Discussion
Choice of treatment for ureteral stones not only depends on stone-related factors such as size, location and density but also depends upon patient’s symptoms and comorbidities. Despite numerous technological advances in the minimally invasive treatment modalities such as URSL and SWL, there are inherent risks which cannot be completely eliminated. Therefore for non-urgent, asymptomatic, small and especially distal ureteric stones attempt of conservative treatment or MET seems logical. The primary aim of MET is not only to facilitate expulsion of stones along the length of the ureter but also reduce the chances of obstruction, ureteric colics, need for hospitalizations and surgical procedures. Alfa-blockers are an established therapy for stone expulsion. Alfa-receptors are found throughout the length of ureter, density is particularly high in distal ureters. Many studies have also found α1D receptors in high density in distal ureter72-74. In a network meta-analysis by Sridharan et al75 comparing all the alfa-blockers for ureteral stones, authors noted SER to be best with terazosin and SET to be best with silodosin and authors of the study concluded silodosin of be the best alfa-blocker. Other groups of drugs such as Calcium channel blockers and PDEI have also found success as MET, whereas role of other drugs such as NSAIDS76, 77 and corticosteroids is controversial. Distal ureter stones present unique atmosphere to the drug therapies due to rich receptor density and short distance to be traversed along the length of ureter to bladder and more often than not such stones if asysmptomatic are subjected MET. Thus aim of this study was to compare the efficacy of three commonly used of drug groups i.e. alfa-blockers, CCB’s and PDEI for distal ureteric stones as medical expulsive therapy.
In this large network meta-analysis with 50 RCT’s and 12,382 patients, both direct and indirect evidence was sought to compare the efficacy of above mentioned group of drugs in terms of SER and SET. For the primary outcome i.e. SER there were 14 treatment groups and data was available from all the 50 RCT’s and we found NAF-S followed by TADplusTAM-S, TADplusSILO and TAM-S were the best treatments and nifedipine the worst. Furthermore, in our subgroup analysis of individual drugs, we noted naftopidil to be the highest ranked and nifedipine lowest ranked. We also noted that apart from nifedipine and sildenafil all the treatment groups were more effective than control group for stone expulsion. Our results are in line with previously performed network meta-analysis78 for ureteral stones (irrespective of site) by Liu et al, they also found NAF-S to be the best treatment group followed by tadalafil plus silodosin. High density of α1D in the lower ureter could explain the efficacy of naftopidil in the present study. Nifedipine has been studied in a large RCT by Pickard et al51 and was found to be no more effective than placebo irrespective of stone size and location. Nifedipine has been compared to tamsulosin in a previously conducted meta-analysis by Wang et al10 and was found to be less efficacious than tamsulosin in terms of SER and SET. Finally, Amer et al79 in a systematic review concluded that CCB’s are no more effective than control group for SER and SET. Thus our results establish naftopidil plus steroids as the best treatment, naftopidil as best individual treatment and nifedipine as the worst treatment modality for lower ureteric stones.
For stone expulsion time, results in this review were derived from 32 studies including 6417 patients and found TADplusSILO followed by NIF-S and SILO to be highest ranked for SET and NAF-S to be the worst. In the previous meta-analysis by Liu et al78, tadalafil plus silodosin was the best followed by tamsulosin plus tadalafil and corticosteroids, tamsulosin plus steroids for SET. Their analysis did not contain nifedipine plus steroid group, also nifedipine and antispasmodics were the worst. From data on individual drugs in this study, silodosin was highest ranked and naftopidil worst. Silodosin has been noted for rapid onset of action for patients with benign prostatic enlargement with lower urinary tract symptoms in phase III trials80. With silodosin improvent in urine flow is noted within 2-6 hours of drug administration80. Thus corollary to effect in BPH patients its effect on SER and SET can be attributed to rapid onset of action and selective α1Aantagonistic properties. In a review by Sridharan et al75, authors concluded that silodosin may be the best alfa-blockers for MET. Considering the data available from individual drug treatment subgroup where best treatment for SER was naftopidil followed by silodosin and for SET silodosin was highest ranked and naftopidil lowest ranked. Thus individual drug subgroup data from this study suggests that silodosin may be the best drug among other alfa-blockers, PDEI and CCB’s. Before suggesting silodosin as the best dug for MET we must admit two important limitations. First, this study lacked comparison of silodosin to older alfa-blockers such as terazosin and doxazosin. We excluded them from this review as they are not commonly in use. Secondly, side effect profile of each drug treatment was not considered in this study. Retrograde ejaculation is a fairly common complications seen with silodosin and may be of concern younger patients.
Limitations
There are several limitations in this study; firstly out of 50 studies included in this studies 20 were at high risk of bias contributing to overall low quality of evidence. Evidence generated from this review ranged from very low to high for various comparisons. In this study, there were a total of 105 comparisons of which 27 were direct and 78 indirect. Using CINeMA approach 36 comparisons were Very Low, 46 were Low, 18 were moderate and only 5 were rated as high. Another important limitation of this study is that the control group was variably defined across different studies and only 16 trials were placebo controlled. Dose of various active drug treatments were also variable for some drugs such as in the study by Lv et al17 authors used naftopidil in 50mg once a day dose, in the study by Zhou et al65 10 mg once a day was used and Kumar et al45 used 75 mg once a day dose. Also, we amalgamated all the corticosteroids used as adjunctive with various drugs one group i.e. steroids. There was significant inconsistency in the network analysis used for primary outcome SER using global and node splitting approaches. However, we performed sensitivity analysis according to studies at low or unclear risk of bias and studies with placebo group as control for SER and did not find much difference compared to the original network. We also did not assess the side effect profile of each of the drug as primary aim of this review was to assess the efficacy. From methodology point of view we included studies limited to English language and excluded conference abstracts. We acknowledge that conference abstracts are an important source of grey literature but we also understand that they are not peer reviewed and lack data in various domains. Certain studies on drug treatments such as terazosin, doxazosin and anticholinergics were excluded as these are not commonly used for this indication. Finally, we acknowledge the inherent limitations of the frequentist approach used for this network meta-analysis81.