Knowledge Translation: SUSPEND(ing) medical expulsive therapy belief

In Knowledge Translation by Jared Paty1 Comment

Editor’s Note: This week we are fortunate to get a great review of the recent SUSPEND article on medical expulsive therapy (MET) in the setting ofunnamed acute renal colic. We are doubly lucky to have the post reviewed by a urologist, Dr. Michael Leveridge (who not only is a great surgeon but knows how to rock a moustache). He reveals some of the thoughts of colleagues who participated in the #urojc twitter journal club on the article. This kind of cross-disciplinary collaboration is something we are looking forward to doing more of at BoringEM in the year to come! 

Citation

Pickard, R., Starr, K., MacLennan, G., Lam, T., Thomas, R., Burr, J., … & McClinton, S. (2015). Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. The Lancet.

Background

Renal colic is a common cause for emergency room visits, with men and women having a lifetime incidence of 12% and 7% respectively [1]. Pain in these patients is theorized to be a result of increased pressure within the urinary tract proximal to the stone, causing an increase in peristalsis and smooth muscle spasm in the ureter and the release of pain mediators such as prostaglandin from distension of the renal capsule. [2] In addition to pain management, selective alpha-1 receptor antagonists such as tamsulosin and calcium channel blockers such as nifedipine are widely used off-label as medical expulsive therapy (MET) for ureteral stones. The rationale for this use is the inhibition of ureter spasm, which allows for more efficient peristalsis, relaxation of the ureterovesical junction and faster stone clearance. Tamsulosin achieves this through blockade of alpha-1-adrenergic receptors, which are highly concentrated in the distal ureters. Similarly, CCBs (mostly nifedipne) inhibit calcium influx, thus preventing smooth muscle contraction in the ureter wall. [2]

The evidence behind this practice, however, is highly controversial. A number of systematic reviews and meta-analyses have concluded that MET is effective, resulting in greater rates of stone expulsion, thus the use of MET for renal colic is recommended. [3,4] These reviews have been criticized for the inclusion of poor quality, heterogeneous studies that have small sample sizes, inadequate blinding, and poor methodological design. [5,6,7] Given the lack of high quality, blinded, randomized controlled trials assessing the effects of MET, the SUSPEND trial was initiated.

Clinical Question

Does either tamsulosin or nifedipine increase the likelihood of spontaneous stone passage compared to placebo, and if so, which is more effective?

Population18-65 years of age presenting with ureteric colic and a stone of =<10mm confirmed by CT KUB.

*exclusions: those needing immediate intervention, septic patients, eGFR <30mL/min, already on or unable to take alpha-blocker or calcium channel stabilizer. Over 65 excluded due to need for titration of nifedipine dosing.
InterventionSelf administration of either tamsulosin 400 mcg or nifedipine 30 mg orally once daily until spontaneous passage occurred, need for intervention was agreed upon, or for 4 weeks, whichever came first.
ControlPlacebo
Outcome1. Spontaneous passage of stone in 4 weeks, defined as absence of need for intervention to assist passage.

2. 1. Number of days of analgesic use, visual analogue pain scale at 4 weeks, time to stone passage, health status, safety

Results

n=1167 with 31 lost to follow-up

Primary Outcome

The spontaneous passage of stones within 4 weeks  occurred in 81% of the tamsulosin group, 80% in the nifedipine group and 80% in the placebo group.

InterventionAdjusted Odds Ratio (95% CI)p-value
MET vs placebo1.06 (0.70-1.60)0.78
Tamsulosin vs placebo1.09 (0.67-1.78)0.73
Nifedipine vs placebo1.03 (0.68-1.58)0.88

Secondary Outcomes

Days of analgesic use

  • Mean: Tamsulosin 11.6 days vs nifedipine 10.7 days vs placebo 10.5 days
  • MET vs placebo difference = 0.6 (-1.6-2.8); p=0.45

VAS Pain Scale at 4 weeks

  • MET vs placebo difference 0 (-0.4 to 0.4); p=0.96

Time to Stone Passage

  • Mean time: Tamsulosin 16.5 days vs nefedipine 16.2 days vs placebo 15.9 days
  • Adjusted MET vs. placebo difference 0.6 (-2.6 to 4.0) days, p=0.71

Safety

  • 3 adverse reactions in the nifedipine group (flank pain/diarrhea/vomiting, malaise/chestpain/headache, severe chest pain/SOB/arm pain)
  • 1 adverse reaction in placebo group (headache/dizziness/abdominal pain)

Limitations

Urologic intervention as surrogate for efficacy:

  • The primary outcome was determined by lack of any required intervention to assist stone passage. While this is pragmatic and fits in with the study design, it is an imprecise measurement of the exact influence of MET on stone passage. While the patient-reported time to stone passage was assessed as a secondary measure (more on that below), this is an imprecise measure of stone passage following drug therapy.
  • Furthermore, 74.6% of the stones identified through the study were ≤5 mm in size, and stones of such size rarely necessitate an intervention. Thus the data should be interpreted with caution for patients with larger stones.

Secondary outcomes had low response rates (62% of participants):

  • The fact that attrition was relatively high for the 4-week follow-up survey, the collection of secondary outcome data was incomplete. Thus, secondary outcomes should be interpreted with appropriate skepticism. While the authors note there were no differences between the two groups, they noted younger people were less likely to return questionnaires, potentially introducing bias. Nonetheless, the primary outcome was well powered.

Conclusions

Author conclusions

“The results of our trial… showed that use of tamsulosin and nifedipine did not affect the proportion of patients needing further intervention to clear their stone during 4 weeks. “

“We found no evidence that the drugs reduced pain, hastened time to stone passage, or improved health state.”

Our Thoughts

Ultimately, this study generates evidence that tamsulosin or nifedipine have minimal role in the acute setting of renal colic. While there are a few arguable points regarding subgroups and statistical methodology (see discussion about this on EM Literature of Note) [8], the completion of this rigorous, high-quality study shows that benefits from the routine use of MET are insignificant.

Take Home Points

  • This blinded, randomized controlled trial indicated no benefit to the use of MET for ureteric stone, showing it to be no better than placebo at improving likelihood of stone clearance
  • This study showed no reduction in pain or decrease in time to passage as reported by patients
  • There study showed no significant benefit to using MET to improve stone clearance for stones

References

  1. Worcester EM, Coe FL. Nephrolithiasis. Prim Care. 2008;35(2):369-91, vii.
  2. Golzari SE, Soleimanpour H, Rahmani F, et al. Therapeutic approaches for renal colic in the emergency department: a review article. Anesth Pain Med. 2014;4(1):e16222.
  3. Lu Z et al. Tamsulosin for ureteral stones: a systematic review and meta-analysis of a randomized control trial. Urologia Internationalis 2012; 89(1):107-115
  4. Campschroer T, Zhu Y, Duijvesz D, Grobbee DE, Lock MTWT. Alpha-blockers as medical expulsive therapy for ureteral stones. Cochrane Database of Systematic Reviews 2014, Issue 4.
  5. Available at: http://www.emlitofnote.com/2014/04/sadly-inadequate-cochrane-review-of.html. Accessed September 9, 2015.
  6. Available at: http://rebelem.com/use-tamsulosin-renal-colic-facilitate-stone-passage/?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+REBELEM+%28R.E.B.E.L.+EM%29. Accessed September 9, 2015.
  7. Available at: http://thesgem.com/2014/04/sgem71-like-a-rolling-kidney-stone-a-systematic-review-of-renal-colic/. Accessed September 9, 2015.
  8. Available at: http://www.emlitofnote.com/2015/05/finally-end-to-tamulosin-for-renal-colic.html. Accessed September 9, 2015.

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