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SILDENAFIL VERSUS INTRACAVERNOUS INJECTION THERAPY: EFFICACY AND PREFERENCE IN PATIENTS ON INTRACAVERNOUS INJECTION FOR MORE THAN 1 YEAR
0022-5347/00/1644-1197/0 THE JOURNAL OF UROLOGY® Copyright © 2000 by AMERICAN UROLOGICAL ASSOCIATION, INC.®
Vol. 164, 1197–1200, October 2000 Printed in U.S.A.
SILDENAFIL VERSUS INTRACAVERNOUS INJECTION THERAPY: EFFICACY AND PREFERENCE IN PATIENTS ON INTRACAVERNOUS INJECTION FOR MORE THAN 1 YEAR DIMITRIOS G. HATZICHRISTOU, APOSTOLOS APOSTOLIDIS, VASILIOS TZORTZIS, EVANGELOS IOANNIDES, KONSTANTINOS YANNAKOYORGOS AND ATHANASIOS KALINDERIS From the Department of Urology, School of Medicine and Center for Sexual Dysfunction, Aristotle University of Thessaloniki, Thessaloniki, Greece
ABSTRACT
Purpose: To our knowledge comparative data on the effectiveness of and patient preference for intracavernous injection therapy and sildenafil are still not available. We evaluated the efficacy of sildenafil as well as patient preference in a group of impotent men on intracavernous injection for more than a year. Materials and Methods: Patients on intracavernous injection therapy for more than a year without neurological disease and/or a contraindication to sildenafil treatment were recruited for study. In phase 1 we determined the efficacy of 50 and 100 mg. sildenafil citrate at home. In phase 2 responders to sildenafil were asked to use the preferred dose orally for a month and choose intracavernous injection or sildenafil. In phase 3 patients were asked to continue either treatment for 3 more months. Patient preferences were reported at the end of phases 2 and 3. Results: Of the 180 men recruited 155 with a mean age of 56.4 ⫾ 12.6 years on intracavernous injection for a mean of 26 ⫾ 9 months accepted and were included in our series. Overall 116 men (74.8%) responded to sildenafil during study phase 1. After 1 month of treatment 71 responders (61.2%) preferred to continue with the oral drug, 31 (26.7%) returned to intracavernous injection and 14 (12.1%) used each drug alternately. Three months later 74 of the 116 responders (63.8%) preferred oral treatment and 38 (32.8%) chose intracavernous injection, while 4 (3.4%) continued to use each treatment alternately. Conclusions: Sildenafil is highly effective in intracavernous injection responders, although a certain group prefer to continue intracavernous injection. While sildenafil should be considered first line treatment, men with erectile dysfunction should be aware of all treatment options available because nonresponders to sildenafil may respond to intracavernous injection. KEY WORDS: penis, impotence, vasodilator agents
Intracavernous injection therapy is a historical cornerstone in the treatment of male erectile dysfunction.1, 2 The efficacy and safety profile of intracavernous injected vasoactive drugs made them first line treatment in patients with various causes of erectile dysfunction for almost 15 years.2 However, a high withdrawal rate and low long-term patient compliance associated with this treatment indicated that an oral drug was more than desirable.2, 3 The development and approval of sildenafil were revolutionary in the field of impotence since for the first time it provided effective and safe oral treatment for erectile dysfunction.4, 5 Sildenafil represents a challenge not only to untreated patients, but also to those previously treated with intracavernous pharmacotherapy. Others have reported the response rate, safety profile and quality of life issues of the various intracavernous pharmacological treatments6 –11 as well as sildenafil more recently.4, 5 However, to our knowledge comparative data on the effectiveness of and patient preference for the 2 types of therapy are not available, especially in men already on an intracavernous injection protocol. We evaluated the efficacy of sildenafil as well as preference in men with erectile dysfunction who were previously successfully treated with intracavernous injection for a long period. MATERIALS AND METHODS
The population sample in our study comprised men on an intracavernous injection regimen who presented to our anAccepted for publication May 12, 2000.
drology unit for regular followup. According to standard protocol at our facility candidates for intracavernous injection are impotent, between ages 18 and 80 years, and have a history of erectile dysfunction of more than 6 months. In addition, they have no significant penile curvature, symptomatic uncontrolled heart disease, history of a cardiovascular episode within the last 6 months or severe psychiatric illness, such as uncontrolled depression, bipolar disorder or psychosis. For study purposes patients were recruited during a 3-month period according to certain inclusion criteria, including maintenance on an intracavernous injection regimen for more than a year, absent known neuropathy and no contraindications to sildenafil. When recruiting men with cardiovascular disease, American College of CardiologyAmerican Heart Association guidelines were adapted.12 Study design included 3 phases (fig. 1). During the initial titration phase patients were asked to attempt sexual intercourse at least twice using 50 mg. sildenafil citrate. Those who did not respond to this dose were asked to repeat the trial using a 100 mg. dose. Positive response was defined as erection adequate for satisfactory sexual intercourse based exclusively on patient reports. In phase 2 all responders to 50 or 100 mg. sildenafil were asked to use sildenafil for 1 month at the preferred dose. At the end of the month they were asked to elect intracavernous injection, sildenafil or each treatment alternately. During phases 1 and 2 all patients abstained from intracavernous injection. In phase 3 patients were asked to elect sildenafil or intracavernous injection for
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FIG. 1. Study design
3 more months. At the end of phase 3 they were questioned on their final treatment preferences. To evaluate further the effectiveness of sildenafil versus intracavernous injection therapy as well as preferences patients were categorized into groups according to the dose and intracavernous agent used, including 10 or less and greater than 10 to 20 g. alprostadil, and 0.05 to 0.3, 0.35 to 0.6 and 0.7 to 1 ml. of combined 30 mg. papaverine, 1 mg. phentolamine and 10 g. prostaglandin per ml. of solution. Results are expressed as the mean plus or minus standard deviation. RESULTS
During the 3-month recruitment period 214 men with erectile dysfunction on the intracavernous injection protocol had a scheduled followup visit at our outpatient clinic, of whom 180 (84.1%) were eligible for study. A total of 25 men (13.9%) refused, reporting fear of adverse effects of the new drug, while the remaining 155, 21 to 78 years old (mean age 56.4 ⫾ 12.6) accepted and were included in our study sample. Mean duration of the intracavernous injection protocol was 26 ⫾ 9 months (range 13 to 49). Table 1 shows the etiology of erectile dysfunction as documented in patient records. Psychogenic disorder was diagnosed in 38% of cases, including a psychiatric disorder in 9% (depression or anxiety disorder treated with antidepressants or minor tranquilizers). The diagnosis of psychogenic erectile dysfunction in 29% of patients was based on exclusion of any organic cause by an unremarkable medical history, normal laboratory tests, normal nocturnal penile tumescence and rigidity monitoring and/or normal hemodynamic evaluation. Medical history was also unremarkable in another 20% of patients in whom the initial diagnostic evaluation revealed cavernous arterial insufficiency and/or focal veno-occlusive dysfunction associated with blunt perineal trauma. In the
remaining 42% of cases at least 1 medical condition was associated with impotence, including diabetes mellitus, hypertension, cardiovascular disease and hypercholesterolemia. Of the patients 60% were current or former smokers. Intracavernous injection therapy consisted of 5 to 20 g. alprostadil in 95 participants (61.3%) and 0.05 to 1 ml. of combined 30 mg. papaverine, 1 mg. phentolamine and 10 g. prostaglandin E1 per ml. of solution in 60 (38.7%). The alprostadil dose was 10 or less and 15 or 20 g. in 60 (63.1%) and 35 (36.9%) patients, respectively. The dose of the combined solution was 0.05 to 0.3, 0.35 to 0.6 and 0.7 to 1 ml. in 23 (38.3%), 22 (36.7%) and 15 (25%) patients, respectively. Overall 116 of the 155 participants (74.8%) responded to sildenafil during phase 1, including 44 (37.9%) on the 50 and 72 (62.1%) on the 100 mg. dose. Table 2 lists the efficacy rate per group. The overall relative efficacy of sildenafil in those on alprostadil only and on the combined solution was 86.3% and 43.3%, respectively. The response rate was higher for the 100 than for the 50 mg. dose in all patient groups. We noted no correlation of the dose of vasoactive agents or sildenafil with erectile dysfunction etiology. At the end of phase 2, 71 of the 116 sildenafil responders (61.2%) preferred to continue with oral treatment, 31 (26.7%) elected to return to intracavernous injection and 14 (12.1%) elected to use each therapy alternately (table 3). At the end of the study or phase 3, 74 of the 116 sildenafil responders (63.8%) preferred sildenafil, 38 (32.8%) intracavernous injection and 4 (3.4%) each treatment alternately (table 3). The preference for sildenafil increased in alprostadil users from 63.4% initially to 70.7% at study end but decreased in those previously on greater than 0.35 ml. of the combined solution from 46.7% initially to 26.7% at study end. In addition, the number of patients who initially elected each treatment alternately decreased from 14 (12%) to 4 (3.4%) at study end. Of the 7 former alprostadil users on each therapy alternately 6 eventually elected sildenafil. All former combined solution users on each therapy alternately elected intracavernous injection only, while 3 who initially elected sildenafil returned to intracavernous injection. Those patients had previously used the greater than 0.35 ml. dose of the combined solution, indicating that the main reason for their final decision was erectile response quality. Overall 116 of the 155 study patients (74.8%) responded to sildenafil, while 74 (47.7%) continued with the oral drug only at study end (fig. 2). Adverse events were reported by 30 patients (19.3%), including headache in 12 (7.7%), nasal congestion in 18 (11.6%), dyspepsia in 6 (3.9%), flushing in 10 (6.5%) and abnormal vision in 3 (1.9%). All characterized the side effects as mild to moderate, transient and no reason for treatment discontinuation. DISCUSSION
Introduction of the intracavernous injection of vasoactive agents dramatically changed the field of erectile dysfunction.2 Despite the high efficacy, safety profile and even possible improvement in spontaneous erection reported for the selfinjection of vasoactive agents, patient compliance with this type of treatment remained low, leading to a high withdrawal TABLE 2. Sildenafil efficacy per group
TABLE 1. Etiological factors identified in study sample Medical Condition
No. Pts. (%)
Psychogenic disorder 59 (38) Blunt perineal trauma 31 (20) Diabetes mellitus 37 (23.9) Hypertension 33 (21.3) Cardiovascular disease 12 (7.7) Hypercholesterolemia 27 (17.4) Cigarette smoking 93 (60) Some patients had more than 1 medical condition or risk factor for erectile dysfunction.
Alprostadil (g.): 10 or less Greater than 10–20 Combined papaverine, phentolamine ⫹ prostaglandin E1 (ml.): 0.05–0.3 0.35–0.6 0.7–1
No. Sildenafil (%)
No. Pts.
50 Mg.
100 Mg.
No. No Response (%)
60 35
23 (38.3) 10 (28.6)
31 (51.7) 18 (51.4)
6 (10) 7 (20)
23 22 15
8 (34.8) 3 (13.6) 0
11 (47.8) 9 (40.9) 3 (20)
4 (17.4) 10 (45.5) 12 (80)
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SILDENAFIL VERSUS INTRACAVERNOUS INJECTION THERAPY TABLE 3. Sildenafil responder preferences at 1 month and at study end No. Pts. Alprostadil (g.): 10 or Less Greater than 10–20 Combined papaverine, phentolamine ⫹ prostaglandin E1 (ml.): 0.05–0.3 0.35–0.6 0.7–1 Alprostadil (g.): 10 or Less Greater than 10–20 Combined papaverine, phentolamine ⫹ prostaglandin E1 (ml.): 0.05–0.3 0.35–0.6 0.7–1
FIG. 2. Differences in efficacy of sildenafil and preference by group in overall study sample of 155 patients. Tri-mix, combined papaverine, phentolamine and prostaglandin E1.
rate.3, 1, 11 A recent review of the literature indicated that 15% of men offered the choice of intracavernous pharmacotherapy do not accept it, 40% discontinued treatment within the initial 3 months, 15% to 25% withdraw by the end of year 2 and only 20% to 30% continue for more than 3 years.2 Fear of needles, injected drug volume, adverse effects, failure to coincide with the patient and partner desire for more spontaneous erections, practical problems when administering intracavernous injection and the recovery of spontaneous erections are reported as the most common causes of such a high discontinuation rate.1–3, 6 –11 Limited patient compliance with intracavernous injection combined with the introduction of the long awaited, highly selective, safe and effective oral agent sildenafil as well as the widely accepted concept of a patient-goal oriented approach to erectile dysfunction has made oral therapy the first choice of men with erectile dysfunction and clinicians. Several studies and clinical trials proved its efficacy and safety for treating erectile dysfunction of various etiologies.4, 5 With a response rate of approximately 70% it is the only efficacious oral treatment available.4 Moreover, drug efficacy as well as tolerability was maintained in the initial long-term study.5 However, to our knowledge there are still no available data on the efficacy of sildenafil for various degrees of erectile tissue impairment, the comparative efficacy of oral versus intracavernous pharmacotherapy or patient preference for either treatment. Such data
No. Injection (%)
No. Sildenafil (%)
No. Injection ⫹ Sildenafil (%)
After 1 mo. 54 28
13 (24.1) 7 (25)
35 (64.8) 17 (60.7)
6 (11.1) 4 (14.3)
19 12 3
5 (26.3) 5 (41.7) 1 (33.3)
12 (63.2) 5 (41.7) 2 (66.7)
2 (10.5) 2 (16.6) 0
After 3 mos. 54 28
13 (24.1) 8 (28.6)
39 (72.2) 19 (67.8)
2 (3.7) 1 (3.6)
19 12 3
6 (31.6) 8 (66.7) 3 (100)
12 (63.1) 4 (33.3) 0
1 (5.3) 0 0
are important because thousands of men with erectile dysfunction worldwide who are currently treated with intracavernous injection are willing to change to the new oral therapy, while clinicians are urgently seeking information on the efficacy of intracavernous injection in nonresponders to sildenafil. To evaluate the comparative efficacy of the 2 most popular treatments of erectile dysfunction as well as patient preferences we offered men with erectile dysfunction of various etiologies treated previously with intracavernous injection for a long period the alternative of oral sildenafil. Since the majority of patients who discontinue intracavernous pharmacotherapy do so within the initial few months to a year,2, 3 we considered that a followup of more than a year was a safe inclusion criterion, so that we would avoid any false-positive results when considering final patient preference. Men with known neurological disease, such as paraplegia and multiple sclerosis, were excluded from study because it is known that intracavernous injection bypasses the neural pathway by direct action on the corporeal tissue. Although the Food and Drug Administration investigation did not identify any association of the initially reported death of sildenafil users with the medication, 13.9% of eligible patients refused to enter the protocol due to fear of the cardiovascular systemic effects of sildenafil. Of our study sample 38% of participants had a psychogenic disorder and 62% organic disease. A history of chronic illness involved diabetes mellitus in 23.9% of cases and hypertension in 21.3%, whereas 20% of the patients had erectile dysfunction associated with blunt perineal trauma. Such a sample represents a typical group of erectile dysfunction cases of various etiologies. Most patients were on alprostadil, while 38.7% were on a combined papaverine, phentolamine and prostaglandin E1 solution. In our practice this combined solution is administered in nonresponders to 20 g. alprostadil and in alprostadil responders with drug associated penile pain. Patients were categorized according to the vasoactive agent dose used at home. Such categorization was based on previous study findings indicating that the necessary dose of vasoactive agent solution reflects the severity of underlying corporeal tissue pathology.13, 14 Most patients in our study sample responded to alprostadil or a low dose of the combined solution. Such data are typical of the population treated at erectile dysfunction clinics. Only 23.9% of our participants were on a high dose, indicating severe erectile impairment. In our dose response phase we used the 2 most commonly effective sildenafil doses (50 and 100 mg.). Men who did not achieve sexual intercourse with the lower dose received the higher dose. The overall response to each dose was 74.8%, high enough to prove the efficacy of sildenafil for erectile dysfunction of various etiologies. As expected, 100 mg. were more efficacious than 50 mg. (62.1% versus 37.9%). A significant 25.2% of our study group did not respond to any sildenafil dose. The lack of efficacy even in patients on a low dose of vasoactive
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agents may be attributable to the various mechanisms of action of the 2 treatments. When injected intracorporeally, vasoactive agents have a direct relaxing effect on cavernous smooth muscle and arteries that is independent of sexual desire, whereas sildenafil provokes an erectile response in association with sexual stimulation.1, 2, 4 Therefore, the indirect mechanism of the action of sildenafil may be more easily biased than the direct action of intracavernous injection, especially in men with significant psychological inhibition. Another study finding is that the response rate to sildenafil was significantly lower in responders to a moderate or high dose of the combined solution. As discussed, others reported that the necessary dose of vasoactive agents reflects the degree of underlying hemodynamic13 and corporeal smooth muscle14 impairment. Thus, the efficacy of sildenafil in patients responding to 0.35 to 0.6 and 0.7 to 1 ml. of the combined solution was 54.5% and 20%, respectively. These rates represent a significant decrease from the 80% to 90% efficacy noted in the alprostadil and lower dose combined solution groups. An identically high response in the latter groups may be due to a similar degree of erectile tissue pathology, since 20 g. alprostadil should be considered as effective as 0.3 ml. of the combined solution.15 Such data clearly indicate that a subgroup of sildenafil nonresponders may respond to intracavernous injection and, therefore, intracavernous injection should be considered optional treatment when sildenafil fails. Interestingly when patients were asked to elect either type of treatment after the initial trial of the oral drug at the end of phase 2 only 61.2% of the responders preferred to continue sildenafil, whereas 26.7% elected to return to intracavernous injection. Three months later patient preference remained relatively unchanged since 63.8% elected to continue with sildenafil. The number of patients who decided to continue with intracavernous injection increased to 32.8%, while the number using each type of treatment alternately dramatically decreased from 12.1% at the end of phase 2 to 3.4% at study end. Therefore, despite the 74.8% efficacy of sildenafil in intracavernous injection users, 74 of the 155 study participants (47.7%) benefited from oral therapy. Such data may be explained by the previous observation that men who remain on intracavernous injection for a long period benefit by a significant positive impact on quality of life issues.9 The highest preference rate for sildenafil was noted in men on low dose alprostadil, who are expected to have less severe erectile impairment, while the lowest preference rate was observed in those on the high dose of combined solution. These results coincide with the low response rate in these groups. A possible explanation for the difference in efficacy and preference may be that intracavernous injection results in more rigid erection by direct relaxation of the cavernous smooth muscle. On the other hand, sildenafil has an indirect path of erectile tissue relaxation and may induce a more functional than rigid erection, especially in men with more severe cavernous smooth muscle pathology. It is inevitable that patients who have already achieved intracavernous injection associated rock hard rigid erections may not be satisfied with functional rigidity. Therefore, it becomes clear that efficacy, expressed as erectile response quality, should be considered the most critical determinant of preference in men with erectile dysfunction. There is another factor in the mechanism of action of sildenafil that may be a possible reason for the preference and efficacy differences noted. Sildenafil acts within 1 hour of oral intake,4 whereas intracavernously injected vasoactive agents may induce erection within 10 to 15 minutes after injection.1 Thus, although each treatment is considered pharmacotherapy on demand, it appears that intracavernous injection has an advantage over sildenafil by inducing more rapid response erection, although sildenafil provides more physiological erection. On the other hand, it is a challenge to propose a novel oral
treatment option to patients responding to minimally invasive therapy, such as intracavernous injection. Initially 12.1% of responders overcame the therapeutic dilemma by using each treatment alternately. A possible explanation is that providing a new treatment option that would treat the symptom but not change the perspective for definitive therapeutic results may not be believed by patients. Such an observation confirms the necessity for a patient oriented approach to treating erectile dysfunction. CONCLUSIONS
The high efficacy and preference rates of sildenafil in men with erectile dysfunction on intracavernous pharmacotherapy for a long period confirm its place as first line treatment for erectile dysfunction of various etiologies. However, some responders to sildenafil continue to use intracavernous injection. Differences in the characteristics of the pharmacologically induced erectile response seem to be a critical parameter for patient preference. Differences in efficacy of and patient preference for the 2 types of therapy clearly indicate that physicians should inform patients about and offer all available options. Especially for those who do not respond to sildenafil, intracavernous injection may be the treatment of choice. Comparative drug efficacy studies in patients with various degrees of erectile impairment are underway and it is anticipated that they may provide valuable data on better clinical management of erectile dysfunction. REFERENCES
1. Fallon, B.: Intracavernous injection therapy for male erectile dysfunction. Urol Clin North Am, 22: 833, 1995 2. Hatzichristou D. G.: Current treatment and future perspectives for erectile dysfunction. Int J Impot Res, suppl., 10: S3, 1998 3. Vardi, Y., Sprecher, E. and Gruenwald, I.: Logistic regression and survival analysis of 450 impotent patients treated with injection therapy: long-term dropout parameters. J Urol, 163: 467, 2000 4. Goldstein, I., Lue, T. F., Padma-Nathan, H. et al: Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. N Engl J Med, 338: 1397, 1998 5. Morales, A., Gingell, C., Collins, M. et al: Clinical safety of oral sildenafil citrate (VIAGRA) in the treatment of erectile dysfunction. Int J Impot Res, 10: 69, 1998 6. Porst, H.: The rationale for prostaglandin E1 in erectile failure: a survey of worldwide experience. J Urol, 155: 802, 1996 7. Virag, R., Shoukry, K., Floresco, J. et al: Intracavernous selfinjection of vasoactive drugs in the treatment of impotence: 8-year experience with 615 cases. J Urol, 145: 287, 1991 8. Sundaram, C. P., Thomas, W., Pryor, L. E. et al: Long-term follow-up of patients receiving injection therapy for erectile dysfunction. Urology, 49: 932, 1997 9. Willke, R. J., Yen, W., Parkerson, G. R., Jr. et al: Quality of life effects of alprostadil therapy for erectile dysfunction: results of a trial in Europe and South Africa. Int J Impot Res, 10: 239, 1998 10. Gupta, R., Kirschen, J., Barrow, R. C., II et al: Predictors of success and risk factors for attrition in the use of intracavernous injection. J Urol, 157: 1681, 1997 11. Lehmann, K., Casella, R., Blochlinger, A. et al: Reasons for discontinuing intracavernous injection therapy with prostaglandin E1 (alprostadil). Urology, 53: 397, 1999 12. Cheitlin, M. D., Hutter, A. M., Jr., Brindis, R. G. et al: ACC/AHA expert consensus document. Use of sildenafil (Viagra) in patients with cardiovascular disease. American College of Cardiology/ American Heart Association. J Am Coll Cardiol, 33: 273, 1999 13. Martins, F. E. and Padma-Nathan, H.: Diffuse veno-occlusive dysfunction: the underlying hemodynamic abnormality resulting in failure to respond to intracavernous pharmacotherapy. J Urol, 156: 1942, 1996 14. Nehra, A., Goldstein, I., Pabby, A. et al: Mechanisms of venous leakage: a prospective clinicopathological correlation of corporeal function and structure. J Urol, 156: 1320, 1996 15. Kulaksizoglu, H., Hakim, L. S., Nehra, A. et al: Comparison of alprostadil sterile powder (Caverject) with trimix: nomogram and patient satisfaction. J Urol, suppl., 157: 180, abstract 699, 1997
Vol. 164, 1197–1200, October 2000 Printed in U.S.A.
SILDENAFIL VERSUS INTRACAVERNOUS INJECTION THERAPY: EFFICACY AND PREFERENCE IN PATIENTS ON INTRACAVERNOUS INJECTION FOR MORE THAN 1 YEAR DIMITRIOS G. HATZICHRISTOU, APOSTOLOS APOSTOLIDIS, VASILIOS TZORTZIS, EVANGELOS IOANNIDES, KONSTANTINOS YANNAKOYORGOS AND ATHANASIOS KALINDERIS From the Department of Urology, School of Medicine and Center for Sexual Dysfunction, Aristotle University of Thessaloniki, Thessaloniki, Greece
ABSTRACT
Purpose: To our knowledge comparative data on the effectiveness of and patient preference for intracavernous injection therapy and sildenafil are still not available. We evaluated the efficacy of sildenafil as well as patient preference in a group of impotent men on intracavernous injection for more than a year. Materials and Methods: Patients on intracavernous injection therapy for more than a year without neurological disease and/or a contraindication to sildenafil treatment were recruited for study. In phase 1 we determined the efficacy of 50 and 100 mg. sildenafil citrate at home. In phase 2 responders to sildenafil were asked to use the preferred dose orally for a month and choose intracavernous injection or sildenafil. In phase 3 patients were asked to continue either treatment for 3 more months. Patient preferences were reported at the end of phases 2 and 3. Results: Of the 180 men recruited 155 with a mean age of 56.4 ⫾ 12.6 years on intracavernous injection for a mean of 26 ⫾ 9 months accepted and were included in our series. Overall 116 men (74.8%) responded to sildenafil during study phase 1. After 1 month of treatment 71 responders (61.2%) preferred to continue with the oral drug, 31 (26.7%) returned to intracavernous injection and 14 (12.1%) used each drug alternately. Three months later 74 of the 116 responders (63.8%) preferred oral treatment and 38 (32.8%) chose intracavernous injection, while 4 (3.4%) continued to use each treatment alternately. Conclusions: Sildenafil is highly effective in intracavernous injection responders, although a certain group prefer to continue intracavernous injection. While sildenafil should be considered first line treatment, men with erectile dysfunction should be aware of all treatment options available because nonresponders to sildenafil may respond to intracavernous injection. KEY WORDS: penis, impotence, vasodilator agents
Intracavernous injection therapy is a historical cornerstone in the treatment of male erectile dysfunction.1, 2 The efficacy and safety profile of intracavernous injected vasoactive drugs made them first line treatment in patients with various causes of erectile dysfunction for almost 15 years.2 However, a high withdrawal rate and low long-term patient compliance associated with this treatment indicated that an oral drug was more than desirable.2, 3 The development and approval of sildenafil were revolutionary in the field of impotence since for the first time it provided effective and safe oral treatment for erectile dysfunction.4, 5 Sildenafil represents a challenge not only to untreated patients, but also to those previously treated with intracavernous pharmacotherapy. Others have reported the response rate, safety profile and quality of life issues of the various intracavernous pharmacological treatments6 –11 as well as sildenafil more recently.4, 5 However, to our knowledge comparative data on the effectiveness of and patient preference for the 2 types of therapy are not available, especially in men already on an intracavernous injection protocol. We evaluated the efficacy of sildenafil as well as preference in men with erectile dysfunction who were previously successfully treated with intracavernous injection for a long period. MATERIALS AND METHODS
The population sample in our study comprised men on an intracavernous injection regimen who presented to our anAccepted for publication May 12, 2000.
drology unit for regular followup. According to standard protocol at our facility candidates for intracavernous injection are impotent, between ages 18 and 80 years, and have a history of erectile dysfunction of more than 6 months. In addition, they have no significant penile curvature, symptomatic uncontrolled heart disease, history of a cardiovascular episode within the last 6 months or severe psychiatric illness, such as uncontrolled depression, bipolar disorder or psychosis. For study purposes patients were recruited during a 3-month period according to certain inclusion criteria, including maintenance on an intracavernous injection regimen for more than a year, absent known neuropathy and no contraindications to sildenafil. When recruiting men with cardiovascular disease, American College of CardiologyAmerican Heart Association guidelines were adapted.12 Study design included 3 phases (fig. 1). During the initial titration phase patients were asked to attempt sexual intercourse at least twice using 50 mg. sildenafil citrate. Those who did not respond to this dose were asked to repeat the trial using a 100 mg. dose. Positive response was defined as erection adequate for satisfactory sexual intercourse based exclusively on patient reports. In phase 2 all responders to 50 or 100 mg. sildenafil were asked to use sildenafil for 1 month at the preferred dose. At the end of the month they were asked to elect intracavernous injection, sildenafil or each treatment alternately. During phases 1 and 2 all patients abstained from intracavernous injection. In phase 3 patients were asked to elect sildenafil or intracavernous injection for
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FIG. 1. Study design
3 more months. At the end of phase 3 they were questioned on their final treatment preferences. To evaluate further the effectiveness of sildenafil versus intracavernous injection therapy as well as preferences patients were categorized into groups according to the dose and intracavernous agent used, including 10 or less and greater than 10 to 20 g. alprostadil, and 0.05 to 0.3, 0.35 to 0.6 and 0.7 to 1 ml. of combined 30 mg. papaverine, 1 mg. phentolamine and 10 g. prostaglandin per ml. of solution. Results are expressed as the mean plus or minus standard deviation. RESULTS
During the 3-month recruitment period 214 men with erectile dysfunction on the intracavernous injection protocol had a scheduled followup visit at our outpatient clinic, of whom 180 (84.1%) were eligible for study. A total of 25 men (13.9%) refused, reporting fear of adverse effects of the new drug, while the remaining 155, 21 to 78 years old (mean age 56.4 ⫾ 12.6) accepted and were included in our study sample. Mean duration of the intracavernous injection protocol was 26 ⫾ 9 months (range 13 to 49). Table 1 shows the etiology of erectile dysfunction as documented in patient records. Psychogenic disorder was diagnosed in 38% of cases, including a psychiatric disorder in 9% (depression or anxiety disorder treated with antidepressants or minor tranquilizers). The diagnosis of psychogenic erectile dysfunction in 29% of patients was based on exclusion of any organic cause by an unremarkable medical history, normal laboratory tests, normal nocturnal penile tumescence and rigidity monitoring and/or normal hemodynamic evaluation. Medical history was also unremarkable in another 20% of patients in whom the initial diagnostic evaluation revealed cavernous arterial insufficiency and/or focal veno-occlusive dysfunction associated with blunt perineal trauma. In the
remaining 42% of cases at least 1 medical condition was associated with impotence, including diabetes mellitus, hypertension, cardiovascular disease and hypercholesterolemia. Of the patients 60% were current or former smokers. Intracavernous injection therapy consisted of 5 to 20 g. alprostadil in 95 participants (61.3%) and 0.05 to 1 ml. of combined 30 mg. papaverine, 1 mg. phentolamine and 10 g. prostaglandin E1 per ml. of solution in 60 (38.7%). The alprostadil dose was 10 or less and 15 or 20 g. in 60 (63.1%) and 35 (36.9%) patients, respectively. The dose of the combined solution was 0.05 to 0.3, 0.35 to 0.6 and 0.7 to 1 ml. in 23 (38.3%), 22 (36.7%) and 15 (25%) patients, respectively. Overall 116 of the 155 participants (74.8%) responded to sildenafil during phase 1, including 44 (37.9%) on the 50 and 72 (62.1%) on the 100 mg. dose. Table 2 lists the efficacy rate per group. The overall relative efficacy of sildenafil in those on alprostadil only and on the combined solution was 86.3% and 43.3%, respectively. The response rate was higher for the 100 than for the 50 mg. dose in all patient groups. We noted no correlation of the dose of vasoactive agents or sildenafil with erectile dysfunction etiology. At the end of phase 2, 71 of the 116 sildenafil responders (61.2%) preferred to continue with oral treatment, 31 (26.7%) elected to return to intracavernous injection and 14 (12.1%) elected to use each therapy alternately (table 3). At the end of the study or phase 3, 74 of the 116 sildenafil responders (63.8%) preferred sildenafil, 38 (32.8%) intracavernous injection and 4 (3.4%) each treatment alternately (table 3). The preference for sildenafil increased in alprostadil users from 63.4% initially to 70.7% at study end but decreased in those previously on greater than 0.35 ml. of the combined solution from 46.7% initially to 26.7% at study end. In addition, the number of patients who initially elected each treatment alternately decreased from 14 (12%) to 4 (3.4%) at study end. Of the 7 former alprostadil users on each therapy alternately 6 eventually elected sildenafil. All former combined solution users on each therapy alternately elected intracavernous injection only, while 3 who initially elected sildenafil returned to intracavernous injection. Those patients had previously used the greater than 0.35 ml. dose of the combined solution, indicating that the main reason for their final decision was erectile response quality. Overall 116 of the 155 study patients (74.8%) responded to sildenafil, while 74 (47.7%) continued with the oral drug only at study end (fig. 2). Adverse events were reported by 30 patients (19.3%), including headache in 12 (7.7%), nasal congestion in 18 (11.6%), dyspepsia in 6 (3.9%), flushing in 10 (6.5%) and abnormal vision in 3 (1.9%). All characterized the side effects as mild to moderate, transient and no reason for treatment discontinuation. DISCUSSION
Introduction of the intracavernous injection of vasoactive agents dramatically changed the field of erectile dysfunction.2 Despite the high efficacy, safety profile and even possible improvement in spontaneous erection reported for the selfinjection of vasoactive agents, patient compliance with this type of treatment remained low, leading to a high withdrawal TABLE 2. Sildenafil efficacy per group
TABLE 1. Etiological factors identified in study sample Medical Condition
No. Pts. (%)
Psychogenic disorder 59 (38) Blunt perineal trauma 31 (20) Diabetes mellitus 37 (23.9) Hypertension 33 (21.3) Cardiovascular disease 12 (7.7) Hypercholesterolemia 27 (17.4) Cigarette smoking 93 (60) Some patients had more than 1 medical condition or risk factor for erectile dysfunction.
Alprostadil (g.): 10 or less Greater than 10–20 Combined papaverine, phentolamine ⫹ prostaglandin E1 (ml.): 0.05–0.3 0.35–0.6 0.7–1
No. Sildenafil (%)
No. Pts.
50 Mg.
100 Mg.
No. No Response (%)
60 35
23 (38.3) 10 (28.6)
31 (51.7) 18 (51.4)
6 (10) 7 (20)
23 22 15
8 (34.8) 3 (13.6) 0
11 (47.8) 9 (40.9) 3 (20)
4 (17.4) 10 (45.5) 12 (80)
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SILDENAFIL VERSUS INTRACAVERNOUS INJECTION THERAPY TABLE 3. Sildenafil responder preferences at 1 month and at study end No. Pts. Alprostadil (g.): 10 or Less Greater than 10–20 Combined papaverine, phentolamine ⫹ prostaglandin E1 (ml.): 0.05–0.3 0.35–0.6 0.7–1 Alprostadil (g.): 10 or Less Greater than 10–20 Combined papaverine, phentolamine ⫹ prostaglandin E1 (ml.): 0.05–0.3 0.35–0.6 0.7–1
FIG. 2. Differences in efficacy of sildenafil and preference by group in overall study sample of 155 patients. Tri-mix, combined papaverine, phentolamine and prostaglandin E1.
rate.3, 1, 11 A recent review of the literature indicated that 15% of men offered the choice of intracavernous pharmacotherapy do not accept it, 40% discontinued treatment within the initial 3 months, 15% to 25% withdraw by the end of year 2 and only 20% to 30% continue for more than 3 years.2 Fear of needles, injected drug volume, adverse effects, failure to coincide with the patient and partner desire for more spontaneous erections, practical problems when administering intracavernous injection and the recovery of spontaneous erections are reported as the most common causes of such a high discontinuation rate.1–3, 6 –11 Limited patient compliance with intracavernous injection combined with the introduction of the long awaited, highly selective, safe and effective oral agent sildenafil as well as the widely accepted concept of a patient-goal oriented approach to erectile dysfunction has made oral therapy the first choice of men with erectile dysfunction and clinicians. Several studies and clinical trials proved its efficacy and safety for treating erectile dysfunction of various etiologies.4, 5 With a response rate of approximately 70% it is the only efficacious oral treatment available.4 Moreover, drug efficacy as well as tolerability was maintained in the initial long-term study.5 However, to our knowledge there are still no available data on the efficacy of sildenafil for various degrees of erectile tissue impairment, the comparative efficacy of oral versus intracavernous pharmacotherapy or patient preference for either treatment. Such data
No. Injection (%)
No. Sildenafil (%)
No. Injection ⫹ Sildenafil (%)
After 1 mo. 54 28
13 (24.1) 7 (25)
35 (64.8) 17 (60.7)
6 (11.1) 4 (14.3)
19 12 3
5 (26.3) 5 (41.7) 1 (33.3)
12 (63.2) 5 (41.7) 2 (66.7)
2 (10.5) 2 (16.6) 0
After 3 mos. 54 28
13 (24.1) 8 (28.6)
39 (72.2) 19 (67.8)
2 (3.7) 1 (3.6)
19 12 3
6 (31.6) 8 (66.7) 3 (100)
12 (63.1) 4 (33.3) 0
1 (5.3) 0 0
are important because thousands of men with erectile dysfunction worldwide who are currently treated with intracavernous injection are willing to change to the new oral therapy, while clinicians are urgently seeking information on the efficacy of intracavernous injection in nonresponders to sildenafil. To evaluate the comparative efficacy of the 2 most popular treatments of erectile dysfunction as well as patient preferences we offered men with erectile dysfunction of various etiologies treated previously with intracavernous injection for a long period the alternative of oral sildenafil. Since the majority of patients who discontinue intracavernous pharmacotherapy do so within the initial few months to a year,2, 3 we considered that a followup of more than a year was a safe inclusion criterion, so that we would avoid any false-positive results when considering final patient preference. Men with known neurological disease, such as paraplegia and multiple sclerosis, were excluded from study because it is known that intracavernous injection bypasses the neural pathway by direct action on the corporeal tissue. Although the Food and Drug Administration investigation did not identify any association of the initially reported death of sildenafil users with the medication, 13.9% of eligible patients refused to enter the protocol due to fear of the cardiovascular systemic effects of sildenafil. Of our study sample 38% of participants had a psychogenic disorder and 62% organic disease. A history of chronic illness involved diabetes mellitus in 23.9% of cases and hypertension in 21.3%, whereas 20% of the patients had erectile dysfunction associated with blunt perineal trauma. Such a sample represents a typical group of erectile dysfunction cases of various etiologies. Most patients were on alprostadil, while 38.7% were on a combined papaverine, phentolamine and prostaglandin E1 solution. In our practice this combined solution is administered in nonresponders to 20 g. alprostadil and in alprostadil responders with drug associated penile pain. Patients were categorized according to the vasoactive agent dose used at home. Such categorization was based on previous study findings indicating that the necessary dose of vasoactive agent solution reflects the severity of underlying corporeal tissue pathology.13, 14 Most patients in our study sample responded to alprostadil or a low dose of the combined solution. Such data are typical of the population treated at erectile dysfunction clinics. Only 23.9% of our participants were on a high dose, indicating severe erectile impairment. In our dose response phase we used the 2 most commonly effective sildenafil doses (50 and 100 mg.). Men who did not achieve sexual intercourse with the lower dose received the higher dose. The overall response to each dose was 74.8%, high enough to prove the efficacy of sildenafil for erectile dysfunction of various etiologies. As expected, 100 mg. were more efficacious than 50 mg. (62.1% versus 37.9%). A significant 25.2% of our study group did not respond to any sildenafil dose. The lack of efficacy even in patients on a low dose of vasoactive
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SILDENAFIL VERSUS INTRACAVERNOUS INJECTION THERAPY
agents may be attributable to the various mechanisms of action of the 2 treatments. When injected intracorporeally, vasoactive agents have a direct relaxing effect on cavernous smooth muscle and arteries that is independent of sexual desire, whereas sildenafil provokes an erectile response in association with sexual stimulation.1, 2, 4 Therefore, the indirect mechanism of the action of sildenafil may be more easily biased than the direct action of intracavernous injection, especially in men with significant psychological inhibition. Another study finding is that the response rate to sildenafil was significantly lower in responders to a moderate or high dose of the combined solution. As discussed, others reported that the necessary dose of vasoactive agents reflects the degree of underlying hemodynamic13 and corporeal smooth muscle14 impairment. Thus, the efficacy of sildenafil in patients responding to 0.35 to 0.6 and 0.7 to 1 ml. of the combined solution was 54.5% and 20%, respectively. These rates represent a significant decrease from the 80% to 90% efficacy noted in the alprostadil and lower dose combined solution groups. An identically high response in the latter groups may be due to a similar degree of erectile tissue pathology, since 20 g. alprostadil should be considered as effective as 0.3 ml. of the combined solution.15 Such data clearly indicate that a subgroup of sildenafil nonresponders may respond to intracavernous injection and, therefore, intracavernous injection should be considered optional treatment when sildenafil fails. Interestingly when patients were asked to elect either type of treatment after the initial trial of the oral drug at the end of phase 2 only 61.2% of the responders preferred to continue sildenafil, whereas 26.7% elected to return to intracavernous injection. Three months later patient preference remained relatively unchanged since 63.8% elected to continue with sildenafil. The number of patients who decided to continue with intracavernous injection increased to 32.8%, while the number using each type of treatment alternately dramatically decreased from 12.1% at the end of phase 2 to 3.4% at study end. Therefore, despite the 74.8% efficacy of sildenafil in intracavernous injection users, 74 of the 155 study participants (47.7%) benefited from oral therapy. Such data may be explained by the previous observation that men who remain on intracavernous injection for a long period benefit by a significant positive impact on quality of life issues.9 The highest preference rate for sildenafil was noted in men on low dose alprostadil, who are expected to have less severe erectile impairment, while the lowest preference rate was observed in those on the high dose of combined solution. These results coincide with the low response rate in these groups. A possible explanation for the difference in efficacy and preference may be that intracavernous injection results in more rigid erection by direct relaxation of the cavernous smooth muscle. On the other hand, sildenafil has an indirect path of erectile tissue relaxation and may induce a more functional than rigid erection, especially in men with more severe cavernous smooth muscle pathology. It is inevitable that patients who have already achieved intracavernous injection associated rock hard rigid erections may not be satisfied with functional rigidity. Therefore, it becomes clear that efficacy, expressed as erectile response quality, should be considered the most critical determinant of preference in men with erectile dysfunction. There is another factor in the mechanism of action of sildenafil that may be a possible reason for the preference and efficacy differences noted. Sildenafil acts within 1 hour of oral intake,4 whereas intracavernously injected vasoactive agents may induce erection within 10 to 15 minutes after injection.1 Thus, although each treatment is considered pharmacotherapy on demand, it appears that intracavernous injection has an advantage over sildenafil by inducing more rapid response erection, although sildenafil provides more physiological erection. On the other hand, it is a challenge to propose a novel oral
treatment option to patients responding to minimally invasive therapy, such as intracavernous injection. Initially 12.1% of responders overcame the therapeutic dilemma by using each treatment alternately. A possible explanation is that providing a new treatment option that would treat the symptom but not change the perspective for definitive therapeutic results may not be believed by patients. Such an observation confirms the necessity for a patient oriented approach to treating erectile dysfunction. CONCLUSIONS
The high efficacy and preference rates of sildenafil in men with erectile dysfunction on intracavernous pharmacotherapy for a long period confirm its place as first line treatment for erectile dysfunction of various etiologies. However, some responders to sildenafil continue to use intracavernous injection. Differences in the characteristics of the pharmacologically induced erectile response seem to be a critical parameter for patient preference. Differences in efficacy of and patient preference for the 2 types of therapy clearly indicate that physicians should inform patients about and offer all available options. Especially for those who do not respond to sildenafil, intracavernous injection may be the treatment of choice. Comparative drug efficacy studies in patients with various degrees of erectile impairment are underway and it is anticipated that they may provide valuable data on better clinical management of erectile dysfunction. REFERENCES
1. Fallon, B.: Intracavernous injection therapy for male erectile dysfunction. Urol Clin North Am, 22: 833, 1995 2. Hatzichristou D. G.: Current treatment and future perspectives for erectile dysfunction. Int J Impot Res, suppl., 10: S3, 1998 3. Vardi, Y., Sprecher, E. and Gruenwald, I.: Logistic regression and survival analysis of 450 impotent patients treated with injection therapy: long-term dropout parameters. J Urol, 163: 467, 2000 4. Goldstein, I., Lue, T. F., Padma-Nathan, H. et al: Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. N Engl J Med, 338: 1397, 1998 5. Morales, A., Gingell, C., Collins, M. et al: Clinical safety of oral sildenafil citrate (VIAGRA) in the treatment of erectile dysfunction. Int J Impot Res, 10: 69, 1998 6. Porst, H.: The rationale for prostaglandin E1 in erectile failure: a survey of worldwide experience. J Urol, 155: 802, 1996 7. Virag, R., Shoukry, K., Floresco, J. et al: Intracavernous selfinjection of vasoactive drugs in the treatment of impotence: 8-year experience with 615 cases. J Urol, 145: 287, 1991 8. Sundaram, C. P., Thomas, W., Pryor, L. E. et al: Long-term follow-up of patients receiving injection therapy for erectile dysfunction. Urology, 49: 932, 1997 9. Willke, R. J., Yen, W., Parkerson, G. R., Jr. et al: Quality of life effects of alprostadil therapy for erectile dysfunction: results of a trial in Europe and South Africa. Int J Impot Res, 10: 239, 1998 10. Gupta, R., Kirschen, J., Barrow, R. C., II et al: Predictors of success and risk factors for attrition in the use of intracavernous injection. J Urol, 157: 1681, 1997 11. Lehmann, K., Casella, R., Blochlinger, A. et al: Reasons for discontinuing intracavernous injection therapy with prostaglandin E1 (alprostadil). Urology, 53: 397, 1999 12. Cheitlin, M. D., Hutter, A. M., Jr., Brindis, R. G. et al: ACC/AHA expert consensus document. Use of sildenafil (Viagra) in patients with cardiovascular disease. American College of Cardiology/ American Heart Association. J Am Coll Cardiol, 33: 273, 1999 13. Martins, F. E. and Padma-Nathan, H.: Diffuse veno-occlusive dysfunction: the underlying hemodynamic abnormality resulting in failure to respond to intracavernous pharmacotherapy. J Urol, 156: 1942, 1996 14. Nehra, A., Goldstein, I., Pabby, A. et al: Mechanisms of venous leakage: a prospective clinicopathological correlation of corporeal function and structure. J Urol, 156: 1320, 1996 15. Kulaksizoglu, H., Hakim, L. S., Nehra, A. et al: Comparison of alprostadil sterile powder (Caverject) with trimix: nomogram and patient satisfaction. J Urol, suppl., 157: 180, abstract 699, 1997