#6 Medication to speed up kidney stone passage

Calcium channel blockers and alpha blockers are both smooth muscle relaxants and so could theoretically relax the smooth muscle of the ureter and speed up the passage of kidney stones. Given that kidney stones can take several weeks to pass and often are rated as 10/10 pain, treatments to speed up the passage of stones would be greatly welcomed.

A Cochrane meta analysis in 2014 found 32 studies, making a total of 5864 patients with kidney stones, and showed that alpha blockers, mainly tamsulosin, increased the likelihood that a stone would pass by 4 weeks with a number needed to treat of 4. Tamsulosin was better than the calcium channel blocker, nifedipine, in this review.

The problem is that the 32 trials in the review are of fairly poor quality. They were small, the largest having 150 patients and the others have less or much less than that. And most of the studies had an unclear risk of selection bias, which as we discussed last week, is one of the most important measures of trial quality. A lot of the trials also didn’t do any blinding.

Since this Cochrane review a very high quality randomised controlled trial has been published in The Lancet in 2015. They randomised 1, 167 patients with kidney stones less than 10mm to one of three group: One groups were given the alpha-blocker tamsulosin at 400micrograms per day, the second group got the calcium channel blocker nifedipine at 30mg per day and the third group got a daily placebo.

On average, these patients were 43 years old, 80% were men and 20% were women. The average stone size was 4.5 mm, though 25% were greater than 5mm.

The primary outcome was how many people had passed their stone by 4 weeks in each group.

The results were very different to the Cochrane review. They showed no difference – about 80% had passed the stone by 4 weeks no matter whether they got tamsulosin, nifedipine or placebo. There was a 10% absolute increase in stone passage with tamsulosin if the stone was greater than 5mm. It went from 61% with placebo and nifedipine to 71% with tamsulosin, though this was not statistically significant. You could argue that as only 25% of the patients in the trial had stones bigger than 5mm, this analysis was not powered to detect a 10% difference in outcomes. This improvement in stone clearance with tamsulosin for larger stones certainly fits with what the Cochrane review had showed. What we really need now is a large, well designed study, like this one but only looking at stones greater than 5mm to see whether this holds true.

In terms of adverse events, 3 people developed serious adverse events in the nifedipine group and 1 in the placebo group. There were no serious adverse events in the tamsulosin group.  In terms of how many people stopped due to adverse events, for nifedipine the number needed to harm was 10 and for tamsulosen the number needed to harm was 25

So what do we do with all this?

We now have a very high quality, well designed trial that shows that tamsulosen and nifedipine are of no benefit in improving stone passage rates or reducing the need for some sort of intervention, but we have data from 32 other smaller and crappier studies saying that it does. Which is the better evidence – a large, well designed randomised controlled trial or a meta analysis of smaller studies?

And while this can frustrate some people I think this is the beauty of evidence based medicine. Evidence is not black and white. It’s often grey.  And we can use our own opinions or our patients opinions to guide what you do based on the scenario in front of us

You could easily argue:  1) There didn’t seem to be any major adverse events with tamsulosen, there is some evidence that it works, especially for stones greater than 5mm, it’s only for 4 weeks, maybe I’ll give it a try. Or 2) If they couldn’t find a benefit in a large well done study it probably doesn’t work.  And I guess both would be right.

It’s a beautiful thing.

What would you do if you had a kidney stone base on all this evidence? I think we can agree that there is no benefit for nifedipine but would you take tamsulosin? Say, if you had a stone greater than 5mm?

Currently, the guidelines in Europe (European Association of Urologists) and America (American Urological Association) both recommend medical expulsion therapy if the stone is less than 10mm and provided there is no indication for urgent stone removal.

The scary thing is that this is not the only example of where a meta analysis was “proved wrong” by a large, well designed randomised controlled trial. A study has found that large, definitive randomised controlled trials differ in the results of the meta-analysis that preceded it about 35% of the time.

 

References:

  1. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60933-3/abstract
  2. http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008509.pub2/full
  3. http://www.nejm.org/doi/full/10.1056/NEJM199708213370806#t=abstract
  4. Music Polyrhythmics – El Fuego

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