Qualitative Synthesis. Apomorphine versus placebo

Apomorphine versus placebo. In total, there were five placebo-controlled trials.^{248–250, 252, 253}

Harms. The occurrence of any adverse events across the trials was reported poorly. In one trial, ²⁴⁸ the rate of any adverse events was numerically slightly higher in patients receiving apomorphine than in those receiving placebo (37.8 versus 24.5 percent, respectively). Another trial²⁵⁰ reported only two patients who had experienced headaches after receiving placebo. Only one trial²⁴⁸explicitly stated that none of the patients died during the trial. In two trials, ^{248, 250} the rate of serious adverse events did not differ between patients receiving apomorphine and placebo. In the first trial, ²⁴⁸ four patients had one or more serious adverse events. Specifically, of the two patients in the apomorphine arms (2–3 mg), one had chest infection/severe cough/cough syncope and the other one had moderate unstable angina pectoris. In the placebo arm, two patients had angina pectoris. In the second trial, ²⁵⁰ no serious adverse events had occurred. The other three trials did not report whether or not patients had experienced any serious adverse events.^{249, 252, 253} In two trials, ^{248, 253} the proportion of patients who withdrew due to adverse events was numerically higher in the apomorphine arms compared with placebo arms (5–10 percent versus 1 percent); in the other trial, ²⁴⁹ none of the patients withdrew due to adverse events. Other trials^{250, 252} failed to report whether any patients withdrew due to adverse events. The most common adverse event reported across trials was nausea^{148, 248, 249, 252, 253} ranging from 7.0 percent²⁵² to 44 percent²⁵³ in the apomorphine arms and from 0.4 percent²⁴⁸ to 5.0 percent²⁴⁹ in the placebo arms. Other commonly reported adverse events were headache, dizziness, and yawning. In general, these events had occurred numerically more frequently in apomorphine arms than in placebo arms.^{248, 252, 253}

Efficacy. The three trials^{248, 252, 253} that measured the mean percentage of successful intercourse attempts found that this parameter was higher among patients who received apomorphine compared with those who received placebo; this finding was statistically significant. The mean percentage of successful intercourse attempts observed in apomorphine groups in these trials ranged from 38 percent²⁴⁸ to 51 percent, ²⁵³ whereas the corresponding treatment response observed in the placebo groups ranged from 28 percent²⁴⁸ to 34 percent.²⁵² The difference for each comparison between apomorphine and placebo groups in the three trials was statistically significant (p ≤ 0.01). The results for the above-mentioned endpoint, whether based on responses obtained from patients or from their partners, did not differ.^{252, 253}

Two trials^{252, 253} showed that patients who received apomorphine had a statistically significant higher percentage of attempts resulting in erections firm enough for intercourse than those in placebo group. For example, in one trial²⁵² the percentages of attempts resulting in erections firm enough for intercourse in the apomorphine (3 mg) and placebo groups were 46.9 percent and 32.3 percent respectively (p < 0.001). In the other trial, ²⁵³ the corresponding percentages were 53.1 (apomorphine 5 mg) and 34.5 (placebo), respectively (p 0.01).

The mean IIEF score for the “Erectile Function (EF) domain” obtained from two trials^{249, 253} were not consistent. For example, in the first trial, ²⁴⁹ differences in mean IIEF “EF” domain scores between patients receiving apomorphine and placebo were not statistically significant (13.81 versus 13.24; p = 0.52). In contrast, the authors of the other trial²⁵³ observed a statistically significantly greater mean IIEF score (“erectile function” domain) in the apomorphine group compared with placebo (actual mean IIEF values were not provided; p ≤ 0.01).

There was no statistically significant difference between apomorphine and placebo groups in the proportion of patients who answered “yes” to the GEQ (“ Has the treatment you have been taking over the past two or four weeks improved your erections? ”) combined with an improvement of ≥ 5 points in the IIEF “EF” domain (22.92 percent versus 17.31 percent, p = 0.48).²⁴⁹

The proportion of patients with positive response on rigidity (≥ 40 percent) was numerically greater in the apomorphine compared with the placebo group (4/6 versus 0/6).²⁵⁰

Apomorphine mono (dose/dosing 1) versus apomorphine mono (dose/dosing 2). In total, two trials compared different doses/dosing of apomorphine in patients with ED. ^{252, 253}

Harms. The incidence of several adverse events such as nausea, yawning, and dizziness across trials was numerically greater in patients receiving higher doses (4–6 mg) than lower doses of apomorphine (2–3 mg).^{252, 253} In one trial, ²⁵³ a dose-optimization schedule (2–6 mg) was associated with fewer events of nausea (30 percent of patients) than the fixed doses of apomorphine (5 and 6 mg: 38 and 49 percent of patients, respectively). Statistical test results for significance were not reported.

Efficacy. Neither of the two trials^{252, 253} identified a dose-response effect on the percentages of successful intercourse attempts and attempts resulting in erections firm enough for intercourse. For example, in one trial²⁵² the percentage of successful intercourse attempts was similar in patients who received 3 and 4 mg doses of apomorphine (48.4 versus 49.6 percent, respectively; p > 0.4). In the other trial, ²⁵³ the percentage of successful intercourse attempts was numerically similar for patients in two dose-escalation (2–4 mg and 2–4 mg to 5–6 mg) and two fixed-dose (5 mg and 6 mg) apomorphine groups, ranging from 45.1 percent (2–4 mg) to 50.9 percent (5 mg).

Apomorphine mono versus sildenafil mono. Five trials compared the efficacy/safety of apomorphine monotherapy to that of sildenafil monotherapy^{114, 117, 120, 148, 159}

Harms. In two trials, ^{117, 159} the number of patients who experienced any adverse event(s) was numerically greater in the sildenafilgroups (94.0 and 35.7 percent, respectively) in comparison with the apomorphine groups (64.0 versus 21.8 percent, respectively). In another trial, ¹²⁰ the proportions of patients with any adverse events in sildenafil and apomorphine groups were 7 percent (3/43) and 14 percent (6/43), respectively. One trial¹¹⁷ explicitly stated that none of the patients had died during the trial and reported that five patients had had at least one serious adverse event; of these patients, three were receiving sildenafil (deterioration of arthritic shoulder in one patient and myocardial infarction/atrial fibrillation in two patients) and two were receiving apomorphine (myocardial infarction and deterioration in Dupuytren's contracture). In another trial, ¹⁵⁹ serious adverse events occurred in two patients from the sildenafil group (exacerbation of chronic bursitis and stroke) and in two patients from the apomorphine group (stricture of the urethra and sudden cardiac death). The number of patients with vasodilation was numerically higher in the 50 mg sildenafil than in the 3 mg apomorphine group (6 versus 0)¹⁴⁸

In three trials, ^{117, 120, 159} the number of patients who withdrew due to adverse events ranged from one¹⁵⁹ to three¹¹⁷ for theapomorphine arms and from zero^{120, 159} to two¹¹⁷ for the sildenafil arms.

Some specific adverse events that occurred in one trial in sildenafil versus apomorphine groups were headache (16 versus 5 percent) and nausea (3.2 versus 5.6 percent).¹¹⁷ In another trial, ¹⁵⁹ the proportions of patients with headache in the sildenafil versus apomorphine groups were 10.3 versus 3.2 percent, respectively.

Efficacy. All five trials^{114, 117, 120, 148, 159} measuring the number of successful intercourse attempts showed that the mean percentage of successful intercourse attempts was higher in patients who had received sildenafil (range 62.7–81.0 percent) compared with those receiving apomorphine (range 28.3–62.7 percent). The observed differences were statistically significant. In fact, in three trials, ^{117, 120, 159} the percentage of successful intercourse attempts in the sildenafil groups was about twice as that in the apomorphine groups. For example, in one trial, ¹¹⁷ the percentages of successful intercourse attempts in sildenafil and apomorphine groups were 75.1 percent (95 percent CI: 69.2–81.0) and 35.3 percent (95 percent CI: 29.4–41.3) respectively, with a mean difference of 39.7 percent (95 percent CI: 33.0–46.5) between the two groups. In the other trial, ¹²⁰ the corresponding values of the mean percentage of successful intercourse attempts in the sildenafil (50–100 mg) and apomorphine (2–3 mg) groups, regardless the dose, were 63.7 and 32.1 percent, respectively (p < 0.01). Similarly, in another trial, ¹¹⁴ overall, patients receiving sildenafil (50–100 mg) had a statistically significantly greater mean percent of successful intercourse attempts than those receiving apomorphine (2–3 mg) (73.1 versus 62.7 percent, p = 0.0004).

The use of sildenafil was shown to be more efficacious than apomorphine in improving (i.e., increasing) IIEF scores for “erectile function” as well as for other domains (e.g. “intercourse satisfaction, ” “overall satisfaction”).^{117, 148, 159} For example, the mean IIEF score values for the “EF” domain in patients who received sildenafil and apomorphine were 25.2 (95 percent CI: 23.7–26.7) and 15.9 (95 percent CI: 14.4–17.3), respectively, with a mean difference of 9.3 (95 percent CI: 7.6–11.1) between the two groups.¹¹⁷ In the other trial, ¹⁵⁹ the corresponding least square mean values for the IIEF “EF” domain were 23.1 (95 percent CI: 21.8–24.4) and 15.7 (14.5–17.0), with a mean difference of 7.2 (95 percent CI: 5.5–8.8).

The proportions of patients who answered “yes” to questions 1 and 2 of GAQ (Question 1: “Compared with having no treatment at all for your erection problem, has the medication you have been taking over the past 4 weeks improved your erections? ”; Question 2: “Compared with having no treatment at all for your erection problem, has the medication you have been taking over the past 4 weeks improved your ability to have sexual intercourse? ”) were numerically higher in the sildenafil group than in the apomorphinegroup (94.8 and 93.9 percent versus 51.7 percent and 48.7 percent, respectively).¹¹⁷ Similarly, in the other trial, ¹⁵⁹ statistically significant differences were observed between patients receiving sildenafil and apomorphine with respect to GAQ-Q1 (88.7 percent versus 43.1 percent, p < 0.0001).

In the same trials, ^{117, 159} the mean EDITS scores for patient satisfaction were higher in patients receiving sildenafil (82.5 and 74.0, respectively) compared with those receiving apomorphine (46.8 and 47.0, respectively).

According to results obtained from two trials, ^{117, 120} more patients preferred sildenafil than apomorphine. The percent of patients who preferred sildenafil over apomorphine across these trials ranged from 65.1 percent¹²⁰ to 96.6 percent.¹¹⁷ In contrast, the percentage of patients who preferred apomorphine over sildenafil ranged from 2.3 percent¹²⁰ to 3.4 percent.¹¹⁷