Alpha‐blockers as medical expulsive therapy for ureteral stones

Thijs Campschroer; Xiaoye Zhu; Robin WM Vernooij; MTW Tycho Lock

doi:10.1002/14651858.CD008509.pub3

. 2018 Apr 5;2018(4):CD008509. doi: 10.1002/14651858.CD008509.pub3

Alpha‐blockers as medical expulsive therapy for ureteral stones

Thijs Campschroer ^1,^✉, Xiaoye Zhu ², Robin WM Vernooij ³, MTW Tycho Lock ^2,⁴

Editor: Cochrane Urology Group

PMCID: PMC6494465 PMID: 29620795

Abstract

Background

Ureteral colic is a common reason for patients to seek medical care. Alpha‐blockers are commonly used to improve stone passage through so‐called medical expulsive therapy (MET), but their effectiveness remains controversial. This is an update of a 2014 Cochrane review; since that time, several large randomised controlled trials (RCTs) have been reported, making this update relevant.

Objectives

To assess effects of alpha‐blockers compared with standard therapy for ureteral stones 1 cm or smaller confirmed by imaging in adult patients presenting with symptoms of ureteral stone disease.

Search methods

On 18 November 2017, we searched CENTRAL, MEDLINE Ovid, and Embase. We also searched ClinicalTrials.gov and the WHO Portal/ICTRP to identify all published/unpublished and ongoing trials. We checked all references of included and review articles and conference proceedings for articles relevant to this review. We sent letters to investigators to request information about unpublished or incomplete studies.

Selection criteria

We included RCTs of ureteral stone passage in adult patients that compared alpha‐blockers versus standard therapy.

Data collection and analysis

Two review authors screened studies for inclusion and extracted data using standard methodological procedures. We performed meta‐analysis using a random‐effects model. Primary outcomes were stone clearance and major adverse events; secondary outcomes were stone expulsion time, number of pain episodes, use of diclofenac, hospitalisation, and surgical intervention. We assessed the quality of evidence on a per‐outcome basis using the GRADE approach.

Main results

We included 67 studies with 10,509 participants overall. Of these, 15 studies with 5787 participants used a placebo.

Stone clearance: Based on the overall analysis, treatment with an alpha‐blocker may result in a large increase in stone clearance (risk ratio (RR) 1.45, 95% confidence interval (CI) 1.36 to 1.55; low‐quality evidence). A subset of higher‐quality, placebo‐controlled trials suggest that the likely effect is probably smaller (RR 1.16, 95% CI 1.07 to 1.25; moderate‐quality evidence), corresponding to 116 more (95% CI 51 more to 182 more) stone clearances per 1000 participants.

Major adverse events: Based on the overall analysis, treatment with an alpha‐blocker may have little effect on major adverse events (RR 1.25, 95% CI 0.80 to 1.96; low‐quality evidence). A subset of higher‐quality, placebo‐controlled trials suggest that alpha‐blockers likely increase the risk of major adverse events slightly (RR 2.09, 95% CI 1.13 to 3.86), corresponding to 29 more (95% CI 3 more to 75 more) major adverse events per 1000 participants.

Patients treated with alpha‐blockers may experience shorter stone expulsion times (mean difference (MD) ‐3.40 days, 95% CI ‐4.17 to ‐2.63; low‐quality evidence), may use less diclofenac (MD ‐82.41, 95% CI ‐122.51 to ‐42.31; low‐quality evidence), and likely require fewer hospitalisations (RR 0.51, 95% CI 0.34 to 0.77; moderate‐quality evidence), corresponding to 69 fewer hospitalisations (95% CI 93 fewer to 32 fewer) per 1000 participants. Meanwhile, the need for surgical intervention appears similar (RR 0.74, 95% CI 0.53 to 1.02; low‐quality evidence), corresponding to 28 fewer surgical interventions (95% CI 51 fewer to 2 more) per 1000 participants.

A predefined subgroup analysis (test for subgroup differences; P = 0.002) suggests that effects of alpha‐blockers may vary with stone size, with RR of 1.06 (95% CI 0.98 to 1.15; P = 0.16; I² = 62%) for stones 5 mm or smaller versus 1.45 (95% CI 1.22 to 1.72; P < 0.0001; I² = 59%) for stones larger than 5 mm. We found no evidence suggesting possible subgroup effects based on stone location or alpha‐blocker type.

Authors' conclusions

For patients with ureteral stones, alpha‐blockers likely increase stone clearance but probably also slightly increase the risk of major adverse events. Subgroup analyses suggest that alpha‐blockers may be less effective for smaller (5 mm or smaller) than for larger stones (greater than 5 mm).

Plain language summary

Alpha‐blockers for ureteral stones in adult patients with symptoms of stone disease

Review question

Does medical treatment with alpha‐blockers improve the outcomes of patients with stones stuck in their ureter?

Background

Stones stuck in the ureter, which is the tube that transports urine from the kidney to the bladder, often cause pain and make people see a doctor. Depending on which part of the ureter the stone is stuck in and the size of the stone, it will often pass into the bladder on its own over the course of weeks. If the stone does not come out by itself, people often need to have procedures done to remove the stone.

Alpha‐blockers are medications that relax muscles in the urinary tract and may make the stone pass into the bladder faster. However, they can cause unwanted effects. We updated an existing Cochrane Review from 2014 to look into the effects of alpha‐blockers.

Study characteristics

Based on our latest search of the literature from November 2017, we included 64 studies with 10,509 participants. Of these, 15 studies compared alpha‐blockers with placebo with 5787 participants. A placebo is a pill that looks and tastes exactly like the real medication, so participants did not know what they were getting. These were the higher‐quality studies, which we trusted more.

Key results

Based on the subset of higher‐quality studies that used a placebo, alpha‐blockers likely resulted in more people passing their stones. However, these patients are likely to experience slightly more serious unwanted effects of this medication.

People taking alpha‐blockers may pass their stones in a shorter time, may use less diclofenac (which is a type of pain medication), and are likely to be admitted to the hospital less often. Meanwhile, the need for surgery for their stones was similar.

Upon completing additional analyses, we found that effects of alpha‐blockers may be different in people with small (5 mm or smaller) versus larger (larger than 5 mm) stones. It appears that this medication works better in people with larger stones. We could find no difference in how well alpha‐blockers work, no matter where in the ureter the stone is stuck or what type of alpha‐blocker is used.

Authors' conclusions

For patients with stones stuck in the ureter, alpha‐blockers likely make passing the stone easier but cause slightly more unwanted effects. It appears that alpha‐blockers work better in people with larger (greater than 5 mm) rather than smaller (5 mm or smaller) stones.

Quality of the evidence

The quality of the evidence for most outcomes was moderate or low, meaning that we have moderate or low confidence in most of the reported results.

Summary of findings

Background

Description of the condition

Urinary stone disease refers to the formation of stones or calculi in the urinary tract and is one of the most common reasons for patients to visit a urology practice; it affects about 5% to 10% of the population (Ramello 2000). An even higher frequency of up to 12% has been reported from other parts of the world, and stone disease is rare in only a few geographical areas (e.g. Greenland, coastal areas of Japan) (Tiselius 2003). One study showed an increase in lifetime prevalence of stone disease ranging from 7.14% to 11.62% over a 10‐year period (2000‐2010) (Turney 2011). The incidence and prevalence rates of kidney stones may be affected by genetic, nutritional, and environmental factors. Caucasian males are more likely than Asians, Hispanics, and African Americans to develop urinary stones (Pearle 2007). Besides the probability of stone formation, stone composition and location in the urinary tract may differ among countries (Ramello 2000). Furthermore, in the USA, over 2 million outpatient visits for a primary diagnosis of urinary stones were recorded in 2000 (UDA 2012). Hospital outpatient visits increased by 40% between 1994 and 2000, and physician office visits increased by 43% between 1992 and 2000. Also in the USA, the total estimated annual cost for stone disease was over US $10.3 billion in 2006 ‐ showing an almost five‐fold increase in six years (US $2.1 billion in 2000) and representing a 50% increase since 1994. A further increase in costs to over US $3 billion for emergency department visits was seen in the USA in 2009 (Ghani 2014). This rise could be explained only in part by the increasing prevalence of stone disease (Pearle 2005).

The natural history of urinary stone disease is characterised by specific steps ‐ from formation of Randall’s plaques to development of stones that cause renal or ureteral colic (Matlaga 2007). Symptoms include flank or abdominal pain radiating to the groin or external genitalia. Although some patients with ureteral stones might remain asymptomatic, many have pain and generally seek medical care. An acute episode of colic is the result of a stone entering the ureter and causing an intermittent rise in pressure in the pyelocalyceal system. Spontaneous passage does occur with most of these stones. Stone size and location are the two most important predictors of stone passage (Miller 1999). Passage rates of 68% for stones smaller than 5 mm and 47% for stones greater than 5 mm and up to 10 mm have been reported (Preminger 2007).

Current treatment modalities for ureteral stones include extracorporeal shockwave lithotripsy (ESWL); (flexible or semi‐rigid) ureteroscopy; percutaneous nephrolithotomy; open surgery, laparoscopic surgery, or robot‐assisted surgery; and observation with analgesia with or without adjuvant medications to facilitate stone passage (AUA Guideline 2016 Surgical Management of Stones; EAU guidelines on diagnosis and conservative management of urolithiasis 2016).

According to the guidelines of the European Association of Urology (EAU; EAU guidelines on diagnosis and conservative management of urolithiasis 2016) and the American Urologic Association (AUA; AUA Guideline 2016 Surgical Management of Stones), among patients with a newly diagnosed ureteral stone 10 mm or smaller whose symptoms are controlled, observation with periodic evaluation is an option for initial treatment. These patients may be offered an appropriate medical expulsive therapy to facilitate stone passage during the observation period. However, patients should be informed about the attendant risks of medical expulsive therapy (including associated drug side effects) and should be told that these agents are administered for an 'off‐label' use (Preminger 2007).

Description of the intervention

Different modalities of medical expulsive therapy have been evaluated, including alpha‐blockers, calcium channel blockers, corticosteroids, and combinations of these. However, most experience has been acquired with alpha‐blockers (Hollingsworth 2006; Michel 2006; Singh 2007).

How the intervention might work

Both α‐ and β‐adrenergic receptors are present in the human ureter, although α‐receptors predominate. More specifically, α1‐receptors are important in lower ureteric physiology, and higher densities of α1‐receptors have been discovered in the lower ureters of animals and humans (Nakada 2008). In the ureter, α1‐receptor antagonists inhibit basal tone and decrease peristaltic frequency and amplitude. Consequently, intraureteral pressure might decrease and fluid transport might increase according to some study authors (Morita 1987). These receptors appear to be ideal targets for pharmacotherapy, as they represent the greatest impediment to stone passage (Sterrett 2008). Several trials in the past have assessed effects of alpha‐blockers; most have reported favourable effects on stone clearance. We summarised this information in our previous review (Campschroer 2014).

Why it is important to do this review

Given the high rates of spontaneous passage ureteral stones, a study of medical expulsive therapy is warranted. Effective medical expulsive therapy confers several potential benefits. First, it may decrease the duration of symptoms of ureteral stones and, therefore, the rate of complications such as urinary tract infection (UTI), hydronephrosis, and kidney function impairment. Second, it can potentially decrease the use of more invasive interventions, such as ESWL and ureteroscopy, and therefore may decrease the rate of possible complications associated with these procedures. Last, medical expulsive therapy is likely to spare limited healthcare resources, such as physician time and hospital beds.

Despite the joint Guideline provided by the EAU and the AUA, considerable controversy persists concerning the best treatment approach for ureteral stones and the effectiveness of alpha‐blocker use as medical expulsive therapy. Several published randomised controlled trials (RCTs) on this topic have presented conflicting conclusions. We have prepared an up‐to‐date systematic review of all available data from recent RCTs using the highest methodological standards and have applied the GRADE approach to rate the quality of evidence.

In summary, combining the studies performed so far provides the opportunity to produce an overall effect estimate of alpha‐blockers as medical expulsive therapy for ureteral stones. The direction and magnitude of this effect can be used to guide decisions about clinical practice.

This current Cochrane Review presents an update of the previous Cochrane Review (Campschroer 2014). Since the last search was conducted (9 July 2012), several new studies have been published, making an update of this Cochrane Review necessary.

Objectives

To assess effects of alpha‐blockers compared with standard therapy for ureteral stones 1 cm or smaller confirmed by imaging in adult patients presenting with symptoms of ureteral stone disease.

Methods

Criteria for considering studies for this review

Types of studies

We included all RCTs and quasi‐RCTs (trials in which investigators allocated participants to treatment using alternation, alternate medical records, date of birth, or other predictable methods) undertaken to investigate alpha‐blockers for the treatment of adult patients with ureteral stones. We included eligible studies regardless of their publication status or language of publication.

Types of participants

Inclusion criteria

Adult patients (aged 18 years or older)
Symptoms of ureteral stones including flank or abdominal pain, possibly radiating to the groin or external genitalia
Diagnosis confirmed upon imaging (e.g. plain film of the kidney, ureter, and bladder (KUB); computed tomography (CT); intravenous pyelography (IVP); ultrasonography (US))
Single stone measuring 10 mm or smaller

Exclusion criteria

Evidence of UTI or hydronephrosis with complicated factors (e.g. sepsis, uncontrollable pain, deterioration of renal function)
Kidney or ureteral abnormalities (e.g. single kidney, ureteral malformation)
Pregnant or lactating women
Bilateral stones
Taking an alpha‐blocker or a calcium channel blocker, or having allergies to these medications

Types of interventions

Interventions include medical expulsive therapy with alpha‐blockers to treat patients with ureteral stones versus one of two comparators: (1) standard therapy (e.g. non‐steroidal anti‐inflammatory drugs (NSAIDs), corticosteroids, antispasmodics), or (2) placebo. When one study assessed multiple alpha‐blockers, we combined arms for the comparison of alpha‐blockers versus standard therapy or placebo. We conducted subgroup analyses to explore whether effects differ among various alpha‐blockers.

We excluded studies in which researchers evaluated alpha‐blockers as an adjuvant to surgery or lithotripsy. If patients used other medication such as anticholinergics or antispasmodics as an adjuvant to trial medication, we evaluated only comparable groups (e.g. patients in a standard therapy group using anticholinergics vs patients in the trial group using anticholinergics combined with trial medication).

Types of outcome measures

Primary outcomes

Stone clearance (dichotomous outcome defined as percentage of participants identified as stone‐free by diagnostic imaging on the last day of the study trial, or participants who were symptom‐free at the end of the trial, or participants who had expelled their stone and brought it with them to the follow‐up visit)
Major adverse events (dichotomous outcome defined as the number of participants who experienced orthostatic hypotension, collapse, syncope, palpitations, or tachycardia)

Secondary outcomes

Stone expulsion time (continuous outcome defined as days from start of inclusion until stone expulsion)
Pain episodes (continuous outcome defined as number of pain episodes)
Diclofenac use (continuous outcome defined as cumulative dosage of diclofenac in milligrams)
Hospitalisation (dichotomous outcome defined as percentage of participants needing hospital admission because of uncontrollable pain or complicating factors such as UTI or sepsis)
Surgical intervention (dichotomous outcome defined as the number of participants who require surgical intervention as the result of uncontrolled pain and/or hydronephrosis within the trial period)

Main outcomes for 'Summary of findings' tables

We present 'Summary of findings' tables to report the following outcomes listed according to priority.

Comparison 1 (Analysis 1): alpha‐blockers versus standard therapy or placebo (Table 1).

Summary of findings for the main comparison. Alpha‐blockers compared with standard therapy for ureteral stones.

Alpha‐blockers compared with standard therapy for ureteral stones
Patient or population: adult patients presenting with symptoms of ureteral stone disease Setting: single or multicenter Intervention: alpha‐blocker Comparison: standard therapy
Outcomes	No. of participants  (studies)  Follow‐up	Quality of the evidence  (GRADE)	Relative effect  (95% CI)	*Anticipated absolute effects (95% CI)**
				Risk with standard therapy	Risk difference with alpha‐blockers
Stone clearance	10509  (67 RCTs)	⊕⊕⊝⊝  LOW^a,b,c	RR 1.45  (1.36 to 1.55)	Study population
				619 per 1000	278 more per 1000  (223 more to 340 more)
Major adverse events	3124  (18 RCTs)	⊕⊕⊝⊝  LOW^a,d	RR 1.25  (0.80 to 1.96)	Study population
				20 per 1000	5 more per 1000  (4 fewer to 19 more)
Stone expulsion time	6031  (37 RCTs)	⊕⊕⊝⊝  LOW^a,c,e	‐		MD 3.4 lower  (4.17 lower to 2.63 lower)
Pain episodes	1363  (15 RCTs)	⊕⊕⊝⊝  LOW^a,c,f	‐		MD 0.66 lower  (0.91 lower to 0.42 lower)
Dose of diclofenac	4373  (14 RCTs)	⊕⊕⊝⊝  LOW^a,c,g	‐		MD 82.41 mg lower  (122.51 lower to 42.31 lower)
Hospitalisation	1876  (13 RCTs)	⊕⊕⊕⊝  MODERATE^a	RR 0.51  (0.34 to 0.77)	Study population
				141 per 1000	69 fewer per 1000  (93 fewer to 32 fewer)
Surgical intervention	3292  (19 RCTs)	⊕⊕⊝⊝  LOW^a,d	RR 0.74  (0.53 to 1.02)	Study population
				109 per 1000	28 fewer per 1000  (51 fewer to 2 more)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: confidence interval; MD: mean difference; RCT: randomised controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence.  High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.  Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.  Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

Alpha‐blockers compared with placebo for ureteral stones
Patient or population: adult patients presenting with symptoms of ureteral stone disease Setting: single or multicenter Intervention: alpha‐blocker Comparison: placebo
Outcomes	No. of participants  (studies)  Follow‐up	Quality of the evidence  (GRADE)	Relative effect  (95% CI)	*Anticipated absolute effects (95% CI)**
				Risk with placebo	Risk difference with alpha‐blockers
Stone clearance	5787  (15 RCTs)	⊕⊕⊕⊝  MODERATE^a	RR 1.16  (1.07 to 1.25)	Study population
				728 per 1000	116 more per 1000  (51 more to 182 more)
Major adverse events	1650  (10 RCTs)	⊕⊕⊕⊝  MODERATE^b	RR 2.09  (1.13 to 3.86)	Study population
				26 per 1000	29 more per 1000  (3 more to 75 more)
Stone expulsion time	3240  (7 RCTs)	⊕⊕⊝⊝  LOW^c,d	‐		MD 1.98 lower  (3.71 lower to 0.24 lower)
Pain episodes	215  (2 RCTs)	⊕⊕⊝⊝  LOW^c,e	‐		MD 0.39 lower  (1.07 lower to 0.29 higher)
Dose of diclofenac (mg)	3576  (4 RCTs)	⊕⊕⊝⊝  LOW^d,f	‐		MD 126.32 lower  (181.73 lower to 70.9 lower)
Hospitalisation	500  (2 RCTs)	⊕⊕⊕⊝  MODERATE^e	RR 0.84  (0.48 to 1.47)	Study population
				96 per 1000	15 fewer per 1000  (50 fewer to 45 more)
Surgical intervention	1458  (5 RCTs)	⊕⊕⊕⊕  HIGH	RR 0.93  (0.70 to 1.24)	Study population
				127 per 1000	9 fewer per 1000  (38 fewer to 30 more)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: confidence interval; MD: mean difference; RCT: randomised controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence.  High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.  Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.  Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

Date	Event	Description
18 November 2017	New search has been performed	In this update we have added 35 new studies. GRADE approach has been applied to assess the quality of evidence.
18 November 2017	New citation required and conclusions have changed	In this update we have added 35 new studies. GRADE approach has been applied to assess the quality of evidence.The conclusion of the review has changed.

Date	Event	Description
2 April 2014	Amended	First published
9 July 2012	New search has been performed	Assessed as up‐to‐date

Database	Search terms
CENTRAL	MeSH descriptor Ureterolithiasis explode all trees MeSH descriptor Ureteral Obstruction, this term only MeSH descriptor Colic, this term only (ureterolithiasis):ti,ab,kw in Clinical Trials (ureteral colic):ti,ab,kw or (ureteral stone):ti,ab,kw or (ureteral calcul):ti,ab,kw in Clinical Trials (1 OR 2 OR 3 OR 4 OR 5) MeSH descriptor Adrenergic alpha‐Antagonists explode all trees tamsulosin or doxazosin* or alfuzosin* or terazosin* or silodosin:ti,ab,kw in Clinical Trials (alpha blocker or alpha‐blocker*):ti,ab,kw in Clinical Trials (7 OR 8 OR 9) (6 AND 10)
MEDLINE	exp Ureterolithiasis/ Ureteral Obstruction/ Colic/ ureterolithiasis.tw. (ureter$ adj3 (stone$ or calcul$ or colic)).tw. or/1‐5 exp Adrenergic alpha‐Antagonists/ alpha blocker$.tw. alpha receptor antagonist$.tw. exp Prazosin/ tamsulosin.tw. doxazosin$.tw. alfuzosin.tw. terazosin.tw. silodosin.tw. or/7‐15 and/6,16
Embase	Ureter Stone/ Ureter Obstruction/ ureterolithiasis.tw. (ureter$ adj3 (stone$ or calcul$ or colic)).tw. kidney colic/ or kidney pain/ or/1‐5 exp Alpha Adrenergic Receptor Blocking Agent/ alpha blocker$.tw. tamsulosin$.tw. doxazosin$.tw. alfuzosin.tw. terazosin.tw. silodosin.tw. or/7‐13 and/6,14
ClinicalTrials.gov	(Alpha‐blocker OR tamsulosin OR alfuzosin OR silodosin OR doxazosin OR naftopidil OR terazosin) AND (stone OR ureter OR calculus OR calculi)
Conference proceedings	1. Proceedings of major (mainly renal and stone‐disease) conferences from 2005 to March 2016 2. EAU (European Association of Urology) 3. AUA (American Urological Association) 4. ESD (Experts in Stone Disease) 5. WCE (World Congress of Endourology) 6. SIU (Société Internationale d'Urologie)

Potential source of bias	Assessment criteria
Random sequence generation Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence	Low risk of bias: Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimization (minimization may be implemented without a random element, and this is considered to be equivalent to being random).
	High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention.
	Unclear: Insufficient information about the sequence generation process to permit judgement.
Allocation concealment Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment	Low risk of bias: Randomization method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web‐based, and pharmacy‐controlled, randomization; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes).
	High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non‐opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.
	Unclear: Randomization stated but no information on method used is available.
Blinding of participants and personnel Performance bias due to knowledge of the allocated interventions by participants and personnel during the study	Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Blinding of outcome assessment Detection bias due to knowledge of the allocated interventions by outcome assessors.	Low risk of bias: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Incomplete outcome data Attrition bias due to amount, nature or handling of incomplete outcome data.	Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods.
	High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘as‐treated’ analysis done with substantial departure of the intervention received from that assigned at randomization; potentially inappropriate application of simple imputation.
	Unclear: Insufficient information to permit judgement
Selective reporting Reporting bias due to selective outcome reporting	Low risk of bias: The study protocol is available and all of the study’s pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified (convincing text of this nature may be uncommon).
	High risk of bias: Not all of the study’s pre‐specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre‐specified; one or more reported primary outcomes were not pre‐specified (unless clear justification for their reporting is provided, such as an unexpected adverse event); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.
	Unclear: Insufficient information to permit judgement
Other bias Bias due to problems not covered elsewhere in the table	Low risk of bias: The study appears to be free of other sources of bias.
	High risk of bias: Had a potential source of bias related to the specific study design used; stopped early due to some data‐dependent process (including a formal‐stopping rule); had extreme baseline imbalance; has been claimed to have been fraudulent; had some other problem.
	Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient rationale or evidence that an identified problem will introduce bias.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Stone clearance	67	10509	Risk Ratio (M‐H, Random, 95% CI)	1.45 [1.36, 1.55]
2 Major adverse events	18	3124	Risk Ratio (M‐H, Random, 95% CI)	1.25 [0.80, 1.96]
3 Stone expulsion time	37	6031	Mean Difference (IV, Random, 95% CI)	‐3.40 [‐4.17, ‐2.63]
4 Pain episodes	15	1363	Mean Difference (IV, Random, 95% CI)	‐0.66 [‐0.91, ‐0.42]
5 Dose of diclofenac	14	4373	Mean Difference (IV, Random, 95% CI)	‐82.41 [‐122.51, ‐42.31]
6 Hospitalisation	13	1876	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.34, 0.77]
7 Surgical intervention	19	3292	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.53, 1.02]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Stone clearance	16	5509	Risk Ratio (M‐H, Random, 95% CI)	1.17 [1.08, 1.27]
1.1 Stone size ≤ 5 mm	14	2622	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.98, 1.15]
1.2 Stone size 6‐10 mm	10	2887	Risk Ratio (M‐H, Random, 95% CI)	1.45 [1.22, 1.72]
2 Stone expulsion time	6	3148	Mean Difference (IV, Random, 95% CI)	‐3.39 [‐5.82, ‐0.97]
2.1 Stone size ≤ 5 mm	6	1264	Mean Difference (IV, Random, 95% CI)	‐1.07 [‐1.99, ‐0.15]
2.2 Stone size 6‐10 mm	4	1884	Mean Difference (IV, Random, 95% CI)	‐5.99 [‐7.16, ‐4.82]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Stone clearance	60	9370	Risk Ratio (M‐H, Random, 95% CI)	1.44 [1.34, 1.54]
1.1 Distal ureter	57	8576	Risk Ratio (M‐H, Random, 95% CI)	1.46 [1.36, 1.57]
1.2 Mid or proximal ureter	9	794	Risk Ratio (M‐H, Random, 95% CI)	1.28 [0.99, 1.66]
2 Stone expulsion time	32	5599	Mean Difference (IV, Random, 95% CI)	‐3.67 [‐4.50, ‐2.85]
2.1 Distal ureter	32	5453	Mean Difference (IV, Random, 95% CI)	‐3.43 [‐4.26, ‐2.60]
2.2 Mid or proximal ureter	2	146	Mean Difference (IV, Random, 95% CI)	‐8.64 [‐19.75, 2.48]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Stone clearance	67	10897	Risk Ratio (M‐H, Random, 95% CI)	1.49 [1.39, 1.58]
1.1 Tamsulosin	54	8896	Risk Ratio (M‐H, Random, 95% CI)	1.47 [1.37, 1.59]
1.2 Alfuzosin	6	391	Risk Ratio (M‐H, Random, 95% CI)	1.51 [1.14, 2.01]
1.3 Doxazosin	7	441	Risk Ratio (M‐H, Random, 95% CI)	1.49 [1.29, 1.72]
1.4 Terazosin	2	119	Risk Ratio (M‐H, Random, 95% CI)	1.44 [1.10, 1.89]
1.5 Naftopidil	3	270	Risk Ratio (M‐H, Random, 95% CI)	2.02 [1.01, 4.03]
1.6 Silodosin	6	780	Risk Ratio (M‐H, Random, 95% CI)	1.39 [1.20, 1.61]
2 Major adverse events	18	3003	Risk Ratio (M‐H, Random, 95% CI)	1.98 [1.12, 3.48]
2.1 Tamsulosin	13	2062	Risk Ratio (M‐H, Random, 95% CI)	1.24 [0.62, 2.47]
2.2 Alfuzosin	5	323	Risk Ratio (M‐H, Random, 95% CI)	5.51 [1.46, 20.83]
2.3 Doxazosin	2	133	Risk Ratio (M‐H, Random, 95% CI)	3.84 [0.47, 31.11]
2.4 Silodosin	3	361	Risk Ratio (M‐H, Random, 95% CI)	6.25 [0.74, 52.57]
2.5 Naftopidil	1	124	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3 Stone expulsion time	35	6212	Mean Difference (IV, Random, 95% CI)	‐3.56 [‐4.25, ‐2.87]
3.1 Tamsulosin	30	5052	Mean Difference (IV, Random, 95% CI)	‐3.07 [‐4.04, ‐2.09]
3.2 Alfuzosin	3	180	Mean Difference (IV, Random, 95% CI)	‐4.75 [‐6.63, ‐2.88]
3.3 Doxazosin	4	263	Mean Difference (IV, Random, 95% CI)	‐4.73 [‐6.15, ‐3.32]
3.4 Terazosin	2	119	Mean Difference (IV, Random, 95% CI)	‐4.42 [‐5.36, ‐3.48]
3.5 Naftopidil	1	86	Mean Difference (IV, Random, 95% CI)	‐1.80 [‐2.80, ‐0.80]
3.6 Silodosin	4	512	Mean Difference (IV, Random, 95% CI)	‐4.98 [‐6.43, ‐3.52]
4 Pain episodes	15	1595	Mean Difference (IV, Random, 95% CI)	‐0.71 [‐0.89, ‐0.52]
4.1 Tamsulosin	13	992	Mean Difference (IV, Random, 95% CI)	‐0.69 [‐0.98, ‐0.41]
4.2 Alfuzosin	1	58	Mean Difference (IV, Random, 95% CI)	‐0.32 [‐0.82, 0.18]
4.3 Doxazosin	3	190	Mean Difference (IV, Random, 95% CI)	‐0.76 [‐0.92, ‐0.60]
4.4 Terazosin	2	119	Mean Difference (IV, Random, 95% CI)	‐0.67 [‐1.16, ‐0.17]
4.5 Naftopidil	1	86	Mean Difference (IV, Random, 95% CI)	‐0.80 [‐1.23, ‐0.37]
4.6 Silodosin	2	150	Mean Difference (IV, Random, 95% CI)	‐0.89 [‐2.05, 0.26]
5 Dose of diclofenac [mg]	14	4429	Mean Difference (IV, Random, 95% CI)	‐78.11 [‐113.25, ‐42.97]
5.1 Tamsulosin	12	4135	Mean Difference (IV, Random, 95% CI)	‐87.60 [‐131.98, ‐43.21]
5.2 Doxazosin	1	57	Mean Difference (IV, Random, 95% CI)	‐63.46 [‐72.88, ‐54.04]
5.3 Terazosin	1	56	Mean Difference (IV, Random, 95% CI)	‐64.29 [‐74.17, ‐54.41]
5.4 Silodosin	2	181	Mean Difference (IV, Random, 95% CI)	‐54.72 [‐89.91, ‐19.53]
6 Hospitalisation	13	2028	Risk Ratio (M‐H, Random, 95% CI)	0.44 [0.29, 0.66]
6.1 Tamsulosin	11	1606	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.38, 0.86]
6.2 Alfuzosin	2	110	Risk Ratio (M‐H, Random, 95% CI)	0.35 [0.09, 1.45]
6.3 Doxazosin	2	132	Risk Ratio (M‐H, Random, 95% CI)	0.19 [0.01, 3.05]
6.4 Silodosin	2	180	Risk Ratio (M‐H, Random, 95% CI)	0.26 [0.12, 0.55]
7 Surgical intervention	19	3404	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.55, 0.99]
7.1 Tamsulosin	16	2820	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.59, 1.13]
7.2 Alfuzosin	1	58	Risk Ratio (M‐H, Random, 95% CI)	0.47 [0.09, 2.35]
7.3 Doxazosin	2	133	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.15, 1.11]
7.4 Silodosin	3	393	Risk Ratio (M‐H, Random, 95% CI)	0.29 [0.06, 1.31]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Stone clearance	15	5787	Risk Ratio (M‐H, Random, 95% CI)	1.16 [1.07, 1.25]
2 Major adverse events	10	1650	Risk Ratio (M‐H, Random, 95% CI)	2.09 [1.13, 3.86]
3 Stone expulsion time	7	3240	Mean Difference (IV, Random, 95% CI)	‐1.98 [‐3.71, ‐0.24]
4 Pain episodes	2	215	Mean Difference (IV, Random, 95% CI)	‐0.39 [‐1.07, 0.29]
5 Dose of diclofenac	4	3576	Mean Difference (IV, Random, 95% CI)	‐126.32 [‐181.73, ‐70.90]
6 Hospitalisation	2	500	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.48, 1.47]
7 Surgical intervention	5	1458	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.70, 1.24]

Methods	Study design: parallel RCT. Study duration: June 2008 to December 2009. Follow‐up/Treatment duration: 4 weeks.
Participants	Country: Saudi Arabia. Setting: single centre. Adults > 18 years of either sex; single, unilateral, newly diagnosed condition; 4‐10 mm in transverse diameter; distal ureteral stones; normal kidney function. Number: treatment group 75; control group 75. Median age (range, years): treatment group 34 (20‐67); control group 36 (19‐72). Sex, M/F: treatment group: 50/25; control group: 53/22. Exclusion criteria: history of ipsilateral ureteral endoscopic or surgical manipulations or ESWL; patients with symptomatic UTI; those pregnant or lactating; patients already receiving alpha‐blockers, beta‐blockers, calcium channel antagonists, or corticosteroids; serious medical conditions; refused randomisation; lost to follow‐up during the study period.
Interventions	Treatment group Tamsulosin 0.4 mg once daily. Hydration, analgesia (diclofenac 100 mg) as needed. Control group Placebo. Hydration, analgesia (diclofenac 100 mg) as needed.
Outcomes	Stone passage rate. Stone passage time. Weekly stone passage rate. Episodes of renal colic. Need for analgesia. Drug adverse events.
Funding sources	None stated.
Declarations of interest	None stated.
Notes	Baseline assessment included non‐contrast spiral CT and furthermore weekly follow‐ups with KUB and US. NCCT was repeated at end of study to confirm stone status.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Patients were allocated randomly in 1:1 ratio into either group." Comment: This method of random sequence generation was considered to have low risk of bias.
Allocation concealment (selection bias)	Low risk	Quote: "Using sealed envelopes." Comment: This method of allocation concealment was considered to have low risk of bias.
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "Both treating physicians and patients were blinded to randomization." Comment: double‐blind and therefore low risk of bias.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No blinding of outcome assessments described. Comment: No description was available; therefore this method of outcome assessment was considered to have unclear risk of bias.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Quote: "17 patients were excluded due to not accepting randomization (6) and loss to follow‐up during study period (4 in group A and 7 in group B)." Comment: Owing to relatively high numbers of exclusions and losses to follow‐up, incomplete outcome data were stated and risk of bias was unclear.
Selective reporting (reporting bias)	Low risk	No quotes available. Expected outcomes were reported according to objectives. Comment: Risk of reporting bias therefore was considered to be low.
Other bias	Low risk	No quotes available. The study appears to be free of other sources of bias. Comment: No other sources of bias could be found; therefore risk of other bias was considered to be low.

Methods	Study design: RCT. Study duration: September 2004 to August 2007. Follow‐up/Treatment duration: 4 weeks.
Participants	Country: India. Setting: single centre. Patients with stone < 10 mm in size in the distal ureter; evaluated with KUB, US, intravenous urography, and NCCT in selected patients. Number: treatment group 1: 34; treatment group 2: 34; control group: 34. Median age (range, years): treatment group 1: 31.4 (15‐56); treatment group 2: 38.7 (19‐60); control group: 35.3 (22‐58). Sex, M/F: treatment group 1: 26/8; treatment group 2: 28/6; control group: 24/10. Exclusion criteria: UTI; severe hydroureteronephrosis; diabetes mellitus; multiple stones; hypotension; pregnancy; previous spontaneous stone expulsion; distal ureteral surgery; history of intake of warfarin/alpha‐blocker/calcium channel blocker/steroids and cimetidine.
Interventions	Treatment group 1 Tamsulosin 0.4 mg once daily. Treatment group 2 Alfuzosin 10 mg once daily. Control group Placebo. All groups received 75 mg diclofenac intramuscularly and were advised to drink at least 3 L of fluids.
Outcomes	Stone passage. Time for passage. Total diclofenac dosage. Number of pain episodes.
Funding sources	None.
Declarations of interest	None.
Notes	Follow‐up weekly with KUB and US.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "The patients were randomized to 3 groups." Comment: Randomisation was stated, but no information on method used was available; therefore risk of selection bias was considered to be unclear.
Allocation concealment (selection bias)	Unclear risk	No quotes available. Insufficient information to permit judgement. Comment: Owing to insufficient information, risk of allocation concealment was considered to be unclear.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	No quotes available. No blinding described. Comment: Owing to insufficient information, risk of performance bias was considered to be unclear.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No quotes available. No blinding of outcome assessments described. Comment: Owing to insufficient information, risk of detection bias was considered to be unclear.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Quote: “Spontaneous stone expulsion was observed in 28 of 34 patients (82.3%) in group 1, 24 of 34 (70.5%) in group 2, and 12 of 34 (35.2%) patients in group 3.” Comment: Stone expulsion rate was reported for all participants; therefore, probably none were lost to follow‐up and accordingly risk of bias was considered low.
Selective reporting (reporting bias)	Low risk	No quotes available. Expected outcomes were reported according to objectives. Comment: Risk of reporting bias was therefore considered to be low.
Other bias	Low risk	No quotes available. The study appears to be free of other sources of bias. Comment: No other sources of bias could be found; therefore risk of other bias was considered to be low.

Methods	Study design: RCT. Study duration: 1 January to 31 October 2010. Follow‐up/Treatment duration: 28 days.
Participants	Country: Pakistan. Setting: single centre. Patients with stone ≤ 8 mm in the distal 1/3 ureter; evaluated with KUB, US, or IVU (if required). Number: treatment group: 49; placebo group: 48. Mean age, SD, years: overall: 36.34; range: 18‐57. Sex, M/F: not reported. Exclusion criteria: age < 18 years; ureteric obstruction; distal ureteric stricture; previous ureteral surgery; solitary kidney; aberrant ureteral anatomy (e.g. ureteral ectopia, ureterocoele, mega‐ureter); UTI; radiolucent stone.
Interventions	Treatment group Tamsulosin 0.4 mg once daily. Placebo group Placebo. Both groups were given tab diclofenac sodium 50 mg, 1 tab 8 hourly for pain control on required basis.
Outcomes	Stone passage rate. Time for stone passage. Need for analgesics. Need for hospitalisation. Drug adverse effects.
Funding sources	None.
Declarations of interest	None.
Notes	Participants were evaluated with plain X‐ray KUB after 2 weeks and 4 weeks.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Patients were randomly assigned into one of the two groups." Comment: Randomisation was stated but no information on method used was available; therefore risk of selection bias was considered to be unclear.
Allocation concealment (selection bias)	Unclear risk	No quotes available. Insufficient information to permit judgement. Comment: Owing to insufficient information, risk of allocation concealment was considered to be unclear.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	No quotes available. No blinding described. Comment: Owing to insufficient information, risk of performance bias was considered to be unclear.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No quotes available. No blinding of outcome assessments described. Comment: Owing to insufficient information, risk of detection bias was considered to be unclear.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Quote: “Three patients lost to follow up, therefore 97 out of 100 patients were evaluated.” Comment: Small number of participants were lost to follow‐up; accordingly, risk of bias was considered low.
Selective reporting (reporting bias)	Low risk	No quotes available. Expected outcomes were reported according to objectives. Comment: Risk of reporting bias was therefore considered to be low.
Other bias	Low risk	No quotes available. Study appears to be free of other sources of bias. Comment: No other sources of bias could be found; therefore risk of other bias was considered low.

Methods	Study design: RCT. Study duration: March 2008 and November 2009. Follow‐up/Treatment duration: 30 days.
Participants	Country: Saudi Arabia. Setting: single centre. Patients with stone ≤ 10 mm in the distal ureter; evaluated with KUB, US, and NCCT in selected patients. Number: treatment group 1: 29; treatment group 2: 30; control group: 28. Mean age, SD, years: treatment group 1: 40.7 ± 14.8; treatment group 2: 41.1 ± 15.2; control group: 38.9 ± 13.3. Sex, M/F: treatment group 1: 19/10; treatment group 2: 18/12; control group: 19/9. Exclusion criteria: age < 18 years; pregnant or lactating women; history of previous surgery on the ipsilateral ureter; stone larger than 10 mm; multiple stones; bilateral ureteric stones; solitary kidney; UTI; moderate or severe hydronephrosis; currently on alpha‐blocker therapy; known allergy to tamsulosin or alfuzosin; contraindications to non‐steroidal anti‐inflammatory agents; renal insufficiency.
Interventions	Treatment group 1 Tamsulosin 0.4 mg once daily. Treatment group 2 Alfuzosin 10 mg once daily. Control group Diclofenac sodium only. All groups received 50 mg diclofenac every 12 hours for 1 week, then 75 mg diclofenac intramuscularly as needed up to 2 times per day.
Outcomes	Stone passage rate. Time for stone passage. Frequency of pain attacks. Complications of medications.
Funding sources	None.
Declarations of interest	None.
Notes	Follow‐up visits on a weekly basis with urine analysis, serum creatinine measurement, plain X‐ray KUB, and abdominal ultrasonography. Abdominal CT was performed for participants with radiolucent stones if the stone was not expulsed by the end of study.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "A total of 90 patients with distal ureteral stones ≤10 mm in diameter were randomly divided into 3 equal groups and given medications for 30 days." Comment: Randomisation was stated but no information on method used was available; therefore risk of selection bias was considered to be unclear.
Allocation concealment (selection bias)	Unclear risk	No quotes available. Insufficient information to permit judgement. Comment: Owing to insufficient information, allocation concealment was considered to have unclear risk of bias.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	No quotes available. No blinding described. Comment: Owing to insufficient information, risk of performance bias was considered to be unclear.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No quotes available. No blinding of outcome assessments described. Comment: Owing to insufficient information, risk of detection bias was considered to be unclear.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	No quotes available. No intention‐to‐treat analysis. Comment: Owing to lack of intention‐to‐treat analysis, risk of attrition bias was considered to be unclear.
Selective reporting (reporting bias)	Low risk	No quotes available. Expected outcomes were reported according to objectives. Comment: Risk of reporting bias was therefore considered to be low.
Other bias	Low risk	No quotes available. Study appears to be free of other sources of bias. Comment: No other sources of bias could be found; therefore risk of other bias was considered to be low.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Stone clearance	5	4133	Risk Ratio (M‐H, Random, 95% CI)	1.09 [1.06, 1.13]
2 Major adverse events	2	515	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.51, 1.72]
3 Stone expulsion time	3	2891	Mean Difference (IV, Random, 95% CI)	‐1.72 [‐5.13, 1.68]
4 Pain episodes	1	119	Mean Difference (IV, Random, 95% CI)	0.0 [‐0.72, 0.72]
5 Dose of diclofenac	2	3386	Mean Difference (IV, Random, 95% CI)	‐173.28 [‐277.60, ‐68.95]
6 Hospitalisation	1	403	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.49, 1.52]
7 Surgical intervention	3	605	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.38, 2.32]

Methods	Study design: double‐blinded RCT. Study duration: May 2007 to May 2009. Follow‐up: 4 weeks.
Participants	Country: Qatar. Setting: single centre. Patients with distal ureteral stones of 10 mm or smaller, evaluated by KUB, US, and NCCT before treatment. Number: treatment group: 50; control group: 50. Mean age ± SD, years: treatment group: 37.18 ± 9.38; control group: 36.13 ± 9.32. Sex, M/F: treatment group: 32/18; control group: 29/21. Exclusion criteria: age < 18 years; non‐radiopaque stones; multiple stones; severe hydronephrosis; pregnancy; hypotension; peptic ulcer; history of endoscopic or open ureteral surgery; use of calcium channel blocker.
Interventions	Treatment group Tamsulosin 0.4 mg once daily. Control Placebo.
Outcomes	Stone expulsion rate. Time for stone passage. Number of pain episodes. Need for diclofenac injection. Total diclofenac dosage. Blood pressure. Possible side effects.
Funding sources	None stated.
Declarations of interest	None stated.
Notes	Sample size calculated. Weekly follow‐up with KUB, US, and urine analysis.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Patients were randomized between study and placebo medications using a computer‐generated random number assignment, adjusted at a ratio of 1:1." Comment: This method of random sequence generation was considered to have low risk of bias.
Allocation concealment (selection bias)	Low risk	Quote: "Randomization data were kept strictly confidential, in sealed envelops, accessible only to the pharmacist at the end of the study." Comment: This method of allocation concealment was considered to have low risk of bias.
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "The investigators and patients were masked to the type of the treatment throughout the study." Comment: double‐blind; therefore low risk of bias.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: “The investigators and patients were masked to the type of the treatment throughout the study.” Comment: Personnel responsible for outcome assessments were blinded; therefore risk of detection bias was considered to be low.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Quote: “Four patients in the placebo group were lost to follow‐up.” Comment: Four participants in the placebo group were lost to follow‐up and were excluded from analysis. It is unclear whether this had a clinically relevant impact on the intervention effect estimate; therefore risk of attrition bias was considered to be unclear.
Selective reporting (reporting bias)	Low risk	No quotes available. Expected outcomes were reported according to objectives. Comment: Risk of reporting bias therefore was considered to be low.
Other bias	Low risk	No quotes available. Study appears to be free of other sources of bias. Comment: No other sources of bias could be found; therefore risk of other bias was considered low.

Methods	Study design: RCT. Study duration: December 2013 to June 2015. Follow‐up/Treatment duration: 4 weeks.
Participants	Country: India. Setting: single centre. Patients with stone ≤ 10 mm in the distal ureter; evaluated with KUB, US, and NCCT in selected patients. Number: treatment group 1: 40; treatment group 2: 40; control group: 40. Mean age, SD, years: treatment group 1: 35 ± 8.5; treatment group 2: 32 ± 7.5; control group: 34 ± 8.5. Sex, M/F: treatment group 1: 28/12; treatment group 2: 32/8; control group: 30/10. Exclusion criteria: age < 18 years; previous surgery on ipsilateral ureter; bilateral ureteral calculus; multiple stones; solitary kidney; intolerant or hypersensitive to alpha‐blockers; contraindicated for NSAIDs; renal insufficiency; pregnant and lactating women
Interventions	Treatment group 1 Tamsulosin 0.4 mg once daily. Treatment group 2 Silodosin 8 mg once daily. Control group All groups received 50‐100 mg diclofenac.
Outcomes	Stone passage rate. Blood pressure. Time for stone passage. Number of pain attacks. Hospital re‐admissions. Adverse effects.
Funding sources	None.
Declarations of interest	None.
Notes	Follow‐up visits on a weekly basis with urine analysis, serum creatinine measurement, plain X‐ray KUB, and abdominal ultrasonography. Abdominal CT was performed for all participants by end of study.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No quote available. Comment: Randomisation was stated but no information on method used was available; therefore risk of selection bias was considered to be unclear.
Allocation concealment (selection bias)	Unclear risk	No quotes available. Insufficient information to permit judgement. Comment: Owing to insufficient information, allocation concealment was considered to have unclear risk of bias.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	No quotes available. No blinding described. Comment: Owing to insufficient information, risk of performance bias was considered to be unclear.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No quotes available. No blinding of outcome assessments described. Comment: Owing to insufficient information, risk of detection bias was considered to be unclear.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Quote: "Out of the 120 patients included in the study, patients were divided randomly into three groups of 40 patients." Comment: All participants completed the study; therefore risk of attrition bias was considered to be low.
Selective reporting (reporting bias)	High risk	No quotes available. Comment: Blood pressure was not reported in the Results section (as a secondary outcome measurement); therefore risk of reporting bias was considered to be high.
Other bias	Low risk	No quotes available. Study appears to be free of other sources of bias. Comment: No other sources of bias could be found; therefore risk of other bias was considered low.

Methods	Study design: RCT. Study duration: June 2007 until July 2008. Follow‐up: 4 weeks.
Participants	Country: Iran. Setting: single centre. Patients with distal ureteral stones and UVJ stones 3 to 6 mm; 18‐60 years; diagnosed with KUB and US. Number: treatment group: 50; control group: 46. Age limits, years: treatment group: 20‐50; control group: 19‐54. Sex, M/F: treatment group: 21/29; control group: 14/32. Exclusion criteria: radiolucent stone on KUB; acute hydronephrosis (grades 2 and 3) on sonography; presence of UTI; history of peptic ulcer disease; systolic blood pressure < 100; consumers of calcium antagonist drugs; solitary kidney; diabetes mellitus; pregnancy; previous distal ureteral surgery; creatinine over 1.4 for males and 1.2 for females; pain resistant to conservative treatment; NSAID intolerance or adverse events of tamsulosin during the study; participant withdrawal from the study at any time; occurrence of any unforeseen complications during the study.
Interventions	Control group Standard pain medication (indomethacin). Treatment group Tamsulosin 0.4 mg once daily. Researchers emphasised that all participants should drink 2 L of water daily.
Outcomes	Stone expulsion time. Stone expulsion rate. Mean stone size. Stone location. Amount of analgesic consumption. Possible complications caused by stones during the study period. Possible side effects from medications or intolerance recorded and used for statistical analysis.
Funding sources	None stated.
Declarations of interest	None stated.
Notes	Follow‐up was every 2 weeks with KUB, US, or CT. Not all abbreviations were explained in the text.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: “patients were randomly assigned to a control group (n = 46) and study group (n = 50).” Comment: Randomisation was stated but no information on method used was available; therefore selection bias was considered to have unclear risk.
Allocation concealment (selection bias)	Unclear risk	No quotes available. Insufficient information to permit judgement. Comment: Owing to insufficient information, allocation concealment was considered to have unclear risk of bias.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	No quotes available. No blinding described. Comment: Owing to insufficient information, risk of performance bias was considered to be unclear.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No quotes available. No blinding of outcome assessments described. Comment: Owing to insufficient information, risk of detection bias was considered to be unclear.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	No quotes available. No intention‐to‐treat analysis. Comment: Owing to lack of intention‐to‐treat analysis, risk of attrition bias was considered to be unclear.
Selective reporting (reporting bias)	High risk	No quotes available. Comment: Results on pain episodes were not reported; therefore risk of reporting bias was considered to be high.
Other bias	Low risk	No quotes available. Study appears to be free of other sources of bias. Comment: No other sources of bias could be found; therefore we considered risk of other bias to be low.

Methods	Study design: prospective RCT. Study duration: December 2007 and November 2008. Follow‐up: 3 weeks.
Participants	Country: Spain. Setting: single centre. Patients with distal ureteral stones diagnosed with KUB, ultrasound, and/or urography. Number: treatment group: 35; control group: 35. Mean age of both study groups not mentioned. Sex, M/F: not mentioned. Exclusion criteria: urinary infection; anatomical alterations; multiple lithiases; urinary derivation; other factors hindering the removal of calculi.
Interventions	Control group Standard pain medication (ibuprofen, tramadol). Treatment group Tamsulosin 0.4 mg once daily and same pain medication as control group. Researchers emphasised that all participants should drink 2 L of water daily.
Outcomes	Stone expulsion time. Stone expulsion rate. Amount of analgesic consumption. Possible complications caused by stones during the study period. Possible side effects from medications or intolerance recorded and used for statistical analysis. Need for hospitalisation.
Funding sources	None stated.
Declarations of interest	None stated.
Notes	Assessment of trial results was conducted at 10 days and 30 days. On day 30, stone expulsion was assessed by plain X‐ray, ultrasonography, or urography.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: “Patients were divided randomly into 2 treatment groups.” Comment: Randomisation was stated but no information on method used was available; therefore risk of selection bias was considered to be unclear.
Allocation concealment (selection bias)	Unclear risk	No quotes available. Insufficient information to permit judgement. Comment: Owing to insufficient information, allocation concealment was considered to have unclear risk of bias.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	No quotes available. No blinding described. Comment: Owing to insufficient information, risk of performance bias was considered to be unclear.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No quotes available. No blinding of outcome assessments described. Comment: Owing to insufficient information, risk of detection bias was considered to be unclear.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No quotes available. Comment: All participants completed the study; therefore risk of attrition bias was considered to be low.
Selective reporting (reporting bias)	Low risk	No quotes available. Expected outcomes were reported according to objectives. Comment: Risk of reporting bias was therefore considered to be low.
Other bias	Low risk	No quotes available. Study appears to be free of other sources of bias. Comment: No other sources of bias could be found; therefore risk of other bias was considered to be low.

Methods	Study design: single‐centre RCT. Study duration: unclear. Follow‐up/treatment: maximum 2‐week treatment.
Participants	Country: Italy. Setting: single centre. Patients with symptomatic ≤ 10 mm distal ureteral stones, diagnosed with NCCT. Number: treatment group: 50; control group: 46. Mean age ± SD, years: treatment group: 46.3 ± 10.9; control group: 44.5 ± 11.3. Sex, M/F: treatment group: 36/14; control group: 26/20. Exclusion criteria: UTI; severe hydronephrosis; diabetes; ulcer disease; hypotension or hypertension treated with alpha‐blockers or calcium antagonists; pregnancy; multiple stones; history of spontaneous stone expulsion; ureteral stricture.
Interventions	Treatment group Tamsulosin 0.4 mg once daily. Standard therapy Diclofenac 100 mg daily. Control group Standard therapy Diclofenac 100 mg daily. Aescin (an anti‐oedema extract of the horse chestnut tree) 80 mg daily.
Outcomes	Stone expulsion rate. Expulsion time. Need for analgesics. Need for hospitalisation. Drug side effects.
Funding sources	None stated.
Declarations of interest	None stated.
Notes	Aescin = standard therapy at this centre. Included participants from the study by Autorino et al 2005.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “Randomization, not blinded, was performed using a stratified permuted randomization algorithm.” Comment: This method of random sequence generation was considered to have low risk of bias.
Allocation concealment (selection bias)	Unclear risk	No quotes available. Insufficient information to permit judgement. Comment: Owing to insufficient information, allocation concealment was considered to have unclear risk of bias.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	No quotes available. No blinding described. Comment: Owing to insufficient information, risk of performance bias was considered to be unclear.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No quotes available. No blinding of outcome assessments described. Comment: Owing to insufficient information, risk of detection bias was considered to be unclear.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No quotes available. Comment: All participants were included in the analysis; therefore risk of attrition bias was considered to be low.
Selective reporting (reporting bias)	Low risk	No quotes available. Expected outcomes were reported according to objectives. Comment: Risk of reporting bias was therefore considered to be low.
Other bias	Low risk	No quotes available. Study appears to be free of other sources of bias. Comment: No other sources of bias could be found; therefore risk of other bias was considered to be low.

Methods	Study design: RCT. Study duration: 11 March 2011 to 11 September 2011. Follow‐up/Treatment duration: 28 days.
Participants	Country: Pakistan. Setting: single centre. Patients with lower ureteric stones. Number: treatment group: 30; control group: 30. Mean age ± SD, years: overall: 33.15 ± 8.97; control group: 33.87 ± 9.61; tamsulosin group: 32.43 ± 8.33. Sex, M/F: control group: 19/11; tamsulosin group: 18/12. Exclusion criteria: obstruction; stone size > 1 cm; UTI.
Interventions	Treatment group Tamsulosin 4 mg once daily. Control group Diclofenac 50 mg on demand twice daily.
Outcomes	Stone size. Stone passage rate. Stone expulsion time.
Funding sources	None stated.
Declarations of interest	None stated.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “The patients satisfying the inclusion criteria were randomly divided in to 2 groups by random number table.” Comment: This method of random sequence generation was considered to have low risk of bias.
Allocation concealment (selection bias)	Unclear risk	No quotes available. Insufficient information to permit judgement. Comment: Owing to insufficient information, allocation concealment was considered to have unclear risk of bias.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	No quotes available. No blinding described. Comment: Owing to insufficient information, risk of performance bias was considered to be unclear.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No quotes available. No blinding of outcome assessments described. Comment: Owing to insufficient information, risk of detection bias was considered to be unclear.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No quotes available. Comment: All participants completed the study; therefore risk of attrition bias was considered to be low.
Selective reporting (reporting bias)	High risk	No quotes available. Comment: Primary outcomes were not prespecified; therefore risk of reporting bias was considered to be high.
Other bias	Low risk	No quotes available. Study appears to be free of other sources of bias. Comment: No other sources of bias could be found; therefore risk of other bias was considered to be low.

Methods	Study design: RCT. Study duration: January 2010 and February 2011. Follow‐up/Treatment duration: 28 days.
Participants	Country: Turkey. Setting: single centre. Stones in the lower one‐third of the ureter. Number: treatment group 1: 25; treatment group 2: 25; control group: 25. Mean age ± SD, years: 36.8 ± 11.3 overall. Sex, M/F: not mentioned. Exclusion criteria: proximal or intramural part of ureteral stone; active urinary tract infection; ureterohydronephrosis; acute renal failure; fever; multiple ureteral stones; history of surgery or endoscopic procedure of urolithiasis; chronic renal failure; diabetes mellitus; peptic ulcer; concomitant treatment with alpha‐blocker and beta‐blocker, calcium antagonists, or nitrates; pregnancy; lactation; patient desire for immediate stone removal.
Interventions	Treatment group 1 Tamsulosin 0.4 mg once daily. Treatment group 2 Nifedipine 30 mg once daily. Control group Diclofenac sodium 50 mg. All participants were encouraged to maintain water intake of 2‐2.5 L/d.
Outcomes	Stone expulsion rate. HU of stones. Expulsion time. Rate of pain relief therapy. Mean analgesic consumption. Drug side effects.
Funding sources	None.
Declarations of interest	None.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “Randomization was performed using the Power Analysis & Sample Size Software (PASS_ ) for Windows (NCSS Inc., Kaysville, UT). According to the software, the patients were randomly assigned to one of the following three groups.” Comment: This method of random sequence generation was considered to have low risk of bias.
Allocation concealment (selection bias)	Unclear risk	No quotes available. Insufficient information to permit judgement. Comment: Owing to insufficient information, allocation concealment was considered to have unclear risk of bias.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	No quotes available. No blinding described. Comment: Owing to insufficient information, risk of performance bias was considered to be unclear.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No quotes available. No blinding of outcome assessments described. Comment: Owing to insufficient information, risk of detection bias was considered to be unclear.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No quotes available. Comment: All participants completed the study; therefore risk of attrition bias was considered to be low.
Selective reporting (reporting bias)	Unclear risk	No quotes available. Comment: Owing to insufficient information to permit judgement, risk of reporting bias was considered to be unclear.
Other bias	Low risk	No quotes available. Study appears to be free of other sources of bias. Comment: No other sources of bias could be found; therefore risk of other bias was considered to be low.

Methods	Study design: prospective double‐blind RCT. Study duration: April 2007 and February 2009. Follow‐up/Treatment duration: 7 days.
Participants	Country: USA. Setting: single centre. All ureteral stones. Number: treatment group: 53; placebo group: 47. Mean age: treatment group: 40.62; placebo group: 44.52. Sex, M/F: treatment group: 26% male; placebo group: 30% male. Exclusion criteria: younger than 18 years; stone larger than 1 cm; infected stones; obstructing stones in solitary kidneys; currently taking Levitra, nifedipine, or steroids; requiring immediate surgical intervention; pregnant; already taking tamsulosin before enrolment.
Interventions	Treatment group Tamsulosin 0.4 mg once daily and standard analgesia (Vicodin and ibuprofen). Placebo group Placebo drug and standard analgesia (Vicodin and ibuprofen).
Outcomes	Stone expulsion rate. Pain score. Drug side effects. Mean analgesic consumption.
Funding sources	None.
Declarations of interest	None.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Quote: "using a convenience sample." Comment: This method of random sequence generation was considered to have high risk of bias.
Allocation concealment (selection bias)	Unclear risk	No quotes available. Insufficient information to permit judgement. Comment: Owing to insufficient information, allocation concealment was considered to have unclear risk of bias.
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "double‐blinded, placebo‐controlled." Comment: double‐blind; therefore low risk of bias.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No quotes available. No blinding of outcome assessments described. Comment: Owing to insufficient information, risk of detection bias was considered to be unclear.
Incomplete outcome data (attrition bias)   All outcomes	High risk	Quote: "Of the 127 patients enrolled during this study, 15 were lost to follow‐up, and 12 received surgical intervention before the 7‐day mark, leaving 100 patients for analysis." Comment: Owing to a reasonable number of participants lost to follow‐up, risk of attrition bias was considered to be high.
Selective reporting (reporting bias)	Low risk	No quotes available. Expected outcomes were reported according to objectives. Comment: Risk of reporting bias was therefore considered to be low.
Other bias	Low risk	No quotes available. Study appears to be free of other sources of bias. Comment: No other sources of bias could be found; therefore risk of other bias was considered to be low.

Methods	Study design: DB RCT. Study duration: June 1999 to January 2002. Follow‐up/Treatment duration: probably 7 days.
Participants	Country: Slovakia. Setting: inpatients. Patients, 17‐76 years, with X‐ray‐verified lower urinary tract stones < 10 mm. Number: treatment group: 51; control group: 53 enrolled/51 evaluated. Age range, years: treatment group: 18‐76; control group: 17‐74. Sex, M/F: treatment group: 32/19; control group: 33/18. Exclusion criteria: pregnant women; new and decompensated diabetes mellitus; febrile state; advanced ureterohydronephroses; UTI; grave polyvalent allergies.
Interventions	Treatment group Tamsulosin 0.4 mg. Standard therapy. Control group Standard therapy 1 amp Tramal 50 mg – analgeticum + 1 amp diazepam 5 mg – anxiolyticum in 150 mL physiological saline infusion solution applied IV. These participants were also given the following per os: 3 × 2 tablets Yellon per 20 mg – antiexudativum and non‐steroid antirheumatic Veral, 3 times daily per 50 mg. All participants were made to keep a drinking regimen of at least 2.5 L of water or weak tea daily.
Outcomes	Stone expulsion rate.
Funding sources	None stated.
Declarations of interest	None stated.
Notes	Study authors stated the study model was a double blind RCT but described no blinding.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "we have applied a double blind randomized study." Comment: Randomisation was stated but no information on method used was available; therefore risk of selection bias was considered to be unclear.
Allocation concealment (selection bias)	Unclear risk	No quotes available. Insufficient information to permit judgement. Comment: Owing to insufficient information, allocation concealment was considered to have unclear risk of bias
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	No quotes available. No blinding described. Comment: Owing to insufficient information, risk of performance bias was considered to be unclear.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No quotes available. No blinding of outcome assessments described. Comment: Owing to insufficient information, risk of detection bias was considered to be unclear.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Quote: "As two pts. were excluded from group “A” because during treatment they developed acute obstruction pyelonephritis, both groups consisted of a rather unusual identical number of experimental and standardly treated pts. (51)." Comment: In the light of the small number of participants lost to follow‐up, risk of attrition bias was stated as low.
Selective reporting (reporting bias)	Low risk	No quotes available. Expected outcomes were reported according to objectives. Comment: Risk of reporting bias was therefore considered to be low.
Other bias	Low risk	No quotes available. Study appears to be free of other sources of bias. Comment: No other sources of bias could be found; therefore risk of other bias was considered to be low.

PERMALINK

Alpha‐blockers as medical expulsive therapy for ureteral stones

Thijs Campschroer

Xiaoye Zhu

Robin WM Vernooij

MTW Tycho Lock

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Inclusion criteria

Exclusion criteria

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Main outcomes for 'Summary of findings' tables

Summary of findings for the main comparison. Alpha‐blockers compared with standard therapy for ureteral stones.

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

1.

Data extraction and management

Assessment of risk of bias in included studies

2.

3.

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

'Summary of findings' tables and application of GRADE

Results

Description of studies

Results of the search

Included studies

Excluded studies

Risk of bias in included studies

Allocation

Blinding

Incomplete outcome data

Selective reporting

4.

Other potential sources of bias

Effects of interventions

Summary of findings 2. Alpha‐blockers compared with placebo for ureteral stones.

1. Alpha‐blockers versus standard therapy or placebo

Primary outcomes

1.1 Stone clearance

1.1. Analysis.

1.2 Major adverse events

1.2. Analysis.

Secondary outcomes

1.3 Stone expulsion time

1.3. Analysis.

1.4 Pain episodes

1.4. Analysis.

1.5 Dose of diclofenac

1.5. Analysis.

Methods	Study design: double‐blind placebo‐controlled RCT. Study duration: unknown. Follow‐up/Treatment duration: 90 days.
Participants	Country: South Korea. Setting: multi‐centre. Patients > 20 years of age with a single ureteral stone. The maximal diameter of the stones was 3 ± 10 mm. Number: treatment group: 64; placebo group: 60. Mean age ± SD, years: treatment group: 48.1 ± 14.2; placebo group: 42.33 ± 12.58. Sex, M/F: treatment group: 49/15; placebo group: 41/19. Exclusion criteria: presence of multiple ureter stones; renal or hepatic dysfunction; febrile urinary tract infection; breastfeeding or pregnant women; solitary kidney; hypersensitivity to naftopidil; current use of alpha‐blockers, calcium channel blockers, or corticosteroid within 4 weeks; moderate to severe cardiovascular or cerebrovascular disease; significant active medical illness or genetic disorders.
Interventions	Treatment group Naftopidil 75 mg once daily. Placebo group All participants received aceclofenac 100 mg or combination treatment with tramadol 37.5 mg and acetaminophen 325 mg.
Outcomes	Primary outcome measures Stone‐free rate. Secondary outcome measures Stone‐free rate at 28th day of study. Quantity of analgesics used. Rate of active treatment.
Funding sources	None.
Declarations of interest	None.
Notes	Participants were followed up at days 14 (visit 1), 28 (visit 2), 60 (visit 3), and 90 (visit 4) after initiation of medication.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomization was carried out by the Medical Research Collaboration Center of Seoul National University Bundang Hospital using random permuted blocks of different sizes. The size of the next block was randomly chosen from the available block sizes." Comment: This method of random sequence generation was considered to have low risk of bias.
Allocation concealment (selection bias)	Low risk	Quote: "The size of the next block was randomly chosen from the available block sizes. Randomization was stratified by each recruiting study site." Comment: This method of allocation concealment was considered to have low risk of bias.
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "One person packed the 14‐day supply of tablets for each patient. All study staff at all hospitals were blinded to treatment allocation and remained blind until the end of the trial." Comment: double‐blind; therefore low risk of bias.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No quotes available. No blinding of outcome assessments described. Comment: Owing to insufficient information, risk of detection bias was considered to be unclear.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No quotes available. Figure 1 shows a detailed flow diagram of participant follow‐up, including information regarding loss to follow‐up, exclusion due to adverse events, or need for intervention. Comment: Detailed information on participant follow‐up was available; risk of attrition bias was considered to be low.
Selective reporting (reporting bias)	Low risk	No quotes available. Expected outcomes were reported according to objectives. Comment: Information on primary and secondary outcomes was presented in detail in the protocol at www.clinicaltrials.gov. Risk of reporting bias was therefore considered to be low.
Other bias	Low risk	No quotes available. Study appears to be free of other sources of bias. Comment: No other sources of bias could be found; therefore risk of other bias was considered to be low.

Methods	Study design: RCT. Study duration: NS. Follow‐up/Treatment duration: 1 week.
Participants	Country: Korea. Setting: multi‐centre. Patients with ureteral stones. Number: treatment group: 19; control group: 21. Mean age ± SD, years: treatment group: 54.05 ± 12.63; control group: 45.19 ± 12.27. Sex, M/F: treatment group: 12/7; control group: 12/9. Exclusion criteria: uncontrolled pain with conservative therapy; multiple stones; pregnancy; SCr ≥ 2.5 mg/dL; prior ureteral surgery; urinary tract obstruction; ureteral splints.
Interventions	Treatment group (group 3) Tamsulosin 0.2 mg. Control group (group 4) Diclofenac sodium for 1 week. Four treatment arms, of which the first 2 underwent ESWL (groups 1 and 2); groups 3 and 4 did not want to undergo ESWL.
Outcomes	Stone clearance. Change in pain score.
Funding sources	Study was supported by research funds from Astellas Phama Korea, Inc.
Declarations of interest	None stated.
Notes	Dong Il Kang; only the abstract was written in English and therefore was interpretable.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	No quotes available. Comment: Participants were those who did not want to undergo ESWL; therefore risk of selection bias was considered to be high.
Allocation concealment (selection bias)	Unclear risk	No quotes available. Insufficient information to permit judgement. Comment: Owing to insufficient information, risk of allocation concealment was considered to be unclear.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	No quotes available. No blinding described. Comment: Owing to insufficient information, risk of performance bias was considered to be unclear.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No quotes available. No blinding of outcome assessments described. Comment: Owing to insufficient information, risk of detection bias was considered to be unclear.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	No quotes available. Comment: Owing to insufficient information to permit judgement, risk of attrition bias was considered to be unclear.
Selective reporting (reporting bias)	Unclear risk	No quotes available. Comment: Owing to insufficient information to permit judgement, risk of reporting bias was considered to be unclear.
Other bias	Unclear risk	No quotes available. Comment: Owing to insufficient information to permit judgement, risk of other sources of bias was considered to be unclear.

Methods	Study design: prospective DB RCT. Study duration: October 2006 to October 2010. Follow‐up/Treatment duration: 4 weeks.
Participants	Country: Egypt. Setting: single centre. Patients with distal third ureteral stones. Number: treatment group: 48; placebo group: 46. Mean age ± SD, years: group 1: 36.2 ± 6; group 2: 35.3 ± 5.7. Sex, M/F: NS. Exclusion criteria: UTI; ureteral strictures; renal impairment; solitary functioning kidney; pregnancy; lactation; sensitivity to alpha‐blockers.
Interventions	Group 1: placebo group. Group 2: tamsulosin group. Group 3: Uralyt group. Group 4: Uralyt and tamsulosin group. All participants were advised to increase fluid intake to more than 2 L per day and to receive IM injection of 75 mg of diclofenac sodium.
Outcomes	Mean stone size. Analgesic needs. Stone passage rate.
Funding sources	None stated.
Declarations of interest	None stated.
Notes	Non‐enhanced spiral CT was done at the end of study period for all participants.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “Patients were prospectively randomized through a computer generated randomization process into four equal groups.” Comment: This method of random sequence generation was considered to have low risk of bias.
Allocation concealment (selection bias)	Low risk	Quote: “The investigators and the patients were blinded to the treatment given, until the end of the study.” Comment: Randomisation method was described and would not allow investigator/participant to know or influence the intervention group before eligible participant entered into the study. Therefore this method of allocation concealment was considered to have low risk of bias.
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: “The investigators and the patients were blinded to the treatment given, until the end of the study.” Comment: double‐blind; therefore low risk of bias.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No quotes available. No blinding of outcome assessments described. Comment: Owing to insufficient information, risk of detection bias was considered to be unclear.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Quote: “5 cases were lost to follow‐up (2 in the control group and one in each of the other three groups).” Comment: Owing to the small number of participants lost to follow‐up, risk of attrition bias was considered to be low.
Selective reporting (reporting bias)	High risk	No quotes available. Comment: Primary outcomes were not prespecified; therefore risk of reporting bias was considered to be high.
Other bias	Low risk	No quotes available. Comment: Owing to insufficient information to permit judgement, risk of other sources of bias was considered to be unclear.

Methods	Study design: RCT. Study duration: not described. Follow‐up/Treatment duration: 4 weeks.
Participants	Country: Turkey. Setting: not described. Patients with distal third ureteral stones 4‐10 mm. Number: treatment group: 37; control group: 34. Mean age ± SD, years: not described. Sex, M/F: not described. Exclusion criteria: not described.
Interventions	Group 1: tamsulosin group. Group 2: corticosteroid group. Group 3: tamsulosin and corticosteroid group. Group 4: control group. Data for groups 1 and 4 were used for the review.
Outcomes	Stone expulsion rate. Need for surgical intervention. Drug adverse events.
Funding sources	None stated.
Declarations of interest	None stated.
Notes	Conference abstract. Follow‐up on weekly basis with imaging (not discussed in detail).
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: “A total of 134 patients with distal ureteral stone of 4‐10 mm were randomized into 4 groups.” Comment: Randomisation stated but no information on method used was available; therefore selection bias was considered to be at unclear risk of bias.
Allocation concealment (selection bias)	Unclear risk	No quotes available. Insufficient information to permit judgement. Comment: Owing to insufficient information, allocation concealment was considered to be at unclear risk of bias.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	No quotes available. No blinding described. Comment: Owing to insufficient information, risk of performance bias was considered to be unclear.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No quotes available. No blinding of outcome assessments described. Comment: Owing to insufficient information, risk of detection bias was considered to be unclear.
Incomplete outcome data (attrition bias)   All outcomes	High risk	No quotes available. 6 patients in control group lost to follow‐up. Comment: losses to follow‐up not balanced between treatment groups; therefore risk of attrition bias was considered to be high.
Selective reporting (reporting bias)	Unclear risk	No quotes available. Comment: Owing to insufficient information to permit judgement, risk of reporting bias was considered to be unclear.
Other bias	Unclear risk	No quotes available. Comment: Owing to insufficient information to permit judgement, risk of other sources of bias was considered to be unclear.

Methods	Study design: RCT. Study duration: August 2006 to November 2007. Follow‐up/Treatment duration: 14 days.
Participants	Country: USA. Setting: ED/single centre. Patients > 18 years, CT‐confirmed single distal ureteral stone. Number: treatment group: 39; control group: 41. Mean age ± SD, years: treatment group: 47 ± 14; control group: 45 ± 12. Sex, M/F: treatment group: 32/6; control group: 24/15. Exclusion criteria: allergy or sensitivity to study drug (tamsulosin hydrochloride); sulfa/sulfonamide allergy; lithiasis of ureteral intramural tract; AKI or CKD; fever; presence of multiple ureteral stones; peptic ulcer disease; liver failure; pregnancy; breastfeeding; history of urinary surgery; history of endoscopic treatment; concomitant treatment with any of the following pharmaceuticals: ‐lytic drugs, calcium channel antagonists, nitrates, and vardenafil hydrochloride; inability to use study pain scale; inability to read, write, and speak English.
Interventions	Treatment group Tamsulosin 0.4 mg daily for 10 days. Standard analgesic therapy. Control group Standard analgesic therapy Ibuprofen: 800 mg orally, 3 times daily. Oxycodone: 5 to 10 mg orally, every 4 to 6 hours as needed for pain.
Outcomes	Spontaneous passage rate. Stone expulsion time. Number of episodes of colicky pain. Number of return visits to the ED or unscheduled primary care visits. Amount of opioid analgesic used. Number of days of missed work or inability to perform usual functions. Adverse events. Self‐reported pain scores.
Funding sources	This study was funded by an academic grant from the Maine Medical Center Mentored Research Committee.
Declarations of interest	None stated.
Notes	Follow‐up with all participants at 2, 5, and 14 days post discharge from the ED. Sample size calculated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “Randomization was accomplished by using a table of random numbers.” Comment: This method of random sequence generation was considered to be at low risk of bias.
Allocation concealment (selection bias)	Low risk	Quote: “The information on group assignment was contained in a sealed envelope within each study packet, and the envelopes were clearly labelled “do not open until informed consent is obtained.” Comment: This method of allocation concealment was considered to be at low risk of bias.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	No quotes available. No blinding described. Comment: Owing to insufficient information, risk of performance bias was considered to be unclear.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No quotes available. No blinding of outcome assessments described. Comment: Owing to insufficient information, risk of detection bias was considered to be unclear.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No quotes available. Participants lost to follow‐up (4), discontinued intervention (2), excluded because the stone was located in the proximal ureter (1). Comment: Losses to follow‐up were balanced across treatment groups; therefore risk of attrition bias was considered to be low.
Selective reporting (reporting bias)	Low risk	No quotes available. Expected outcomes were reported according to objectives. Comment: Risk of reporting bias was therefore considered to be low.
Other bias	Low risk	No quotes available. Study appears to be free of other sources of bias. Comment: No other sources of bias could be found; therefore risk of other bias was considered to be low.

Methods	Study design: multi‐centre, randomised DB placebo‐controlled trial. Study duration: October 2010 until March 2014. Follow‐up/Treatment duration: 28 days.
Participants	Country: Australia. Setting: emergency departments. Patients 18 years or older with symptoms suggestive of ureteric colic and a calculus demonstrated in the distal ureter on CT scan. Number: treatment group: 202; placebo group: 201. Median age, years (IQR): treatment group: 45.5 (35‐55); placebo group: 46 (37‐55). Sex: treatment group: 78.8% men; placebo group: 84.1% men. Exclusion criteria: temperature > 38 degrees C; estimated GFR less than 60 mL/min per 1.73 m²; calculus greater than 10 mm; solitary kidney; transplanted kidney; history of ureteral stricture; known allergic reaction to study medication; current calcium channel blocker or alpha‐blocker use; hypotension (systolic blood pressure < 100 mm Hg); pregnancy; planning pregnancy.
Interventions	Treatment group Tamsulosin 0.4 mg daily. Recommended regimen: indomethacin 25 to 50 mg 3 times daily orally and oxycodone 5 to 10 mg 3 times daily. Placebo group Placebo drug. Recommended regimen: indomethacin 25 to 50 mg 3 times daily orally and oxycodone 5 to 10 mg 3 times daily. Analgesia was given at the discretion of the treating physician.
Outcomes	Stone expulsion rate. Stone expulsion time. Unplanned re‐presentations to the ED or hospital admission. Total analgesia requirements. Pain scores measured on the verbal numerical pain scale. Need for urological intervention. Complications including infection, renal impairment, and days off work. Adverse events from study drugs.
Funding sources	Grant from the Queensland Emergency Medicine Research Foundation.
Declarations of interest	None stated.
Notes	Power calculation was performed. Intention‐to‐treat‐principle. Telephone contacts at 7, 14, 21, and 28 days with pelvic non‐contrast CT at day 28.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The randomization sequence was produced with a computer‐generated program in permuted blocks of random lengths stratified by hospital and stone size." Comment: This method of random sequence generation was considered to be at low risk of bias.
Allocation concealment (selection bias)	Low risk	Quote: "Once informed consent was obtained and patients were deemed appropriate for discharge, they were allocated to the next sequentially numbered study medication pack." Comment: This method of allocation concealment was considered to be at low risk of bias.
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "Investigators, the treating physician, and patients were blinded to the allocation for the duration of the study and data analysis." Comment: double‐blind; therefore low risk of bias.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: “Investigators, the treating physician, and patients were blinded to the allocation for the duration of the study and data analysis.” Comment: Personnel responsible for outcome assessments were blinded; therefore risk of detection bias was considered to be low.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Quote: "Similar proportions of patients with missing and nonmissing outcome data." Comment: Missing outcome data were balanced in numbers across both groups, and reasons for missing data were similar; therefore risk of attrition bias was considered to be low.
Selective reporting (reporting bias)	Low risk	No quotes available. Expected outcomes were reported according to objectives. Comment: Risk of reporting bias was therefore considered to be low.
Other bias	Low risk	No quotes available. Study appears to be free of other sources of bias. Comment: No other sources of bias could be found; therefore risk of other bias was considered to be low.

Methods	Study design: randomised prospective trial. Study duration: February 2013 and December 2013. Follow‐up/Treatment duration: 4 weeks.
Participants	Country: Romania. Setting: single centre. Patients 18 years or older with unilateral, non‐impacted, uncomplicated ureteral stones smaller than 1 cm. Number: treatment group 1: 50; treatment group 2: 50; control group: 50. Mean age ± SD, years: treatment group 1: 43.5 ± 13.31; treatment group 2: 44.26 ± 13.00; control group: 45.14 ± 11.58. Sex, M/F: treatment group 1: 27/23; treatment group 2: 31/19; control group: 26/24. Exclusion criteria: fever; UTI; high‐grade hydronephrosis; hypotension; acute or chronic renal failure; single kidney; urinary congenital anomalies; multiple or bilateral ureteral stones; history of open surgery or endoscopic procedures in the urinary tract; diabetes; peptic ulcer; concomitant treatment with alpha‐ or beta‐blockers, calcium antagonists, steroid, nitrates; pregnant or lactating women; patients requiring immediate stone removal.
Interventions	Treatment group 1 Tamsulosin 0.4 mg daily. Diclofenac sodium 50 mg/12 h. Treatment group 2 Silodosin 8 mg daily. Diclofenac sodium 50 mg/12 h. Control group Diclofenac sodium 50 mg/12 h.
Outcomes	Stone expulsion rate. Stone expulsion time. Mean number of pain episodes. Rates of interventions/Hospital re‐admissions. Drug adverse events.
Funding sources	None stated.
Declarations of interest	None stated.
Notes	Follow‐up at 14 ± 2 days with urinalysis, KUB, and ultrasonography.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The randomization process was achieved by means of sealed envelopes equally nominating one of the three treatment alternative." Comment: This method of random sequence generation was considered to be at low risk of bias.
Allocation concealment (selection bias)	Low risk	Quote: "Allocation concealment was performed using the SNOSE method (sequentially‐numbered, opaque, sealed envelopes)." Comment: This method of allocation concealment was considered to be at low risk of bias.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	No quotes available. No blinding described. Comment: Owing to insufficient information, risk of performance bias was considered to be unclear.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No quotes available. No blinding of outcome assessments described. Comment: Owing to insufficient information, risk of detection bias was considered to be unclear.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No quotes available. Comment: All participants completed the study; therefore risk of attrition bias was considered to be low.
Selective reporting (reporting bias)	Low risk	No quotes available. Expected outcomes were reported according to objectives. Comment: Risk of reporting bias was therefore considered to be low.
Other bias	Low risk	No quotes available. Study appears to be free of other sources of bias.   Comment: No other sources of bias could be found; therefore risk of other bias was considered to be low.

Methods	Study design: :double‐blind RCT. Study duration: September 2006 to September 2008. Follow‐up/Treatment duration: 21 days.
Participants	Country: Switzerland. Setting: outpatient, single centre. Patients ≥ 18 years with single ureteral stone ≤ 7 mm below the common iliac vessels, as assessed on NCCT. Number: treatment group: 50; control group: 50. Median age, years (IQR): treatment group: 36 (30–44); control group: 41 (33–54). Sex, M/F: treatment group: 39/6; control group: 36/9. Exclusion criteria: presence of multiple ureteral stones; renal insufficiency (eGFR < 60 mL/min/1.73 m²); UTI; a solitary kidney; pregnancy; history of ureteral surgery or previous endoscopic procedures; hypersensitivity to tamsulosin or current alpha‐blocker, calcium antagonist, or corticosteroid medication.
Interventions	Treatment group Tamsulosin 0.4 mg once daily. Control group Placebo.
Outcomes	Stone expulsion rate. Time to stone passage. Required total amount of analgesic. Reported maximum daily pain score until stone expulsion. Intervention rate. Safety of therapy.
Funding sources	None.
Declarations of interest	None.
Notes	Sample size calculated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Enrolled patients underwent randomisation in a 1:1 fashion in blocks of 10 to receive either a daily single dose of tamsulosin (0.4 mg) or placebo. The sequence of randomisation was computer generated and was performed by the university hospital pharmacy using DatInf Randlist software v.1.0 (DatInf GmbH, Tübingen, Germany)." Comment: This method of random sequence generation was considered to be at low risk of bias.
Allocation concealment (selection bias)	Low risk	Quote: "Randomisation data were kept strictly confidential in sealed envelopes, accessible only to the primary and senior investigator." Comment: This method of allocation concealment was considered to have low risk of bias.
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "The patient, the attending urologist were not aware of study arm assignments until the final assessment of outcome." Comment: double‐blind.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: "Personnel responsible for outcome assessments were blinded." Comment: double‐blind; therefore low risk of bias.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Quote: "Patients were included in the final analysis on an intention‐to‐treat basis. Patients who experienced stone expulsion before first medication, who withdrew their consent, or who were lost to follow‐up were excluded from the analysis." Comment: missing outcome data and losses to follow‐up balanced in numbers across both groups; therefore risk of attrition bias was considered to be low.
Selective reporting (reporting bias)	Low risk	No quotes available. Expected outcomes were reported according to objectives. Comment: Risk of reporting bias was therefore considered to be low.
Other bias	Low risk	No quotes available. Study appears to be free of other sources of bias. Comment: No other sources of bias could be found; therefore risk of other bias was considered to be low.

Methods	Study design: clinical trial (unknown type). Study duration: January 2004 and September 2007. Follow‐up/Treatment duration: 2 weeks.
Participants	Country: Korea. Setting: NS. Patients with symptomatic distal ureteral stones. Number: treatment group 1: 42; treatment group 2: 66; treatment group 3: 72. Mean age ± SD, years: NS. Sex, M/F: NS. Exclusion criteria: NS.
Interventions	Treatment group 1 Furosemide 40 mg daily. Treatment group 2 Furosemide 40 mg daily. Tamsulosin 0.4 mg daily. Treatment group 3 Furosemide 40 mg daily. Tamsulosin 0.4 mg daily. Deflazacort 24 mg daily.
Outcomes	Stone passage rate. Time spent for stone‐expulsion. Adverse events.
Funding sources	None stated.
Declarations of interest	None stated.
Notes	Conference abstract. Follow‐up time: 2 weeks, visits at 1st and 2nd weeks after medication.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No quotes available. Comment: randomisation stated but no information on method used was available; therefore risk of selection bias was considered to be unclear.
Allocation concealment (selection bias)	Unclear risk	No quotes available. Insufficient information to permit judgement. Comment: Owing to insufficient information, allocation concealment was considered to be at unclear risk of bias.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	No quotes available. No blinding described. Comment: Owing to insufficient information, risk of performance bias was considered to be unclear.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No quotes available. No blinding of outcome assessments described. Comment: Owing to insufficient information, risk of detection bias was considered to be unclear.
Incomplete outcome data (attrition bias)   All outcomes	High risk	No quotes available. 61 patients excluded from the study; no details available. Comment: large number of patients excluded from the study without clarification. Therefore, risk of attrition bias was considered to be high.
Selective reporting (reporting bias)	Low risk	No quotes available. Expected outcomes were reported according to objectives. Comment: Risk of reporting bias was therefore considered to be low.
Other bias	Unclear risk	No quotes available. No information on baseline data. Comment: Owing to insufficient information to permit judgement, risk of other sources of bias was considered to be unclear.

Methods	Study design: RCT. Study duration: July 2007 to December 2008. Follow‐up/Treatment duration: 4 weeks.
Participants	Country: Bangladesh. Setting: NS. Distal ureteral stones (juxtavesical tract and ureterovesical junction), 1 cm or smaller. Number: treatment group 1: 33; treatment group 2: 33; control group: 32. Mean age, years: treatment group 1: 46.6; treatment group 2: 47.4; control group: 42.8. Sex, M/F: treatment group 1: 20/12; treatment group 2: 21/10; control group: 17/11. Exclusion criteria: UTI; severe hydronephrosis; a solitary kidney; extra stone in the upper urinary system; underwent previous surgery for a urinary system stone; a non‐opaque stone; diseases such as diabetes or hypertension; pregnant women; those whose renal reserve was reduced by more than 50%.
Interventions	Treatment group 1 Tamsulosin 0.4 mg daily. Ciprofloxacin 500 mg, twice a day. Diclofenac sodium for routine use during pain episodes. Treatment group 2 Nifedipine 20 mg daily (slow‐release preparation). Ciprofloxacin 500 mg, twice a day. Diclofenac sodium for routine use during pain episodes. Control group Ciprofloxacin 500 mg, twice a day. Diclofenac sodium for routine use during pain episodes. All participants received 2500 mL hydration daily.
Outcomes	Stone passage rate. Stone expulsion time. Stone size. Mean diclofenac sodium dosage. Drug adverse events. Hospitalisation.
Funding sources	None stated.
Declarations of interest	None stated.
Notes	Follow‐up weekly with renal ultrasonography, X‐ray KUB, urinalysis, and serum creatinine measurements.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No quotes available. Comment: randomisation stated but no information on method used was available; therefore risk of selection bias was considered to be unclear.
Allocation concealment (selection bias)	Unclear risk	No quotes available. Insufficient information to permit judgement. Comment: Owing to insufficient information, allocation concealment was considered to have unclear risk of bias.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	No quotes available. No blinding described. Comment: Owing to insufficient information, risk of performance bias was considered to be unclear.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No quotes available. No blinding of outcome assessments described. Comment: Owing to insufficient information, risk of detection bias was considered to be unclear.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No quotes available. Comment: Low percentage of loss to follow‐up in each group (< 5%); therefore risk of attrition bias was considered to be low.
Selective reporting (reporting bias)	High risk	No quotes available. Comment: Mean diclofenac sodium dosage and drug adverse events were not described as outcome parameters in the Methods section; therefore risk of reporting bias was considered to be high.
Other bias	Low risk	No quotes available. Study appears to be free of other sources of bias. Comment: No other sources of bias could be found; therefore risk of other bias was considered to be low.