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Rechallenge prior sildenafil nonresponders

Abstract

To assess inappropriate use as a cause of sildenafil (Viagra™) failure and the feasibility of successfully rechallenging nonresponding patients, a total of 60 consecutive erectile dysfunction (ED) patients who first presented to our hospital and claimed poor response to sildenafil were enrolled into the study. The International Index of Erectile Function-5 (IIEF-5) was used to evaluate their baseline ED status and a self-administered sildenafil-use questionnaire composed of nine questions (SUQ-9) to assess how they had used sildenafil. A total of 44 subjects consent to rechallenge with sildenafil and were given thorough instruction based on individual answers to SUQ-9 and four doses of sildenafil 100 mg. After a 4-week follow-up, end point efficacy of rechallenge was evaluated using the IIEF-5 and the global assessment question (GAQ), ‘After the treatment, did you have successful sexual intercourse?’ Of the 60 subjects, 44 (77.3%) had one or more areas of major suboptimal use of sildenafil: 18 (30.0%) did not know that sexual stimulation was necessary for sildenafil to work, 36 (60.0%) attempted to use sildenafil less than four times, and 27 (45.0%) took a maximal dose less than 100 mg. Of the 44 patients undergoing sildenafil rechallenge, 34 (77.3%) completed the follow-up, while seven (15.9%) received only GAQ assessment by telephone interview and three (6.8%) were lost to follow-up. The total follow-up rate was 93.2% (41/44). Based on answers to the GAQ, the response rate to rechallenge was 58.5% (24/41). The mean improvement in the IIEF-5 score was 8.4±5.5 in responders (P <0.05). With individualized thorough instruction based on answers to SUQ-9 and scheduled follow-up, a high success rate was achieved by rechallenge with sildenafil in prior failures. The efficacy of sildenafil could be improved to a great extent by adequate education of patients and continuing medical education given to primary-care physicians.

Introduction

Sildenafil citrate (Viagra™), the first phosphodiesterase type 5 inhibitor for the treatment of erectile dysfunction (ED),1 has launched ED therapy into a new era. Sildenafil currently is viewed as the first-line treatment with high response rate around 70% and mild side effects.2,3 Only when this oral pharmacological therapy fails need further treatment be considered.4

Education about how to use sildenafil properly plays an important role in achieving the best response. Barada5 recently reported that it was possible to salvage sildenafil-unresponsive ED patients using rechallenge with sildenafil in conjunction with proper patient education, dose titration, and more attempts. Our experience is similar to that of Barada: some sildenafil-unresponsive ED patients may have been using the drug incorrectly. Therefore, we designed this study to assess the suboptimal use in a subset of ED patients in whom there was no response to sildenafil and to study the feasibility of re-challenging with sildenafil.

Materials and methods

From December 2001 to May 2002, we reviewed the medical and sexual histories of ED patients who first presented or were referred to our outpatient clinic with claims of poor response to sildenafil. We selected 60 consecutive cases who had no contraindications for sildenafil, such as nitroglycerine use, a history of radical prostatectomy, penile fibrosis, or retinitis pigmentosa.

After a complete history taking and physical examination, all subjects were instructed to complete two self-administered questionnaires: a Chinese version of the International Index of Erectile Function-5 (IIEF-5)6 to evaluate baseline ED status and a sildenafil-use questionnaire composed of nine questions (SUQ-9) designed by us (see Table 1) to assess previous use of sildenafil. After assessment of the completed questionnaires, patients were offered rechallenge with sildenafil. If this was rejected, they were offered other treatment options such as intracavernous injection or prosthesis implantation.

Table 1 Sildenafil-use questionnaire (SUQ-9) and distribution of answers from 60 prior sildenafil nonresponders before rechallenge

For patients who chose rechallenge, thorough instruction based on answers to SUQ-9 was conducted. It was suggested that four doses of sildenafil 100 mg be tried and patients be scheduled for outpatient follow-up 2 and 4 weeks following rechallenge. If patients achieved sexual intercourse with sildenafil 100 mg, they were permitted to reduce the dose to 50 mg. At the 2-week visit, preliminary results were assessed. For those with poor response, instruction on the optimal use of sildenafil was repeated. Those who had not used sildenafil in this period were encouraged to seek the chance to use it. At the 4-week visit, a global assessment question (GAQ) was asked, ‘After the treatment, did you have successful intercourse’, followed by another IIEF-5 assessment. If patients missed the 4-week visit, the GAQ was asked by telephone. End point IIEF-5 score was not available for these patients.

Data were analyzed using descriptive statistics, χ2 test, Fisher's exact test and t-test. A P-value of 0.05 or less was considered statistically significant.

Results

Table 1 lists the contents of SUQ-9 and the distribution of answers of 60 subjects to it. Based on the responses to SUQ-9, major suboptimal use of sildenafil was defined as meeting at least one of the following conditions: taking a maximal dose less than 100 mg, making less than four attempts to take sildenafil, and not knowing the necessity of sexual stimulation for Viagra to work. In all, 44 subjects (77.3%) had major suboptimal use of sildenafil in at least one area. Half of the 60 subjects obtained sildenafil without a prescription: 25 (41.6%) men from drugstores, four (6.7%) from abroad, and one (1.7%) from friend. There was no significant difference in the rate of the major suboptimal use between patients who obtained sildenafil with or without a prescription (Table 2).

Table 2 Areas of major suboptimal use of sildenafil in patients with or without prescriptions among 60 prior sildenafil nonresponders

Of the 60 subjects, 44 (73.3%) chose rechallenge with sildenafil, three (5.0%) used intracavernous alprostadil injection, six (10.0%) received penile prosthesis implantation, and seven (11.7%) declined any further treatment. The comparison of patients rechallenged with sildenafil and those who refused rechallenge is listed in Table 3. Of the 44 subjects who consent to rechallenge, the medium age, ED duration, and baseline IIEF-5 score was 65.5, 3 y, and 6, respectively, and 63.6% had one or more comorbidities, including diabetes mellitus (38.6%), hypertension (18.0%), coronary artery disease (4.5%), stroke (4.5%), major psychosis (2.3%), prostate cancer treated with radiotherapy (2.3%), alcoholism (2.3%), and liver cirrhosis with hepatoma (2.3%).

Table 3 Comparisons of patients rechallenged with sildenafil (rechallengers) and those who refused rechallenge (non-rechallengers) in 60 sildenafil nonresponders

Of the 44 patients rechallenged with sildenafil, 34 (77.3%) completed the 4-week follow-up, providing end point IIEF-5 scores and GAQ assessments; seven (15.9%) were followed up with telephone interviews and provided only end point GAQ assessments and three (6.8%) were lost to follow-up. The starting dose of sildenafil was 100 mg in 40 (90.9%) patients. Four patients (9.1%) refused the 100 mg dose and started with a dose of 50 mg. These patients were encouraged to increase the dose to 100 mg if they did not achieve sexual intercourse with 50 mg.

GAQ assessments revealed a response rate of 58.5% (24/41). The response rate was similar between those who previously obtained sildenafil with or without prescription (12/21=57.1% vs 12/20=60.0%). However, the subgroup of obtaining with prescription showed a higher rate of completing the scheduled follow-ups than of those without prescription (20/23=87.0% vs 14/21=66.7%).

The optimal dose of sildenafil to achieve sexual intercourse was 100 mg in 21 patients (87.5%) and 50 mg in three (12.5%). Six patients (14.6%) reported mild adverse events such as headache (two patients), facial flushing (two), or both (two), but none discontinued treatment because of side effects. There were trends that the responders were younger, had less severity of ED, and shorter duration of ED than nonresponders, in spite of P-values being >0.05 (Table 4). The mean improvement of IIEF-5 score from baseline was 8.4±5.5 and 1.4±2.8 for the 22 responders and 12 nonresponders, respectively (P<0.05).

Table 4 Comparisons between responders and nonresponders among 41 patients who were rechallenged with sildenafil

Table 5 compares the response rate, age, ED duration, and baseline IIEF-5 score between the 34 patients who completed the 4-week scheduled follow-up and the seven patients who did not fulfill it and answered GAQ by telephone interview. A higher response rate was observed in subjects who had completed the follow-ups than that of those who did not (64.7 vs 28.6%).

Table 5 Comparisons between 34 men who completed the scheduled follow-ups and seven men who answered GAQ by telephone interview

Discussion

The cumulative probability of achieving successful intercourse in men with ED treated with sildenafil increases with the number of attempts and reaches a plateau at eighth attempt.7 In clinical practice, it is very difficult to ask patients to try so many times before giving up, so less than four attempts was chosen as an inadequate attempt in this study.

Sildenafil at doses higher than 100 mg has successfully salvaged previous nonresponders, but is limited by a significantly higher incidence of adverse effects and a high treatment discontinuation rate.8 Thus, setting a maximal dose of sildenafil of 100 mg as the upper limit was appropriate in this study.

This study demonstrated a high response rate of 58.5% among patients who were rechallenged with sildenafil following previous treatment failure with the same drug. A similar response rate 53.9% (41/76) was reported after re-education of men who were initially sildneafil nonresponders.5 The reported efficacy of sildenafil may be influenced by the assessment methods, treatment duration, and the duration of follow-up. IIEF, a patient log, and a GAQ are used to assess the efficacy of sildenafil.2 In our study, no patient log was available to calculate the percentage of successful attempts at sexual intercourse and our follow-up period was only 4 weeks. These factors may make our study less comprehensive than previous trials. The IIEF-5 score combined with a GAQ were used to assess treatment outcome in our ED patients. A double-blind, placebo-controlled study would have avoided bias such as subjective reports and placebo effects. However, it would have been extremely difficult to persuade the previous sildenafil nonresponders to enter such a study.

To buy medicines from drugstores without prescription is illegal, but in fact is a common phenomenon in Taiwan. In our study, half of the 60 sildenafil nonresponders obtained sildenafil without prescription and most of them were from drugstores. ED may be an early sign of cardiovascular diseases9,10 and the presenting symptom of underlying diseases such as diabetes mellitus or other endocrinopathy. Therefore, patients who do not seek medical advice may lose the opportunity for early diagnosis and treatment of these diseases. Illegal obtaining of sildenafil raises another concern about the purity of medicine. In addition to the legal and purity issues, the lack of instruction from physicians of how to use sildenafil may reduce the response rate.

A good follow-up is also a key factor for successful treatment. In our study, the response rate in men who completed the follow-ups and who did not complete was 64.7 and 28.6%, respectively, in spite the latter were even younger and had a little less severe ED than the former (Table 5). Therefore, public awareness of the importance of correct medical advice for ED and regular follow-ups is necessary.

Our study showed that the rate of suboptimal use of sildenafil between patients with and without prescriptions was similar (Table 2). This indicated the possibility that the primary-care physicians who had prescribed sildenafil did not provide adequate education to ED patients, that they were inexperienced in the new oral drug in ED management, or that patients did not return for follow-up. With the introduction of newer drugs and an increased awareness of ED treatment modalities, more patients may visit primary-care physicians for ED. Thus, continuing medical education of primary-care physicians in ED will be extremely useful.

Previous reports have demonstrated that patients with mild or vasculogenic ED have a better response to sildenafil, while patients with severe or neurogenic ED have a lower response, and no particular factor predicts absolute failure with sildenafil.11 The 60 previous sildenafil nonresponders in this study had a higher incidence of having DM comorbidity than our regular ED patients in clinical practice (36.6 vs 20.4%), and most of them had severe ED (78.3% having baseline IIEF-5 score <11), which indicated that they were prone to be sildenafil treatment failures. After intensive education based on individual answers to SUQ-9, a 58.5% response rate was achieved. We believe thorough instruction is important for the cases who are taken as difficult to treat and the application of SUQ-9 is an effective analysis tool to help rechallenge sildenafil treatment failures.

According to Krane,4 ‘The concept that sildenafil is the only viable option is all too pervasive and should be re-examined by ED patients and the physicians who may be treating them’.However, in our study, seven (11.7%) patients refused therapy after prior sildenafil failure; none of the 17 patients who did not respond to sildenafil rechallenge were willing to receive other therapies. Therefore, it is extremely important that new cases of ED be assessed properly and the patients educated and followed regularly in order to obtain optimal results.

Conclusions

In order to treat true sildenafil nonresponders, factors such as insufficient attempts, inadequate dosing, lack of sexual stimulation, or other suboptimal uses should first be corrected. Besides, having a food follow-up will yield a high response rate to sildenafil rechallenge.

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Correspondence to B-P Jiann.

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Jiann, BP., Yu, CC., Su, CC. et al. Rechallenge prior sildenafil nonresponders. Int J Impot Res 16, 64–68 (2004). https://doi.org/10.1038/sj.ijir.3901143

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Keywords

  • sildenafil (Viagra™) failure
  • inappropriate use
  • IIEF-5
  • rechallenge

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