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NIHR Signal Two common drugs do not help more people pass kidney stones

Published on 23 May 2015

doi: 10.3310/signal-000103

This large, high quality trial found that people with a single kidney stone taking tamsulosin or nifedipine drugs for up to four weeks were no more likely to pass the stone spontaneously than those taking a placebo. This suggests that these drugs should not be offered to people with renal colic who are managed with a "watch-and-wait" approach. About 80% of participants in either arm of this trial were able to pass the stone spontaneously, without a further procedure. The prevalence of kidney stones in high income countries has increased over the last 20 years. Problems with stones were associated with 25,000 hospital admissions in England in 2012, costing £11.6 million.

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Why was this study needed?

The number of cases of kidney stone disease is rising. Lifetime risk is about 12% in men and 6% in women. Renal colic is a type of severe abdominal pain caused by kidney stones, and is a common reason for people to seek emergency care.

Two previous meta-analyses (2009 and 2012) concluded that tamsulosin and nifedipine helped people with renal colic to pass stones. However, they emphasised these results may not be reliable due to limitations in the sample size and quality of the included trials. The NIHR funded this trial called SUSPEND, to resolve the uncertainty about the benefit of tamsulosin and nifedipine in the routine care of people with renal colic. This trial set out to establish whether these drugs increased the likelihood of spontaneous stone passage, and if so, which drug was better.

What did this study do?

The NIHR funded, SUSPEND study was a randomised, placebo-controlled trial recruiting 1,167 adults with renal colic across 24 NHS hospitals. They were randomly assigned to receive up to 4 weeks' daily treatment with either tamsulosin (400 micrograms), nifedipine (30 milligrams) or placebo. The primary outcome was spontaneous stone passage by four weeks, as defined by needing no interventions to help the stone pass. Participants, clinicians and trial personnel were not aware of treatment allocation. This was a large, well designed randomised controlled trial conducted in a routine care setting which allows for direct translation of its results into standard clinical practice.

What did it find?

  • Neither drug had significant effect on the likelihood of spontaneous stone passage compared with placebo. Further intervention was not needed by 80% of the placebo group compared with 81% of the tamsulosin group (adjusted risk difference 1.3%, 95% confidence interval -5.7 to 8.3) and 80% of the nifedipine group (adjusted risk difference 0.5%, 95% CI -5.6 to 6.5).
  • There was also no significant difference in intervention rates comparing tamsulosin with nifedipine (adjusted risk difference 0.8%, 95% CI -4.5 to 6.1).
  • Results were adjusted for stone location, size and hospital.
  • There were no differences between the three groups in other outcomes: need for pain relief, time for the stone to pass, or health status of participants.

What does current guidance say on this issue?

NICE Clinical Knowledge Summaries (2015) on the management of acute renal colic states that drug treatments – "medical expulsive therapy" (MET) - 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.

Guidelines from the British Association of Urological Surgeons (2008) and the European Association of Urology (2015) also recommend that MET with tamsulosin and nifedipine can increase the likelihood of stone passage and thus reduce the need for further interventions. These drugs may be used as part of routine clinical practice but are not licensed for this particular use. This means that this is an "off-label" use.

What are the implications?

The trial was large, methodologically robust and addressed a population and decision problem representative of clinical practice. The results imply that tamsulosin and nifedipine should not be offered to people with renal colic who are managed with a “watch-and-wait” approach. Renal colic is a common and very painful condition. Drug treatments that help stone passage would still be beneficial for the 20% of people in this trial who went on for further intervention to remove the stone. Current guidance on this issue may need to be reconsidered.

Citation

Pickard R, Starr K, MacLennan G et al. Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. Lancet. 2015 May 18. [Epub ahead of print].

This project was funded by the National Institute for Health Research HTA Programme (project number 08/71/01).

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; 2008.

Bultitude M, Rees J. Management of renal colic. BMJ. 2012;345:e5499.

Campschroer T, Zhu Y, Duijvesz D, et al. Alpha-blockers as medical expulsive therapy for ureteral stones. Cochrane Database Syst Rev. 2014; (4):CD008509.

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

Seitz C, Liatsikos E, Porpiglia F, Tiselius HG, Zwergel U. Medical therapy to facilitate the passage of stones: what is the evidence? Eur Urol. 2009;56(3):455-71.

Türk C, Knoll T, Petrik A, et al. Guidelines on urolithiasis. Arnhem: European Association of Urology; 2015

Turney BW, Reynard JM, Noble JG, Keoghane SR. Trends in urological stone disease. BJU Int. 2012;109(7):1082-7.

Why was this study needed?

The number of cases of kidney stone disease is rising. Lifetime risk is about 12% in men and 6% in women. Renal colic is a type of severe abdominal pain caused by kidney stones, and is a common reason for people to seek emergency care.

Two previous meta-analyses (2009 and 2012) concluded that tamsulosin and nifedipine helped people with renal colic to pass stones. However, they emphasised these results may not be reliable due to limitations in the sample size and quality of the included trials. The NIHR funded this trial called SUSPEND, to resolve the uncertainty about the benefit of tamsulosin and nifedipine in the routine care of people with renal colic. This trial set out to establish whether these drugs increased the likelihood of spontaneous stone passage, and if so, which drug was better.

What did this study do?

The NIHR funded, SUSPEND study was a randomised, placebo-controlled trial recruiting 1,167 adults with renal colic across 24 NHS hospitals. They were randomly assigned to receive up to 4 weeks' daily treatment with either tamsulosin (400 micrograms), nifedipine (30 milligrams) or placebo. The primary outcome was spontaneous stone passage by four weeks, as defined by needing no interventions to help the stone pass. Participants, clinicians and trial personnel were not aware of treatment allocation. This was a large, well designed randomised controlled trial conducted in a routine care setting which allows for direct translation of its results into standard clinical practice.

What did it find?

  • Neither drug had significant effect on the likelihood of spontaneous stone passage compared with placebo. Further intervention was not needed by 80% of the placebo group compared with 81% of the tamsulosin group (adjusted risk difference 1.3%, 95% confidence interval -5.7 to 8.3) and 80% of the nifedipine group (adjusted risk difference 0.5%, 95% CI -5.6 to 6.5).
  • There was also no significant difference in intervention rates comparing tamsulosin with nifedipine (adjusted risk difference 0.8%, 95% CI -4.5 to 6.1).
  • Results were adjusted for stone location, size and hospital.
  • There were no differences between the three groups in other outcomes: need for pain relief, time for the stone to pass, or health status of participants.

What does current guidance say on this issue?

NICE Clinical Knowledge Summaries (2015) on the management of acute renal colic states that drug treatments – "medical expulsive therapy" (MET) - 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.

Guidelines from the British Association of Urological Surgeons (2008) and the European Association of Urology (2015) also recommend that MET with tamsulosin and nifedipine can increase the likelihood of stone passage and thus reduce the need for further interventions. These drugs may be used as part of routine clinical practice but are not licensed for this particular use. This means that this is an "off-label" use.

What are the implications?

The trial was large, methodologically robust and addressed a population and decision problem representative of clinical practice. The results imply that tamsulosin and nifedipine should not be offered to people with renal colic who are managed with a “watch-and-wait” approach. Renal colic is a common and very painful condition. Drug treatments that help stone passage would still be beneficial for the 20% of people in this trial who went on for further intervention to remove the stone. Current guidance on this issue may need to be reconsidered.

Citation

Pickard R, Starr K, MacLennan G et al. Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. Lancet. 2015 May 18. [Epub ahead of print].

This project was funded by the National Institute for Health Research HTA Programme (project number 08/71/01).

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; 2008.

Bultitude M, Rees J. Management of renal colic. BMJ. 2012;345:e5499.

Campschroer T, Zhu Y, Duijvesz D, et al. Alpha-blockers as medical expulsive therapy for ureteral stones. Cochrane Database Syst Rev. 2014; (4):CD008509.

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

Seitz C, Liatsikos E, Porpiglia F, Tiselius HG, Zwergel U. Medical therapy to facilitate the passage of stones: what is the evidence? Eur Urol. 2009;56(3):455-71.

Türk C, Knoll T, Petrik A, et al. Guidelines on urolithiasis. Arnhem: European Association of Urology; 2015

Turney BW, Reynard JM, Noble JG, Keoghane SR. Trends in urological stone disease. BJU Int. 2012;109(7):1082-7.

Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial

Published on 23 May 2015

Pickard, R.,Starr, K.,MacLennan, G.,Lam, T.,Thomas, R.,Burr, J.,McPherson, G.,McDonald, A.,Anson, K.,N'Dow, J.,Burgess, N.,Clark, T.,Kilonzo, M.,Gillies, K.,Shearer, K.,Boachie, C.,Cameron, S.,Norrie, J.,McClinton, S.

Lancet , 2015

BACKGROUND: Meta-analyses of previous randomised controlled trials concluded that the smooth muscle relaxant drugs tamsulosin and nifedipine assisted stone passage for people managed expectantly for ureteric colic, but emphasised the need for high-quality trials with wide inclusion criteria. We aimed to fulfil this need by testing effectiveness of these drugs in a standard clinical care setting. METHODS: For this multicentre, randomised, placebo-controlled trial, we recruited adults (aged 18-65 years) undergoing expectant management for a single ureteric stone identified by CT at 24 UK hospitals. Participants were randomly assigned by a remote randomisation system to tamsulosin 400 mug, nifedipine 30 mg, or placebo taken daily for up to 4 weeks, using an algorithm with centre, stone size (</=5 mm or >5 mm), and stone location (upper, mid, or lower ureter) as minimisation covariates. Participants, clinicians, and trial personnel were masked to treatment assignment. The primary outcome was the proportion of participants who did not need further intervention for stone clearance within 4 weeks of randomisation, analysed in a modified intention-to-treat population defined as all eligible patients for whom we had primary outcome data. This trial is registered with the European Clinical Trials Database, EudraCT number 2010-019469-26, and as an International Standard Randomised Controlled Trial, number 69423238. FINDINGS: Between Jan 11, 2011, and Dec 20, 2013, we randomly assigned 1167 participants, 1136 (97%) of whom were included in the primary analysis (17 were excluded because of ineligibility and 14 participants were lost to follow-up). 303 (80%) of 379 participants in the placebo group did not need further intervention by 4 weeks, compared with 307 (81%) of 378 in the tamsulosin group (adjusted risk difference 1.3% [95% CI -5.7 to 8.3]; p=0.73) and 304 (80%) of 379 in the nifedipine group (0.5% [-5.6 to 6.5]; p=0.88). No difference was noted between active treatment and placebo (p=0.78), or between tamsulosin and nifedipine (p=0.77). Serious adverse events were reported in three participants in the nifedipine group (one had right loin pain, diarrhoea, and vomiting; one had malaise, headache, and chest pain; and one had severe chest pain, difficulty breathing, and left arm pain) and in one participant in the placebo group (headache, dizziness, lightheadedness, and chronic abdominal pain). INTERPRETATION: Tamsulosin 400 mug and nifedipine 30 mg are not effective at decreasing the need for further treatment to achieve stone clearance in 4 weeks for patients with expectantly managed ureteric colic. FUNDING: UK National Institute for Health Research Health Technology Assessment Programme.

In high income countries like Sweden, Canada or the US, kidney stones are common, affecting more than 10% of the population. A recent study found that between 2009 and 2010 there were over 83,000 recorded hospital episodes of kidney stones in England. This represents a 63% increase over 10 years. Kidney stones are more common in men than women, and recurrence rates are high. Complications can include narrowing and obstruction of the tube connecting the kidney to the bladder (ureteric stricture), irreversible kidney damage, and life threatening infection.

Author Commentary

The SUSPEND study was commissioned to determine whether the use of the oral drugs nifedipine and tamsulosin were effective at increasing the chance that people with ureteric colic would spontaneously pass their stone without the need for further intervention. The trial was carried out in 24 centres across the UK NHS with wide inclusion criteria related to existing clinical care guidance to ensure generalisability of the findings. Neither drug resulted in a reduction in need for intervention compared to placebo nor was this finding changed when relevant factors such as stone size and stone location were taken into account. This trial has been definitive in ruling out any clinically significant benefit of tamsulosin and nifedipine at the dosage and duration used for patients with ureteric colic. In our judgment these drugs should not continue to be offered or used for this off-label indication.

Professor Sam McClinton, Consultant Urologist NHS Grampian & Professor of Urology, University of Aberdeen