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A Randomized, Double-Blind Comparison of

the NK1 Antagonist, Aprepitant, Versus
Ondansetron for the...

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Ambulatory Anesthesia
Section Editor: Peter S. A. Glass

A Randomized, Double-Blind Comparison of the NK1

Antagonist, Aprepitant, Versus Ondansetron for the
Prevention of Postoperative Nausea and Vomiting
Tong J. Gan, MD*
Christian C. Apfel, MD, PhD
Anthony Kovac, MD
Beverly K. Philip, MD
Neil Singla, MD, PhD
Harold Minkowitz, MD
Ashraf S. Habib, MBBCh, MSc,
FRCA*
Jennifer Knighton, MS#
Alexandra D. Carides, PhD#
Hong Zhang, PhD#
Kevin J. Horgan, MD#
BACKGROUND: Antiemetics currently in use are not totally effective. Neurokinin-1
receptor antagonists are a new class of antiemetic that have shown promise for
chemotherapy-induced nausea and vomiting. This is the first study evaluating the
efficacy and tolerability of the neurokinin-1 receptor antagonist, aprepitant, for the
prevention of postoperative nausea and vomiting.
METHODS: In this multicenter, double-blind trial, we randomly assigned 805 patients
receiving general anesthesia for open abdominal surgery to a preoperative dose of
aprepitant 40 mg orally, aprepitant 125 mg orally, or ondansetron 4 mg IV.
Vomiting, nausea, and use of rescue therapy were assessed over 48 h after surgery.
Treatments were compared using logistic regression.
RESULTS: Incidence rates for the primary end point (complete response [no vomiting
and no use of rescue] over 0 24 h after surgery, tested for superiority of aprepitant)
were not different across groups (45% with aprepitant 40 mg, 43% with aprepitant
125 mg, and 42% with ondansetron). The incidence of no vomiting (0 24 h) was
higher with aprepitant 40 mg (90%) and aprepitant 125 mg (95%) versus ondan-
setron (74%) (P 0.001 for both comparisons), although between-treatment use of
rescue and nausea control was not different. Both aprepitant doses also had higher
incidences of no vomiting over 0 48 h (P 0.001). No statistically significant
differences were seen among the side effect profiles of the treatments.
CONCLUSIONS: Aprepitant was superior to ondansetron for prevention of vomiting
in the first 24 and 48 h, but no significant differences were observed between
aprepitant and ondansetron for nausea control, use of rescue, or complete response.
(Anesth Analg 2007;104:10829)

Judith K. Evans, MD#

Francasca C. Lawson, MD#

The Aprepitant-PONV Study

Group**

N ausea and vomiting are common postoperative

complications, and can occur in up to 80% of
patients at high risk for postoperative nausea and
vomiting (PONV) without antiemetic prophylaxis
From the *Department of Anesthesiology, Duke University
Medical Centre, Durham, North Carolina; Department of Anesthe-
siology and Perioperative Care, University of California, San Fran-
cisco, Medical Center at Mt. Zion, San Francisco, California;
University of Kansas Medical Center, Kansas City, Kansas; De-
partment of Anesthesiology, Perioperative and Pain Medicine,
Brigham and Womens Hospital, Boston, Massachusetts; Hunting-
ton Memorial Hospital, Clinical Management Services, Inc., Pasa-
dena, California; Memorial Hermann Memorial City Hospital,
Houston, TX; and #Merck Research Laboratories, Blue Bell,
Pennsylvania.
Accepted for publication February 2, 2007.
**Participating primary investigators in the Aprepitant Protocol
090 Study Group were Farshad Ahadian, MD; David Andres, MD;
Christian Apfel, MD; J. Todd S. Blood, MD; Keith Allen Candiotti,
MD; Jacques E. Chelly, MD, MBA, PhD; Paul Cook, MD; Robert
DAngelo, MD; Donald Edmondson, MD; Lee A. Fleisher, MD;
(1 4). However, currently available antiemetics, in-
cluding IV 5HT3 receptor antagonists, do not pro-
vide complete protection (5), and there is still a
Tong Joo Gan, MD; Ralf Gebhard, MD; Kevin Gingrich, MD;
Jeffrey A. Grass, MD; Scott Groudine, MD; John Hatridge, MD;
Timothy Houden, MD; Michael B. Howie, MD; Piotr K. Janicki,
MD; Daniel Katz, MD; Bupesh Kaul, MD; Robert Knapp, DO;
Anthony L. Kovac Jr., MD; Kathryn K. Lauer, MD; J. Lance
Lichtor, MD; Timothy Melson, MD; Harold Minkowitz, MD;
Kelly Myers, MD; Peter H. Norman, MD; Michael H. Pearman,
MD; Beverly K. Philip, MD; James Philip, MD; Neil K. Singla,
MD; Marvin Tark, MD; Paul F. White, PhD, MD; and Thomas A.
Witkowski, MD.
This study was funded by Merck and Co., Inc.
National Clinical Trials Registry number: NCT00090155 (http://
www.clinicaltrials.gov).
Address correspondence and reprint requests to Tong J. Gan,
MD, Department of Anesthesiology, Duke University Medical Cen-
tre, Durham, NC 27710. Address e-mail to gan00001@mc.duke.edu.
Copyright 2007 International Anesthesia Research Society
DOI: 10.1213/01.ane.0000263277.35140.a3

1082 Vol. 104, No. 5, May 2007

medical need for more effective therapies to prevent
PONV.
Substance P, a regulatory peptide that is the pre-
ferred endogenous ligand at neurokinin-1 (NK1) re-
ceptors, is found in the gastrointestinal tract (vagal
afferents) and areas of the central nervous system
thought to be involved in the vomiting reflex (includ-
ing the nucleus tractus solitarii and area postrema)
(6 9). Although 5HT3 receptor antagonists have ques-
tionable efficacy against centrally induced emesis,
nonpeptide NK1 receptor antagonists have demon-
strated activity against both peripheral and central
emetic stimuli in animal models (10 14). Evidence sug-
gesting the potential efficacy of NK1 receptor antagonists
against PONV was obtained in pilot studies of two other
compounds in this class that were assessed in patients
undergoing major gynecologic surgery (15,16).
Aprepitant is the first NK1 receptor antagonist
available for clinical use as an antiemetic (17). As part
of combination therapy with other antiemetics,
aprepitant is approved for use and recommended in
consensus guidelines for the prevention of chemo-
therapy induced nausea and vomiting (CINV) (18); the
clinical profile of aprepitant suggests that it may
provide benefit against PONV as well. Aprepitant is a
highly selective, brain-penetrating NK1 antagonist
with a long half-life of 9 12 h and preclinical efficacy
against opioid-induced emesis (11,12,17). The present
study is the first to evaluate the efficacy and side effect
profile of oral aprepitant for the prevention of PONV.
An active antiemetic, IV ondansetron, was chosen as
the control. Therefore, the objective of this study was
to compare the clinical profile of aprepitant versus
that of ondansetron. The primary efficacy hypothesis
was that in the 24 h after surgery, the proportion of
patients with complete response, defined as no vom-
iting and no use of rescue therapy, would be signifi-
cantly higher among those taking aprepitant than
among those taking ondansetron.
METHODS
Twenty-nine centers participated in this study
(protocol 090), conducted from September 26, 2003 to
November 24, 2004. Appropriate IRB approval was ob-
tained, and all patients gave written informed consent.
Eligible patients were at least 18-yr-old, were sched-
uled to undergo open abdominal surgery requiring an
overnight hospital stay, met criteria of ASA physical
status of I-III, and were scheduled to receive general
anesthesia including nitrous oxide with volatile anes-
thetics. Patients were excluded who were pregnant or
breast-feeding, undergoing surgery requiring routine
placement of a nasogastric or oral-gastric tube, or receiv-
ing spinal regional or propofol-maintained anesthesia.
Also excluded were those who had vomiting of any
organic etiology, had vomited for any reason within 24 h
of surgery, or had abnormal laboratory values as speci-
fied by the protocol (alanine aminotransferase or aspar-
tate aminotransferase 2.5 upper limit of normal,
Vol. 104, No. 5, May 2007
bilirubin 1.5 upper limit of normal, or creatinine
1.5 upper limit of normal). Medications metabolized
by CYP3A4 and known to have a narrow therapeutic
index were prohibited, and patients taking such medi-
cations who were unable to discontinue them for the
duration of the study were excluded.
Patients were allocated to a treatment group within
each clinical site using a computer-generated random
allocation schedule stratified according to gender. To
ensure blinding among staff employed by the sponsor
who were involved with the study, the randomization
schedule was generated by a statistician who was
otherwise uninvolved with the study. On the day of
surgery, patients were randomized to one of three
preoperative treatments: oral aprepitant 40 mg, oral
aprepitant 125 mg, or IV ondansetron 4 mg. Matching
placebos were used to maintain blinding. Blinded
allocation schedules and supplies of aprepitant were
provided by the sponsor, and each study site desig-
nated an unblinded pharmacist to receive, store, and
prepare the ondansetron and saline placebo.
Patients received aprepitant or placebo 13 h before
anticipated induction of anesthesia, and ondansetron
or placebo by push over 25 min before induction,
according to the prescribing information for ondanse-
tron. Anesthesia consisted of optional premedication
with a benzodiazepine; induction with any anesthetic;
opioids; neuromuscular blocking drugs; maintenance
of anesthesia with nitrous oxide (50%70%) with a
volatile anesthetic; and the reversal of neuroblockade
with neostigmine (25 mg) in combination with either
atropine or glycopyrrolate. Patients could not receive
additional prophylactic antiemetics within 24 h pre-
operatively, intraoperatively, or postoperatively, al-
though patients could request rescue antiemetics for
established PONV.
All intraoperative medications and the duration of
anesthesia were recorded. The time of last suture/staple
was recorded as T0 (hours). Efficacy was assessed at
0 48 h (at 0, 2, 6, 24, and 48 h) after surgery. Patients
were monitored continuously in the postanesthesia
care unit, and emetic episodes and/or use of rescue
therapy were recorded throughout the hospital stay.
An emetic episode was defined as one or more con-
tinuous episodes of vomiting (oral expulsion of stom-
ach contents) or retching (an attempt to vomit that is
not productive of stomach contents); distinct episodes
were those occurring at least 1 min apart. Nausea was
assessed at 2, 6, 24, and 48 h postoperatively, at any
time the patient complained of nausea, and immedi-
ately before administration of rescue medication. Pa-
tients rated nausea on an 11-point Verbal Rating Scale
(VRS), with 0 equal to no nausea and 10 equal to
nausea as bad as it could be. Rescue medication was
offered if the patient had more than one episode of
vomiting or retching, if the patient had nausea lasting
longer than 15 min, or if the patient requested it for
established nausea (VRS score 0) or vomiting.
2007 International Anesthesia Research Society 1083
 Safety was assessed by physical examinations and
laboratory tests, and included 12-lead electrocardio-
grams performed at baseline and 24 h postoperatively;
all adverse events were recorded until 14 days after
surgery. Additional safety assessments included
awakening time (interval between end of surgery and
patients ability to obey commands) and duration of
recovery from anesthesia (postanesthesia recovery
score of 8 on a 0 10 scale) (19).
Patients were discharged 24 h postoperatively
based on clinical criteria. For patients discharged
before 48 h, the study coordinator contacted the
patient at the 48-h timepoint to record emetic epi-
sodes, nausea VRS, and/or rescue therapy. Adverse
events occurring within 14 days of surgery were
documented at a follow-up visit or call required
within 3 wk after surgery.
The sponsor managed the data and performed the
analyses for this study, which were reviewed by the
primary authors and others. The primary efficacy end
point was the proportion of patients with complete
response, defined as no vomiting and no use of rescue
therapy, in the 24 h after surgery, to be tested for
superiority of aprepitant. Secondary end points were
no vomiting 0 24 h, no rescue therapy 0 24 h, and no
vomiting 0 48 h. The primary efficacy analyses were
conducted on a modified intent-to-treat (MITT) popu-
lation, which included all patients who received study
drug, underwent surgery under general anesthesia,
and had at least one posttreatment assessment. Treat-
ment comparisons were made with logistic regression
models that included terms for treatment and sites.
Although gender was a stratification factor in the
randomization, 10% of the patients were male; there-
fore, the model did not include gender as a factor. A
step-down procedure was used to account for mul-
tiple tests within the primary hypothesis (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. A
similar method was used to account for the two
dose-level comparisons for each secondary end point,
as well as for the multiple secondary end points
themselves. The single highest VRS score recorded for
each patient over 0 24 h was considered the indi-
vidual peak nausea score; treatment groups were
compared using Wilcoxons ranked sum test. A post
hoc analysis was performed to determine percentages
of patients in each treatment group with peak nausea
VRS scores in the range of 0 (i.e., no nausea) to 4 (no
significant nausea), based on recent research on nau-
sea categorization scales suggesting that a VRS score
of 4 is a relevant cutoff representing no nausea to mild
nausea (20). Kaplan-Meier curves were generated for
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 compared among
1084 Aprepitant versus Ondansetron for PONV Prevention
treatment groups using a Poisson regression analysis,
which included factors for use of rescue medication.
Based on a sample size of 240 evaluable patients per
treatment group, the study had 90% power to detect a
15 percentage-point difference between the aprepitant
125 mg group and the ondansetron group for the
primary end point, assuming a 50% response rate for
ondansetron and a rate of 65% for aprepitant 125 mg.
RESULTS
Patient Enrollment
Disposition of the 805 patients randomized into the
study is shown in Figure 1. All randomized patients
who received study drug (n 766) were included in
the tolerability assessments; data were excluded from
39 patients who either did not receive any study drug
(n 34) or who, due to incorrect preparation of the
vial for IV administration at the study site, received
either placebo for aprepitant and placebo for ondan-
setron, or active aprepitant and active ondansetron
(n 5). The efficacy analyses excluded these 39
patients plus another 14 patients who either did not
undergo surgery but did receive drug (n 1), did not
have posttreatment efficacy assessments (n 2), or
did not receive Vial B but received active drug in
Bottle A (n 11). An additional 19 patients, for whom
significant violations of study conduct and data col-
lection occurred at one site, were also excluded from
the efficacy analyses before unblinding occurred, al-
though safety data from these 19 patients were in-
cluded in the safety assessments.
No differences were noted among groups in terms
of reasons for discontinuation, and no patients discon-
tinued due to an adverse event. The treatment groups
also did not differ in terms of patient baseline charac-
teristics, including risk factors for PONV (Table 1).
Among patients (10%) who did not undergo gyne-
cologic surgery, procedures included prostatectomy,
intestinal resection, hernia repair, bladder surgery,
cholecystectomy, or nephrectomy.
Efficacy
No significant interactions were observed between
treatment and investigative site, age, duration of sur-
gery, or risk factors for PONV. As shown in Figure 2,
there was no significant difference in the percentage of
patients with no vomiting and no rescue (complete
response) over 0 24 h between aprepitant 40 mg (45%)
or 125 mg (43%) and ondansetron (42%; P 0.5 for
both odds ratios of aprepitant:ondansetron). Likewise,
in a post hoc sensitivity analysis accounting for the 19
patients excluded from the MITT analysis, the rates of
complete response did not differ among groups (45%,
44%, and 42% for aprepitant 40 mg, 125 mg, and
ondansetron, respectively; P 0.5 for both odds
ratios). Thus, the primary hypothesis that aprepitant
would have been superior to ondansetron with respect
to complete response was not met. Over 0 24 h, the
ANESTHESIA & ANALGESIA
Figure 1. Study flow chart.
treatments did not differ significantly in terms of no
use of rescue therapy (45%, 44%, and 46% for aprepi-
tant 40 mg, 125 mg, and ondansetron, respectively)
(Fig. 3). However, larger proportions of patients in
both aprepitant groups had no vomiting compared
with the ondansetron group (odds ratios 3.2 for
aprepitant 40 mg versus ondansetron and 6.8 for aprepi-
tant 125 mg versus ondansetron; P 0.001 for both
ratios) (Fig. 4). Similar results were observed for the
0 48 h interval (odds ratios 2.7 for aprepitant 40 mg
versus ondansetron and 6.9 for aprepitant 125 mg
versus ondansetron; P 0.001 for both ratios) (Fig. 4).
Vol. 104, No. 5, May 2007
When rates of incidence of vomiting were adjusted for
use of rescue therapy in the Poisson regression analysis,
the ratio of episodes of vomiting (aprepitant:ondansetron)
was 1:4 for aprepitant 40 mg and 1:7 for aprepitant 125 mg.
During the first 48 h after surgery, both doses of
aprepitant delayed the time to first vomiting com-
pared with ondansetron (P 0.001) (Fig. 5).
The distributions of peak nausea VRS scores were not
different across treatment groups (median 5.0 in all
groups; lower 25% 0.0 in all groups; upper 25% 7.5
in the aprepitant 40 mg group, 8.0 in the aprepitant 125
mg group, and 8.0 in the ondansetron group). Fifty
2007 International Anesthesia Research Society 1085
Table 1. Baseline Characteristics by Treatment Group, for All Patients Who Received Active Study Drug
Aprepitant 40 mg Aprepitant 125 mg Ondansetron 4 mg
(N 261) (N 252) (N 253)
Female (n; %) 245 (94) 238 (94) 239 (95)
Age (years)
Mean SD 46 11.2 44 9.4 45 11.2
Range 2283 2378 1882
Race (n; %)
African-American 45 (17) 63 (25) 49 (19)
White 185 (71) 161 (64) 167 (66)
Asian 3 (1) 4 (2) 6 (2)
Other 28 (11) 24 (10) 31 (12)
Type of surgery* (n; %)
Gynecologic 228 (92) 224 (94) 223 (91)
Other 20 (8) 15 (6) 23 (9)
Number of risk factors for PONV (n; %)
0 0 (0) 1 (0.4) 1 (0.4)
1 8 (3) 5 (2) 6 (2)
2 62 (24) 55 (22) 60 (24)
3 121 (46) 114 (45) 106 (42)
4 70 (27) 77 (31) 80 (32)
Nitrous oxide* (n; %) 245 (99) 234 (98) 243 (99)
Postoperative opioid use 024 h* (n; %) 247 (99.6) 238 (99.6) 244 (99)
Duration of anesthesia* (hr mean; SD) 2.0 1.0 2.0 1.0 2.2 1.2
History of PONV (n; %) 79 (30) 83 (33) 81 (32)
History of motion sickness (n; %) 76 (29) 62 (25) 64 (25)
Tobacco use (n; %)
Never 147 (56) 175 (69) 152 (60)
Ex-user 50 (19) 32 (13) 47 (19)
Current 64 (25) 45 (18) 54 (21)
ASA status (n; %)
I 55 (21) 64 (25) 61 (24)
II 171 (66) 152 (60) 160 (63)
III 35 (13) 36 (14) 32 (13)
* Modified intent-to-treat population (aprepitant 40 mg N 248; aprepitant 125 mg N 239 for duration of anesthesia, N 238; ondansetron N 246).
Nonsmoker; female; history of postoperative nausea and vomiting (PONV) and/or motion sickness; use of postoperative opioids.

Figure 2. Percentages of patients achieving complete re-
sponse (no vomiting and no use of rescue therapy) in the
first 24 h after surgery, by treatment group. For each group,
the error bar represents the value of the upper bound of the
95% confidence interval for the percentage of patients
achieving the end point.
percent of patients in the aprepitant 40 mg group and
49% of patients in the aprepitant 125 mg group had peak
scores 0 4, compared with 43% of patients in the ondan-
setron group. As for the primary end point, sensitivity
analyses performed for each secondary end point showed
that the between-treatment results were unchanged regard-
less of inclusion or exclusion of the 19 patients originally
excluded from the MITT efficacy analyses.
Safety
A summary of adverse events is displayed in Table
2. No significant differences were observed in the
incidences of serious clinical adverse events reported
in the three treatment groups. One patient in the
aprepitant 40 mg group with myeloproliferative dis-
order died 28 days postoperatively. The death was
determined by the investigator not to have been
related to study drug. One serious adverse event, a
case of mild constipation, which prolonged the hospi-
tal stay of a patient who received aprepitant 125 mg,
was considered related to study drug. Two patients (1
in the aprepitant 125 mg group and 1 in the ondanse-
tron group) had a serious adverse event consistent
with respiratory depression but neither was consid-
ered related to study drug, and there were no reported
serious adverse events consistent with excessive seda-
tion. There was no between-treatment difference in
the incidence of most of the common adverse events
including headache (Table 2). The treatment groups
did not differ significantly in terms of awakening
time, duration of recovery from anesthesia, or per-
centages of patients with QTc interval prolongations
on electrocardiograms performed 24 h after surgery
(Table 2).

1086 Aprepitant versus Ondansetron for PONV Prevention ANESTHESIA & ANALGESIA

Figure 3. Percentages of patients with no use of rescue
therapy in the first 24 h after surgery, by treatment group.
For each group, the error bar represents the value of the
upper bound of the 95% confidence interval for the percent-
age of patients achieving the end point.
Figure 4. Percent of patients with no vomiting 0 24 h after
surgery and percent of patients with no vomiting 0 48 h
after surgery, by treatment group. For each group, the error
bar represents the value of the upper bound of the 95%
confidence interval for the percentage of patients achieving
the end point. For 0 24 h, n 248 for aprepitant 40 mg, n
239 for aprepitant 125 mg, and n 246 for ondansetron 4
mg. For 0 48 h, n 247 for aprepitant 40 mg, n 236 for
aprepitant 125 mg, and n 245 for ondansetron 4 mg.
Figure 5. Kaplan-Meier curves for the time to first vomiting
during the 48 h following surgery. The time to first vomiting
was delayed by aprepitant; P 0.001 based on the log-rank test.
DISCUSSION
The NK1 antagonist, aprepitant, is currently used
for the prevention of CINV, but data suggest that
drugs of this class may also have efficacy in the
Vol. 104, No. 5, May 2007
prevention of PONV. This study compared aprepitant
with ondansetron, an active treatment widely used for
prevention of PONV, in patients undergoing open
abdominal surgery. Aprepitant was evaluated at two
doses (40 and 125 mg), selected based on earlier
studies of aprepitant for prevention of CINV (22,23);
however, the study was not designed formally to
compare these doses. Several risk factors were repre-
sented in the patient population, which consisted
mainly of women (94%); about one-third of patients
had a history of PONV, about two-thirds were non-
smokers, and all but four patients received postopera-
tive opioids. The primary hypothesisthat aprepitant
would be superior to ondansetron for complete re-
sponse 0 24 h after surgerywas not met.
Comparisons for each variable of the primary end
point (no vomiting and no use of rescue) showed that
aprepitant provided better protection against vomit-
ing in the initial 24 h after surgery. The difference
between aprepitant and ondansetron was even more
pronounced when antiemetic efficacy was assessed
over a longer period (0 48 h after surgery), consistent
with the shorter half-life of ondansetron compared
with that of aprepitant. Aprepitant also delayed the
time to first vomiting compared with ondansetron.
For the no-vomiting end points, efficacy may not
necessarily be attributable only to study drug, as some
patients who had no vomiting may have received
rescue therapy. However, an additional analysis that
accounted for use of rescue therapy showed that, on
average, four to seven episodes of vomiting were
recorded in the ondansetron group for every one
episode recorded in each of the aprepitant groups.
Furthermore, smaller studies have reported that on-
dansetron may be more effective if administered at the
end of surgery rather than before induction (24),
which suggests that the efficacy of ondansetron in the
present study may be less than what it might have
been if ondansetron had been given at the end of
surgery. However, the study was not designed to
assess this possibility, as the design called for ondan-
setron to be given before induction according to the
label.
By contrast with the incidence of no vomiting, the
groups were not different in terms of use of rescue
therapy, the other variable of complete response.
Although explicit criteria were provided regarding the
administration of rescue therapy, the perception of
nausea is subjective, and the frequency at which
rescue therapy was offered, or the threshold for ad-
ministration of rescue for nausea, may have differed
among institutions or clinical staff caring for the
patient. Thus, a patient with slight nausea may have
received rescue (and therefore failed the complete
response end point), whereas another patient who did
not take rescue despite moderate or severe nausea
may have achieved the complete response end point.
Indeed, of 289 patients who had nausea assessed
2007 International Anesthesia Research Society 1087
Table 2. Summary of Adverse Events (AEs)
Percentage of patients

Aprepitant 40 mg Aprepitant 125 mg Ondansetron 4 mg

(N 261) (N 252) (N 253)
With 1 clinical AE* 69 69 75
With drug-related clinical AEs* 4 4 6
With serious clinical AEs* 9 5 8
Discontinued due to a clinical AE* 0 0 0
With most common clinical AEs (10% in any
treatment group)
Pruritus 14.9 13.1 15.4
Constipation 10.3 8.3 9.1
Nausea 13.4 11.9 14.6
Pyrexia 4.6 7.1 10.3
With most common laboratory AEs (in 2% in any
treatment group)
Decreased hemoglobin 2.8 2.9 2.8
With QTc interval prolongation at 24 h (%)
30 ms 40.7 37.9 37.2
3060 ms 8.1 8.6 8.4
60 ms 0.8 1.3 1.3
All patients who took study drug were included in the tolerability analyses and displays.
* Pairwise treatment comparisons were made using Fishers exact test. Tests of significance were performed and the corresponding risk differences and 95% confidence intervals calculated using
a method by Miettinen and Nurminen (21); no multiplicity adjustment was used.
Considered by the investigator to be possibly, probably, or definitely related to study drug.
Nausea and vomiting were considered AE if they occurred after 48 h after surgery, or at any time if serious, drug-related, or resulted in discontinuation.
The 95% confidence interval (10.5, 1.2) for ondansetron versus aprepitant 40 mg did not include 0, whereas the confidence interval for ondansetron versus aprepitant 125 mg did include
0 (8.3, 1.9).
Among all patients with test results reported postbaseline (aprepitant 40 mg N 248; aprepitant 125 mg N 243; ondansetron 4 mg N 248).
Among randomized patients who took at least one dose of active study medication and had at least one postbaseline QTc measurement (N 236, 232, and 239 for the respective groups).

within 1 h before the administration of rescue medi-
cation, 71 patients (25%) had no significant nausea
(VRS 4); 114 (39%) had a VRS 57, and 104 (36%) had
a VRS 8. It is therefore possible that frequent use of
rescue therapy, or its variable relationship with nau-
sea, may have influenced the incidence of complete
response.
The distributions of peak nausea scores did not
differ significantly across groups, although the pro-
portion of patients in the aprepitant 40 mg group with
no significant nausea exceeded that in the ondanse-
tron group by 7 percentage points. These data suggest
that the antinausea effect of aprepitant may be at least
similar to that of ondansetron, which has been shown
to prevent nausea as well as emesis (25). Additional
analyses of nausea data will be included in a separate
report.
Minimizing the incidence of postoperative vomit-
ing has a range of potential benefits, including de-
creasing the likelihood of serious complications, such
as aspiration, and allowing the patient to be dis-
charged and/or to resume normal activities sooner.
Reducing the likelihood that a patient will vomit can
also be of particular importance after gastro-esophageal
surgery, neurosurgery, or procedures requiring wir-
ing of the jaw. Pharmacoeconomic benefits may also
be realized; a previous study on cost-analysis showed
that the incidence of vomiting determined the rate of
unexpected hospital admission and hence increased
costs (26). Thus, reducing the likelihood that a patient
1088 Aprepitant versus Ondansetron for PONV Prevention
will actually vomit can be expected to have direct and
favorable clinical consequences.
The adverse event profiles across all three groups
were typical of surgical patients and did not differ
significantly. Gastrointestinal disorders were the most
commonly reported serious adverse events. Among
all adverse events, pruritus, nausea beyond 48 h,
constipation, and decreased hemoglobin were the
most commonly reported and incidence rates did not
differ across groups. No between-treatment differ-
ences were seen for other laboratory assessments,
including electrocardiogram findings at 24 h after
surgery. Special attention was given to certain safety
variables in order to evaluate the possibility of a drug
interaction between aprepitant, which is a dose-
dependent CYP3A4 inhibitor (17), and other CYP3A4-
metabolized drugs commonly used in the perioperative
setting, such as fentanyl or midazolam. The findings
indicated that aprepitant did not appear to differ from
ondansetron in terms of potential influence on the
pharmacodynamics of midazolam or fentanyl.
In conclusion, aprepitant was generally well toler-
ated in this study, which assessed more than 700
patients undergoing general anesthesia. Although
aprepitant did not show superiority for the complete
response, nausea control and rescue antiemetic use, its
prevention of vomiting was better than that of ondan-
setron for both the 24- and 48-h postoperative periods.
Further studies of aprepitant are needed to demon-
strate efficacy in other populations including children.
ANESTHESIA & ANALGESIA
ACKNOWLEDGMENTS
The authors thank Dr. T. Reiss for his helpful comments on
the manuscript.
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