Acceptance, Efficacy and Preference of Sildenafil in Patients on Long Term Auto-Intracavernosal Therapy

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Acceptance, efﬁcacy and preference of Sildenaﬁl in patients on long term auto-intracavernosal therapy: a study with follow-up at one year

J BuvatÃ, A Lemaire and J Ratajczyk

Centre ETPARP, 3 rue Carolus, 59000 Lille, France

Purpose: To assess the acceptance, long term efficacy and preference of Sildenafil in impotent patients previously on auto-intracavernosal therapy. Material and methods: The patients were the 107 men (mean age 58.4 y) on auto-intracavernosal therapy (auto-IC) for more than 6 months (mean duration 32.7 months > 12 months in 100) who were consecutively seen within 6 months of the launch of Sildenafil in France. If there was no contra-indications to Sildenafil they were proposed a trial of Sildenafil at home. Following this trial they were given the possibility to change their therapy and were followed for 1 y at 3 months intervals. Results: Three patients had contra-indications to Sildenafil. Of the remaining 104, 45 (43%) refused the trial, mainly because they were afraid of possible cardiac risks (n ¼ 21, including 51% of the psychogenic and mixed patients compared to 8% of the predominantly organic ones). Among the 59 who tried it, Sildenafil gave good results in 46 (78%), including 100% of the predominantly psychogenic and 61.5% of the predominantly organic ones) with minimum effective doses of 25 mg in 7, 50 mg in 18 and 100 mg in 21. It failed in 9 (15%) and gave average results in 4 (penetration with a non fully satisfying erection). There was a clear relationship between the sensitivity to Sildenafil and that to Alprostadil, the vasoactive agent predominantly used for the auto-ICIs. Every 46 patients with good result of Sildenafil elected to continue with this drug, including 3 who used both Sildenafil and auto-ICIs in alternance. Every 4 patients with average results elected to continue with auto-ICI including 1 who also used Sildenafil in alternance. Five of the 50 patients with good or average results were lost to follow-up within 6 months. At the 1 y follow-up visit, 43 of the 45 others were still using Sildenafil, in alternance with auto-ICI in 1. No one reported a decrease in efficacy with time. The 2 patients with average results still in the study were on auto-ICIs. Conclusion: Sildenafil is highly effective in the impotent men previously treated with auto-ICI and its efficacy is maintained at least for 1 y. When tried and effective it is preferred by most men but almost half of our patients refused trying it. International Journal of Impotence Research (2002) 14, 483–486. doi:10.1038=sj.ijir.3900913

Keywords: erectile dysfunction; Sildenaﬁl; intracavernosal therapy; preference

Sildenafil has revolutionized the treatment of erec- addition we assessed the adherence to Sildenafil tile dysfunction and is now considered as the first treatment, and the results at 1 y in the patients who option in this field.1 However this treatment is not changed for this drug. accepted by every patient, and it may be less effective than the intracavernosal injections of vaso-active agents (ICI). In this study, we intended assessing the acceptance and efficacy of Sildenafil in Materials and methods a particular category of patients, those previously on long term auto-intracavernosal therapy (auto-ICI). In The patients were the 107 impotent males on auto-ICI therapy since at least 6 months (more than 12 months *Correspondence: J Buvat, 3 rue Carolus, 59000 Lille, France. in 100) who were consecutively seen in our center for Tel: þ 333 20 93 50 70, fax: þ 333 20 93 98 46, regular follow-up within 6 months of the launch of 1 E-mail: [email protected] Sildenafil (Viagra ) in France (October 1998). They Received 22 April 2002; accepted 29 May 2002 were 35 to 70 y old (mean 58.4) with a mean duration Sildenafil in men on auto-ICI therapy J Buvat et al 484 of auto-ICI therapy of 32.7 months. According to intercourse due to insufficient rigidity or duration, medical and sexual history, as well as to the results of and a failure of Sildenafil as the failure of at least 2 the tests performed before starting auto-ICIs, the attempts with the dose of 100 mg. etiology of erectile dysfunction was considered as IV. Following the initial trial, the patients able to predominantly psychogenic in 41, predominantly penetrate on Sildenafil were proposed to change organic in 38 and mixed in 28. The main potential their treatment for this drug. On request they were organic factors identified in the 2 last categories were allowed to use both treatments in alternance, on diabetes in 10, vascular or tissular in 58, and condition of leaving an interval of at least 24 h neurological in 15 (several factors were associated between using Sildenafil and injecting themselves in 17). The vaso-active agents used for the injections and vice versa. were Alprostadil alone (PGE1) in 83, bimix (PGE1 þ V. The patients who decided to continue with Phentolamine), or trimix (PGE1 þ Phentolamine þ Sildenafil were then followed up at 3 months Papaverine) in 21 (we use these associations only in intervals for one year in order to assess the long the case of failure of PGE1 alone) and Moxisylyte in 3. term results and tolerance of this drug, as well as the The study design included 5 phases: final preference of the patients. I. Checking for contra-indications to Sildenafil. The following were considered as exclusion criteria: recent (< 6 months) myocardial infarction or stroke, Results unstable angina, retinitis pigmentosa, treatment with nitrates or Nitric Oxyde donors (Linsidomine, Nicorandil). Three (2.8%) of the 107 impotent patients on long- II. In the case there were no contra-indications term auto-ICI had contra-indications to this drug (all proposing to the patients a trial of Sildenafil at home 3 were taking nitrates for coronary heart disease). after detailed information on the effectiveness, Among the 104 presenting no contra-indication 45 expected adverse events, and safety of this treat- (43%) refused the trial and 59 (57%) accepted it. ment. Because our study started only a few months The proportion of those who refused was higher in after the mediatic turmoil which followed the case of psychogenic contribution to erectile dys- announcement of several fatalities in american function (predominantly psychogenic group 15=40: men on Viagra1, many men and=or female partners 37.5%, mixed group 19=27: 70%, predominantly expressed important concerns regarding possible organic 11=37: 30%). The main reason alleged for cardiac risks of this medication. These were given refusing the trial was the fear of possible risks of more details on the absence of significant difference Sildenafil despite our detailed information, essen- in the rates of deaths as well as of the different types tially cardiac risks (n ¼ 21: 20% of all the patients of cardiovascular events in the patients on Sildenafil who were proposed the trial, including 8 of the with respect to those on placebo in the pre- predominantly psychogenic [20% of this category], registration double blind placebo controlled stu- 10 of the mixed [37%] and only 3 of the predomi- dies.2 The persistance of the Food and Drug nantly organic cases [8%]). Eighteen other patients Administration, and later of the corresponding (17%) alleged they did not have any reason for french ‘‘Agence du Me´dicament’’, in their official changing since they were fully satisfied with the opinion that Sildenafil was safe on condition of auto-ICI (psychogenic: 5=40: 12%, mixed: 7=27: 26%, respecting its specific contra-indications were also organic: 6=37: 11%). It seemed to us that in some of commented. these cases the fear of possible risks might in fact be III. The patients who accepted the trial were the real underlying reason. Four of the patients proposed to start with the dose of 50 mg, or 25 mg if mainly alleged the longer time to erection with they were more than 65 y old, if they had significant Sildenafil compared to ICI. Lastly 2 alleged the cost hepatic or renal insufficiency (one case in this of Sildenafil. In this study, they had to pay for their study), or if they remained afraid of the possible medications. Both were on triple mix and used a low cardiac risks. The tablet was taken 1 hour before an dose of PGE1, resulting in a lower cost of the anticipated attempt of intercourse, having avoided injections with respect to Sildenafil. to take previously a fatty meal, or more than one The results of the Sildenafil trial are listed in glass of alcoholic drink. The requirement of a sexual Table 1. Overall 78% of the patients reported good stimulation to induce erection, on the contrary of results and 7% average results, while Sildenafil following the ICI, was emphasized to them. The totally failed in 15%. All the predominantly psy- dose was then gradually increased up to 100 mg in chogenic patients had good results (100%) while the case the previous step had failed at least twice to rate of total failures was higher in the mixed (12.5%) result in an erection allowing penetration and a and predominantly organic (31%) groups. The satisfying intercourse. A good result was defined by highest failure rate was in the small subgroup of an erection adequate for penetration and satisfactory the 7 diabetic patients. In the 46 cases reporting sexual intercourse, an average result as the possibility good results with Sildenafil, the minimum effective of penetration followed by a non fully satisfactory dose was 25 mg in 7 (15%), 50 mg in 18 (39%) and

International Journal of Impotence Research Sildenaﬁl in men on auto-ICI therapy J Buvat et al

Table 1 Results of the trial of Sildenaﬁl (up to 100 mg at least twice) in 59 men previously on auto-ICI 485

All the cases Organic Psychogenic Mixed Diabetic

No tested cases 59 26 25 8 7 Good results* 46 (78%) 16 (61.5%) 25 (100%) 5 (62.5%) 4 (57%) Average results* 4 (7%) 2 (8%) — 2 (25%) — Failure** 9 (15%) 8 (31%) — 1 (12.5%) 3 (43%)

*Satisfying intercourse. **Intercourse with non fully satisfying erection.

100 mg in 21 (46%). The results were also compared patient reported a decrease in the efficacy of this to the type and dosage of the ICI (Table 2). Triple drug with time. mixture 1 contained 10 mg of PGE1, 8 mg of papa- Overall 22 of the 104 patients (21%) reported at verine and 0.2 mg of phentolamine=ml and Triple least 1 side effect following the use of Sildenafil. mixture 2 10 mg of PGE1, 20 mg of papaverine and These included headache in 10, flushing in 10, 0.8 mg of phentolamine=ml. They were used at doses dyspepsia in 5, nasal congestion in 2 and visual of 0.5 to 2 ml per ICI. Triple Mix 1 was only used in changes in 2 (blue haze in 1 and an increase of the patients resistant to 20 mg of PGE1, or in those brightness in 1). All these side effects were mild to having problems of painful erection with the moderate in intensity and transient in duration effective dose of PGE1. Triple mixture 2 was used (limited to 1 to 24 hours following the intake of a only in the patients resistant to both PGEI and Triple tablet). No one led to permanent discontinuation of Mix 1, thus in the patients with the most severe the treatment. impotence as regards their sensitivity to the ICI. There was clearly a relationship between the success of Sildenafil and the sensitivity of the Discussion patients to ICI. Sildenafil failed in only 1 of the 29 patients requiring 10 mg or less of PGE1, compared to 23% of the patients requiring 20 mg of PGE1 and 4=6, Our study confirms that Sildenafil is highly effective 67%, of those only sensitive to Triple mixture 2. All in the impotent patients treated with auto-ICI before the 7 patients responding to the low dose of 25 mg were sensitive to a low or medium dose of PGE1 (10 mg or less). Following the trial, all the 46 patients with good results elected to continue Sildenafil including 3 who requested to use both treatments in alternance. Three of the 4 patients with average results elected to stay on auto-ICI, while the fourth started to use both treatments in alternance. Figure 1 shows the preference of these 50 preceding patients at the different stages of the study. Five patients were lost to follow-up (2 at 3 months and 3 at 6 months), including 2 of the 4 patients with average results. After 12 months 2 of 45 patients (4%) were on auto-ICI (the 2 patients with average results of Sildenafil still in the study), Figure 1 Preference for Sildenafil or Intracavernosal Therapy only 1 was still using both types of therapies (2%), (ICT) of the 50 patients previously on ICT who responded to and 42=45 were using only Sildenafil. No one Sildenafil.

Table 2 Results of the trial of Sildenaﬁl according to the type and the dose of drug required for the auto-ICI

Failure Average Good Success Success Success No patients of Sild. result result 25 mg 50 mg 100 mg

< 10 mg PGE1 4 ——4 (100%) 1 3 — 10 mg PGE1 27 1 (4%) 1 25 (93%) 6 10 9 20 mg PGE1 13 3 (23%) — 10 (77%) — 28 Triple Mix 1 9 1 (11%) 1 7 (78%) — 34 Triple Mix 2 6 4 (67%) 2 (33%) — ——— All the cases 59 9 4 46 7 18 21

Triple Mix 1: PGE1 10 mg, Papav. 8 mg, Phentol. 0.2 mg=ml. Triple Mix 2: PGE1 20 mg, Papav. 20 mg, Phentol. 0.8 mg=ml.

International Journal of Impotence Research Sildenafil in men on auto-ICI therapy J Buvat et al 486 the launch of this oral therapy. Our success rate of activity must be the first consideration before 78% fits well with those of 75% in the patients of advising patients with known or possible cardio- Hatzichristou et al,3 70% in these of McMahon et al4 vascular disease to resume having sex, or before and 69% in these of Giuliano et al.5 In our patients initiating any therapy for erectile dysfunction. the success rate was clearly higher in the subgroup Likewise the association with nitrates or nitric oxide with psychogenic impotence than in that with donors must be definitively contra-indicated. predominantly organic origin. As Hatzichristou et al,3 we found an inverse relationship between the effectiveness of Sildenafil and the dose of vasoactive agents required for the effectiveness of the auto-ICI Conclusions therapy, ie higher was the dose of the auto-ICI or the strength of the mixture required, lower was the The high efficacy and preference rates of Sildenafil success rate of Sildenafil. The rate of the adverse in men with erectile dysfunction previously on events was close to that reported in unselected auto-ICI confirms its place as first line treatment for populations treated with Sildenafil, and lower than erectile dysfunction of various etiologies. Never- that of the patients previously on auto-ICI of theless the fact that Sildenafil failed in some men 3 Hatzichristou et al. All the adverse events were successfully treated with auto-ICI shows that every mild or moderate, and transient in nature. patients should be informed about the potential In our series all the patients who tried Sildenafil effectiveness of this second therapy in case of failure and obtained good results elected to continue with of Sildenafil. Success rates of 33%4 to 88%7 have this drug. This rate of 100% was higher than the been reported with injection therapy in patients 3 61% reported by Hatzichristou et al and the 48.5% refractory to Sildenafil. 4 reported by Mac Mahon et al. Eight percent of our Our study also stresses the frequent concerns of patients elected to continue with both drugs. The the couple regarding the cardiac safety of Sildenafil. corresponding figures were respectively of 7% and These are not always clearly expressed and are at the 32% in the studies by Hatzichristou et al and origin of one of the main psychological resistances 3 Mac Mahon et al. As in the study by Hatzichristou to this pharmacological therapy. A brief review of this rate decreased with time with only 1 patient the safety data likely to reassure them should be still using both drugs after 1 y in our study. considered before any prescription of this drug. One of the original aspects of our study is the 12 months follow-up. The effectiveness and tolerance to Sildenafil remained stable all this time. All the patients remained on Sildenafil, except 2 having References obtained only average results. This very high continuation rate may seem amazing because of 1 Krane R, Brock G, Eardley I, Fourcroy J, Giuliano F, Hutter A, the one hour time interval between dosing and Teloken C, Vickers M. Oral non endocrine treatment. In: intercourse in patients previously used to auto-ICI, Proceedings of the 1st International Consultation on Erectile with a much shorter interval. In fact it confirms the Dysfunction, July 1 – 3, 1999, Paris, Jardin A, Wagner G, Khoury high motivation of these men having previously S, Giuliano F, Padma-Nathan H, Rosen R eds., Erectile Dysfunction, Health Publication Ltd, 2000, pp 243 – 303. regularly used auto-ICI therapy for almost 3 y in 2 Morales A, Gingell C, Collins M, Wicker PA, Osterloh IH. average, and how a pill meets the needs of the ED Clinical safety of oral Sildenafil citrate (VIAGRATM) in the patients much more than auto-ICI therapy. treatment of erectile dysfunction. Int J Impot Research 1998; 10: The other original aspect of this study is the very 69 – 74. high rate of patients having refused the trial of 3 Hatzichristou D, Apostolidis A, Tzortzis V, Ioannides E, Yannakoyorgos K, Kalinderis A. Sildenafil versus intracaver- Sildenafil (43%). This rate of refusal was not nous injection therapy: Efficacy and preference in patients on reported in the other studies. The main reason intracavernous injection for more than 1 year. J Urol 2000; 164: alleged for refusing it was the fear of possible 1197 – 1200. cardiac risks of this drug. This fear resulted from 4 McMahon C, Samali R, Johnson H. Efficacy, safety and patient acceptance of Sildenafil citrate as treatment for erectile the many papers published in the lay-press which dysfunction. J Urol 2000; 164: 1192 – 1196. had exaggerated these risks following the report of 5 Giuliano F, Montorsi F, Mirone V, Rossi D, Sweeney M for the fatalities in american men supposed to have used Sildenafil multicenter study group. Switching from intracaver- Sildenafil. In fact this fear of using Sildenafil is still nous prostaglandine E1 injections to oral Sildenafil citrate in persisting in 2002 in many french patients with ED, patients with erectile dysfunction: results of a multicenter european study. J Urol 2000; 164: 708 – 711. or in their partners, although after more than 11 000 6 Sadovsky R, Miller T, Moskowitz M, Hackett G. Three-year patients years of observations in clinical trials, and update of Sildenafil citrate (Viagra1)efficacy and safety. prescription to more than 10 millions patients Int J Clinical Practice 2001; 55: 115 – 128. worldwide, there is no evidence to support this 7 Shabsigh R, Padma-Nathan H, Gittleman M, Mc Murray J, Kaufman J, Goldstein I. Intracavernous alprostadil alfadex drug as a cause of serious cardiovascular effects, (Edex=Viridal) is effective and safe in patients with erectile 2,6 including myocardial infarction and death. Never- dysfunction after failing sildenafil (Viagra). Urology 2000; 55: theless the cardiac risk associated with sexual 477 – 480.

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