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.