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Satisfaction Profiles in Men Using Intracavernosal Injection Therapy
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ORIGINAL RESEARCH—ED PHARMACOTHERAPY Satisfaction Profiles in Men Using Intracavernosal Injection Therapy jsm_2093
512..517
Wayland Hsiao, MD,*† Nelson Bennett, MD,*‡ Patricia Guhring, RN,* Joseph Narus, NP,‡ and John P. Mulhall, MD*‡ *Weill Cornell Medical College, Department of Urology, New York, NY, USA; †Weill Cornell Medical College, Center for Male Reproductive Medicine, New York, NY, USA; ‡Memorial Sloan Kettering Cancer Center, Department of Surgery, Urology Section, New York, NY, USA DOI: 10.1111/j.1743-6109.2010.02093.x
ABSTRACT
Introduction. Intracavernosal injection therapy (ICI) is a well-established second-line therapy used in the treatment of erectile dysfunction (ED). Controversy exists as to whether oral phosphodiesterase type 5 inhibitors (PDE5i) or injection therapy lead to higher satisfaction. Aim. This study addressed ICI satisfaction in a modern cohort of patients in the PDE5i era. Methods. Patients on ICI for at least 6 months were included in our study. Patients were administered the International Index of Erectile Function (IIEF) at the initial visit. On subsequent visits, patients were administered the IIEF and the Erection Hardness Scale (EHS). Main Outcome Measures. Study end points were change in baseline scores in the satisfaction domains (SD) of the IIEF, type of injection medication used, and predictors of satisfaction. Multiple logistic regressions were performed for predictors of satisfaction. Results. One hundred twenty-two patients met inclusion criterion. Mean time to follow-up was 25 ⫾ 12 months (range 6–106 months). Sixty-five percent of patients continued injections at the time of follow-up. When SD scores were examined, intercourse SD scores increased from 4.8 ⫾ 1.7 at baseline to 12.3 ⫾ 3.1 (P < 0.01); overall SD scores increased from 4.1 ⫾ 1.8 to 7.2 ⫾ 2.0 (P < 0.05). On multivariate analysis, predictors of satisfaction included older age (odds ratio [OR] = 2.1), younger partner age (OR = 2.5), clinically significant increase in the erectile function domain score (OR = 3.1), and attainment of a “fully rigid” erection (EHS 4) (OR = 6.8). Conclusions. We have evaluated satisfaction in a modern cohort of ICI patients. While dropout rates are significant, for those patients who continue to inject, we have found high levels of satisfaction using the IIEF, the gold standard for evaluation of erectile function. On multivariate analysis, we found that older age, younger partner age, and fully rigid erections were predictors of increased satisfaction. ICI remains a robust second-line therapy in the treatment of ED even in the era of PDE5i. Hsiao W, Bennett N, Guhring P, Narus J, and Mulhall JP. Satisfaction profiles in men using intracavernosal injection therapy. J Sex Med 2011;8:512–517. Key Words. Erectile Dysfunction; Intracavernosal Therapy; Treatment Satisfaction; Self-Injection Therapy for ED
Introduction
S
ince its introduction in 1982, intracavernosal injection therapy (ICI) has become a wellestablished treatment for men with erectile dysfunction (ED) with a high rate of clinical efficacy [1–3]. Even in the era of phosphodiesterase type 5
J Sex Med 2011;8:512–517
inhibitors (PDE5i), the high efficacy of ICI makes it an attractive second-line option for the treatment of ED in patients with contraindications to PDE5i, significant side effects from PDE5i, or failure of PDE5i. Although ICI is successful in achieving a penetration-quality erection in many men with high levels of satisfaction, its use is © 2010 International Society for Sexual Medicine
ICI Satisfaction limited by a historically high dropout rate [2–5]. Significant controversy exists over which therapy (oral agents versus ICI) leads to higher patient satisfaction [4,6,7]. Although a number of studies have evaluated factors involved in continued ICI use in patients since the late 1980s [5,8–12], few studies have evaluated the ICI satisfaction of a modern cohort of patients in the PDE5i era. Kim et al. [13] studied patients who had been on ICI for at least 1 year. After 3 months of sildenafil therapy, 66% of oral responders continued to use ICI (31% exclusively and 35% alternating with PDE5 inhibitors), citing better erection quality as the main reason to continue ICI [13]. Conversely, Purvis et al., reported dropout rates of up to 40% with lack of spontaneity, unsatisfactory erections, needle phobia, and pain reported as reasons for discontinuation [3,14]. In the pre-PDE5i era, Porst et al. reported that 66.7% of patients had discontinued alprostadil use at 4 years of follow-up [9], while Linet et al. [8] reported a 31% dropout rate at 6 months. In fact, ICI dropout rate have been reported to be as high as 80% with a mean follow-up of 11 months [12]. However, dropout rates are also significant with oral treatment. Souverein et al., in a review of pharmacy records, reported a discontinuation rate of 45–47% with a mean follow-up of 18 months [15], and Jiann et al. reported oral treatment discontinuation rates up to 57% at a mean follow-up of 3 years [16]. The gold standard instrument for erectile function assessment, the International Index of Erectile Function (IIEF), has two domains dealing with satisfaction. We wished to test the hypothesis that men on long-term ICI therapy have high levels of satisfaction with ICI. Furthermore, we wished to identify factors associated with increased satisfaction. Patients and Methods
Patients After obtaining institutional review board approval, we identified patients in our sexual medicine practice that we had prescribed ICI for the treatment of ED. Patients who had been on ICI for at least 6 months were identified and comprise our study population. All patients had failed PDE5i use (defined as an IIEF erectile function domain [EFD] <22 and patient reporting inability to consistently have sexual intercourse) and were enrolled after the introduction of PDE5i to clinical practice. Trimix was ordered from an approved
513 U.S. compounding pharmacy. Patients with a history of radical pelvic surgery were excluded from our study. The patient’s clinical records were reviewed and abstracted for demographic, comorbidity, and prior treatments of ED.
Outcomes All patients using ICI completed a baseline IIEF at their initial office visit. Patients return to clinic within 4–6 months of being trained in ICI and then at least once a year thereafter. On subsequent clinic return visits, patients were self-administered an IIEF as well as an Erection Hardness Score (EHS). The most recent IIEF score and EHS score were used for analysis and compared to baseline scores. The IIEF is a 15-question validated instrument to assess sexual function and can be divided into five domains: EFD (Q1–5, 15, max score 30); orgasm function domain (Q9–10, max score 10); sexual desire (Q11–12, max score 10); intercourse satisfaction (Q6–8, max score 15); and overall satisfaction (Q13–14, max score 10). The maximum total score possible is 75. Two domains deal with satisfaction, the intercourse satisfaction domain (SD) and the overall SD. The EHS is a validated instrument comprising of one question rated on a scale of 0–4 (“How would you rate the hardness of your erection?”) [17]. A score of 0 indicates no erection; 1 indicates that the penis is larger but not hard; 2 indicates that the penis is hard but not hard enough for penetration; 3 indicates that the penis is hard enough for penetration but not completely hard; and 4 indicates that the penis is completely hard and fully rigid. The primary end points of our study were (i) change in baseline scores on the SD of the IIEF, specifically intercourse satisfaction (Q 6–8; max score 15) and overall satisfaction (Q 13–14; max score 10); (ii) type of ICI medication used; (iii) and predictors of satisfaction. Satisfaction was defined as a combined ⱖ5-point increase in the combined SD. Statistical Analysis All statistical analyses were performed using SPSS for Windows (SPSS 10.1, SPSS Inc., Chicago, IL, USA). Pearson correlation coefficient was generated for the correlation between EFD score and SD. Multiple logistic regressions were performed with satisfaction as the dependent variable. Included in this model were the patients’ age (by J Sex Med 2011;8:512–517
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decade), the partners’ age (by decade), the change in EFD score, and the EHS score. Results
Baseline Characteristics One hundred twenty-two men met the inclusion criteria and were included in the analysis. The mean age was 68 ⫾ 32 years old and the mean duration of ED was 3.6 ⫾ 4.2 years. Comorbidities included hyperlipidemia (41%), hypertension (34%), diabetes mellitus (16%), and coronary artery disease (10%). When number of vascular comorbidities were considered, 10% of men had one comorbidity, 42% had two, 36% had three, and 12% of men had four or greater comorbidities. Outcomes All patients had attempted PDE5i use without consistent success. Our mean time of follow-up was 25 ⫾ 12 months (range 6–106 months) and 65% of patients continued to inject at the time of follow-up. The injection agent used (at the time of last follow-up) was: 85% trimix, 10% bimix, 2% papaverine, and 3% Prostaglandin E1 (PGE1) monotherapy. Baseline IIEF-EF domain score was 12.4 ⫾ 8.7 which increased to 25.5 ⫾ 3.4 on ICI (P < 0.01). At baseline, the proportion of patients having mild, moderate, and severe ED was 14%, 47%, and 39%, respectively. These proportions changed on ICI to 32%, 6% and 0%, respectively, with 62% of patients having scores ⱖ26 (no ED). When SD scores were examined, intercourse SD scores increased from 4.8 ⫾ 1.7 at baseline to 12.3 ⫾ 3.1 (P < 0.01); overall SD scores increased from 4.1 ⫾ 1.8 to 7.2 ⫾ 2.0 (P < 0.05). Finally, the total score for both SD (max score 25) increased from 8.9 ⫾ 1.8 to 19.5 ⫾ 2.4 after ICI treatment (Figure 1). When EFD scores and satisfaction scores were correlated, the Pearson correlation coefficient between EFD scores on ICI and total satisfaction scores was 0.68 (P < 0.001). Baseline mean ⫾ standard deviation (median) EHS was 1.9 ⫾ 0.4 (2) and this value rose to 3.2 ⫾ 0.6 (3) on ICI treatment (P < 0.01). On treatment, 86% of men had EHS ⱖ3. Predictors of Satisfaction (Table 1) Further analysis was performed to identify predictors of satisfaction. Logistic regression analysis demonstrated statistically significant predictors of ⱖ5-point improvement in the combined SD score including older age (odds ratio [OR] = 2.1), J Sex Med 2011;8:512–517
Figure 1 Change in International Index of Erectile Function scores in patients on intracavernosal injection therapy in the erectile function, combined satisfaction, intercourse satisfaction, and overall satisfaction domains.
younger partner age (OR = 2.5), clinically significant increase in the EFD score (OR = 3.1), and attainment of a “fully rigid” erection (EHS 4) (OR = 6.8). Satisfaction on ICI was associated with a lower ICI discontinuation rate (19%) than in dissatisfied patients (58%) (P < 0.01). Satisfaction was also associated with higher frequency of ICI (1.8 vs. 0.3 times per week) (P = 0.018).
Effect of Total Testosterone Level The mean total T levels were 396 ⫾ 211 ng/dL in our cohort. Thirty-one patients (25.4%) of patients presented with total T <300 ng/dL. Of this group, 19 patients (15.6%) had total T 250–299 ng/dL, five patients (4.1%) had total T 200–249, and seven patients (5.7%) had total T <200 ng/dL. When comparing satisfaction in all pts with total T <300 ng/dL with pts with total T ⱖ300 ng/dL, there was no significant difference in SD score and total T <300 ng/dL was not predictive of satisfacTable 1 Logistic regression analysis was performed to identify predictors of ⱖ5-point improvement in the combined satisfaction domains score Characteristic Increase in 10 years in patient age Decrease of 10 years in partner age Increase of ⱖ6 points on the EF domain score Obtaining an EHS 4 (fully rigid) erection
Odds ratio
95% CI
P value
2.1 2.5
1.6–3.3 1.4–6.1
<0.01 <0.01
3.1
2.0–7.1
<0.01
6.8
3.2–19.0
<0.001
Older patient age, younger partner age, ⱖ6 point improvement in EF domain score and fully rigid erection were predictors of satisfaction. EHS = Erection Hardness Scale; CI = confidence interval; EF = erectile function.
ICI Satisfaction tion in multivariate analysis. If we compare patients with total T <200 ng/dL (7 patients) to those with total T ⱖ300 ng/dL, there is a trend toward a difference in satisfaction score between the two groups (11.2 for those with total T ⱖ300 ng/dL and 9.4 for those with total T <200 ng/dL, P = 0.07). Interestingly, total T <200 ng/dL was a weak predictor of failure to get a ⱖ5-point improvement in SD score with ICI (OR 0.88, 95% confidence interval [CI] 0.62–0.96, P < 0.05). Discussion
ICI was introduced as a concept in 1982 and has established itself as an effective and safe secondline erectogenic therapy [18,19]. Its advantages include its high degree of efficacy, its reproducibility, its speed of onset, and duration of erection. Despite this, dropout rates are significant with estimates of 30–80% of men dropping out by 2–5 years after commencing treatment [3,5,10,14,20]. While dropout rates are significant, it has been our clinical experience that men who continue ICI have a high level of satisfaction. In the era of modern erectogenic pharmacotherapy, the focus has shifted from solely efficacy to the dual outcomes of effectiveness and satisfaction. Numerous tools now exist to define treatment satisfaction, including but not limited to the IIEF and the erectile dysfunction inventory of treatment satisfaction (EDITS) [21,22]. In the assessment of satisfaction, understanding those factors that predict satisfaction permits clinicians to counsel patients and individualize therapy for men with ED. Mulhall et al. previously identified 37 patients with a good erectogenic response to both sildenafil citrate and penile injection therapy [6]. Patients were assessed using the IIEF as well as the EDITS. In that study, there was similar erectile function as measured by the IIEF in response to both therapies, but higher treatment satisfaction as measured by the IIEF and EDITS in response to ICI. In our current study, we have evaluated predictors of satisfaction and continued usage in a contemporary cohort of 122 men with at least 6 months of ICI usage. All patients had failed PDE5i use, which was defined as an IIEF EFD <22 and patient reporting inability to consistently have sexual intercourse. At a mean follow-up of over 2 years, over one-third of patients had discontinued ICI use. Increased satisfaction was associated with increased frequency of ICI use and lower attrition rates and improvements in satisfaction are consis-
515 tent with those found in other studies [4]. In addition, although a quarter of our patients presented with low testosterone, when we compared patients with low testosterone (which we define as <300 ng/dL) to those with normal testosterone, we found at most a weak correlation between testosterone levels and ICI satisfaction. We used an increase of at least 5 points in the combined SD as a marker of satisfaction. While somewhat arbitrary, this 5-point change is sensitive enough to detect the 6–10-point improvement observed in both SD in several PDE5i studies [23–25]. In addition, our mean increase in satisfaction scores is similar to increases in satisfaction seen with PDE5i use [23–25], and correlations of EFD scores with satisfaction for ICI patients are similar to what is seen with PDE5i use [26]. Finally, this change equates to the 1-point change per question deemed significant for the erectile function domain [21]. Identification of predictors of satisfaction is critical to the acceptance of any ED therapy. Studies prior to the PDE5i era have implicated patient age, mode of injection (autoinjector vs. standard injection), smoking status, duration of erection, and satisfaction with sexual life as predictors of satisfaction [14,27]. In our study, the predictors of satisfaction included older patient age, young partner age, a clinically meaningful increase in IIEF-EFD score, and obtaining a fully rigid erection. There is conflicting data from that literature regarding satisfaction based on age of the patient; however, our study does agree with the data from the pre-PDE5 inhibitor era that better erection does lead to better treatment satisfaction. While any discussion of mechanism is speculative, older age is clearly associated with increased satisfaction in our study. Possible reasons include the greater likelihood of being in a long-term relationship, decreased needle fear, lower anxiety, or perhaps fewer body image issues. The fact that partner age is related to satisfaction again emphasizes the multi-person effects of ED as well as emphasizes the need to consider partner preferences and satisfaction in any ED treatment [28]. It is also possible that younger partner age may be a marker of increased patient interest in sexual activity and greater motivation to continue with injections. Finally, patients with optimal erection improvements (obtaining a EHS 4 erection) in erection hardness have been shown to have greater sexual satisfaction and greater confidence [17]. Goldstein et al. have previously shown that an EHS score of 4 was 23.7 times more likely to result J Sex Med 2011;8:512–517
516 in successful sexual intercourse than an EHS score of 3 [29]. This is consistent with our data and indicates that an EHS score of 4 should be the goal for erection hardness for patients on ICI. In fact, an inability to achieve an EHS score of 4 on ICI may lead a patient to choose other ED treatments (i.e., penile implant). About one-third of our patients discontinued ICI by the time of last follow-up. The reasons for dropout are numerous and include: needle phobia, partner aversion to injection therapy, needle pain, unsatisfactory erections, selection of an alternative ED treatment, and loss of sexual partner. While the reported dropout rates on ICI in the prePDE5i era are high (range 46–80%) [2–5,10], it is uncertain whether satisfaction and dropout rates from those studies can be generalized to a contemporary ED population. The percentage of men seeking treatment for ED has increased significantly with the introduction of PDE5i also as a result of changing societal attitudes toward ED and aging. In addition, the modern-day ED patient has an array of treatment choices to him not available over a decade ago and old assumptions are being challenged. In fact, in recent studies of injection pain, up to 40% of men reported no pain at all with needle insertion and over 60% reported no pain with injection medication [30]. Therefore, any study of satisfaction that we wish to apply to the current ED population must be derived from the post-PDE5i era. Our study fulfills this criterion because it assesses satisfaction of a contemporary cohort of ED patients. We observed a dropout rate of 35% with a mean follow-up of over 2 years, which is lower than what is seen in most of the literature. In the pre-PDE5i era, Porst et al. reported a 66.7% ICI discontinuation rate at 4 years [9]; and Linet et al. reported 31% dropout rate at 6 months. Other studies have reported discontinuation rates as high as 80% with a mean follow-up of 11 months [12]. However, dropout rates are also significant with oral treatment. Souverein et al., in a review of pharmacy records, reported a discontinuation rate of 45–47% with a mean follow-up of 18 months [15], and Jiann et al. reported oral treatment discontinuation rates up to 57% at a mean follow-up of 3 years [16]. Clearly, there is a great heterogeneity in the literature regarding dropout rates. Beyond just dropout rates, though, is a matter of choice. Kim et al. showed that when patients on ICI for 1 year were given the choice of injection or oral therapy, 66% of patients continued injection therapy, either alone or alternating with oral agents [13]. It is notable, J Sex Med 2011;8:512–517
Hsiao et al. however, that when Guiliano et al. examined a population of PDE5i naïve patients on ICI, 69% of men preferred sildenafil. However, it would be difficult to apply the findings of that study (in a PDE5i naïve population) to our current patient population (of which all patients had failed PDE5i therapy). This study has a number of significant limitations including absence of data on those patients who had dropped out, the absence of use of a true satisfaction questionnaire such as the EDITS, and the relatively small number of patients. In addition, while all patients had “failed” PDE5i use, we did not separate those patients unable to attain a penetration hardness erection vs. those who had inconsistent response to PDE5i. However, we believe that the use of the IIEF as an inventory, the long-term follow-up, and the use of multivariate analysis to define predictors of satisfaction are significant strengths. Conclusions
We have evaluated treatment satisfaction in a modern cohort of long-term ICI patients well into the PDE5i era. While over a third of patients had stopped ICI at the time of follow-up, those that continued to inject had high levels of satisfaction as measured by the IIEF, the gold standard for the evaluation of erectile function. We found that older age, younger partner age, frequent ICI use, and fully rigid erections were predictors of satisfaction. This information is helpful to clinician to help them identify those who are more likely to be satisfied with ICI. ICI remains a robust second-line therapy in the treatment of ED in the era of PDE5i. Acknowledgments
Dr. Hsiao is supported by a grant from the Frederick J. and Theresa Dow Wallace Fund of the New York Community Trust. Corresponding Author: John P. Mulhall MD, Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 353 E. 68th St., New York, NY 10021, Tel: (646)422-4359; Fax: (212)9880768; E-mail: [email protected] Conflict of Interest: None. Statement of Authorship
Category 1 (a) Conception and Design John P. Mulhall; Nelson Bennett; Joseph Narus; Patricia Guhring
ICI Satisfaction (b) Acquisition of Data John P. Mulhall; Joseph Narus; Patricia Guhring (c) Analysis and Interpretation of Data Wayland Hsiao; John P. Mulhall; Nelson Bennett
Category 2 (a) Drafting the Article Wayland Hsiao; John P. Mulhall (b) Revising It for Intellectual Content Wayland Hsiao; John P. Mulhall
Category 3 (a) Final Approval of the Completed Article John P. Mulhall; Wayland Hsiao References 1 Fallon B. Intracavernous injection therapy for male erectile dysfunction. Urol Clin North Am 1995;22:833–45. 2 Mulhall JP. Intracavernosal injection therapy: A practical guide. Tech Urol 1997;3:129–34. 3 Mulhall JP, Jahoda AE, Cairney M, Goldstein B, Leitzes R, Woods J, Payton T, Krane RJ, Goldstein I. The causes of patient dropout from penile self-injection therapy for impotence. J Urol 1999;162:1291–4. 4 Hassan A, El-Hadidy M, El-Deeck BS, Mostafa T. Couple satisfaction to different therapeutic modalities for organic erectile dysfunction. J Sex Med 2008;5:2381–91. 5 Sundaram CP, Thomas W, Pryor LE, Sidi AA, Billups K, Pryor JL. Long-term follow-up of patients receiving injection therapy for erectile dysfunction. Urology 1997;49:932–5. 6 Mulhall JP, Simmons J. Assessment of comparative treatment satisfaction with sildenafil citrate and penile injection therapy in patients responding to both. BJU Int 2007;100:1313–6. 7 Montorsi F, Althof SE, Sweeney M, Menchini-Fabris F, Sasso F, Giuliano F. Treatment satisfaction in patients with erectile dysfunction switching from prostaglandin E(1) intracavernosal injection therapy to oral sildenafil citrate. Int J Impot Res 2003;15:444–9. 8 Linet OI, Ogrinc FG. Efficacy and safety of intracavernosal alprostadil in men with erectile dysfunction. The Alprostadil Study Group. N Engl J Med 1996;334:873–7. 9 Porst H, Buvat J, Meuleman E, Michal V, Wagner G. Intracavernous Alprostadil Alfadex—An effective and well tolerated treatment for erectile dysfunction. Results of a long-term European study. Int J Impot Res 1998;10:225–31. 10 Althof SE, Turner LA, Levine SB, Risen C, Kursh E, Bodner D, Resnick. Why do so many people drop out from autoinjection therapy for impotence? J Sex Marital Ther 1989;15:121–9. 11 Irwin MB, Kata EJ. High attrition rate with intracavernous injection of prostaglandin E1 for impotency. Urology 1994;43:84–7. 12 Weiss JN, Badlani GH, Ravalli R, Brettschneider N. Reasons for high drop-out rate with self-injection therapy for impotence. Int J Impot Res 1994;6:171–4. 13 Kim SC, Chang IH, Jeon HJ. Preference for oral sildenafil or intracavernosal injection in patients with erectile dysfunction already using intracavernosal injection for >1 year. BJU Int 2003;92:277–80.
517 14 Purvis K, Egdetveit I, Christiansen E. Intracavernosal therapy for erectile failure—Impact of treatment and reasons for dropout and dissatisfaction. Int J Impot Res 1999;11:287–99. 15 Souverein PC, Egberts AC, Meuleman EJ, Urquhart J, Leufkens HG. Incidence and determinants of sildenafil (dis)continuation: The Dutch cohort of sildenafil users. Int J Impot Res 2002;14:259–65. 16 Jiann BP, Yu CC, Su CC, Tsai JY. Compliance of sildenafil treatment for erectile dysfunction and factors affecting it. Int J Impot Res 2006;18:146–9. 17 Mulhall JP, Goldstein I, Bushmakin AG, Cappelleri JC, Hvidsten K. Validation of the erection hardness score. J Sex Med 2007;4:1626–34. 18 Virag R. Intracavernous injection of papaverine for erectile failure. Lancet 1982;2:938. 19 Brindley GS. Cavernosal alpha-blockade: A new technique for investigating and treating erectile impotence. Br J Psychiatry 1983;143:332–7. 20 Casabe A, Bechara A, Cheliz G, Romano S, Rey H, Fredotovich N. Drop-out reasons and complications in self-injection therapy with a triple vasoactive drug mixture in sexual erectile dysfunction. Int J Impot Res 1998;10:5–9. 21 Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A. The international index of erectile function (IIEF): A multidimensional scale for assessment of erectile dysfunction. Urology 1997;49:822–30. 22 Althof SE, Corty EW, Levine SB, Levine F, Burnett AL, McVary K, Stecher V, Seftel AD. EDITS: Development of questionnaires for evaluating satisfaction with treatments for erectile dysfunction. Urology 1999;53:793–9. 23 Seftel AD, Buvat J, Althof SE, McMurray JG, Zeigler HL, Burns PR, Wong DG. Improvements in confidence, sexual relationship and satisfaction measures: Results of a randomized trial of tadalafil 5 mg taken once daily. Int J Impot Res 2009;21:240–8. 24 Becher E, Tejada Noriega A, Gomez R, Decia R. Sildenafil citrate (Viagra) in the treatment of men with erectile dysfunction in southern Latin America: A double-blind, randomized, placebo-controlled, parallel-group, multicenter, flexible-dose escalation study. Int J Impot Res 2002;14(2 suppl):S33–41. 25 Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. N Engl J Med 1998; 338:1397–404. 26 Montorsi F, Padma-Nathan H, Glina S. Erectile function and assessments of erection hardness correlate positively with measures of emotional well-being, sexual satisfaction, and treatment satisfaction in men with erectile dysfunction treated with sildenafil citrate (Viagra). Urology 2006;68:26–37. 27 Rowland DL, Boedhoe HS, Dohle G, Slob AK. Intracavernosal self-injection therapy in men with erectile dysfunction: Satisfaction and attrition in 119 patients. Int J Impot Res 1999;11:145–51. 28 Moskovic DJ, Mohamed O, Sathyamoorthy K, et al. The female factor: Predicting compliance with a postprostatectomy erectile preservation program. J Sex Med 2010 August 31 [Epub ahead of print] doi: 10.1111/j.17436109.2010.02014.x. 29 Goldstein I, Mulhall JP, Bushmakin AG, Cappelleri JC, Hvidsten K, Symonds T. The erection hardness score and its relationship to successful sexual intercourse. J Sex Med 2008;5:2374–80. 30 Albaugh J, Ferrans CE. Patient-reported pain with initial intracavernosal injection. J Sex Med 2009;6:513–9.
J Sex Med 2011;8:512–517
ORIGINAL RESEARCH—ED PHARMACOTHERAPY Satisfaction Profiles in Men Using Intracavernosal Injection Therapy jsm_2093
512..517
Wayland Hsiao, MD,*† Nelson Bennett, MD,*‡ Patricia Guhring, RN,* Joseph Narus, NP,‡ and John P. Mulhall, MD*‡ *Weill Cornell Medical College, Department of Urology, New York, NY, USA; †Weill Cornell Medical College, Center for Male Reproductive Medicine, New York, NY, USA; ‡Memorial Sloan Kettering Cancer Center, Department of Surgery, Urology Section, New York, NY, USA DOI: 10.1111/j.1743-6109.2010.02093.x
ABSTRACT
Introduction. Intracavernosal injection therapy (ICI) is a well-established second-line therapy used in the treatment of erectile dysfunction (ED). Controversy exists as to whether oral phosphodiesterase type 5 inhibitors (PDE5i) or injection therapy lead to higher satisfaction. Aim. This study addressed ICI satisfaction in a modern cohort of patients in the PDE5i era. Methods. Patients on ICI for at least 6 months were included in our study. Patients were administered the International Index of Erectile Function (IIEF) at the initial visit. On subsequent visits, patients were administered the IIEF and the Erection Hardness Scale (EHS). Main Outcome Measures. Study end points were change in baseline scores in the satisfaction domains (SD) of the IIEF, type of injection medication used, and predictors of satisfaction. Multiple logistic regressions were performed for predictors of satisfaction. Results. One hundred twenty-two patients met inclusion criterion. Mean time to follow-up was 25 ⫾ 12 months (range 6–106 months). Sixty-five percent of patients continued injections at the time of follow-up. When SD scores were examined, intercourse SD scores increased from 4.8 ⫾ 1.7 at baseline to 12.3 ⫾ 3.1 (P < 0.01); overall SD scores increased from 4.1 ⫾ 1.8 to 7.2 ⫾ 2.0 (P < 0.05). On multivariate analysis, predictors of satisfaction included older age (odds ratio [OR] = 2.1), younger partner age (OR = 2.5), clinically significant increase in the erectile function domain score (OR = 3.1), and attainment of a “fully rigid” erection (EHS 4) (OR = 6.8). Conclusions. We have evaluated satisfaction in a modern cohort of ICI patients. While dropout rates are significant, for those patients who continue to inject, we have found high levels of satisfaction using the IIEF, the gold standard for evaluation of erectile function. On multivariate analysis, we found that older age, younger partner age, and fully rigid erections were predictors of increased satisfaction. ICI remains a robust second-line therapy in the treatment of ED even in the era of PDE5i. Hsiao W, Bennett N, Guhring P, Narus J, and Mulhall JP. Satisfaction profiles in men using intracavernosal injection therapy. J Sex Med 2011;8:512–517. Key Words. Erectile Dysfunction; Intracavernosal Therapy; Treatment Satisfaction; Self-Injection Therapy for ED
Introduction
S
ince its introduction in 1982, intracavernosal injection therapy (ICI) has become a wellestablished treatment for men with erectile dysfunction (ED) with a high rate of clinical efficacy [1–3]. Even in the era of phosphodiesterase type 5
J Sex Med 2011;8:512–517
inhibitors (PDE5i), the high efficacy of ICI makes it an attractive second-line option for the treatment of ED in patients with contraindications to PDE5i, significant side effects from PDE5i, or failure of PDE5i. Although ICI is successful in achieving a penetration-quality erection in many men with high levels of satisfaction, its use is © 2010 International Society for Sexual Medicine
ICI Satisfaction limited by a historically high dropout rate [2–5]. Significant controversy exists over which therapy (oral agents versus ICI) leads to higher patient satisfaction [4,6,7]. Although a number of studies have evaluated factors involved in continued ICI use in patients since the late 1980s [5,8–12], few studies have evaluated the ICI satisfaction of a modern cohort of patients in the PDE5i era. Kim et al. [13] studied patients who had been on ICI for at least 1 year. After 3 months of sildenafil therapy, 66% of oral responders continued to use ICI (31% exclusively and 35% alternating with PDE5 inhibitors), citing better erection quality as the main reason to continue ICI [13]. Conversely, Purvis et al., reported dropout rates of up to 40% with lack of spontaneity, unsatisfactory erections, needle phobia, and pain reported as reasons for discontinuation [3,14]. In the pre-PDE5i era, Porst et al. reported that 66.7% of patients had discontinued alprostadil use at 4 years of follow-up [9], while Linet et al. [8] reported a 31% dropout rate at 6 months. In fact, ICI dropout rate have been reported to be as high as 80% with a mean follow-up of 11 months [12]. However, dropout rates are also significant with oral treatment. Souverein et al., in a review of pharmacy records, reported a discontinuation rate of 45–47% with a mean follow-up of 18 months [15], and Jiann et al. reported oral treatment discontinuation rates up to 57% at a mean follow-up of 3 years [16]. The gold standard instrument for erectile function assessment, the International Index of Erectile Function (IIEF), has two domains dealing with satisfaction. We wished to test the hypothesis that men on long-term ICI therapy have high levels of satisfaction with ICI. Furthermore, we wished to identify factors associated with increased satisfaction. Patients and Methods
Patients After obtaining institutional review board approval, we identified patients in our sexual medicine practice that we had prescribed ICI for the treatment of ED. Patients who had been on ICI for at least 6 months were identified and comprise our study population. All patients had failed PDE5i use (defined as an IIEF erectile function domain [EFD] <22 and patient reporting inability to consistently have sexual intercourse) and were enrolled after the introduction of PDE5i to clinical practice. Trimix was ordered from an approved
513 U.S. compounding pharmacy. Patients with a history of radical pelvic surgery were excluded from our study. The patient’s clinical records were reviewed and abstracted for demographic, comorbidity, and prior treatments of ED.
Outcomes All patients using ICI completed a baseline IIEF at their initial office visit. Patients return to clinic within 4–6 months of being trained in ICI and then at least once a year thereafter. On subsequent clinic return visits, patients were self-administered an IIEF as well as an Erection Hardness Score (EHS). The most recent IIEF score and EHS score were used for analysis and compared to baseline scores. The IIEF is a 15-question validated instrument to assess sexual function and can be divided into five domains: EFD (Q1–5, 15, max score 30); orgasm function domain (Q9–10, max score 10); sexual desire (Q11–12, max score 10); intercourse satisfaction (Q6–8, max score 15); and overall satisfaction (Q13–14, max score 10). The maximum total score possible is 75. Two domains deal with satisfaction, the intercourse satisfaction domain (SD) and the overall SD. The EHS is a validated instrument comprising of one question rated on a scale of 0–4 (“How would you rate the hardness of your erection?”) [17]. A score of 0 indicates no erection; 1 indicates that the penis is larger but not hard; 2 indicates that the penis is hard but not hard enough for penetration; 3 indicates that the penis is hard enough for penetration but not completely hard; and 4 indicates that the penis is completely hard and fully rigid. The primary end points of our study were (i) change in baseline scores on the SD of the IIEF, specifically intercourse satisfaction (Q 6–8; max score 15) and overall satisfaction (Q 13–14; max score 10); (ii) type of ICI medication used; (iii) and predictors of satisfaction. Satisfaction was defined as a combined ⱖ5-point increase in the combined SD. Statistical Analysis All statistical analyses were performed using SPSS for Windows (SPSS 10.1, SPSS Inc., Chicago, IL, USA). Pearson correlation coefficient was generated for the correlation between EFD score and SD. Multiple logistic regressions were performed with satisfaction as the dependent variable. Included in this model were the patients’ age (by J Sex Med 2011;8:512–517
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decade), the partners’ age (by decade), the change in EFD score, and the EHS score. Results
Baseline Characteristics One hundred twenty-two men met the inclusion criteria and were included in the analysis. The mean age was 68 ⫾ 32 years old and the mean duration of ED was 3.6 ⫾ 4.2 years. Comorbidities included hyperlipidemia (41%), hypertension (34%), diabetes mellitus (16%), and coronary artery disease (10%). When number of vascular comorbidities were considered, 10% of men had one comorbidity, 42% had two, 36% had three, and 12% of men had four or greater comorbidities. Outcomes All patients had attempted PDE5i use without consistent success. Our mean time of follow-up was 25 ⫾ 12 months (range 6–106 months) and 65% of patients continued to inject at the time of follow-up. The injection agent used (at the time of last follow-up) was: 85% trimix, 10% bimix, 2% papaverine, and 3% Prostaglandin E1 (PGE1) monotherapy. Baseline IIEF-EF domain score was 12.4 ⫾ 8.7 which increased to 25.5 ⫾ 3.4 on ICI (P < 0.01). At baseline, the proportion of patients having mild, moderate, and severe ED was 14%, 47%, and 39%, respectively. These proportions changed on ICI to 32%, 6% and 0%, respectively, with 62% of patients having scores ⱖ26 (no ED). When SD scores were examined, intercourse SD scores increased from 4.8 ⫾ 1.7 at baseline to 12.3 ⫾ 3.1 (P < 0.01); overall SD scores increased from 4.1 ⫾ 1.8 to 7.2 ⫾ 2.0 (P < 0.05). Finally, the total score for both SD (max score 25) increased from 8.9 ⫾ 1.8 to 19.5 ⫾ 2.4 after ICI treatment (Figure 1). When EFD scores and satisfaction scores were correlated, the Pearson correlation coefficient between EFD scores on ICI and total satisfaction scores was 0.68 (P < 0.001). Baseline mean ⫾ standard deviation (median) EHS was 1.9 ⫾ 0.4 (2) and this value rose to 3.2 ⫾ 0.6 (3) on ICI treatment (P < 0.01). On treatment, 86% of men had EHS ⱖ3. Predictors of Satisfaction (Table 1) Further analysis was performed to identify predictors of satisfaction. Logistic regression analysis demonstrated statistically significant predictors of ⱖ5-point improvement in the combined SD score including older age (odds ratio [OR] = 2.1), J Sex Med 2011;8:512–517
Figure 1 Change in International Index of Erectile Function scores in patients on intracavernosal injection therapy in the erectile function, combined satisfaction, intercourse satisfaction, and overall satisfaction domains.
younger partner age (OR = 2.5), clinically significant increase in the EFD score (OR = 3.1), and attainment of a “fully rigid” erection (EHS 4) (OR = 6.8). Satisfaction on ICI was associated with a lower ICI discontinuation rate (19%) than in dissatisfied patients (58%) (P < 0.01). Satisfaction was also associated with higher frequency of ICI (1.8 vs. 0.3 times per week) (P = 0.018).
Effect of Total Testosterone Level The mean total T levels were 396 ⫾ 211 ng/dL in our cohort. Thirty-one patients (25.4%) of patients presented with total T <300 ng/dL. Of this group, 19 patients (15.6%) had total T 250–299 ng/dL, five patients (4.1%) had total T 200–249, and seven patients (5.7%) had total T <200 ng/dL. When comparing satisfaction in all pts with total T <300 ng/dL with pts with total T ⱖ300 ng/dL, there was no significant difference in SD score and total T <300 ng/dL was not predictive of satisfacTable 1 Logistic regression analysis was performed to identify predictors of ⱖ5-point improvement in the combined satisfaction domains score Characteristic Increase in 10 years in patient age Decrease of 10 years in partner age Increase of ⱖ6 points on the EF domain score Obtaining an EHS 4 (fully rigid) erection
Odds ratio
95% CI
P value
2.1 2.5
1.6–3.3 1.4–6.1
<0.01 <0.01
3.1
2.0–7.1
<0.01
6.8
3.2–19.0
<0.001
Older patient age, younger partner age, ⱖ6 point improvement in EF domain score and fully rigid erection were predictors of satisfaction. EHS = Erection Hardness Scale; CI = confidence interval; EF = erectile function.
ICI Satisfaction tion in multivariate analysis. If we compare patients with total T <200 ng/dL (7 patients) to those with total T ⱖ300 ng/dL, there is a trend toward a difference in satisfaction score between the two groups (11.2 for those with total T ⱖ300 ng/dL and 9.4 for those with total T <200 ng/dL, P = 0.07). Interestingly, total T <200 ng/dL was a weak predictor of failure to get a ⱖ5-point improvement in SD score with ICI (OR 0.88, 95% confidence interval [CI] 0.62–0.96, P < 0.05). Discussion
ICI was introduced as a concept in 1982 and has established itself as an effective and safe secondline erectogenic therapy [18,19]. Its advantages include its high degree of efficacy, its reproducibility, its speed of onset, and duration of erection. Despite this, dropout rates are significant with estimates of 30–80% of men dropping out by 2–5 years after commencing treatment [3,5,10,14,20]. While dropout rates are significant, it has been our clinical experience that men who continue ICI have a high level of satisfaction. In the era of modern erectogenic pharmacotherapy, the focus has shifted from solely efficacy to the dual outcomes of effectiveness and satisfaction. Numerous tools now exist to define treatment satisfaction, including but not limited to the IIEF and the erectile dysfunction inventory of treatment satisfaction (EDITS) [21,22]. In the assessment of satisfaction, understanding those factors that predict satisfaction permits clinicians to counsel patients and individualize therapy for men with ED. Mulhall et al. previously identified 37 patients with a good erectogenic response to both sildenafil citrate and penile injection therapy [6]. Patients were assessed using the IIEF as well as the EDITS. In that study, there was similar erectile function as measured by the IIEF in response to both therapies, but higher treatment satisfaction as measured by the IIEF and EDITS in response to ICI. In our current study, we have evaluated predictors of satisfaction and continued usage in a contemporary cohort of 122 men with at least 6 months of ICI usage. All patients had failed PDE5i use, which was defined as an IIEF EFD <22 and patient reporting inability to consistently have sexual intercourse. At a mean follow-up of over 2 years, over one-third of patients had discontinued ICI use. Increased satisfaction was associated with increased frequency of ICI use and lower attrition rates and improvements in satisfaction are consis-
515 tent with those found in other studies [4]. In addition, although a quarter of our patients presented with low testosterone, when we compared patients with low testosterone (which we define as <300 ng/dL) to those with normal testosterone, we found at most a weak correlation between testosterone levels and ICI satisfaction. We used an increase of at least 5 points in the combined SD as a marker of satisfaction. While somewhat arbitrary, this 5-point change is sensitive enough to detect the 6–10-point improvement observed in both SD in several PDE5i studies [23–25]. In addition, our mean increase in satisfaction scores is similar to increases in satisfaction seen with PDE5i use [23–25], and correlations of EFD scores with satisfaction for ICI patients are similar to what is seen with PDE5i use [26]. Finally, this change equates to the 1-point change per question deemed significant for the erectile function domain [21]. Identification of predictors of satisfaction is critical to the acceptance of any ED therapy. Studies prior to the PDE5i era have implicated patient age, mode of injection (autoinjector vs. standard injection), smoking status, duration of erection, and satisfaction with sexual life as predictors of satisfaction [14,27]. In our study, the predictors of satisfaction included older patient age, young partner age, a clinically meaningful increase in IIEF-EFD score, and obtaining a fully rigid erection. There is conflicting data from that literature regarding satisfaction based on age of the patient; however, our study does agree with the data from the pre-PDE5 inhibitor era that better erection does lead to better treatment satisfaction. While any discussion of mechanism is speculative, older age is clearly associated with increased satisfaction in our study. Possible reasons include the greater likelihood of being in a long-term relationship, decreased needle fear, lower anxiety, or perhaps fewer body image issues. The fact that partner age is related to satisfaction again emphasizes the multi-person effects of ED as well as emphasizes the need to consider partner preferences and satisfaction in any ED treatment [28]. It is also possible that younger partner age may be a marker of increased patient interest in sexual activity and greater motivation to continue with injections. Finally, patients with optimal erection improvements (obtaining a EHS 4 erection) in erection hardness have been shown to have greater sexual satisfaction and greater confidence [17]. Goldstein et al. have previously shown that an EHS score of 4 was 23.7 times more likely to result J Sex Med 2011;8:512–517
516 in successful sexual intercourse than an EHS score of 3 [29]. This is consistent with our data and indicates that an EHS score of 4 should be the goal for erection hardness for patients on ICI. In fact, an inability to achieve an EHS score of 4 on ICI may lead a patient to choose other ED treatments (i.e., penile implant). About one-third of our patients discontinued ICI by the time of last follow-up. The reasons for dropout are numerous and include: needle phobia, partner aversion to injection therapy, needle pain, unsatisfactory erections, selection of an alternative ED treatment, and loss of sexual partner. While the reported dropout rates on ICI in the prePDE5i era are high (range 46–80%) [2–5,10], it is uncertain whether satisfaction and dropout rates from those studies can be generalized to a contemporary ED population. The percentage of men seeking treatment for ED has increased significantly with the introduction of PDE5i also as a result of changing societal attitudes toward ED and aging. In addition, the modern-day ED patient has an array of treatment choices to him not available over a decade ago and old assumptions are being challenged. In fact, in recent studies of injection pain, up to 40% of men reported no pain at all with needle insertion and over 60% reported no pain with injection medication [30]. Therefore, any study of satisfaction that we wish to apply to the current ED population must be derived from the post-PDE5i era. Our study fulfills this criterion because it assesses satisfaction of a contemporary cohort of ED patients. We observed a dropout rate of 35% with a mean follow-up of over 2 years, which is lower than what is seen in most of the literature. In the pre-PDE5i era, Porst et al. reported a 66.7% ICI discontinuation rate at 4 years [9]; and Linet et al. reported 31% dropout rate at 6 months. Other studies have reported discontinuation rates as high as 80% with a mean follow-up of 11 months [12]. However, dropout rates are also significant with oral treatment. Souverein et al., in a review of pharmacy records, reported a discontinuation rate of 45–47% with a mean follow-up of 18 months [15], and Jiann et al. reported oral treatment discontinuation rates up to 57% at a mean follow-up of 3 years [16]. Clearly, there is a great heterogeneity in the literature regarding dropout rates. Beyond just dropout rates, though, is a matter of choice. Kim et al. showed that when patients on ICI for 1 year were given the choice of injection or oral therapy, 66% of patients continued injection therapy, either alone or alternating with oral agents [13]. It is notable, J Sex Med 2011;8:512–517
Hsiao et al. however, that when Guiliano et al. examined a population of PDE5i naïve patients on ICI, 69% of men preferred sildenafil. However, it would be difficult to apply the findings of that study (in a PDE5i naïve population) to our current patient population (of which all patients had failed PDE5i therapy). This study has a number of significant limitations including absence of data on those patients who had dropped out, the absence of use of a true satisfaction questionnaire such as the EDITS, and the relatively small number of patients. In addition, while all patients had “failed” PDE5i use, we did not separate those patients unable to attain a penetration hardness erection vs. those who had inconsistent response to PDE5i. However, we believe that the use of the IIEF as an inventory, the long-term follow-up, and the use of multivariate analysis to define predictors of satisfaction are significant strengths. Conclusions
We have evaluated treatment satisfaction in a modern cohort of long-term ICI patients well into the PDE5i era. While over a third of patients had stopped ICI at the time of follow-up, those that continued to inject had high levels of satisfaction as measured by the IIEF, the gold standard for the evaluation of erectile function. We found that older age, younger partner age, frequent ICI use, and fully rigid erections were predictors of satisfaction. This information is helpful to clinician to help them identify those who are more likely to be satisfied with ICI. ICI remains a robust second-line therapy in the treatment of ED in the era of PDE5i. Acknowledgments
Dr. Hsiao is supported by a grant from the Frederick J. and Theresa Dow Wallace Fund of the New York Community Trust. Corresponding Author: John P. Mulhall MD, Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 353 E. 68th St., New York, NY 10021, Tel: (646)422-4359; Fax: (212)9880768; E-mail: [email protected] Conflict of Interest: None. Statement of Authorship
Category 1 (a) Conception and Design John P. Mulhall; Nelson Bennett; Joseph Narus; Patricia Guhring
ICI Satisfaction (b) Acquisition of Data John P. Mulhall; Joseph Narus; Patricia Guhring (c) Analysis and Interpretation of Data Wayland Hsiao; John P. Mulhall; Nelson Bennett
Category 2 (a) Drafting the Article Wayland Hsiao; John P. Mulhall (b) Revising It for Intellectual Content Wayland Hsiao; John P. Mulhall
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J Sex Med 2011;8:512–517