NIHR Signal Drugs may help people pass larger kidney stones

Published on 30 May 2017

Three-quarters of people with a large (more than 5mm) single kidney stone will pass the stone within six weeks if they take an alpha-blocker. About half of those taking placebo or no treatment pass the stone in the same period.

Renal colic is a severe pain in the flank and is usually caused by kidney stones when they move into the ureter, the tube between the kidney and bladder. Most small stones pass into the urine without treatment.

Evidence for drug treatment is contradictory. A recent UK trial did not find that drugs made any difference to who went on to require a surgical intervention. This review suggests that people with larger stones of more than 5mm may benefit from alpha-blockers. However, there are some limitations of the review in terms of applicability to the UK.

If a sized based approach is used to inform treatment, this will require a scan rather than ultrasound in order to measure stone size accurately.

Drugs may help people pass larger kidney stones

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Why was this study needed?

Kidney stones affect 2 to 3% of people in the UK and the rates are increasing. There were over 21,000 hospital admissions in England in 2014/15 for kidney stones that had entered the ureter.

There is conflicting evidence of the effectiveness of drugs to help pass stones and decrease the duration of symptoms, complications or need for more invasive interventions. Two meta-analyses in 2009 and 2012 concluded they did, although emphasized the results may not be reliable due to study limitations. In 2015, SUSPEND, a large high quality UK trial found two commonly used drugs (the alpha-blocker tamsulosin and the calcium-channel blocker nifedipine) had no benefit compared to placebo. However, concerns were raised that effectiveness may be dependent on the size and location of the stone and this was not analysed. 

This review set out to review all studies into this question and to establish whether alpha-blockers increase the likelihood of stone passage, and if benefit varied by stone size or location.

What did this study do?

This systematic review and meta-analysis included 55 trials of 5,990 people with renal colic.

Trials compared alpha-blockers with placebo or no treatment for between one and six weeks. Alpha-blockers used were tamsulosin (40 trials), alfuzosin (six trials), silodosin (six trials), terazosin (four trials), doxazosin (four trials) and naftopidil (three trials).

SUSPEND was included and was the only trial from the UK to address this issue. The majority of the other trials were from countries in Asia where only around 50% of people pass stones spontaneously; this may reduce the application of these review findings to the UK.

Few studies concealed the allocation from investigators adequately and this may have led to bias that might reduces our confidence in the findings. The differences between the trials in types of drugs used could also have meant trials were too varied to pool together. After analysis, the researchers thought that neither of these problems was important enough to reduce our confidence in the overall direction of their findings.

What did it find?

  • People taking alpha-blockers were 49% more likely to pass the stone compared with placebo or no treatment (risk ratio [RR] 1.49, 95% confidence interval [CI] 1.39 to 1.61). Stone passage occurred in 75.8% of people treated with alpha-blockers compared to 48.4% with placebo or no treatment. Further analyses indicated no difference between alpha-blockers.
  • There was a 57% increased chance of stone passage for people with large stones of 5mm to 10mm treated with alpha-blockers compared to placebo or no treatment (RR 1.57, 95% CI 1.17 to 2.27).
  • There was no benefit of treatment with an alpha-blocker compared to placebo or no treatment for people with small stones of less than 5mm.
  • People receiving alpha-blockers had a 56% lower risk of surgical intervention than those receiving placebo or no treatment (RR 0.44, 95% CI 0.37 to 0.52).
  • There were no differences between the groups in adverse events, which were uncommon.

What does current guidance say on this issue?

NICE Clinical Knowledge Summaries (2015) on the management of acute renal colic states that drug treatments with either an alpha-blocker such as tamsulosin or a calcium channel blocker such as nifedipine may be used to try and facilitate spontaneous stone passage.

The European Association of Urology (updated in 2017) also recommends an alpha-blocker or calcium-channel blocker. They say this increases the likelihood of stone passage, reducing the need for further interventions. They are particularly recommended for stones larger than 5mm and people who are otherwise medically stable.

These drugs are not licensed for this condition, which means that this is an “off-label” use.

What are the implications?

The evidence for using alpha-blockers for people in the UK with renal colic remains uncertain. On balance, it is likely that alpha-blockers help clear larger stones (more than 5mm) in uncomplicated cases and lower the rates of surgical intervention. However, the improvement in expulsion rate was smaller in the better quality trials such as the one conducted in a UK population.

If a size based approach is used to inform the decision, this will require imaging which is better than ultrasound for measuring stone size. CT scans are not currently routine practice despite guidelines recommending their use. This may have cost and workforce implications.

Citation and Funding

Hollingsworth JM, Canales BK, Rogers MA, et al. Alpha blockers for treatment of ureteric stones: systematic review and meta-analysis. BMJ. 2016; 355:i6112.

No funding information was provided for this study.

Bibliography

British Association of Urological Surgeons. Guidelines for acute management of first presentation of renal/ ureteric lithiasis. London: The British Association of Urological Surgeons Limited; 2012.

NICE CKS. Renal or ureteric colic – acute. London: National Institute for Health and Care Excellence Clinical Knowledge Summaries; 2015.

Pickard R, Starr K, MacLennan G et al. Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. Lancet. 2015;386(9991):341-9.

Türk C, Knoll T, Petrik A, et al. Guidelines on urolithiasis. Arnhem: European Association of Urology; 2017.

Why was this study needed?

Kidney stones affect 2 to 3% of people in the UK and the rates are increasing. There were over 21,000 hospital admissions in England in 2014/15 for kidney stones that had entered the ureter.

There is conflicting evidence of the effectiveness of drugs to help pass stones and decrease the duration of symptoms, complications or need for more invasive interventions. Two meta-analyses in 2009 and 2012 concluded they did, although emphasized the results may not be reliable due to study limitations. In 2015, SUSPEND, a large high quality UK trial found two commonly used drugs (the alpha-blocker tamsulosin and the calcium-channel blocker nifedipine) had no benefit compared to placebo. However, concerns were raised that effectiveness may be dependent on the size and location of the stone and this was not analysed. 

This review set out to review all studies into this question and to establish whether alpha-blockers increase the likelihood of stone passage, and if benefit varied by stone size or location.

What did this study do?

This systematic review and meta-analysis included 55 trials of 5,990 people with renal colic.

Trials compared alpha-blockers with placebo or no treatment for between one and six weeks. Alpha-blockers used were tamsulosin (40 trials), alfuzosin (six trials), silodosin (six trials), terazosin (four trials), doxazosin (four trials) and naftopidil (three trials).

SUSPEND was included and was the only trial from the UK to address this issue. The majority of the other trials were from countries in Asia where only around 50% of people pass stones spontaneously; this may reduce the application of these review findings to the UK.

Few studies concealed the allocation from investigators adequately and this may have led to bias that might reduces our confidence in the findings. The differences between the trials in types of drugs used could also have meant trials were too varied to pool together. After analysis, the researchers thought that neither of these problems was important enough to reduce our confidence in the overall direction of their findings.

What did it find?

  • People taking alpha-blockers were 49% more likely to pass the stone compared with placebo or no treatment (risk ratio [RR] 1.49, 95% confidence interval [CI] 1.39 to 1.61). Stone passage occurred in 75.8% of people treated with alpha-blockers compared to 48.4% with placebo or no treatment. Further analyses indicated no difference between alpha-blockers.
  • There was a 57% increased chance of stone passage for people with large stones of 5mm to 10mm treated with alpha-blockers compared to placebo or no treatment (RR 1.57, 95% CI 1.17 to 2.27).
  • There was no benefit of treatment with an alpha-blocker compared to placebo or no treatment for people with small stones of less than 5mm.
  • People receiving alpha-blockers had a 56% lower risk of surgical intervention than those receiving placebo or no treatment (RR 0.44, 95% CI 0.37 to 0.52).
  • There were no differences between the groups in adverse events, which were uncommon.

What does current guidance say on this issue?

NICE Clinical Knowledge Summaries (2015) on the management of acute renal colic states that drug treatments with either an alpha-blocker such as tamsulosin or a calcium channel blocker such as nifedipine may be used to try and facilitate spontaneous stone passage.

The European Association of Urology (updated in 2017) also recommends an alpha-blocker or calcium-channel blocker. They say this increases the likelihood of stone passage, reducing the need for further interventions. They are particularly recommended for stones larger than 5mm and people who are otherwise medically stable.

These drugs are not licensed for this condition, which means that this is an “off-label” use.

What are the implications?

The evidence for using alpha-blockers for people in the UK with renal colic remains uncertain. On balance, it is likely that alpha-blockers help clear larger stones (more than 5mm) in uncomplicated cases and lower the rates of surgical intervention. However, the improvement in expulsion rate was smaller in the better quality trials such as the one conducted in a UK population.

If a size based approach is used to inform the decision, this will require imaging which is better than ultrasound for measuring stone size. CT scans are not currently routine practice despite guidelines recommending their use. This may have cost and workforce implications.

Citation and Funding

Hollingsworth JM, Canales BK, Rogers MA, et al. Alpha blockers for treatment of ureteric stones: systematic review and meta-analysis. BMJ. 2016; 355:i6112.

No funding information was provided for this study.

Bibliography

British Association of Urological Surgeons. Guidelines for acute management of first presentation of renal/ ureteric lithiasis. London: The British Association of Urological Surgeons Limited; 2012.

NICE CKS. Renal or ureteric colic – acute. London: National Institute for Health and Care Excellence Clinical Knowledge Summaries; 2015.

Pickard R, Starr K, MacLennan G et al. Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. Lancet. 2015;386(9991):341-9.

Türk C, Knoll T, Petrik A, et al. Guidelines on urolithiasis. Arnhem: European Association of Urology; 2017.

Alpha blockers for treatment of ureteric stones: systematic review and meta-analysis

Published on 3 December 2016

Hollingsworth, J. M.,Canales, B. K.,Rogers, M. A.,Sukumar, S.,Yan, P.,Kuntz, G. M.,Dahm, P.

Bmj Volume 355 , 2016

OBJECTIVE: To investigate the efficacy and safety of alpha blockers in the treatment of patients with ureteric stones. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Cochrane Central Register of Controlled Trials, Web of Science, Embase, LILACS, and Medline databases and scientific meeting abstracts to July 2016. REVIEW METHODS: Randomized controlled trials of alpha blockers compared with placebo or control for treatment of ureteric stones were eligible. : Two team members independently extracted data from each included study. The primary outcome was the proportion of patients who passed their stone. Secondary outcomes were the time to passage; the number of pain episodes; and the proportions of patients who underwent surgery, required admission to hospital, and experienced an adverse event. Pooled risk ratios and 95% confidence intervals were calculated for the primary outcome with profile likelihood random effects models. Cochrane Collaboration's tool for assessing risk of bias and the GRADE approach were used to evaluate the quality of evidence and summarize conclusions. RESULTS: 55 randomized controlled trials were included. There was moderate quality evidence that alpha blockers facilitate passage of ureteric stones (risk ratio 1.49, 95% confidence interval 1.39 to 1.61). Based on a priori subgroup analysis, there seemed to be no benefit to treatment with alpha blocker among patients with smaller ureteric stones (1.19, 1.00 to 1.48). Patients with larger stones treated with an alpha blocker, however, had a 57% higher risk of stone passage compared with controls (1.57, 1.17 to 2.27). The effect of alpha blockers was independent of stone location (1.48 (1.05 to 2.10) for upper or middle stones; 1.49 (1.38 to 1.63) for lower stones). Compared with controls, patients who received alpha blockers had significantly shorter times to stone passage (mean difference -3.79 days, -4.45 to -3.14; moderate quality evidence), fewer episodes of pain (-0.74 episodes, -1.28 to -0.21; low quality evidence), lower risks of surgical intervention (risk ratio 0.44, 0.37 to 0.52; moderate quality evidence), and lower risks of admission to hospital (0.37, 0.22 to 0.64; moderate quality evidence). The risk of a serious adverse event was similar between treatment and control groups (1.49, 0.24 to 9.35; low quality evidence). CONCLUSIONS: Alpha blockers seem efficacious in the treatment of patients with ureteric stones who are amenable to conservative management. The greatest benefit might be among those with larger stones. These results support current guideline recommendations advocating a role for alpha blockers in patients with ureteric stones. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration No CRD42015024169.

Expert commentary

The pain of renal colic is described as the worst any man or woman can experience. Alpha-blockers relax smooth muscle and are prescribed to improve urine flow in men with prostate problems, but they have also been used ‘off licence’ to increase stone passage in patients with renal colic.

This comprehensive review shows us that prescribing alpha-blockers in patients with stones 5mm or larger will increase the likelihood of stone passage, reducing the need for surgery and readmissions to hospital. This does not apply universally, and for smaller stones they are a waste of time, so check the stone size.

Mr Trevor J Dorkin, Consultant Urological Surgeon at Newcastle Urology, The Freeman Hospital, Newcastle upon Tyne