Phosphodiesterase inhibitors for treatment of voiding dysfunction: An overview of experimental and clinical evidence

Table 1 Initial evidence based in epidemiological studies of a common pathophysiology between lower urinary tract symptoms and erectile dysfunction

Ref.	Number of participants	Major conclusion
Cologne Male Survey
Braun et al[6]	4000	72.2% of patients with ED had concomitant LUTS Only 37.7% had LUTS without ED
Population-based cohort study in Brazil
Moreira et al[7]	602	Incidence of ED was 65.5 cases per 1000 person-years Relative risk of ED was 1.8-7.5 in patients with LUTS
Sexual dysfunction in European men
Vallancien et al[8]	1274	Prevalence ED-Mild (55%), severe (70%) LUTS Prevalence of ED was 55% in men with mild LUTS and increased to 70% in severe LUTS
Association of LUTS in Japanese men with erectile dysfunction
Terai et al[9]	3189	Severity of ED was significantly associated with moderate to severe IPSS, RR = 1.5 which persisted after adjustment for age
Boston Area Community Health survey
Brookes et al[10]	2301	Strong association was observed between the AUA-SI associated to ED and ED after adjusting for age

ED: Erectile dysfunction; LUTS: Lower urinary tract symptoms; RR: Relative risk; IPSS: International Prostatic Score Symptoms; AUA-SI: American Urological Association Symptom Index.

Table 2 Randomized clinical trials and meta-analyses with strong evidence for the use of phosphodiesterase inhibitors in patients with lower urinary tract symptoms due to benign prostatic obstruction

Ref.	Design of study	Placebo run-in	Participant/inclusion criteria	End point	Major conclusion
Sairam et al[11]	Not RCT	No	112 male patients All taking sildenafil Inclusion criteria was presence ED	Assess relationship between ED and LUTS; if sildenafil influences LUTS in patients with ED	No relation between ED score and LUTS before treat ED Sildenafil improves ED and LUTS
McVary et al[14]	Open-label, randomized, double-blind, placebo-controlled	No	369 patients were randomized to sildenafil 100 mg (n = 189) or placebo (n = 180) during 12 wk/Men with ED and LUTS	Change IPSS, QoL,BPHII, Qmax, SEAR, and EDITS	Sildenafil improve IIEF, IPSS, BPHII, IPSS QoL and SEAR score Qmax not altered
McVary et al[15]	Randomized, double-blind, placebo-controlled	Yes	281 men randomized to tadalafil 5 mg daily, followed by dose escalation to 20 mg/Men aged 45 yr or higher and IPSS > 12	Change IPSS, QoL, BPHII, Qmax, and IIEF	Tadalafil improve IPSS, QoL, BPHII, and IIEF Qmax not altered
Stief et al[16]	Randomized, double-blind, placebo-controlled	No	222 men were randomized to vardenafil 10 mg twice daily or placebo/age 45-64 yr, IPSS ≥ 12, with or without ED	Change in IPSS, Qmac, PVR, and IIEF	Vardenafil improve IPSS, IIEF, and QoL Qmax and PVR not altered
Roehrborn et al[17]	Randomized, double-blind, placebo-controlled	Yes	1058 men were randomized to receive daily tadalafil 2.5, 5, 10 or 20 mg/age greater than 45 yr, IPSS ≥ 12, and Qmax between 4-15 mL/s	Change in IPSS, IIEF, QoL, BPHII, GAQ, and Qmax	Tadalafil improve IPSS and GAQ in all doses But, dose higher than 5 mg had minimal improvement with higher side effects Qmax not altered
Porst et al[20]	Meta-analysis		1026 men, tadalafil (n = 505) compared to placebo (n = 521). Data pooled from four multinational study/age ≥ 45 yr, presence of LUTS/BPO	Change in IPSS, QoL, BPHII, and IIEF	Tadalafil improve IPSS, QoL, BPHII, and IIEF compared with placebo
Gacci et al[18]	Meta-analysis		Twelve studies, been seven studies (n = 3214) comparing PDEi vs placebo, and five (n = 216) on the combination of PDEi with ∝-blockers vs∝-blockers alone/Men with LUTS/BPO	Change in IPSS, IIEF, and Qmax Identify best candidates for treatment with PDEi based on clinical features	PDEi alone improve IPSS, IIEF, but not Qmax Association of PDEi with ∝-blockers improve IPSS, IIEF, and Qmax
Yan et al[19]	Meta-analysis		515 patients (seven studies)/patients with LUTS/BPO and ED	Compare combination of PDEi with ∝-blockers vs∝-blockers alone. Change IPSS, QoL, BPHII, Qmax, and IIEF	Combination of PDEi with ∝-blockers has additive favorable effects compared with PDEi monotherapy

RCT: Randomized control trial; ED: Erectile dysfunction; LUTS: Lower urinary tract symptoms; IPSS: International prostatic symptoms score; QoL: Quality of life; BPHII: Benign Prostatic Hyperplasia Impact Index; Qmax: Peak flow rate; SEAR: Self-esteem and relationship; EDITS: Erectile Dysfunction Inventory of Treatment Satisfaction Index Score; IIEF: International Index of Erectile Function; PVR: Postvoid residual urine volume; GAQ: Global Assessment Question; BPO: Benign prostatic obstruction; PDEi: Phosphodiesterase inhibitors.

Table 3 Studies evaluating the combination of phosphodiesterase inhibitors and alpha-blockers in patients with lower urinary tract symptoms

Ref.	Design of study	Placebo run-in	Participant /Inclusion criteria	End point	Major conclusion
Oelke et al[44]	Randomized, multicentric, placebo controlled, and parallel-group	Yes	Men ≥ 45 yr of age with BPO/LUTS, IPSS ≥ 13, and Qmax between 4-15 mL/s 512 men were randomized to placebo (n = 172), tadalafil 5 mg (n = 171) or tamsulosin 0.4 mg (n = 168); Men ≥ 45 yr of age with BPO/LUTS, IPSS ≥ 13, and Qmax between 4-15 mL/s	Compare effect of tadalafil 5 mg once daily with placebo on BPO/LUTS	Tadalafil 5 mg and tamsulosin 0.4 mg had similar improvement in BPO/LUTS and Qmax compared with placebo However, only tadalafil caused a significant improvement in QoL, treatment satisfaction, and erectile function
Regadas et al[45]	Randomized, double-blind, and placebo controlled	No	Men ≥ 45 yr of age, BOOI ≥ 20 and IPSS ≥ 14 A total of 40 men were randomized to tadalafil 5 mg/tamsulosin 0.4 mg (n = 20) or tamsulosin 0.4 mg /placebo (n = 20) Men ≥ 45 yr of age, BOOI ≥ 20 and IPSS ≥ 14	Observe changes in urodynamic variables (Qmax and PdetQmax)	Combination of tamsulosin/tadalafil decrease after-load (pdetQmax) and has potential to protect detrusor smooth muscle Additionally, the combination resulted in a significant improvement in IPSS compared with tamsulosin/placebo
Bechara et al[46]	Randomized, double-blind, and crossover study	No	History of LUTS/BPO of at least six months Thirty men were randomized to tamsulosin 0.4 mg or tamsulosin 0.4 mg/tadalafil 20 mg daily History of LUTS/BPO of at least six months	Acess efficacy and safety of combination of tamsulosin with tadalafil compared with tamsulosin alone	Combination therapy had more significative impact in IPSS and ED compared with tamsulosin alone
Kaplan et al[39]	Randomized, double-blind study	No	Men aged 50-76 yr with untreated LUTS and ED Sixty two patients were randomized to receive alfuzosin 10 mg (n = 20), sildenafil 25 mg (n = 21), or a combination of both (n = 20) Men aged 50-76 yr with untreated LUTS and ED	Acess efficacy and safety of combination of alfuzosin with sildenafil	Only sildenafil or combination improve ED Improvement in IPSS was observed with three treatments
Gacci et al[47]	Randomized, double-blind placebo-controlled trial	Yes	Men with persistent storage LUTS Sixty men were randomized to tamsulosin 0.4 mg or tamsulosin 0.4 mg/vardenafil 10 mg Men with persistent storage LUTS	Acess efficacy and safety of combination of tamsulosin with vardenafil	Combination therapy had more significative impact in IPSS and ED compared with tamsulosin alone

BPO/LUTS: Benign prostatic hyperplasia/lower urinary tract symptoms; Qmax: Peak flow rate; QoL: Quality of life; IPSS: International Prostatic Symptoms Score; PdetQmax: Detrusor pressure at maximum flow; ED: Erectile dysfunction; BOOI: Bladder outlet obstruction index.