3.6 Sensitivity analyses
The sensitivity analyses are presented in Supplementary Tables 10-15.
The sensitivity analyses were consistent with the results of the main
analysis. The results did not change when the analyses for all
interventions on the outcomes excluded studies with non diabetic macular
edema, and excluded studies with fewer than 20 eyes.
4DISCUSSION
Treatment choice should not be based
only on the effectiveness of the treatment, but also on the management
of adverse events and long-term tolerability. This systematic review and
network meta-analysis involving 16 studies that enrolled 834 eyes (575
patients) provided moderate certainty evidence, which investigated the
safety of triamcinolone acetonide by different routes of administration
and placebo treatment for ME. Intraocular pressure was selected as an
outcome index for safety evaluation. This paper had comparative data
from randomized trials with objective outcome measures that were
essential to understand which routes of injection with triamcinolone
acetonide offer the optimal balance of efficacy and safety in the
management of these patients. The network meta-analysis found that, in
early treatment (in 4 weeks), there was no significant difference in the
risk of IOP between triamcinolone acetonide by different routes of
administration and placebo. Nevertheless, although not statistically
significant, our results indicate that RITA is the safest route of
injection and IVTA ranked first in the risk of IOP. With the extension
of treatment time, IVTA, SCTA and STiTA increased the risk of IOP
elevation. This risk did differ significantly between them and placebo.
According to the ranking and SUCRA values, it was found that compared to
the other routes of injection,
the incidence of IOP with RITA was even lower.
Despite several attempts to establish its route of administration, only
IVTA has been used as a second-line therapy for DME and RVO by
guidelines.38-40 However, triamcinolone acetonide is
not an approved medication for DME. It has been used off-label.
According to the statistical results, IVTA may be associated with a have
the higher risk of IOP from 4 to 36 weeks of follow-up. This effect
seems to persist even in comparison with placebo or other routes of
administration. For instance, a randomized controlled trial showed that
the IOP change from baseline was significantly higher in the IVT group
than in the STiTA group after injection.33 Two RCTs
found that the addition of IVTA +
IVB significantly increased the risk
of IOP at the end of the study period compared with
IVB.30,32 From a head-to-head trial, IVTA increased
the risk of IOP compared with placebo.26 Our results
are in accordance with previous reports. which are consistent with the
comparison of the network meta-analysis. Of note, a meta-analysis of IOP
percentage increases from baseline levels indicated that there exists an
increase in the IOP measure at its peak 4 weeks after the injection.
However, 24 weeks after the injection, the increase in IOP compared to
its preoperative level showed a decrease.41 In
summary, our study shows that IOP elevation is a significant side effect
of IVTA injection. Careful follow-up of IOP is required after IVTA
injections.
Currently, only triamcinolone
suspension, released by the FDA in 2021, has been approved for the
treatment of macular edema associated with uveitis as a suprachoroidal
injection. However, there were few studies related to SCTA
administration, and 2 RCTs were finally included according to our
inclusion criteria.22,37 They only reported that
regarding IOP elevation both IVTA and SCTA have insignificantly
different effects. These data are consistent with those reported by the
HULK study and the TYBEE study following CLS-TA
injection.42-43 All of these studies prove that TA
injection has a similar effect on IOP either injected intravitreally or
in the suprachoroidal space. It is noteworthy that, our network
meta-analysis results shed light on the IOP effects of SCTA compared
with the placebo group. SCTA had statistically a significant effect on
IOP (MD, 2.42 [95% CrI, 4.53, 0.19] at the 24th week. Intriguingly,
as suggested by the SUCRA ranking scheme,
SCTA was ranked last at the 24th
week. IVTA was ranked last at the 4th and 12th weeks.
As suggested by the SUCRA ranking scheme, RITA was consistently ranked
first from 4 to 24 weeks, and STiTA was ranked behind RITA. Nonetheless,
it is important to note that our network meta-analysis only included two
clinical trials using RITA. Thus, the clinical significance may still be
limited and unclear. hence, further research is mandatory in this
context. Maggio et al found that RITA was proposed, which had the
advantage of being associated with fewer side effects when compared with
IVTA, including a reduced risk of steroid-induced cataract and IOP rise,
and no risk of endophthalmitis and rhegmatogenous retinal
detachment.44 This agreed with our study, we can
conclude that RITA/STiTA appear to be valid alternatives to IVTA/SCTA in
terms of safety outcome with a lower risk of IOP elevation. In this
paper, the safety of RITA has been verified, the balanced use of RITA
combined with the therapeutic effect is still required.
Grzybowski et al recommend a
stepwise therapy: retrobulbar or sub-Tenon’s corticosteroids in moderate
pseudophakic cystoid macular edema (PCME) and intravitreal
corticosteroids in recalcitrant PCME.45 Moreover, the
IOP increases after any routes of triamcinolone acetonide application
are not rare, although the temporary
interruption of treatment is generally not required.46Considering this, careful follow-up of IOP is required after TA
administration via different routes therapy.