The authors have declared that no competing interests exist.
Conceived and designed the experiments: GZ. Performed the experiments: CL RK. Analyzed the data: CL JL. Contributed reagents/materials/analysis tools: WW. Wrote the paper: CL. Checked and revised the manuscript: KC SPW.
Current address: Kangda Road 1#, Haizhu District, Guangzhou, 510230, Guangdong, China
Alfuzosin has been widely used to treat benign prostatic hyperplasia and prostatitis, and is claimed to be a selective agent for the lower urinary tract with low incidence of adverse side-effects and hypotensive changes. Recently, several randomized controlled trials have reported using Alfuzosin as an expulsive therapy of ureteral stones. Tamsulosin, another alpha blocker, has also been used as an agent for the expulsive therapy for ureteral stones. It is unclear whether alfuzosin has similar efficacy as Tamsulosin in the management of ureteral stones.
To perform a systematic review and analysis of literatures comparing Alfuzosin with Tamsulosin or standard conservative therapy for the treatment of ureteral stones less than 10 mm in diameter.
A systematic literature review was performed in December 2014 using Pubmed, Embase, and the Cochrane library databases to identify relevant studies. All randomized and controlled trials were included. A subgroup analysis was performed comparing Alfuzosin with control therapy on the management of distal ureteral stones.
Alfuzosin provided a significantly higher stone-free rate than the control treatments (RR: 1.85; 95% confidence interval [CI], 1.35–2.55; p<0.001), and a shorter stone expulsion time (Weighted mean difference [WMD]: -4.20 d, 95%CI, -6.19 to -2.21; p<0.001), but it has a higher complication rate (RR: 2.02; 95% CI, 1.30–3.15; p<0.01). When Alfuzosin was compared to Tamsulosin, there was no significant difference in terms of stone-free rate (RR: 0.90; 95% CI, 0.79–1.02; p = 0.09) as well as the stone expulsion time (WMD: 0.52 d, 95%CI, -1.61 to 2.64; p = 0.63). The adverse effects of Alfuzosin were similar to those of Tamsulosin (RR: 0.88; 95% CI, 0.61–1.26; p = 0.47).
Alfuzosin is a safe and effective agent for the expulsive therapy of ureteral stones smaller than 10 mm in size. It is more effective than therapeutic regiment without alpha blocker. It is equivalent to Tamsulosin in its effectiveness and safety profile. Adverse effects should always be kept in mind when use this class of drugs.
Urolithiasis is now one of the main public health problems world-wide. The prevalence is estimated to be 13% in the United States, 5–9% in Europe and 1–5% in Asia[
For medical expulsive therapy, Tamsulosin had been shown to be an effective medication for the expulsive therapy of ureteral stones. This claim was supported by several meta-analysis of randomized controlled trials (RCTs) [
A systematic review was performed in December 2014 using PubMed, Embase, and Cochrane library databases to identify relevant randomized and controlled trials. Searches were restricted to publications in English involving adult population. The date range of articles searched was from 1966 to December 2014. Searches were performed in each database using the search strategy: ((alfuzosin) OR uroxatral) AND ureteral stone. Additional searches were carried out from reference lists of publications in this field.
Article selection was carried out according to the search strategy recommended in the Preferred Reporting Items for Systematic Reviews and Meta-analysis criteria (
The full text of the included studies was reviewed and assessed by two independent reviewers. The methodological quality of the trials was assessed using the Cochrane Collaboration criteria (Jadad scale) for RCTs[
A standardized data collection form was used for recording the extracted data. All pertinent information such as the period and location of the study performed, numbers of participants, and type and dose of the drugs administered, were recorded. Extracted data for the analysis included stone-free rate, stone expulsion time, need for analgesics, pain episodes, and complication rate. Stone expulsion rate, defined as the rate of patient with spontaneous stone expulsion without intervention during the study period, was considered as the primary outcome in this meta-analysis. The stone expulsion time and other indicators were considered as the secondary outcome measures.
A meta-analysis was performed to assess the overall outcome of Alfuzosin therapy compared with control therapy. In addition, four of the nine studies also compared of Alfuzosin to Tamsulosin treatment, and the overall analysis of the two alpha-1blocking agents was performed independently. A subgroup analysis was performed comparing Alfuzosin with the control therapy on the management of distal ureteric stones. Risk ratios (RR) were used for binary variables; weighted mean difference (WMD) was used for the continuous data and displayed as means and standard deviations. The fixed effect model (Mantel-Haenszel method) was used for the pooled estimates, if no significant heterogeneity was detected; otherwise, the random effect model was used. The overall effects were determined by the z test, and p < 0.05 was considered statistically significant. The statistical heterogeneity across studies was assessed by the chi-square test and inconsistency (I2), and I2 >50% suggesting substantial statistical heterogeneity[
Nine studies that met our selection criteria were entered for the analysis. There included 291 patients who received Alfuzosin 10 mg p.o, 134 cases received Tamsulosin 0.4mg p.o, and 280 cases received conservative therapy,
Study | Country | Study period | Paints (n) | Stone size (mm) | Stone location | Additional medications | I/C |
F (weeks) | Study quality |
---|---|---|---|---|---|---|---|---|---|
USA | 2008 | 34 35 | 3.96 3.67 | LU | NR | Alfuzosin 10 mg Control | 4 | 5 | |
Korean | 2012 | 36 30 34 | 5.81 5.73 5.59 | LU | Trospium chloride (50 mg, tablet) every 8 hours | Alfuzosin 10 mg Tamsulosin 0.4mg Control | 4 | 5 | |
Iraq | 2013 | 40 40 32 | 5.94 5.58 5.65 | UU LU | Diclofenac potassium orally 50 mg and/or diclofenac sodium as an intramuscular injection of 75 mg on demand | Alfuzosin 10 mg Tamsulosin 0.4 mg Control | 4 | 4 | |
Turkey | 2011 | 34 33 | 6.83 7.13 | LU | Drink at least 3 L of fluids daily; Diclofenac injection (75 mg) intramuscularly on demand for pain relief | Alfuzosin 10 mg Control | 2 | 4 | |
China | 2011 | 33 34 | 6.7 6.9 | UU LU | Dologesic (paracetamol+dextropropoxyphene) 4 tablets daily on a demand basis for 2 weeks | Alfuzosin10 mg Control | 6 | 3 | |
India | 2008 | 34 34 34 | 6.70 6.17 6.35 | LU | Drink at least 3 L of fluids daily; Diclofenac injection (75 mg) intramuscularly on demand for pain relief | Alfuzosin10 mg Tamsulosin 0.4 mg Control | 4 | 5 | |
KSA | 2010 | 30 30 28 | 5.47 4.97 5.39 | LU | Diclofenac sodium (50 mg, tablet) every 12 hours for 1 week; Diclofenac sodium injection (75 mg, amp) as needed | Alfuzosin 10 mg Tamsulosin 0.4 mg Control | 4 | 3 | |
India | 2014 | 35 35 | 6.26 6.37 | LU | Diclofenac sodium (50 mg, tablet) every 12 hours for 1 week; Diclofenac sodium injection (75 mg, amp) as needed | Alfuzosin 10 mg Control | 4 | 5 | |
Mexico | 2009 | 15 15 | 5.80 6.43 | LU | Buscopan 10 mg/8h plus ketorolac 10 mg/8h | Alfuzosin 10 mg Control | 4 | 2 |
NR = not record; UU = upper ureter; LU = lower ureter; F = follow-up
# Control group receiving placebo or dologesic
* Using Jadad scale (score from 0 to 5)
Diclofenac injections and oral non-steroidal anti-inflammatory drugs (NSAIDs) were widely used alone or in combination. Pain episodes and the need of analgesic were recorded as part of data collection in almost all of the studies. They were presented as averages with no standard deviations calculation. Seven of the nine studies showed no significant difference between the Alfuzosin and the control therapy in term of pain episodes and analgesics use (p>0.05, respectively) while as two studies revealed otherwise (p = 0.03, p<0.05, respectively). The difference between the Alfuzosin and Tamsulosin group was not statistically significant in terms of pain episodes in each study (p>0.05, respectively),
Studies | No. of Analgaesic Use (n) | No. of Pain Episodes(n) | |||||||
---|---|---|---|---|---|---|---|---|---|
Additional treatments | A | T | C | A | T | C | |||
Opioidmedications (tablets) | 8.63 | - | 9.41 | 0.45 | - | - | - | ||
Morphine equivalents | 7.59 | - | 8.36 | 0.83 | |||||
No record | - | - | - | - | - | - | - | ||
Diclofenac injections 75mg /Diclofenac sodium (tablets) | - | - | - | - | 1.64 | 1.38 | 2.45 | > 0.05 |
|
Diclofenac(tablets) | 4.36 | - | 3.75 | 0.57 | - | - | - | ||
Diclofenac injections75mg | 17.0 | - | 16.0 | 0.87 | - | - | - | ||
NSAIDs (tablets) | 1.5 | - | 6.9 | 0.03 | |||||
Diclofenac injections75mg | 1 | 0.88 | 6.2 | <0.05 |
0.82 | 0.58 | 5.5 | <0.05 |
|
Diclofenac injection75mg | - | - | - | - | 1.43 | 1.24 | 1.75 | 0.04 | |
Diclofenac injection75mg | - | - | - | - | 1.80 | - | 2.82 | <0.001 | |
No record | - | - | - | - | - | - | - |
*Alfuzosin compared with control therapy A = Alfuzosin; T = Tamsulosin; C = control; NSAIDs = nonsteroidal antiinflammatory drugs
There was a significantly higher stone expulsion rate following treatment with Alfuzosin as compared with control therapy (RR: 1.85; 95%CI, 1.35, 2.55; p<0.001). Alfuzosin also provided a shorter stone expulsion time (WMD: -4.20 d, 95%CI, -6.19 to -2.21; p<0.001). The pooled effect of adverse events reported by seven studies showed a higher complication rate for Alfuzosin treatment (RR: 2.02; 95% CI, 1.30–3.15; p<0.01). However, there was no significant difference between the two treatments in terms of pain episodes (WMD: -0.68, 95%CI, -1.48 to 0.01; p = 0.05) (
The central square of each horizontal line represents the RR or WMD for each study. The lines demonstrate the range of the 95% CI. The vertical line at an RR of 1 or at WMD of 0 is the line of no effect. % Weight indicates the influence exerted by each study on the pooled RR or WMD. CI = confidence interval; M-H = Mantel-Haenszel; IV = inverse variance; SD = standard deviation.
Funnel plot for evaluation of publication bias. Vertical solid line represents the logarithmic transformation of the overall estimated treatment effect (ie, log [RR]), diagonal dotted lines represent pseudo–95% confidence limits for estimated treatment effect, and the circles represent treatment effects of each of the 9 studies. In the absence of publication bias, graph should represent a funnel, with individual studies clustered around the overall estimated treatment effect symmetrically.
There was no significant difference between Alfuzosin and Tamsulosin therapy in terms of stone expulsion rate (RR: 0.90; 95% CI, 0.79–1.02; p = 0.09) and stone expulsion time (WMD: 0.52 d, 95%CI, -1.61 to 2.64; p = 0.63). The difference in complication rates between Alfuzosin and Tamsulosin therapy was not statistically significant (RR: 0.88; 95% CI, 0.61–1.26; p = 0.47). Pooled analysis showed a lower frequency of retrograde ejaculation in the Alfuzosin-treated group than in the Tamsulosin-treated group (RR: 0.27; 95% CI, 0.08–0.89; p = 0.03) (
Refer to legend in
Subgroup analysis categorized by stone locations (comparing the trials that included stones located in the upper ureter and lower ureter) showed that Alfuzosin provided a significantly higher stone expulsion rate than the control therapy for upper ureteral stones (RR: 3.00; 95%CI, 1.31–6.86; p = 0.004) as well as the lower ureteral stones (RR: 1.78; 95%CI, 1.28–2.46; p = 0.0005), respectively (
Refer to legend in
In this systematic review and meta-analysis, which included 9 studies with 705 patients, we noted that the use of Alfuzosin was associated with a significantly improved stone clearance rate and decreased the expulsion time. Furthermore the efficacy extended to stones located in both upper and lower ureter. Compared with patients who received control conservative treatment alone, patients who received Alfuzosin were 85% more likely to pass the ureteral stones. The stone expulsion time of Alfuzosin therapy for ureteric calculi was shorter in the pooled analysis, since the overall WMD of -4.20 days denoted a mean decrease in the expulsion time of 4.2 days.
To our knowledge, this is the first evidence-based analysis of RCTs to study the efficacy of Alfuzosin alone or in combination with other non-alpha blocker medication in the management of ureteral calculi. Alfuzosin exhibits no pharmacological uroselectivity for any of the alpha-1 subtype receptors, however, it did prove to have less side-effects and blood pressure changes as reported in the literature [
The sensitivity analysis of our study suggests that the effect estimate is robust. Potential sources of heterogeneity include the stone size and location. Subgroup analysis revealed a lower effect of heterogeneity when the study of mean stone size less than 4mm was excluded. In the subgroup analysis of stones by location, the effect of Alfuzosin was shown to be superior for upper ureteral stones than lower ureteral stones in respect to spontaneous stone passage rate (overall RR: 3.00 and overall RR: 1.78, respectively). It is opposite to that of Tamsulosin as a previous meta-analysis reported[
The present analysis based on the currently available RCTs revealed that Alfuzosin might significantly increase the adverse effects up to 102%, as compared with conservative therapy with an overall RR of 2.02, and 95% CI ranging from 1.30 to 3.15. The frequency of overall side-effects was not statistically different between Alfuzosin and Tamsulosin. Whereas retrograde ejaculation was approximately 70% lower in the Alfuzosin group than in the Tamsulosin group, this suggests Alfuzosin might have an advantage when used to treat male patients afflicting with ureteral stone.
The pain episodes and the need of analgesic are important indicators of the treatment effect for symptomatic relief. A significant decrease of pain episodes were reported by three RCTs[
Publication bias is a potential limitation in any systematic review, and it might lead to overestimation of the therapy effect for the null or non-significant outcomes might not to be submitted and published [
Alfuzosin is associated with significantly increased stone passage rate and decreased stone expulsion time. Its efficacy is comparable to that of Tamsulosin. In addition the effectiveness of the Alfuzosin therapy extends to stones in all locations. Adverse effects of Alfuzosin are similar to that of Tamsulosin with the exception of retrograde ejaculation. This suggests that Alfuzosin might have an advantage in treating male patients with ureteral stones. Nevertheless the adverse effects of Alfuzosin should always be kept in mind when prescribe this class of therapy. This study is a meta-analysis of published data. The best data should be derived from a high quality prospective random controlled trial. We are currently planning on such a project.
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This work was financed by grants from National Natural Science Foundation of China (NO. 81370804 and NO. 81170652), Colleges and universities in Guangzhou Yangcheng scholars research project (No. 12A017S), and Science and technology project in Guangzhou (the People's Livelihood Special Major Science and Technology, No.201300000096).