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Three Part Question

In [adult patients presenting to the Emergency Department with distal ureteral calculi] how does [tadalafil compared to alpha receptor blockers] increase the [time and success of spontaneous stone passage]?

Clinical Scenario

A 33-year-old patient presents to ED with a 5 mm calculus in the right distal ureter. You heard about a new type of medical expulsion therapy, tadalafil, which supposedly has a high ureteral stone expulsion rate as well as significant pain control. You wonder how it might compare to α-receptor blockers, such as tamsulosin or silodosin.

Search Strategy

Medline 1966-11/15 using OVID interface, Cochrane Library (2015), and Embase
(exp ureteral obstruction/ or exp ureteral calculi/ or exp renal colic) AND [(exp adrenergic alpha-antagonists/ or tamsulosin.mp or silodosin.mp) AND (exp phosphodiesterase-5 inhibitors/ or tadalafil.mp)]. Limit to human, English language

Search Outcome

43 studies were identified; two papers addressed the clinical question.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Kumar et al, 2015 India	Outpatients age 18 and older with a confirmed distal ureteral stone 5-10mm in size were included.	This was a three-arm, double-blind, randomized controlled trial comparing the stone expulsion rate among 270patients randomized to one of three therapies: tamsulosin 0.5mg daily (Group A), silodosin 8mg daily(Group B), and tadalafil 10mg daily(Group C).	Stone Expulsion Rate (Primary Outcome)	Patients treated with silodosin (Group B) had a higher expulsion rate than those treated with tamsulosin (Group A, 83.3% vs 64.4%, p=0.006) and tadalafil (Group C, 83.3% vs 66.67%, p=0.16). The difference between Groups A and C was not statistically significant (p=0.875).	This small pilot study was powered to detect relatively large differences between groups and thus smaller differences may have been missed. The study did not include a placebo arm. Patients with hydronephrosis were excluded, which may limit generalizability.
			Stone Expulsion Time	Group B had a shorter time to stone expulsion than Groups A (14.8 vs 16.5 days, p=0.005) and B (14.8 vs 16.2 days, p=0.013). There was no statistically significant difference in expulsion time between groups A and C (p=0.648).
			Total Analgesic Use	Group B had a lower total analgesic use (195±10.2 mg) that was significantly lower than Groups A (220±10.8 mg, p<0.001) and C (215±12.4 mg, p<0.001). Group C did have a lower total analgesic use than Group A, but this difference was not statistically significant (p=0.08).
			Pain Episodes	Group B had a statistically significant lower total episodes of pain (0.8 +/- 0.9) than Groups A (1.7+/- 1.2, p<0.001) and C (1.6 +/- 0.8, p<0.001). The difference between groups A and C were not statistically significant (p=0.07).
			Adverse Reactions	There were no statistically significant differences in adverse reactions (headache, dizziness, backache, and orthostatic hypotension) between groups. The rate of orthostatic hypotension was three times greater in Group C (10%) as compared to Group B (3.3%), however the difference was not statistically significant (p=0.08).
Jayant et al 2014 India	Outpatients age 18 and older with a confirmed distal ureteral stone 5-10mm in size were included.	This was a double-blind randomised controlled trial comparing the rate of stone expulsion among 240 patients randomised to receive either tamsulosin 0.4 mg daily alone (Group A) or tamsulosin 0.4 mg daily plus tadalafil 10 mg once daily (Group B).	Stone Expulsion Rate	Group B had a higher stone expulsion rate than Group A (83.6% vs. 65.5%, p=0.031)	Small sample size limits evaluation of possible increase in rates of adverse effects, including potentially dangerous ones such as orthostatic hypotension. This study does not address the question of whether tadalafil alone is superior to treatment with tamsulosin. Large number of exclusion criteria may limit generalisability.
			Mean Expulsion Time	Group B had a shorter expulsion time than Group A (14.9 vs. 16.7 days, p=0.003).
			Mean Analgesic Use	Group B had a lower total analgesic use than Group A (1.87 vs. 2.9, p<0.001)
			Mean Number of Colic Episodes	Group B had a lower mean number of colic episodes than Group A (0.45 vs. 1.60, p<0.001).
			Mean Number of Hospital Visits	Group B had a lower mean number of hospital visits than Group A (2.2 vs. 2.85, p=0.001).
			Adverse Effects	There was no statistically significant difference in rates of adverse effects, but there was a trend towards increased rates of adverse effects in Group B compared to Group A.

Comment(s)

α-adrenergic antagonists such as tamsulosin have been used to treat patients with renal colic based on the presumption that relaxation of ureteric smooth muscle will improve the rate of spontaneous stone expulsion. However, studies examining the efficacy of this therapy have yielded conflicting results, with a large recent randomised, controlled trial suggesting no benefit (3). Furthermore, α-adrenergic antagonists are associated with potentially significant adverse effects such as orthostatic hypotension. Tadalafil is a PDE5 inhibitor that acts on the NO/cyclic guanasine monophosphate (cGMP) pathway to increased levels of cGMP within smooth muscle cells, inducing relaxation. It has been approved for treatment of lower urinary tract symptoms from prostatic hyperplasia as well as erectile dysfunction. Its smooth muscle relaxation effects may also improve the rate of spontaneous ureteral stone expulsion, thus offering an alternative to α-adrenergic antagonists. The available literature is currently limited to two small RCTs conducted by a single research group in India. One of those trials directly compared monotherapy with tadalafil to tamsulosin and identified no significant differences between the therapies. The other trial compared a combination of tadalafil and tamsulosin to tamsulosin alone and suggested more frequent and faster stone expulsion using combination therapy. Although no statistically significant differences in adverse events were observed, the study was likely underpowered to detect differences in relatively infrequent outcomes such as orthostatic hypotension.

Clinical Bottom Line

The available literature suggests that tadalafil is neither more efficacious nor safer than tamsulosin. Combined therapy with tamsulosin and tadalafil may increase stone passage rate and decrease expulsion time relative to tamsulosin alone, however larger studies are needed to establish efficacy and safety of combination therapy.

References

1. Kumar S, Jayant K, Agrawal MM et al. 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.
2. Jayant K, Agrawal R, Agrawal S Tamsulosin versus tamsulosin plus tadalafil as medical expulsive therapy for lower ureteric stones: A randomized controlled trial. International Urology 2014;21: 1012-1015.
3. Pickard R , Starr K , MacLennan G , et al . Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. Lancet 2015:386;341–9.