SWITCHING FROM INTRACAVERNOUS PROSTAGLANDIN E1 INJECTIONS TO ORAL SILDENAFIL CITRATE IN PATIENTS WITH ERECTILE DYSFUNCTION: RESULTS OF A MULTICENTER EUROPEAN STUDY

0022-5347/00/1643-0708/0 THE JOURNAL OF UROLOGY® Copyright © 2000 by AMERICAN UROLOGICAL ASSOCIATION, INC.®

Vol. 164, 708 –711, September 2000 Printed in U.S.A.

SWITCHING FROM INTRACAVERNOUS PROSTAGLANDIN E1 INJECTIONS TO ORAL SILDENAFIL CITRATE IN PATIENTS WITH ERECTILE DYSFUNCTION: RESULTS OF A MULTICENTER EUROPEAN STUDY FRANC ¸ OIS GIULIANO,*,† FRANCESCO MONTORSI, VINCENZO MIRONE,‡ DOMINIQUE ROSSI MICHAEL SWEENEY§ FOR THE SILDENAFIL MULTICENTER STUDY GROUP㛳

AND

From the Department of Urology, CHU de Biceˆtre, AP-HP Le Kremlin Biceˆtre and Hoˆpital Salvator, Marseille, France, Istituto San Raffaele, Milan and Universita` di Napoli Federico II, Napoli, Italy, and Pfizer, Inc., New York, New York

ABSTRACT

Purpose: Intracavernous injection is a well established medical therapy for erectile dysfunction. We assessed the rate of success when patients with erectile dysfunction who were effectively treated with intracavernous injections of prostaglandin E1 were changed to oral therapy with sildenafil citrate. Materials and Methods: Only patients effectively managing erectile dysfunction by the intracavernous injection of 20 ␮g. or less prostaglandin E1 for more than 6 months were eligible for study enrollment. After a 4-week run-in phase while intracavernous prostaglandin E1 therapy continued and a 48-hour washout period 176 patients with erectile dysfunction received open label sildenafil orally for 12 weeks. Satisfaction with treatment was evaluated by the 11-item erectile dysfunction index of treatment satisfaction questionnaire. A successful change to sildenafil was prospectively defined as a questionnaire score of 0 to 100 after sildenafil that was greater than or equal to the score after intracavernous prostaglandin E1. Results: Of the 176 patients 69% (95% confidence limit 62 to 76) successfully changed from intracavernous prostaglandin E1 injections to oral sildenafil and elected to continue oral treatment. Mean satisfaction score after sildenafil and prostaglandin E1 was 73.8 and 63.9, respectively (p ⬍0.001). Only 3 patients (1.7%) discontinued therapy because of treatment related adverse events. Conclusions: More than two-thirds of the men with erectile dysfunction who were stable on intracavernous injections of 20 ␮g. or less prostaglandin E1 successfully changed to oral sildenafil, as determined by maintained or enhanced treatment satisfaction. KEY WORDS: impotence, alprostadil, patient satisfaction, penile erection, penis

During the last several years the management of erectile dysfunction has changed markedly because of our improved understanding of the mechanism of penile erection, identification of underlying risk factors and introduction of new treatments. In 1998 the first effective oral treatment for erectile dysfunction, sildenafil citrate, was introduced in many countries. Sildenafil is a selective inhibitor of phosphodiesterase type 5, and effective and well tolerated for erectile

dysfunction of various etiologies.1–3 Available treatment options for this condition now include sexual-psychosexual or marital therapy, oral drug therapy, vacuum constriction devices, intracavernous injection therapy with vasoactive agents such as prostaglandin E1, papaverine and phentolamine, transurethral prostaglandin E1 delivery, penile implants and vascular surgery. Even before sildenafil became available patients with erectile dysfunction strongly preferred the least invasive form of therapy, such as oral medication. Jarow et al reported that 298 of 377 patients (79%) elected this treatment despite a low rate of response.4 Intracavernous injection is a well established medical treatment for erectile dysfunction.5, 6 Advantages of intracavernous injection of vasoactive agents that directly relax corporeal smooth muscle include broad based efficacy, relative safety and rapid onset of action.7 The side effects are primarily local, including penile pain and fibrosis and priapism. Intracavernous injection therapy is contraindicated in sickle cell anemia and other conditions that increase the risk of priapism. In various studies evaluating intracavernous prostaglandin E1 injection therapy discontinuation rates were relatively high.6, 8 –11 With the availability of sildenafil, many patients with erectile dysfunction are asking physicians to change treatment from intracavernous injection to oral sildenafil. We evaluated the success rate when patients with erectile dysfunction who were stable on intracavernous pros-

Accepted for publication April 20, 2000. Supported by Pfizer, Inc. * Requests for reprints: Department of Urology, CHU de Biceˆtre, 78 rue du General Leclerc, AP-HP Le Kremlin Biceˆtre, France. † Financial interest and/or other relationship with Pfizer, ICOSLilly, Schering-Plough, Abbott, TAP Pharmaceuticals, Nitromed, Bayer AG and Merck. ‡ Financial interest and/or other relationship with Essex, ICOSLilly, Takeda Chemical Industries and Pfizer. § Financial interest and/or other relationship with Pfizer. 㛳 Participating institutions and investigators: E. Amar and E. Blanc, G. H. Bichat-C. I. Bernard, M.-O. Bitker, Pitie´-Salpe´trie` Hoˆpital and F. Cour, Centre Me´dico-Chirugical, Paris; M. Belicar, Hoˆpital Sud, Amiens; O. Bouchot, Hoˆtel Dieu, Nantes; F. Giuliano and Y. Hammoudi, CHU de Biceˆtre, Biceˆtre; D. Rossi, Hoˆpital Salvator, Marseille; and M. Schouman, Hoˆpital du Bon Secours, Metz, France; and W. Artibani and E. Pescatori, Universita´ di Modena, Modena; E. Belgrano and G. Savoca, Universita` delgi Studi di Trieste, Trieste; V. Gentile and P. di Palma, Universita` La Sapienza and Universita` Cattolica, Rome; F. Menchini-Fabris and P. Rossi, Universita` di Pisa, Pisa; V. Mirone and A. Palmieri, Universita` Federico II di Napoli, Napoli; and F. Montorsi and L. Barbieri, Istituto San Raffaele, Milan, Italy. 708

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taglandin E1 injection therapy were changed to oral sildenafil in a clinical practice setting. METHODS

Study inclusion criteria were age 18 years or older with a documented diagnosis of erectile dysfunction more than 6 months in duration, effective use of intracavernous prostaglandin E1 injection therapy for more than 6 months and a stable dose of 20 ␮g. or less for more than 3 months, a stable relationship for 6 months or more and written informed consent. Exclusion criteria were genital anatomical deformities that significantly impaired erection, major hematological, renal, or hepatic abnormalities, other sexual disorders considered to be the primary diagnosis, a major psychiatric disorder that was not well controlled with treatment, significant cardiovascular disease, stroke or myocardial infarction within the previous 6 months, sitting blood pressure less than 90/50 or greater than 180/110 mm. Hg, a history of retinitis pigmentosa, a prescription for and/or the use of nitrates or nitric oxide donors and the use of a vacuum device, or other medication or therapy for erectile dysfunction except intracavernous prostaglandin E1 injections. Our study with a 16-week, multicenter, open label design was performed at 16 centers in France and Italy. Patient 1 started treatment on January 12, 1998 and the final patient completed treatment on January 14, 1999. After a 4-week run-in phase from weeks ⫺4 to 0 during which patients continued to receive intracavernous prostaglandin E1 injection therapy on at least 2 occasions sildenafil was given for 12 weeks from weeks 0 to 12. A 48-hour washout period separated the 2 treatment phases. Because patients entering the study were on effective erectile dysfunction therapy, all those enrolled were changed to open label treatment with sildenafil, reflecting the clinical practice situation. The 50 mg. initial dose of sildenafil was adjusted to 100 or 25 mg. based on therapeutic response and tolerability. Patients were instructed to ingest sildenafil as required approximately 1 hour before sexual activity with a maximum dose frequency of once daily. The etiology of erectile dysfunction was classified by the investigator as organic, psychogenic or mixed based on the medical history and physical examination. The 11-item erectile dysfunction index of treatment satisfaction questionnaire12 was used to assess patient attitude toward and expectations of medical treatment for erectile dysfunction at weeks 0 and 12. This questionnaire is a brief, self-administered, unidimensional, psychometrically validated instrument for assessing patient satisfaction with treatment modalities for erectile dysfunction. Questionnaire items evaluate overall satisfaction with treatment, the degree to which treatment meets patient expectations, likelihood of continued treatment, ease of use, satisfaction with treatment onset and duration, confidence in the ability to engage in sexual activity, overall partner satisfaction with treatment, partner opinion on continued patient treatment, naturalness of achieving erection with treatment and naturalness of erection with treatment. Each questionnaire item was scored on a scale of 0 to 4 with higher scores indicating greater treatment satisfaction. To create a metric score that was easier to interpret we calculated an individual overall mean score by multiplying the mean score on all 11 questions by 25, resulting in a treatment satisfaction range of 0 — extremely low to 100 — extremely high. The primary outcome measure of our study was the proportion of patients who successfully changed to sildenafil. A successful change was prospectively defined as a patient with an erectile dysfunction index of treatment satisfaction mean satisfaction score after sildenafil treatment at week 12 or the discontinuation of treatment that was greater than or equal to the mean questionnaire satisfaction score after intracavernous prostaglandin E1 treatment at week 0. Patients lost to followup

after confirmation that they received at least 1 dose of sildenafil were considered to have been changed unsuccessfully. Secondary efficacy measures included questions 3 (“When you attempted sexual intercourse, how often were you able to penetrate your partner?”) and 4 (“During sexual intercourse, how often were you able to maintain your erection after you had penetrated your partner?”) of the International Index of Erectile Dysfunction (IIED) questionnaire13 at weeks 0 and 12, and an event diary of erectile activity at weeks ⫺4 through 12. Responses to each question on the IIED were rated on a scale of 1—almost never and/or never to 5—almost always and/or always with a score of 0 indicating no attempted sexual intercourse. In the event diary patients were asked to record the date and dose of medication, sexual stimulation and whether sexual intercourse was successful. Adverse events during treatment and up to 7 days after the last dose of sildenafil were recorded. The investigator was asked to classify each adverse event as definitely related, of uncertain relationship or not related to the study medication and report immediately any serious adverse event. Physical examination, sitting blood pressure and heart rate measurement, and standard hematology and blood chemistry laboratory tests were performed at screening and at the end of treatment visit. Intent to treat analysis of all efficacy variables included all patients with at least 1 assessment after week 0 who received at least 1 dose of sildenafil. To be eligible for safety analysis inclusion patients received at least 1 dose of sildenafil. We calculated the mean response scores of the erectile dysfunction index of treatment satisfaction questionnaire and each international index of erectile dysfunction question as well as the mean number of successful attempts at sexual intercourse monthly per treatment. The between treatment difference was analyzed for each parameter using the paired t test and commercially available computer software. RESULTS

Table 1 shows the demographics and dosing parameters of the 176 patients who changed from prostaglandin E1 injection therapy to oral sildenafil. The mean duration of erectile dysfunction in these men was 4.3 years, the mean duration of intracavernous injection therapy with prostaglandin E1 was 21 months and the mean dose of intracavernous prostaglandin E1 was 13 ␮g. The mean final dose of sildenafil was 83.9 mg. Of the patients with erectile dysfunction 69% (95% confidence interval [CI] 62 to 76) successfully changed from intracavernous prostaglandin E1 injection therapy to oral sildenafil, as indicated by a mean erectile dysfunction index of treatment satisfaction score after sildenafil treatment of greater than or equal to the mean score after intracavernous

TABLE 1. Demographics and dose parameters Parameter

Sildenafil

No. pts. 76 Mean age (range) 56 (23–80) Mean yrs. erectile dysfunction (range) 4.3 (0.5–24.1) Erectile dysfunction etiology (% pts.): Organic 42 Psychogenic 34 Mixed 24 Mean prostaglandin E1 injection therapy: Mos. duration (range) 21 (2–97)* ␮g. Dose (range) 13 (2–20) Median No. sildenafil doses (range) 46 (1–84) Final mg. sildenafil dose (% pts.): 25 2 50 30 100 69 Mean final sildenafil dose (mg.) 83.9 * One patient on intracavernous prostaglandin E1 for 2 months was enrolled in the study and included in the analysis.

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therapy (fig. 1). The mean score after sildenafil versus prostaglandin E1 treatment was 73.8 versus 63.9 (p ⬍0.001, fig. 1). Mean score plus or minus standard error for the question on confidence in the ability to engage in sexual activity was similar in patients on sildenafil and prostaglandin E1 (3.04 ⫾ 1.0 and 3.09 ⫾ 0.8, respectively). Mean response scores for international index of erectile dysfunction questions 3 and 4 were comparable after treatment with prostaglandin E1 and sildenafil (4.1 and 4.0, and 4.2 and 4.1, respectively, fig. 2). Data from the event log of erectile activity indicated a mean of 3.6 successful attempts at sexual intercourse per 4 attempts overall monthly for prostaglandin E1 versus 10.9 per 13.7 attempts for sildenafil (p ⬍0.001). Success with prostaglandin E1 was significantly higher than with sildenafil (90% versus 79%, p ⬍0.001). The most common adverse events during sildenafil treatment were flushing, headache and abdominal pain (table 2). Of these adverse events 95% were mild or moderate. The 12 weeks of treatment were completed by 151 of the 176 patients (85.8%) on sildenafil (table 2). Only 3 men (1.7%) discontinued therapy because of treatment related adverse events, including headache and flushing in 1, dizziness, nausea and vomiting in 1 and asthenia, headache and nausea in 1. Serious adverse events in 3 cases during sildenafil treatment involved peritonitis and a perforated sigmoid colon diverticulum, penile infection and osteonecrosis of the femur head in 1 each. These events were considered to be unassociated with therapy. Sildenafil was discontinued in 13 patients (7.4%) because of an insufficient response. Laboratory tests showed no evidence of sildenafil related abnormalities.

FIG. 2. Mean response scores of IIED questions 3 (Q3) on achieving and 4 (Q4) on maintaining erection after intracavernous prostaglandin E1 (PGE1) injection therapy at week 0 and after sildenafil treatment at week 12. Bars represent plus or minus standard error.

TABLE 2. Most common adverse events and reasons for discontinuing sildenafil treatment Adverse Event

No. Pts. (%)

Overall 176 Flushing 24 (13.6) Headache 16 (9.1) Abdominal pain 7 (4) Completed treatment 151 (85.8) Discontinued treatment 25 (14.2) Insufficient response 13 (7.4) Adverse event 4 (2.3) Lost to followup, protocol violation or consent withdrawn 8 (4.5) Adverse event occurred in 3% or more of patients.

DISCUSSION

Our study was designed to assess the success rate when patients with erectile dysfunction who were successfully treated with intracavernous prostaglandin E1 injections were changed to oral sildenafil. Sildenafil therapy is noninvasive and discrete, and facilitates erection only in response to sexual stimulation. As a result, men with erectile dysfunction are asking their clinicians whether they may switch from other therapy to sildenafil. As in clinical practice, our patients changed to sildenafil in an open label fashion. We did not evaluate the success rate of a change to placebo because of the ethical issues involved. Moreover, the response in patients on placebo in clinical trials of sildenafil have been previously published.1, 2 Our patients had used intracavernous prostaglandin E1 injection therapy for a mean of 21 months, indicating chronic erectile dysfunction, with a mean maintenance dose of 13 ␮g. This maintenance dose of prostaglandin E1 is similar to that

FIG. 1. A, proportion of patients successfully changed from intracavernous prostaglandin E1 (PGE1) injection therapy to oral sildenafil. Bar represents 95% CI. B, mean erectile dysfunction index of treatment satisfaction (EDITS) scores after intracavernousal prostaglandin E1 injection therapy at week 0 and after sildenafil treatment at week 12. Bars represent plus or minus standard error.

in previous reports of effective prostaglandin E1 therapeutic doses. In a study of 162 patients with erectile dysfunction Porst et al reported a mean dose of 13.4 ␮g. after 1 year of treatment.14 Moreover, the series of Ismail et al demonstrating that the mean maintenance dose of prostaglandin E1 increased linearly with patient age the mean dose was 13.7 ␮g. in men 51 to 60 years old.15 Thus, our patients with a mean age of 56 years appear to be representative of those in a clinical practice situation who are on an effective and therapeutic dose of prostaglandin E1 for erectile dysfunction. Our data show that more than two-thirds of the men who were satisfied with intracavernous prostaglandin E1 injections for managing erectile dysfunction successfully changed to oral sildenafil treatment. The success rate of the treatment change was evaluated with a validated 11-item erectile dysfunction index of treatment satisfaction questionnaire, which is a reliable (test-retest reliability coefficient 0.98) and internally consistent (Cronbach’s ␣ 0.90) instrument for assessing patient satisfaction with medical treatments for erectile dysfunction.12 The IIED mean scores for questions 3 and 4 on achieving and maintaining erection were comparable after the 2 treatments, indicating that patients achieved and maintained erection at least most times. Interestingly data from the event diary of erectile activity indicated that patients achieved significantly more successful attempts at sexual intercourse monthly while on oral sildenafil than intracavernous prostaglandin E1 (10.9 versus 3.6). Possible explanations for this marked difference in the 2 modalities include the advantages of oral treatment (noninvasive, simple to use and discrete) and the fact that sildenafil was supplied as part of a clinical trial, while prostaglandin E1 was supplied by the patient. Although the number of successful attempts monthly was greater with sildenafil than with prostaglandin E1, success was greater with prostaglandin E1 than with sildenafil (90% versus 79%). A possible explanation for this difference is the requirement of adequate sexual stimulation for sildenafil to be effective. Conversely no sexual stimulation is necessary to achieve erection after intracavernous prostaglandin E1 injection.

PROSTAGLANDIN E1 VERSUS SILDENAFIL CITRATE FOR ERECTILE DYSFUNCTION

Intracavernous injection therapy with vasoactive agents is effective in many men with erectile dysfunction.5, 6 Despite the beneficial effects intracavernousal prostaglandin E1 injection is associated with a high rate of patient initiated discontinuation of treatment.6, 8, 9 Similar or higher rates of discontinuation were reported for other intracavernous vasoactive agents.16, 17 These high rates of discontinuation were partially attributed to the invasive nature of injection, treatment side effects, and patient and/or partner dissatisfaction with pharmacologically induced erection.7 Due to the availability of oral sildenafil many drawbacks to long-term erectile dysfunction treatment have been addressed. In our study the rate of withdrawal from sildenafil due to an insufficient response or adverse event was less than 10%, which is considerably lower than that reported for prostaglandin E1.6, 8, 9 Only 3 patients (1.7%) discontinued sildenafil because of treatment related adverse events. Sildenafil treatment duration was 12 weeks, whereas successful intracavernousal injection therapy lasted a minimum of 6 months. This disparity may have influenced the patient satisfaction rate. Nevertheless, preliminary data demonstrate that the rate of discontinuation from all causes remained relatively low in patients with erectile dysfunction during sildenafil treatment years 1 and 2 (12.9% and 9%, respectively).18, 19 These low rates of withdrawal imply that men continued to be satisfied with sildenafil during long-term treatment. Additional data on patient withdrawal from therapy after 2 years of sildenafil are needed to confirm this suggestion. Mean age of our patients was 56 years and the etiology of erectile dysfunction was psychogenic in 24%. Men with these characteristics may have a more favorable pharmacological response to either therapy than those who are older with a higher percent of erectile dysfunction due to an organic etiology. The results of our study provide important information for clinicians managing erectile dysfunction. Before oral sildenafil was available the most effective and common pharmacological treatment of erectile dysfunction was intracavernous injection. Because it is an invasive technique that necessitates patient training and dose titration in the office, this treatment was predominantly prescribed by erectile dysfunction specialists and urologists. Our study provides initial evidence that the majority of patients with erectile dysfunction who are effectively treated with intracavernous injection are more satisfied with therapy after changing to oral sildenafil. The change to oral sildenafil, which is easier to initiate, resulted in the management of most erectile dysfunction cases in the primary care setting.20 This change in practice patterns may facilitate the identification and elimination of modifiable risk factors associated with erectile dysfunction that are generally more easily addressed by primary care physicians, such as medication, cigarette smoking, endocrine conditions and general cardiovascular risk factors, before or during treatment.20 As a result, male sexual function may come to be viewed as an integral part of male general health rather than as a separate and unrelated issue. In conclusion, more than two-thirds of the patients with erectile dysfunction who were stable on intracavernous injections of 20 ␮g. or less prostaglandin E1 successfully changed to treatment with oral sildenafil, as measured by maintained or enhanced treatment satisfaction.

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