Summary of findings 1. Primary summary of findings.

Primary summary of findings' Estimates of effects and certainty of the evidence of antiemetic drugs for prevention of postoperative nausea and vomiting in adults after general anaesthesia

Patient or population: adults undergoing any type of surgery under general anaesthesia Interventions: antiemetic drugs (single drugs and drug combinations)* Comparator (reference): placebo (or no treatment) Outcomes: all primary outcomes and drug class‐specific adverse effects** Setting: inpatient and outpatient

Outcomes

Effects and confidence in the estimate of effects (network meta‐analysis)

Aprepitant*

Ramosetron*

Granisetron*

Dexamethasone*

Ondansetron*

Fosaprepitant*

Droperidol*

Vomiting (or dry retching) within 24 hours postoperatively

Total studies: 282; total participants: 50,812; number of treatments: 65 (36 drug combinations, 28 single drugs, placebo)

Placebo (comparator) 300 per 1000a (30%)

RR 0.26 (0.18 to 0.38) Network estimate

222 fewer per 1000 (246 fewer to 186 fewer)

RR 0.44 (0.32 to 0.59) Network estimate

168 fewer per 1000 (204 fewer to 123 fewer)

RR 0.45 (0.38 to 0.54) Network estimate

165 fewer per 1000 (186 fewer to 138 fewer)

RR 0.51 (0.44 to 0.57) Network estimate

147 fewer per 1000 (168 fewer to 471 fewer)

RR 0.55 (0.51 to 0.60) Network estimate

135 fewer per 1000 (147 fewer to 120 fewer)

RR 0.06 (0.02 to 0.21) Network estimate

282 fewer per 1000 (294 fewer to 237 fewer)

RR 0.61 (0.54 to 0.69) Network estimate

117 fewer per 1000 (138 fewer to 93 fewer)

⊕⊕⊕⊕ High Confidence in network estimate

⊕⊕⊕⊕ High Confidence in network estimate

⊕⊕⊕⊕ High Confidence in network estimate1

⊕⊕⊕⊕ High Confidence in network estimate1

⊕⊕⊕⊕ High Confidence in network estimate1

⊕⊕⊕⊖ Moderate Confidence in network estimate due to incoherence

⊕⊕⊕⊖ Moderate Confidence in network estimate due to publication bias and heterogeneity1,2

Rank 65 (0.0607)

Rank 20 (0.6760) rank 3 of 28 single drugs

Rank 36 (0.4361) rank 5 of 28 single drugs

Rank 38 (0.4234) rank 6 of 28 single drugs

Rank 41 (0.3588) rank 8 of 28 single drugs

Rank 48 (0.2974) rank 13 of 28 single drugs

Rank 4 (0.9189) rank 1 of 28 single drugs

Rank 55 (0.2320) rank 20 of 28 single drugs

Based on 94 participants (1 RCT) and indirect evidence (84%)

Based on 618 participants (6 RCTs) and indirect evidence (32%)

Based on 2270 participants (16 RCTs) and indirect evidence (18%)

Based on 4804 participants (43 RCTs) and indirect evidence (27%)

Based on 14,435 participants (77 RCTs) and indirect evidence (21%)

Based on indirect evidence only

Based on 6156 participants (41 RCTs) and indirect evidence (22%)

Serious adverse events (SAEs) within 7 days postoperatively

Total studies: 28; total participants: 10,766; number of treatments: 22 (8 drug combinations, 13 single drugs, placebo)

Placebo (comparator) 14 per 1000b (1.43%)

RR 1.39 (0.26 to 7.36) Network estimate

5 more per 1000 (10 fewer to 89 more)

RR 0.89 (0.05 to 15.74) Network estimate

2 fewer per 1000 (13 fewer to 206 more)

RR 1.21 (0.11 to 13.15) Network estimate

3 more per 1000 (12 fewer to 170 more)

RR 1.16 (0.28 to 4.85) Network estimate

2 more per 1000 (10 fewer to 54 more)

RR 1.62 (0.32 to 8.10) Network estimate

9 more per 1000 (10 fewer to 99 more)

No studies were found that looked at SAEs

RR 0.88 (0.08 to 9.71) Network estimate

2 fewer per 1000 (13 fewer to 122 more)

⊖⊖⊖⊖ Very low Confidence in network estimate due to study limitations, imprecision, incoherence3

⊕⊖⊖⊖ Very low Confidence in network estimate due to study limitations and imprecision4

⊕⊖⊖⊖ Very low Confidence in network estimate due to study limitations and imprecision5

⊕⊖⊖⊖ Very low Confidence in network estimate due to study limitations and imprecision5

⊕⊖⊖⊖ Very low Confidence in network estimate due to study limitations and imprecision5

⊕⊕⊖⊖ Low Confidence in network estimate due to imprecision6

Rank 14 (0.5020)

Rank 17 (0.4421) rank 11 of 13 single drugs

Rank 8 (0.5366) rank 7 of 13 single drugs

Rank 16 (0.4612) rank 10 of 13 single drugs

Rank 15 (0.4632) rank 9 of 13 single drugs

Rank 20 (0.3708) rank 12 of 13 single drugs

Rank 7 (0.5430) rank 6 of 13 single drugs

Based on indirect evidence only

Based on 236 participants (1 RCT) and indirect evidence (46%)

Based on 401 participants (2 RCTs) and indirect evidence (7%)

Based on 376 participants (3 RCTs) and indirect evidence (4%)

Based on 833 participants (3 RCTs) and indirect evidence (34%)

Based on 304 participants (2 RCTs) and indirect evidence (24%)

Any adverse events (any AEs) within 7 days postoperatively

Total studies: 61; total participants: 19,423; number of treatments: 27 (11 drug combinations, 15 single drugs, placebo)

Placebo (comparator) 377 per 1000b (37.68%)

RR 0.87 (0.78 to 0.97) Network estimate

49 fewer per 1000 (83 fewer to 11 fewer)

RR 1.00 (0.65 to 1.54) Network estimate

0 fewer/more per 1000 (132 fewer to 204 more)

RR 0.92 (0.80 to 1.05) Network estimate

30 fewer per 1000 (75 fewer to 19 more)

RR 0.77 (0.55 to 1.08) Network estimate

87 fewer per 1000 (170 fewer to 30 more)

RR 0.95 (0.88 to 1.01) Network estimate

19 fewer per 1000 (45 fewer to 4 more)

No studies were found that looked at any AE

RR 0.89 (0.81 to 0.98) Network estimate

41 fewer per 1000 (72 fewer to 8 fewer)

⊕⊖⊖⊖ Very low Confidence in network estimate due to study limitations, imprecision, incoherence

⊕⊖⊖⊖ Very low Confidence in network estimate due to study limitations and imprecision5

⊕⊕⊕⊖ Moderate Confidence in network estimate due to imprecision

⊕⊕⊖⊖ Low Confidence in network estimate due to study limitations and imprecision

⊕⊕⊖⊖ Low Confidence in network estimate due to study limitations and imprecision

⊕⊕⊖⊖ Low Confidence in network estimate due to study limitations and imprecision

Rank 23 (0.3129)

Rank 6 (0.6589) rank 3 of 15 single drugs

Rank 18 (0.4159) rank 11 of 15 single drugs

Rank 11 (0.5436) rank 7 of 15 single drugs

Rank 4 (0.7526) rank 2 of 15 single drugs

Rank 16 (0.4655) rank 9 of 15 single drugs

Rank 10 (0.6164) rank 6 of 15 single drugs

Based on indirect evidence only

Based on 173 participants (2 RCTs) and indirect evidence (43%)

Based on 699 participants (6 RCTs) and indirect evidence (3%)

Based on 1152 participants (6 RCTs) and indirect evidence (82%)

Based on 4892 participants (12 RCTs) and indirect evidence (4%)

Based on 1622 participants (2 RCTs) and indirect evidence (21%)

Headache within 7 days postoperatively

Total studies: 208; total participants: 42,445; number of treatments: 53 (29 drug combinations, 23 single drugs, placebo)

Placebo (comparator) 96 per 1000b (9.56%)

RR 0.86 (0.35 to 2.11) Network estimate

13 fewer per 1000 (62 fewer to 107 more)

RR 1.13 (0.93 to 1.37) Network estimate

12 more per 1000 (7 fewer to 36 more)

RR 1.20 (1.01 to 1.42) Network estimate

19 more per 1000 (1 more to 40 more)

RR 0.85 (0.63 to 1.13) Network estimate

14 fewer per 1000 (36 fewer to 12 more)

RR 1.16 (1.06 to 1.28) Network estimate

15 more per 1000 (6 more to 27 more)

No studies were found that looked at headache

RR 0.76 (0.67 to 0.86) Network estimate

23 fewer per 1000 (32 fewer to 13 fewer)

⊕⊕⊖⊖ Low Confidence in network estimate due to imprecision6

⊕⊕⊖⊖ Low Confidence in network estimate due to study limitations and imprecision

⊕⊖⊖⊖ Very low Confidence in network estimate due to study limitations, imprecision, incoherence

⊕⊕⊖⊖ Low Confidence in network estimate due to imprecision6

⊕⊕⊕⊖ Moderate Confidence in network estimate due to imprecision

⊕⊕⊕⊖ Moderate Confidence in network estimate due to study limitations

Rank 31 (0.4543

Rank 24 (0.5349) rank 10 of 23 single drugs

Rank 40 (0.3416) rank 16 of 23 single drugs

Rank 45 (0.2914) rank 19 of 23 single drugs

Rank 19 (0.5806) rank 8 of 23 single drugs

Rank 44 (0.3082) rank 18 of 23 single drugs

Rank 13 (0.6563) rank 5 of 23 single drugs

Based on 120 participants (1 RCT) and indirect evidence (73%)

Based on 1529 participants (14 RCTs) and indirect evidence (38%)

Based on 1639 participants (15 RCTs) and indirect evidence (43%)

Based on 1678 participants (13 RCTs) and indirect evidence (52%)

Based on 12,260 participants (57 RCTs) and indirect evidence (22%)

Based on 3679 participants (22 RCT) and indirect evidence (26%)

Constipation within 7 days postoperatively

Total studies: 43; total participants: 11,481; number of treatments: 23 (10 drug combinations, 12 single drugs, placebo)

Placebo (comparator) 74 per 1000b (7.39%)

RR 1.03 (0.59 to 1.80) Network estimate

2 more per 1000 (30 fewer to 129 more)

RR 0.74 (0.39 to 1.40) Network estimate

19 fewer per 1000 (45 fewer to 30 more)

RR 0.59 (0.21 to 1.63) Network estimate

30 fewer per 1000 (58 fewer to 47 more)

RR 0.83 (0.21 to 3.25) Network estimate

13 fewer per 1000 (58 fewer to 167 more)

RR 1.02 (0.71 to 1.46) Network estimate

1 more per 1000 (21 fewer to 34 more)

No studies were found that looked at constipation

No studies were found that looked at constipation

⊖⊖⊖⊖ Very low Confidence in network estimate due to study limitations, imprecision, incoherence3

⊕⊖⊖⊖ Very low Confidence in network estimate due to study limitations and imprecision5

⊕⊖⊖⊖ Very low Confidence in network estimate due to study limitations and imprecision5

⊕⊕⊖⊖ Low Confidence in network estimate due to imprecision6

⊕⊖⊖⊖ Very low Confidence in network estimate due to study limitations and imprecision5

Rank 12 ( 0.4889)

Rank 14 (0.4638) rank 7 of 12 single drugs

Rank 5 (0.6692) rank 3 of 12 single drugs

Rank 2 (0.7350) rank 1 of 12 single drugs

Rank 7 (0.5802) rank 5 of 12 single drugs

Rank 13 (0.4677) rank 6 of 12 single drugs

Based on indirect evidence only

Based on 280 participants (2 RCTs) and indirect evidence (84%)

Based on 230 participants (3 RCTs) and indirect evidence (13%)

Based on 327 participants (3 RCTs) and indirect evidence (19%)

Based on 1475 participants (8 RCTs) and indirect evidence (12%)

Wound infection within 7 days postoperatively

Total studies: 32; total participants: 4369; number of treatments: 10 (3 drug combinations, 6 single drugs, placebo)

Placebo (comparator) 4 per 1000b (0.44%)

No studies were found that looked at wound infection

No studies were found that looked at wound infection

No studies were found that looked at wound infection

RR 0.91 (0.45 to 1.87) Network estimate

0 fewer/more per 1000 (2 fewer to 3 more)

RR 1.28 (0.01 to 115.24) Network estimate

1 more per 1000 (4 fewer to 457 more)

No studies were found that looked at wound infection

No studies were found that looked at wound infection

⊕⊖⊖⊖ Very low Confidence in network estimate due to study limitations and imprecision5

⊕⊖⊖⊖ Very low Confidence in network estimate due to imprecision and incoherence7

Rank 10 (0.3885)

Rank 8 (0.4272) Rank 5 of 6 single drugs

Rank 9 (0.3974) rank 6 of 6 single drugs

Based on 3199 participants (24 RCTs) and indirect evidence (1%)

Based on indirect evidence only

Extrapyramidal symptoms within 7 days postoperatively

Total studies: 64; total participants: 10,724; number of treatments: 30 (13 drug combinations, 16 single drugs, placebo)

Placebo (comparator) 8 per 1000b (0.79%)

No studies were found that looked at extrapyramidal symptoms

RR 0.73 (0.01 to 37.44) Network estimate

2 fewer per 1000 (8 fewer to 292 more)

RR 0.90 (0.23 to 3.57) Network estimate

1 fewer per 1000 (6 fewer to 21 more)

RR 0.70 (0.17 to 2.80) Network estimate

2 fewer per 1000 (7 fewer to 14 more)

RR 0.73 (0.39 to 1.38) Network estimate

2 fewer per 1000 (5 fewer to 3 more)

No studies were found that looked at extrapyramidal symptoms

RR 1.36 (0.89 to 2.08) Network estimate

3 more per 1000 (1 fewer to 9 more)

⊕⊖⊖⊖ Very low Confidence in network estimate due to study limitations, imprecision, incoherence3

⊕⊖⊖⊖ Very low Confidence in network estimate due to study limitations and imprecision5

⊕⊕⊖⊖ Low Confidence in network estimate due to imprecision6

⊕⊖⊖⊖ Very low Confidence in network estimate due to study limitations and imprecision5

⊕⊕⊖⊖ Low Confidence in network estimate due to imprecision6

Rank 22 (0.4778)

Rank 8 (0.5409) Rank 5 of 16 single drugs

Rank 12 (0.5109) Rank 6 of 16 single drugs

Rank 4 (0.5865) Rank 2 of 16 single drugs

Rank 3 (0.6026) Rank 1 of 16 single drugs

Rank 29 (0.3456) Rank 15 of 16 single drugs

Based on indirect evidence only

Based on 330 participants (5 RCTs) and indirect evidence (37%)

Based on 1031 participants (4 RCTs) and indirect evidence (49%)

Based on 751 participants (7 RCTs) and indirect evidence (53%)

Based on 3270 participants (22 RCTs) and indirect evidence (11%)

Sedation within 7 days postoperatively

Total studies: 117; total participants: 21,440; number of treatments: 44 (19 drug combinations, 24 single drugs, placebo)

Placebo (comparator) 130 per 1000b (13%)

RR 0.43 (0.01 to 21.65) Network estimate

74 fewer per 1000 (129 fewer to 870 more)

RR 0.89 (0.72 to 1.10) Network estimate

14 fewer per 1000 (36 fewer to 13 more)

RR 1.00 (0.86 to 1.17) Network estimate

0 fewer/more per 1000 (18 fewer to 22 more)

RR 1.00 (0.91 to 1.09) Network estimate

0 fewer/more per 1000 (12 fewer to 12 more)

RR 0.87 (0.79 to 0.96) Network estimate

17 fewer per 1000 (41 fewer to 5 fewer)

No studies were found that looked at sedation

RR 0.99 (0.96 to 1.01) Network estimate

1 fewer per 1000 (5 fewer to 1 more)

⊕⊖⊖⊖ Very low Confidence in network estimate due to imprecision and incoherence7

⊕⊕⊖⊖ Low Confidence in network estimate due to study limitations and imprecision

⊕⊖⊖⊖ Very low Confidence in network estimate due to study limitations and imprecision5

⊕⊕⊕⊕ High Confidence in network estimate

⊕⊕⊕⊖ Moderate Confidence in network estimate due to imprecision1

⊕⊕⊖⊖ Low Confidence in network estimate due study limitations8

Rank 26 ( 0.4880)

Rank 10 (0.6518) Rank 6 of 24 single drugs

Rank 13 (0.6263) Rank 8 of 24 single drugs

Rank 24 (0.4996) Rank 15 of 24 single drugs

Rank 25 (0.4982) Rank 16 of 24 single drugs

Rank 9 (0.6623) Rank 5 of 24 single drugs

Rank 18 (0.5152) Rank 11 of 24 single drugs

Based on indirect evidence only

Based on 581 participants (5 RCTs) and indirect evidence (85%)

Based on 850 participants (9 RCTs) and indirect evidence (33%)

Based on 1290 participants (9 RCTs) and indirect evidence (2%)

Based on 6092 participants (36 RCTs) and indirect evidence (39%)

Based on 3739 participants (21 RCTs) and indirect evidence (1%)

Arrhythmia within 7 days postoperatively

Total studies: 25; total participants: 5067; number of treatments: 18 (5 drug combinations, 12 single drugs, placebo)

Placebo (comparator) 43 per 1000b (4.25%)

No studies were found that looked at arrhythmia

RR 1.30 (0.80 to 2.10) Network estimate

13 more per 1000 (9 fewer to 47 more)

RR 0.95 (0.04 to 21.59) Network estimate

2 fewer per 1000 (41 fewer to 885 more)

RR 0.81 (0.44 to 1.51) Network estimate

8 fewer per 1000 (24 fewer to 22 more)

RR 1.27 (0.47 to 3.43) Network estimate

12 more per 1000 (23 fewer to 104 more)

No studies were found that looked at arrhythmia

RR 0.88 (0.31 to 2.48) Network estimate

4 fewer per 1000 (20 fewer to 64 more)

⊕⊕⊖⊖ Low Confidence in network estimate due to imprecision6,9

⊕⊖⊖⊖ Very low Confidence in network estimate due to study limitations and imprecision5

⊕⊕⊖⊖ Low Confidence in network estimate due to imprecision6

⊕⊖⊖⊖ Very low Confidence in network estimate due to study limitations and imprecision5

⊕⊖⊖⊖ Very low Confidence in network estimate due to study limitations and imprecision5

Rank 13 (0.4400)

Rank 18 (0.3138) Rank 12 of 12 single drugs

Rank 8 (0.4688) Rank 5 of 12 single drugs

Rank 6 (0.5380) Rank 3 of 12 single drugs

Rank 17 (0.3492) Rank 11 of 12 single drugs

Rank 7 (0.4981) Rank 4 of 12 single drugs

Based on 140 participants (1 RCT), no indirect evidence available

Based on 50 participants (1 RCT) and indirect evidence (35%)

Based on 189 participants (3 RCTs) and indirect evidence (2%)

Based on 1643 participants (4 RCTs) and indirect evidence (16%)

Based on 659 participants (7 RCTs) and indirect evidence (22%)

QT prolongation within 7 days postoperatively

Total studies: 18; total participants: 4440; number of treatments: 13 (4 drug combinations, 8 single drugs, placebo)

Placebo (comparator) 21 per 1000b (2.12%)

RR 0.96 (0.19 to 4.92) Network estimate

1 fewer per 1000 (17 fewer to 82 more)

RR 0.62 (0.08 to 4.76) Network estimate

8 fewer per 1000 (19 fewer to 79 more)

No studies were found that looked at QT prolongation

RR 0.75 (0.05 to 12.06) Network estimate

5 fewer per 1000 (20 fewer to 232 more)

RR 0.93 (0.18 to 4.76) Network estimate

1 fewer per 1000 (17 fewer to 79 more)

No studies were found that looked at QT prolongation

RR 1.29 (0.71 to 2.34) Network estimate

6 more per 1000 (6 fewer to 28 more)

⊕⊖⊖⊖ Very low Confidence in network estimate due to imprecision and incoherence7

⊖⊖⊖⊖ Very low Confidence in network estimate due to study limitations, imprecision, incoherence3

⊕⊖⊖⊖ Very low Confidence in network estimate due to study limitations and imprecision5

⊕⊕⊖⊖ Low Confidence in network estimate due imprecision6

⊕⊕⊖⊖ Low Confidence in network estimate due imprecision6

Rank 6 (0.4552)

Rank 9 (0.4264) Rank 6 of 8 single drugs

Rank 3 (0.6133) Rank 2 of 8 single drugs

Rank 4 (0.5370) Rank 3 of 8 single drugs

Rank 5 (0.4773) Rank 4 of 8 single drugs

Rank 11 (0.3348) Rank 8 of 8 single drugs

Based on indirect evidence only

Based on indirect evidence only

Based on 149 participants (1 RCT) and indirect evidence (49%)

Based on 60 participants (1 RCT) and indirect evidence (82%)

Based on 303 participants (3 RCTs) and indirect evidence (1%)

NMA‐SoF table definitions: Network estimates are reported as risk ratio (RR) with confidence interval. Anticipated absolute effects compare two risks by calculating the difference between risks of the intervention group and the control group. Certainty of evidence (confidence) is reported for network estimates only. Ranking of treatments includes all single drugs and combinations of drugs and is based on the P score (a value on a continuous 0 to 1 scale), which measures the extent of certainty that a treatment is better than another treatment, averaged over all competing treatments. Larger P scores indicate better treatments. In addition, the rank of the treatment out of all single drugs is indicated. Information is given on the numbers of participants and studies included in the direct comparison and the contribution of indirect evidence (indirect evidence proportion).

* Selection criteria for presentation of interventions in this primary ‘Summary of findings table’: single antiemetic drugs of direct interest with important beneficial effect and with high or moderate certainty of evidence for the primary outcome (vomiting) were selected for presentation. These were aprepitant, ramosetron, granisetron, dexamethasone, ondansetron, fosaprepitant, and droperidol. ** Relevant adverse effects were selected according to the substance class: NK1 receptor antagonists (aprepitant, fosaprepitant): headache; 5‐HT3 receptor antagonists (ramosetron, granisetron, ondansetron): headache, constipation; corticosteroids (dexamethasone): wound infection; D2 receptor antagonists (droperidol): extrapyramidal symptoms, sedation, arrhythmia, QT prolongation

GRADE Working Group grades of evidence (certainty of evidence). Highcertainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate. the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of effect. Very low certainty: we have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect.

Explanatory footnotes to baseline risks (assumed control risks): a Baseline risk (assumed control risk) for vomiting within 24 hours was obtained from the consensus guideline on postoperative nausea and vomiting (Gan‐2014). The general incidence of vomiting after surgery is about 30%. b The baseline risk is based on the total events of all placebo groups included in the relevant outcome of the current network meta‐analysis (mean control group risk across studies). Explanatory footnotes to the ratings of the confidence in the network estimates: 1 Evidence only for recommended and high doses because low doses showed no clinically important effect. 2 Serious concerns for publication bias and heterogeneity. Publication bias and heterogeneity are overlapping domains for which we downgraded only once. 3 Serious concerns for study limitations and incoherence, and very serious concerns for imprecision. 4 Very serious concerns for study limitations and imprecision. 5 Serious concerns for study limitations and very serious concerns for imprecision. 6 Very serious concerns for imprecision. 7 Very serious concerns for imprecision and serious concerns for incoherence. 8 Very serious concerns for study limitations. 9 Poorly connected to the network. Only direct evidence is available.