Conceptualization, H.K.; methodology, H.K.; software, E.A., G.J.C. and H.K.; validation, E.A. and H.J.K.; formal analysis, E.A. and G.J.C.; investigation, E.A. and G.J.C.; resources, E.A. and H.J.K.; data curation, E.A. and G.J.C.; writing—original draft preparation, H.J.K. and E.A.; writing—review and editing, H.K.; visualization, H.J.K.; supervision, H.K.; project administration, H.K. All authors have read and agreed to the published version of the manuscript.

Figure 1. Schematic flow diagram of the study selection.

Figure 1. Schematic flow diagram of the study selection.

Figure 2. PRISMA flow diagram of the search for randomized controlled trials and the inclusion and exclusion criteria [10]. Figure 2. PRISMA flow diagram of the search for randomized controlled trials and the inclusion and exclusion criteria [10].

Figure 3. Forest plot of studies comparing the effectiveness of palonosetron with that of ramosetron on PON. (A) Early, (B) late, and (C) overall. The size of the filled squares of risk ratios reflects the effect size of individual trials. Horizontal bars represent 95% confidence intervals of difference. The diamond shape depicted the pooled estimates and uncertainty of the combined effects on early, late, and overall PON. The combined results showed no evidence of differences between palonosetron and ramosetron. For subgroup analysis, the pooled estimates of palonosetron showed that it was more effective than ramosetron in preventing early and late PON when they were administered early (*). Conversely, the pooled estimates of ramosetron indicated that it was more effective than palonosetron in preventing early PON when they were administered late (†).

Figure 3. Forest plot of studies comparing the effectiveness of palonosetron with that of ramosetron on PON. (A) Early, (B) late, and (C) overall. The size of the filled squares of risk ratios reflects the effect size of individual trials. Horizontal bars represent 95% confidence intervals of difference. The diamond shape depicted the pooled estimates and uncertainty of the combined effects on early, late, and overall PON. The combined results showed no evidence of differences between palonosetron and ramosetron. For subgroup analysis, the pooled estimates of palonosetron showed that it was more effective than ramosetron in preventing early and late PON when they were administered early (*). Conversely, the pooled estimates of ramosetron indicated that it was more effective than palonosetron in preventing early PON when they were administered late (†).

Figure 4. Forest plot of studies comparing the effectiveness of palonosetron with that of ramosetron on POV. (A) Early, (B) late, and (C) overall. The size of the filled squares of risk ratios reflects the effect size of individual trials. Horizontal bars represent 95% confidence intervals of difference. The diamond depicted the pooled estimates and uncertainty of the combined effect. The combined results showed no evidence of differences between palonosetron and ramosetron for early and overall POV. Notwithstanding, palonosetron was more effective than ramosetron in preventing late POV (*). For subgroup analysis, the pooled estimates of palonosetron indicated that it was more effective than ramosetron in preventing the overall POV when they were administered early (†), while the pooled estimates presented no evidence of differences between palonosetron and ramosetron when they were administered late.

Figure 4. Forest plot of studies comparing the effectiveness of palonosetron with that of ramosetron on POV. (A) Early, (B) late, and (C) overall. The size of the filled squares of risk ratios reflects the effect size of individual trials. Horizontal bars represent 95% confidence intervals of difference. The diamond depicted the pooled estimates and uncertainty of the combined effect. The combined results showed no evidence of differences between palonosetron and ramosetron for early and overall POV. Notwithstanding, palonosetron was more effective than ramosetron in preventing late POV (*). For subgroup analysis, the pooled estimates of palonosetron indicated that it was more effective than ramosetron in preventing the overall POV when they were administered early (†), while the pooled estimates presented no evidence of differences between palonosetron and ramosetron when they were administered late.

Figure 5. Forest plot of studies comparing the effectiveness of palonosetron with that of ramosetron on PONV. (A) Early, (B) late, and (C) overall. The size of the filled squares of risk ratios reflects the effect size of individual trials. Horizontal bars represent 95% confidence intervals of difference. The diamond depicted the pooled estimates and uncertainty of the combined effect. The combined results showed no evidence of differences between palonosetron and ramosetron for early, late, and overall PONV. For subgroup analysis, no evidence of differences was observed between palonosetron and ramosetron according to administration time.

Figure 5. Forest plot of studies comparing the effectiveness of palonosetron with that of ramosetron on PONV. (A) Early, (B) late, and (C) overall. The size of the filled squares of risk ratios reflects the effect size of individual trials. Horizontal bars represent 95% confidence intervals of difference. The diamond depicted the pooled estimates and uncertainty of the combined effect. The combined results showed no evidence of differences between palonosetron and ramosetron for early, late, and overall PONV. For subgroup analysis, no evidence of differences was observed between palonosetron and ramosetron according to administration time.

Figure 6. Forest plot of studies comparing the effectiveness of palonosetron with that of ramosetron on (A) retching, (B) complete response, and (C) use of rescue antiemetics. The diamond shape depicted the pooled estimates and uncertainty of the combined effect. The combined results showed no evidence of differences between palonosetron and ramosetron for the complete response and use of rescue antiemetics. On the other hand, palonosetron was more effective than ramosetron in preventing retching (*). For subgroup analysis, no evidence of differences was observed between palonosetron and ramosetron for the complete response according to administration time. Whereas, the pooled estimates demonstrated that palonosetron was more effective than ramosetron in the prevention of retching when they were administered early and late (†) and in the use of rescue antiemetics when they were administered early (*).

Figure 6. Forest plot of studies comparing the effectiveness of palonosetron with that of ramosetron on (A) retching, (B) complete response, and (C) use of rescue antiemetics. The diamond shape depicted the pooled estimates and uncertainty of the combined effect. The combined results showed no evidence of differences between palonosetron and ramosetron for the complete response and use of rescue antiemetics. On the other hand, palonosetron was more effective than ramosetron in preventing retching (*). For subgroup analysis, no evidence of differences was observed between palonosetron and ramosetron for the complete response according to administration time. Whereas, the pooled estimates demonstrated that palonosetron was more effective than ramosetron in the prevention of retching when they were administered early and late (†) and in the use of rescue antiemetics when they were administered early (*).

Figure 7. Funnel plots of (A) early PON, (B) early POV, (C) late PON, (D) late POV, (E) overall PON, (F) overall POV, (G) rescue antiemetics, and (H) headache. The horizontal axis demonstrates the log of risk ratio, and the vertical axis shows the inverse of the standard error.

Figure 7. Funnel plots of (A) early PON, (B) early POV, (C) late PON, (D) late POV, (E) overall PON, (F) overall POV, (G) rescue antiemetics, and (H) headache. The horizontal axis demonstrates the log of risk ratio, and the vertical axis shows the inverse of the standard error.

Table 1. Study characteristics of included studies.

Table 1. Study characteristics of included studies.

SourceAge (yrs)Sex (M/F)Weight (kg)Height (cm)ASA-PSRisk Factors for PONVType of AnesthesiaDuration of Anesthesia (min)Type of SurgeryChattopadhyay 2015 [26]18–350/10958.8 [7.2]NRI-II≥2
(F, nonsmoking)SA60.5 (4.1)Elective cesarean deliveryKim 2013 [28]20–650/7465 [1.3]164.5 [4.9]I-II≥3
(F, IV-PCA, nonsmoking)GA169.39 (87.6)Laparoscopic surgeryKim 2015 [29]NR0/8859 [9]158 [5]NR≥2 (F, nonsmoking)GA146 (44)Gynecologic laparoscopic surgeryLee 2015 [30]NR0/7060.1 [4.9]155.3 [3.1]I-II≥1 (F)GA128.1 (47.5)Laparoscopic hysterectomyPark 2013 [31]≥200/10061.8 [8.5]158.9 [5.8]I-II≥1 (IV-PCA)GA143.4 (53.8)Gynecologic laparoscopic surgeryRoh 2014 [40]20–650/196NRNRNR≥1 (IV-PCA)GA168 (66)Lumbar spinal surgerySwaika 2011 [32]18–700/5852.8 [6.9]NRI-II≥1 (F)GA56.1 (8.0)Laparoscopic cholecystectomyYatoo 2016 [33]18–6531/2965.4 [4.8]157.4 [7.2]I-II≥0GA42.6 (9.4)Elective laparoscopic surgeryBang 2017 [34]20–490/8759.21 [9.54]159.02 [4.97]I-II≥3 (F, nonsmoker, IV-PCA)GA40 (9.6)Gynecologic laparoscopic surgeryPark 2021 [35]20–700/10858.6 [10.6]160.6 [5.9]I-II≥2 (F, IV-PCA)GA40.7 (11.2)Gynecologic laparoscopic surgeryPatel 2018 [36]18–60NRNRNRI-II≥0GANRLaparoscopic surgeryPiplai 2012 [37]18–65NR54.4 [8.22]NRI-II≥1 (F)GA43.4 (6.46)Laparoscopic cholecystectomySavalia 2021 [27]18–60NRNRNRI-II≥0GANRMiddle ear surgeryYoon 2016 [38]≥200/26260.1 [7.1]158.2 [5.7]I-II≥2 (F, IV-PCA)GA51.2 (11.1)Oncologic gynecologic surgerySong 2017 [41]20–85NRNRNRI-II≥0GA55 (14)Spinal surgeryAhluwalia 2015 [42]25–400/6054.52 [5.21]154.27 [2.87]I-II≥1 (F)GA133.62 (9.83)Middle ear surgeryVinvay 2017 [39]20–5046/1458.63 [9.99]155.53 [8.28]I-II≥0GANRElective laparoscopic surgery and ENT surgery

Table 2. Further study characteristics of included studies.

Table 2. Further study characteristics of included studies.

SourceData Collection PeriodDose of Palonosetron/RamosetronAdministration TimingRescue AntiemeticsChattopadhyay 2015 [26]0–2/2–24/24–48 h0.075 mg/0.3 mgImmediate after clamping of the fetal umbilical cordMetoclopramide 10 mgKim 2013 [28]0–1/1–6/6–24/24/48 h0.075 mg/0.3 mgJust prior to induction of anesthesia1st choice, propofol 20 mg, metoclopramide 10 mg;
2nd choice, ondansetron 4 mg or/and dexamethasone 4 mgKim 2015 [29]Arrival PACU/
discharge PACU/
24 h/48 h/72 h0.075 mg/0.3 mg10 min at the end of operationMetoclopramide 10 mgLee 2015 [30]0–6/6–24/24–48 h0.075 mg/0.3 mgAt the end of the operation, prior to extubationMetoclopramide 10 mgPark 2013 [31]0–6/6–24/24–48 h0.075 mg/0.3 mgImmediately before the induction of anesthesiaMetoclopramide 10 mgRoh 2014 [40]PACU/0–6/6–24/24–48/48–72 h0.075 mg/0.3 mgImmediately before the induction of anesthesiaMetoclopramide 10 mgSwaika 2011 [32]0–2/2–6/6–24 h0.075 mg/0.3 mgJust at the end of operation before extubationOndansetron 4 mgYatoo 2016 [33]0–4/4–12/24–48 h0.075 mg/0.3 mg5 min before the inductionMetoclopramide 0.15 mg/kgBang 2017 [34]0–2 h/2–48 h
/30 min/60 min/
90 min/120 min/6 h/48 h0.075 mg/0.3 mgPalonosetron: immediately before anesthesia induction
Ramosetron: 30 min before the end of operation1st choice, Ondansetron 4 mg;
2nd choice Ramosetron 0.3 mgPark 2021 [35]PACU/0–6/6–24/24–48 h0.075 mg/0.3 mgMixed with IV-PCAMetoclopramide 10 mgPatel 2018 [36]0–6/6–24/24–72 h0.075 mg/0.3 mgJust before induction of anesthesiaOndansetron 4 mgPiplai 2012 [37]0–3/3–24/24–48/48–72 h0.075 mg/0.3 mgBefore induction of anesthesiaMetoclopramide 10 mgSavalia 2021 [27]0–6/6–12/12–24/24–48 h0.075 mg/0.3 mgBefore the end of operationNRYoon 2016 [38]0–3/3–24/24–48 h0.075 mg/0.3 mgPalonosetron: immediately after anesthesia induction
Ramosetron: 30 min before the end of operationMetoclopramide 10 mgSong 2017 [41]0–6/6–48/0–48 h0.075 mg/0.3 mg20 min before the end of operation and 24 h after operationMetoclopramide 10 mgAhluwalia 2015 [42]0–2/2–24/24–48 h0.075 mg/0.3 mgBefore shifting the patient from operation room to PACUMetoclopramide 10 mgVinay 2017 [39]0–4/5–12/12 h-overall0.075 mg/0.3 mgBefore shifting the patient from operation room to PACUMetoclopramide 10 mg

Table 3. Risk of bias 2.0.

Table 3. Risk of bias 2.0.

SourceBias Arising from the Randomization ProcessBias Due to Deviations from the Intended InterventionsBias Due to Missing Outcome DataBias in Measurement of the OutcomeBias in Selection of the Reported ResultOverall Risk of BiasChattopadhyay 2015 [26]LowLowLowLowSome concernSome concernKim 2013 [28]LowLowLowLowSome concernSome concernKim 2015 [29]LowLowLowLowLowLowLee 2015 [30]Some concernLowLowLowSome concernHighPark 2013 [31]Some concernLowLowLowSome concernHighRoh 2014 [40]LowLowLowLowSome concernSome concernSwaika 2011 [32]Some concernLowLowSome concernSome concernHighYatoo 2016 [33]Some concernLowSome concernSome concernSome concernHighBang 2017 [34]LowLowLowLowSome concernSome concernPark 2021 [35]Some concernLowLowLowLowSome concernPatel 2018 [36]Some concernLowLowLowLowSome concernPiplai 2012 [37]Some concernLowLowLowSome concernHighSavalia 2021 [27]Some concernLowSome concernSome concernSome concernHighYoon 2016 [38]Some concernLowLowSome concernSome concernHighSong 2017 [41]LowLowLowLowLowLowAhluwalia 2015 [42]Some concernLowLowLowSome concernHighVinay 2017 [39]LowLowLowSome concernSome concernHigh

Table 4. The results of meta-analysis and GRADE evidence quality for each outcome.

Table 4. The results of meta-analysis and GRADE evidence quality for each outcome.

No of StudiesNo of PatientsConventional Meta-AnalysisTrial Sequential AnalysisNNTQuality AssessmentQualityRR with 95% CIHeterogeneity (I2)Publication Bias (Egger’s Test)Conventional Test BoundaryMonitoring BoundaryRISROBInconsistencyIndirectnessImprecisionPublication BiasEarly PON121263RR: 1.048; 95% CI 0.811 to 1.35446.34−1.090; 95% CI −2.489 to 0.308Not crossNot cross9.5% (1263 of 13,314 patients)NNTH: 741; 95% CI NNTH 25 to ∞ to NNTBNot seriousNot seriousNot seriousNot seriousNot serious⨁⨁⨁⨁
HighEarly POV101097RR: 0.734; 95% CI 0.421 to 1.28219.610.933; 95% CI −0.638 to 2.503Not crossNot cross4.7% (1097 of 23,261 patients)NNTB: 174; 95% CI NNTH 48 to ∞ to NNTB 31Not seriousNot seriousNot seriousNot seriousNot serious⨁⨁⨁⨁
HighEarly PONV91200RR: 0.984; 95% CI 0.831 to 1.16445.57NANot crossNot cross19.9% (1200 of 6016 patients)NNTB: 413; 95% CI NNTH 20 to ∞ to NNTB 19Not seriousNot seriousNot seriousNot seriousNA⨁⨁⨁⨁
HighLate PON121489RR: 1.033; 95% CI 0.753 to 1.41757.93−0.877; 95% CI −2.344 to 0.591Not crossNot cross10.1% (1489 of 14,733 patients)NNTB: 1911; 95% CI NNTH 25 to ∞ to NNTB 24Not seriousSeriousNot seriousNot seriousNot serious⨁⨁⨁◯
ModerateLate POV101097RR: 0.604; 95% CI 0.404 to 0.9030.00.072; 95% CI −0.675 to 0.819CrossNot cross15.4% (1097 of 7127 patients)NNTB: 27; 95% CI NNTB 15 to NNTB 163Not seriousNot seriousNot seriousNot seriousNot serious⨁⨁⨁⨁
HighLate PONV91200RR: 0.983; 95% CI 0.800 to 1.2090.0NANot crossNot cross23.3% (1200 of 5144 patients)NNTB: 432; 95% CI NNTH 20 to ∞ to NNTB 18Not seriousNot seriousNot seriousNot seriousNA⨁⨁⨁⨁
HighOverall PON131323RR: 1.045; 95% CI 0.893 to 1.22248.75−1.148; 95% CI −2.312 to 0.156Not crossNot cross15.2% (1323 of 8707 patients)NNTH: 68; 95% CI NNTH 16 to ∞ to NNTB 31Not seriousNot seriousNot seriousNot seriousNot serious⨁⨁⨁⨁
HighOverall POV141359RR: 0.879; 95% CI 0.624 to 1.24038.77−0.238; 95% CI −1.844 to 0.737CrossNot cross7.2% (1359 of 18,799 patients)NNTB: 111; 95% CI NNTH 43 to ∞ to NNTB 24Not seriousNot seriousNot seriousNot seriousNot serious⨁⨁⨁⨁
HighOverall PONV91200RR: 1.073; 95% CI 0.957 to 1.20311.41NANot crossNot cross46.0% (1200 of 2607 patients)NNTB: 432; 95% CI NNTH 20 to ∞ to NNTB 18Not seriousNot seriousNot seriousNot seriousNA⨁⨁⨁⨁
HighRescue Anti-emetics131448RR: 0.815; 95% CI 0.617 to 1.07756.55−0.372; 95% CI −2.364 to 1.620Not crossNot cross19.4% (1448 of 7458 patients)NNTB: 111; 95% CI NNTH 43 to ∞ to NNTB 24Not seriousSeriousNot seriousNot seriousNot serious⨁⨁⨁◯
ModerateRetching7592RR: 0.525; 95% CI 0.390 to 0.7070.0 CrossCross33.0% (592 of 1792 patients)NNTB: 7; 95% CI NNTB 5 to NNTB 13Not seriousNot seriousNot seriousSeriousNA⨁⨁⨁◯
ModerateComplete Response7547RR: 1.028; 95% CI 0.961 to 1.100