Long-Term Adverse Events

We identified two observational studies reporting longer term adverse effects related to silodosin treatment.^106,108 These studies were observational and therefore have limited internal validity. We did not assess strength of evidence for long-term adverse events but provide the information descriptively because it represents the best available evidence. Adverse events described in the one trial reporting data were similar to those identified in silodosin RCTs.

Marks et al. analyzed adverse effects in a 40-week open label extension of a previous RCT (cumulative treatment duration of 52 weeks).¹⁰⁸ Of the 661 participants who enrolled in the extension, 435 completed the extension, with all patients taking silodosin 8 mg once a day. Thirty-four percent discontinued treatment due to adverse effects. A total of 431 experienced 924 adverse events. Twenty-nine patients (4.4%) experienced serious adverse events including two deaths; none of the serious adverse events, including the deaths, were considered drug-related by the researchers. Criteria for determining whether serious adverse events were drug-related were not described in the report. The most common adverse events were retrograde ejaculation (21%), diarrhea (4%), and nasopharyngitis (4%).

Yoshimura et al. reviewed FDA data for adverse effects associated with ABs and found the data on silodosin insufficient to compare with other ABs.¹⁰⁶

Efficacy and Patient Demographic and Clinical Characteristics

We identified two posthoc analyses that evaluated the effect of our prespecified patient demographic or clinical characteristics on the efficacy of silodosin.^31,32 Novara et al. pooled data (n=1484) from two previous RCTs^28,30 to examine the effect of age, BMI, and baseline LUTS severity on response to treatment using linear regression models.³² Treatment was the only predictive variable after adjusting for age, BMI, and baseline LUTS severity. Kawabe et al. stratified participants according to baseline LUTS severity and found that both levels of severity achieve improvements in LUTS over placebo.³¹

Dosing of Silodosin

We identified two noninferiority trials comparing different silodosin doses.^20,23 Choo et al. compared silodosin 4 mg taken twice daily with 8 mg taken once daily for 12-weeks in a population of Korean men with LUTS (n=532).²³ Mean age was 64 and mean baseline I-PSS score was 19. Risk of bias was moderate. They found no differences in any outcome or adverse effect.

Seki et al. compared silodosin 4 mg taken once daily with 4 mg taken twice daily for 12-weeks in a population of older Japanese men with LUTS and OAB symptoms (n=268).²⁰ Mean age was 72 and mean baseline I-PSS score was 20. The trial was open-label and risk of bias was high. They found no differences in mean changes in I-PSS scores or adverse effects.

Silodosin Versus Tamsulosin

The only comparative effectiveness trials we identified compared silodosin with tamsulosin. Eight trials randomized males with LUTS attributed to BPH (n=1705) to silodosin 8 mg daily versus tamsulosin 0.2 to 0.4 mg daily. All trials lasted 4- to 12-weeks (Table 5).^22,24-29,31 Mean age of the participants was 67 years and mean I-PSS score at baseline was 18 (range 17 to 20) in silodosin and tamsulosin arms. Six trials conducted in Asia used a 0.2 mg dose of tamsulosin, a dose lower than the generally recommended 0.4 mg dose utilized in the United States and Europe^22,24-27,31 Two trials conducted in Europe or India used a 0.4 mg dose of tamsulosin.^22,28 Only the European trial reported race/ethnicity, and all its participants were white.²⁸ Three trials were crossover studies (4 week phases each) and only data from the first-phases of these trials were used in the analyses.^24,27,29 Two trials reported industry sponsorship.^25,28 Overall risk of bias was low in two trials,^22,28 moderate in four trials,^24-26,31 and high in two trials.^27,29

Table 5

Evidence overview: silodosin versus tamsulosin.

Three trials conducted responder analysis (defined as >25 percent reduction in I-PSS score).^26,28,31 Response to treatment was similar with silodosin and tamsulosin. Given a mean baseline I-PSS score for these studies of 19 points, this equated to about a 5-point reduction from baseline, exceeding established MDD for individuals with mean I-PSS scores similar to enrollees. Silodosin and tamsulosin were similar in improving mean I-PSS scores (moderate SoE). Mean reductions in I-PSS scores were 7.8 and 7.2 points with silodosin and tamsulosin when we pooled trials using either dose of tamsulosin. Results were similar in trials using tamsulosin 0.4 mg. Both treatments reduced mean I-PSS scores by more than the MDD of three points. Overall improvement in the I-PSS QoL also was similar with silodosin and tamsulosin, but heterogeneity between studies was substantial (I² = 76%), thereby reducing our confidence (moderate SoE). No indicators of disease progression/treatment failure were reported.

Among RCTs with parallel group designs, study withdrawal for any reason was similar with silodosin and tamsulosin (low SoE). Withdrawal due to an adverse effect was higher with silodosin (moderate SoE). The most common adverse effect, abnormal ejaculation, was reported by 16 percent with silodosin versus 2 percent with tamsulosin. Trials reported that withdrawals due to adverse effects were only observed with silodosin^24,27 and that abnormal ejaculation was the most common.^24,27,29 Chapple et al. reported serious adverse effects including supraventricular arrhythmia, prostate cancer, and death in approximately one percent of participants overall but didn't report results by study arm.²⁸

Tolterodine Versus Placebo

One 12-week trial compared tolterodine 4 mg daily (n=217) with placebo (n=222) in men with LUTS and OAB symptoms. Individuals with a baseline postvoid residual of >200 ml were excluded. Mean age was 62 and mean baseline I-PSS score was 20.⁵⁸ OAB symptoms were evaluated using bladder diaries. Most participants were white (81%). The trial was conducted in the United States and was industry-sponsored. Overall risk of bias was low.

Changes in I-PSS score and I-PSS QoL were similar with tolterodine and placebo (low SoE). Urinary retention was reported in two participants with tolterodine and three participants with placebo.

There was insufficient SoE for overall withdrawals and withdrawal due to adverse effects. Dry mouth was reported more frequently with tolterodine than placebo (7% vs. 2%).

Tolterodine/AB Combination Versus Placebo

One 12-week trial compared the combination of tolterodine 4 mg and tamsulosin 0.4 mg daily (n=225) with placebo (n=222) in males with LUTS and OAB symptoms.⁵⁸ Individuals with baseline postvoid residual >200 ml were excluded. Mean age was 61 and mean baseline I-PSS was 20. The trial was conducted in the United States and was industry-sponsored. Risk of bias was low.

Combination therapy improved mean change in I-PSS (MD = -1.80) and I-PSS QoL more than placebo (low SoE).

Rates of withdrawal due to adverse effects were higher with combination therapy than placebo (low SoE).

Tolterodine/AB Combination Versus AB Monotherapy

Four trials randomized males with LUTS and OAB symptoms (n=1249) to a combination of tolterodine 4 mg plus AB versus AB monotherapy with tamsulosin, doxazosin, or alfuzosin (Table 6).^41,52,56,58 OAB symptoms were generally evaluated using bladder diaries. Mean age was 63 and mean baseline I-PSS score was 20 (range = 19 to 24). One study was a multicenter study from several countries (Europe, North America, Asia, and South Africa),⁵⁶ and one was a multicenter study performed in the United States;⁵⁸ the others were conducted in South Korea⁵² and Pakistan,⁴¹ All but one study reported industry sponsorship. Overall risk of bias for three trials was low and one trial had high risk of bias.⁴¹

Table 6

Evidence overview: tolterodine/AB combination versus AB monotherapy.

Only the one high risk of bias trial⁴¹ conducted a responder analysis, defined as a 3-point improvement in I-PSS score from baseline. Although the proportion of responders was greater in the combination group than the AB monotherapy group (77% vs. 29%), SoE was insufficient. Pooled results from all trials found mean changes in I-PSS scores were similar with combination and monotherapy (WMD = -0.19) (moderate SoE). Pooled results from three studies showed mean change in I-PSS QoL was similar between combination and monotherapy (low SoE).^52,56,58

There were six incidences of acute urinary retention (AUR) in the combination group and two in the monotherapy group (insufficient evidence).^52,56,58 No other indicators of disease progression/treatment failure were reported. Withdrawal for any reason or due to adverse effects was similar with combination and monotherapy (low SoE). The proportion reporting one or more adverse effect was similar with combination and monotherapy in the one trial reporting this outcome (insufficient SoE).⁵⁶

Tolterodine/AB or 5-ARI Combination Versus AB or 5-ARI Monotherapy

One 52-week trial compared a combination of tolterodine 4 mg daily plus doxazosin 4 mg daily (AB) and/or dutasteride 0.5 mg daily (5-ARI) (n=50) versus doxazosin and/or dutasteride monotherapy (n=87) in men with LUTS and storage symptoms.⁵⁴ Individuals with a baseline postvoid residual of >250 ml were excluded. The men were older, with a mean age of 76, and mean baseline I-PSS score was 18. The trial was conducted in Taiwan. Industry-sponsorship was not reported. Overall risk of bias was high.

Mean change in I-PSS score for the tolterodine plus doxazosin/dutasteride combined group was -8.9 points and -6.5 points for the doxazosin/dutasteride group (insufficient SoE).

Acute urinary retention requiring catheterization was reported for two participants (4%) in the tolterodine plus doxazosin/dutasteride combined group and three (3.5%) in the doxazosin/dutasteride group. Withdrawals and proportions with adverse effects were not reported by treatment arm. Dry mouth was reported more frequently with tolterodine plus doxazosin/dutasteride combined therapy (14% vs. 6%), leading to study withdrawal of six combination participants. However, SoE was insufficient for all efficacy and harms outcomes.

Tolterodine Versus AB

Two 12-week trials compared tolterodine with AB monotherapy.^40,58 Data were not pooled due to the heterogeneity in study populations in terms of LUTS severity.

One trial compared tolterodine 4 mg (n=217) with tamsulosin 0.4 mg (n=222).⁵⁸ Mean age was 62 and mean baseline I-PSS was 20. The trial was conducted in the United States and was industry-sponsored. Overall risk of bias was low.

Mean changes in I-PSS (MD = 0.90) and I-PSS QoL (MD = -0.10) were similar with tolterodine and tamsulosin groups (low SoE). Three cases of acute urinary retention were reported with tolterodine compared to none with tamsulosin. Overall withdrawals and withdrawal due to adverse effects were similar with tolterodine and tamsulosin (insufficient SoE). Dizziness was reported more frequently with tamsulosin than tolterodine (6% vs. 1%).

One trial compared tolterodine 4 mg (n=108) with doxazosin 4 mg daily (n=94) in participants with predominant storage LUTS.⁴⁰ Those with baseline postvoid residual >250 ml were excluded. Mean age was 69 and mean baseline I-PSS was 11.5, substantially lower than the previous trial. The trial was conducted in Taiwan. Industry sponsorship was not reported. No blinding was reported and overall risk of bias was high.

Mean changes in I-PSS (MD = -0.20) and I-PSS QoL (MD = -0.20) were similar with tolterodine and doxazosin groups (insufficient evidence). No participants developed urinary retention. No other indicators of disease progression or treatment failure were reported. Rates of total withdrawals and withdrawal due to adverse effects were similar with tolterodine and doxazossin (insufficient evidence).

Solifenacin Versus Placebo

One 12-week trial compared solifenacin 3 (n=43), 6 (n=43), or 9 mg (n=44) doses daily to placebo (n=92) in men with LUTS and OAB symptoms.⁴⁴ Individuals with a baseline postvoid residual of >200 ml were excluded. Mean age was 65 and mean baseline I-PSS score was 19. Nearly all men were white. The trial was conducted in several sites in Europe and was industry-sponsored. Risk of bias was moderate.

Improvement in LUTS was similar with solifenacin 6 mg with placebo in improving I-PSS scores (MD = -0.30) (low SoE). Urinary retention requiring catheterization was reported in one participant allocated to solifenacin 9 mg.

Evidence was insufficient regarding comparative withdrawals and withdrawal due to adverse effects. Dry mouth was reported more often with solifenacin (6%) versus placebo (0%).

Solifenacin AB Combination Versus Placebo

Three 12-week trials (n=1857) compared a solifenacin-AB combination with placebo in men with LUTS and OAB symptoms (Table 7).^44,45,47 Trials combined solifenacin doses of 3, 6, or 9 mg with tamsulosin 0.4 mg. Two studies excluded patients with baseline postvoid residuals >150⁴⁵ or >200 ml,⁴⁴ respectively. Mean age of participants was 66 and mean baseline I-PSS score was 18 (range 18 to 19). Participants were predominantly white (99%). Two trials were conducted in Europe.^44,45 One trial enrolled participants from both Europe and the United States.⁴⁷ All were industry-sponsored and had low risk of bias.

Table 7

Evidence overview: solifenacin/AB combination versus placebo.

Solifenacin-AB combination improved LUTS more than placebo (moderate SoE). Mean reduction in I-PSS scores with combination was 7.3 points compared with 5.7 points with placebo (WMD = -1.5). The magnitude of effect of combination therapy with 9 mg solifenacin appeared lower than with 6 mg. Combination therapy was similar to placebo in reducing I-PSS QoL scores (low SoE). Among the three trials, 11 cases of urinary retention were reported with combination therapy and none with placebo.

Withdrawal for any reason was similar with combination therapy and placebo (low SoE). Withdrawal due to adverse effects and the proportion of participants reporting ≥1 adverse effect were similar with combination therapy and placebo (insufficient SoE). Combination therapy was more likely to cause dry mouth and constipation than placebo.

Solifenacin AB Combination Versus AB Monotherapy

Seven 12-week trials^{42-45,50,51,55} with 3147 participants contributed to the analysis of solifenacin plus tamsulosin versus tamsulosin monotherapy in men with LUTS and OAB symptoms (Table 8). Participants had a mean age of 66 and a mean baseline I-PSS score of 17 (range 14 to 19); and 96 percent were white. Five trials examined solifenacin, 5 mg^{42,43,50,51,55} and two examined solifenacin, 6 mg.^44,45 Dosage of tamsulosin varied geographically. Three studies were conducted in South Korea^42,43,51 and one in Japan;⁵⁰ these trials used the lower than recommended daily 0.2 mg tamsulosin dose. One trial was conducted in the United States⁵⁵ and two in Europe,^44,45 these trials used a daily 0.4 mg tamsulosin dose. All trials except one⁵¹ reported industry sponsorship; Seo et al. did not report a funding source. Overall risk of bias was moderate.

Table 8

Evidence overview: solifenacin/AB combination versus AB monotherapy.

Combination therapy was similar to AB monotherapy in improving LUTS (moderate SoE). Improvement in mean I-PSS score from baseline was similar with solifenacin 5 or 6 mg plus tamsulosin 0.2 or 0.4 mg versus tamsulosin alone (WMD = -0.29). Combination therapy lowered I-PSS QoL score more than tamsulosin, but the difference between groups was not clinically significant, indicating equivalence (moderate SoE). Evidence from four trials using solifenacin 3 to 9 mg^44,45,50,55 and reporting acute urinary retention showed no statistical difference in rates, but evidence was insufficient to draw conclusions due to the wide confidence intervals. No other indicators of disease progression/treatment failure were reported.

Withdrawal for any reason or due to adverse effects was similar with both treatments (low SoE). More participants reported one or more adverse effects with combination treatment than monotherapy (moderate SoE). Combination therapy was more likely than placebo to cause dry mouth and constipation.

Fesoterodine AB Combination Versus AB Monotherapy

Two trials (n=990), one 12-weeks⁵³ and one 4-weeks in duration,⁴⁶ compared fesoterodine/AB combination therapy with AB monotherapy in men with LUTS and OAB symptoms (Table 9).^46,53 Mean age was 66 and mean baseline I-PSS score was 19 (range 16 to 19). Most participants were white (81%) in one trial that reported race/ethnicity.⁵³ Participants were randomized to daily doses of fesoterodine 4 mg combined with various ABs (most frequently tamsulosin 0.4 mg) versus the AB alone. One trial (n=943) was multinational⁵³ and the other (n=47) was conducted in Greece.⁴⁶ One trial reported industry sponsorship⁵³ and the other did not report sponsorship.⁴⁶ Overall risk of bias was moderate for one trial⁵³ and high for the other.⁴⁶

Table 9

Evidence overview: fesoterodine/AB combination versus AB monotherapy.

Improvement in mean I-PSS scores was similar with fesoterodine-AB combination and AB monotherapy (low SoE). Acute urinary retention was infrequent in the one study that reported this outcome (≤1%) and only one participant in each study arm required catheterization.⁵³ Konstantinidis et al. did not report AUR.⁴⁶

Withdrawal for any reason, withdrawal due to adverse effects, and reporting at least one adverse effect were more frequent with combination treatments than with monotherapy (low SoE). Dry mouth and constipation were more frequent with combination therapy than monotherapy.

Oxybutynin AB Combination Versus AB Monotherapy

One 12-week trial (n=420) trial compared oxybutynin 10 mg tablets and AB combination therapy with AB monotherapy.⁵⁷ Individuals with a baseline postvoid residual of >200 ml were excluded. Mean age of the participants was 63 and mean baseline I-PSS score was 20. Most participants were white (90%). Participants were randomized to daily doses of oxybutynin 10 mg combined with tamsulosin 0.4 mg versus placebo with tamsulosin 0.4 mg monotherapy. The trial was conducted in the United States and reported industry sponsorship. Risk of bias was moderate.

Oxybutynin-AB combination therapy improved mean I-PSS scores more than AB monotherapy (WMD = -1.70) (insufficient evidence).

Rates of total withdrawals, withdrawal due to adverse effects, and proportions of participants with ≥1 adverse event were similar with oxybutynin-AB combination therapy and AB monotherapy (insufficient evidence).

Darifenacin AB Combination Versus AB Monotherapy

Two 12-week trials (n=161) compared darifenacin/AB combination therapy with AB monotherapy in men with LUTS and OAB symptoms (Table 10).^39,49 Participants with a baseline postvoid residual of >150 ml were excluded. Mean age was 63 and mean baseline I-PSS score was 17. Race/ethnicity were not reported in either trial. Participants were randomized to daily doses of darifenacin 7.5 mg combined with doxazosin 4 mg⁴⁹ or tamsulosin 0.4 mg³⁹ versus the AB alone. One trial was conducted in Turkey⁴⁹ and the other in India.³⁹ Neither trial reported industry sponsorship. Risk of bias was low in one trial³⁹ and moderate in the other.⁴⁹

Table 10

Evidence overview: darifenacin/AB combination versus AB monotherapy.

Statistical differences between mean change in IPSS scores from baseline were unclear and strength of evidence was insufficient for this outcome. Overall, one trial reported acute urinary retention in four participants with combination therapy and one with AB monotherapy Withdrawals and withdrawals due to adverse effects were similar (insufficient SoE).

Trospium AB Combination Versus AB Monotherapy

One 12-week trial (n=58) compared trospium 45 mg daily doses with AB to AB monotherapy in men with LUTS and OAB symptoms.⁴⁸ Individuals with a baseline postvoid residual of >100 ml were excluded. Mean age was 58 and mean baseline I-PSS score was 15.3. This trial was conducted in Turkey. Sponsorship was not reported. Risk of bias was moderate.

Evidence was insufficient to assess efficacy for any outcome. Rates of total withdrawals were not reported. One or more adverse effects were reported in nine (35 percent) trospium participants versus five (23%) placebo patients.

Mirabegron Versus Placebo

One 12-week trial (n=200)⁶⁵ assessed the efficacy of mirabegron at 50 mg (n=70) and 100 mg doses (n=65) with placebo (n=65) in males with LUTS attributed to BPH. The study enrolled patients with I-PSS ≥8, was conducted in the United States and Canada and was funded by industry. Mean age of participants was 63. The study had low risk of bias.

Mean I-PSS score changes from baseline were -6.2, -4.8, and -5.0 in the 50 mg, 100 mg, and placebo groups. Differences between treatments were not significant. The information provided was insufficient for effect size calculation or pooling across dose levels for any outcome or adverse effect (insufficient SoE).

Mirabegron AB Combination Versus AB Monotherapy

One 8-week trial⁶⁴ (n=94) compared 50 mg of mirabegron combined with 0.2 mg tamsulosin versus tamsulosin monotherapy in males with LUTS attributed to BPH and OAB. It was conducted in Asia and used a 0.2 mg dose of tamsulosin. All patients were pretreated with tamsulosin. Patients with a postvoid residual >100 ml were excluded; mean age was 75. The study had high risk of bias (open label). The evidence was insufficient for mean change in I-PSS score and adverse effects.

Tadalafil Versus Placebo

Ten eligible 12-week trials randomized men with LUTS attributed to BPH (n=3516) to tadalafil versus placebo (Table 11).^{70,74,77,79,83-85,87,90,91} Mean age of the participants was 63 and mean baseline I-PSS score was 17.5 (range 16.4 to 21.8). In the five trials that reported race/ethnicity, most participants were white (86%).^{79,83,84,87,90} Approximately 75 percent of participants had ED history. Subjects typically had to have an IPSS score of 13 or greater, a Qmax ranging from 4 to 15 mL/sec, and a post-void residual volume of less than 300 mL at baseline for inclusion. All participants in Egerdie et al. were sexually active and had BPH-LUTS and ED.⁸³ The dose of tadalafil used most frequently was 5 mg daily (seven trials); followed by 2.5 mg tadalafil (three trials). One trial was a dose finding study, evaluating doses of 2.5, 5, 10, and 20 mg⁹⁰ and others evaluated 20 mg doses.^87,91 Four trials were multinational studies,^79,83,84,90 one was conducted in the United States and Canada,⁸⁷ one in the United States,⁹¹ and four were conducted in Asia.^70,74,77,85 All trials reported industry sponsorship and had low to moderate risk of bias.

Table 11

Evidence overview: tadalafil versus placebo.

Tadalafil improved LUTS more than placebo (low to moderate SoE). One trial conducted a responder analysis, defined as a ≥3 point reduction from baseline I-PSS score.⁹¹ Forty-nine percent responded with tadalafil compared with 36 percent with placebo (low SoE). Tadalafil 5 mg improved mean I-PSS scores from baseline more than placebo (WMD = -1.8) (moderate SoE). Tadalafil improved I-PSS scores by 5.5 points compared with 3.4 points with placebo. Both treatments reduced I-PSS scores greater than the MDD (3 points indicating slight improvement). Tadalafil 10 mg daily⁹⁰ and tadalafil 20 mg daily^87,90 showed larger effect sizes suggesting a dose-response relationship (test for subgroup differences I²=76 percent, p=0.006). Seven trials reported BII.^{74,79,83-85,90,91} Tadalafil 5 mg improved BII scores more than placebo (WMD -0.52), with both treatments showing improvements greater than MDD (-1.7 with tadalafil and -1.1 with placebo), which was greater than the MDD of 0.40 suggesting that most patients would notice benefits with tadalafil 5 mg. Tadalafil, 5 mg was better than placebo in improving BII scores (moderate SoE). Changes in I-PSS QoL were similar with tadalafil and placebo (WMD = -0.27) (high SoE). Mean changes from baseline were -1 and -0.7 points with tadalafil and placebo. Incidence of acute urinary retention was rare, reported in two participants with placebo in two trials.^74,90 No other indicators of disease progression/treatment failure were reported.

Study withdrawal for any reason was similar with tadalafil 5 mg and placebo (high SoE). However, participants allocated to tadalafil 5 mg were more likely to withdraw due to an adverse effect and report more than one adverse effect (high SoE); the absolute difference was small, two and six percent. The proportion of withdrawals due to adverse effects increased at higher doses but the differences between doses was not significant. The proportion reporting at least one adverse effect was higher with tadalafil 5 mg than placebo, 29 percent versus 22 percent (high SoE). One trial included “increased erections secondary to sexual stimulation” based on specific questioning of an investigator as part of any treatment emergent adverse events.⁹¹ However, only a small number of men taking taldalafil(7) or placebo(3) reported this outcome. A higher proportion of adverse effects at higher doses indicated a dose-response relationship (I²=76%, p=0.006), but only three trials evaluated doses greater than 10 mg.^87,90,91 Four trials reported that dyspepsia was an adverse effect associated with tadalafil use (3% vs. 0% for placebo).^77,79,87,90 Short-term, serious adverse effects were rare and reported in similar proportions with tadalafil and placebo (approximately 1 percent each). Three myocardial infarction deaths were reported in three trials, two with tadalafil,^83,84 and one with placebo.⁸⁷

Tadalafil AB Combination Versus AB Monotherapy

Four trials randomized males with BPH (n=224) to tadalafil combined with an AB or to AB monotherapy (Table 12).^71,72,75,88 Two 3-month trials compared tadalafil 10 mg daily⁷² or 20 mg on alternate days⁸⁸ combined with alfuzosin 10 mg to alfuzosin 10 mg monotherapy. Two trials evaluated tadalafil combined with tamsulosin 0.4 mg versus tamsulosin 0.4 mg monotherapy: a 1-month trial evaluated tadalafil 5 mg daily⁷⁵ and a 4-month trial evaluated tadalafil 10 mg daily.⁷¹ Mean age of the participants was 61 and mean baseline I-PSS score was 19.4 (range 15.5 to 21.3). Nearly all participants had ED history.^71,72,88 Subjects had to meet a minimum IPSS score at baseline, ranging from 8 to 12 or greater. Several trials did not include flowmetry data as inclusion criteria. For the trials that did, men were typically required to have a Qmax from 5 to 15 mL/sec. Trials were conducted in India,^71,72 Italy,⁸⁸ and Brazil.⁷⁵ All trials were open-label except Regadas et al.⁷⁵ and overall risk of bias therefore ranged from moderate to high.

Table 12

Evidence overview: combined tadalafil/AB versus AB monotherapy.

Combination therapy was similar to AB monotherapy (Tadalafil 5-20 mg combined with AB was similar to AB monotherapy in improving mean I-PSS scores from baseline (WMD = -2.0), (insufficient SoE). Mean reductions in I-PSS scores were similar; 10.4 and 8.6 with combination and monotherapy. Improvement in mean I-PSS QoL scores was also similar with combination treatment and monotherapy, however only open label (high risk of bias) trials reported this outcome^71,72,88 (low SoE).

Evidence was insufficient for overall withdrawals and withdrawals due to adverse effects. An additional double-blinded trial conducted in the United States (n=318) enrolled males already receiving stable AB therapy for LUTS and randomized them to tadalafil 5 mg or placebo, while continuing their AB therapy.⁸¹ Mean age was 67 and baseline I-PSS score was 13.6. Mean change in I-PSS scores from baseline was similar with combination therapy and monotherapy in men already receiving AB monotherapy at enrollment.⁸¹ There were no differences in withdrawals or withdrawals due to adverse effects, and no serious adverse effects were reported. No trials reported serious drops in blood pressure with combination therapy. Occasional cases of hypotention, which may be mild, were reported.

Tadalafil Combination Versus 5-ARI Monotherapy or 5-ARI/AB Combination

One 26-week (n=696) compared combined tadalafil 5 mg and finasteride 5 mg daily versus placebo and finasteride 5 mg daily.⁷³ Mean age was 64 and mean baseline I-PSS score was 17.3. Most participants were white (86%) and had ED history (65%). The trial had sites in the United States, Latin America, and Europe. The trial reported industry sponsorship, and overall risk of bias was low though the study duration of 26 weeks may be too short to demonstrate effectiveness of finasteride that may require longer follow-up.

Combined tadalafil/finasteride therapy improved mean I-PSS scores more than finasteride monotherapy (MD = -1.0) (low SoE). Combined therapy improved I-PSS scores by 5.5 points compared with 4.5 points with finasteride monotherapy. I-PSS QoL improvement was similar with combination and monotherapy (MD = -0.2) (low SoE). Mean changes from baseline were -1.1 and -0.9 points with combination and monotherapy, respectively. Study withdrawal for any reason was greater with finasteride monotherapy compared with combination therapy (low SoE). There was insufficient evidence regarding withdrawals due to adverse effects and the proportion reporting at least one adverse effect. Two participant deaths were reported, one each in the combined (metastatic pancreatic carcinoma) and finasteride/placebo (cerebrovascular accident) arms. Erectile dysfunction as an adverse effect was reported in five finasteride/placebo participants compared with one combined therapy patient.

One 3-month trial (n=132) evaluated combined tadalafil 10 mg daily with “standard therapy” for BPH defined as either an AB or finasteride versus placebo with “standard therapy” for BPH.⁸⁰ Mean age was 65 and mean baseline I-PSS score was 13.4. The trial was conducted in Iran. Industry sponsorship was not reported and risk of bias was moderate.

Combined tadalafil/standard therapy improved I-PSS scores by 5.4 points compared with 2.3 points with standard therapy/placebo (insufficient SoE). Combined tadalafil/standard therapy also improved I-PSS QoL scores more than standard therapy/placebo (MD = -0.6). Mean changes from baseline were -1.1 and -0.5 points with combined tadalafil/standard therapy and standard therapy/placebo.

Six and four participants in the combined tadalafil/standard therapy and standard therapy placebo groups withdrew from the trial due to adverse effects (insufficient evidence)

Tadalafil Versus Tamsulosin

Four 3-month trials compared tadalafil 2.5, 5, or 10 mg daily with tamsulosin 0.2 or 0.4 mg daily (Table 13).^71,74,79,85 Mean age was 63 and mean baseline I-PSS score was 17.4 (range 16.8 to 20.6). Most participants were white (77%) in one multinational trial reporting race/ethnicity.⁷⁹ Most participants had an ED history.^71,79,85 The most frequently investigated dose level of tadalafil was 5mg; one trial studied a 2.5 mg dose^74,79,85 and one trial evaluated 10 mg.⁷¹ Two trials conducted in Japan and Korea allocated participants to tamsulosin 0.2 mg daily, a dose lower than the 0.4 mg dose used in the United States.^74,85 The multinational trial⁷⁹ and the Indian trial evaluating tadalafil 10 mg⁷¹ allocated participants to tamsulosin 0.4 mg. Three trials reported industry sponsorship.^74,79,85 Overall risk of bias was low to high for the four trials; Singh was open-label.⁷¹

Table 13

Evidence overview: tadalafil versus tamsulosin.

Tadalafil 5 mg and tamsulosin were similar in improving mean I-PSS scores (moderate SoE) and I-PSS QoL (low SoE).

Evidence was insufficient for the outcomes of study withdrawal for any reason and proportion of participants reporting at least one adverse effect, but withdrawal due to adverse effects was higher with tadalafil (moderate SoE). Kim et al. reported that two subjects in each treatment arm reported serious adverse events: pleural effusion with metastatic lung adenocarcinoma and lumbar spinal stenosis with tadalafil and acute myocardial infarction and inguinal hernia with tamsulosin.⁸⁵ Yokoyama et al reported four serious adverse effects with tadalafil (colon cancer with metastatic liver carcinoma, hospitalization because of injury, hypertension, lumbar spinal stenosis) and one with placebo (malignant lymphoma).⁷⁴ Oelke et al. reported two serious adverse effects with each treatment.⁷⁹ Singh et al. reported that no serious adverse effects occurring during the study period.⁷¹

Tadalafil Versus Alfuzosin

Two 3-month trials (n=93) compared tadalafil with alfuzosin 10 mg daily (Table 14).^72,88 Neither trial evaluated the FDA approved dose level of 5 mg of tadalafil but studied higher doses. Kumar et al. compared tadalafil 10 mg daily with alfuzosin 10 mg daily.⁷² Liguori et al. compared tadalafil 20 mg taken on alternate days with alfuzosin 10 mg daily.⁸⁸ Mean age of the participants was 61 and mean baseline I-PSS score was 16.2 (range 14.7 to 17.3). All participants had a history of ED. Trials were conducted in India⁷² and Italy.⁸⁸ Neither trial reported sponsorship. Both trials were open-label with high overall risk of bias.

Table 14

Evidence overview: tadalafil versus alfuzosin.

Alfuzosin 10 mg improved mean I-PSS scores more than tadalafil 10 or 20 mg) (low SoE). Mean reductions in I-PSS scores were 4.1 and 7.2 points with tadalafil and alfuzosin, respectively. I-PSS QoL also improved more with alfuzosin than tadalafil (low SoE).

Study withdrawal for any reason and withdrawal due to an adverse effect were similar with tadalafil and alfuzosin (insufficient SoE). Liguori et al. reported one participant discontinued treatment with tadalafil (back pain, headaches) versus three with alfuzosin (dizziness, constipation).⁸⁸ Kumar et al. reported two participants developed occasional headaches with tadalafil.⁷² No serious adverse effects were reported.

Sildenafil Versus Placebo

One 3-month trial (n = 369) compared sildenafil 50 mg (increasing to 100 mg at 2 weeks) with placebo.⁹² Participants could return to the 50 mg dose if the 100 mg dose was not tolerated. Baseline mean I-PSS score was not reported, but a minimum of 12 was required for enrollment. Mean age was 60 and most participants were white (82%); all were experiencing ED in addition to LUTS attributed to BPH. The trial was conducted in the United States, reported industry sponsorship, and had low overall risk of bias.

Sildenafil improved mean I-PSS scores more than placebo (-6.3 vs. -1.9 points) (Low SoE). BII mean change was also greater with sildenafil (-2.0 points) than placebo (-0.9 points) (insufficient evidence). Mean change in I-PSS QoL was larger with sildenafil than placebo, -1.0 and -0.3 (insufficient evidence).

Evidence was insufficient for overall withdrawals, withdrawals due to adverse effects, and proportion reporting one or more adverse effects. Headache and dyspepsia were reported more frequently with sildenafil than placebo (11% vs. 3% and 6% vs. 1%, respectively). Two serious adverse effects were reported with sildenafil, including one severe acute cerebrovascular stroke.

Sildenafil AB Combination Versus AB Monotherapy

Four trials (n=281) compared sildenafil combined with an AB with AB monotherapy (Table 15).^76,78,86,93 The combinations studied varied. Two 3-month trials evaluated sildenafil combined with alfuzosin 10 mg, one used daily sildenafil 25 mg,⁹³ the other sildenafil 50 mg (dosing frequency not reported).⁷⁸ One 4-month trial evaluated sildenafil 50 mg combined with doxazosin 2 mg but the frequency of administration was not reported.⁷⁶ An 8-week trial evaluated sildenafil 25 mg taken 4 days per week combined with tamsulosin 0.4 mg daily.⁸⁶ Mean age of the participants was 61 and mean baseline I-PSS score was 17.7 points (range 15.6 to 19.9). Three trials enrolled males with a history of ED.^76,86,93 Trials were conducted in Egypt,⁷⁶ Turkey,^78,86 and the United States.⁹³ The U.S. trial reported industry sponsorship and the Egyptian trial reported receiving no support. All trials were open label or otherwise inadequately blinded and enrolled patients after they failed to respond to AB monotherapy. Overall risk of bias was mostly high.

Table 15

Evidence overview: sildenafil/AB combination versus AB monotherapy.

Mean reductions in I-PSS scores were 5.4 with combination and 3.9 with monotherapy with both treatments exceeding MDD. However, the strength of evidence was insufficient due to the study limitations and imprecision in measurement.^76,78,93 In the trial without data sufficient for pooling, improvement in mean I-PSS scores was similar with combination or monotherapy (-6.4 vs. -5.4) and over 8 weeks.⁸⁶

Evidence was insufficient for overall withdrawals and withdrawals due to adverse effects. Kaplan et al. reported three participants withdrew due to gastric upset and dizziness with combination therapy and two withdrew due to dizziness with alfuzosin.⁹³ No serious adverse effects were reported. Abolyosr et al. reported slight dizziness and blurring of vision, mainly in participants who took combined therapy.⁷⁶ Tuncel et al. did not report withdrawals or adverse effects.⁸⁶

Sildenafil Versus AB

Three trials (n=181) compared sildenafil versus an AB (Table 16).^76,86,93 One compared sildenafil 25 mg daily with alfuzosin 10 mg daily over 12 weeks⁹³ and compared sildenafil 25 mg taken 4 days per week with tamsulosin 0.4 mg daily over 8 weeks.⁸⁶ Abolyosr et al. compared sildenafil 50 mg with doxazosin 2 mg over 16 weeks; frequency of administration was not reported. The doxazosin 2 mg dose was generally lower that what is typically administered. Mean age of the participants was 61^76,86,93 and mean baseline I-PSS was 16.3 (range 14.9 to 17.1). All participants had ED history. Trials were conducted in Egypt,⁷⁶ Turkey,⁸⁶ and the United States.⁹³ The U.S. study reported industry sponsorship and the Egyptian trial reported receiving no support. All trials were open label and overall risk of bias was high.

Table 16

Evidence overview: sildenafil versus AB monotherapy.

Mean reduction in I-PSS scores was -2.2 with sildenafil and -3.2 with alfuzosin or doxazosin (insufficient SoE).^76,93 Mean reduction with sildenafil 25 mg was 4 points versus 5.4 points for tamsulosin 0.4 mg (insufficient SoE).⁸⁶

Evidence was insufficient for overall withdrawals and withdrawals due to adverse effects. Kaplan et al. reported two participants using sildenafil withdrew due to flushing and dyspepsia and two using alfuzosin withdrew with dizziness.⁹³ Abolyosr et al. and Tuncel et al. did not report withdrawals.^76,86

Vardenafil Versus Placebo

One trial compared vardenafil 10 mg twice daily to placebo.⁸⁹ The 8-week trial randomized 222 participants with a mean age of 56 and a mean baseline I-PSS score of 17. Nearly all participants were white (99%). Approximately 60 percent of participants reported ED or ejaculatory problems. The trial was industry sponsored, conducted in Germany, and had low risk of bias.

LUTS improved more with vardenafil than placebo (low SoE). Mean I-PSS scores decreased 5.9 with vardenafil and 3.6 with placebo, both exceeding the MDD.

Study withdrawal due to adverse effects and the proportion reporting one or more adverse effect (30% vs. 16%) was higher with vardenafil than placebo (low SoE). Common adverse effects included headaches, flushing, and dyspepsia. Serious adverse effects were reported in two participants with vardenafil (myocardial infarction and hypertensive crisis) and three with placebo (hematochezia, meniscus injury, and knee surgery).

Vardenafil AB Combination Versus AB Monotherapy

One double-blinded trial (n=60) compared vardenafil 10 mg daily combined with tamsulosin 0.4 mg to tamsulosin monotherapy over 12 weeks.⁸² Mean age of the participants was 67 and mean baseline I-PSS score was 19.6. The trial was conducted in Italy. No industry sponsorship was indicated and overall risk of bias was moderate.

Mean reductions in I-PSS scores were 5.8 with combination and 3.7 with monotherapy, both achieving MDD (insufficient SoE).

One withdrawal was reported with tamsulosin. No participant withdrew due to adverse effects. Persistent adverse effects were reported in three participants with combination therapy (headache with flushing, headache with stomach pain, stomach pain) and two with tamsulosin (headache, flushing). No serious adverse effects were reported.