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Anesthesia & Analgesia:
doi: 10.1213/ANE.0b013e31829847a1
Ambulatory Anesthesia: Research Report

Reevaluation of the Effectiveness of Ramosetron for Preventing Postoperative Nausea and Vomiting: A Systematic Review and Meta-Analysis

Mihara, Takahiro MD*; Tojo, Kentaro MD*; Uchimoto, Kazuhiro MD*; Morita, Satoshi PhD; Goto, Takahisa MD*

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From the Departments of *Anesthesiology and Critical Care Medicine and Biostatistics and Epidemiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Accepted for publication April 5, 2013.

Published ahead of print June 11, 2013.

Funding: None.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Takahiro Mihara, MD, Department of Anesthesiology and Critical Care Medicine, Yokohama City University Graduate School of Medicine, 3–9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. Address e-mail to miharaxxxtotoro@yahoo.co.jp.

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Abstract

BACKGROUND: Ramosetron has been shown to have a very strong effect for preventing postoperative nausea and vomiting (PONV) in previous meta-analyses. However, these previous meta-analyses included a number of studies by Fujii et al. which have now been proven to have been fabricated. In the present meta-analysis, we reevaluated the effectiveness of ramosetron in preventing PONV after excluding Fujii et al.’s randomized controlled trials.

METHODS: We searched MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, and Web of Science. All double-blind randomized controlled trials that tested the efficacy of ramosetron compared with a placebo or other drugs as a control in the prophylaxis of PONV were considered to be eligible. The first postoperative 24 hours were divided into early (0−6 hours) and late (6–24 hours) time periods, and we collected these data separately.

RESULTS: A total of 1372 patients were included in the final analysis. Compared with a placebo, ramosetron reduced the incidence of early postoperative nausea (PON) (relative risk [RR] [95% confidence interval] 0.59 [0.47–0.73]: number needed to treat [NNT] [95% confidence interval] 6.0 [4.3–9.7]), late PON (RR 0.65 [0.49–0.85]: NNT 7.2 [4.6–16.6]), early postoperative vomiting (POV) (RR 0.48 [0.31–0.74]: NNT 14.8 [8.3–70.4]), and late POV (RR 0.50 [0.35–0.73]: NNT 12.3 [7.1–47.6]). Compared with ondansetron, ramosetron reduces early POV (RR 0.50 [0.28–0.90]: NNT 24.1 [10.7–98.0]) and late POV (RR 0.53 [0.34–0.81]: NNT 27.2 [12.0–102.0]) but not PON.

CONCLUSIONS: Ramosetron has a significant effect for preventing PONV compared with a placebo, but less than that reported in previous analyses. Ramosetron also has statistically significant differences in preventing early and late POV compared with ondansetron, but the clinical significance may be questioned because the NNTs are large.

Postoperative nausea and vomiting (PONV) are common complications after anesthesia. It is important to prevent PONV because it is strongly associated not only with patient dissatisfaction, but also with dehydration, electrolyte imbalance, and disruption of surgical repair.1,2 5-Hydroxy-tryptamine receptor 3 (5-HT3) antagonists (e.g., ondansetron, granisetron, and ramosetron) are used to prevent PONV. Ramosetron, a new 5-HT3 receptor antagonist, has a higher affinity and more prolonged activity than previously developed 5-HT3 antagonists such as ondansetron.3 A recent meta-analysis4 has shown that ramosetron is very effective for preventing PONV.

Fujii et al. published numerous research papers which purported to reveal the strong effects of 5-HT3 antagonists in preventing PONV. However, their studies have been widely criticized in the literature5–11 and have now been confirmed to have been fabricated. Carlisle7 concluded in his article that “the data showed such unusual distributions as to suggest that sampling had not been random and that, therefore, the data should be excluded from any meta-analysis.” Actually, the results of meta-analyses6,7,12 that summarized the effectiveness of granisetron for preventing PONV were altered by excluding randomized controlled trials (RCTs) by Fujii et al. The Japanese Society of Anesthesiologists set up a Special Investigation Committee to investigate this issue on March 10, 2012. This committee reported13 that “the number of fabricated papers is 172 (including 126 papers in RCT, double-blind manner). Only 3 papers are verified authentic and 37 papers have not been proven either fabricated or not fabricated.”

A meta-analysis that summarized 22 studies on ramosetron in preventing PONV4 was published in 2011. However, it included 14 studies by Fujii et al. We believe that the conclusion will change if ramosetron is reevaluated without Fujii et al.’s studies; thus, the effectiveness of ramosetron in preventing PONV needs to be reevaluated urgently. The aim of this meta-analysis was to reevaluate the effectiveness of ramosetron for preventing PONV without Fujii et al.’s RCTs.

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METHODS

We conducted a systematic review and meta-analysis for RCTs that tested the efficacy of ramosetron compared with a placebo or other drug as a control in the prophylaxis of PONV. We followed the recommendations of the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement.14,15

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Systematic Search

We searched MEDLINE, the Cochrane Central Register of Controlled Trials (CENTRAL), Embase, and Web of Science up to August 23, 2012. In addition, the reference lists of the retrieved full articles were searched. The following search strategy combining free text and Medical Subject Headings terms was set up for PubMed: (ramosetron[tw] OR nasea[tw] OR methanon[tw] OR YM 060[tw] OR YM-060[tw] OR YM060[tw]) AND (PONV[tw] OR ((postoperative OR postanaesthetic OR postanesthetic OR surgical) AND (nausea OR emesis OR vomiting OR retching))) AND (randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized [tiab] OR placebo [tiab] OR drug therapy [sh] OR randomly [tiab] OR trial [tiab] OR groups [tiab]) NOT (animals [mh] NOT humans [mh]).

Two authors (TM and KT) independently scanned the titles and abstracts of reports identified by the variety of search strategies described above. If eligibility could not be determined from the title or abstract, the full paper was retrieved. Potentially relevant studies, chosen by at least 1 author, were retrieved and evaluated in full-text versions. The articles that met the inclusion criteria were assessed separately by 2 authors (TM and KT), and any discrepancies were resolved through discussion.

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Inclusion and Exclusion Criteria

We searched for all double-blinded RCTs that tested the efficacy of ramosetron compared with a placebo or other drug as a control in the prophylaxis of PONV and included those that compared ramosetron versus ondansetron or placebo in this study. We excluded studies that were reported by Fujii et al. We excluded studies that did not include details of postoperative nausea (PON) and/or postoperative vomiting (POV), or the early and/or late periods. We also excluded data from abstracts, posters, case reports, comments or letters to the editor, reviews, and animal studies. Eligibility was not restricted by language, type of surgery, anesthetic technique, or patient age.

The primary outcome from the present meta-analysis concerned PON and POV between ramosetron and ondansetron or a placebo in the early and/or late periods (defined later in this section). The secondary outcome concerned the need for rescue antiemetics and/or side effects. Nausea was defined as a subjectively unpleasant sensation associated with awareness of the urge to vomit. An episode of vomiting was defined as either vomiting (expulsion of stomach contents) or retching (an involuntary attempt to vomit but not productive of stomach contents).

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Data Collection

A data collection sheet was created and included data on: (1) number of patients in study, (2) age, (3) ASA physical status, (4) risk factors for PONV, (5) type of anesthesia, (6) type of surgery, (7) dose of ramosetron or other antiemetic drug, (8) route of administration, (9) timing of administration of ramosetron, (10) number of cases of PON in early period and (11) late period, (12) number of cases of POV in early period and (13) late period, (14) need for rescue antiemetics in early period and (15) late period, and (16) side effects (headache, dizziness, and drowsiness). Data of early and late time periods of the first postoperative 24 hours were collected separately. When the first postoperative 24 hours was divided into 2 time periods (e.g., 0–6 and 6–24 hours), the first time period was defined as the early period and the second time period as the late period. When the first postoperative 24 hours was divided into 3 parts, the time period just before 6 hours was defined as the early period, and the time period just after 6 hours as the late period (e.g., when 24 hours was divided into 0–6, 6–12, and 12–24 hours, we defined 0–6 hours as the early period, and 6–12 hours as the late period). Values originally provided as percentages were converted back into actual patient numbers for analysis. If the data were reported only in graphs which indicated percentages or numbers of patients, we measured the lengths of the graphs to obtain the percentages or numbers of patients. A baseline antiemetic (dexamethasone) was used in some studies for ethical reasons. Such studies were included, and a “dexamethasone and ramosetron versus dexamethasone” study was counted as a “ramosetron versus placebo” study. If ramosetron or ondansetron were administered by different routes or at different dosages in the same study, data with 0.3 mg of IV ramosetron or 4 mg of IV ondansetron were used because these are the most common routes and dosages. Two authors (TM and KU) extracted the data independently from the studies included and then cross-checked the data. Disagreements were resolved by discussion between the 2 authors. If no agreement could be reached, a third author (TG) arbitrated.

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Statistical Analysis

Dichotomous data were summarized using relative risk (RR) with a 95% confidence interval (CI). If the 95% CI included a value of 1, we considered the difference not to be statistically significant. For statistically significant differences in outcome, the number needed to treat (NNT) was calculated to estimate the overall clinical impact of the intervention. Heterogeneity was quantified with the I2 statistic. We used the fixed effect model if I2 < 25% and the random effect model (Dersimonian and Laird method) if I2 > 25% to combine the results of the studies. Forest plots were used to graphically represent and evaluate the effects of treatment. Publication bias was assessed using a funnel plot and an Egger regression asymmetry test16 and was considered to be positive if P < 0.1 in the regression asymmetry test. We assessed the risk of bias as described by the Cochrane Handbook for Systematic Reviews of Interventions. We assessed the risk of bias in sequence generation, allocation sequence concealment, blinding of patients, blinding of health care providers, blinding of data collectors, blinding of outcome assessors, incomplete outcome data, selective outcome reporting, and other bias. Sensitivity analyses were performed for the primary outcomes of early PON/late PON/early POV/late POV according to the anesthetic technique (general versus regional anesthesia), use of baseline antiemetics (combination versus single therapy), timing of administration (end of surgery versus others), definition of early/late period (0–6/6–24 hours for early/late period versus others), and risk of bias (low versus high or unclear). Statistical analyses were performed using the R statistical software package version 2.13.0 (R Foundation for Statistical Computing, Vienna, Austria).

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RESULTS

The search of MEDLINE, the Cochrane Central Register of Controlled Trials (CENTRAL), Embase, and Web of Science databases produced 148 citations. After adjusting for duplicates, 56 citations remained. Of these, 24 studies were discarded because, after reviewing the title and abstracts, it appeared that these articles clearly did not meet the criteria. The full texts of the remaining 32 citations (17 citations17–33 and 15 Fujii et al. studies) were examined in more detail. It appeared that 20 studies did not meet the inclusion criteria for the following reasons: 15 were written by Fujii et al. (Appendix); 2 were not double-blind studies; 2 did not report details of PON/POV in the early and late periods; and 1 did not include a control group (Fig. 1). Twelve studies17–28 thus met the inclusion criteria and were included in this systematic review and meta-analysis.

Figure 1
Figure 1
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A total of 1371 patients (365 who received ramosetron vs 369 who received a placebo, and 317 who received ramosetron vs 320 who received ondansetron) were included in the final analysis (Table 1). Regional anesthesia (spinal anesthesia, combined epidural and spinal anesthesia, femoral nerve block) with sedation was used in 2 studies,22,25 inhaled anesthesia with nitrous oxide was used in 3 studies,18,19,23 inhaled anesthesia without nitrous oxide was used in 3 studies,17,24,26 and total IV anesthesia was used in 3 studies.20,21,28 One study did not mention the type of general anesthesia used.27 Ramosetron was given at the end of surgery in 10 studies,17,19,21–28 before the induction of anesthesia in 1 study,18 and after the induction of anesthesia in 1 study.20 The definition of early/late period was 0–6/6–24 hours in 5 studies.21–23,26,27 One study23 did not use 4 mg but rather 8 mg of ondansetron. We did not include this study for analysis of “ramosetron versus ondansetron” because we intended to compare 0.3 mg of ramosetron with 4 mg of ondansetron. The dose of ramosetron was 0.3 mg in 11 studies and 4 µg/kg in 1 study.18 We included this study18 (4 µg/kg of ramosetron for adults; mean body weight = 58 kg) because the actual dose was close to 0.3 mg. Ramosetron was administered IV in all studies.

Table 1
Table 1
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Ramosetron Versus Placebo
Early and Late PON

Seven studies18,20–24,28 compared the effectiveness of ramosetron with a placebo for early and late PON. The combined results from these 7 studies showed that ramosetron caused a statistically significant reduction in the incidence of both early PON (RR [95% CI] 0.59 [0.47–0.73]: I2 0%: NNT [95% CI] 6.0 [4.3–9.7]) and late PON (RR 0.65 [0.49–0.85]: I2 32%: NNT 7.2 [4.6–16.6]), compared with the placebo (Fig. 2).

Figure 2
Figure 2
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Early and Late POV

Seven studies18,20–24,28 compared the effectiveness of ramosetron with a placebo for early and late POV. The combined results from these 7 studies showed that ramosetron caused a statistically significant reduction in the incidence of both early POV (RR 0.48 [0.31–0.74]: I2 0%: NNT 14.8 [8.3–70.4]) and late POV (RR 0.50 [0.35–0.73]: I2 0%: NNT 12.3 [7.1–47.6]), compared with the placebo (Fig. 3).

Figure 3
Figure 3
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Rescue Need

Six studies18,20–23,28 compared the effectiveness of ramosetron with a placebo for rescue need in the early and late periods. The combined results from these 6 studies showed that ramosetron caused a statistically significant reduction in the incidence of both early rescue need (RR 0.51 [0.35–0.74]: I2 18.8%: NNT 10.5 [6.9–22.5]) and late rescue need (RR 0.57 [0.42–0.77]: I2 0%: NNT 13.7 [6.9–92.6]), compared with the placebo.

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Side Effects

Five studies18,20,21,23,24 compared side effects such as headache or dizziness with ramosetron or a placebo. The combined results from these 5 studies showed that there was no significant difference in the incidence of headache (RR 1.20 [0.87–1.65]: I2 0%) or dizziness (RR 0.95 [0.59–1.53]: I2 0%), compared with the placebo.

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Ramosetron Versus Ondansetron
Early and Late PON

Six studies17,19,25–28 compared the effects of ramosetron and ondansetron on early and late PON. The combined results from these 6 studies showed that ramosetron did not have a differential effect in reducing the incidence of either early PON (RR 0.79 [0.51–1.23]: I2 71.1%) or late PON (RR 0.78 [0.60–1.02]: I2 32.8%), compared with ondansetron (Fig. 4).

Figure 4
Figure 4
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Early and Late POV

Six studies17,19,25–28 compared the effects of ramosetron and ondansetron on early and late POV. The combined results from these 6 studies showed that ramosetron caused a statistically significant reduction in the incidence of both early POV (RR 0.50 [0.28–0.90]: I2 7.5%: NNT 24.1 [10.7–98.0]) and late POV (RR 0.53 [0.34–0.81]: I2 0%: NNT 27.2 [12.0–102.0]), compared with ondansetron (Fig. 5).

Figure 5
Figure 5
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Rescue Need

Six studies17,19,25–28 compared the effect of ramosetron with ondansetron on rescue need in the early and late periods. The combined results from these 6 studies showed that ramosetron did not have a differential effect in reducing the incidence of early rescue need (RR 0.76 [0.54–1.05]: I2 18.1%) and late rescue need (RR 0.73 [0.50–1.07]: I2 28%), compared with ondansetron.

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Side Effects

Four studies17,19,26,27 compared the side effects with ramosetron or ondansetron. The combined results from these 4 studies showed that there was no significant difference in the incidence of headache (RR 0.91 [0.42–1.98]: I2 40.5%) or dizziness (RR 0.58 [0.32–1.06]: I2 0%), when compared with ondansetron.

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Risk of Bias

A low risk of bias was attributed to 5 studies (Table 2). Eleven studies had an adequate sequence generation, and 6 studies had an adequate method of allocation concealment. Patients, health care providers, data collectors, and outcome assessors were adequately blinded in 12, 12, 9, and 10 studies, respectively.

Table 2
Table 2
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Funnel Plot and Sensitivity Analysis

Publication bias was assessed using a funnel plot and Egger regression asymmetry test for all primary outcomes (i.e., early and late PON/POV compared with a placebo or ondansetron). No regression asymmetry test results for the funnel plots were statistically significant (P = 0.19, 0.36, 0.41, 0.29, respectively, for early PON, late PON, early POV, late POV in ramosetron versus placebo, and P = 0.35, 0.65, 0.54, 0.45, respectively, for early PON, late PON, early POV, late POV in ramosetron versus ondansetron).

Excluding studies that were done under (1) regional anesthesia or (2) inhaled anesthesia with nitrous oxide, or restricting the analysis to studies without baseline antiemetics, or to studies where ramosetron was administered at the end of surgery, or to studies in which the definition of early/late period was 0 to 6/6 to 24 hours or to studies with a low risk of bias did not change the direction of the results of our primary outcome, although some of the comparisons were no longer statistically significant. The results of the sensitivity analysis are presented in Table 3.

Table 3
Table 3
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DISCUSSION

This meta-analysis suggests that ramosetron causes a statistically significant reduction in the incidence of early PON, late PON, early POV, and late POV, compared with a placebo (Figs. 2 and 3). When compared with ondansetron, there were no significant differences in preventing PON (Fig. 4). We found that ramosetron has statistically significant differences in preventing early and late POV, compared with ondansetron (Fig. 5).

The aim of this meta-analysis was to reevaluate the effectiveness of ramosetron in preventing PONV without Fujii et al.’s RCTs. Previously, Kim et al.4 reported on a meta-analysis of ramosetron for the prevention of PONV, which revealed that ramosetron had a strong effect in preventing early PON (RR 0.4), early POV (RR 0.3), and late POV (RR 0.3), but not late PON, when compared with a placebo. However, their meta-analysis included 14 RCTs by Fujii et al., as described above, and thus needs to be reevaluated. Our reevaluation of the effects of ramosetron compared with a placebo reveals that it has a significant, but less, effect in preventing early PON (RR 0.59), early POV (RR 0.48), and late POV (RR 0.50) than did previous meta-analyses; it also reveals the significant effectiveness of ramosetron in preventing late PON (RR 0.65). The results of the present analysis are in line with the results of another previous meta-analysis by Carlisle,7 which emphasized the need to reevaluate the effects of antiemetics and other interventions without Fujii et al.’s RCTs.

Kim et al.’s4 meta-analysis did not reveal a differential effect between ramosetron and ondansetron in preventing PONV. Interestingly, although the pharmacological mechanism of ramosetron and ondansetron is the same (i.e., 5-HT3 receptor antagonists), our combined results reveal that ramosetron has statistically significant differences in preventing early and late POV, compared with ondansetron (Fig. 5). However, the clinical significance of these differences may be questioned because their NNTs are large (NNT [95% CI] for early POV = 24.1 [10.7–98.0]: NNT for late POV = 27.2 [12.0–102.0]). Ramosetron has a higher affinity to 5-HT3 receptors than ondansetron. This high affinity of ramosetron may be one of the reasons why 0.3 mg of ramosetron has statistically significant differences in preventing POV than 4 mg of ondansetron.

We expected that ramosetron would have an advantage over ondansetron in the late, rather than the early period, because the elimination half-life of ramosetron (9 hours)3 is longer than that of ondansetron (3.5 hours).34 However, our results showed that their effectiveness in the early and late period in preventing PON and/or POV and in reducing rescue need were similar. Thus, we could not confirm the potential advantage of ramosetron, at least in the first postoperative 24 hours.

This meta-analysis suggests that rescue need is reduced by using ramosetron, when compared with a placebo, in both the early and late periods. On the contrary, when compared with ondansetron, ramosetron did not have a statistically significant difference in reducing early and late rescue need.

In our results, the CIs for side effects such as headache or dizziness with ramosetron compared with a placebo or ondansetron were wide. Thus, we cannot draw firm conclusions as to whether ramosetron is associated with increased side effects or not. Previous meta-analyses reported that 5-HT3 antagonists caused a significant increase in the incidence of headache (versus placebo,35 versus traditional drugs,36 versus droperidol36). However, these studies did not include ramosetron, but rather other 5-HT3 antagonists such as ondansetron or granisetron. Whether ramosetron is associated with increased side effects or not needs to be elucidated in future trials.

We used the fixed effect model if I2 < 25% to combine results of the studies and checked the results using the random effect model. There was no difference with either analysis.

The present study has some limitations. First, there were only 12 well-designed double-blind RCTs after the exclusion of Fujii et al.’s RCTs. Therefore, we were only able to combine 7 studies to compare ramosetron (365 patients) and a placebo (369 patients), and likewise only 6 studies to compare ramosetron (317 patients) and ondansetron (320 patients). This sample size was relatively small, and thus our combined results regarding side effects are inconclusive because of the wide CIs. Second, we could not assess the severity of PONV, because the scale of severity of PONV varied from study to study. Some studies quantified severity using a visual analog scale (0–10 or 0–100), others using an 11-point numerical rating scale (0–10), others using a verbal rating scale (none, mild, moderate, severe), and one using the modified Rhodes index. Thus, we could not combine these results. However, we believe that rescue need does reflect the severity of PONV because rescue antiemetics were used in response to severe nausea22–24,26,28 or patient requests in most studies. Ramosetron undoubtedly has a greater effect in reducing rescue need than a placebo, and accordingly we believe that ramosetron is likely to reduce the severity of PONV. Third, the definition of early and late periods differed among the included studies. The definition of early/late period was 0 to 6/6 to 24 hours in 5 studies,21–23,26,27 while the other 7 studies used different definitions (Table 1). The results of the effect of ramosetron for preventing PON and/or POV in the early and late periods may well be influenced by the definition of early/late period. Thus, we conducted subgroup analysis according to the definition of the early and late periods (Table 3), and we confirmed that the results were not affected by this subgroup analysis.

In conclusion, this meta-analysis excluding Fujii et al.’s RCTs suggests that 0.3 mg of ramosetron is safe and effective for preventing both early and late PONV compared with a placebo. This meta-analysis also suggests that ramosetron has statistically significant differences in preventing early and late POV compared with ondansetron, but its clinical significance is unclear.

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APPENDIX

List of Fujii et al. studies excluded from this meta-analysis:

1. Fujii Y, Uemura A, Tanaka H. Prophylaxis of nausea and vomiting after laparoscopic cholecystectomy with ramosetron: randomised controlled trial. Eur J Surg 2002;168:583–6

2. Fujii Y, Tanaka H, Kawasaki T. Benefits and risks of granisetron versus ramosetron for nausea and vomiting after breast surgery: a randomized, double-blinded, placebo-controlled trial. Am J Ther 2004;11:278–82

3. Fujii Y, Tanaka H, Ito M. A randomized clinical trial of a single dose of ramosetron for the prevention of vomiting after strabismus surgery in children: a dose-ranging study. Arch Ophthal 2005;123:25–8

4. Fujii Y, Tanaka H. Prevention of nausea and vomiting with ramosetron after total hip replacement. Clin Drug Investig 2003;23:405–9

5. Fujii Y, Tanaka H. Randomized, double-blind, placebo-controlled, dosed-finding study of the antiemetic effects and tolerability of ramosetron in adults undergoing middle ear surgery. Clin Ther 2003;25:3100–8

6. Fujii Y, Tanaka H. Double-blind, placebo-controlled, dose-ranging study of ramosetron for the prevention of nausea and vomiting after thyroidectomy. Clin Ther 2002;24:1148–53

7. Fujii Y, Tanaka H. Comparison of granisetron and ramosetron for the prevention of nausea and vomiting after thyroidectomy. Clin Ther 2002;24:766–72

8. Fujii Y, Tanaka H, Somekawa Y. A randomized, double-blind, placebo-controlled trial of ramosetron for preventing nausea and vomiting during termination of pregnancy. Int J Obstet Anesth 2004;13:15–8

9. Fujii Y, Tanaka H, Kobayashi N. Prevention of nausea and vomiting after middle ear surgery: granisetron versus ramosetron. Laryngoscope 1999;109:1988–90

10. Fujii Y, Tanaka H, Ito M. Ramosetron compared with granisetron for the prevention of vomiting following strabismus surgery in children. Br J Ophthalmol 2001;85:670–2

11. Fujii Y, Tanaka H. Results of a prospective, randomized, double-blind, placebo-controlled, dose-ranging trial to determine the effective dose of ramosetron for the prevention of vomiting after tonsillectomy in children. Clin Ther 2003;25:3135–3142

12. Fujii Y, Saitoh Y, Tanaka H, Toyooka H. Ramosetron vs granisetron for the prevention of postoperative nausea and vomiting after laparoscopic cholecystectomy. Can J Anaesth 1999;46:991–3

13. Fujii Y, Saitoh Y, Tanaka H, Toyooka H. Ramosetron for preventing postoperative nausea and vomiting in women undergoing gynecological surgery. Anesth Analg 2000;90:472–5

14. Fujii Y, Saitoh Y, Tanaka H, Toyooka H. Comparison of ramosetron and granisetron for preventing postoperative nausea and vomiting after gynecologic surgery. Anesth Analg 1999;89:476–9

15. Fujii Y, Saitoh Y, Kobayashi N. Prevention of vomiting after tonsillectomy in children: granisetron versus ramosetron. Laryngoscope 2001;111:255–8

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DISCLOSURES

Name: Takahiro Mihara, MD.

Contribution: This author helped design and conduct the study, analyze the data, and write the manuscript.

Attestation: Takahiro Mihara has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

Name: Kentaro Tojo, MD.

Contribution: This author helped conduct the study and analyze the data.

Attestation: Kentaro Tojo has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Kazuhiro Uchimoto, MD.

Contribution: This author helped conduct the study and analyze the data.

Attestation: Kazuhiro Uchimoto has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Satoshi Morita, PhD.

Contribution: This author helped analyze the data.

Attestation: Satoshi Morita has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Takahisa Goto, MD.

Contribution: This author helped write the manuscript.

Attestation: Takahisa Goto has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

This manuscript was handled by: Peter S. A. Glass, MB, ChB.

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