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The Role of Medical Expulsive Therapy for Ureteral Stones: Against MET
EUF-292; No. of Pages 2 E U R O P E A N U R O L O G Y F O C U S X X X ( 2 0 17 ) X X X – X X X
available at www.sciencedirect.com journal homepage: www.europeanurology.com/eufocus
Point of Focus Debate: Against
The Role of Medical Expulsive Therapy for Ureteral Stones: Against Jacob M. Patterson a,*, Oliver J. Wiseman b a
Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK; b Cambridge University Hospitals NHS Trust, Cambridge, UK
The use of a-adrenoceptor antagonists, in particular tamsulosin, has been popularised as medical expulsive therapy (MET) in the management of ureteric stones as a result of the widely referenced meta-analyses by Hollingsworth et al. [1] and a more extensive study by Seitz et al. [2], which has also been widely used since 2009 as a basis for guidelines on this topic [3]. Their conclusions, and those of subsequent meta-analyses, included the importance of future goodquality randomised controlled trials (RCTs), as most of the studies in the meta-analysis were small and of poor methodological quality. In the Seitz meta-analysis, only 14/ 47 studies had a Jadad score of 3, with moderate heterogeneity and mild publication bias. Different a-blockers and doses were used, and different adjunctive medications. The authors also concluded: “The vast majority of randomized studies incorporated into the present systematic review are small, single-centre studies, limiting the strength of our conclusions”. Data heterogeneity is the biggest challenge to these meta-analyses; it is well understood that small, single-centre RCTs tend to overestimate treatment effects, irrespective of bias, and meta-analysis of such studies amplifies this effect. To address issues arising from criticised meta-analyses, Pickard and colleagues [4] published in 2015 a report on their RCT, the SUSPEND study, incorporating nearly 1200 patients from 24 UK centres. This large, well-powered, well-designed, and robust study showed no statistical difference between placebo and either tamsulosin or nifedipine in terms of the primary study endpoint. Approximately 80% of the patients in each group needed no further intervention for their stones at 4 wk, which represents a reasonable and highly pragmatic surrogate for stone passage. Extensive subgroup analysis of the data also failed to show any difference between active treatment and placebo for
stones, irrespective of size or anatomical stone location within the ureter. The SUSPEND study was criticised, however, for its lack of confirmation of stone passage with, for example, computed tomography (CT) or kidneyureter-bladder X-ray, and for its apparently high rate of non-intervention in the placebo arm. Another recent study looking specifically at MET for distal ureteral stones by Furyk et al. [5] came to similar conclusions to those for SUSPEND, showing similarly high stone passage rates of 87% with tamsulosin compared with 81.9% for placebo, but no differences in the time to stone passage, analgesic requirements, or need for subsequent intervention. This study also used radiological rather than clinical criteria (CT-confirmed passage of stone) to assess the endpoints, affirming the pragmatism of SUSPEND. It is interesting, therefore, that the American Urological Association urolithiasis guidelines [6] included the Furyk paper but declined to include SUSPEND owing to its apparently high non-intervention rate compared with the published literature, even though these rates are similarly high in both papers. Another RCT by Sur et al. [7] comparing the effects of silodosin, a newer a1a adrenoceptor antagonist, against placebo again showed no difference in primary endpoint of enhanced rates of stone passage (52% with silodosin vs 44% for placebo; p = 0.2). This study showed statistical significance for distal ureteral stones (p < 0.01), but this was based on subgroup analysis in a study not powered to show such a difference, so meaningful conclusions are hard to draw. It is challenging as a practicing clinician, therefore, to know what to believe, and more importantly what to tell our patients to allow the best treatment choices. Guidelines, meta-analyses, and large systematic reviews support the use of MET, yet good-quality RCTs tell us that there is little or
* Corresponding author. Sheffield Teaching Hospitals NHS Foundation Trust, Department of Urology, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, UK. Tel.: +44 77 75930906; fax: +44 114 2798318. E-mail address: [email protected] (J.M. Patterson). http://dx.doi.org/10.1016/j.euf.2017.02.013 2405-4569/© 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Patterson JM, Wiseman OJ, The Role of Medical Expulsive Therapy for Ureteral Stones: Against. Eur Urol Focus (2017), http://dx.doi.org/10.1016/j.euf.2017.02.013
EUF-292; No. of Pages 2 2
E U R O P E A N U R O L O G Y F O C U S X X X ( 2 0 17 ) X X X – X X X
no evidence to support the ongoing use of off-licence medications with their attending (albeit modest) risks and cost concerns. Sylvester and colleagues [8] have recently addressed this issue, debating the conflict in general between systematic reviews and RCTs and focusing specifically on the evidence in this field. As well as highlighting the advantages of good RCTs, including minimisation of bias and ability to answer specific questions through good design, their conclusion was that the SUSPEND trial [4] may present better quality of evidence in this field as opposed to the meta-analyses, including the Seitz study [2]. They also highlighted the importance of guideline developers using all the tools to assess methodological quality of systematic reviews and meta-analysis to ensure their outcomes are robust, before assigning them a higher level of evidence than single RCTs. In conclusion, the findings of the high-quality SUSPEND study, with its pragmatic primary endpoint that mirrors contemporary clinical practice, are more persuasive than meta-analyses based on poor-quality, inadequately powered studies that are subject to publication bias. We therefore no longer advocate the use of MET in our patients. We also believe that the European Association of Urology guidelines group should believe the findings of the SUSPEND study too, and stop advocating the use of MET.
Coloplast, EMS, and Olympus, has received a research grant from Porges
Conflicts of interest: Oliver J. Wiseman is a consultant for Boston
trials and meta-analyses disagree. Eur Urol. In press. doi:10.1016/j.
Scientific and Porges Coloplast. a speaker for Boston Scientific, Porges
eururo.2016.11.023
Coloplast, and is a director of UroScreen. Jacob M. Patterson is a consultant for Porges Coloplast and Boston Scientific and an investigator for NeoTract.
References [1] Hollingsworth JM, Rogers MAM, Kaufman SR, et al. Medical therapy to facilitate urinary stone passage: a meta-analysis. Lancet 2006; 368:1171–9. [2] 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;56:455–71. [3] Turk C, Petrik A, Sarica K, et al. EAU guidelines on diagnosis and conservative management of urolithiasis. Eur Urol 2016;69:468–74. [4] Pickard R, Starr K, MacLennan G, et al. Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebocontrolled trial. Lancet 2015;386:341–9. [5] 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;67:86–95, e2. [6] Assimos D, Krambeck A, Miller NM, et al. Surgical management of stones: American Urological Society/Endourological Society guideline, part II. J Urol 2016;196:1161–9. [7] Sur RL, Shore N, L’Esperance J, et al. Silodosin to facilitate passage of ureteral stones: a multi-institutional, randomized, double-blinded, placebo-controlled trial. Eur Urol 2015;67:959–64. [8] Sylvester RJ, Canfield SE, Lam TBL, et al. Conflict of evidence: resolving discrepancies when findings from randomized controlled
Please cite this article in press as: Patterson JM, Wiseman OJ, The Role of Medical Expulsive Therapy for Ureteral Stones: Against. Eur Urol Focus (2017), http://dx.doi.org/10.1016/j.euf.2017.02.013
available at www.sciencedirect.com journal homepage: www.europeanurology.com/eufocus
Point of Focus Debate: Against
The Role of Medical Expulsive Therapy for Ureteral Stones: Against Jacob M. Patterson a,*, Oliver J. Wiseman b a
Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK; b Cambridge University Hospitals NHS Trust, Cambridge, UK
The use of a-adrenoceptor antagonists, in particular tamsulosin, has been popularised as medical expulsive therapy (MET) in the management of ureteric stones as a result of the widely referenced meta-analyses by Hollingsworth et al. [1] and a more extensive study by Seitz et al. [2], which has also been widely used since 2009 as a basis for guidelines on this topic [3]. Their conclusions, and those of subsequent meta-analyses, included the importance of future goodquality randomised controlled trials (RCTs), as most of the studies in the meta-analysis were small and of poor methodological quality. In the Seitz meta-analysis, only 14/ 47 studies had a Jadad score of 3, with moderate heterogeneity and mild publication bias. Different a-blockers and doses were used, and different adjunctive medications. The authors also concluded: “The vast majority of randomized studies incorporated into the present systematic review are small, single-centre studies, limiting the strength of our conclusions”. Data heterogeneity is the biggest challenge to these meta-analyses; it is well understood that small, single-centre RCTs tend to overestimate treatment effects, irrespective of bias, and meta-analysis of such studies amplifies this effect. To address issues arising from criticised meta-analyses, Pickard and colleagues [4] published in 2015 a report on their RCT, the SUSPEND study, incorporating nearly 1200 patients from 24 UK centres. This large, well-powered, well-designed, and robust study showed no statistical difference between placebo and either tamsulosin or nifedipine in terms of the primary study endpoint. Approximately 80% of the patients in each group needed no further intervention for their stones at 4 wk, which represents a reasonable and highly pragmatic surrogate for stone passage. Extensive subgroup analysis of the data also failed to show any difference between active treatment and placebo for
stones, irrespective of size or anatomical stone location within the ureter. The SUSPEND study was criticised, however, for its lack of confirmation of stone passage with, for example, computed tomography (CT) or kidneyureter-bladder X-ray, and for its apparently high rate of non-intervention in the placebo arm. Another recent study looking specifically at MET for distal ureteral stones by Furyk et al. [5] came to similar conclusions to those for SUSPEND, showing similarly high stone passage rates of 87% with tamsulosin compared with 81.9% for placebo, but no differences in the time to stone passage, analgesic requirements, or need for subsequent intervention. This study also used radiological rather than clinical criteria (CT-confirmed passage of stone) to assess the endpoints, affirming the pragmatism of SUSPEND. It is interesting, therefore, that the American Urological Association urolithiasis guidelines [6] included the Furyk paper but declined to include SUSPEND owing to its apparently high non-intervention rate compared with the published literature, even though these rates are similarly high in both papers. Another RCT by Sur et al. [7] comparing the effects of silodosin, a newer a1a adrenoceptor antagonist, against placebo again showed no difference in primary endpoint of enhanced rates of stone passage (52% with silodosin vs 44% for placebo; p = 0.2). This study showed statistical significance for distal ureteral stones (p < 0.01), but this was based on subgroup analysis in a study not powered to show such a difference, so meaningful conclusions are hard to draw. It is challenging as a practicing clinician, therefore, to know what to believe, and more importantly what to tell our patients to allow the best treatment choices. Guidelines, meta-analyses, and large systematic reviews support the use of MET, yet good-quality RCTs tell us that there is little or
* Corresponding author. Sheffield Teaching Hospitals NHS Foundation Trust, Department of Urology, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, UK. Tel.: +44 77 75930906; fax: +44 114 2798318. E-mail address: [email protected] (J.M. Patterson). http://dx.doi.org/10.1016/j.euf.2017.02.013 2405-4569/© 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Patterson JM, Wiseman OJ, The Role of Medical Expulsive Therapy for Ureteral Stones: Against. Eur Urol Focus (2017), http://dx.doi.org/10.1016/j.euf.2017.02.013
EUF-292; No. of Pages 2 2
E U R O P E A N U R O L O G Y F O C U S X X X ( 2 0 17 ) X X X – X X X
no evidence to support the ongoing use of off-licence medications with their attending (albeit modest) risks and cost concerns. Sylvester and colleagues [8] have recently addressed this issue, debating the conflict in general between systematic reviews and RCTs and focusing specifically on the evidence in this field. As well as highlighting the advantages of good RCTs, including minimisation of bias and ability to answer specific questions through good design, their conclusion was that the SUSPEND trial [4] may present better quality of evidence in this field as opposed to the meta-analyses, including the Seitz study [2]. They also highlighted the importance of guideline developers using all the tools to assess methodological quality of systematic reviews and meta-analysis to ensure their outcomes are robust, before assigning them a higher level of evidence than single RCTs. In conclusion, the findings of the high-quality SUSPEND study, with its pragmatic primary endpoint that mirrors contemporary clinical practice, are more persuasive than meta-analyses based on poor-quality, inadequately powered studies that are subject to publication bias. We therefore no longer advocate the use of MET in our patients. We also believe that the European Association of Urology guidelines group should believe the findings of the SUSPEND study too, and stop advocating the use of MET.
Coloplast, EMS, and Olympus, has received a research grant from Porges
Conflicts of interest: Oliver J. Wiseman is a consultant for Boston
trials and meta-analyses disagree. Eur Urol. In press. doi:10.1016/j.
Scientific and Porges Coloplast. a speaker for Boston Scientific, Porges
eururo.2016.11.023
Coloplast, and is a director of UroScreen. Jacob M. Patterson is a consultant for Porges Coloplast and Boston Scientific and an investigator for NeoTract.
References [1] Hollingsworth JM, Rogers MAM, Kaufman SR, et al. Medical therapy to facilitate urinary stone passage: a meta-analysis. Lancet 2006; 368:1171–9. [2] 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;56:455–71. [3] Turk C, Petrik A, Sarica K, et al. EAU guidelines on diagnosis and conservative management of urolithiasis. Eur Urol 2016;69:468–74. [4] Pickard R, Starr K, MacLennan G, et al. Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebocontrolled trial. Lancet 2015;386:341–9. [5] 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;67:86–95, e2. [6] Assimos D, Krambeck A, Miller NM, et al. Surgical management of stones: American Urological Society/Endourological Society guideline, part II. J Urol 2016;196:1161–9. [7] Sur RL, Shore N, L’Esperance J, et al. Silodosin to facilitate passage of ureteral stones: a multi-institutional, randomized, double-blinded, placebo-controlled trial. Eur Urol 2015;67:959–64. [8] Sylvester RJ, Canfield SE, Lam TBL, et al. Conflict of evidence: resolving discrepancies when findings from randomized controlled
Please cite this article in press as: Patterson JM, Wiseman OJ, The Role of Medical Expulsive Therapy for Ureteral Stones: Against. Eur Urol Focus (2017), http://dx.doi.org/10.1016/j.euf.2017.02.013