Table 10

⇐ ПредыдущаяСтр 9 из 41Следующая ⇒

Serious Adverse Events in Sidenafil vs. Placebo (data from RCTs).

Six deaths during four trials, ^88, ^123, ^126, ¹⁷¹ and one death during the open-label phase of the study⁹⁵ were reported. Four of the eight deaths occurred in placebo groups, one resulting from myocardial infarction.¹²⁶ The reasons for the other three deaths were not reported.^123, ¹⁷¹ Two deaths occurred in participants treated with sildenafil; one of these resulted from an accident, ¹²³ and the other from cardiac arrest.⁸⁸ For more details on serious adverse events in each trial, please refer to Table 10.

Efficacy. In the trials reporting mean scores for IIEF “EF” domain and IIEF-Q3/Q4, the proportions of patients with successful intercourse attempts, and improved erection demonstrated that participants receiving sildenafil (regardless of mono/combination therapy or dosage and duration) experienced a statistically significant greater improvement in erectile function compared with those receiving placebo. These improvements were observed for the mean total “EF domain” scores (38 trials), ⁷⁹^–^84, ⁸⁶^–^88, ^90, ^91, ^97, ^98,^102, ^104, ¹⁰⁷^–^109, ^115, ^122, ^123, ^125, ^126, ^128, ^135, ^137, ^142, ^143, ^147, ^149, ^156, ^160, ¹⁶⁴^–^167, ¹⁷¹ mean IIEF Q3–Q4 scores (35 trials), ⁷⁹^–^84, ⁸⁶^–^88, ^90, ^91, ^94, ⁹⁷^–^99, ^101, ¹⁰⁷^–^109, ^115, ^123, ^125, ^126, ^131, ^133, ^137, ^138, ^142, ^143, ^147, ^149, ^151, ^165, ¹⁶⁷ the proportion of successful intercourse attempts (25 trials), ⁸⁰^–^84, ^87, ^94, ^97, ^98, ^101, ^109, ^115, ^125, ^126, ^131, ^137, ^138, ^142, ^143, ^147, ^151, ^156, ^166, ^167, ¹⁷¹and the proportion of patients with improved erection (based on their responses to GEQ-Q1) (all 40 trials).⁷⁹^–^90, ⁹³^–^98, ¹⁰⁷^–^109, ^115,^125, ^126, ^128, ^131, ^133, ^137, ^138, ^142, ^143, ^147, ^149, ^151, ^156, ^165, ^167, ^168, ¹⁷¹

All trials (i.e., those that reported mean scores for the five IIEF domains) except for one, ¹⁶⁴ yielded statistically significant higher mean IIEF scores in participants treated with sildenafil compared with placebo-treated participants for two IIEF domains (“Intercourse Satisfaction” and “Overall Satisfaction”).^79, ^80, ⁸²^–^84, ^87, ^88, ^90, ^91, ^97, ^104, ¹⁰⁷^–^109, ^115, ^122, ^123, ^125, ^126, ^137, ^138, ^142,^143, ^147, ^149, ^156, ^160, ¹⁶⁵^–^167, ¹⁷¹ In general, the results for two IIEF domains of “Sexual Desire” and “Orgasmic Function” were less consistent that those for three other domains (i.e., “Erectile Function, ” “Intercourse Satisfaction, ” and “Overall Satisfaction”).

Specifically, in 17 trials no statistically significant difference was shown in mean IIEF scores for “Sexual Desire” between sildenafiland placebo groups.^84, ^88, ^90, ^91, ^104, ^108, ^115, ^123, ^125, ^138, ^142, ^143, ^149, ^156, ^164, ¹⁶⁵ In six trials, ^109, ^115, ^125, ^143, ^156, ¹⁶⁴ the between-group (sildenafil versus placebo) differences for mean scores of “Orgasmic Function” were not statistically significant.

All seven trials^85, ^88, ^89, ^93, ^95, ^96, ¹⁶⁸ that assessed and reported the mean number of grade 3–4 erections per week, yielded a statistically significant increase in the mean number of erections among participants treated with sildenafil (range 1.3⁹³–6.5¹⁶⁸) compared with placebo-treated participants (range 0.6^88, ^93, ⁹⁵–3.32¹⁶⁸). Similarly, two other trials^86, ¹³⁸ showed that participants treaded with sildenafil compared with those on placebo, experienced a significantly greater mean number of erections (grade 3–4) per month. The ranges for the mean numbers of erections were 4.3–6.9 (sildenafil) and 2.4–3.1 (placebo). Five trials^93, ^105, ^132, ^146,¹⁶⁸ indicated a statistically significant longer mean duration of erections (≥ 60 percent rigidity) for participants treated with sildenafil compared with those who received placebo.

In nine trials, mean EDITS scores indicated that participants exhibited a statistically significant higher degree of treatment satisfaction after being treated with sildenafil compared with placebo.^84, ^90, ^109, ^143, ^147, ^156, ^160, ¹⁶⁷

The beneficial effect of sildenafil use found in trials of participants with psychogenic ED^96, ¹¹⁰ or distinct clinical subgroups (e.g. spina bifida, depression, diabetes, stable coronary artery disease, Parkinson's disease, congestive heart failure, multiple sclerosis, prostate cancer)^78, ^79, ^81, ^84, ^91, ^93, ^94, ^98, ^99, ^101, ^102, ^104, ¹⁰⁷^–^109, ^115, ^123, ^128, ^131, ^133, ^143, ^147, ^160, ^164, ^165, ^167, ^168, ¹⁷⁵ were consistent with those of other trials conducted in patients with ED of mixed etiology or those with clinically heterogeneous conditions.

Reports of only four trials provided treatment efficacy subgroup analyses (i.e., stratification of efficacy results) with respect to baseline severity of ED.^81, ^90, ¹²⁸ The evidence from these trials indicated that participants with mild/moderate ED (IIEF score 11–25) after taking sildenafil tended (statistically nonsignificant trends) to experience a greater degree of improvement in erectile function as measured by mean scores for responses to “EF domain” and Q3–Q4 of the IIEF questionnaire and the proportion of patients with improved erections (i.e., those who responded “yes” to GEQ-Q1) compared with those with severe ED (IIEF ≤ 10).

Efficacy subgroup analyses with respect to duration of ED (0–3, 3–6, and > 6 years) and age (18–49, 50–64, and ≥ 65 years) were reported in two trials.^94, ¹⁰¹ In both trials sildenafil was shown to have improved erectile function (i.e., mean IIEF-Q3/Q4 scores and percentage of patients who responded “yes” to GEQ-Q1) regardless of the participants' age and the duration of ED. The results of analyses provided for these trials did not reveal any treatment effect modification by the above-mentioned factors. In another trial, younger age (p = 0.034) and a shorter duration of ED (p = 0.028) were found to be predictive of a greater baseline-to-endpoint improvement in erectile function (i.e., mean scores for the IIEF “EF” domain and “Intercourse Satisfaction” domain).¹⁵⁶

Reports of five trials provided the treatment efficacy stratification analyses by ED origin (i.e., organic, psychogenic, and mixed).^86,^88, ^96, ^134, ¹⁴² The improvements in erectile function (mean scores for IIEF “EF” domain and percentage of patients who responded “yes” to GEQ-Q1) were observed regardless of the origin of ED in patients receiving sildenafil compared with those receiving placebo, without identifying the origin of ED as a treatment effect modifier or predictor.

Sildenafil dose/dosing 1 versus sildenafil dose/dosing 2. Six studies assessed the efficacy and harm profiles for different doses (i.e., 10 mg, 25 mg, 50 mg, and 100 mg) of sildenafil monotherapy.^78, ^85, ^86, ^93, ^96, ¹³⁷ Additionally, two other trials^157, ¹⁶¹examined and compared two different dosage regimens of sildenafil (i.e., fixed versus flexible, different timing of administration).

Harms. In one trial, ¹³⁷ which reported the incidence of any adverse events, specifically, events in > 5 percent of participants in one or more treatment groups, the proportions of participants experiencing at least one adverse event (due to all causes) in either thesildenafil 25 mg, 50 mg, and 100 mg treatment groups were 49, 61, and 72 percent, respectively. The corresponding dose-specific proportions observed in another trial, ⁸⁶a were 32, 69, and 86 percent, respectively. Both trials indicated a numerically increasing trend in the incidence of any adverse events observed with the higher dose of sildenafil. In one trial, ⁹⁶ the proportion of patients with any adverse events (i.e., events in > 5 percent of patients) observed in the 25 mg and 50 mg sildenafil groups were numerically higher (59 and 45 percent, respectively) compared with the 10 mg sildenafil group (24 percent). None of these three trials^86, ^96, ¹³⁷reported any statistical test results for the observed between-treatment differences. In two trials, ^85, ⁹³ the number of participants with treatment-related adverse events did not differ across the 25 mg and 50 mg sildenafil treatment groups. Of the events observed across the trials, ^78, ^85, ^86, ^93, ^96, ¹³⁷ headache, myalgia, nausea, dyspepsia, and flushing were the most frequently experienced and were mild to moderate or transient in nature.

A total of four serious adverse events were reported in two studies.^93, ⁹⁶ These trials compared 25 mg to 50 mg, ⁹³ and 10 mg to 25 mg and 50 mg of sildenafil.⁹⁶ One participant (4.7 percent) in the 25 mg sildenafil group discontinued the treatment because of pneumococcal pneumonia (the authors did not consider this a serious adverse event).⁹³ There were three other instances of serious adverse events (myocardial infarction, renal cell carcinoma, and epileptic crisis) in one trial.⁹⁶ The group designation of the participants experiencing these events were not reported.

Withdrawals due to adverse events were reported in five trials.^85, ^86, ^93, ^96, ¹³⁷ The rate of discontinuation ranged from 0 percent⁸⁵to 3 percent⁹⁶ for the 10 mg dose of sildenafil, from 0 percent¹³⁷ to 4.7 percent^93, ⁹⁶ for the 25 mg dose, from 0 percent⁸⁵a to 11 percent⁹⁶ for the 50 mg dose, and from 2 percent⁸⁶a to 4 percent¹³⁷ for the 100 mg dose.

Safety data was not reported for the trial that compared different timing of sildenafil (100 mg) administration in relation to food and sexual activity.¹⁶¹ In the trial¹⁵⁷ comparing “nightly” (50 mg) and “as needed” (50 mg to 100 mg) sildenafil dosing regimens, the proportion of withdrawals due to adverse events was similar across the two groups (approximately 7 percent). The authors of this trial did not report the incidence of any adverse events. Overall, more participants experienced adverse events (headache, flushing, dyspepsia, and rhinitis) in the “as needed” compared with the “nightly” group. Reportedly, none of the participants in this trial developed a serious adverse event.¹⁵⁷

Efficacy. All six trials^78, ^85, ^86, ^93, ^96, ¹³⁷ assessing the efficacy of different doses of sildenafil monotherapy (10 mg, 25 mg, 50 mg, and 100 mg), demonstrated a dose-response trend for sildenafil toward improving erectile function. Although none of these trials provided a formal statistical test for the observed between-arm (sildenafil versus placebo) differences, the degree of improvement tended to increase numerically with a higher dose of sildenafil. For example, the range for the mean IIEF Q-3 and Q-4 scores for three sildenafil dose arms in two trials^86, ¹³⁷ were as follows: 25 mg (Q-3: 3.18–3.20, and Q-4: 2.99–3.10), 50 mg (Q-3: 3.50–3.65, and Q-4: 3.50–3.64), and 100 mg (Q-3: 3.79–4.00 and Q-4: 3.63–3.90). The proportion of participants with an improved erection (based on GEQ-Q1) across four trials^86, ^93, ^96, ¹³⁷ ranged from 50 to 79 percent for 25 mg and from 52 to 88 percent for 50 mg sildenafil arms. In two trials, ^86, ¹³⁷ the corresponding proportion of participants who received 100 mg sildenafil ranged from 84 to 88 percent. The authors of two trials, ^78, ⁸⁶ reported dose-response treatment effects associated with administration of 25 mg, ^78, ⁸⁶ 50 mg, ^78, ⁸⁶ and 100 mg⁸⁶ of sildenafil with respect to mean scores for the IIEF “EF” domain (no numerical data provided; p < 0.001)⁸⁶and IIEF-Q1 (25 mg: 3.7, versus 50 mg: 4.5).⁷⁸ In two other trials^85, ⁹³ the participants' mean duration of penile rigidity (> 80 percent and > 60 percent, respectively) in minutes at the base and the tip of the penis was shown to increase numerically with higher doses of sildenafil (10 mg versus 25 mg versus 100 mg). In one trial, ⁸⁵ the mean duration of penile rigidity at the base of the penis for participants receiving 10 mg sildenafil was 3.5 minutes (95 percent CI: 1.6–7.3). The ranges for the mean duration of penile rigidity (> 60 percent or > 80 percent) in two trials, ^85, ⁹³ were 5.0 to 8.0 minutes (in participants receiving 25 mg sildenafil) and 10.1 to 11.2 minutes (in participants receiving 50 mg sildenafil). The proportions of participants who achieved grades 3–4 erections in the 25 mg, 50 mg, and 100 mg sildenafil groups were 72, 80, and 85 percent, respectively.⁸⁶ The mean number of erections per week (grades 3–4) was also shown to be numerically greater in two trials.^93, ⁹⁶ For example, the mean number of erections per week in one trial among participants who received 10 mg, 25 mg, and 50 mg sildenafil was 2.8, 3.0, and 3.6, respectively.⁹⁶

In two trials, ^157, ¹⁶¹ the efficacies of two different dosage regimens of sildenafil were compared. In one trial, ¹⁵⁷ participants received either a fixed dose (50 mg every night) or a flexible dose (50 or 100 mg, as needed) of sildenafil for 12 months; in the other trial¹⁶¹participants were randomly assigned to receive 100 mg/d of sildenafil either 1 hour before/during a meal or 30–60 minutes before sexual activity. In the first trial, ¹⁵⁷ the effect of a fixed dose of sildenafil given every night was maintained to a greater extent compared with that achieved with a flexible dosage of sildenafil. Specifically, the proportion of patients with a normal IIEF score (i.e., mean IIEF “EF” domain score ≥ 26) at 12 months in the two treatment groups (the “fixed 50 mg nightly” arm versus the “50–100 mg, as needed” arm), was similar (66.7 versus 67.3 percent, respectively); however, the corresponding proportions for the two groups after 1 month of post-treatment followup were 60.4 percent (95 percent CI: 45.3–74.2) versus 8.2 percent (95 percent CI: 2.3–19.6) in favor of nightly dosage group. The 13-month (i.e., one month after the 12-month treatment stopped) end-point mean peak systolic velocity (PSV) values for participants in the “nightly” and “as needed” groups were 37.0 (SD = 10.4) cm/s versus 26.5 (SD = 8.9) cm/s, respectively, favoring the “nightly” group. In the other trial, ¹⁶¹ the time between sildenafil administration and intercourse attempt (0–0.5 to > 10 hours) had no statistically significant effect on the mean IIEF “EF” domain score and the proportion of intercourse attempts (based on SEP-Q2; p = 0.56), however, a longer period of time between taking sildenafil and intercourse attempt was associated with a statistically significant reduction in successful intercourse attempts (based on SEP-Q3; 92.8 percent at 1.5–2 hours versus 81.6 percent at > 10 hours; p = 0.003). No statistically significant differences were observed for EDITS scores between the study arms (p > 0.80).¹⁶¹

Sildenafil monotherapy versus sildenafil in combination. This review included nine trials¹⁰⁴^–^106, ^112, ^150, ^158, ^162, ^169, ¹⁷³ in which the efficacy and harm of mono- versus combination therapy of sildenafil were compared. In these trials, sildenafil was used in combination with PLC and acetyl-L-carnitine (ALC), ¹⁰⁴ intranasal PT-141, ¹⁰⁵ psychotherapy, ¹⁰⁶ propionyl-L-carnitine (PLC), ¹¹²dihydro-ergotamine (DHE), ¹⁵⁰ cabergoline, ¹⁶² atorvastatin, ^158, ¹⁶⁹ quinapril, ¹⁵⁸ and alfuzosin.¹⁷³

Harms. In general, harms were poorly reported in four trials.^106, ^150, ^158, ¹⁶⁹ The incidence of any adverse events were reported in only one¹⁶² of the nine trials.¹⁰⁴^–^106, ^112, ^150, ^158, ^162, ^169, ¹⁷³ This study reported a higher proportion of participants with one or more adverse events in the combination arm (cabergoline and sildenafil) compared with the sildenafil monotherapy arm (12.2 versus 2.0 percent, p = 0.001).¹⁶² In two trials no serious adverse events were reported during the trial period.^112, ¹⁷³ The remaining seven studies did not report serious adverse events.¹⁰⁴^–^106, ^150, ^158, ^162, ¹⁶⁹

Five studies reported information regarding withdrawals due to adverse events.^104, ^105, ^112, ^162, ¹⁷³ There were no withdrawals due to adverse events in three of these trials in any of the compared treatment groups, ^81, ^105, ¹¹² and two trials^162, ¹⁷³ reported higher rates of withdrawals in sildenafil combination therapy than in sildenafil monotherapy. These rates were 5.8 percent with sildenafil/cabergoline therapy compared with 1.0 percent in sildenafil monotherapy, ¹⁶² and 14.5 percent with sildenafil/alfuzosintherapy compared with 9.5 percent in sildenafil monotherapy.¹⁷³

Efficacy. In all nine trials, participants who received combination therapies, in comparison with those who received sildenafil alone, were shown to have experienced numerical or statistically significant improvements for mean IIEF (or IIEF-5) scores for the “EF domain” and individual Q1–Q15 items, ^104, ^106, ^158, ^162, ^169, ¹⁷³ higher frequency of penetration and maintenance of erection (mean scores for IIEF-Q3/Q4), ^112, ^150, ^162, ¹⁷³ improved mean duration of rigidity of the tip/base of the penis (≥ 60 percent), ¹⁰⁵ and a greater proportion of participants with improved erection (positive responses to GEQ-Q1).¹¹² However, in three trials^104, ^158, ¹⁶⁹there was no statistically significant difference between the combination therapy and monotherapy groups in mean PSV values^104,¹⁵⁸ or the proportion of patients with improved erection (positive responses to GEQ-Q1).¹⁶⁹

Sildenafil versus other active treatment. This review included five trials in which the efficacy and harms for sildenafil and other active treatment were compared.^106, ^124, ^132, ^155, ¹⁷³ These therapies were psychotherapy, ¹⁰⁶ continuous positive air pressure (CPAP), ¹⁵⁵ phentolamine, ¹²⁴ Ro70-0004 (i.e., α 1A-adrenoceptor antagonist), ¹³² and alfuzosin.¹⁷³

Harms. Among these five trials, ^106, ^124, ^132, ^155, ¹⁷³ the incidence of any adverse event was reported in only one, in which more participants were found to have experienced one or more adverse event in the 40 mg phentolamine treatment group as compared with the flexible-dose (25 mg to 100 mg) sildenafil treatment group (41.2 versus 33.3 percent).¹²⁴ More patients in the phentolamine group than in the sildenafil group experienced respiratory (17.6 versus 8.9 percent) and digestive (12.6 versus 9.8 percent) adverse events. The most frequent adverse events that occurred during the trial were headache and rhinitis.¹²⁴ In the phentolamine treatment group, three participants (2.5 percent) experienced serious adverse events, as compared with only one participant (0.8 percent) in the sildenafil treatment group. These events were flushing, chest pain, shortness of breath with tachycardia in one participant, and cerebrovascular event and worsening of existing pterygium in the other two participants. One participant in the sildenafil treatment group experienced a rupture of the Achilles tendon.¹²⁴

The rate of withdrawals due to adverse events was reported in two trials, ^124, ¹⁷³ in which it was higher among participants receivingphentolamine¹²⁴ or alfuzosin¹⁷³ than among those receiving sildenafil alone. The rates of withdrawals due to adverse events in participants treated with sildenafil in two trials were < 1.0 percent¹²⁴ and 9.5 percent.¹⁷³ The corresponding rates for participants treated with phentolamine and alfuzosin were 3.4 percent¹²⁴ and 10 percent, ¹⁷³ respectively.

Efficacy. In two trials^124, ¹⁵⁵ sildenafil use was associated with a statistically significant increase in the proportion of successful intercourse attempts, the mean IIEF “EF” domain score, and improved erections (GEQ-Q1), in comparison with the use of CPAP¹⁵⁵and phentolamine.¹²⁴ In two other trials, ^132, ¹⁷³ administration of sildenafil resulted in only numerical improvement in the mean duration of rigidity at the base/tip of the penis (> 60 percent), ¹³² mean IIEF scores for the “EF domain, ” as well as the frequency of penetration/maintenance of the erection (mean scores for IIEF-Q3/Q4), ¹⁷³ in comparison with treatment with Ro70-0004¹³² oralfuzosin.¹⁷³ In one trial, ¹⁰⁶ post-treatment mean IIEF scores were lower among those treated with sildenafil in comparison with those treated with psychotherapy, but the statistical significance was marginal (52.8 versus 62.5, p = 0.049).

⇐ Предыдущая 4 5 6 7 8910 11 12 13 Следующая ⇒

© 2023 :: MyLektsii.ru :: Мои Лекции
Все материалы представленные на сайте исключительно с целью ознакомления читателями и не преследуют коммерческих целей или нарушение авторских прав.
Копирование текстов разрешено только с указанием индексируемой ссылки на источник.