Prescribe tamsulosin (typically 0.4 mg daily) or nifedipine (typically 30 mg daily) for patients with lower ureteral calculi, to speed stone passage and to avoid surgical intervention. Stength of recommendation: A: Meta-analysis of randomized controlled trials

Ewigman, Bernard

Hickner, John

Stevermer, James J.

University of Missouri: MOspace

PURLs® Priority Updates from the Research Literature from the Family Physicians Inquiries Network224 VOL 57, NO 4 / APRIL 2008  THE JOURNAL OF FAMILY PRACTICEFAST TRACKNEW FEATUREILLUSTRATIVE CASEA 52-year-old man presents to your offi ce for follow-up 2 days after he was seen in the ED and diagnosed with a distal ureter-al calculus, his fi rst. His pain is reasonably well controlled, but he has not yet passed the stone. Is there anything you can do to help him pass the stone? Yes. Patients who are candidates for observation should be offered a tri-al of “medical expulsive therapy” using an α−antagonist or a calcium chan-nel blocker. Until now, medical therapy for kidney stones consisted of pain relief only.The ordeal of a fi rst stone is all too common—the lifetime prevalence of kidney stones is 5.2%—and the prob-ability of recurrence is about 50%.2,3NHANES data show increasing preva-lence between the periods 1976-1980 and 1988-1996.3 One fi fth to one third of kidney stones require surgical intervention.4 In a cohort of 245 pa-tients presenting to an ED in Canada, 50 (20%) required further procedures, including lithotripsy. Stones ≥ 6 mm in size were much less likely to pass (OR = 10.7, 95% CI 4.6-24.8).5 The burden on the healthcare system is signifi cant; there are approximately 2 million out-patient visits annually for this problem, and diagnosis and treatment costs about $2 billion annually.6❚ Watch and waitThe standard approach is a period of watchful waiting and pain control, with urgent urological referral for patients with evidence of upper urinary tract infection, high grade obstruction, inadequate pain or nausea control, or insuffi cient renal re-serve.2,4 Most patients treated with watch-ful waiting pass their stone within 4 weeks. Any stones that don’t pass within 8 weeks are unlikely to pass spontaneously.2,7❚  Medical therapy has been proposed for decadesMedications that relax ureteral smooth muscle to help pass ureteral stones have Drugs help passmore ureteral stonesEvidence supports use of tamsulosin, nifedipinePrescribe tamsulosin (typically 0.4 mg daily) or nifedipine (typ-ically 30 mg daily) for patients with lower ureteral calculi, to speed stone passage and to avoid surgical intervention. Strength of recommendation A: Meta-analysis of randomized controlled trialsSingh A, Alter HJ, Littlepage A. A systematic review of medical therapy to facilitate passage of ureteral calculi. Ann Emerg Med. 2007; 50:552-563.1Practice changer PURLs methodologyThis study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and ﬁ ndings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls. James J. Stevermer, MD, MSPH Department of Family and Community Medicine,University of Missouri-Columbiastevermerj@health.missouri.eduBernard Ewigman, MD, MSPH Department of Family Medicine, The University of Chicago P U R L s  E D I T O RJohn Hickner, MD, MScDepartment of Family Medicine, The University of ChicagoPatients who are candidates for observation should be offered a trial of “medical expulsive therapy” using an α-antagonist or nifedipine224_JFP0408   224 3/19/08   12:38:35 PMCopyright® Dowden HealthMe i  For personal use onlyFor mass reproduction, content licensing and permissions contact Dowden Health Media.FAST TRACK VOL 57, NO 4 / APRIL 2008 225www.jfponline.combeen proposed for decades.8 Prior to 2000, however, only 1 randomized con-trolled trial (RCT) of medical therapy for ureteral stones had been published.9 A subsequent meta-analysis found 9 stud-ies and showed that medical therapy did increase the chances that a stone would pass.10 The Singh meta-analysis found 13 subsequently published studies and near-ly tripled the number of patients evalu-ated.STUDY SUMMARY❚  A well-done meta-analysisThis meta-analysis is based on 16 studies of α-antagonists (most used tamsulosin) and 9 studies of nifedipine, a calcium channel blocker.1 The studies were identi-fi ed by a comprehensive search strategy that included Medline, EMBASE, and the Cochrane Controlled Trials Register from January 1980 to January 2007. The authors included all randomized trials or controlled clinical trials of medical thera-py for adults with acute ureteral colic. The authors assessed the studies for quality using the Jadad scale, a validat-ed scale of study quality. Higher scores represent better quality, including better documentation of randomization, blind-ing, and follow-up. The authors specifi ed their planned sensitivity analyses, and used the random effects model to synthe-size the results, which tends to provide a more conservative estimate of the effect. In other words, this was a very well done meta-analysis.Twenty-two studies met the inclu-sion criteria: 13 of α-antagonists, 6 of nifedipine, and 3 of both. In 13 of the 16 studies of α-antagonists, tamsulosin (Flomax) was the study drug. The results from the terazosin (Hytrin) and doxazo-sin (Cardura) studies were included with the tamsulosin studies. The Jadad quality scores of the 22 studies were fairly low, with a median of 2 (range of 0 to 3) on the 5-point scale. The most common de-duction was because the study was not double-blinded.❚  α-Antagonist studiesThese 16 studies enrolled 1235 patients with distal ureteral stones. Mean stone size ranged from 4.3 to 7.8 mm. α-An-tagonists improved the stone expulsion rate (RR= 1.59, 95% CI 1.44-1.75; NNT = 3.3). The mean time to expulsion of the stone ranged from 2.7 to 14.2 days and duration of therapy ranged from 1 to 7 weeks. In the 9 trials that reported the time to stone expulsion, the stone came out between 2 and 6 days earlier than the control groups. Adverse effects were reported in 4% of patients receiving the active medica-tion; most were mild. ❚  Nifedipine studiesThere were 686 patients in the 9 trials of nifedipine. The mean stone size was 3.9 to 12.8 mm. Some studies included stones in the more proximal as well as the distal ureter. The stone passed 2 to 6 days earlier with tamsulosin ILLUSTRATION © 2008 JENNIFER FAIRMAN, CT SCAN: © 2008 RADIOLOGY ROUNDS, SUSANNA LEE, MD, PHD AND DR. MICHAEL MAHERMedical therapy makes sense“Therapy using either α-antagonists or calcium channel blockers augments the stone expulsion rate compared to standard therapy for moderately sized distal ureteral stones.” 1  CT showing distal ureteral stoneC O N T I N U E D225_JFP0408   225 3/19/08   12:38:39 PMFAST TRACK226 VOL 57, NO 4 / APRIL 2008  THE JOURNAL OF FAMILY PRACTICEPURLs®A growing numberof physicians across specialties are using medical therapy in patients with ureteral stonesNifedipine treatment increased the rate of stone expulsion (RR = 1.5, 95% CI 1.34-1.68; NNT = 3.9). Time to stone ex-pulsion was shorter in 7 of the 9 studies. Adverse effects were reported in 15% of the patients. Most of these were mild—nausea, vomiting, asthenia, and dyspepsia. WHAT’S NEW❚  Strong evidence for use of medical therapy The new fi ndings from the Singh meta-analysis reviewed in this PURL supports physicians who have already adopted this practice and should encourage usage by those who have not yet done so.❚  Inpatients in academic medical centers There is a growing trend to use tamsulo-sin to facilitate passage of ureteral stones. The University Health System Consor-tium (www.uhc.org) has complete clinical data on inpatients with ureteral stones, from 64 academic medical centers and teaching hospitals, between 2003 and 2007. We used this database to analyze trends in the use of tamsulosin in 4300 inpatients with ureteral stones (ICD 9 code 5921). In 2003, only 3.3% of patients with a discharge diagnosis of ureteral stone received tamsulosin. In 2007, 34.1% of patients with ureteral stones discharged from these hospitals received tamsulo-sin, with similar rates of use when strat-ifi ed by the specialty of the attending physician at discharge (family medicine, emergency medicine, internal medicine, urology) (FIGURE 1). We noted a wide range in the rate of adoption of this practice among academic medical cen-ters: 48% in the centers with the highest rate of usage and 4.4% in the centers with the lowest rate.❚  Outpatients from a sample of US practicesThe use of tamsulosin or nifedipine in outpatient practice was infrequent even 2 or 3 years ago. We used the National Ambulatory Medical Care Survey data (www.cdc.gov/nchs/about/major/ahcd/ahcd1.htm) from 2004 and 2005 (the most recent available), which provides a sample of all US outpatient practices. Only 7% of an estimated 1,345,000 patients diagnosed with ureteral stones were prescribed either tamsulosin or nifedipine, and urologists cared for most of those.These unpublished data show that physicians in academic medical centers are increasingly adopting the practice of using tamsulosin or nifedipine for expul-sion of ureteral stones, that urologists ap-pear to be the fi rst to begin using these medications in outpatients several years ago, and that this practice is being adopt-ed actively in selected academic medical centers.  CAVEATS❚  Is either drug better? Too little data to tell Our conclusion is that the strengths of this meta-analysis outweigh the weak-nesses, the fi ndings across studies are consistent, and the use of smooth-muscle relaxants for this indication makes sense from a mechanistic point of view.The quality of a meta-analysis is only as good as the quality of the in-cluded studies, and, in this case, the overall quality of studies was not uni-Source: Unpublished data from the University Health System Consortium% of inpatients in academic medical centerswho received tamsulosin for ureteral stones, by year40200FIGURE 1Percent2003 2004 2005 2006 20073.3%8.8%17.2%27.5%34.1%226_JFP0408   226 3/19/08   12:38:46 PM VOL 57, NO 4 / APRIL 2008 227www.jfponline.comUse drug therapy for ureteral stonesformly high. Median Jadad score, a summary measure of study quality, was 2, and the highest score was 3 (of a maximum of 5). The most common problem was lack of blinding, which can be critical in studies with subjec-tive outcomes such as pain. We doubt that the lack of blinding led to any sig-nifi cant misclassifi cation of outcome in this study, however. Patients either passed the stone or they didn’t, or had a surgical interven-tion or not. It is reassuring that, when the best quality studies (Jadad score = 3) were analyzed separately, the results were equally good. There have not been suffi cient head-to-head trials to know if one is better than the other. We prefer α-antagonists because of the lower apparent side-effect profi le. Our analysis of the UHC data shows that most of the physicians who are using medical therapy are using tam-sulosin primarily for this diagnosis. The majority of the patients in the studies included in the meta-analysis had been referred to a urologist. This raises the possibility that this treatment may not be as effective in patients with less severe symptoms for whom urological consultation is not necessary. CHALLENGES TO IMPLEMENTATION❚  This change should be easy to put into practiceTamsulosin is the best studied of the drugs, but also the most expensive. Based on the estimated number need to treat (NNT) of between 3 and 4 to prevent a surgical intervention and an estimated cost of around $90 for 1 month (www.drugstore.com, February 16, 2008), tam-sulosin seems like a good investment to avoid surgical intervention. The evidence for the other α-antago-nists is consistent with that of tamsulosin, but there are fewer data, so it is not clear that the other agents will work as well.Many people with renal colic are diagnosed and treated in the emergency department; they may not see their fam-ily physician until some time after the stone is diagnosed. It is unclear what ef-fect this delay might have on medication effectiveness.Neither tamsulosin nor nifedipine have an FDA indication for ureterolithiasis. However, they are prescribed commonly, and most physicians are familiar with their use and adverse-effect profi les. ■AcknowledgementWe acknowledge Sofi a Medvedev, PhD of the University HealthSystem Consortium (UHC) in Oak Brook, IL for analysis of the UHC Clinical Database and the National Ambulatory Medical Care Survey data.References 1.   Singh A, Alter HJ, Littlepage A. A systematic review of medical therapy to facilitate passage of ureteral calculi. Ann Emerg Med. 2007; 50:552-563. 2.   Teichman JM. Clinical practice. Acute renal col-ic from ureteral calculus. N Engl J Med. 2004; 350:684-693. 3.   Stamatelou KK, Francis ME, Jones CA, Nyberg LM, Curhan GC. Time trends in reported prevalence of kidney stones in the United States: 1976-1994. Kidney International. 2003; 63:1817-1823. 4.   American Urological Association. Clinical Guidelines: Ureteral Calculi. Last updated 2007. Available at: http://www.auanet.org/guidelines/uretcal07.cfm. Accessed February 11, 2008. 5.   Papa L, Stiell IG, Wells GA, Ball I, Battram E, Ma-honey JE. Predicting intervention in renal colic pa-tients after emergency department evaluation. Can J Emerg Med. 2005; 7:78-86. 6.   Pearle MS, Calhoun EA, Curhan GC, Urologic Dis-eases of America Project. Urologic diseases in America project: urolithiasis. J Urol. 2005; 173:848-857. 7.   Morse RM, Resnick MI. Ureteral calculi: natural his-tory and treatment in an era of advanced technol-ogy. J Urol. 1991; 145:263-265. 8.   Peters HJ, Eckstein W. Possible pharmacological means of treating renal colic. Urol Res. 1975; 3:55-59. 9.   Borghi L, Meschi T, Amato F, Novarini A, Giannini A, Quarantelli C, et al. Nifedipine and methylpredniso-lone in facilitating ureteral stone passage: a ran-domized, double-blind, placebo-controlled study. J Urol. 1994; 152:1095-1098.10.   Hollingsworth JM, Rogers MA, Kaufman SR, Brad-ford TJ, Saint S, Wei JT, et al. Medical therapy to facilitate urinary stone passage: a meta-analysis. Lancet. 2006; 368:1171-1179.Drugs used in the meta-analysis studiesα-AntagonistsTamsulosin (Flomax)Terazosin (Hytrin)Doxazosin (Cardura)Calcium channel blockersNifedipine (Adalat, Nifedical, Procardia)FAST TRACKTamsulosin is the best studied of the drugs, but also the most expensive227_JFP0408   227 3/19/08   12:38:50 PM

Drugs help pass more ureteral stones

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