It wasn’t so long ago that there was absolute consensus on the use of medical expulsive therapy (MET) for the treatment of ureterolithiasis. The 2007 American Urological Association/European Association of Urology combined guidelines decreed the use of alpha-blockers the law of the land for ureteral stones managed by observation.¹ Even as recently as 2014, the Cochrane review on the topic was unequivocally in favor of alpha-blockers for MET for ureterolithiasis.²

Now, the evidence has virtually turned on its head.

This comes as no surprise to those who have been following the tale spun by those disavowing the use of tamsulosin. The foundational medical evidence reads like a classic setup for medical reversal. When the 2014 Cochrane review was conducted, it identified 32 studies evaluating the use of MET for ureterolithiasis. Of these, only seven studies had adequate blinding to treatment for physicians and patients. Only six studies reported a mechanism for blinding group allocation. Another eight studies reported outcomes not matching their methods. Most trials involved fewer than 100 patients, were conducted in the Balkans and southeast Asia, and included sponsorship bias. Only two trials were of high-quality and prospectively registered, and these two were among those failing to show a benefit for MET.

The Latest Evidence

However, since that most recent Cochrane review, three significant, high-quality trials assessing the utility of tamsulosin for ureterolithiasis have been published. The first, published in The Lancet in 2015, tested three arms: nifedipine, tamsulosin, and placebo.³ The primary outcome was eventual need for urological intervention, not radiological stone passage. Across all three groups, approximately 20 percent of all participants ultimately underwent urological intervention, with no reliable difference between the groups. Secondary outcomes, such as use of pain medication and days until stone passage, however, relied upon patient self-reporting and were returned in only 62 percent of patients. No differences in the secondary outcomes for analgesic use, time to stone passage, and health status were seen between the three groups.

The next trial, published in the Annals of Emergency Medicine, specifically required follow-up imaging to assess for stone passage.⁴ Unfortunately, only 78 percent of those enrolled returned for the required 28-day scan, reducing the study’s statistical power. Stone passage was 87 percent in the tamulosin arm versus 82 percent with placebo, with the bulk of the observed difference coming from patients for whom stone size was greater than 5 mm. While there are threats to internal validity with this study and potential subgroups with benefit, these results still further erase the certainty of benefit associated with tamsulosin.

Third, we have another prospective trial published in JAMA Internal Medicine, this one split into two phases, an initial “patient-reported” passage phase followed by a “CT follow-up” phase.⁵ Approximately half of the 512 patients were enrolled in each phase, with the overall results broadly consistent with the other trials. Patient-reported passage was similar as were all secondary measures of resource utilization, subsequent urological intervention, and disability. There was a 6 percent absolute advantage from tamsulosin with regard to radiological evidence of stone passage during the CT follow-up phase. However, unlike the prior studies, there was no benefit observed with regard to stone passage for stones greater than 5 mm in size, and instead, the subgroup favoring tamsulosin in this cohort related to stone location. The few upper ureteral stones enrolled were observed to have a higher passage rate with tamsulosin than with placebo.

Finally, the last bit of evidence comes from a study presented at the 33rd Annual Congress of the European Association of Urology in April and is not yet available in manuscript.⁶ These authors aimed primarily to evaluate the effect of MET on stone passage specifically focused on the subgroups previously identified for possible benefit. This observational study of 3,127 patients whose stone passage was compared via multivariate analysis showed no associated benefit for MET regardless of stone size or location.

Conclusion: Limited to No Benefit from Tamsulosin

The long story made short: Any benefit from tamsulosin for ureterolithiasis is small and fleeting. When multiple trials fail to consistently show benefit from a specific treatment, this does not eliminate the possibility of a beneficial effect, but the expected effect size should be quite small. Tamsulosin and other alpha-blockers are generally well-tolerated but do have rare adverse effects, particularly in older adults. As the expected benefit diminishes, the risk-benefit ratio converges to unity and the value of this treatment vanishes.

The most recent publication from the European Association of Urology on this topic, published back in 2016, held the view that any benefit, if one were likely, would be restricted to ureteral stones greater than 5 mm in size.⁷ This is a similar conclusion to the recently updated Cochrane review.⁸ As these guidelines and reviews continue to be updated, I expect any recommendations for the use of MET to further narrow or disappear entirely. As always, generalizing aggregate data from trials to an individual clinical scenario is imprecise, and it remains reasonable to offer tamsulosin on a case-by-case basis. If any benefit is to be derived, it appears those with larger, proximal ureteral stones are the best candidates for therapy. That said, the strength of the evidence is limited, and it may be conclusively found that the use of tamsulosin has no benefit at all.

Complete the CME activity.

The opinions expressed herein are solely those of Dr. Radecki and do not necessarily reflect those of his employer or academic affiliates.

References

1. Preminger GM, Tiselius HG, Assimos DG, et al. 2007 guideline for the management of ureteral calculi. J Urol. 2007;178(6):2418-2434.
2. Campschroer T, Zhu Y, Duijvesz D, et al. Alpha-blockers as medical expulsive therapy for ureteral stones. Cochrane Database Syst Rev. 2014;(4):CD008509.
3. Pickard R, Starr K, MacLennan G, et al. Medical expulsive therapy in ad ults with ureteric colic: a multicentre, randomised, placebo-controlled trial. Lancet. 2015;386(9991):341-349.
4. Furyk JS, Chu K, Banks C, et al. Distal ureteric stones and tamsulosin: a double-blind, placebo-controlled, randomized, multicenter trial. Ann Emerg Med. 2016;67(1):86-95.e2.
5. Meltzer AC, Burrows PK, Wolfson AB, et al. Effect of tamsulosin on passage of symptomatic ureteral stones: a randomized clinical trial [published online ahead of print June 18, 2018]. JAMA Intern Med.
6. Shah TT, Gao C, O’Keefe A, et al. The effects of medically expulsive therapy (MET) on spontaneous stone passage (SSP) in patients presenting with acute ureteric colic. J Urol. 2018;199(4S):e387-e388.
7. Türk C, Knoll T, Seitz C, et al. Medical expulsive therapy for ureterolithiasis: the EAU recommendations in 2016. Eur Urol. 2017;71(4):504-507.
8. Campschroer T, Zhu X, Vernooij RW, et al. Alpha-blockers as medical expulsive therapy for ureteral stones. Cochrane Database Syst Rev. 2018;4:CD008509.