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Medical therapy to facilitate urinary stone passage:
John M Hollingsworth, Mary A M Rogers, Samuel R Kaufman, Timothy J Bradford, Sanjay Saint, John T Wei, Brent K Hollenbeck Summary
Background Medical therapies to ease urinary-stone passage have been reported, but are not generally used. If eﬀ ective, Lancet 2006; 368: 1171–79
such therapies would increase the options for treatment of urinary stones. To assess eﬃ
cacy, we sought to identify See Comment page 1138
and summarise all randomised controlled trials in which calcium-channel blockers or α blockers were used to treat Department of Urology
urinary stone disease.
(J M Hollingsworth MD,
T J Bradford MD, J T Wei MD,
B K Hollenbeck MD); Division of
Methods We searched MEDLINE, Pre-MEDLINE, CINAHL, and EMBASE, as well as scientiﬁ c meeting abstracts, up General Medicine, Department
to July, 2005. All randomised controlled trials in which calcium-channel blockers or α blockers were used to treat of Internal Medicine
ureteral stones were eligible for inclusion in our analysis. Data from nine trials (number of patients=693) were pooled. (M A M Rogers PhD,
The main outcome was the proportion of patients who passed stones. We calculated the summary estimate of eﬀ ect S R Kaufman MA, S Saint MD);
Veterans Aﬀ airs/University of
associated with medical therapy use using random-eﬀ ects and ﬁ xed-eﬀ ects models.
Michigan Patient Safety
Findings Patients given calcium-channel blockers or α blockers had a 65% (absolute risk reduction=0·31 95% CI (M A M Rogers, S R Kaufman,
0·25–0·38) greater likelihood of stone passage than those not given such treatment (pooled risk ratio 1·65; 95% CI S Saint); Center for Practice
Management and Outcomes
1·45–1·88). The pooled risk ratio for α blockers was 1·54 (1·29–1·85) and for calcium-channel blockers with steroids Research, Ann Arbor Veterans
was 1·90 (1·51–2·40). The proportion of heterogeneity not explained by chance alone was 28%. The number needed Aﬀ airs Health Services Research
to treat was 4.
& Development Center of
Excellence, Ann Arbor (S Saint),
Interpretation Although a high-quality randomised trial is necessary to conﬁ rm its eﬃ
cacy, our ﬁ ndings suggest that Correspondence to:
medical therapy is an option for facilitation of urinary-stone passage for patients amenable to conservative Brent K Hollenbeck
management, potentially obviating the need for surgery.
1500 E Medical Center Dr TC 3875-0330, Ann Arbor, Introduction
these drug classes stems from our understanding of MI 48109-0330, USA firstname.lastname@example.org
The lifetime risk of urinary stone disease (urolithiasis) is ureteral smooth-muscle physiology and urinary estimated to be between 5% and 12% in Europe and the obstruction.11–17 Despite growing evidence from clinical USA,1–4 aﬄ icting 13% of men and 7% of women.5 Since trials in support of its eﬃ 50% of patients will have a recurrence of renal colic used. Two explanations for underuse are: ﬁ rst, that within 5 years of their ﬁ rst episode,6 urolithiasis is a minimally invasive surgical techniques, such as chronic disease with substantial economic consequences shock-wave lithotripsy and ureteroscopy have evolved to and great public health importance. In the USA alone, allow for resolution of stone burden,18,19 but carry nearly 2 million outpatient visits were needed for the measurable risks and are costly;18,20–27 and second, that disease in 2000, with expenditures for inpatient and reports of empirical data for medical therapies have outpatient claims totalling US$2·1 billion.7 appeared only in urological publications, and therefore, Although patients with urolithiasis might be the availability of such therapies might not be well known asymptomatic, many have pain and thus commonly to physicians from other disciplines. Since many present to emergency or outpatient departments. specialists—such as emergency-department physicians, Provided that these patients do not need renal pelvic internists, and family practitioners—serve as the initial decompression—ie, they do not have a solitary kidney or conduit into the health-care system for patients with obstructing pyelonephritis—and that pain relief can be urolithiasis, a knowledge gap might exist. Therefore, we obtained, a trial of conservative non-surgical therapy is obtained data from clinical trials to derive a quantitative warranted, since many of these stones pass spontaneously. estimate of ureteral-stone expulsion associated with Indeed, studies have shown spontaneous passage rates medical therapy.
of 71%–98% for small (≤5 mm) distal ureteral stones,8–10
with urinary-stone size and location being the two most Methods
important predictors of stone passage.9 In view of this Eligibility criteria
relation, investigators have sought ways of assisting the We used guidelines from the Quality of Reporting of
process with the use of drugs, thereby reducing the need
Meta-Analyses conference.28 Inclusion criteria were established before the search. Randomised controlled Use of calcium-channel blockers and adrenergic trials of urolithiasis in any language were eligible. Only α-antagonists for expulsive medical therapy has been those studies in which a calcium-channel blocker or an proposed as a way to enhance stone passage. Interest in adrenergic α-antagonist was used as the main therapy www.thelancet.com Vol 368 September 30, 2006
antispasmolytics, anticholinergic therapy, or cortico- 19 additional articles identiﬁed through steroids. In the instance of many publications from a single institution or group, we contacted the primary investigator to determine whether these reports were generated from the same study population. Results from duplicate populations were excluded. We speciﬁ ed a minimum follow-up period of one week to allow for and from parallel search by reference librarian Search strategy
English and non-English language publications were searched for human studies relating to expulsive medical therapy from Jan 1, 1981, to July 31, 2005. We did an electronic search of MEDLINE, Pre-MEDLINE, CINAHL, and EMBASE. We searched by exploding and combining the following medical subject heading terms: “calcium channel blocking agent” with “urolithiasis” and “alpha adrenergic receptor blocking agent” with 9 trials assessed ureteral-stone passage related to expulsive medical therapy “urolithiasis”. A research librarian at the University of Michigan Medical School did an independent search to Figure 1: Study selection process
conﬁ rm the exhaustiveness of our search.
In an eﬀ ort to identify further reports, we hand searched for ureteral-stone disease were included; therefore, we abstracts from the annual meetings of the World Congress excluded trials in which medical therapy was examined of Endourology, the European Association of Urology, as an adjuvant to surgery. For the purpose of ascertaining and the American Urological Association between 1999 trial eligibility, control groups were deﬁ ned a priori as and 2005. We corresponded with the ﬁ rst or senior those not having received any additional medical therapy authors of the published trials and conference abstracts to ease urinary-stone passage—eg, other vasodilators, that met our inclusion criteria to clarify questions about Location
Mean stone size
For those who completed For those who completed Data are number (SD) unless otherwise indicated. All studies took place in outpatient settings. n/a=data not available. *Values are for the starting population unless indicated otherwise. Table 1: Study and patient summary characteristics
www.thelancet.com Vol 368 September 30, 2006
their studies, and to ﬁ nd out about unpublished or Collaboration33—ie, method of randomisation, conceal-continuing studies. We also contacted major drug ment of allocation, blinding, loss to follow-up, and manufacturers to inquire about unpublished industry- intention-to-treat analysis. We then did sensitivity analyses based on the criteria for which there was variation from the Cochrane criteria.
Data reviews and statistical analysis
Subgroup analyses by drug type were done on the basis Two reviewers independently extracted data from every of a priori decisions and included an assessment of study using a standardised form. To reduce bias, one of tamsulosin alone, nifedipine alone, all adrenergic the reviewers was blinded to the source of the publication α antagonists, and the combined use of nifedipine and and to the authors’ names. Inconsistencies between corticosteroids. Studies that used chemically diﬀ erent reviewers’ data were resolved through discussion until a drugs with similar mechanisms of action (such as consensus was reached. We were able to contact tamsulosin and terazosin) or diﬀ erent formulations of investigators from ﬁ ve of the studies for which we needed the same drug (such as nifedipine immediate-release clariﬁ cation. Three of the four drug companies with versus sustained-release) were grouped together for which we corresponded replied to our inquiries.
We wanted our ﬁ ndings to be generalisable to all adults Stata version 9.0 (Stata Corp, College Station, Texas) with ureteral stones amenable to a trial of conservative was used for all calculations.
management. The primary endpoint in the studies was the proportion of patients who passed stones (cumulative Role of the funding source
incidence). Therefore, we summarised eﬀ ect size using a The sponsors had no role in study design, data collection, pooled risk ratio with 95% CIs, comparing the proportion data analysis, data interpretation, or writing of the report. of patients taking medical therapy who passed stones The corresponding author had full access to all the data in with the proportion of those not taking medical therapy the study and had ﬁ nal responsibility for the decision to (controls) who passed stones. We used both submit for publication.
Mantel-Haenszel ﬁ xed-eﬀ ects and DerSimonian and Laird random-eﬀ ects models to produce across-study risk ratios. Since both models yielded similar results, the 415 studies were identiﬁ ed in the electronic database Mantel-Haenszel ﬁ xed-eﬀ ects model only is reported search (ﬁ gure 1). The review of meeting abstracts yielded here. Except where indicated otherwise, we did our 19 additional studies. We excluded from detailed review analysis on an intention-to-treat basis with the assumption any articles that were either non-research reports, such that dropouts failed to pass their stones. To assess heterogeneity, we used Cochran’s Q-test of heterogeneity (which follows a χ² distribution) and the I² statistic (which measures the proportion of inconsistency in individual studies that cannot be explained by chance).29 On the basis of the pooled risk ratio and the baseline risk, we calculated the number needed to treat (NNT). The 95% CIs for numbers needed to treat were calculated with the Newcombe-Wilson hybrid score method.30 To assess the eﬀ ect of individual studies on the summary estimate of eﬀ ect, we did an inﬂ uence analysis, in which the pooled estimates were recalculated omitting one study at a time. We assessed publication bias using Rosenthal’s fail-safe number—ie, the number of non-signiﬁ cant, unpublished studies that would be needed to reduce a statistically signiﬁ cant observed result to non-signiﬁ cance at α=0·05).31 We also calculated the more recently described Rosenberg fail-safe number,32 which is weighted by study variance and, therefore, might be more appropriate to meta-analyses that combine weighted eﬀ ect sizes. Publication bias is generally regarded as a concern if the fail-safe number is less than 5n +10, when n is the number of studies included in the meta-analysis.
Since there is no gold standard for assessment of the validity of randomised controlled trials, we add-ressed quality on the basis of every study’s conformity with the criteria suggested by the Cochrane Figure 2: Percentage of patients who passed stones stratiﬁ ed by study group and mean stone size
www.thelancet.com Vol 368 September 30, 2006
both of these studies also received treatment with the Treatment group
Number needed to
antispasmolytic phloroglunicol or its trimethoxy-benzene event rate*
derivative. Similarly, Staerman and colleagues38 randomly Control group event rate
assigned patients nifedipine versus phloroglucinol.
Červenàkov and colleagues randomly assigned patients standard therapy (including the antispasmolytic, diazepam) versus standard therapy and tamsulosin.35 Because of the smooth-muscle relaxation activity of antispasmolytics, the control groups of these trials were given potentially active therapies that might have promoted ureteral-stone passage. *Based on relative risk=1·65 applied to the control group event rates.
For this reason, they were not eligible for inclusion in our Table 2: Number needed to treat for various background proportions of spontaneous stone passage
main analysis. Indeed, corticosteroids have been shown to increase stone passage rates.39 Although these studies did as editorials or commentaries, or studies on the wrong not meet the strict inclusion criteria, we did a separate topic—eg, trials that used diﬀ erent interventions, trials sensitivity analysis in which their data were used to with diﬀ erent outcomes measured, or observational examine the eﬀ ect of their inclusion on the overall risk studies. There were ﬁ ve additional randomised studies that In seven of the studies pooled, both treatment and made a substantial contribution to the literature, control groups received scheduled or on-demand doses of including the ﬁ rst trial of expulsive medical therapy.34–38 non-steroidal anti-inﬂ ammatory drugs (NSAIDs).40–46 These These studies were excluded from the ﬁ nal meta-analysis drugs are highly eﬀ ective in the symptomatic relief of acute because none of them had a true control group. Speciﬁ cally, renal colic.47,48 Additionally, NSAIDs might augment Borghi and colleagues34 randomly assigned patients nife- urinary stone expulsion.49,50 Yet the only randomised, dipine and corticosteroids versus corticosteroids alone. double-blind, placebo-controlled trial to investigate the Dellabella and co-workers36,37 did two studies examining eﬀ ect of NSAIDs on stone-passage rates showed no the eﬃ cacy of medical therapy. In their ﬁ rst,36 patients diﬀ erence between NSAIDs and control.51 None of the with urolithiasis were randomly assigned tamsulosin and studies that we pooled were designed to examine the eﬀ ect corticosteroids versus corticosteroids alone. 2 years later, of NSAIDs on our primary outcome; however, we did a in their second study,37 patients were randomly assigned post-hoc subgroup analysis for the studies that included tamsulosin or nifedipine and corticosteroids versus NSAIDs in both treatment and control groups, as well as See Online for webtable 1
corticosteroids alone. Additionally, the control groups in for the two studies in which no NSAIDs were used.52,53 We then reviewed the remaining 38 articles in detail to determine if they met inclusion criteria. The ﬁ nal study Risk ratio
population consisted of nine relevant trials that examined Controlled
the use of calcium-channel blockers or α blockers to augment urinary-stone passage.40–46,52,53
693 patients were randomised into the nine trials included in the meta-analysis (table 1). All patients were treated on an outpatient basis. The mean age of participants ranged from 34·4 years to 46·5 years, and the percentage of women in the studies varied from 25% to 60%. Mean stone size ranged from 3·9 mm to 7·8 mm. In all but one study,40 treated patients had stones located in the distal third of the ureter. There were 12 dropouts No control group
across all nine trials; seven patients from the intervention groups and ﬁ ve from the control groups.
The medical treatments and follow-up as well as the primary and secondary outcomes and recorded side- eﬀ ects are shown in webtable 1. Treatment duration ranged from 7 days to 6 weeks, or until stone passage if before than 6 weeks. Follow-up varied from 15 days to 48 days. In some trials, several drugs were given to the treatment groups; for three studies, corticosteroids were given to the treatment groups in addition to the calcium- Figure 3: Forest plot of risk ratios of stone passage, stratiﬁ ed by presence of control group
channel blocker nifedipine.40,42,43 The treatment and Sizes of data markers are proportional to the weight of each study in the meta-analysis. Horizontal bars=95% CI.
control groups received NSAIDs in seven trials.40–46 www.thelancet.com Vol 368 September 30, 2006
The primary outcome of interest—the proportion of patients who passed their stones—occurred more often Percentage of patients who
Risk ratio (95%
passed their stones
in the treatment groups than in the control groups in all nine studies. Figure 2 shows the percentage of patients who passed stones, stratiﬁ ed by study group α blockers
and mean stone size for each of the studies. In six trials, information was available for the mean time to stone passage; mean time to passage ranged from 6 days in several treatment groups to 20 days in one control group.40,42,43,45,46,52 In ﬁ ve of these six trials, the treatment group had shorter mean times to stone expulsion than The ﬁ xed-eﬀ ects Mantel-Haenszel pooled risk ratio was 1·65 (95% CI, 1·45–1·88), p<0·0001, indicating a
65% higher risk of stone passage associated with medical therapy. There was no signiﬁ cant heterogeneity in the studies pooled (χ2 test, p=0·196). The I2 statistic was 28%. The pooled risk diﬀ erence was 0·31 (0·25–0·38). The number needed to treat was 4. When Calcium-channel blockers
dropouts were excluded, the pooled risk ratio was 1·66 (1·46–1·88), p<0·0001. The baseline occurrence of stone passage in the control group, across all nine studies, was 0·47. Table 2 shows the eﬀ ect of varying the background occurrence of spontaneous stone passage on the number needed to treat, which ranged from three patients (background occurrence=60%) to 16 patients (background occurrence=10%). The Rosenthal fail-safe number was calculated as 175 studies, and the Rosenberg fail-safe N was 105 additional non-signiﬁ cant studies necessary to reduce the pooled risk ratio to Calcium-channel blockers+steroids vs steroids Figure 3 shows the study-speciﬁ c risk ratios and the pooled estimate for the nine studies included, and for the ﬁ ve that did not have a true control. When these ﬁ ve α blockers vs calcium-channel blockers
studies were analysed with the previous nine, the overall risk ratio remained signiﬁ cant at 1·52 (1·39–1·65), p<0·0001. There was no signiﬁ cant heterogeneity with inclusion of these studies (χ2=13·30, p=0·425). The I2 statistic was 2·3%, which indicates that the variation in eﬀ ect estimates is probably due to sampling error within trials rather than heterogeneity across trials.
The four studies in which treatment groups were given Data are % (number) unless otherwise indicated. *Control groups also received phloroglucinol (or its trimethoxy tamsulosin (without calcium-channel blockers) were benzene derivative). Both treatment and control groups received cotrimoxazole and diclofenac. †Treatment and pooled. This yielded a risk ratio of 1·52 (1·23–1·86), control groups received a cocktail of medications including diazepam, tramadol, aesculus, and diclofenac. ‡Control group also received phloroglucinol. Both treatment and control groups received ketoprofene.
p<0·0001. When all studies in which an α blocker was used (n=5) were summarised, the pooled risk ratio was Table 3: Outcomes of the studies pooled and of the studies excluded for absence of a true control,
1·54 (1·29–1·85), p<0·0001. In the two studies in which stratiﬁ ed by treatment regimen
the intervention was nifedipine (without α blockers), the risk ratio was 1·51 (1·18–1·94), p=0·001. In three trials, to pool the two studies in which neither treatment groups the intervention was nifedipine with corticosteroids. nor control group received NSAIDs.52,53 The resulting risk When pooled, these studies resulted in a risk ratio of ratio was 1·74 (1·29–2·33), p<0·0001. The pooled risk 1·90 (1·51–2·40), p<0·0001. None of the pooled risk ratio for the seven studies in which NSAIDs were used in ratios showed statistically signiﬁ cant heterogeneity both treatment and control groups was 1·63 (1·41–1·88), across studies.
Although the eﬀ ects of calcium-channel blockers and In some studies, corticosteroids were used in the α blockers cannot be statistically isolated from those of treatment group; in others, they were used in both the other medications used, we did a subgroup analysis treatment and control groups. Table 3 summarises the www.thelancet.com Vol 368 September 30, 2006
given tamsulosin reported lower analogue pain scores.44 Fewer days lost from work, fewer emergency department visits, and fewer surgical procedures in the treatment group than in the control group were reported in one trial.40 Side-eﬀ ects were not rigorously reported for all studies. However, the occurrence of therapy-related transient hypotension and palpitations was low at Discussion
The pooled results of the randomised trials suggest that
pharmacotherapy helps with passage of distal ureteral stones. Patients treated medically with calcium-channel blockers or α blockers had a 65% greater likelihood of spontaneous stone passage than did patients not given these drugs. This beneﬁ cial eﬀ ect was consistent for both types of medical therapy. With the low risk-proﬁ le of these drugs and their wide therapeutic window, our Figure 4: Inﬂ uence analysis
results suggest that treating physicians should consider a new algorithm for the management of urolithiasis, in results for the 14 randomised controlled trials listed in which treatment begins with a course of medical the forest plot (ﬁ gure 3), with consideration of steroid therapy, unless medically contraindicated.
use. When the studies of α blockers versus control41,44,46,52,53 Our ﬁ ndings are consistent with what is understood were compared with those of α blockers and of ureteral pathophysiology associated with urinary-stone corticosteroids versus control,43 the incremental beneﬁ t obstruction. In animal models, ureteral stones result in of steroid use was small. A similar ﬁ nding was noted for increased amplitude of ureteral smooth-muscle steroid use with calcium-channel blockers. There were contraction, decreased frequency of contractions, and three studies in which the eﬀ ects of α blockers could be decreased ureteral pressure.12 Evidence suggests that directly compared with that of calcium-channel relaxing the ureter in the region of the stone and blockers.37,43,52 Two of these studies43,52 reported no increasing hydrostatic pressure proximal to the stone signiﬁ cant diﬀ erence in stone expulsion for the two drug help to facilitate ureteral stone passage.17 Such relaxation types, but one study37 noted that α blockers were better can be accomplished by giving adrenergic α-antagonists than calcium-channel blockers (risk ratio 1·26; and calcium-channel blockers,13,15 the eﬀ ects of which 1·10–1·44).
are mediated through the active calcium-channel pumps We did an inﬂ uence analysis, in which the pooled and adrenergic α-1 receptors present in ureteral smooth estimates were recalculated omitting one study at a time. Figure 4 shows that the summary estimate of eﬀ ect remained signiﬁ cant throughout this analysis. Resim expulsive medical therapy for urolithiasis. Several and colleagues’44 study had the largest eﬀ ect on the overall studies have reported that patients given such treatment estimate; with its omission, the overall risk ratio was 1·73 have a signiﬁ cantly reduced time to stone passage,42,43,45,46,52 signiﬁ cantly fewer pain episodes,44,46 lower analogue pain Additionally, the three studies that included a scores,44 and need signiﬁ description of the randomisation procedure (webtable 2) analgesics.42,43,46 With the caveat that side-eﬀ ects were were analysed separately. The pooled risk ratio from this poorly categorised in these trials, calcium-channel analysis was 2·14 (1·60–2·86), p<0·0001. We did a blockers and α blockers seemed to be well tolerated, separate sensitivity analysis of the six studies for which since there were only four patients across all studies See Online for webtable 2
there was no loss to follow-up (webtable 2). The pooled who discontinued therapy.42,43risk ratio from this analysis was 1·52 (1·30–1·77), When medical therapy for urolithiasis is successful, p<0·0001. Finally, only those studies that were published surgical intervention is unnecessary. This advantage is as full manuscripts were pooled (webtable 2). The pooled important because the risks related to surgical risk ratio from this analysis was 1·68 (1·42–1·97), intervention are not trivial.23–25,27 Studies have reported
overall complication rates after ureteroscopy of 10–20%, Three trials showed less need for analgesics in the with major complications—eg, ureteral perforation, treatment group than in the control group, as expressed avulsion, and stricture—occurring in 3–5% of by the mean amount of diclofenac used.42,43,46 Two studies procedures.21–23 Accumulation of perirenal ﬂ uid and showed fewer episodes of acute pain in patients given subcapsular bleeds have been reported in 15–32% of expulsive therapy,44,46 and one study showed that patients patients treated with shock-wave lithotripsy.20,27 This risk www.thelancet.com Vol 368 September 30, 2006
is even more problematic since the re-treatment rate for occurrence of stone passage in the controls is lower shock-wave lithotripsy ranges from 4–50%.18,54 (30%), the sample size required would be 532; if the Furthermore, the potential cost savings of expulsive occurrence is higher (60%), the study would require medical therapies in lieu of surgical interventions is 110 patients.
large. In the USA alone, total annual expenditure for Thus the published evidence provides support for the individuals with inpatient and outpatient claims for a use of expulsive medical therapy in the treatment of primary diagnosis of urolithiasis increased by 50% urolithiasis. Although minimally invasive procedures between 1994 and 2000. Of the US$2·1 billion spent on have evolved that allow for resolution of stone burden this disease in 2000, $490 million were for emergency with less morbidity than traditional open surgery, these department services.7 These numbers do not take into procedures expose patients to anaesthetic and surgical account the indirect costs, such as lost wages from risks that might be unnecessary. Although a large missed work.
conﬁ rmatory trial is advisable, our ﬁ ndings suggest that Surgical intervention for urolithiasis is costly, with medical therapy might provide a viable alternative to reported estimates ranging from US$2645 for surgery in patients with urolithiasis who are amenable to
ureteroscopy to $4225 for shock-wave lithotripsy, with conservative management.
repeated therapy often needed.18,26 Expulsive medical Contributors
therapy, which relies mainly on generic drugs, is J M Hollingsworth participated in the study conception and design, the
inexpensive. Based on drug-cost data obtained from the acquisition of data, the analysis and interpretation of data, drafting of the
University of Michigan pharmacy, costs would range manuscript, critical revision of the manuscript, the statistical analyses,
and has seen and approved the ﬁ nal version. M A M Rogers participated from US$10·74, for a 28-day course of doxazosin, to in the analysis and interpretation of data, drafting of the manuscript, $104·41 for a 42-day course of tamsulosin, the only critical revision of the manuscript, statistical analyses, supervision of the non-generic medication. study, and has seen and approved the ﬁ nal version. S R Kaufman participated in the analysis and interpretation of data, critical revision of Our main meta-analysis is potentially limited by clinical the manuscript, statistical analyses, administrative and technical (not statistical) heterogeneity, in view of the variation in support, supervision of the study, and has seen and approved the ﬁ nal the drugs given to the diﬀ erent treatment groups. To version. T J Bradford participated in the acquisition of data, the analysis address this issue, we analysed drug classes separately. and interpretation of data, critical revision of the manuscript, administrative support for the study, and has seen and approved the Both classes of drugs seemed to be beneﬁ cial, though the ﬁ nal version. S Saint participated in the study conception and design, results suggested that there might be an additive eﬀ ect the interpretation of data, critical revision of the manuscript, when combined with corticosteroids. Further exploration administrative and technical support, supervision of the study, and has of combined treatments might be useful.
seen and approved the ﬁ nal version. J T Wei participated in the analysis and interpretation of data, critical revision of the manuscript, Furthermore, our results might have been aﬀ ected by supervision of this study, and has seen and approved the ﬁ nal version. publication bias, in which positive studies are more likely B K Hollenbeck participated in the study conception and design, the to be submitted and published than negative ones. acquisition of data, analysis and interpretation of data, drafting of the Although the fail-safe numbers did not show evidence of manuscript, critical revision of the manuscript, supervision of the study, and has seen and approved the ﬁ nal version. publication bias, this potential drawback can only be
adequately assessed through registration of prospective Conﬂ ict of interest statement
J M Hollingsworth, M A M Rogers, S R Kaufman, T J Bradford, and trials and not through retrospective review of published B K Hollenbeck declare that they have no conﬂ ict of interest. S Saint and studies, as exists here.55 We did speciﬁ cally ask T J Wei have been paid consultants to Sanoﬁ Aventis within the past investigators and the drug companies about unpublished 5 years (none of Sanoﬁ Aventis’ products were used in the trials studies in our correspondence. All ﬁ ve investigators and one of the three drug companies that responded to our Acknowledgments
inquiry denied knowledge of unpublished data.
We thank Loris Borghi, Thomas Cooper, Bora Küpeli, Sefa Resim, Erdal Yilmaz, and Christopher Parow, director of Global Scientiﬁ c limitation relates to the overall quality of the trials, eight Support at Abbott Laboratories, for responding to our enquiries about of which were not blinded and six of which did not their studies; Joyce Chen from Global Drug Information Services at describe the randomisation procedures in detail. Schering-Plough Corporation, who provided us with an additional Additionally, most studies were done in Mediterranean literature search at our unsolicited request; Rita Galin, Russian interpreter from the University of Michigan Health System, for her countries, and it is unknown whether the treatment help in translating an article for review; and Alison Grodzinski, response would vary in patients from diﬀ erent settings. research librarian at the University of Michigan Medical School, who A deﬁ nitive high-quality randomised controlled trial is did an independent literature search to conﬁ rm the exhaustiveness of cacy of calcium-channel our own. J M Hollingsworth is supported by a National Institutes of Health research-training grant (T32 DK007758). M A M Rogers is blockers and α blockers in patients with urolithiasis. supported by a Blue Cross Blue Shield of Michigan Foundation award Since preliminary studies tend to overestimate treatment (793.RFP) an Agency for Healthcare Research and Quality award (R01 eﬀ ects, we used the lower conﬁ dence limit of the pooled HS015571). S R Kaufman is supported by a National Institutes of Health/National Institute of Diabetes and Digestive and Kidney relative risk (1·45) and determined that a two-armed trial Diseases award (R21 DK067451-01A1) and a Blue Cross Blue Shield of would need to include 226 patients (113 in each arm), in Michigan Foundation Award (793.RFP). T J Bradford is supported by a view of the background occurrence of stone passage of DOD FY05 Idea Development with Nested Resident and Medical 0·47, with α=0·05 (two-sided) and power=0·90. If the Student Traineeship Award (PC051081). S Saint is supported by a www.thelancet.com Vol 368 September 30, 2006
National Institutes of Health/National Institute of Diabetes and 20 Rubin JI, Arger PH, Pollack HM, Banner MP, Coleman BG, Digestive and Kidney Diseases award (R21 DK067451-01A1), an Mintz MC. Kidney changes after extracorporeal shock wave Advanced Career Development Award from the Department of lithotripsy: CT evaluation. Radiology 1987; 162: 21–24.
Veterans Aﬀ airs Health Services Research and Development Oﬃ 21 Harmon WJ, Sershon PD, Blute ML, Patterson DE, Segura JW. (RCD-00-006), a Merit Award from the VA Health Services Research Ureteroscopy: current practice and long-term complications. J Urol ce (SAF 04-031), and a grant from the Blue Cross 1997; 157: 28–32.
Blue Shield of Michigan Foundation (793.RFP). 22 Schuster TG, Hollenbeck BK, Faerber GJ, Wolf JSJ. Complications J T Wei is supported by a National Institutes of Health/The National of ureteroscopy: analysis of predictive factors. J Urol 2001; 166:
Institute of Child Health and Human Development award (U01 HD041249-01), a National Institutes of Health/National Cancer 23 Daniels GF, Garnett JE, Carter MF. Ureteroscopic results and Institute award (R01 CA095662), a National Institutes of Health/ complications: experience with 130 cases. J Urol 1988; 139: 710–13.
National Cancer Institute award (U01 CA111275), a National Cancer 24 el-Faqih SR, Husain I, Ekman PE, Sharma ND, Chakrabarty A, Institute SPORE award (P50 CA069568), a National Institutes of Talic R. Primary choice of intervention for distal ureteric stone:
ureteroscopy or ESWL? Br J Urol 1988; 62: 13–18.
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Trattamento dei linfonodi regionali….pg 12 Chemioterapia………………………………….pg 14 Radioterapia……………………………….……pg 16 Qualità di vita………………………………….pg 18 La struttura portante di queste linee guida si ispira principalmente alle linee guida Lo scopo è quello di dare un’informazione aggiornata e dettagliata , basata s