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Medical Expulsive Therapy is Useful for Urinary Calculi
Opposing Views 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57
Medical Expulsive Therapy Is Useful for Urinary Calculi PRO PREVIOUS prospective studies suggest that 95% of ureteral stones will pass spontaneously within 6 weeks of diagnosis. Moreover the smaller the stone, the higher the likelihood of spontaneous stone passage.1 I continue to believe that medical expulsive therapy (MET) to facilitate stone passage has a valuable role in the current management of ureteral calculi and should be used to increase the possibility of spontaneous stone passage. Since 1966 a myriad of medical therapies have been suggested to facilitate stone passage, including Tanderil, glucagon, indomethacin and epidural morphine. Yet it was not until 1994 when a randomized, prospective trial suggested that the alpha blocker nifedipine could significantly increase the rate of stone passage and minimize time to passage. Since that time several randomized prospective trials have suggested that calcium channel blockers and alpha blockers can be used to increase the rate of stone passage by 20% to 30%, reduce time to stone passage by 2 to 4 days and reduce the amount of pain medication required to treat patients with ureteral calculi. In fact, 2 large meta-analyses suggest that MET with alpha blockers or calcium channel blockers performed better than treatment with placebo in facilitating the spontaneous passage of ureteral calculi.2,3 Nevertheless, concerns have been raised over the initial prospective trials exploring the use of tamsulosin and nifedipine for medical expulsive therapy. Some investigators question the use of adjunctive medications such as steroids and antiinflammatory medications, which may cloud the results. Moreover many of the initial prospective trials performed had a mean sample size of 50 patients or less, which was not considered robust. Finally, some criticize these studies because the treatment arms were not blinded. While the usefulness of medical expulsive therapy continues to be questioned, the pathophysiology of ureteral obstruction appears to support the use of alpha blockers and calcium channel blockers to facilitate stone passage. In vitro and in vivo studies suggest that ureteral stones result in increased
0022-5347/16/1953-0001/0 THE JOURNAL OF UROLOGY® Ó 2016 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
AND
RESEARCH, INC.
muscle contraction amplitude, decreased contraction frequency and increased ureteral pressure. Relaxation of the ureter in the region of the stone should facilitate stone passage. Therefore, a reduction in ureteral pressure accomplished by adrenergic alpha antagonists or calcium channel blockers should be able to promote stone passage. These effects are mediated through the active calcium channel pumps and adrenergic alpha-1 receptors present in ureteral smooth muscle. In fact, an in vivo study which used ureteral pressure transducers placed in the ureter suggested that medical treatment with nifedipine or tamsulosin significantly reduced ureteral contraction frequency and pressure generation in the ureter.4 Recent studies also suggest that MET is a viable treatment for pediatric patients with ureteral calculi. In a multi-institutional retrospective study of stones smaller than 10 mm there appeared to be a greater than 10% increase in stone passage in patients who received tamsulosin vs analgesic therapy only. Yet in the largest prospective clinical trial to date, in more than 1,100 patients there did not appear to be a significant improvement in stone passage rates when patients were provided tamsulosin or nifedipine vs placebo.5 In this trial the need for intervention was used as a surrogate for stone passage and no actual imaging studies were performed to determine whether stones were still present in the ureter, representing a risk of silent ureteral obstruction. Medical expulsive therapy also results in significant cost savings compared to standard endoscopic or shock wave lithotripsy for managing ureteral stones. Since MET relies mostly on generic medications, a 1-month course of therapy should cost less than $100 USD compared to more than $2,500 USD for ureteroscopy and shock wave lithotripsy. In addition, studies have suggested that MET maintains its cost-effectiveness even with a small increase in spontaneous passage. Savings of more than $1,000 USD can be realized with medical expulsive therapy vs observation alone. There is no doubt that a definitive, high quality, randomized controlled trial is warranted to confirm
http://dx.doi.org/10.1016/j.juro.2015.12.066 Vol. 195, 1-3, March 2016 Printed in U.S.A.
www.jurology.com Dochead: Opposing Views
DIS 5.4.0 DTD JURO13188_proof 12 December 2015 6:09 pm EO:
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58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114
OPPOSING VIEWS
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the efficacy of calcium channel blockers or alpha blockers in patients with ureteral calculi. This trial should be performed in patients with stones located throughout the ureter, with and without steroid therapy. Although recent evidence suggests that MET may not be effective in facilitating spontaneous stone passage, I continue to believe that medical expulsive therapy with tamsulosin is an inexpensive and safe option which demonstrates efficacy in properly selected patients. Moreover the economic savings realized can provide a costeffective alternative to surgical stone removal. Glenn M. Preminger Comprehensive Kidney Stone Center Duke University Medical Center Durham, North Carolina
CON THE AUA guideline on the management of ureteral calculi included a contemporary meta-analysis identifying a 29% improvement in stone passage using alpha blocker therapy for active ureteral stones smaller than 1 cm.1 For some time now medical expulsive therapy has been central in the management of actively passing ureteral stones in the emergency room and outpatient settings. Numerous randomized trials have identified an advantage with MET for ureteral stone passage. However, the most compelling studies have also included the use of steroids in both randomization arms. A recent Cochrane database review highlighted the inconsistent practices in many of these studies and showed that only a minority of studies involved blinding of any kind.6 Furthermore, many of the studies were small and were not always placebo controlled. Subsequently the stage was set for more advanced studies to be conducted to further understand all aspects of MET for ureteral stones. In 2015 several high level studies demonstrated limited or no overall benefit for MET in reducing time to stone passage, analgesic use or requirements for intervention. The most significant work was the well publicized SUSPEND trial. The study was a multicenter, randomized, placebo controlled trial enrolling 1,167 patients, thus making it the largest level I study to date.7 Patients were randomized to 0.4 mg tamsulosin, 30 mg nifedipine or placebo. There was no difference among the groups in the rate of spontaneous stone passage rate by 4 weeks and no difference was noted in the secondary outcomes of analgesic use or time to stone passage. Notably final stone status was not verified by radiographs in this study. Nevertheless, I would expect more evidence of a “MET effect” from a cohort of patients this large if indeed MET was such an efficacious approach. Dochead: Opposing Views
Hermanns et al conducted a randomized, doubleblind, placebo controlled trial using tamsulosin vs placebo for distal ureteral stones smaller than 7 mm and they found no statistical difference in the passage rate by 21 days.8 Sur et al published a multiinstitutional, randomized, double-blind, placebo controlled trial using silodosin as the alpha blocker.9 Overall there was no difference in time to stone passage, stone related visits, interventions or the use of analgesics. A higher rate of stone passage was seen in the silodosin arm for distal ureteral stones only. There were 52 patients analyzed with a distal stone in the silodosin arm vs 59 patients in the placebo arm, and despite the relatively small sample size of this subgroup, silodosin proved more effective than placebo. While this study highlights that silodosin is probably effective for distal ureteral stones, this may also indicate that silodosin is a better agent than tamsulosin for MET. Another important consideration regarding MET is the relatively high rate of spontaneous stone passage for ureteral stones, particularly distal stones. As such, we question whether the cost and side effects justify its universal use for ureteral stones, even distal stones. To this end our group recently surveyed a population of stone formers from our metabolic stone unit. After presenting the latest clinical reports in layperson’s language as a preamble to completing the survey, 49% of the 200 patients queried stated that they would still take tamsulosin if they were passing a stone. Notably only a third of the respondents would be willing to take tamsulosin with steroids. This finding illustrates that patient preference dictates the need for more effective medical therapies and the new evidence amplifies the need for further understanding of the precise clinical benefit of MET. Perhaps even more consideration should be given to the concomitant use of steroids in select patients. I concede that MET has been shown to have benefits after shock wave lithotripsy and ureteroscopy. At this point this is current practice but I believe this is a different subgroup of patients than those passing a de novo ureteral stone. I also concede that in the ureter, distal stones are most suited for MET, perhaps using silodosin rather than tamsulosin. Recent studies have failed to demonstrate a substantial benefit of MET for stones in the proximal and mid ureter, or for that matter, in the renal pelvis. I believe that limiting MET primarily to postoperative patients and those with de novo distal stones represents a practice change for many urologists and emergency room physicians. The next logical step is to help patients and other clinicians evaluate the evidence and design more studies to identify a practical, consistent, evidence-based
DIS 5.4.0 DTD JURO13188_proof 12 December 2015 6:09 pm EO:
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OPPOSING VIEWS
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approach to MET. In light of the current evidence, MET is useful for urinary calculi only sometimes, more specifically only for select distal stones and after stone fragmentation.
3
Stephen Y. Nakada Department of Urology University of Wisconsin School of Medicine and Public Health Madison, Wisconsin
REFERENCES 1. Preminger GM, Tiselius HG, Assimos DG et al: 2007 guideline for the management of ureteral calculi. J Urol 2007; 178: 2418. 2. Hollingsworth JM, Rogers MA, Kaufman SR et al: Medical therapy to facilitate urinary stone passage: a meta-analysis. Lancet 2006; 368: 1171. 3. Seitz C, Liatsikos E, Porpiglia F et al: Medical therapy to facilitate the passage of stones: what is the evidence? Eur Urol 2009; 56: 455. 4. Davenport K, Timoney AG and Keeley FX Jr: Effect of smooth muscle relaxant drugs on proximal human ureteric activity in vivo: a pilot study. Urol Res 2007; 35: 207.
Dochead: Opposing Views
5. 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: 341. 6. Campschroer T, Zhu Y, Duijvesz D et al: Alphablockers as medical expulsive therapy for ureteral stones. Cochrane Database Syst Rev 2014; 4: CD008509. 7. Pickard R, Starr K, MacLennan G et al: Use of drug therapy in the management of symptomatic ureteric stones in hospitalised adults: a multicentre, placebo-controlled, randomised controlled trial and cost-effectiveness analysis of a calcium
channel blocker (nifedipine) and an alpha-blocker (tamsulosin) (the SUSPEND trial). Health Technol Assess 2015; 19: 1. 8. Hermanns T, Sauermann P, Rufibach K et al: Is there a role for tamsulosin in the treatment of distal ureteral stones of 7 mm or less? Results of a randomised, double-blind, placebo-controlled trial. Eur Urol 2009; 56: 407. 9. 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.
DIS 5.4.0 DTD JURO13188_proof 12 December 2015 6:09 pm EO:
253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276
Medical Expulsive Therapy Is Useful for Urinary Calculi PRO PREVIOUS prospective studies suggest that 95% of ureteral stones will pass spontaneously within 6 weeks of diagnosis. Moreover the smaller the stone, the higher the likelihood of spontaneous stone passage.1 I continue to believe that medical expulsive therapy (MET) to facilitate stone passage has a valuable role in the current management of ureteral calculi and should be used to increase the possibility of spontaneous stone passage. Since 1966 a myriad of medical therapies have been suggested to facilitate stone passage, including Tanderil, glucagon, indomethacin and epidural morphine. Yet it was not until 1994 when a randomized, prospective trial suggested that the alpha blocker nifedipine could significantly increase the rate of stone passage and minimize time to passage. Since that time several randomized prospective trials have suggested that calcium channel blockers and alpha blockers can be used to increase the rate of stone passage by 20% to 30%, reduce time to stone passage by 2 to 4 days and reduce the amount of pain medication required to treat patients with ureteral calculi. In fact, 2 large meta-analyses suggest that MET with alpha blockers or calcium channel blockers performed better than treatment with placebo in facilitating the spontaneous passage of ureteral calculi.2,3 Nevertheless, concerns have been raised over the initial prospective trials exploring the use of tamsulosin and nifedipine for medical expulsive therapy. Some investigators question the use of adjunctive medications such as steroids and antiinflammatory medications, which may cloud the results. Moreover many of the initial prospective trials performed had a mean sample size of 50 patients or less, which was not considered robust. Finally, some criticize these studies because the treatment arms were not blinded. While the usefulness of medical expulsive therapy continues to be questioned, the pathophysiology of ureteral obstruction appears to support the use of alpha blockers and calcium channel blockers to facilitate stone passage. In vitro and in vivo studies suggest that ureteral stones result in increased
0022-5347/16/1953-0001/0 THE JOURNAL OF UROLOGY® Ó 2016 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
AND
RESEARCH, INC.
muscle contraction amplitude, decreased contraction frequency and increased ureteral pressure. Relaxation of the ureter in the region of the stone should facilitate stone passage. Therefore, a reduction in ureteral pressure accomplished by adrenergic alpha antagonists or calcium channel blockers should be able to promote stone passage. These effects are mediated through the active calcium channel pumps and adrenergic alpha-1 receptors present in ureteral smooth muscle. In fact, an in vivo study which used ureteral pressure transducers placed in the ureter suggested that medical treatment with nifedipine or tamsulosin significantly reduced ureteral contraction frequency and pressure generation in the ureter.4 Recent studies also suggest that MET is a viable treatment for pediatric patients with ureteral calculi. In a multi-institutional retrospective study of stones smaller than 10 mm there appeared to be a greater than 10% increase in stone passage in patients who received tamsulosin vs analgesic therapy only. Yet in the largest prospective clinical trial to date, in more than 1,100 patients there did not appear to be a significant improvement in stone passage rates when patients were provided tamsulosin or nifedipine vs placebo.5 In this trial the need for intervention was used as a surrogate for stone passage and no actual imaging studies were performed to determine whether stones were still present in the ureter, representing a risk of silent ureteral obstruction. Medical expulsive therapy also results in significant cost savings compared to standard endoscopic or shock wave lithotripsy for managing ureteral stones. Since MET relies mostly on generic medications, a 1-month course of therapy should cost less than $100 USD compared to more than $2,500 USD for ureteroscopy and shock wave lithotripsy. In addition, studies have suggested that MET maintains its cost-effectiveness even with a small increase in spontaneous passage. Savings of more than $1,000 USD can be realized with medical expulsive therapy vs observation alone. There is no doubt that a definitive, high quality, randomized controlled trial is warranted to confirm
http://dx.doi.org/10.1016/j.juro.2015.12.066 Vol. 195, 1-3, March 2016 Printed in U.S.A.
www.jurology.com Dochead: Opposing Views
DIS 5.4.0 DTD JURO13188_proof 12 December 2015 6:09 pm EO:
j
1
58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114
OPPOSING VIEWS
2
115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171
the efficacy of calcium channel blockers or alpha blockers in patients with ureteral calculi. This trial should be performed in patients with stones located throughout the ureter, with and without steroid therapy. Although recent evidence suggests that MET may not be effective in facilitating spontaneous stone passage, I continue to believe that medical expulsive therapy with tamsulosin is an inexpensive and safe option which demonstrates efficacy in properly selected patients. Moreover the economic savings realized can provide a costeffective alternative to surgical stone removal. Glenn M. Preminger Comprehensive Kidney Stone Center Duke University Medical Center Durham, North Carolina
CON THE AUA guideline on the management of ureteral calculi included a contemporary meta-analysis identifying a 29% improvement in stone passage using alpha blocker therapy for active ureteral stones smaller than 1 cm.1 For some time now medical expulsive therapy has been central in the management of actively passing ureteral stones in the emergency room and outpatient settings. Numerous randomized trials have identified an advantage with MET for ureteral stone passage. However, the most compelling studies have also included the use of steroids in both randomization arms. A recent Cochrane database review highlighted the inconsistent practices in many of these studies and showed that only a minority of studies involved blinding of any kind.6 Furthermore, many of the studies were small and were not always placebo controlled. Subsequently the stage was set for more advanced studies to be conducted to further understand all aspects of MET for ureteral stones. In 2015 several high level studies demonstrated limited or no overall benefit for MET in reducing time to stone passage, analgesic use or requirements for intervention. The most significant work was the well publicized SUSPEND trial. The study was a multicenter, randomized, placebo controlled trial enrolling 1,167 patients, thus making it the largest level I study to date.7 Patients were randomized to 0.4 mg tamsulosin, 30 mg nifedipine or placebo. There was no difference among the groups in the rate of spontaneous stone passage rate by 4 weeks and no difference was noted in the secondary outcomes of analgesic use or time to stone passage. Notably final stone status was not verified by radiographs in this study. Nevertheless, I would expect more evidence of a “MET effect” from a cohort of patients this large if indeed MET was such an efficacious approach. Dochead: Opposing Views
Hermanns et al conducted a randomized, doubleblind, placebo controlled trial using tamsulosin vs placebo for distal ureteral stones smaller than 7 mm and they found no statistical difference in the passage rate by 21 days.8 Sur et al published a multiinstitutional, randomized, double-blind, placebo controlled trial using silodosin as the alpha blocker.9 Overall there was no difference in time to stone passage, stone related visits, interventions or the use of analgesics. A higher rate of stone passage was seen in the silodosin arm for distal ureteral stones only. There were 52 patients analyzed with a distal stone in the silodosin arm vs 59 patients in the placebo arm, and despite the relatively small sample size of this subgroup, silodosin proved more effective than placebo. While this study highlights that silodosin is probably effective for distal ureteral stones, this may also indicate that silodosin is a better agent than tamsulosin for MET. Another important consideration regarding MET is the relatively high rate of spontaneous stone passage for ureteral stones, particularly distal stones. As such, we question whether the cost and side effects justify its universal use for ureteral stones, even distal stones. To this end our group recently surveyed a population of stone formers from our metabolic stone unit. After presenting the latest clinical reports in layperson’s language as a preamble to completing the survey, 49% of the 200 patients queried stated that they would still take tamsulosin if they were passing a stone. Notably only a third of the respondents would be willing to take tamsulosin with steroids. This finding illustrates that patient preference dictates the need for more effective medical therapies and the new evidence amplifies the need for further understanding of the precise clinical benefit of MET. Perhaps even more consideration should be given to the concomitant use of steroids in select patients. I concede that MET has been shown to have benefits after shock wave lithotripsy and ureteroscopy. At this point this is current practice but I believe this is a different subgroup of patients than those passing a de novo ureteral stone. I also concede that in the ureter, distal stones are most suited for MET, perhaps using silodosin rather than tamsulosin. Recent studies have failed to demonstrate a substantial benefit of MET for stones in the proximal and mid ureter, or for that matter, in the renal pelvis. I believe that limiting MET primarily to postoperative patients and those with de novo distal stones represents a practice change for many urologists and emergency room physicians. The next logical step is to help patients and other clinicians evaluate the evidence and design more studies to identify a practical, consistent, evidence-based
DIS 5.4.0 DTD JURO13188_proof 12 December 2015 6:09 pm EO:
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OPPOSING VIEWS
229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252
approach to MET. In light of the current evidence, MET is useful for urinary calculi only sometimes, more specifically only for select distal stones and after stone fragmentation.
3
Stephen Y. Nakada Department of Urology University of Wisconsin School of Medicine and Public Health Madison, Wisconsin
REFERENCES 1. Preminger GM, Tiselius HG, Assimos DG et al: 2007 guideline for the management of ureteral calculi. J Urol 2007; 178: 2418. 2. Hollingsworth JM, Rogers MA, Kaufman SR et al: Medical therapy to facilitate urinary stone passage: a meta-analysis. Lancet 2006; 368: 1171. 3. Seitz C, Liatsikos E, Porpiglia F et al: Medical therapy to facilitate the passage of stones: what is the evidence? Eur Urol 2009; 56: 455. 4. Davenport K, Timoney AG and Keeley FX Jr: Effect of smooth muscle relaxant drugs on proximal human ureteric activity in vivo: a pilot study. Urol Res 2007; 35: 207.
Dochead: Opposing Views
5. 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: 341. 6. Campschroer T, Zhu Y, Duijvesz D et al: Alphablockers as medical expulsive therapy for ureteral stones. Cochrane Database Syst Rev 2014; 4: CD008509. 7. Pickard R, Starr K, MacLennan G et al: Use of drug therapy in the management of symptomatic ureteric stones in hospitalised adults: a multicentre, placebo-controlled, randomised controlled trial and cost-effectiveness analysis of a calcium
channel blocker (nifedipine) and an alpha-blocker (tamsulosin) (the SUSPEND trial). Health Technol Assess 2015; 19: 1. 8. Hermanns T, Sauermann P, Rufibach K et al: Is there a role for tamsulosin in the treatment of distal ureteral stones of 7 mm or less? Results of a randomised, double-blind, placebo-controlled trial. Eur Urol 2009; 56: 407. 9. 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.
DIS 5.4.0 DTD JURO13188_proof 12 December 2015 6:09 pm EO:
253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276