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.