We searched PubMed, Cochrane Library, and Embase databases for relevant randomized controlled trials (RCTs). We identified 12648 studies. After records of duplicates and not relevant were removed, fifty-five full papers were assessed. Thirty-one studies were excluded because of duplicate data, incorrect comparators, and incorrect outcomes. Finally, 24 RCTs were included in this review (Fig. 1).
Baseline characteristics of included patients are summarized in table 1. Twenty-four RCTs (including 5130 patients) were published between 1997 and 2018. Seventeen trials enrolled in non-diabetic patients. Four trials included only diabetic patients. Three trials included mixed patients. The follow-up time of the studies varied from 4 weeks to 140 days. In our NMA, the NSAID included ketorolac, bromfenac, nepafenac, diclofenac, and indomethacin, the CS included prednisolone, betamethasone, fluorometholone, and dexamethasone.
Table 1 Characteristics of trials included in the network meta-analysis
Study
|
Location
|
Sample
|
Age
|
Interventions
|
Drugs
|
Follow-up
|
Patients
|
Almeida 2008[18]
|
Canada
|
53:53
|
71(45-92)
|
Steroid+NSAID VS Steroid
|
Prednisolone 1% (postop) + Ketorolac 0.5% (preop + postop) VS Prednisolone 1% (postop)
|
4 W
|
mix (diabetes, glaucoma, macular disease, Pseudoexfoliation syndrome, hypertension)
|
Asano 2008[19]
|
Japan
|
69:69
|
66
|
NSAID VS Steroid
|
diclofenac 0.1% VS betamethasone 0.1% (postop)
|
8 W
|
low risk (uveitis and diabetes were excluded)
|
Campa 2018[15]
|
Italy
|
48:48:48
|
78.21±7.87; 77±5.93; 78.75±7.96
|
Steroid+ NSAID VS Steroid
|
nepafenac 0.1% (preop + postop) + dexamethasone 1.32 mg (postop) VS bromfenac (preop + postop) + dexamethasone 1.32 mg (postop) VS dexamethasone 1.32 mg (postop)
|
5 W
|
low risk (diabetic retinopathy and retinal vein occlusion were excluded)
|
Cervantes-Coste 2009[20]
|
Mexico
|
30:30
|
72.6±10.5: 71.2±8.8
|
Steroid+ NSAID VS Steroid
|
nepafenac 0.1% (preop + postop) +
dexamethasoe (postop) VS dexamethasoe (postop)
|
6 W
|
mix (including diabetics and other patients)
|
Chatziralli 2011[21]
|
Greece
|
70:68
|
74.3±7.3; 74.0±7.6
|
Steroid+ NSAID VS Steroid
|
ketorolac tromethamine 0.5% (preop + postop) +dexamethasone 0.1% (preop + postop) VS dexamethasone 0.1% (preop + postop)
|
6 W
|
mix (diabetes, glaucoma, macular disease, Pseudoexfoliation syndrome, hypertension)
|
Donnenfeld 2006[22]
|
USA
|
75:25
|
73
|
Steroid+ NSAID VS Steroid
|
Prednisolone 1% (postop) + Ketorolac 0.4% (preop + postop) VS Prednisolone 1% (postop)
|
12 W
|
low risk (uveitis and diabetes were excluded)
|
Elsawy 2013[23]
|
Egypt
|
35:35
|
NR
|
Steroid+ NSAID VS Steroid
|
ketorolac tromethamine 0.4% + dexamethasone 0.1% VS dexamethasone 0.1% (postop)
|
12 W
|
diabetes
|
Italian Diclofenac Study Group 1997[24]
|
Italy
|
121:108
|
68.3±7.4; 67.5±7.7
|
NSAID VS Steroid
|
diclofenac 0.1% (postop) VS dexamethasone 0.1% (postop)
|
140 D
|
low risk (a senile cataract without vitreoretinal pathology)
|
Miyake 1999[25]
|
Japan
|
36:37
|
68.2±7.2;69.9±8.2
|
NSAID VS Steroid
|
Diclofenac 0.1% VS Fluometholone 0.1% (preop + postop)
|
5 W
|
glaucoma
|
Miyanaga 2009[26]
|
Japan
|
25:24:23
|
74 (48-86); 71 (46-86); 70 (41-83)
|
NSAID VS Steroid+ NSAID VS Steroid
|
Bromfenac 0.1% VS Betamethasone 0.1% and Fluometholone 0.1% + Bromfenac 0.1% VS Betamethasone 0.1% and Fluometholone 0.1% (postop)
|
8 W
|
low risk (uveitis and diabetes were excluded)
|
Miyake 2007[27]
|
Japan
|
25:25
|
65.4±7; 65.8±7.1
|
NSAID VS Steroid
|
diclofenac 0.1% (postop) VS fluorometholone 0.1% (postop)
|
5 W
|
low risk (uveitis and diabetes were excluded)
|
Miyake 2011[28]
|
Japan
|
28:27
|
64.3±7.8; 65.7±12.2
|
NSAID VS Steroid
|
nepafenac 0.1% (preop + postop) VS fluorometholone 0.1% (preop + postop)
|
5 W
|
mix (without diabetes retinopathy, glaucoma, macular disease, Pseudoexfoliation syndrome)
|
Moschos 2012[29]
|
Greece
|
38:41
|
76.68±10.72; 76.71±8.82
|
Steroid+ NSAID VS Steroid
|
Dexamethasone 0.1% (postop) + Diclofenac 0.1% (preop + postop) VS Dexamethasone 0.1% (postop)
|
4 W
|
low risk (uveitis and diabetes were excluded)
|
Pollack 2017[30]
|
multicentre
|
87:88
|
68.1±8.6; 69.4±7.6
|
Steroid+ NSAID VS Steroid
|
nepafenac 0.1% (preop + postop) + dexamethasone 0.1% (postop) VS dexamethasone 0.1% (postop)
|
3 M
|
diabetes
|
Rossetti 1996[31]
|
Italy
|
42:46
|
74.2±8.8; 72.9±9.4
|
Steroid+ NSAID VS Steroid
|
diclofenac sodium (preop + postop) + dexamethasone (postop) VS dexamethasone (postop)
|
6 M
|
low risk (maculopathy and diabetes were excluded)
|
Singh 2012[32]
|
USA
|
125:126
|
66.6±9.3; 66.4±9.7
|
Steroid+ NSAID VS Steroid
|
nepafenac 1% (preop + postop) + prednisolone acetate (postop) VS prednisolone acetate (postop)
|
3 M
|
diabetes
|
Singh 2017[33]
|
multicentre
|
587:593
|
67.2±8.5; 67.4±8.3
|
Steroid+ NSAID VS Steroid
|
nepafenac 0.3% (preop + postop) + prednisolone acetate (postop) VS prednisolone acetate (postop)
|
3 M
|
diabetes
|
Ticly 2014[34]
|
Brazil
|
37:44
|
67.1±10.8; 66.1±8.7
|
Steroid+ NSAID VS Steroid
|
Prednisolone 1% + Ketorolac 0.4% VS Prednisolone 1% (preop + postop)
|
5 W
|
low risk (uveitis and diabetes were excluded)
|
Tzelikis 2018[35]
|
Brazil
|
112:112
|
68.32±9.08
|
Steroid+ NSAID VS Steroid
|
nepafenac 0.3% + prednisolone 1.0% VS prednisolone 1.0% (preop + postop)
|
12 W
|
low risk (uveitis and diabetes were excluded)
|
Wang 2013[36]
|
China
|
83:84
|
73.37±9.17
|
Steroid+ NSAID VS Steroid
|
Prednisolone 15 mg + Bromfenac 0.1% VS Prednisolone 15 mg + Fluometholone 0.1% or Dexamethasone 0.1% (postop)
|
8 W
|
age-related cataract without any other ocular diseases
|
Wielders 2018[14]
|
European
|
270:265:265
|
69.70±8.94;71.23±8.73;70.41±8.91
|
NSAID VS Steroid VS NSAID+Steroid
|
bromfenac 0.09% VS dexamethasone 0.1% VS dexamethasone 0.1% + bromfenac 0.09% (preop + postop)
|
12 W
|
nondiabetics
|
Wittpenn 2008[37]
|
USA
|
268:278
|
70:70
|
Steroid+ NSAID VS Steroid
|
ketorolac 0.4% (preop + postop) + prednisolone acetate 1% (postop) VS prednisolone acetate 1% (postop)
|
4 W
|
low risk (without maculopathy and retinal-vascular anomalies)
|
Yavas 2007[38]
|
Turkey
|
121:58
|
64; 65
|
Steroid+ NSAID VS Steroid
|
Prednisolone 1% (postop) + Indomethacin 0.1% (postop or preop + postop) VS Prednisolone 1% (postop)
|
4 W
|
low risk (hypertension and diabetes were excluded)
|
Zaczek 2014[39]
|
Sweden
|
75:77
|
70.4±7.4; 68.3±7.5
|
Steroid+ NSAID VS Steroid
|
nepafenac 0.1% + dexamethasone 0.1% (preop + postop) VS dexamethasone 0.1% (postop)
|
4 W
|
low risk (uveitis and diabetes were excluded)
|
W: Weeks, M: Months, D: days, NSAID: inflammatory drugs
Quality of evidence
We included RCTs in this NMA. There was an assessment of the risk of bias within RCTs in Figure 2. The majority of studies were marked as "unclear" for selection bias because they did not report sufficient information associated to judge selection bias. Eleven RCTs were open-label non-masked studies and marked as "high risk" for performance bias. Eight RCTs were marked as "low risk" for performance bias. We judged nine studies as "high risk" and ten studies as "low risk" in terms of detection bias. Two studies were assigned a "high risk" of bias for attrition bias. Only one trial was marked as a "high risk" of bias for incomplete data. The quality of evidence of included RCTs was low to moderate (Fig. 2).
Pairwise and network meta-analyses
This NMA included 24 relevant studies, which compared the incidence of CME with NSAID, CS, and combination therapy after cataract surgery. The main findings of pairwise and network meta-analyses were presented in table 2. Sixteen studies reported the incidence of CME in non-diabetics. The results of pairwise and network meta-analysis showed NSAID and combination of both drugs were significantly superior to the CS alone in non-diabetics (RR 0.33, 95% CI 0.23 to 0.48; RR 0.24, 95% CI 0.14 to 0.40; RR 0.23, 95% CI 0.14 to 0.37; RR 0.19, 95% CI 0.11 to 0.33). There were only four studies compared to CS with combination therapy in terms of the incidence of CME in diabetics. The result of pairwise comparisons showed combination therapy significantly reduced the risk of developing CME after cataract surgery (RR 0.25, 95% CI 0.17 to 0.36). Twenty-four studies including diabetics and non-diabetics (mixed populations) reported NSAID and combination therapy significantly reduced the risk of developing CME after cataract surgery than CS in both pairwise and network meta-analysis (RR 0.30, 95% CI 0.22 to 0.43; RR 0.34, 95% CI 0.27 to 0.41; RR 0.20 95% CI 0.12 to 0.34; RR 0.21, 95% CI 0.15 to 0.30). There were six studies reported the results of adverse events, which included mild pain, dry eyes, keratitis, and posterior vitreous detachment. The result of pairwise comparisons showed that the combination of NSAID and CS significantly reduced the risk of developing adverse events than CS (RR 0.77, 95% CI 0.63, 0.94).
Table 2 Summary of main findings of pairwise and network meta-analyses
Parameters
|
Direct pairwise meta-analysis
|
Network meta-analysis
|
No. of samples
|
RR (95% CI)
|
P
|
Heterogeneity I2
|
RR (95% CI)
|
CME with Non-diabetics
|
|
|
|
|
|
NSAID VS CS
|
1077
|
0.33 (0.23, 0.48)
|
0.528
|
0.0%
|
0.24 (0.14, 0.40)
|
NSAID VS NSAID+CS
|
584
|
1.81 (0.68, 4.83)
|
-
|
-
|
1.25 (0.62, 2.55)
|
NSAID+CS VS CS
|
2295
|
0.23 (0.14, 0.37)
|
0.913
|
0.0%
|
0.19 (0.11, 0.33)
|
CME with Diabetics
|
|
|
|
|
|
NSAID+CS VS CS
|
1692
|
0.25 (0.17, 0.36)
|
0.957
|
0.0%
|
-
|
CME with Mixed Populations
|
|
|
|
|
|
NSAID VS CS
|
1132
|
0.30 (0.22, 0.43)
|
0.455
|
0.0%
|
0.20 (0.12, 0.34)
|
NSAID VS NSAID+CS
|
584
|
1.81 (0.68, 4.83)
|
-
|
-
|
0.98 (0.55, 1.74)
|
NSAID+CS VS CS
|
4968
|
0.34 (0.27, 0.41)
|
0.549
|
0.0%
|
0.21 (0.15, 0.30)
|
Adverse Events
|
|
|
|
|
|
NSAID VS CS
|
539
|
0.87 (0.71, 1.06)
|
-
|
-
|
0.89 (0.65, 1.22)
|
NSAID VS NSAID+CS
|
535
|
1.20 (0.95, 1.50)
|
-
|
-
|
1.15 (0.85, 1.57)
|
NSAID+CS VS CS
|
2760
|
0.77 (0.63, 0.94)
|
0.72
|
0.0%
|
0.77 (0.47, 1.27)
|
CS: corticosteroid, NSAID: non-steroidal anti-inflammatory drugs, CI: confidence interval, CME: cystoid macular edema, RR: relative risk
Rank probabilities
The SUCRA ranking profiles of comparable treatments (NSAID, CS, a combination of both drugs) in non-diabetics and mixed populations. The treatment with the largest cumulative was more likely to develop CME after cataract surgery. The combination therapy showed a significant advantage over the single drugs and the less likely to develop CME (Fig. 3).
Network meta-analysis of the efficacy of various NSAID and CS
Network plot (Fig. 4. a), network meta-analysis (Fig. 4. b), and SUCRA ranking (Fig. 4. c) were assessed in terms of the incidence of CME. The Figure 4-a showed a network plot of comparisons on different outcomes of treatment incidence of CME after cataract surgery. The Figure 4-b showed the results of pooled estimates of the network meta-analysis. Diclofenac was significantly reduced the risk of developing CME than betamethasone (RR 0.32, 95% CI 0.19 to 0.54). Bromfenac was significantly reduced the risk of developing CME than dexamethasone and fluorometholone (RR 2.11, 95% CI 1.07 to 4.19; RR 6.17, 95% CI 1.15 to 33.1). Diclofenac and nepafenac showed a significant advantage over the fluorometholone (RR 7.78, 95% CI 2.50 to 24.83; RR 0.18, 95% CI 0.07 to 0.44). The Figure 4-c showed the results of the SUCRA score of each treatment. In terms of efficacy of NSAIDs, diclofenac was the most likely to reduce the odds of developing CME compared with bromfenac and nepafenac. In terms of efficacy of CS, dexamethasone was the most likely to reduce the odds of developing CME compared with betamethasone and fluorometholone.
Funnel plots
The funnel plots for the odds of developing CME after cataract surgery were presented in Figure 5. The comparison-funnel plots were symmetrical and did not reveal any obvious publication bias.
Inconsistency assessment
The results of the inconsistency test were shown in figure 6. For direct and indirect estimates, the results of the loop included 0 according to the three forest plots. Therefore, the reports of inconsistency assessment were robust.
Rank probabilities
Fig. 3 showed SUCRA ranking profiles of comparable treatments (NSAID, CS, a combination of both drugs) in non-diabetics and mixed populations. The treatment with the largest cumulative was more likely to develop CME after cataract surgery. The combination therapy showed a significant advantage over the single drugs and the less likely to develop CME.
Network meta-analysis of the efficacy of various NSAID and CS
Network plot (Fig. 4a), network meta-analysis (Fig. 4b), and SUCRA ranking (Fig. 4c) were assessed in terms of the incidence of CME. Fig. 4a showed a network plot of comparisons on different outcomes of treatment incidence of CME after cataract surgery. Fig. 4b showed the results of pooled estimates of the network meta-analysis. Diclofenac was significantly reduced the risk of developing CME than betamethasone (RR 0.32, 95% CI 0.19 to 0.54). Bromfenac was significantly reduced the risk of developing CME than dexamethasone and fluorometholone (RR 2.11, 95% CI 1.07 to 4.19; RR 6.17, 95% CI 1.15 to 33.1). Diclofenac and nepafenac showed a significant advantage over the fluorometholone (RR 7.78, 95% CI 2.50 to 24.83; RR 0.18, 95% CI 0.07 to 0.44). Fig. 4c showed the results of the SUCRA score of each treatment. In terms of efficacy of NSAIDs, diclofenac was the most likely to reduce the odds of developing CME compared with bromfenac and nepafenac. In terms of efficacy of CS, dexamethasone was the most likely to reduce the odds of developing CME compared with betamethasone and fluorometholone.
Funnel plots
The funnel plots for the odds of developing CME after cataract surgery were presented in fig. 5. The comparison-funnel plots were symmetrical and did not reveal any obvious publication bias.
Inconsistency assessment
The results of the inconsistency test were shown in fig. 6. For direct and indirect estimates, the results of the loop included 0 according to the three forest plots. Therefore, the reports of inconsistency assessment were robust.