Efficacy of Phosphodiesterase Type 5 Inhibitors in Patients With Erectile Dysfunction After Nerve-Sparing Radical Prostatectomy

A Systematic Review and Meta-Analysis

Hyeok Jun Goh; Jeong Min Sung; Kwang Hyun Lee; Jung Ki Jo; Kyu Nam Kim

Transl Androl Urol. 2022;11(2):124-138.

Abstract and Introduction

Abstract

Background: Nerve-sparing radical prostatectomy (NSRP) had to be performed because approximately 94% of patients are diagnosed with localized prostate cancer (PCa). Although NSRP is generally done to improve functional outcomes, erectile dysfunction (ED) is one of the most prevailing complications after radical prostatectomy (RP). Phosphodiesterase type 5 inhibitors (PDE5-Is) are the most well-known treatment agent for postoperative ED. This study aimed to assess the efficacy of PDE5-Is in patients with ED after NSRP.

Methods: In this systematic literature review, randomized controlled trials on the efficacy and safety of PDE5-Is in patients who underwent NSRP were searched in MEDLINE, EMBASE, and the Cochrane Controlled Trials Register using the OVID platform. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Cochrane Review Methods. The quality of the evidence of the outcome data was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach.

Results: A total of 14 trials involving 2,822 patients were included. Significant improvements in the International Index of Erectile Function—Erectile Function (IIEF) domain score [mean difference (MD) =4.93; 95% confidence interval (CI): 4.14–5.71; P<0.00001] and erectile function recovery events [odds ratio (OR) =2.06; 95% CI: 1.45–2.94; P<0.0001] were observed after PDE5-I treatment. A higher positive response to Sexual Encounter Profile (SEP) question 2 (OR =2.27; 95% CI: 1.80–2.86; P<0.00001) and question 3 (OR =2.78; 95% CI: 1.97–3.91; P<0.00001) was also found after PDE5-I treatment. However, the incidence of treatment-emergent adverse events (TEAEs) was higher after PDE5-I treatment than after placebo treatment (OR =2.91; 95% CI: 1.84–4.61). Furthermore, the incidence of headache (OR =3.38; 95% CI: 2.40–4.75) and flushing (OR =9.44; 95% CI: 4.30–20.70) was also significantly higher after PDE5-I treatment (P<0.00001). In terms of the quality of the evidence of the outcome data, inconsistency problems were detected in all outcomes and imprecision problems in most outcomes.

Discussion: PDE5-I treatment was more effective to placebo treatment in patients with ED after NSRP. No clinically serious complications were found in spite of the incidence of TEAEs being higher after PDE5-I treatment.

Introduction

One in six men had been diagnosed with prostate cancer (PCa) in their lifetime, making PCa the most common type of cancer among men in Western countries.^[1,2] Approximately 94% of patients are diagnosed with localized PCa and thus need to undergo nerve-sparing radical prostatectomy (NSRP).^[2,3] The number of radical prostatectomy (RP) operation has been rapidly increasing over years, and the age of patients seeking for this treatment has also increased correspondingly.^[4]

Despite the fact that NSRP is usually performed to promote the functional outcomes, such as erectile function, erectile dysfunction (ED) results frequently after the procedure. Postoperative ED has been reported in 15–18% of patients who undergo NSRP.^[5,6] It is a condition that can potentially take a toll on the patients' everyday life.^[4] Therefore, if postoperative ED is less likely to occur, more patients will decide to receive NSRP.^[7] Various factors affect the development and severity of postoperative ED; these include patient age, preoperative potency, stage of the tumor, and surgeon's experience.^[8–12] Postoperative ED can also cause vascular damage, neural injury, and smooth muscle damage.^[13,14]

The emergence of phosphodiesterase type 5 inhibitors (PDE5-Is) has innovated ED treatment with a success rate of approximately 60–70%.^[15,16] PDE5-Is are the most common treatment agent for postoperative ED. The efficacy and adverse effects of PDE5-Is have been reported; however, there is insufficient evidence to demonstrate the optimal use of PDE5-Is for penile rehabilitation. Several errors were found in meta-analyses and systematic reviews that have been performed to assess the efficacy and adverse effects of PDE5-Is.^[17–19] Therefore, we performed a systematic review and meta-analysis of randomized controlled trials to evaluate the efficacy and safety of PDE5-Is in patients with ED after NSRP.

We present the following article in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-21-881/rc).

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Abstract and Introduction
Methods
Results
Discussion
Conclusions
References

Table 1. Characteristics of the included randomized controlled trials
Study	Year	Country/region	Intervention	Control	Sample size		Treatment period	Surgical approach
Study	Year	Country/region	Intervention	Control	Intervention	Control	Treatment period	Surgical approach
Aydogdu et al. (26)	2011	Turkey	Tadalafil 20 mg/day	Placebo	32	33	6 months	BNSRP
Bannowsky et al. (31)	2008	Germany	Sildenafil 25 mg/day	Placebo	23	18	52 weeks	UNSRP
								BNSRP
Bannowsky et al. (28)	2010	Germany	Sildenafil 25 mg/day	Placebo	23	18	78 weeks	UNSRP
								BNSRP
Bannowsky et al. A (25)	2012	Germany	Vardenafil 5 mg/day	Placebo	12	12	12 months	UNSRP
Bannowsky et al. B (25)			Vardenafil 10 mg/day		12
Brock et al. A (35)	2003	United States and Canada	Vardenafil 10 mg on demand	Placebo	140	140	3 months	UNSRP
Brock et al. B (35)			Vardenafil 20 mg on demand		147			BNSRP
Canat et al. A (22)	2015	Turkey	Tadalafil 20 mg three times/week	Placebo	38	34	12 months	BNSRP
Canat et al. B (22)			Tadalafil 20 mg on demand		40
Cavallini et al. (33)	2005	Italy	Sildenafil 100 mg on demand	Placebo	35	29	4 months	BNSRP
Montorsi et al. (34)	2004	Canada, Germany, Italy, The Netherlands, Spain, United States, and United Kingdom	Tadalafil 20 mg on demand	Placebo	201	102	3 months	BNSRP
Montorsi et al. A (30)	2008	Europe, United States, Canada, and South Africa	Vardenafil 10 mg/day	Placebo	137	145	9 months	BNSRP
Montorsi et al. B (30)			Vardenafil 10 mg (5 to 20 mg) on demand		141
Montorsi et al. A (23)	2014	Nine European countries and Canada	Tadalafil 5 mg/day	Placebo	138	141	9 months	BNSRP
Montorsi et al. B (23)			Tadalafil 20 mg on demand		143
Mulhall et al. A (24)	2013	53 sites in the United States	Avanafil 100 mg on demand	Placebo	99	100	3 months	BNSRP
Mulhall et al. B (24)			Avanafil 200 mg on demand		99
Nehra et al. A (32)	2005	United States and Canada	Vardenafil 10 mg on demand	Placebo	140	140	3 months	UNSRP
Nehra et al. B (32)			Vardenafil 20 mg on demand		147			BNSRP
Pace et al. (27)	2010	Italy	Sildenafil 50 or 100 mg/day	Placebo	20	20	6 months	BNSRP
Padma-Nathan et al. A (29)	2008	North America, France, Belgium, and Australia	Sildenafil 50 mg/day	Placebo	40	42	9 months	BNSRP
Padma-Nathan et al. B (29)		North America, France, Belgium, and Australia	Sildenafil 100 mg/day		41

BNSRP, bilateral nerve-sparing radical prostatectomy; UNSRP, unilateral nerve-sparing radical prostatectomy.

Table 2. Sensitivity analysis of primary and secondary outcomes
Outcome	Studies, n	Phosphodiesterase type 5 inhibitors, n	Control patients, n	OR or MD	95% CI	P value for effect	P value for heterogeneity	I² (%)
The improvements in IIEF score
Total studies	11 (22–25,27–29,31,33,34,35)	1,143	1,004	4.93	4.14 to 5.71	<0.00001	0.005	53
Including only studies with low risk of bias	6 (23,24,29,33–35)	973	856	4.99	3.78 to 6.20	<0.00001	0.002	65
The incidence of erectile function recovery events
Total studies	5 (23,26,27,30,34)	807	732	2.06	1.45 to 2.94	<0.0001	0.11	42
Including only studies with low risk of bias	4 (23,26,30,34)	787	712	2.07	1.40 to 3.05	0.0002	0.07	52
The incidence of TEAEs
Total studies	8 (23,24,27,29,30,32,34,35)	1,766	1,660	2.91	1.84 to 4.61	<0.00001	<0.00001	89
Including only studies with low risk of bias	7 (23,24,29,30,32,34,35)	1,746	1,640	2.91	1.84 to 4.61	<0.00001	<0.00001	89

n, the number of cases; OR, odds ratio; MD, mean difference; CI, confidence interval; IIEF, International Index of Erectile Function—Erectile Function; TEAEs, treatment-emergent adverse events.

Table 3. GRADE summary of findings table
Outcomes	Studies, n	Patients, n		Anticipated absolute effects (95% CI)		Relative effect (95% CI)	Quality of evidence (GRADE)
Outcomes	Studies, n	PDE5-Is	Placebo	Risk with PDE5-Is	Risk with placebo	Relative effect (95% CI)	Quality of evidence (GRADE)
IIEF domain score	11 RCTs	1,143	1,004	The IIEF domain score was 4.93 higher (from 4.14 higher to 5.71 higher)			⨁⨁⨁◯ MODERATE¹
Recovery events in relation to the IIEF domain score	5 RCTs	252/807 (31.2%)	143/732 (19.5%)	138 more per 1,000 (from 65 more to 221 more)	195 per 1,000	OR =2.06 (1.45 to 2.94)	⨁⨁◯◯ LOW^1,2
Response to SEP question 2	7 RCTs	447/987 (45.3%)	233/886 (26.3%)	185 more per 1,000 (from 128 more to 242 more)	263 per 1,000	OR =2.27 (1.80 to 2.86)	⨁⨁◯◯ LOW^1,2
Response to SEP question 3	7 RCTs	469/1,301 (36.0%)	221/1,209 (18.3%)	201 more per 1,000 (from 123 more to 284 more)	183 per 1,000	OR =2.78 (1.97 to 3.91)	⨁⨁◯◯ LOW^1,2
Incidence of TEAEs	8 RCTs	1,014/1,766 (57.4%)	376/1,209 (31.1%)	157 more per 1,000 (from 110 more to 204 more)	311 per 1,000	OR =1.95 (1.61 to 2.35)	⨁⨁⨁◯ MODERATE¹
Incidence of headache	8 RCTs	207/1,781 (11.6%)	68/1,669 (4.1%)	85 more per 1,000 (from 52 more to 127 more)	41 per 1,000	OR =3.38 (2.40 to 4.75)	⨁⨁◯◯ LOW^1,2

The risk in the intervention group (and its 95% CI) was based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ¹, downgraded by one level owing to inconsistency; ², downgraded by one level owing to imprecision. GRADE Working Group quality of evidence. High quality, we are very confident that the true effect lies close to the estimate of the effect; Moderate quality, we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect; however, there is a possibility that it is substantially different; Low quality, our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect; Very low quality, we have very limited confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of the effect. GRADE, Grading of Recommendations, Assessment, Development, and Evaluation; n, the number of cases; PDE5-I, phosphodiesterase type 5 inhibitor; CI, confidence interval; IIEF, International Index of Erectile Function—Erectile Function; RCT, randomized controlled trial; OR, odds ratio; SEP, Sexual Encounter Profile; TEAEs, treatment-emergent adverse events.