Editors: 1. Please add a clear competing interest statement for all authors to the paper, summarizing your forms.

Transcription

1 Dear Dr. Tonks: Thank you for allowing us to resubmit our manuscript entitled, Should We Still Prescribe Alpha Blockers for Ureteric Stones? A Systematic Review and Meta-Analysis. We greatly appreciate the feedback from the editors and reviewers, in response to which we have made the changes listed below. We very much hope that given our changes, the editors at The BMJ will decide that this manuscript warrants publication. Editors: 1. Please add a clear competing interest statement for all authors to the paper, summarizing your forms. As requested by the editors, we have added the following statement to the end of our paper, Competing interests: All authors have completed the ICMJE uniform disclosure form at and declare: JMH received research grants from the Agency for Healthcare Research and Quality, the Urology Care Foundation, and Blue Cross Blue Shield of Michigan during the conduct of this study. 2. Please mention in the discussion that among 53 studies only a handful concealed allocation adequately and only 6 were masked/blinded. And discuss the implications for bias. As requested by the editors, we now state this limitation and its implications on our findings in our Discussion. In paragraph 2 on page 20, we write, Another limitation pertains to the overall methodological rigor of the pooled studies. Only a handful concealed allocation adequately, and just six studies reported blinding of outcome assessment. Given that the inclusion of less rigorous studies could lead to misestimation of the true intervention effect, we conducted separate sensitivity analyses, in which we recalculated our summary estimates excluding data from nonplacebo-controlled studies and those where the risk of bias was judged high. While our summary estimates were attenuated, the benefit of alpha blockers persisted. 3. Your searches went up to Oct Could they be updated further? As requested by the editors, we have updated our search, which now runs through 10 July In the What This Paper Adds box you mention a focus on patient-centric outcomes. Are these outcomes identified by patients as important or by the investigators who think they are important to patients?

2 To clarify, no patients were involved in setting the research question or the outcome measures. Therefore, we have edited the What This Paper Adds box. It now reads, We found a benefit to medical expulsive therapy for multiple health outcomes such as ureteric stone passage and need for surgical interventions. 5. Please report data on the primary outcome of each trial (outcomes in the MA are a source of controversy for the reviewers). As requested by the editors, we have added a column to Table 1, indicating the primary outcome for each included trial. Of note, the authors of several studies did not differentiate between primary and secondary outcomes. This is conveyed in Table 1, as well. 6. Studies are cited by number in text but by name in figures. This is confusing. In addition to author names, we now include reference numbers in our figures. 7. Page 16: Pickard study is the most influential (Fig S4), reducing RR to 1.23, but other studies almost as influential, and likely to have similar impact on RR. We have expanded the discussion of our influence analysis. In paragraph 3 on page 16, we now write, Among studies where the baseline risk was high, those by Pickard, Furyk, and Desai were noted to be most influential on our pooled estimate of ureteric stone passage (Supplementary Figure 4). With omission of the study by Pickard and colleagues, the pooled risk ratio was 1.23 (1.13 to 1.35; τ ; I %). Removing the Furyk and Desai studies, the pooled risk ratios were 1.22 (1.12 to 1.35; τ ; I %) and 1.17 (1.08 to 1.30; τ ; I %), respectively. 8. There are two versions of figures 3B and 3C, and this is unexplained. It would be better to use consistent RR scale for Fig 3. The two separate forest plots for Figures 3B and 3C conveyed results from our stratified analyses on ureteric stone size (small versus large) and location (upper and middle versus lower). To avoid confusion, we have combined them such that there are now single panels for both Figures 3B and 3C. In addition, we now use a consistent risk ratio scale for Figure Fig S1 would be better ranked by rate than country name. As requested by the editors, we have updated Supplementary Figure 1 such that countries are now ranked by their baseline rate of stone passage (versus their name). 10. Giving p values to 3 decimal places is excessive. As requested by the editors, we have reduced the number of decimal places reported for P- values to two.

3 Reviewer #1: Major comments: 1. Was there an age and/or gender analysis possible? This may be relevant as we all know as urologists doing endourological procedures that ureters in old women and young men are really different in terms of compliance. We are grateful for the reviewer s critique. We agree that these outcomes may be of interest; however, gender-specific outcomes were only reported in two of the 56 studies. The only specificity regarding age was the restriction to adult patients. In meta-regression, we assessed whether the interaction between gender and age modified the risk ratio for stone passage. It did not (P=0.46). Future studies may benefit from either a person-level (hierarchical) metaanalysis when data are available or age-gender-specific reporting. 2. The only comment I have on the reliability of the results is the absence of homogeneity in the assessment of stone passage. Three categories exist: those who got the stones and bring it back; those who did not see the stone and have control imaging; those who did not see the stones and do NOT have control imaging. We never have these figures. While we do not know about those patients who passed their stone and brought it in for analysis, we do know whether patients had follow-up imaging to confirm stone passage based on trial reporting. As we now describe in paragraph 3 on page 15, when we restricted our analysis to studies where computed tomography was used, the risk ratio for stone passage was 1.64 (1.31 to 2.16). When restricted to studies reporting any imaging during follow-up (computed tomography, X-ray, or ultrasound), the risk ratio was 1.54 (1.41 to 1.70). 3. The comments about the reliance of absence of symptoms have to be clarified for the readership page 21, in terms of clinical implications. We have removed the language pertaining to the reliance on symptoms as a marker for stone passage. 4. I think the statement against the Pickard study is not fair. The choice of having chosen a need for subsequent intervention as a primary outcome is highly relevant for surgeons, and probably better in terms of clinical practice than stone passage. This is a discussion that could never end, of course. We agree with the reviewer, and we now acknowledge the relevance of subsequent intervention to surgeons who care for patients with kidney stones in paragraph 1 on page 22. Here we write, A second important difference between the Pickard study and most other randomised controlled trials on medical expulsive therapy relates to how spontaneous stone passage was defined. Imaging evidence has been standard assessment, yet investigators in the Pickard study chose instead absence of need for additional interventions to assist stone passage at four weeks after randomisation. Compelling arguments can be made that this endpoint is highly relevant to surgeons, but the degree to which intervention rates accurately approximate spontaneous stone passage is uncertain.

4 5. But I would go further. If I fully accept the results of the present paper (that is not a revolution but a fact that many other studies grouped together can swallow the results of one RCT, even big), then I have some big issues about clinical practice: a. In France, like in several other countries, an uncomplicated renal colic is treated by medications, with NO indication for imaging in an emergency setting. This means that the size and location of the stone is not known in these cases who go back home. But they are precisely the ones who would benefit from alpha blockers. Thus, the opinion of the authors that focused indications are relevant are not to be translated to clinical practice. The reviewer raises an important point. A stone size-based approach to the use of alpha blockers requires patients with suspected ureteric stones to undergo radiologic testing. Under current guidelines on urolithiasis from the European Association of Urology, immediate imaging is indicated in the evaluation of all patients who present with acute flank pain. However, in many emergency departments, particularly for patients with known histories of urinary stone disease, imaging is deferred until the time of primary or specialty care follow-up, which could delay initiation of expulsive therapy. Moreover, renal ultrasonography is often used as the primary diagnostic tool, from which stone size cannot always be accurately assessed. While a noncontrast computed tomography scan should be obtained subsequently to confirm a stone diagnosis, many times one is not. We now acknowledge these clinical challenges for the implementation of our findings in the Discussion in paragraph 2 on page 23. b. For the deferred imaging, a CT-scan is not necessarily recommended in all patients and some patients can have deferred ultrasound, which is often unable to provide the data needed in terms of size of the stone and location. We refer the reviewer to our response to item #5a above. c. For the surgeon, and the healthcare system, the real issue is really whether this patient will come back to the emergency room, or will need surgery, rather than spontaneous stone passage. We agree with the reviewer. For this reason, we examined other secondary outcomes, including need for surgical intervention and hospitalisation. As described in our Results (paragraph 2, page 17), patients who received alpha blockers had a significantly lower risk of surgical intervention (32 studies, 3758 patients: risk ratio 0.44, 0.37 to 0.52; τ ; I %; moderate quality evidence). Moreover, patients who received alpha blocker therapy needed hospitalisation less often than controls (8 studies, 1007 patients: risk ratio 0.37, 0.22 to 0.64; τ ; I %; moderate quality evidence). d. Spontaneous stone passage is still a blurry item with a lot of potential confounding factors not mentioned by the authors: drinking amount (heterogeneous but really important in order to get the stone out), age, associated medications, gender, prostate size, and number of stones in the ureter.

5 We agree that ureteric stone passage can be affected by a variety of factors. It was for this reason that we only included studies in our meta-analysis that were randomised. The process of randomly assigning patients to treatment or control should attenuate such differences. However, a more clear assessment of the effects of age, associated medications, gender, prostate since, and number of ureteric stones would warrant inclusion of such variables in the design of a large international trial. Our study clearly shows that there are international differences in the baseline rates of stone passage suggesting that it may be possible that there are patient-related factors that modify the observed association. 6. Even if I support the information given here that is probably nearly the best piece of information we can summarize from the literature, it does not clearly gives an answer for clinical practice. Choosing between this paper and the isolated results of the paper from Pickard et al is a difficult decision, that needs further discussion The limits of the study are well stated and in particular the bias of negative study non published. The efforts made by the authors to conduct sensitivity analysis, subgroups examination are sound. To clarify, we are not asking the reader to disregard the study from Pickard and colleagues. Rather, our intent was to integrate findings from it with those from a number of other studies on the same topic. As noted in our Results, the Pickard study was methodologically rigorous and well executed. Despite these strengths, it was not designed to evaluate for heterogeneity in effects across clinically relevant subgroups (e.g., patients with small versus large stones, those with stones in the upper/middle versus lower ureter). Nor was it powered to examine important secondary endpoints (e.g., need for hospitalisation). By pooling data from multiple trials, we are able to achieve the sample sizes necessary to estimate such effects. Minor comments: 1. I do not understand the statement about the stones of lower ureter in the talk home message page 2 as this is not in accordance with the main results of the abstract stating no difference about stone location. We apologize for any confusion. We now write in the first paragraph of the Discussion (page 19), The pooled results of the RCTs suggest that alpha blockers help facilitate the passage of larger ureteric stones regardless of their location. Reviewer #2: 1. My biggest question is whether a meta-analysis is needed or indeed valid in this area. Most people will admit evidence was very weak previously with much heterogeneity in the studies. So when two well-done studies come along is it right to still mix the old weak evidence with the new? Regarding this, I read with interest the recent BMJ blog by Ian Roberts on misleading meta-analyses of small trials ( One does wonder if we will one day discus MET in the same way?

6 We greatly appreciate the reviewer s thoughtful feedback. We are familiar with Mr. Roberts commentary, suggesting that we should discount (or even dismiss) findings from small trials. We are also familiar David Tovey s (Editor in Chief of the Cochrane Collaboration) response, in which the issue of small study bias is acknowledged. However, Mr. Tovey also emphasizes the importance of critically appraising the methodological quality of all identified studies as part of the systematic review approach. As we note in our response to item #6 from Reviewer #1, we do not doubt the internal validity of the findings from the Pickard study. However, the wide variation in baseline stone passage rates across countries (Supplementary Figure 1) does raise the question of their external validity. Such variation could be due to peculiarities of the healthcare systems in particular countries, national differences in the speed with which patients are investigated, or important racial/ethnic differences in the pathology and natural history of urinary stone disease. By accounting for baseline rates of stone passage, we believe our estimates of alpha blockers effects to be more generalizable. We also recognize that not all pooled studies were as methodologically rigorous as the Pickard study. Motivated by this, we conducted separate sensitivity analyses, in which we recalculated our summary estimates excluding data from nonplacebo-controlled studies and those where the risk of bias was judged high. While our summary estimates were attenuated, the benefit of alpha blockers persisted. We acknowledge the possibility of small study bias, as well. Therefore, we calculated the risk ratio for only large studies (sample size >100). This yielded a risk ratio of 1.39 (1.26 to 1.58) for ureteric stone passage. In light of these sensitivity analyses, we feel that blanket acceptance of the findings from Pickard and colleagues, without placing them into context with those from older studies, would be a mistake. 2. Having said that is it correct to change established practice on the basis of a single trial? My own personal thoughts are this has finally resolved that MET does not work in upper or mid ureter, so should not be used for all ureteric colic. The evidence seems strong that it does not work for small <5 mm stones. I am using it selectively for stones 5-10 mm in the distal ureter. Our findings on ureteric stone size would support the reviewer s current practice. 3. I presume the paper is reviewed by a statistician for verification of the complex statistical methods described. The statistical methods used in this meta-analysis are quite standard for analysts who are experienced in this field. Our analysts have over 30 years of combined experience in the design and analysis of clinical research and teach meta-analytic techniques to the Robert Wood Johnson Foundation Clinical Scholars. However, we defer to the editors regarding the need for further statistical review. 4. On page 17, the authors report the summary estimates limited to the moderate/low risk of bias studies. I wonder how much relevance the high risk studies are in this meta-analysis at all. I would also like to understand what the effects on the secondary outcomes were if similarly, high (and maybe even moderate) risk studies were excluded especially as the secondary outcomes in this meta-analysis (intervention) was the primary outcome for SUSPEND.

7 Unfortunately, secondary outcomes were inconsistently captured across the studies. When we subset further by risk of bias, study numbers for pooling are low, affecting the precision of our estimates. That being said, we performed sensitivity analyses for outcomes where there were at least ten studies deemed to be of moderate/low risk of bias. There was one (passage rates for lower ureteric stones), for which we observed a consistent benefit to alpha blocker therapy use (risk ratio 1.38, 1.17 to 1.71; τ ; I %). 5. The point above about outcomes is actually very relevant. The primary outcome here is stone passage. In Supplemental Table 1, the stone passage rate is listed as N/A for the SUSPEND study (Pickard, 2015). Therefore, is data from the Pickard SUSPEND trial contributing to the primary outcome of this meta-analysis? I think this should be made VERY clear if it is not. The primary outcome in SUSPEND was spontaneous stone passage in 4 weeks, defined by the absence of need for additional interventions to assist stone passage at 4 weeks after randomisation. So presumably the results do count as stone passage? If the results do not count as stone passage, can the authors request that data given the importance of that towards a new meta-analysis. I have to say that it is odd that the SUSPEND Trial paper states, We also noted no difference in stone passage at up to 12 weeks but data not shown. One would think that is very relevant data! To clarify, we did include the Pickard study in our main analysis, examining the effects of alpha blocker therapy on stone passage rates. As such, we have corrected Supplemental Table 1 as to avoid any confusion for the reader. We do point out in the Discussion (paragraph 1, page 22) the definition of stone passage in the Pickard trial ( absence of need for additional interventions to assist stone passage at four weeks after randomisation ). 6. It surprises me somewhat in Figure 4A, that when considering the Baseline Risk >60% group, there is still an overall benefit to MET for preventing intervention despite the 2 largest trials (contributing 66% of patients) showing no benefit. (although I guess that is just the weighting of the meta-analysis) We further assessed the weighting methods. When we pooled using a restricted maximumlikelihood random-effects model, the risk ratio was 0.52 (0.35 to 0.85), which is similar to the profile likelihood random-effects model in the manuscript (0.53, 0.33 to 0.78). When we used a bootstrapped DerSimonian-Laird random-effects model with 10,000 repetitions, the risk ratio was 0.52 (0.34 to 0.79). When we conducted a sensitivity analysis model using the upper 95% limit of the level of heterogeneity (which was 77%), the risk ratio was 0.50 (0.29 to 0.86). Therefore, the results were quite robust to the method of pooling. Please keep in mind that the weights are not determined by sample size alone. They are also influenced by the number of events surgical procedures experienced in each trial.

8 7. I suggest mentioning in the discussion that MET is an off licence prescription this would be of relevance to the prescribing readership. As requested by the reviewer, we now include this information in our Introduction. In the first paragraph on page 5, we write, Contemporary practice guidelines from leading professional societies recognize the offlabel use of alpha-adrenergic antagonists (or alpha blockers) as an initial treatment option for patients with newly diagnosed, uncomplicated ureteric stones less than 10 mm in size, whose symptoms are controlled. 8. Page 19 paragraph 2: My understanding was that alpha receptors are primarily located in the distal ureter, which is what I think the authors are saying. Thus, I don t understand how they then conclude that one would expect (alpha blockers) to exert their effect throughout the ureter. Again my understanding is that the evidence for MET in the mid and upper ureter is fairly weak so I am surprised by the strong findings of this meta-analysis to the contrary. The reviewer is correct. Alpha-adrenergic receptors are concentrated in the lower ureter. Yet, we observed benefit to treatment for upper and middle ureteric stones. We now explain on page 20. Here we write, The effects on alpha blockers on passage are thought to result from ureteric smooth muscle relaxation mediated by binding of the drug to alpha-adrenergic receptors in the region of the stone. Yet, while alpha-adrenergic receptors are concentrated in the lower ureter, studies have shown that they are present along the entire length of the human ureter. Thus, one could anticipate that alpha blockers exert their effect throughout the ureter, as we found in our pooled analysis. 9. I am confused by which conclusion is being drawn. At the start of the discussion, the authors state the clear benefit to alpha blockers regardless of stone size or location. Then on page 22 paragraph 2, they state that the average patient presenting to ED with ureteric colic may not be helped (this study) suggests that one with a stone 5 mm in size or larger could (be). We apologize for any confusion. We now write in the first paragraph of the Discussion (page 19), The pooled results of the RCTs suggest that alpha blockers help facilitate the passage of larger ureteric stones regardless of their location. 10. Much is made in the discussion about the SUSPEND trial and rightly so as this has led to the confusion about MET and this repeat meta-analysis. I do feel more discussion about the Furyk trial should also be included, given that both these trials were published at a similar time with fairly similar results (especially as Furyk showed statistical benefit for 5-10mm distal stones).

9 As requested by the reviewer, we now discuss the Furyk trial. In paragraph 2 on page 19, we write, Our findings corroborate results from another high-profile randomised controlled trial reported by Furyk and colleagues (reference #82) that was published shortly after the Pickard study. This double-blind, placebo-controlled, multicenter trial from Australia demonstrated no benefit overall of alpha blocker therapy for patients with lower ureteric calculi less than or equal to 10 mm in terms of spontaneous passage; however, on a prespecified subgroup analysis of large stones (i.e., those 5 to 10 mm), tamsulosin use was associated with significantly higher rates of passage. 11. I feel page 21, paragraph 2 is incorrectly suggesting no patient was re-imaged in the SUSPEND trial. 53% had follow-up imaging in SUSPEND (which compares to ~80% in the Furyk study which mandated CT follow-up). We now clarify that follow-up imaging was obtained for some patients enrolled in the Pickard study. In paragraph 1 on page 22, we write, While additional imaging was obtained when clinically indicated (e.g., for continued pain, development of infection), just over half of participants were reimaged, raising the possibility of silent obstruction and late secondary complications. 12. Ultimately I am not sure that any further meta-analysis is going to answer this question for clinicians and I suspect this debate will rumble on. You either believe one or two modern RCT s or you believe multiple pooled studies. Thus, I am not sure that any further metaanalysis is statistically that valid and should possibly be limited to only the highest quality; lowest risk of bias studies. We kindly refer the reviewer to our responses to item #1 above and item #6 from Reviewer #1 that relate to the additional subgroup and sensitivity analyses, which this study permitted us to perform, as well as the heterogeneity of existing trials with regards to the rates of baseline stone passage. The two modern RCTs (as referred) were conducted in two developed countries, both with a high baseline risk of stone passage. Can one infer that these results would predictably occur in other countries, particularly those with low baseline risks of stone passage? We would argue the importance of well-executed systematic reviews and meta-analyses for assessing the entire body of evidence in order to address a clinical question. Reviewer 3 1. I have no doubt that this meta-analysis has been performed to a high degree of observance of relevant statistical principles and by authors who are well known for their interest in MET (i.e., non-surgical management of acute ureteric obstruction).

10 2. Their previous analysis and the Cochrane review have highlighted the poor quality of the vast majority of the many publications on alpha adrenergic and calcium channel blocking medications, begging the question on the value of merely summating these data in further meta-analyses or, preferably, undertaking one final prospective blinded randomised trial of higher quality than anything previously published. I believe that the study by Pickard et al. published in Lancet (2015,386:341) officially sanctioned by UK NHS research was sufficiently powered and conducted according to the highest possible quality by a clinical trials unit of international renown, to provide a reliable outcome, that MET is of no benefit. We appreciate this reviewer s informed opinion on this matter. While we agree with the assessment that many of the prior studies had serious limitations, we disagree with his conclusion that the Pickard study (of which he has an excellent appreciation in his role as the Chair of the Trial Steering Committee) provides a definitive answer and thereby closure on the question of the role of expulsive therapy for all patients with ureteric stones. First, it is one of the guiding principle of evidence-based clinical practice (and the founding principle of the Cochrane Collaboration) that few questions in healthcare are adequately addressed by reviewing the results of a single study. Instead, systematic reviews serve to summarise the entire body of evidence for a focused clinical question using well-defined, rigorous methodology as we have sought to do herein. Based on our updated literature search, there are 56 unique randomised trials addressing the role of alpha blockers for patients with ureteric stones. While the study by Pickard and colleagues stands out for its methodological rigor, there are other well-designed studies that must also be considered. In the revised manuscript, we have placed an increased focus on the results of our predefined sensitivity analysis focused on studies judged to be of lower risk of bias. Second, there are specific issues of the Pickard study that justify this systematic review: 1) the investigators definition of stone passage, which was selected to conform with clinical practice in the United Kingdom but may not satisfy the information needs of patients, clinicians, and policymakers in other countries including the United States; 2) the high rate of spontaneous stone passage in the Pickard study, which limits the generalizability of its results; and 3) the issue of statistical power to analyze subgroups based on ureteric stone size and location. The point estimates for these analyses in the Pickard study are consistent with a potential benefit of alpha blocker therapy, but the associated confidence intervals are relatively wide. Metaanalyses like ours have an established role in addressing questions as they relate to subgroups. Hollingsworth et al. have obviously felt it necessary to spend time in particularly analysing Pickard et al. Their two major criticisms are that stone passage was not objectively demonstrated by routine imaging and insufficient numbers of patients with larger stones were analysed to conclude that MET was not beneficial, even in this subgroup. Pickard et al. have discussed at length their trial design as being relevant to UK practice, where passage of the stone is assumed from resolution of symptoms and the very small risk of asymptomatic persistent ureteric obstruction thought not to justify the expense and inconvenience of follow-up CT or MR imaging. I would suggest that EU guidelines represent a counsel of perfection unrealised in the majority of European countries; I cannot comment on US practice. As for the possibility that MET is still effective for larger stones (0.5 1 cm), I believe that the numbers in each of the three groups randomised by Pickard et al. (90-100; Tamsulosin, Nifedipine, Placebo) were sufficient to draw the contrary conclusion.

11 We agree with the reviewer that Pickard and colleagues have made an exemplary effort at explaining the rationale of their trial design both in their landmark publication in The Lancet, as well as the more comprehensive Health Technology Assessment report. We would ask that the need for a comprehensive systematic review and meta-analysis not be perceived as criticism of the Pickard study or as an attempt to diminish its importance. Our work, however, does seek to meet the information need of various stakeholders (such as guideline developers) that wish to see the Pickard study placed into the context of the entire body of evidence (as discussed above). Moreover, practice patterns differ, as do patient s values and preferences with regards to acceptable risk for the potential downstream adverse consequences of persistent ureteric stones and renal function deterioration. In response to this and others reviewers comments, the last paragraph of the Discussion (related to unanswered questions and future research) addresses the need to include additional patient-related factors in future trials designs and also also examine patients values and preferences concerning acceptable risk of retained ureteric stones versus the potential inconvenience, radiation exposure, and the direct and indirect costs of repeat imaging. Lastly, based on the width of the confidence intervals (see above), we respectively disagree with the reviewer s opinion about the definitive nature of Pickard study s results when it comes to larger stones. I, therefore, do not believe that the conclusions based on an essentially transatlantic view of the status quo, derived from an updated meta-analysis largely based on suboptimal studies should take precedence over a very good investigation conducted over several hospitals widely distributed in UK. I believe the position of the BMJ should be to endorse the conclusions of Pickard et al. published in 2015 and therefore to decline to publish the submitted meta-analysis. An alternative suggestion would be to accept it for publication and in the same issue of the BMJ conduct a debate on the place of MET between senior authors representing the two points of view. We respectfully reject the notion of an essentially transatlantic view. All authors of this study pride themselves on engaging in a dialogue with colleagues around the world and keeping an open mind. Meanwhile, the Pickard study is only one of many studies addressing this question and its investigators chose to define their primary outcome in a manner best suited to guide clinical practice in the United Kingdom, but this definition does not necessarily align with practice in all other countries. In our opinion, it is also not the place of The BMJ to endorse any given perspective but rather to publish the highest quality science that addresses important questions in healthcare. We hope that the editors and reviewers find that our work meets this criterion. We welcome the suggestion of one or more accompanying commissioned editorials (ideally with opposing perspectives) to stimulate a debate. I was Chair of the Trial Steering Committee for the study published by Pickard et al (Ref 10). As such my position was officially independent of the initial planning of the trial and of the activities of the Data Monitoring Committee. I was responsible to the HTA, who commissioned the trial, for checking governance in the processes of recruitment, adherence to research protocol, investigation of trial violations etc. I took no part in preparing the manuscript published last year. I do not feel biased but I obviously have a clearer view of the quality of this trial than as a casual reader of the publication. I appreciate that you and Dr Hollingsworth may disagree.

12 We very much appreciate this transparent disclosure of a potential intellectual conflict of interest. While we respectfully disagree with some of the reviewer s perspectives, we value his detailed insight into the trial of design and conduct of the Pickard study. Reviewer 4: 1. This manuscript is a comprehensive review and analysis of the current body of RCTs regarding alpha blocker use for the management of ureteric stones. Of the available literature, 53 studies were included in this review and meta-analysis which found that patients had a 50% higher likelihood of passing a ureteric stone with alpha blocker therapy. In addition, patients with larger stones had a 57% higher likelihood of spontaneous stone passage and a 50% higher likelihood of passing a ureteric stone in the upper/middle ureter or the lower ureter. Patients on alpha blocker therapy were found to pass their stones in less time, have fewer surgical interventions and hospitalizations, with less pain and rare adverse outcomes. These data support previous meta-analyses that recommend the use of medical expulsive therapy to facilitate spontaneous passage of ureteric calculi, especially in stones >5 mm in size. The results help to substantiate current clinical care and confirms practice guidelines. I do not have the statistical background to adequately assess the various analyses performed, but believe that data is strong enough to support the authors recommendations. We thank the reviewer for his endorsement of our study. Included with our revision letter is a clean copy of our revised manuscript. We have also attached a version of our revised manuscript in which all of the changes noted above are underlined. On behalf of all the authors, we would like to thank you for your time and consideration, including the time that you took earlier to discuss the response letter with us by telephone. We are happy to clarify any additional issues that you may have. We continue to believe that The BMJ is the ideal venue for this manuscript. Best wishes, John Hollingsworth, MD, MSc Associate Professor University of Michigan Medical School