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A comparative, crossover study of the efficacy and safety of sildenafil and apomorphine in men with evidence of arteriogenic erectile dysfunction

Abstract

The aim of the study was to establish and compare the efficacy and safety of sildenafil and apomorphine in men with arteriogenic erectile dysfunction (ED). In all, 43 men with ED and postinjection max penile systolic velocity <25 cm/s in repeated Doppler ultrasonography were included. Of these, 24 men started on apomorphine 2 mg and 19 on sildenafil 50 mg, the doses titrated up to 3 and 100 mg according to effectiveness and tolerability. Safety was evaluated according to adverse events (AEs) and patient withdrawal. Efficacy was the percentage of attempts resulting in erections firm enough for intercourse, based on event log data. The incidence of AEs with apomorphine 3 mg was higher than with sildenafil 100 mg. Two men on apomorphine 3 mg discontinued treatment due to AEs. The overall success rate of sildenafil was 63.7% compared to 32.1% of apomorphine (Pearson χ2, P<0.01). Of all men, 25 (58.1%) responded to sildenafil 50 mg without the need for dose increase, while only one responded to apomorphine 2 mg. The response to sildenafil 50 mg was age related (analysis of variance, p=0.04). Satisfaction was reported by 76.75 and 13.95% of patients for sildenafil and apomorphine, respectively, but 20.9% were not satisfied with any of the two drugs. In conclusion, this study provides clear evidence that sildenafil, even at 50 mg dose, is more effective than apomorphine 3 mg in men with arteriogenic ED. The fact that one out of five patients is not satisfied with the above-studied drugs shows that new oral agents need to be evaluated for the treatment of this disorder.

Introduction

Erectile dysfunction (ED) has been recognized as a common disorder afflicting as many as 30 million men in the USA and more than 100 million worldwide.1 In the Massachusetts Male Aging Study, the prevalence of ED was shown to be rather a result of age-related conditions, such as diabetes, hypertension and heart disease, than aging itself.2 These conditions and atherosclerosis may reduce penile blood flow or affect smooth muscle relaxation in the corpora resulting in ED,3,4,5 especially in the arteriogenic one which is most likely a smooth muscle disorder.6 The advent of the PDE 5 inhibitor sildenafil citrate revolutionarily changed the management of ED. The efficacy and safety of this first-line oral treatment has been studied either in the general population of men seeking therapy for ED of various etiologies,7,8 or in placebo-controlled trials where selection of impotent participants was subject to rigorous exclusion and inclusion criteria.9,10,11 The newer sublingual drug apomorphine provided clinicians and patients with a drug of rapid onset of action, which allows sexual intercourse to take place in a more spontaneous manner.12 Its efficacy and safety were also recently documented in a review of placebo-controlled studies and in a cross study analysis of phase II and III studies.13,14

Apart from the overall efficacy of sildenafil and apomorphine in the population of men with ED, in everyday clinical practice it would be important for the physician to be able to predict the response to these drugs in each individual case. In this unsponsored study, we assess the efficacy and safety of sildenafil and apomorphine in the treatment of men with evidence of arteriogenic ED.

Patients and methods

Patient recruitment and study design

Male outpatients with ED were investigated for detection of the etiology of their disorder. Only those with repeated peak systolic velocity (PSV) <25 cm/s were initially eligible for enrollment in the study. Further inclusion criteria were ED in a stable relationship for at least 6 months and a written informed consent. The men were excluded from the study if they had penile or testicular deformities, spinal cord injury, hormonal deficiency, severe blood pressure abnormality or a history of retinitis pigmentosa. They were also excluded if they had been treated with vacuum devices or intracavernosal injections and if they had been receiving testosterone or nitrates in any form.

At the first visit a detailed history was taken including parameters of sexual life, the status of the underlying diseases and concomitant drug treatment. For documentation of ED, patients were asked to complete the IIEF-5.15 IIEF-5 is a 5-item version of IIEF, easy and fast to diagnose the presence and severity of ED. With a range of scores from 5 to 25, a score less than or equal to 21 is abnormal. With this index, ED is classified into five severity levels, ranging from none (22–25) to severe (5–7). The men were physically examined and blood samples and hormone levels were also checked. They subsequently underwent color Doppler ultrasonography of the penile arteries pre- and postinjection of 10 μg prostaglandin E1 (PGE1). In the cases with PSV <25 cm/s, the test was repeated 1 week later using 20 μg of PGE1 to confirm arterial disease.

Eventually, 43 men met the criteria to enter this study. Patients were randomly allocated in each initial treatment arm; 24 started on apomorphine 2 mg and 19 on sildenafil 50 mg. They were thoroughly instructed about how to take the drugs, and were ordered to refer any adverse events (AEs) and make at least four attempts at these doses. They were regularly followed up every 2 weeks when the therapeutic response was assessed according to the review of an event log. The initial dose was adjusted to 3 mg for apomorphine and to 100 mg for sildenafil if the patient was not satisfied with the effectiveness of his treatment. This first treatment period was planned to last 6 weeks. After a 1-week washout period, the men switched to the other treatment mode for an equal time of 6 weeks and continued to be followed as mentioned above.

Efficacy and safety evaluations

Efficacy was defined as the percentage of attempts resulting in erections firm enough for intercourse. For better results, the patients were encouraged for manual stimulation of their genitals when starting sexual activity. After the intercourse they completed the event log, which was considered the evidence of the efficacy assessment. After every attempt they replied with ‘yes’ or ‘no’ to the question ‘was the erection firm enough for intercourse?’. With regard to the satisfaction with each studied drug, at the end of the study the men were asked to reply to the question, ‘which drug you were satisfied with?’. The reply options were: ‘apomorphine, sildenafil, both, none’.

Safety was evaluated according to events involving adverse drug reactions and treatment withdrawal. When the AEs were mild and transient, the patients were encouraged to continue treatment. Persistent moderate events affecting the quality of life and the personal activity or life-threatening AEs were causes for withdrawal from the study. At follow-up visits, the safety assessment included physical examination, pulse rate and blood pressure measurements and AEs recording. At the end of each treatment mode blood samples were also checked.

Statistics

The methods used were Pearson's χ2 and analysis of variance (ANOVA). Results were considered statistically significant with a p-value of less than 0.05.

Results

Demographics

Out of the 43 studied men, 29 (67.5%) had a spectrum of comorbidities strongly related with peripheral vascular disease. In all, 15 men (34.9%) suffered from one, nine (20.9%) from two and five (11.6%) from more than two concomitant diseases. The patients who received medications to control comorbidities continued to receive them during the study. Almost all studied men were heavy smokers; from the two nonsmokers included in the study, one was ex-smoker while the other had never smoked. The mean severity of ED was moderate to severe (mean IIEF-5 score: 7.9). The baseline characteristics of the 43 patients enrolled in this study are summarized in Table 1.

Table 1 Patient demographic characteristics at baseline

Efficacy

The study duration was 13 weeks, with a 1-week washout period included. The mean number of intercourse attempts during the 12 weeks of treatment was 13.6 with each drug. Analytically, the enrolled men experienced 196 attempts with apomorphine 2 mg and 392 attempts with apomorphine 3 mg, and recorded 43 (22.1%) and 146 (37.2%) successful attempts, respectively. On the other hand, they experienced 395 attempts with sildenafil 50 mg and 194 with 100 mg, and recorded 256 (64.8%) and 119 (61.3%) successful attempts, respectively. The efficacy of the two medications per received dose is depicted in Figure 1.

Figure 1
figure1

Efficacy of sildenafil and apomorphine per dose.

Only one man responded satisfactorily to apomorphine 2 mg and did not switch to 3 mg. On the contrary, 25 of the studied men (58.1%) did not switch to sildenafil 100 mg because they responded to 50 mg succeeding to 213 out of 278 attempts (76.6%). ANOVA showed that the response to sildenafil 50 mg was age related (P=0.004), but it was not related to the duration of ED (P=0.1), the penile velocity (P=0.3), the IIEF-5 score (P=0.3) and the presence of comorbidity (P=0.5). However, even the 18 men who switched to sildenafil 100 mg recorded 43 successful out of 117 (36.7%) attempts at 50 mg. Irrespective of the dose, 375 out of 589 (63.7%) and 189 out of 588 (32.1%) of the attempts with sildenafil and apomorphine, respectively, were successful for intercourse. This difference was statistically significant (P<0.01). The overall efficacy of the two drugs in this study is depicted in Figure 2.

Figure 2
figure2

Overall efficacy of sildenafil and apomorphine.

In order to assess possible differences in the efficacy of the two regimens in association with the different time points (ie before and after washout period), we evaluated efficacy in relation to the drug given initially. The efficacy for sildenafil was 62.6 and 64.8% before and after the washout, respectively. For apomorphine, the respective values were 31.3 and 32.9% (Figure 3). Satisfaction with the effects of apomorphine and sildenafil at the end of the study is shown in Table 2. Ultimately, 33 men (76.75%) were satisfied with the response to sildenafil and six men (13.95%) with apomorphine. However, nine men (20.9%) were not satisfied with any medication because of poor response.

Figure 3
figure3

Percentage of successful attempts according to the drug with which men started the study.

Table 2 Satisfaction with treatment at the study end, no (%)

Safety

Treatment with sildenafil was well tolerated. Although three patients reported repeated but mild headache and dyspepsia, none discontinued treatment due to AE. Six patients reported several AEs, frequently mild and self-limiting, with apomorphine. Two men discontinued treatment, one because of repeated significant nausea and one because of a syncope episode. The latter occurred to a man who had consumed alcoholic beverage. Table 3 summarizes the tolerability results of the two medications.

Table 3 Summary of adverse events and withdrawals

Discussion

Patients with ED of any etiology used to prefer oral medications to self-injected drugs or surgery, even at the era of unavailability of effective oral treatment. 16 The accessibility to on-demand oral agents, initially to sildenafil and next to apomorphine, had a tremendous impact on the treatment of ED.17,18 As a rational sequel, some interesting trials studied the prognostic factors for response to these agents,19,20,21 although it seems difficult to identify particular patient characteristics predicting success or failure of treatment.22 However, a useful comparison between the two medications is limited by the different study designs, and the fact that their efficacy in clinical trials varies, depending on the different end points and response criteria. Our crossover study of a homogeneous group of men with arteriogenic ED using strict inclusion criteria compares head-to-head apomorphine and sildenafil with regard to efficacy and safety.

Postinjection PSV <25 cm/s has been proposed as a high likelihood of arterial disease.23 An evidence-based assessment of impotence testing concurs that this cutoff point suggests severe penile arterial insufficiency.24 To determine arteriogenic ED, we performed two color Doppler tests, initially injecting PGE1 at the proposed dose of 10 μg25 and subsequently doubling the dose to avoid falsely abnormal results, although repetition is not necessary in majority of the cases.26 Thus, ED of the patients enrolled in this study was considered severe not only by the IIEF-5 score but because of the postinjection PSV as well.

We have defined efficacy as the percentage of satisfactory for intercourse erections from the patient's point of view. The results of the comparative, crossover study reported here demonstrate that sildenafil has a higher effectiveness than apomorphine in the treatment of men with arteriogenic ED. The evaluation of the dose-related effectiveness clearly shows that sildenafil, even at 50 mg is more effective than apomorphine 3 mg. It is remarkable that 58% of these patients satisfactorily respond to sildenafil 50 mg without needing to switch to a higher dose. As this finding is age related, it is probably due to the fact that younger men may have a higher residual vasodilatory capacity of the penile vasculature and erectile tissue, and thus respond more effectively. The overall efficacy of the two drugs shows that about two-third of the attempts with sildenafil and about one-third of the attempts with apomorphine are successful for intercourse. This significant difference in effectiveness is possibly due to the mode of action of the two drugs. While apomorphine stimulates dopamine D2 receptors in hypothalamus, activating central neurological pathways,27 sildenafil acts peripherally, facilitating the erectile response by direct smooth muscle relaxation in the penile arteries and erectile tissue.10 Although guidelines have documented the therapeutic management of ED,28 results like these reported herein provide clear evidence that sildenafil must be the first-line choice in the case of arteriogenic impotence. Nevertheless, apomorphine, because of its reasonable effectiveness, has a place in the therapeutic algorithm of ED alternatively when sildenafil fails to treat and unavoidably when sildenafil is contraindicated.29,30

The reported effectiveness of the two drugs in this study reflects the patient's satisfaction with treatment. The vast majority of men with arteriogenic ED, 76.8%, are satisfied with sildenafil, while only 14% are satisfied with apomorphine. The fact that at least one out of five patients is not satisfied with the medications available, and the fact that one-third of the attempts using the more effective drug, sildenafil, are unsuccessful, show that ample space for new oral therapeutic agents exists. However, no experience is available with the combined use of sildenafil and apomorphine. Hence, according to the data available, we concur with the suggestion that the treatment of a complex, multidimensional psycho-neurovascular entity and the underlying disorders cannot be successfully achieved with a single agent for all cases.31

Side effects of both apomorphine and sildenafil have been previously studied in the general population of men with ED. In a crossover study, the side effects of apomorhine were found to be dose related.21 Interestingly, the incidence of AEs in our study, although in a series of patients with severe comorbidities, was similar to the incidence in the general population and in men with cardiovascular disorders.14,32 At the approved doses of 2 and 3 mg, AEs are generally mild and transient and rarely lead to discontinuation. The withdrawal rate due to AEs in our study was slightly higher than reported elsewhere,33 but the small number of the enrolled men does not permit for estimation of a possible higher risk for discontinuation in this group of patients.

Along the same lines, the AEs profile of sildenafil in our study was similar to those reported previously.34 In conclusion, both drugs have an acceptable safety profile, even in men with arteriogenic ED.

Conclusions

The safety of sildenafil and apomorphine in the treatment of arteriogenic ED is comparable to that reported in the general population of men with ED. This head-to-head study of the efficacy of the two drugs in the treatment of men with arteriogenic ED provides clear evidence that sildenafil, even at 50 mg, is more effective than apomorphine at the approved doses of 2 and 3 mg. However, one out of five patients are not satisfied with any of the two drugs. Hence, the treatment of arteriogenic ED seems to be a complex issue that cannot be entirely managed with the available medications. Additional studies are needed to evaluate the usefulness of new oral agents or combinations of drugs in the treatment of this disorder.

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Perimenis, P., Gyftopoulos, K., Giannitsas, K. et al. A comparative, crossover study of the efficacy and safety of sildenafil and apomorphine in men with evidence of arteriogenic erectile dysfunction. Int J Impot Res 16, 2–7 (2004). https://doi.org/10.1038/sj.ijir.3901119

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Keywords

  • arteriogenic erectile dysfunction
  • apomorphine
  • sildenafil
  • impotence

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