Tadalafil Facilitates the Distal Ureteral Stone Expulsion: A Meta-Analysis

Abstract

Objective:

To assess the efficacy and safety of tadalafil in facilitating the spontaneous passage of distal ureteral stones.

Methods:

The relevant studies were identified by searching MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials up to November 2016. Randomized controlled trials evaluating effects of tadalafil for distal ureteral stones were included.

Results:

Six publications involving 921 patients were included. Compared with tamsulosin monotherapy, tadalafil monotherapy or combined with tamsulosin has a significantly higher stone expulsion rate (relative risk [RR], 1.16; 95% confidence interval [CI], 1.05 to 1.29; p = 0.004; RR, 1.24; 95% CI, 1.09 to 1.42; p = 0.001, respectively) and shorter time to stone expulsion (mean difference [MD], −1.33 days; 95% CI, −2.44 to −0.23; p = 0.02; MD, −1.98 days; 95% CI, −3.08 to −0.88; p = 0.0004, respectively). Statistically significant differences were noted in pain episodes and analgesic use in favor of group tadalafil alone compared to group tamsulosin alone. The analgesic use was significantly lower in the combined group than in the tamsulosin alone group. Although the occurrence of drug-related adverse events in the tadalafil alone or combined with tamsulosin was higher than that in the use of tamsulosin-alone group, the most common adverse events were mild and tolerable.

Conclusions:

Our study suggested that medical expulsive therapy for the distal ureteral stones using tadalafil alone or combined with tamsulosin is safe, efficacious, and well tolerated.

Introduction

Urolithiasis is frequently seen in urology practice and the proportion of ureteral stones is ∼20%. Medical expulsive therapy (MET), in particular a-blockers, has been recommended as supportive medication for patients with ureteral stones¹ and purported to reduce healthcare costs by facilitating stone passage and decreasing the need for interventional procedure.²

Previous high-quality meta-analyses showed a statistically significant benefit for both tamsulosin and nifedipine over controls for the outcome of spontaneous stone passage.^3,4 Recently, a large multicenter randomized controlled trial (RCT) found that neither tamsulosin nor nifedipine showed any clinically useful benefit for promoting stone passage measured by the absence of need for further intervention in 4 weeks for patients with ureteral colic.⁵ Therefore, the benefits of MET seem unclear with such conflicting data.

Previous studies have identified nitrergic fibers in the distal ureter and demonstrated a relaxant effect of nitric oxide pathway on ureteral smooth muscle.^6,7 Since then, investigators focus on how treatment of the nitric oxide pathway can be effectively implemented in clinical practice until phosphodiesterase-5 inhibitors (PDE5Is) emerged. Tadalafil, a PDE5I, acts on the nitric oxide-mediated pathway of smooth muscles and maybe can induce ureteric relaxation. Recently, several investigators^8,9 have assessed the effect of PDE5Is on spontaneous stone passage in patients with expectantly managed ureteral stones. The results of these studies showed a positive benefit with PDE5Is.

Despite the growing number of published trials with a few patients focused on tadalafil facilitates the ureteral stone expulsion, to our knowledge, a quantitative systematic review of RCTs is lacking to date. Therefore, we performed the first meta-analysis including the most recent evidence to assess the efficacy of tadalafil in patients with ureteral stones.

Methods

This study was performed according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement.

Literature search and data sources

We searched the literatures through MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials up to November 2016, with the terms tadalafil, ureteral stone, and RCTs (multiple synonyms for each term). The reference lists from the retrieved documents were also searched. Two authors independently screened all citations and abstracts selected by the search strategy to identify potentially eligible studies.

Inclusion and exclusion criteria

Relevant studies were required to meet the following inclusion criteria: prospective RCTs in humans, evaluate the efficacy and safety of tadalafil for the management of distal ureteral stones, and provide sufficient data for analysis. The primary outcome variables were stone expulsion rate and time to stone passage during treatment period. Secondary variables included the number of pain episodes during follow-up, analgesic use, and adverse effects. We excluded the articles as follows: (1) articles not in English; (2) review or meta-analysis articles; (3) duplicated or updated data; and (4) comments, editorials, letters, and case reports.

Data extraction and quality assessment

Data were independently extracted from the included studies by two authors. The data extracted included the data source, eligibility, methods, participant characteristics, interventions, and results. Any discrepancies among the extracted data were resolved by discussion. The Jadad scoring system¹⁰ was used to assess the quality of the RCTs.

Statistical analysis

The meta-analysis was performed by the Review Manager, version 5.3. Continuous outcomes are presented as a mean difference (MD) with 95% confidence interval (CI). Dichotomous data are presented as relative risk (RR) with 95% CI. Statistical heterogeneity among trials was evaluated using the I² test, with significance set at p < 0.05. Pooled estimates were calculated with the fixed-effect model if no significant heterogeneity was detected (I² ≤ 50%); otherwise, the random-effect model was used. For all statistical analyses, a two-sided value of p < 0.05 was considered statistically significant.

Results

Description of the included studies

The study selection procedure is described in Supplementary Figure S1 (Supplementary Data are available online at www.liebertpub.com/end). Six RCTs^8,11

–15 involving 921 patients were included in this study. All the studies were published within the last 3 years. No significant differences were detected in the baseline information between the groups. The main characteristics of all included studies are presented in Table 1. The Jadad scores were in the range 3–4 (Supplementary Table S1). All studies focused on the treatments' ability to facilitate stone passage. Two RCTs^12,14 assessed the efficacy of tamsulosin plus tadalafil for lower ureteral stones.

Table 1.

Basic Features of the Included Studies

				Treatment Strategy
Study	Stone size (mm)	Pts(n), tadalafil/tamsulosin/combined/placebo	Duration (week)	Tadalafil (mg)	Tamsulosin (mg)	Combined	Main study endpoints
Kumar and colleagues⁸	5–10	90/90/—/—	4	10	0.4	—	Stone expulsion rate, stone expulsion time, number of pain episodes, analgesic use, and side effects
Jayant and colleagues¹²	5–10	—/122/122/—	4	—	0.4	Tadalafil 10 mg plus tamsulosin 0.4 mg	Stone expulsion rate, stone expulsion time, number of pain episodes, analgesic use, and side effects
Puvvada and colleagues¹⁵	5–10	100/100/—/—	4	10	0.4	—	Stone expulsion rate, stone expulsion time, number of pain episodes, analgesic use, and side effects
Kc and colleagues¹³	5–10	44/41/—/—	2	10	0.4	—	Stone expulsion time, analgesic use, number of hospital visits for pain, and adverse effects
Abhishek and colleagues¹¹	4–10	50/50/—/50	2	10	0.4	—	Stone expulsion rate, analgesic use, and pain scale score
Kumar and colleagues¹⁴	5–10	—/31/31/—	6	—	0.4	Tadalafil 10 mg plus tamsulosin 0.4 mg	Stone expulsion rate, stone expulsion time, number of pain episodes, analgesic use, and side effects

Tadalafil vs tamsulosin

Stone expulsion rate and time to stone passage

Four^8,11,13,15 of the RCTs were selected evaluating tadalafil vs tamsulosin for lower ureteral stones. Our pooled analysis showed that treatment with tadalafil significantly improves stone expulsion rate when compared to tamsulosin in the fixed-effect model (Fig. 1A) (Table 2). The result was not affected by using the random-effect model (RR, 1.17; 95% CI, 1.04 to 1.31; p = 0.008)

FIG. 1.

Tadalafil vs tamsulosin: (A) forest plot of stone expulsion rate. (B) Forest plot of stone expulsion time. (C) Forest plot of analgesic use. (D) Forest plot of the number of pain episodes. CI = confidence interval; SD = standard deviation.

Table 2.

Summary of Results of Meta-Analyses

Outcomes	No. of pts (trials)	Pooled effects, RR or MD (95% CI)	Analysis model	p	I² (%)
Tadalafil vs Tamsulosin
Stone expulsion rate	565 (4)	RR, 1.16 (1.05 to 1.29)	Fixed	0.004	17
Stone expulsion time	465 (3)	MD, −1.33 (−2.44 to −0.23)	Random	0.02	53
Analgesic use	265 (2)	MD, −5.03 (−8.42 to −1.63)	Fixed	0.004	0
Pain episodes	265 (2)	MD, −0.12 (−0.37 to 0.13)	Fixed	0.35	0
Headache	465 (3)	RR, 1.51 (0.95 to 2.39)	Fixed	0.08	0
Dizziness	465 (3)	RR, 1.39 (0.85 to 2.28)	Fixed	0.18	0
Backache	465 (3)	RR, 1.45 (0.88 to 2.39)	Fixed	0.14	36
Orthostatic hypotension	465 (3)	RR, 1.18 (0.67 to 2.08)	Fixed	0.57	0
Abnormal ejaculation	261 (2)	RR, 0.52 (0.25 to 1.07)	Fixed	0.08	0
Tadalafil plus tamsulosin vs tamsulosin
Stone expulsion rate	306 (2)	RR, 1.24 (1.09 to 1.42)	Fixed	0.001	0
Stone expulsion time	306 (2)	MD, −1.98 (−3.08 to −0.88)	Fixed	0.0004	2
Analgesic use	306 (2)	MD, −1.03 (−1.23 to −0.83)	Fixed	<0.0001	0
Headache	306 (2)	RR, 1.26 (0.72 to 2.21)	Fixed	0.41	0
Dizziness	306 (2)	RR, 1.26 (0.72 to 2.21)	Fixed	0.41	0
Backache	306 (2)	RR, 1.60 (0.87 to 2.93)	Fixed	0.13	0
Orthostatic hypotension	306 (2)	RR, 1.80 (0.62 to 5.25)	Fixed	0.28	0
Abnormal ejaculation	176 (2)	RR, 0.60 (0.31 to 1.16)	Fixed	0.13	0

Bold values are statistically significant.

CI = confidence interval; MD = mean difference; RR = relative risk.

Three studies^8,13,15 were quantitatively analyzed for the stone expulsion time as the outcome. Our pooled analysis showed that the stone expulsion time was significantly shorter in the tadalafil group than in the tamsulosin group in the random-effect model (Fig. 1B). The result was not affected by using the fixed-effect model (MD, −1.36; 95% CI, −2.11 to −0.61; p = 0.004).

Analgesic use and pain episodes

Although four studies^8,11,13,15 reported the analgesic use during treatment, some studies could not be used for meta-analysis as it was given without a standard deviation and different measure unit from others. Therefore, meta-analysis of the remaining two studies^8,13 revealed that compared with tamsulosin, the analgesic use was significantly lower in the tadalafil group (Fig. 1C). The result was not affected by using the random-effect model. Three studies^8,13,15 reported the number of pain episodes during follow-up. Meta-analysis of two studies^8,13 revealed no statistically significant difference between tadalafil and tamsulosin, and there was no evidence of statistical heterogeneity between studies (Fig. 1D). The result was not affected by using the random-effect model. The later inclusion of the study by Puvvada and colleagues¹⁵ as a sensitivity analysis did not affect the results; however, it introduced significant heterogeneity into the analysis (I² = 89%, p = 0.83), which may result from differences in inclusion criteria.

Safety

Three studies^8,13,15 compared adverse effects between tadalafil and tamsulosin groups. Although our pooled results of three studies showed that the number of headache, dizziness, backache, and orthostatic hypotension of patients in the tadalafil group was higher than the tamsulosin group, no statistically significant difference appeared in these terms (Fig. 2). Meta-analysis of two studies^8,15 revealed no statistically significant difference between tadalafil and tamsulosin for the incidence of abnormal ejaculation (Fig. 2). All the results about the incidence of adverse events were not affected by using the random-effect model.

FIG. 2.

Pooled estimate of drug-related adverse effects between tadalafil and tamsulosin.

Tadalafil plus tamsulosin vs tamsulosin

Efficacy

Two^12,14 of the RCTs evaluated tadalafil plus tamsulosin vs tamsulosin alone for lower ureteral stones (Table 2). Our pooled analysis showed that treatment with tadalafil plus tamsulosin significantly improves the stone expulsion rate when compared to tamsulosin alone in patients with lower ureteral stones in the fixed-effect model (Fig. 3A). The result was not affected by using the random-effect model (RR, 1.24; 95% CI, 1.09 to 1.41; p = 0.001). The stone expulsion time was significantly shorter in the combined group than in the tamsulosin-alone group (Fig. 3B). The result was not affected by using the random-effect model (MD, −2.00; 95% CI, −3.14 to −0.85; p = 0.0007). The analgesic use was significantly lower in the combined group than in the tamsulosin-alone group (Fig. 3C). The result was also not affected by using the random-effect model.

FIG. 3.

Tadalafil plus tamsulosin vs tamsulosin alone: (A) forest plot of stone expulsion rate. (B) Forest plot of stone expulsion time. (C) Forest plot of analgesic use. (D) Forest plot of drug-related adverse effects.

Safety

Adverse effects seem to be more common with tadalafil plus tamsulosin than tamsulosin alone, which included headache, dizziness, backache, and orthostatic hypotension. There was no statistically significant difference between the two groups for the incidence of abnormal ejaculation (Fig. 3D). All the results about the incidence of adverse events were not affected by using the random-effect model.

Sensitivity analyses

Sensitivity analyses were conducted to determine the effect of each study on the pooled analysis and no substantial changes occurred for the corresponding RRs or MDs.

Discussion

Economic burden for stone disease has rapidly increased over the years and most patients with ureteral colic need medical care. Spontaneous passage will occur in most of these stones, associated with stone size and location. This evidence indicates that a potential benefit of MET is most likely for distal ureteral stones >5 mm.¹ The present meta-analysis is the first to evaluate the efficacy and safety of tadalafil as MET for distal ureteral calculi. The main findings are that the use of tadalafil alone or combined with tamsulosin in patients with ureteral stones results in a higher stone expulsion rate and a shorter time to stone expulsion. Also, the use of tadalafil alone or combined with tamsulosin slightly reduces the need for analgesic medication. Adverse effects were more present in the tadalafil group, however, mostly mild to moderate and did not lead to cessation of therapy.

Spontaneous passage chance of distal ureteral stones sized 5–10 mm is 53%.¹⁶ Faster stone expulsion will decrease the rate of complications, the need for invasive interventions, and eventually decrease healthcare costs. A recent study¹⁶ evaluated the efficacy of sexual intercourse in the expulsion of distal ureteral stones (5–10 mm) and found that sexual intercourse 3–4 times/week for married male patients with distal ureteral stone leads to an increase in the expulsion rate. This effect is assumed to be associated with nitric oxide released during sexual intercourse, which will be able to induce ureteral relaxation. As we know, tadalafil acts on the nitric oxide-mediated pathway of smooth muscles. A previous study¹⁷ demonstrated the role of phosphodiesterase inhibitors in relaxation of ureteral muscles in the sequence vardanafil > sildenafil > tadalafil. Basis on the aforementioned, recently, Kumar and colleagues⁸ conducted an RCT to evaluate the potential role of tadalafil in comparison with tamsulosin in ureteral stone expulsion. They found that tadalafil has shown a high ureteral stone expulsion rate and significant pain control. The results are consistent with our meta-analysis. In addition, pooled data analysis of our study showed that the combined use of tadalafil and tamsulosin results in additive favorable effects for ureteral stones compared with tamsulosin monotherapy.

PDE5Is are the first-line medication for erectile dysfunction. Hence, the prescription of tadalafil in cases of lower ureteral stones with erectile dysfunction may provide an additional advantage in the erectile function. Kc and colleagues¹³ reported that 75% patients felt a mild degree of penile tumescence after the intake of tadalafil lasting for 20–30 minutes and no patients developed priapism. Kumar and colleagues¹⁴ found that 12.9% of patients in the tadalafil plus tamsulosin group experienced improvement compared with the tamsulosin-alone group. Therefore, tadalafil is an alternative proposal for patients of lower ureteral stones with erectile dysfunction.

Although tadalafil may induce many adverse events for erectile dysfunction, compared with other PDE5Is, tadalafil 10 mg had the lowest overall rate of all adverse events.¹⁸ Tadalafil has also been approved for treatment of lower urinary tract symptoms from benign prostatic enlargement on the account of it being safe and well tolerated.¹⁹ Recent studies explored the potential role in distal ureteral stones. Our study shows that headache, dizziness, backache, and orthostatic hypotension were the most commonly reported adverse effects in patients treated with tadalafil, and abnormal ejaculation was the most commonly reported with tamsulosin; however, the differences between the two groups were not significant. In addition, even though the occurrence of drug-related adverse effects in the combination use group was higher (no statistical significance) than that in the use of tamsulosin-alone group, the most common adverse effects were mild and tolerable.

Although this study is the first meta-analysis to examine the effect of tadalafil for distal ureteral stones, several limitations should be clarified. First, although we collected all the eligible studies, only six RCT, the sample size was not large enough; this could increase the likelihood of type I and type II errors. Furthermore, well-designed, double-blinded, placebo-controlled, large-scale, multicentric RCTs are suggested to address the clinical question. Second, positive studies are more likely to be published than negative; these results might have been affected by publication bias. Third, only two studies assessed the combination therapy for ureteral stone. Therefore, future research should investigate whether combination therapy with tadalafil and tamsulosin is efficacious in these patients than monotherapy. Fourth, the absence of description of the allocation concealment in all included trails may result in some undetected bias of this study. Finally, the most included study did not assess the impact of tadalafil on the frequency of sexual intercourse of the study population, which also has a potential role in the distal ureteral stone spontaneous expulsion.

Conclusion

MET for the distal ureteral stones using tadalafil alone or combined with tamsulosin is safe, efficacious, and well tolerated. Because of limited quantity and small sample size of included studies, further well-designed, double-blinded multicentric RCTs are strongly encouraged to address the clinical question.

Footnotes

Acknowledgments

This work was collectively supported by grant from National Natural Science Foundation of China (No. 81270841). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article.

Author Disclosure Statement

No competing financial interests exist.

Abbreviations Used

References

Turk

, Petrik

, Sarica

, et al. EAU guidelines on interventional treatment for urolithiasis. Eur Urol, 2016; 69:475–482.

Loftus

, Nyame

, Hinck

, Greene

, Chaparala

, Alazem

, Monga

. Medical expulsive therapy is underused for the management of renal colic in the emergency setting. J Urol, 2016; 195(4 Pt 1):987–991.

Campschroer

, Zhu

, Duijvesz

, Grobbee

, Lock

. Alpha-blockers as medical expulsive therapy for ureteral stones. Cochrane Database Syst Rev, 2014 (4):CD008509.

Seitz

, Liatsikos

, Porpiglia

, Tiselius

, Zwergel

. Medical therapy to facilitate the passage of stones: What is the evidence?. Eur Urol, 2009; 56:455–471.

Pickard

, Starr

, MacLennan

, et al. Medical expulsive therapy in adults with ureteric colic: A multicentre, randomised, placebo-controlled trial. Lancet, 2015; 386:341–349.

Iselin

, Ny

, Larsson

, et al. The nitric oxide synthase/nitric oxide and heme oxygenase/carbon monoxide pathways in the human ureter. Eur Urol, 1998; 33:214–221.

Yucel

, Baskin

. Neuroanatomy of the ureterovesical junction: Clinical implications. J Urol, 2003; 170:945–948.

Kumar

, Jayant

, Agrawal

, Singh

, Agrawal

, Parmar

. Role of tamsulosin, tadalafil, and silodosin as the medical expulsive therapy in lower ureteric stone: A randomized trial (a pilot study). Urology, 2015; 85:59–63.

Shokeir

, Tharwat

, Abolazm

, Harraz

. Sildenafil citrate as a medical expulsive therapy for distal ureteric stones: A randomised double-blind placebo-controlled study. Arab J Urol, 2016; 14:1–6.

10.

Jadad

, Moore

, Carroll

, Jenkinson

, Reynolds

, Gavaghan

, McQuay

. Assessing the quality of reports of randomized clinical trials: Is blinding necessary?. Control Clin Trials, 1996; 17:1–12.

11.

Abhishek

, Shashikant

, Arvind

, Ravindra

, Mahesh

. Comparison of tadalafil and tamsulosin in medical expulsive therapy for ureteric calculus: Prospective, randomized,placebo controlled study. Indian J Urol, 2015; 31:S39.

12.

Jayant

, Agrawal

. Tamsulosin versus tamsulosin plus tadalafil as medical expulsive therapy for lower ureteric stones: A randomized controlled trial. Int J Urol, 2014; 21:1012–1015.

13.

, Shrestha

, Acharya

, Basnet

, Shah

, Shrestha

. Tamsulosin versus tadalafil as a medical expulsive therapy for distal ureteral stones: A prospective randomized study. Investig Clin Urol, 2016; 75:351–356.

14.

Kumar

, Jayant

, Agrawal

, Singh

. Comparative efficacy of tamsulosin versus tamsulosin with tadalafil in combination with prednisolone for the medical expulsive therapy of lower ureteric stones: A randomized trial. Korean J Urol, 2014; 55:196–200.

15.

Puvvada

, Mylarappa

, Aggarwal

, Patil

, Joshi

, Desigowda

. Comparative efficacy of tadalafil versus tamsulosin as the medical expulsive therapy in lower ureteric stone: A prospective randomized trial. Cent European J Urol, 2016; 69:178–182.

16.

Abdel-Kader

. Evaluation of the efficacy of sexual intercourse in expulsion of distal ureteric stones. Int Urol Nephrol. 2017; 49:27–30.

17.

Gratzke

, Uckert

, Kedia

, et al. In vitro effects of PDE5 inhibitors sildenafil, vardenafil and tadalafil on isolated human ureteral smooth muscle: A basic research approach. Urol Res, 2007; 35:49–54.

18.

Chen

, Staubli

, Schneider

, Kessels

, Ivic

, Bachmann

, Kessler

. Phosphodiesterase 5 inhibitors for the treatment of erectile dysfunction: A trade-off network meta-analysis. Eur Urol, 2015; 68:674–680.

19.

Gacci

, Andersson

, Chapple

, et al. Latest evidence on the use of phosphodiesterase type 5 inhibitors for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. Eur Urol, 2016; 70:124–133.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.10 MB