STONE Study – Efficacy of Tamsulosin in Ureteral Colic

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.

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

Size of Stone (mm)	Tamsulosin	Placebo
0 – 5	56.4%	51.7%
> 5	31.4%	34.4%

• 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)

Other Issues

• 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.

Author's 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 Impact To 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.

Read More

• EM Lit of Note: Another Failure for Tamsulosin
• EM Lit of Note: Finally, an End to Tamsulosin for Renal Colic?
• REBEL EM: Does Use of Tamsulosin in Renal Colic Facilitate Stone Passage?
• Core EM: Medical Expulsive Therapy (MET) in Renal Colic
• Core EM: Use of Alpha Blockers in Ureteric Colic – Systematic Review + Meta-Analysis

References :

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