Drugs for preventing postoperative nausea and vomiting in adults after general anaesthesia: a network meta-analysis

Stephanie Weibel, Gerta Rücker, Leopold Hj Eberhart, Nathan L Pace, Hannah M Hartl, Olivia L Jordan, Debora Mayer, Manuel Riemer, Maximilian S Schaefer, Diana Raj, Insa Backhaus, Antonia Helf, Tobias Schlesinger, Peter Kienbaum, Peter Kranke, Stephanie Weibel, Gerta Rücker, Leopold Hj Eberhart, Nathan L Pace, Hannah M Hartl, Olivia L Jordan, Debora Mayer, Manuel Riemer, Maximilian S Schaefer, Diana Raj, Insa Backhaus, Antonia Helf, Tobias Schlesinger, Peter Kienbaum, Peter Kranke

Abstract

Background: Postoperative nausea and vomiting (PONV) is a common adverse effect of anaesthesia and surgery. Up to 80% of patients may be affected. These outcomes are a major cause of patient dissatisfaction and may lead to prolonged hospital stay and higher costs of care along with more severe complications. Many antiemetic drugs are available for prophylaxis. They have various mechanisms of action and side effects, but there is still uncertainty about which drugs are most effective with the fewest side effects.

Objectives: • To compare the efficacy and safety of different prophylactic pharmacologic interventions (antiemetic drugs) against no treatment, against placebo, or against each other (as monotherapy or combination prophylaxis) for prevention of postoperative nausea and vomiting in adults undergoing any type of surgery under general anaesthesia • To generate a clinically useful ranking of antiemetic drugs (monotherapy and combination prophylaxis) based on efficacy and safety • To identify the best dose or dose range of antiemetic drugs in terms of efficacy and safety SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), ClinicalTrials.gov, and reference lists of relevant systematic reviews. The first search was performed in November 2017 and was updated in April 2020. In the update of the search, 39 eligible studies were found that were not included in the analysis (listed as awaiting classification).

Selection criteria: Randomized controlled trials (RCTs) comparing effectiveness or side effects of single antiemetic drugs in any dose or combination against each other or against an inactive control in adults undergoing any type of surgery under general anaesthesia. All antiemetic drugs belonged to one of the following substance classes: 5-HT₃ receptor antagonists, D₂ receptor antagonists, NK₁ receptor antagonists, corticosteroids, antihistamines, and anticholinergics. No language restrictions were applied. Abstract publications were excluded.

Data collection and analysis: A review team of 11 authors independently assessed trials for inclusion and risk of bias and subsequently extracted data. We performed pair-wise meta-analyses for drugs of direct interest (amisulpride, aprepitant, casopitant, dexamethasone, dimenhydrinate, dolasetron, droperidol, fosaprepitant, granisetron, haloperidol, meclizine, methylprednisolone, metoclopramide, ondansetron, palonosetron, perphenazine, promethazine, ramosetron, rolapitant, scopolamine, and tropisetron) compared to placebo (inactive control). We performed network meta-analyses (NMAs) to estimate the relative effects and ranking (with placebo as reference) of all available single drugs and combinations. Primary outcomes were vomiting within 24 hours postoperatively, serious adverse events (SAEs), and any adverse event (AE). Secondary outcomes were drug class-specific side effects (e.g. headache), mortality, early and late vomiting, nausea, and complete response. We performed subgroup network meta-analysis with dose of drugs as a moderator variable using dose ranges based on previous consensus recommendations. We assessed certainty of evidence of NMA treatment effects for all primary outcomes and drug class-specific side effects according to GRADE (CINeMA, Confidence in Network Meta-Analysis). We restricted GRADE assessment to single drugs of direct interest compared to placebo.

Main results: We included 585 studies (97,516 randomized participants). Most of these studies were small (median sample size of 100); they were published between 1965 and 2017 and were primarily conducted in Asia (51%), Europe (25%), and North America (16%). Mean age of the overall population was 42 years. Most participants were women (83%), had American Society of Anesthesiologists (ASA) physical status I and II (70%), received perioperative opioids (88%), and underwent gynaecologic (32%) or gastrointestinal surgery (19%) under general anaesthesia using volatile anaesthetics (88%). In this review, 44 single drugs and 51 drug combinations were compared. Most studies investigated only single drugs (72%) and included an inactive control arm (66%). The three most investigated single drugs in this review were ondansetron (246 studies), dexamethasone (120 studies), and droperidol (97 studies). Almost all studies (89%) reported at least one efficacy outcome relevant for this review. However, only 56% reported at least one relevant safety outcome. Altogether, 157 studies (27%) were assessed as having overall low risk of bias, 101 studies (17%) overall high risk of bias, and 327 studies (56%) overall unclear risk of bias. Vomiting within 24 hours postoperatively Relative effects from NMA for vomiting within 24 hours (282 RCTs, 50,812 participants, 28 single drugs, and 36 drug combinations) suggest that 29 out of 36 drug combinations and 10 out of 28 single drugs showed a clinically important benefit (defined as the upper end of the 95% confidence interval (CI) below a risk ratio (RR) of 0.8) compared to placebo. Combinations of drugs were generally more effective than single drugs in preventing vomiting. However, single NK₁ receptor antagonists showed treatment effects similar to most of the drug combinations. High-certainty evidence suggests that the following single drugs reduce vomiting (ordered by decreasing efficacy): aprepitant (RR 0.26, 95% CI 0.18 to 0.38, high certainty, rank 3/28 of single drugs); ramosetron (RR 0.44, 95% CI 0.32 to 0.59, high certainty, rank 5/28); granisetron (RR 0.45, 95% CI 0.38 to 0.54, high certainty, rank 6/28); dexamethasone (RR 0.51, 95% CI 0.44 to 0.57, high certainty, rank 8/28); and ondansetron (RR 0.55, 95% CI 0.51 to 0.60, high certainty, rank 13/28). Moderate-certainty evidence suggests that the following single drugs probably reduce vomiting: fosaprepitant (RR 0.06, 95% CI 0.02 to 0.21, moderate certainty, rank 1/28) and droperidol (RR 0.61, 95% CI 0.54 to 0.69, moderate certainty, rank 20/28). Recommended and high doses of granisetron, dexamethasone, ondansetron, and droperidol showed clinically important benefit, but low doses showed no clinically important benefit. Aprepitant was used mainly at high doses, ramosetron at recommended doses, and fosaprepitant at doses of 150 mg (with no dose recommendation available). Frequency of SAEs Twenty-eight RCTs were included in the NMA for SAEs (10,766 participants, 13 single drugs, and eight drug combinations). The certainty of evidence for SAEs when using one of the best and most reliable anti-vomiting drugs (aprepitant, ramosetron, granisetron, dexamethasone, ondansetron, and droperidol compared to placebo) ranged from very low to low. Droperidol (RR 0.88, 95% CI 0.08 to 9.71, low certainty, rank 6/13) may reduce SAEs. We are uncertain about the effects of aprepitant (RR 1.39, 95% CI 0.26 to 7.36, very low certainty, rank 11/13), ramosetron (RR 0.89, 95% CI 0.05 to 15.74, very low certainty, rank 7/13), granisetron (RR 1.21, 95% CI 0.11 to 13.15, very low certainty, rank 10/13), dexamethasone (RR 1.16, 95% CI 0.28 to 4.85, very low certainty, rank 9/13), and ondansetron (RR 1.62, 95% CI 0.32 to 8.10, very low certainty, rank 12/13). No studies reporting SAEs were available for fosaprepitant. Frequency of any AE Sixty-one RCTs were included in the NMA for any AE (19,423 participants, 15 single drugs, and 11 drug combinations). The certainty of evidence for any AE when using one of the best and most reliable anti-vomiting drugs (aprepitant, ramosetron, granisetron, dexamethasone, ondansetron, and droperidol compared to placebo) ranged from very low to moderate. Granisetron (RR 0.92, 95% CI 0.80 to 1.05, moderate certainty, rank 7/15) probably has no or little effect on any AE. Dexamethasone (RR 0.77, 95% CI 0.55 to 1.08, low certainty, rank 2/15) and droperidol (RR 0.89, 95% CI 0.81 to 0.98, low certainty, rank 6/15) may reduce any AE. Ondansetron (RR 0.95, 95% CI 0.88 to 1.01, low certainty, rank 9/15) may have little or no effect on any AE. We are uncertain about the effects of aprepitant (RR 0.87, 95% CI 0.78 to 0.97, very low certainty, rank 3/15) and ramosetron (RR 1.00, 95% CI 0.65 to 1.54, very low certainty, rank 11/15) on any AE. No studies reporting any AE were available for fosaprepitant. Class-specific side effects For class-specific side effects (headache, constipation, wound infection, extrapyramidal symptoms, sedation, arrhythmia, and QT prolongation) of relevant substances, the certainty of evidence for the best and most reliable anti-vomiting drugs mostly ranged from very low to low. Exceptions were that ondansetron probably increases headache (RR 1.16, 95% CI 1.06 to 1.28, moderate certainty, rank 18/23) and probably reduces sedation (RR 0.87, 95% CI 0.79 to 0.96, moderate certainty, rank 5/24) compared to placebo. The latter effect is limited to recommended and high doses of ondansetron. Droperidol probably reduces headache (RR 0.76, 95% CI 0.67 to 0.86, moderate certainty, rank 5/23) compared to placebo. We have high-certainty evidence that dexamethasone (RR 1.00, 95% CI 0.91 to 1.09, high certainty, rank 16/24) has no effect on sedation compared to placebo. No studies assessed substance class-specific side effects for fosaprepitant. Direction and magnitude of network effect estimates together with level of evidence certainty are graphically summarized for all pre-defined GRADE-relevant outcomes and all drugs of direct interest compared to placebo in http://doi.org/10.5281/zenodo.4066353.

Authors' conclusions: We found high-certainty evidence that five single drugs (aprepitant, ramosetron, granisetron, dexamethasone, and ondansetron) reduce vomiting, and moderate-certainty evidence that two other single drugs (fosaprepitant and droperidol) probably reduce vomiting, compared to placebo. Four of the six substance classes (5-HT₃ receptor antagonists, D₂ receptor antagonists, NK₁ receptor antagonists, and corticosteroids) were thus represented by at least one drug with important benefit for prevention of vomiting. Combinations of drugs were generally more effective than the corresponding single drugs in preventing vomiting. NK₁ receptor antagonists were the most effective drug class and had comparable efficacy to most of the drug combinations. 5-HT₃ receptor antagonists were the best studied substance class. For most of the single drugs of direct interest, we found only very low to low certainty evidence for safety outcomes such as occurrence of SAEs, any AE, and substance class-specific side effects. Recommended and high doses of granisetron, dexamethasone, ondansetron, and droperidol were more effective than low doses for prevention of vomiting. Dose dependency of side effects was rarely found due to the limited number of studies, except for the less sedating effect of recommended and high doses of ondansetron. The results of the review are transferable mainly to patients at higher risk of nausea and vomiting (i.e. healthy women undergoing inhalational anaesthesia and receiving perioperative opioids). Overall study quality was limited, but certainty assessments of effect estimates consider this limitation. No further efficacy studies are needed as there is evidence of moderate to high certainty for seven single drugs with relevant benefit for prevention of vomiting. However, additional studies are needed to investigate potential side effects of these drugs and to examine higher-risk patient populations (e.g. individuals with diabetes and heart disease).

Conflict of interest statement

General note: our review team included several experts in the field (NLP, DR, MSS, PKi, LHJE, AH, TS, PKr). Review authors (LHJE, PKr) who were involved in the conduct of studies related to the current review did not assess the relevant studies for inclusion or exclusion and were not allowed to extract data or critically appraise the quality of the relevant studies.

Stephanie Weibel has no conflict of interest regarding the topic of this review. Stephanie Weibel is an academic researcher. She has received personal payments for consultancies and lecture fees from Genelux Corporation, San Diego, California, USA (ended March 2014). Genelux Corporation does not produce any products for the intervention of interest in this review. She was involved in the conduct of phase 3 clinical trials related to the current review (“Amisulpride (APD421)” (NCT02646566NCT02449291Kranke 2018), and she was involved in a meta‐analysis on the incidence of postoperative nausea and vomiting that was published recently (Schaefer 2016). She received funding through a one‐time payment from B. Braun‐Stiftung, Melsungen, Germany. The B. Braun‐Stiftung is an independent and non‐profit foundation. She has received lecture fees (topic: systematic reviews and meta‐analyses) from the University of Marburg (2017, 2020).

Gerta Rücker is employed as a statistician at the Institute of Medical Biometry and Statistics of the Medical Center at the University of Freiburg. She received payment for a one‐day course on statistical methods in meta‐analysis from the Grünenthal Group, Aachen, Germany.

Nathan L Pace has no conflict of interest regarding the topic of this review. Nathan L Pace is a non‐practising anaesthetist and statistician faculty member of the University of Utah, receives no private practice income, and has no commercial relationships. He has received payment for development of educational presentations (Barash, Cullen, Stoelting, CLINICAL ANESTHESIA, 8th edition) and has provided consultancy (St Marks Hospital, Salt Lake City, Utah, USA) on topics unrelated to the current review. He has received supplements to attend Cochrane meetings. He also has stocks and shares in companies that have no interest in the topic of this review (TIAA‐CREF, Fidelity, Vanguard, USAA, MorganStanley).

Leopold Eberhart is employed as a clinical and academic anaesthetist with a clinical and research focus on postoperative pain management and postoperative nausea and vomiting. He has no conflict of interest regarding the topic of this review. Leopold Eberhart has received lecture fees (from Baxter GmbH and Fresenius GmbH) and payment for lectures (from Gruenenthal GmbH, Baxter GmbH and Fresenius, GmbH) and has provided consultancy (for Gruenenthal GmbH and ratiopharm GmbH) for topics not related to the current review. He holds a board membership with Gruenenthal GmbH Deutschland, which does not have an interest in the topic of this review. He has been involved in the conduct of phase 2 and phase 3 clinical trials related to the current review (“Amisulpride (APD421)” (NCT02646566NCT02449291Kranke 2018Gan 2017Kranke 2013; “Vestipitant (GW597599)” (NCT01507194); “Buspiron” (Kranke 2012); IMPACT study (Apfel 2004)). He was an author of several papers on postoperative nausea and vomiting.

Hannah Hartl has no conflict of interest regarding the topic of this review. Hannah Hartl is a medical student.

Olivia Jordan has no conflict of interest regarding the topic of this review. Olivia Jordan is a medical student.

Debora Mayer has no conflict of interest regarding the topic of this review. Debora Mayer is a medical student.

Manuel Riemer has no conflict of interest regarding the topic of this review. Manuel Riemer is a medical student.

Maximilian S Schaefer has no conflict of interest regarding the topic of this review. Maximilian S Schaefer is an attending anaesthesiologist. He was involved in a meta‐analysis on the incidence of postoperative nausea and vomiting published recently (Schaefer 2016).

Diana Raj has no conflict of interest regarding the topic of this review. Diana Raj is a consultant in clinical anaesthesiology and a Trustee and Secretary of West of Scotland Anaesthetic Teaching (WOSAT), Scottish Charity SC04663.

Insa Linnea Backhaus has no conflict of interest regarding the topic of this review. Insa Linnea Backhaus earned her PhD in Public Health and is an academic researcher.

Antonia Helf has no conflict of interest regarding the topic of this review. Antonia Helf is a clinical investigator and academic researcher. She was involved in the conduct of phase 3 clinical trials related to the current review (“Amisulpride (APD421)” (NCT02646566NCT02449291)).

Tobias Schlesinger has no conflict of interest. Tobias Schlesinger is a clinical investigator and academic researcher.

Peter Kienbaum is employed as a clinical and academic anaesthetist and has been holding the position of vice chairman of the anaesthesia department for 10 years. His clinical and research work focuses on cardiovascular effects of anaesthetics and recovery after anaesthesia. Peter Kienbaum has been consulting for Baxter Germany, Air Liquide Germany, Orion Pharma Germany, and TEVA ratiopharm Germany, with respect to inhaled anaesthetics and other issues not related to this review. He authored several trial papers unrelated to the current review and was involved in a meta‐analysis on the incidence of postoperative nausea and vomiting published recently (Schaefer 2016).

Peter Kranke is employed as a clinical and academic anaesthetist with a clinical and research focus on obstetric anaesthesia and postoperative nausea and vomiting. He has received lecture fees (from MSD, ratiopharm, Covidien) and has provided consultancy (to MSD, Ratiopharm, Covidien) on topics unrelated to the current review. He has received lecture fees and provided consultancy to Fresenius GmbH. This company manufactures propofol, which may be effective as an antiemetic in reducing PONV. He acted as a consultant for Acacia Ltd. He has been involved in the conduct of phase 2 and phase 3 clinical trials related to the current review (“Amisulpride (APD421)” (NCT02646566NCT02449291Kranke 2018Gan 2017Kranke 2013); “Vestipitant (GW597599)” (NCT01507194); “Buspiron” (Kranke 2012); IMPACT study (Apfel 2004)). He was author of several trial papers and of the consensus guidelines for management of postoperative nausea and vomiting. He has published research reports and editorial views on the topic under review and was involved in a meta‐analysis on the incidence of postoperative nausea and vomiting published recently (Schaefer 2016).