et al. (¹⁰) performed an open-label study with nine patients on maintenance HD who were treated with 50 mg of sildenafil for 3 wk. Those patients had a 60% increase in satisfaction and performance, and no side effects were described. Di Paolo et al. (¹¹) studied six HD patients in an open-label, flexible-dose study and reported improvement of ED with sildenafil without significant side effects, although IIEF scores were not reported. Rosas et al. (^12,13) conducted a 4-wk open-label study in which 15 dialysis patients were treated. Using the global efficacy question of the IIEF, those authors reported improved erections with sildenafil in 66.7% and 63.6% of the patients (^12,13), a result that is comparable to the present report. Chen et al. (¹⁴) treated 34 HD patients in a 6-mo open-label study; treatment was effective in 80% of the patients, with headache being the most common side effect.

As reported in the literature, most patients respond to 50-mg doses of sildenafil, the same dose used in our study. Bellovich et al. (¹⁵) studied 25 HD patients in a placebo-controlled 3-way crossover study. Although significant efficacy was not observed, there were no complications due to sildenafil. Their data differ from ours, but the high initial scores they obtained in the two IIEF questions used to evaluate primary efficacy suggest that those patients did not have significant ED.

So far, the only other double-blind study with dialysis patients was performed by Macdougall et al. (¹⁶) with peritoneal dialysis patients. They reported a significant improvement on sexual function with sildenafil, which was observed to be effective in 71% of the peritoneal dialysis patients. This is similar to our data concerning HD patients, despite the difference in the degree of ED severity at the beginning of the study (which was greater in the Macdougall sample). In contrast, Juergensen et al. (¹⁷) reported that only two out of six peritoneal dialysis patients completing a 12-wk open-label study reported a satisfactory response with sildenafil. However, the small number of patients completing that study makes it difficult to compare their data with the results of other studies.

Tu[Combining Diaeresis]rk et al. (²) treated 20 HD patients with ED, and the response rate was 60%. The patients not responding to treatment had a significantly lower penile blood flow than the responding patients. It seems that in most studies with uremic patients, including the present one, the response to sildenafil is similar to that reported for patients with ED of widespread etiology (⁶).

In general, all studies suggest good tolerability of HD patients to sildenafil. In support of this observation, the drug seemed to be safe and efficacious in our patients. However, extra care is required, because most studies exclude high-risk patients, as was also our case. We feel that sildenafil may be safely used in HD patients without cardiovascular and hepatic diseases. Headache, flushing, and dyspepsia are the most common adverse effects in non-uremic patients (⁶). In the present study, very few side effects were reported in either group, and headaches were more intense in the placebo group. Dyspepsia occurred only in the sildenafil group.

We asked patients not to take sildenafil on dialysis days. There have been reports of hypotension associated with sildenafil use by dialysis patients (¹⁸), although these reports have been disputed (¹⁹). Nitric oxide metabolism may be involved on dialysis hypotension, and we were concerned with the risk of inhibiting phosphodiesterase in patients at risk for HD hypotension. There seems to be no significant clearance of sildenafil during HD (²⁰).

In conclusion, oral sildenafil was an effective and safe treatment for ED in the present sample of selected patients with chronic renal failure on HD.

We thank the following dialysis units for participating in the study: PUCRS (Porto Alegre); Clinirim and Hospital Parque Bele[Combining Acute Accent]m (Porto Alegre); Nefro (Guai[Combining Acute Accent]ba); Prontorim (Cachoeirinha); Hospital Bruno Born (Lageado); and Servic[COMBINING CEDILLA]o de Uro-Nefrologia (Vena[Combining Circumflex Accent]ncio Aires). We thank Professor Ivone Sartor and Marliese Arau[Combining Acute Accent]jo dos Santos for preparing the sildenafil and placebo capsules, and we are also thankful for the editorial support provided by Claudia Buchweitz.