BJA Advance Access published online on May 30, 2007
British Journal of Anaesthesia, doi:10.1093/bja/aem133
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Single-dose aprepitant vs ondansetron for the prevention of postoperative nausea and vomiting: a randomized, double-blind Phase III trial in patients undergoing open abdominal surgery
1 Services d'Anesthesiologie-Reanimation Chirurgicale, CHU, Hôpital de Hautepierre, 1 Avenue de Moliere, Strasbourg 67000, France
2 Department of Anesthesiology, Duke University Medical Centre, Durham, NC 27710, USA
3 Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
4 Universidade Federal de Sao Paulo, Rua Napoleao de Barros, 715-7 o ander, Sao Paulo, Brazil
5 University of Marburg, Abteilung Anaesthesie und Intensivetherapie, Baldingerstr. 1, Marburg, Germany
6 Department of Anaesthesiology, University of Hong Kong, 102 Pokfulam Road, Pokfulam, Hong Kong, Republic of China
7 Clinica Universitaria de Navarra, Avda. Pio XII, 36, Pamplona, Navarra 31008, Spain
8 Department of Anesthesiology, University of Pittsburgh Medical Center, 5230 Centre Avenue, M-140, Pittsburgh, PA 15232, USA
9 Merck Research Laboratories, West Point, PA 19486, USA
* Corresponding author: Services d'Anesthesiologie-Reanimation Chirurgicale, CHU, Hôpitale de Hautepierre, 1 Avenue de Moliere, Strasbourg 67000, France. E-mail: pierre.diemunsch{at}chru-strasbourg.fr
Accepted for publication April 11, 2007.
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Abstract |
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Background: The neurokinin1 antagonist aprepitant is effective for prevention of chemotherapy-induced nausea and vomiting. We compared aprepitant with ondansetron for prevention of postoperative nausea and vomiting.
Methods: Nine hundred and twenty-two patients receiving general anaesthesia for major abdominal surgery were assigned to receive a single preoperative dose of oral aprepitant 40 mg, oral aprepitant 125 mg, or i.v. ondansetron 4 mg in a randomized, double-blind trial. Vomiting episodes, use of rescue therapy, and nausea severity (verbal rating scale) were documented for 48 h after surgery. Primary efficacy endpoints were complete response (no vomiting and no use of rescue therapy) 0–24 h after surgery and no vomiting 0–24 h after surgery. The secondary endpoint was no vomiting 0–48 h after surgery.
Results: Aprepitant at both doses was non-inferior to ondansetron for complete response 0–24 h after surgery (64% for aprepitant 40 mg, 63% for aprepitant 125 mg, and 55% for ondansetron, lower bound of 1-sided 95% CI>0.65), superior to ondansetron for no vomiting 0–24 h after surgery (84% for aprepitant 40 mg, 86% for aprepitant 125 mg, and 71% for ondansetron; P<0.001), and superior for no vomiting 0–48 h after surgery (82% for aprepitant, 40 mg, 85% for aprepitant, 125 mg, and 66% for ondansetron; P<0.001). The distribution of peak nausea scores was lower in both aprepitant groups vs ondansetron (P<0.05).
Conclusions: Aprepitant was non-inferior to ondansetron in achieving complete response for 24 h after surgery. Aprepitant was significantly more effective than ondansetron for preventing vomiting at 24 and 48 h after surgery, and in reducing nausea severity in the first 48 h after surgery. Aprepitant was generally well tolerated.
Keywords: aprepitant; clinical trials; PONV; ondansetron; serotonin (5-hydroxy-tryptamine), antagonism
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Introduction |
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Nausea and vomiting occur in as many as 70–80% of patients in the first 24 h after surgery.1–5 Even among patients who receive antiemetic prophylaxis with i.v. 5HT3 receptor antagonists (RAs) or other drugs, 30–40% still experience postoperative nausea and vomiting (PONV).6 Thus, an unmet medical need for improved PONV prophylaxis exists. A new class of drug known as non-peptide neurokinin1 (NK1) RAs has demonstrated activity against both peripheral and central emetic stimuli in animal models.7–9 Consistent with the idea that antagonism at the NK1 receptor could affect the response to emetic stimuli,10–13 evidence suggesting the potential efficacy of NK1 RAs against PONV was obtained in clinical trials of two different drugs in this class, which were assessed in patients undergoing major gynaecological surgery.14 In one study, a significantly lower incidence of vomiting in the first 24 h after surgery was observed with an NK1 RA given either alone or in combination with a 5HT3 RA, compared with the 5HT3 RA alone.15 In another study, an NK1 RA given to patients with established PONV was superior to placebo in controlling vomiting.16
Aprepitant, a highly selective, brain-penetrant NK1 RA with a long half-life and preclinical efficacy against opioid-induced emesis,7 9 17 has demonstrated efficacy against chemotherapy-induced nausea and vomiting when combined with other antiemetics, and is the first in its class to be approved for this indication.17 To examine the possibility that it may also provide benefit against PONV, an initial Phase IIb/III study of aprepitant vs the 5HT3 RA ondansetron was conducted in patients undergoing open abdominal surgery.18 In that study, which was the first trial of aprepitant for prevention of PONV, the treatments showed similar efficacy for the primary endpoint of complete response (no vomiting and no use of rescue), but aprepitant provided greater protection against vomiting during the first 24 and 48 h after surgery. The present study was conducted to confirm these positive results in an international population, more thoroughly assess the clinical profile of aprepitant by comparing it with ondansetron for no vomiting and other endpoints, and to define better the apparent similarity for complete response seen in the first study comparing aprepitant and ondansetron.
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Methods |
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A total of 42 centres (eight U.S. sites and 34 non-U.S. sites in North America, South America, Europe, Australia, and Asia) participated in this randomized double-blind study (Protocol 091) between May 28, 2004 and April 20, 2005. Approval from the Institutional Review Board for each centre was obtained and all patients gave written informed consent.
Patients
Patients, aged 
18 yr old, ASA I–III, undergoing open abdominal surgery requiring at least one overnight hospital stay and receiving volatile-agent-based general anaesthesia including nitrous oxide were enrolled. Among exclusion criteria were pregnancy/breastfeeding status, need for a nasogastric or oral-gastric tube, use of neuroaxial- or propofol-maintained anaesthesia, vomiting within 24 h before surgery or of any organic aetiology, allergy to any medications to be used before operation or intra-operatively, pre-established need for intensive care or step-down unit care after operation, evidence of disease or history of illness which according to the investigator rendered the patient inappropriate for the study, abnormal preoperative laboratory values (aspartate aminotransferase >2.5xupper limit of normal, alanine aminotransferase >2.5xupper limit of normal, bilirubin >1.5xupper limit of normal, or creatinine >1.5xupper limit of normal), or need for opioid antagonists or benzodiazepine antagonists. Medications known to induce CYP3A4, such as phenytoin, carbamazepine, barbiturates, rifampicin, or rifabutin, were prohibited within 30 days of the study start; those known to be CYP3A4 substrates (terfenadine, pimozide, cisapride, or astemizole) or CYP3A4 inhibitors (clarithromycin, ketoconazole, or itraconazole) were prohibited within 7 days of the study start.
The gender-stratified randomization schedule was computer-generated by the sponsor. In order to ensure in-house blinding, the schedule was created by an assistant statistician who was otherwise not involved with the study. On the day of surgery, patients were randomized to receive one of three antiemetic treatments before operation: oral aprepitant 40 mg, oral aprepitant 125 mg, or i.v. ondansetron 4 mg. Patient and investigator blinding was maintained with matching placebos. The sponsor provided supplies of aprepitant, placebo matching aprepitant, and blinded allocation schedules. Each site designated an unblinded pharmacist otherwise not involved with the study to receive, store, and prepare the ondansetron and saline placebo.
Aprepitant or placebo was given within 3 h of anticipated induction of anaesthesia, and i.v. ondansetron or placebo was infused over 2–5 min immediately before induction, as indicated in the approved prescribing information for ondansetron.19
The anaesthesia regimen consisted of optional premedication with a benzodiazepine; induction with any anaesthetic agent; neuromuscular blocking agents; opioids; maintenance of anaesthesia with nitrous oxide (50–70%) with a volatile anaesthetic; and neostigmine (2–5 mg) as needed. Additional prophylactic antiemetics were prohibited within 24 h before or after surgery except for postoperative rescue therapy, which was offered if the patient requested it, had nausea lasting longer than 15 min, or had >1 episode of vomiting/retching. The type of rescue therapy was chosen by the investigator.
The duration of anaesthesia and all medications given intraoperatively were recorded. From 0 to 48 h after placement of the last suture/staple, all emetic episodes (oral expulsion of stomach contents or non-productive retches) or use of rescue therapy were recorded. Using an 11-point verbal rating score (VRS), patients rated nausea from 0 (‘no nausea’) to 10 (‘nausea as bad as it could be’) at 2, 6, 24, and 48 h after operation, at any time the patient complained of nausea, and just before receiving rescue medication.
Tolerability was evaluated by physical examinations, laboratory tests, and reporting of adverse events (AEs). Twelve-lead electrocardiograms were obtained at baseline and 24 h after surgery, with particular attention paid to QTc intervals. Awakening time (interval between end of surgery and the patient's ability to obey commands) and duration of recovery from anaesthesia (interval between end of surgery and achievement of Aldrete postanaesthesia recovery score of 8 on a 0–10 scale20) were also recorded. Patients were discharged 24 h after operation and if discharged before 48 h were contacted at that timepoint by the study coordinator to record emetic episodes, use of rescue, and nausea VRS assessment. A follow-up visit or telephone call to the clinic was required within 3 weeks of surgery, at which time any AEs occurring within 14 days after surgery were documented.
Statistical analysis
The sponsor managed the data and performed the analyses for this study. The primary endpoints for the efficacy analysis were: (1) complete response (no vomiting and no use of rescue therapy) over 0–24 h after surgery, to be analysed first for non-inferiority of aprepitant, followed by superiority of aprepitant if non-inferiority was demonstrated, and (2) no vomiting over 0–24 h after surgery, to be tested for superiority of aprepitant. Clinical trials are commonly conducted to show non-inferiority of an experimental treatment against an active control. While equivalence trials have the objective of showing similar effects between the treatments investigated, non-inferiority trials have the objective of showing that an experimental treatment has an effect that is better than or not worse than the active control effect. Therapeutic non-inferiority is typically defined in terms of a fixed margin, 
. Non-inferiority is declared when there is a high degree of confidence (based on a 95% CI) that the effect of the control is not greater than that of the treatment by more than . The study was originally designed to test the single hypothesis of superiority of aprepitant for complete response but, while the study was ongoing, results were obtained from the first trial, which prompted reconsideration of the importance of the no vomiting endpoint. An adjustment was therefore made such that superiority of aprepitant for no vomiting and non-inferiority for complete response were assessed as dual primary hypotheses, with sample size increased accordingly to maintain statistical power. These modifications, which were made before completion of enrolment, treatment, and unblinding of the database, did not affect the study design or consent form. The changes were implemented in adherence with standard regulatory guidelines21 and with US and European Union regulatory consent; approval of aprepitant for the PONV indication included the findings of this study.17 22
The secondary efficacy endpoint of this study was no vomiting in the first 48 h after surgery. Exploratory endpoints included no use of rescue in the first 24 h after surgery, peak nausea score (indicating the patient's worst nausea) on the VRS in the first 24 h, and time to first vomiting in the first 48 h.
The therapeutic non-inferiority fixed margin () was calculated as one-half the smallest reported relative effect of ondansetron to placebo (10 percentage points), based on review of placebo-controlled studies showing that prophylaxis with ondansetron is associated with approximately a 20–30% reduction in the incidence of PONV when compared with placebo.23 Because the present trial used a logistical regression analysis for which the natural metric is the odds ratio, the non-inferiority margin of 0.65 was calculated on the odds ratio scale, corresponding to the 10 percentage-point difference on the raw percentage scale. Thus, non-inferiority was formally defined as a lower bound >0.65, and superiority as a lower bound >1, for the 1-sided 95% CI for the odds ratio of aprepitant vs ondansetron. An additional analysis using a more conservative 2-sided CI was also performed using the same definitions for non-inferiority and superiority.
The primary efficacy analyses were performed on a modified intent-to-treat population, which included all patients who received the study drug, underwent protocol-defined surgery, and had at least one post-treatment efficacy assessment. Treatment comparisons for the efficacy endpoints were made using logistical regression models including terms for treatment and investigative sites. Interactions between treatment and investigative sites were tested at a 10% significance level, and all tests of hypotheses used a 2-sided significance level of 5% unless stated otherwise. A step-down procedure was used to account for multiple tests for the two primary hypotheses and also within the primary hypotheses (two doses of aprepitant compared with ondansetron) as follows: aprepitant 125 mg and ondansetron were compared at the 0.05 significance level; if the difference in complete response rate was significant, aprepitant 40 mg was then compared with ondansetron at the 0.05 level. The two aprepitant doses were not formally statistically compared with each other in this study.
The single highest nausea VRS score was calculated for each patient over 0–24 h as the individual peak nausea score; treatment groups were compared using Wilcoxon rank-sum test. On the basis of the recent research on nausea categorization scales suggesting that a VRS score of 4 is a relevant cutoff representing mild (i.e. not significant) nausea,24 a post hoc analysis was conducted comparing percentages of patients in each treatment group with peak scores in the range of 0 (i.e. no nausea) to 4 (no significant nausea). Kaplan–Meier curves were generated for the time to first emesis during the first 48 h and log-rank testing was used to compare treatments. The rates of incidence of emetic episodes were also compared between groups using a Poisson regression analysis, which took into account the use of rescue medication.
The study was powered to achieve a minimum of 80% on both primary hypotheses. Assuming a 1-sided significance level of 0.05, a complete response rate of 45% for ondansetron, and the prespecified non-inferiority margin of 0.65 for the odds ratio of aprepitant 125 mg vs ondansetron, the study had 80% power to declare aprepitant 125 mg to be non-inferior to ondansetron in terms of complete response in the 0–24-h interval. For the no vomiting endpoint (0–24 h), based on a sample size of 280 evaluable patients per treatment group and assuming a 2-sided significance level of 0.05 for superiority testing, the study had 99% power to detect a 15 percentage-point difference between aprepitant 125 mg and ondansetron (e.g. 90 vs 75%).
The primary safety hypothesis was that aprepitant 40 and 125 mg would be well tolerated. The tolerability analyses and displays included all patients who received study drug. Pairwise treatment comparisons were made using Fisher's exact test. Tests of significance were performed and the corresponding risk differences and 95% CI calculated using the method of Miettinen and Nurminen;25 no multiplicity adjustment was used. Relatedness of any AE to study drug was determined by the investigator. In addition, to detect possible drug interactions, serious AEs of excessive sedation and respiratory depression were adjudicated in blinded fashion by two physicians not involved with the study.
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Study population
Figure 1 shows patient accounting. Among 1004 patients screened, a total of 922 patients were randomized. Of these, 30 patients were excluded from the tolerability and efficacy analyses because they either did not receive any study drug (n=25) or received partial study drug that was found after unblinding to have been the inactive (placebo) portion of the regimen (n=5). In addition to these 30 patients, 26 other patients were excluded from the efficacy analyses for various reasons as shown in the figure. Reasons for discontinuation were similar among treatment groups, with a clinical AE (one patient in the aprepitant 40 mg group, three patients in the aprepitant 125 mg group, and two patients in the ondansetron group), loss to follow-up (0, 1, and 1 patient in the three respective groups), and withdrawal of consent (1, 1, and 2 patients in the respective groups) reported most commonly; other reasons included change in surgical/anaesthetic plan or patient loss of eligibility.
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As shown in Table 1, the treatment groups were similar in terms of patient characteristics and other baseline characteristics including types of surgery, secondary diagnoses, types of rescue therapy used in the first 24 h after surgery, and risk factors for PONV. Among patients (<10%) who did not undergo open abdominal gynaecological surgery, procedures included cholecystectomy, hernia repair, intestinal resection, and prostatectomy. No significant interactions (P>0.1) were observed between treatment and investigative site, age, duration of surgery, or risk factors for PONV (smoking status, history of PONV, or history of motion sickness). Although randomization was stratified by gender, gender was not included in the model because <10% of patients were male.
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Efficacy
Complete response was achieved in 64% of patients in the aprepitant 40 mg group (odds ratio of aprepitant to ondansetron=1.4, lower bound of the 1-sided 95% CI=1.08), 63% in the aprepitant 125 mg group (odds ratio=1.4, lower bound of the 1-sided 95% CI=1.04), and 55% in the ondansetron group (Fig. 2). For both doses of aprepitant, the lower bound of the 1-sided 95% CI for the odds ratio was >0.65, indicating non-inferiority according to the prespecified criteria. The additional analysis using a more restrictive 2-sided CI confirmed the non-inferiority of both doses of aprepitant when compared with ondansetron 4 mg (lower bound of 95% CI: aprepitant 40 mg vs ondansetron=1.02; aprepitant 125 mg vs ondansetron=0.99). The lower bound of the 95% CI for the odds ratio of aprepitant 125 mg vs ondansetron was <1 and thus did not meet the superiority criterion. Therefore, according to the step-down procedure, further testing was stopped for the complete response endpoint.
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The percentage of patients with no vomiting over 0–24 h was significantly higher in both the aprepitant 40 mg (84%) and the aprepitant 125 mg group (86%) than in the ondansetron group (71%); the odds ratios were 2.1 for aprepitant 40 mg vs ondansetron and 2.5 for aprepitant 125 mg vs ondansetron (P<0.001 for both ratios) (Fig. 3).
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As shown in Figure 3, both aprepitant groups were also superior to ondansetron for the secondary endpoint of no vomiting over 0–48 h (82% for aprepitant 40 mg, 85% for aprepitant 125 mg, and 66% for ondansetron; P<0.001). Odd ratios for the 0–48 h comparisons were 2.1 (aprepitant 40 mg vs ondansetron) and 2.8 (aprepitant 125 mg vs ondansetron) (P<0.001 for both ratios). Kaplan–Meier curves showed that compared with ondansetron, aprepitant delayed the time to first vomiting episode (P<0.001 based on the log-rank test) (Fig. 4).
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The treatment groups were similar in terms of no use of rescue therapy in the 0–24-h time interval (Table 2). In the Poisson regression analysis, in which rates of incidence of vomiting were adjusted for use of rescue therapy, the ratio of episodes of vomiting was 1:2 for aprepitant 40 mg vs ondansetron and 1:2 for aprepitant 125 mg vs ondansetron. Because it has been reported in the literature that a second (i.e. rescue) dose of ondansetron may not be effective in patients who have already received ondansetron as prophylaxis,26 a subanalysis was performed to examine the effect of ondansetron as rescue after ondansetron as prophylaxis. Among patients in the ondansetron group who took any rescue therapy, the no-vomiting rates were not significantly different among those rescued with ondansetron (no vomiting=74%), those rescued with other medications (no vomiting=77%), and those who used any type of rescue (ondansetron or other medication) (no vomiting=76%).
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The distribution of peak nausea scores was lower in both aprepitant groups vs ondansetron (P<0.05 for both comparisons) (Table 2). More patients in the aprepitant groups had no significant nausea (VRS
4), when compared with the ondansetron group; the odds ratios, favouring aprepitant, were 1.4 (95% CI: 1.0–2.0) for aprepitant 40 mg and 1.3 (95% CI: 1.0–1.9 ) for aprepitant 125 mg. Also, in patients who did not need rescue in the first 24 h, the peak nausea score was lower in the aprepitant 40 mg group when compared with ondansetron, with about 68% of these patients reporting a peak nausea score of 0 in the aprepitant 40 mg group vs about 60% of patients in the ondansetron group.
Tolerability
A summary of AEs is displayed in Table 3. There were no significant between-treatment differences in the incidence of AEs. Four patients (three in the aprepitant 40 mg group and one in the aprepitant 125 mg group) had a serious AE consistent with respiratory depression or excessive sedation, but none of these was considered related to study drug. One serious laboratory AE (increased liver transaminase levels) was reported for a patient in the ondansetron group. The most commonly reported AEs (>5%) were pyrexia, constipation, headache, and bradycardia (Table 3); rates were similar across groups. The treatment groups did not differ in terms of awakening time, duration of recovery from anaesthesia, or percentages of patients with QTc interval prolongations at 24 h after surgery (QTc interval data shown in Table 3).
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Discussion |
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The present study was the second of two trials characterizing the efficacy and tolerability of the NK1 antagonist aprepitant, when orally administered, in a large surgical population who received volatile anaesthetics. For clarity in distinguishing effects of aprepitant vs ondansetron without the potential confounding influence of other prophylactic antiemetics, the study was designed as a comparison of monotherapies. As was observed in the previous study,18 aprepitant provided protection similar to that of ondansetron on the complete response endpoint (no vomiting and no use of rescue therapy over 0–24 h). Also, both doses of aprepitant were significantly better than ondansetron for the prevention of vomiting over 0–24 h. The improved antiemetic efficacy of aprepitant was maintained over 0–48 h, consistent with the short half-life of ondansetron and the longer duration of action of aprepitant (half-life 9–13 h).17 19 Patients taking aprepitant were more than twice as likely to be protected from vomiting when compared with patients taking ondansetron, and aprepitant delayed the time to first vomiting compared with ondansetron. The superiority of aprepitant on the no vomiting endpoint was still apparent in an analysis, which adjusted for use of rescue therapy. Although no formal statistical comparisons between the two aprepitant doses were performed, they appeared to have similar efficacy, suggesting a plateau in response.
Two other aspects of the study results that were of interest concerned: (1) the possible lack of effectiveness of ondansetron as rescue for patients whose initial antiemetic was ondansetron,26 and (2) the timing of administration of prophylactic ondansetron. A subanalysis performed to assess the first of these considerations showed that in this study, vomiting in the ondanestron group was not significantly affected by the type of rescue therapy given (ondansetron vs any other medication including droperidol or dexamethasone). With regard to the second consideration, some small studies have shown that timing of the initial prophylactic dose of ondansetron (i.e. giving ondansetron at the end of surgery rather than before induction) may increase its antiemetic efficacy.27 Because the design of the present study required that prophylactic ondansetron be given before induction according to the product label, it cannot be determined what effect, if any, the timing of administration may have had on the efficacy of ondansetron.
As a more subjective endpoint, nausea can be more difficult to measure than vomiting.28 Based on the VRS used in this population, aprepitant had better antinausea efficacy than ondansetron, as reflected by the significantly lower distribution of VRS scores with aprepitant. The profiles of VRS scores among groups also supported enhanced antinausea efficacy with aprepitant: more patients taking aprepitant had no nausea or no significant nausea, and the most severe level of nausea was reported more often in patients taking ondansetron. While rescue can influence vomiting, nausea can influence the use of rescue, and is subject to interpatient differences both in the experience of nausea itself, and in the threshold at which a patient requests rescue. The intricacies of these relationships pose particular challenges for assessment of total control of PONV.
In general, the incidence and profile of clinical and laboratory AEs, of which pyrexia, constipation, headache, and decreased haemoglobin were most common, were typical of a population of surgical patients and were comparable across groups. As aprepitant has an inhibitory effect on CYP3A4, it was anticipated that awakening time and/or duration of recovery from anaesthesia would be prolonged if aprepitant had a clinically significant interaction with midazolam or fentanyl, both of which are CYP3A4 substrates. However, awakening time and duration of recovery did not differ between the aprepitant and the active control, and there were no study-drug-related AEs consistent with respiratory depression or excessive sedation. On the basis of these results, ondansetron and aprepitant, a dose-dependent inhibitor of CYP3A4,17 did not appear to differ in terms of potential for interaction with CYP3A4-metabolized drugs commonly given to surgical patients, such as midazolam or fentanyl. Similarly, based on visual inspection of data for use of analgesics including opioid(s) across groups, there was no observable indication of a difference between treatments in terms of influence on mechanism(s) of pain.
In this study, the incidence of PONV in untreated patients is not known, but given the previously documented efficacy of aprepitant in the postoperative setting, and the fact that placebo-controlled trials may be unethical if patients in a high-risk population are assigned to receive placebo instead of an effective therapy, the use of a placebo group was not appropriate. Thus, the study demonstrated the improvements in protection against vomiting and nausea afforded by aprepitant when tested against a 5HT3 RA with previously established efficacy in this setting. Aside from enhanced patient comfort and the potential for earlier discharge from the recovery room,29 30 the clinical benefits of improved antiemetic protection are particularly relevant in settings where postoperative vomiting may lead to clinical complications, especially among patients who undergo specific surgeries such as retinal, oesophageal, or maxillary surgeries, or those who require jaw-wiring.29 31–37 Because the efficacy profile of aprepitant 40 mg was not clinically different from that of 125 mg, the 40 mg dose appeared to be adequate to provide improved PONV prophylaxis. Doses <40 mg have not been studied. Further study is needed to characterize the clinical profile of aprepitant in other settings such as primary prevention of PONV in children, treatment of established nausea and vomiting in surgical patients, and efficacy with non-volatile anaesthetic regimens, and its potential usefulness in combination with other antiemetics as a part of a multimodal prophylactic regimen.
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National Clinical Trials Registry number: NCT00090246 [ClinicalTrials.gov] (http://www.clinicaltrials.gov). Primary participants in the Aprepitant Protocol 091 Study Group were: Hector Javier Alfaro, MD; Ramon Alvarado, MD; Keith Allen Candiotti, MD; Jacques E. Chelly, MD; Yu-Fat Chow, MD; Beatriz Chung, MD; Ronaldo Lucio Range Costa, MD; Robert D'Angelo, MD; Pierre Diemunsch, MD; Leopold Eberhart, MD; Guido Fanelli, MD; Ulrich Frucht, MD; Tong Joo Gan, MD; Ralf Gebhard, MD; Fritz Gempeler, MD; Manoel J.B.C. Girao, MD; Daniel Guerrero, MD; Iliana Higareda, MD; Jonny Hobbhahn, MD; Greg Hobbs, MD; Michael Irwin, MD; Bupesh Kaul, MD; Boon Leng Lim, MD/Eugene Yew Ren Chin, MD; Francisco Lopez-Timoneda, MD; Helfried Metzler, MD/Wolfgang Gaurbe, MD; John E. Moodie, MD; Phillippe Olivier, MD; Thomas Pasch, MD; Beverly Philip, MD; Dirk Piorko, MD; Rodolfo Proietti, MD; Javier Pueyo-Villoslada, MD; Norbert Roewer, MD; Emmanuel Samain, MD; Timothy Short, MD; Carlos Silva, MD; Danilo Solera, MD; Marvin D. Tark, MD; Benjamin Tham, MD; Martin Tramer, MD; Maria Antonieta Valez, MD; Humberto Vargas, MD; Ricardo Watanabe, MD; Michael Zimpfer, MD.
Other contributors to the conduct of the study included: Victoria Acedo, MD; Rodrigo Aquino Castro, MD; C.W. Cheung, MD; Federico Duro, MD; A.S. Habib MB, BCh; Robert Knapp, DO; Rose Lanzo, CRTT, CRC; L.H.Y. Lee, ME; Boon Leng Lim, MD; Luis López-Olaondo, MD; Pedro Moñino, MD; London Lucien Peng Jin Ooi, MD; James Philip, MD; Marair Gracio Ferreira Sartori, MD; Alex Tiong Heng Sia, MD; N.C.H. Sun, MD; Benjamin Wai Lum Tham, MD; S.F. Tsang, MD; Francisco López-Timoneda, MD; Su Ling Yu, MD.
The authors wish to thank Dr Kevin Horgan for reviewing and providing helpful commentary on the manuscript, Dr Christopher Lines for assistance with revisions to the manuscript, Ms Arlene Taylor for assistance with the statistical analysis, and Ms Michelle Hinz for assistance in conducting the study.
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Declaration of interest. This study was funded by Merck and Co., Inc. (Sponsor), West Point, PA 19486, USA. Drs Diemunsch, Gan, Philip, Girao, Eberhart, Irwin, Pueyo and Chelly received funding Merck to perform the study. Drs Carides, Reiss, Evans and Lawson are employees of Merck and hold stock options or stock in Merck. 
Participating primary investigators are listed in Acknowledgements.
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References |
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