Can Tamsulosin Get That STONE to Drop?

Written by Anand Swaminathan REBEL EM Medical Category: Renal and Genitourinary

Background: Ureteric (renal) colic is a common, painful condition encountered in the Emergency Department (ED). Sustained contraction of smooth muscle in the ureter as a kidney stone passes the length of the ureter leads to pain. The majority of stones will pass spontaneously (i.e. without urologic intervention). For over a decade, calcium channel blockers (i.e. nifedipine) and, more commonly, alpha adrenoreceptor antagonists (i.e. tamsulosin) have been employed in the treatment of ureteral colic for their potential ability to increase stone passage, reduce pain medication use and reduce urologic interventions. These interventions were mostly based on poor methodologic studies and meta-analyses of these flawed studies (Hollingsworth 2016)

Over the past 3-4 years, a small number of higher-quality RCTs have been published (Ferre 2009, Pickard 2015, Furyk 2016). These studies have demonstrated a lack of benefit for routine use of alpha blockers. However, secondary outcomes suggest a possible benefit in larger stones (> 6 mm). In spite of recent multiple studies, the use of alpha blockers remains an area of active debate.

Article: Meltzer, AC et al. Effect of Tamsulosin on Passage of Symptomatic Ureteral Stones: A Randomized Clinical Trial. JAMA Intern Med 2018 PMID: 29913020

Clinical Question: Is tamsulosin effective in facilitating the ureteral stone expulsion in ED patients presenting with stones < 9 mm in diameter?

Population: Adults > 18 years of age presenting to the ED with a symptomatic urinary stone determined by computed tomography (CT) to be < 9 m in diameter and located in the ureter.

Outcomes:

Primary: Stone passage based on visualization or capture by day 28

Secondary: Stone passed on follow up CT scan, Crossover to open-label tamsulosin, time to stone passage, return to work, use of analgesic medication, hospitalization, surgical intervention and repeated ED visit for urinary stones

Intervention: Tamsulosin 0.4 mg q24

Control: Matched placebo

Design: Multicenter, randomized, double-blind, placebo-controlled study

Excluded: Patients requiring/desiring immediate surgical management, UTI, Prior GU surgery, pregnant patients, breastfeeding mothers, prior tamsulosin hypersensitivity, current use of alpha-blockers or calcium channel blockers, current use of steroids, stone > 9 mm, prior treatment for current ureteral stone, use of vardenafil (contraindication to tamsulosin), known renal insufficiency, fever > 101.5, floppy iris syndrome, planned cataract surgery within 60 days, prisoners, prior enrollment in study

Primary Results

512 patients randomized 267 patients to tamsulosin 245 patients to placebo

15 patients lost to follow up

Stone Size Mean diameter of symptomatic urinary stone was 3.8mm 26% of stones > 5 mm



Critical Findings:

Stone passage as reported by patient (Primary Outcome) Tamsulosin 49.6% vs. placebo 47.3% Relative Risk: 1.05 (95% CI 0.87 – 1.27) No statistically significant difference

There was no significant difference in any of the secondary outcomes

Passage based on symptomatic stone size (preplanned subgroup analysis) No statistically significant difference



Adverse events There was more dizziness amongst patients receiving tamsulosin Amongst males, there was a significantly higher rate of abnormalities with ejaculation in the tamuslosin arm (18.2% vs 7.4%)



Strengths:

Asks a clinically important, patient centered question

Multicenter study

Largest RCT to date on this topic

Randomization and blinding appropriately performed

Study was well protected against the risk of bias (i.e. concealed allocation, masking of patients, study personnel, and outcome assessors, intention-to-treat analysis, and near complete follow-up)

A pre-planned exploratory analysis of subgroups was also performed including size of stone and location of stone in the ureter

Baseline characteristics were similar between groups including stone size

Enrolled participants with stones in any part of the ureter to increase generalizability of study

Study in 2 phases. Phase 1 (single-center) was used to determine passage rate at 28 days in placebo arm in order to establish a target sample size to find a 15% absolute increase in primary outcome in the tamsulosin arm

Follow up to stone passage at 28 days (primary outcome) was excellent. Less than 3% of patients were lost

Almost 50% of patients (238/512) underwent repeat CT scanning at 28 days to assess for stone passage

Limitations:

The study only included patients with CT confirmed ureteral stones. This may exclude a large group of patients in whom ureteral colic was clinically suspected and the provider did not deem a CT was necessary

Study enrollment only available certain hours of the day (ranged from 60-116 hours of availability/week depending on site)

While most baseline characteristics were similar, some were not. More patients in the placebo arm had multiple stones, more patients in the tamsulosin arm had distal ureteral stones

Patients lost to follow up were excluded from the analysis. Instead, investigators could have included them with outcomes matching the null-hypothesis

Target absolute difference may have been set too high. A smaller but still clinically important difference may still be possible

Self-reported adherence to study medication was 82.9% by day 15 and 72.9% by day 28. ≈20% of study population was not using medication at 2 weeks

In cases in which there is more than one stone noted on the CT scan, the physician treating the patient will determine the likely location and dimensions of the stone causing symptoms by reviewing the patient’s ED record.

Most stones were small (75% < 5 mm)

Discussion:

A recent RDCT of ≈ 3300 patients with distal ureteral stones randomized to tamsulosin vs placebo for 4 weeks. 2/3rds of the enrolled patients had stones > 5mm in size. A higher rate of stone passage was seen with tamsulosin (86% vs 79%) for distal ureteral stones. In a subgroup analysis stones >5mm also showed statistically significant benefit with tamsulosin (85.6% vs 74.5%; OR 2.05; 95% CI 1.65 – 2.54). ( The majority of patients (≈75%) in this study had stones < 5 mm.A recent RDCT of ≈ 3300 patients with distal ureteral stones randomized to tamsulosin vs placebo for 4 weeks. 2/3rds of the enrolled patients had stones > 5mm in size.A higher rate of stone passage was seen with tamsulosin (86% vs 79%) for distal ureteral stones.In a subgroup analysis stones >5mm also showed statistically significant benefit with tamsulosin (85.6% vs 74.5%; OR 2.05; 95% CI 1.65 – 2.54). ( Ye 2017

It is important to note that the idea that larger stones will benefit is based on secondary and exploratory analyses only. Additionally, the Ye article is limited as only distal ureteral stones were included. A RDCT primarily examining larger stones is needed.

Even if larger stones will benefit from tamsulosin, the application of this information is limited as it would require us to return to a “CT all ureteral colic patients” approach to management. This would increase radiation exposure and resource utilization with only a small portion of patients benefiting.

Authors Conclusions:

“Tamsulosin did not significantly increase the stone passage rate compared with placebo. Our findings do not support the use of tamsulosin for symptomatic urinary stones smaller than 9 mm. Guidelines for medical expulsive therapy for urinary stones may need to be revised.”

Our Conclusions: We agree with the authors conclusions. This well-done, RDCT did not demonstrate an advantage to medical expulsion therapy with tamsulosin in comparison to placebo at 28 days.

Potential to Impact Current Practice: Current urology guidelines recommend the addition of tamuslosin in the treatment of ureteral colic mainly based on poor quality studies and systematic reviews and meta-analyses including these poorly done studies. This study adds to the growing, high-quality evidence that tamsulosin offers no significant benefit and further challenges current practices.

Bottom Line: Tamsulosin should not routinely be prescribed to patients with ureteral colic and, at this point, it is unclear if there is any subgroup that may benefit. There will be continued conjecture that larger stones may benefit due to inconsistency in the literature and the absence of a RDCT primarily looking at passage of larger stones.

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References:

Hollingsworth JM et al. Alpha blockers for treatment of ureteric stones: systematic review and meta-analysis. BMJ 2016. PMID: 27908918 Al-Ansari et al. Efficacy of Tamsulosin in the Management of Lower Ureteral Stones: A Randomized Double-blind Placebo-controlled Study of 100 Patients. Urology 2010; 75: 4-8. PMID: 20109697 Ferre RM et al. Tamsulosin for Ureteral Stones in the ED: a Randomized, Controlled Trial. Ann of EM 2009; 54: 432-9. PMID: 19200622 Furyk JS et al. Distal ureteric stones and tamsulosin: a double-blind, placebo-controlled, randomized, multicenter trial. Ann Emerg Med 2016; 67(1): 86-95. PMID: 26194935 Hermanns T et al. Is There a Role for Tamsulosin in the Treatment of Distal Ureteral Stones of 7 mm or less? Results of Randomised, Double-Blind, Placebo-Controlled Trial. European Urology 2009; 56(3): 407-12. PMID: 19375849 Picard R et al. Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. Lancet 2015; 386(9991): 341-9. PMID: 25998582 Segura JW et al. The American Urological Association. Ureteral Stones Clinical Guidelines Panel summary report on the management of ureteral calculi. J Urol. 1997;158(5):1915-1921. PMID: 9334635 Singh A et al. A Systemic Review of Medical Therapy to Facilitate Passage of Ureteral Calculi. Ann of EM 2007; 50: 552-63. PMID: 17681643 Vincendeau S et al. Tamsulosin hydrochloride vs Placebo for Management of Distal Ureteral Stones. Arch Intern Med 2010; 170(22): 2021-7. PMID: 21149761 Ye Z et al. Efficacy and safety of tamsulosin in medical expulsion therapy for distal ureteral stones with renal colic: a multicenter, randomized, double-blind, placebo-controlled trial. Eur Urol 2017. PMID: 29137830

Post Peer Reviewed By: Salim R. Rezaie, MD (Twitter: @srrezaie)