Pain Medicine

Section Editor: Spencer S. Liu

Cardiovascular Safety of the Cyclooxygenase-2 Selective

Inhibitors Parecoxib and Valdecoxib in the Postoperative
Setting: An Analysis of Integrated Data
Stephan A. Schug, MD, FANZCA,
FFPMANZCA*
Girish P. Joshi, MBBS, MD,
FFARCSI
Frederic Camu, MD, PhD
Sharon Pan, PhD!
Raymond Cheung, PhD!

BACKGROUND: Studies of parecoxib, the inactive prodrug of the cyclooxygenase-2

selective inhibitor valdecoxib, and valdecoxib for postoperative pain relief in
patients undergoing coronary artery bypass graft surgery revealed an increased
risk of cardiovascular (CV) adverse events compared with placebo. We conducted
this study to address whether parecoxib and valdecoxib increased CV risk in
noncardiac surgery patients.
METHODS: A pooled post hoc analysis was conducted using 2 large datasets: 17
controlled trials of parecoxib for noncardiac studies and 32 studies, including the 17
noncardiac parecoxib studies plus 15 studies of valdecoxib. The 32-study dataset
provided 95% power to detect a twofold increase in the incidence of CV adverse
events assuming a placebo group incidence of 1% (estimated from previous study
data), and 69% power to detect a twofold increase from a 0.5% incidence.
RESULTS: The incidence of total CV events for the 17 parecoxib studies was 0.44% (13
of 2966) in patients who received parecoxib and 0.37% (7 of 1915) in those receiving
placebo (P ! 0.20). In the analysis of 32 studies, the incidence of total CV events
was 0.40% (21 of 5285) in the parecoxib/valdecoxib group compared with 0.50%
(16 of 3226) in the placebo group (P ! 0.20). No significant differences in the
incidence of total or any individual CV event category were observed between the
parecoxib or parecoxib/valdecoxib and placebo groups in the two analyses. When
patients were stratified by number of baseline CV risk factors, no significant
difference in CV events was detected in parecoxib/valdecoxib patients compared
with placebo.
CONCLUSIONS: In the largest analysis of the CV risk of cyclooxygenase selective
inhibitors or nonsteroidal antiinflammatory drugs for perioperative pain management, parecoxib and valdecoxib were not found to increase the risk of CV adverse
events after noncardiac surgery.
(Anesth Analg 2009;108:299 307)

arecoxib sodium (parecoxib; the inactive watersoluble prodrug of the cyclooxygenase-2 [COX-2] selective inhibitor valdecoxib) is a parenteral COX-2
selective inhibitor.1 This drug, currently under investigation in the United States, is registered in Europe
From the *Pharmacology and Anaesthesiology Unit, University
of Western Australia Perth, Australia; Department of Pain Medicine, Royal Perth Hospital, Perth, Australia; University of Texas
Southwestern Medical Center, Dallas, Texas; University of Brussels, Brussels, Belgium; and !Pfizer Inc, New York, New York.
Accepted for publication August 27, 2008.
Supported by Pfizer Inc. Editorial support was provided by C.
Scott, MD, of PAREXEL and was funded by Pfizer Inc.
S.A.S. receives research funding and/or acts as a consultant for
several pharmaceutical companies, including Pfizer Inc. G.J. has
received research grants and honoraria from Pfizer Inc. F.C. acts as
consultant for several pharmaceutical companies, including Pfizer
Inc. S.P. and R.C. are employees of Pfizer Inc.
Address correspondence and reprint requests to Stephan A.
Schug, MD, FANZCA, FFPMANZCA, Department of Pain Medicine, Pharmacology and Anesthesiology Unit, Royal Perth Hospital,
Box X2213 GPO, Perth WA 6847, Australia. Address e-mail to
stephan.schug@uwa.edu.au.
Copyright 2008 International Anesthesia Research Society
DOI: 10.1213/ane.0b013e31818ca3ac

Vol. 108, No. 1, January 2009

and parts of Australasia for short-term use in the

treatment of postoperative pain at a maximum daily
dose of 80 mg. Parecoxib is an effective analgesic and
has a role in multimodal analgesia; it reduces opioid
requirements, improves pain relief on movement, and
reduces opioid-related adverse effects in various major surgery models.2 4 In contrast to nonselective
nonsteroidal antiinflammatory drugs (NSAIDs), it
does not increase the incidence of gastrointestinal
ulcerations with short-term use.5,6 Additionally, parecoxib does not interfere with platelet function,7 which
is particularly advantageous for surgical procedures
in which excessive bleeding poses safety risks to the
patient.
Data that suggest an increased risk of cardiovascular (CV) thromboembolic events with daily, long-term
use of COX-2 selective inhibitors led to the withdrawal
of rofecoxib in 2004 and of valdecoxib in 2005, and
caused general concerns about the use of COX-2
selective inhibitors.8 10 Subsequently, clinical studies
and epidemiologic surveys supported the possible
existence of a class effect, including not only COX-2
299

selective inhibitors but also nonselective NSAIDs, by

which regular use of these compounds may be associated with an increased risk of CV events.10 17
For parecoxib, the general level of concern was
heightened by the increased incidence of CV adverse
events in two short-term coronary artery bypass graft
(CABG) studies.18,19 Because patients undergoing
CABG are at particular risk of CV adverse events, the
results of these two studies could not be generalized to
noncardiac surgical patients. Therefore, a prospective
study of parecoxib followed by valdecoxib, using a list
of predefined, adjudicated, clinically relevant adverse
events (CRAEs), was conducted to determine whether
this risk extended to patients undergoing major noncardiac surgery.4 However, this study was underpowered
to show significant differences in CV thromboembolic
CRAEs in isolation because of the relatively low incidence of these events in noncardiac surgery patients. The
noncardiac surgery study,6 as well as two further parecoxib studies (abdominal hysterectomy20 and total hip
arthroplasty [Study 067, data on file, Pfizer Inc]), did not
show a significant difference in CV thromboembolic
CRAEs between parecoxib-treated and placebo-treated
patients. Therefore, it remains unclear whether patients
undergoing noncardiac surgery are exposed to an increased risk of CV thromboembolic events by the use of
parecoxib and/or valdecoxib.21
A larger sample size is required to answer the
critical question of whether the increased risk of CV
thromboembolic events in CABG can be generalized
to noncardiac surgery patients. To achieve sufficient
power, i.e., 80%, using Fishers exact test with a 5%
two-sided significance level, to exclude a doubling of
CV events from a demonstrated baseline of 1%, a
further prospective study would require a sample size
in the order of 5000 (2500 in each group). As this
recruitment target is unfeasible, an alternative method
to gain relevant data for these patient numbers was to
pool existing parecoxib study data.
Here we report the results of a post hoc pooled
analysis of CV safety data from all clinical studies of
parecoxib in noncardiac surgery completed up to
2004. The goal of the analysis was to include data on
sufficient patients to provide the statistical power to
identify small differences in the incidence of these rare
adverse events. In addition, because valdecoxib is the
active moiety of parecoxib, a second analysis was
conducted pooling data from all studies in which oral
valdecoxib was used after noncardiac surgery with
data from the parecoxib-only studies to achieve the
highest possible statistical power.

METHODS
Study Design
Data Sets
Two post hoc analyses of pooled CV safety data
(adverse events) were performed using the following
data sets provided by Pfizer (Pfizer Inc, New York, NY):
300

Parecoxib CV Safety, Noncardiac Surgery

1. Integrated data from 17 studies in noncardiac

surgery (i.e., excluding the 2 CABG studies). This
analysis included all parecoxib studies completed by the cutoff date of December 31, 2004.
All dental surgery studies were excluded. In all
these studies, patients were randomized to receive either parecoxib 20 80 mg total daily dose
or placebo for up to 10 days postoperatively
(Table 1).
2. Integrated data from 15 valdecoxib noncardiac
studies (Table 2) plus the 17 parecoxib noncardiac surgery studies.
For all studies, institutional review board and ethics
committee approvals were obtained, and patients provided written informed consent (data on file, Pfizer
Inc).2 4,18,19,20,2233,35,36 Patient inclusion/exclusion criteria and details of the interventions have been reported previously for 11 parecoxib2 4,18,19,20,2230 and 5
valdecoxib3133,35,36 studies.

Categorization of Severe Adverse Events

In three of the most recently completed parecoxib

studies (Table 1, Studies 6, 15,20 and 174), CV adverse
events data were evaluated according to a set of
prespecified CRAEs that were adjudicated by a panel
of independent experts. To standardize the criteria for
reported CV adverse events from all the studies
included in the integrated analysis, CRAE categories
initially defined for the four studies listed above were
matched as closely as possible to preferred adverse
event terminology defined in the World Health Organization Adverse Reaction Terminology (WHOART)
Dictionary under any CV thromboembolic event.
CV thromboembolic events were subsequently divided into four categories:
1. Myocardial (cardiac arrest, circulatory failure,
myocardial infarction, myocardial ischemia, ventricular tachycardia)
2. Cerebrovascular
3. Vascular thrombosis (peripheral ischemia, deep
thrombophlebitis)
4. Pulmonary embolism.

Statistical Methods

CV adverse events data for the 17 parecoxib studies

and for the 17 parecoxib plus 15 valdecoxib studies
were pooled for these evaluations. Adverse events
were summarized using the number of patients with a
particular event rather than the number of times the
event occurred. Because an individual patient could
experience more than one adverse event in a particular CV adverse event category or WHOART body
system, the total number of patients with adverse
events cannot be calculated by summing individual
counts within the adverse event categories. Pairwise
comparisons between parecoxib or valdecoxib and
placebo groups for total CV thromboembolic events
and the four WHOART categories were performed
ANESTHESIA & ANALGESIA

Table 1. Summary of Each of 17 Parecoxib Clinical Surgical Studies Included in Integrated Analysis
Study number
(reference)

Surgery

Orthopedic surgery studies

122
Total knee replacement

2a,b

Total hip replacement

33a

Total hip arthroplasty

42a

Total knee arthroplasty

5b

Elective orthopedic

6b,c

Total hip arthroplasty or revision

7b

8b
9b
10b

Bunionectomy

Bunionectomy
Unilateral knee replacement
Bunionectomy

Gynecologic surgery studies

1123
Total abdominal hysterectomy or
myomectomy

1224

Total abdominal hysterectomy or

myomectomy

13b

Elective lower abdominal

gynecologic

1425

Elective lower abdominal

gynecologic

1520c

Gynecologic

162630

Laparoscopic cholecystectomy

Vol. 108, No. 1, January 2009

Comparators
Parecoxib 20 mg IV
Parecoxib 40 mg IV
Ketorolac 30 mg IV
Morphine 4 mg IV
Placebo IV
Parecoxib 20 mg IV
Parecoxib 40 mg IV
Ketorolac 15 mg IV
Morphine 4 mg IV
Placebo IV
Parecoxib 20 mg IV
Parecoxib 40 mg IV
Placebo IV
Parecoxib 20 mg IV
Parecoxib 40 mg IV
Placebo IV
Parecoxib 20 mg IV
Parecoxib 40 mg IV
Placebo IV
Parecoxib 20 mg IV
Parecoxib 40 mg IV
Parecoxib 20 mg IV bid
Parecoxib 20 mg IV qd
Placebo IV
Parecoxib 20 mg IV
(Day 1)
Parecoxib 40 mg IV
(Day 1)
Parecoxib 20 mg IV bid
Parecoxib 20 mg IV qd
Placebo IV
Parecoxib 40 mg IV, then 20 mg IV
Parecoxib 40 mg IV, then placebo IV
Placebo IV
Parecoxib 40 mg IV Placebo IV
Parecoxib 20 mg IV/IM
Parecoxib 40 mg IV/IM
Placebo IV/IM
Parecoxib 20 mg IV
Parecoxib 40 mg IV
Ketorolac 30 mg IV
Morphine 4 mg IV
Placebo IV
Parecoxib 20 mg IV
Parecoxib 40 mg IV
Ketorolac 30 mg IV
Morphine 4 mg IV
Placebo IV
Parecoxib 20 mg IV
Parecoxib 40 mg IV
Placebo IV
Parecoxib 40 mg IM
Morphine 6 mg IM
Morphine 12 mg IM
Placebo IM
Parecoxib 40 mg IV, then 20 mg IV
Parecoxib 20 mg IV bid
Placebo IV bid
Parecoxib 40 mg IV
Placebo IV

Single
dose, n
43
42
42
42
39
43
44
40
38
39

69
67
67
479
479

Multiple
dose, n

32
30
25
65
67
63
65
67
63

161
159
159

459
459

116 (total)

39
38
41
42
42
40
41
42
40
45

62
62
70
70

134
129

152
151
151
127
117
124
550 (total)

32
22
32

216 (total)

422
211
201
(Continued)

2008 International Anesthesia Research Society

301

Table 1. Continued
Study number
(reference)

Surgery

Major noncardiac surgery study

174c
Major orthopedic or general

Comparators

Single
dose, n

Multiple
dose, n

Parecoxib 40 mg IV, then 20 mg IV

Parecoxib 20 mg IV q12h
Placebo IV

1062
533
529

IV, intravenous; IM, intramuscular; TDD, total daily dose.

a
Only in these 3 multiple-dose studies (study numbers 2, 3 and 4) did patients receive parecoxib 80 mg TDD. In study 2, the 87 patients in the multiple-dose phase of the study received
up to 80 mg TDD for up to 5 days. In studies 3 and 4, patients received parecoxib 80 mg TDD in the first 24 h following surgery, and no more than 40 mg TDD on Day 2. In all other studies,
patients received parecoxib 20 60 mg TDD.
b
Studies 2 (020), 5 (037), 6 (067), 7 (077), 8 (078), 9 (081), 10 (089), and 13 (029), data on file, Pfizer Inc.
c
Studies in which cardiovascular adverse events were prespecified as independently adjudicated clinically relevant adverse events (study numbers 6, 15, 17).

using Fishers exact test with two-sided significance

levels of 5% without adjustment for multiple comparisons. Relative risks and 95% confidence intervals
based on the Cochran-Mantel-Haenszel test stratified
by study were calculated. The relative risk of each
respective event was expressed as the ratio of celecoxib to placebo. Comparisons of the incidence of
specific adverse events were not performed as the low
incidence of individual events in each group would
make such analyses unreliable.
In the study in 1050 major noncardiac surgery
patients (Table 1, study 17), the incidence of CRAEs,
including any CV thromboembolic events, was 5 of
525 (1%) in both the parecoxib and placebo groups.4
Unlike patients undergoing CABG surgery, this large
patient population was not considered to have an
increased risk of CV adverse events. Therefore, to
calculate the statistical power in these pooled analyses, a background placebo CV adverse event rate of
1% was assumed. Under this assumption, the power
to detect a twofold increase in the incidence of CV
thromboembolic events compared with placebo, using
Fishers exact test, is approximately 77% using the 17
noncardiac surgery studies (parecoxib sample size,
3000; placebo sample size, 1900), and 95% using the 32
studies (including the valdecoxib studies) (parecoxib
and valdecoxib sample size, 5300; placebo sample,
3200). Assuming an incidence of CV thromboembolic
events in the placebo group of 0.5%, the 32 studies
would provide 69% power to detect a twofold increase.

Incidence of CV Thromboembolic Adverse Events

The post hoc analysis of 17 parecoxib surgery studies

showed no statistically significant differences in the
total CV thromboembolic adverse events or individual
events according to WHOART categories, including
any myocardial, cerebrovascular, vascular thrombosis,
or pulmonary embolic events. Incidences were comparable in patients receiving parecoxib (13 of 2966;
0.44%) or placebo (7 of 1915; 0.37%) (P ! 0.20) (Table
4). In the 32 studies (17 parecoxib plus 15 valdecoxib)
analysis there were also no statistically significant
differences in the incidence of total CV thromboembolic events in the parecoxib/valdecoxib group (21 of
5285; 0.40%) compared with the placebo group (16 of
3226; 0.50%) (P ! 0.20).

Analysis of CV Risk Factors

In the analyses of the 17 parecoxib studies and 15

valdecoxib studies there were no significant differences between the treatment and placebo groups in
the incidence of CV CRAEs when the events were
stratified according to the number of preexisting severe risk factors (angina, coronary atherosclerosis,
myocardial infarction, hypertension, peripheral vascular disease, diabetes, hyperlipidemia, or peripheral
edema) per patient (Table 5). Furthermore, in the
pooled analysis of the 32 studies, there were no
significant differences in the incidence of CV thromboembolic events between the parecoxib and/or
valdecoxib and placebo groups when patients were
stratified by the number of preexisting CV risk factors.

RESULTS
Patients and Demographics

DISCUSSION

The 17 pooled parecoxib studies in noncardiac

surgery included 4881 patients; 2966 received parecoxib 20 80 mg total daily dose and 1915 received
placebo. The 15 pooled valdecoxib noncardiac surgery
studies included 3630 patients (valdecoxib, n " 2319;
placebo, n " 1311). Therefore, the second analysis of
32 studies included 8511 patients (parecoxib and/or
valdecoxib, n " 5285; placebo, n " 3226). There were
no significant differences between the parecoxib or
parecoxib/valdecoxib groups and the placebo group
with respect to baseline and demographic data (Table 3).

The analysis reported here, using data from 8511

patients in 17 parecoxib and 15 valdecoxib placebocontrolled clinical studies, is the largest analysis of CV
safety of any antiinflammatory drug used for perioperative pain relief. The most inclusive population,
encompassing patients in all 32 parecoxib and valdecoxib studies, provided 95% power to detect a doubling of CV thromboembolic events from a 1% placebo
rate and 69% power from a baseline of 0.5%. In the
pooled analyses of this large group of patients, there
was no association between short-term treatment with

302

Parecoxib CV Safety, Noncardiac Surgery

ANESTHESIA & ANALGESIA

Table 2. Summary of Each of 15 Valdecoxib Clinical Surgical Studies Included in Integrated Analysis
Study number
(reference)

Surgery

Orthopedic surgery studies

1a
Orthopedicb

231

Bunionectomy

332

Total knee replacement or

revision

433

Hip replacement

5a

Bunionectomy

6a

Bunionectomy

734
835

Anterior cruciate ligament

reconstruction
Bunionectomy

935

Bunionectomy

Gynecologic surgery studies

10a
Gynecologic

11a

Gynecologicc

12a

Gynecologic

Major noncardiac surgery

13a
General, abdominal, gynecologic,
or thoracic

1436

Inguinal hernia repair

15a37

Laparoscopic cholecystectomy

Single
dose, n

Multiple
dose, n

Valdecoxib 20 mg
Valdecoxib 40 mg
Oxycodone 10 mg/acetaminophen 1000 mg
Ibuprofen 400 mg
Placebo
Valdecoxib 20 mg
Valdecoxib 40 mg
Valdecoxib 80 mg
Placebo
Valdecoxib 20 mg
Valdecoxib 40 mg
Placebo
Valdecoxib 20 mg bid
Valdecoxib 40 mg bid
Placebo
Valdecoxib 40 mg
Oxycodone 10 mg/acetaminophen 1000 mg
Placebo
Valdecoxib 40 mg
Oxycodone10 mg/
Oxycodone 10 mg/acetaminophen 1000 mg
Placebo
Valdecoxib 40 mg
Placebo
Valdecoxib 20 mg qd
Valdecoxib 20 mg bid
Placebo
Valdecoxib 40/20 mg
Valdecoxib 40 mg/placebo
Placebo/placebo

56
57
55
55
NA

NA

Valdecoxib 20 mg
Valdecoxib 40 mg
Oxycodone 10 mg/acetaminophen 1000 mg
Ibuprofen 400 mg
Placebo
Valdecoxib 10 mg
Valdecoxib 20 mg
Valdecoxib 40 mg
Oxycodone 10 mg/acetaminophen 1000 mg
Ibuprofen 400 mg
Placebo
Valdecoxib 20 mg
Valdecoxib 40 mg
Oxycodone 10 mg/acetaminophen 1000 mg
Placebo

67
68
67
78
69
12
13
67
67
11
66
115
87
105
98

63
64
63
73
64

Valdecoxib 10 mg
Valdecoxib 20 mg
Oxycodone 10 mg/acetaminophen 1000 mg
Ibuprofen 400 mg
Placebo
Valdecoxib 20 mg bid
Valdecoxib 40 mg bid
Diclofenac SR 75 mg bid
Placebo
Valdecoxib 20 mg qd
Valdecoxib 20 mg bid
Placebo

45
45
47
42
47

10
13
27
25

68
69
65
67
157
156
155

Comparators

69
70
70
73
73
71
50
42

NA
66
66
69
88
87
84

179
177
157
160
156
127
122
125

NA " not available; SR " slow release.

a
Studies 1 (Study 032), 5 (072), 6 (071), 10 (011), 11 (033), 12 (084), 13 (010), and 15 (145), data on file, Pfizer Inc.
b
Study terminated early due to poor enrollment. 22 patients were randomized and received at least one dose of study medication. No efficacy or safety analyses were performed.
c
Study amended to discontinue enrollment of subjects in the valdecoxib 10 and 20 mg and ibuprofen groups.

Vol. 108, No. 1, January 2009

2008 International Anesthesia Research Society

303

Table 3. Demographic and Baseline Characteristics for the 17 Parecoxib Studies, 15 Valdecoxib Studies, and 32 Total Parecoxib
and/or Valdecoxib Studies
17 Parecoxib studies
Placebo
(n " 1915)
Age, yr
Mean (sd)
Range
Female, n (%)
Race, n (%)
White
Black
Asian
Hispanic
Other
Not listed

15 Valdecoxib studies

32 Total parecoxib and/or

valdecoxib studies

Parecoxib 2080
Valdecoxib 2080
Parecoxib and/or
mg TDD
Placebo
mg TDD
Placebo valdecoxib 2080 mg
(n " 2966)
(n " 1311)
(n " 2319)
(n " 3226)
TDD (n " 5285)

50.3 (15.4)
1890
1450 (75.7)

51.0 (15.6)
1896
2250 (75.9)

46.2 (15.1)
1887
927 (70.7)

47.1 (15.1)
1788
1709 (73.7)

48.7 (15.4)
1890
2377 (73.7)

49.3 (15.5)
1796
3959 (74.9)

1460 (76.2)
156 (8.1)
111 (5.8)
27 (1.4)
32 (1.7)
129 (6.7)

2295 (77.4)
250 (8.4)
123 (4.1)
48 (1.6)
32 (1.1)
218 (7.3)

1024 (78.1)
154 (11.7)
14 (1.1)
46 (3.5)
13 (1.0)
60 (4.6)

1745 (75.2)
296 (12.8)
32 (1.4)
83 (3.6)
32 (1.4)
131 (5.6)

2484 (77.0)
310 (9.6)
125 (3.9)
73 (2.3)
45 (1.4)
189 (5.9)

4040 (76.4)
546 (10.3)
155 (2.9)
131 (2.5)
64 (1.2)
349 (6.6)

TDD " total daily dose.

parecoxib and/or valdecoxib and an increase in CV

thromboembolic events compared with placebo after a
variety of noncardiac surgery. The presence of and the
number of CV risk factors also did not seem to
increase the risk of CV thromboembolic events in
patients treated with either parecoxib and/or valdecoxib or placebo. While it is a post hoc analysis, a
strength of the analysis is that very few surgical
patients are lost to follow-up, unlike longer-term
arthritis studies. There is a high likelihood that all
major adverse events, e.g., CV thromboembolic
events, would be captured in these studies. One
limitation of this post hoc pooled analysis is that the
total number of CV events was extremely low in both
the active treatment and the placebo groups. Therefore, even with the power of the current post hoc
pooled analysis, the ability to make definitive statements regarding the CV safety of parecoxib and
valdecoxib is somewhat limited.
These results are consistent with and support the
findings of large prospective studies using prespecified
and independently adjudicated CV thromboembolic
end-points.4,20 The increased risk of CV thromboembolic
events associated with parecoxib and valdecoxib in two
CABG studies, which had raised concerns about the use

of COX-2 selective inhibitors in the perioperative setting,

does not seem to be generalizable to patients undergoing
noncardiac surgery. In the first of these 2 CABG studies,
parecoxib/valdecoxib was opioid-sparing and effectively relieved postoperative pain; however, there was
a disproportionate, though not statistically significant,
increase in the number of patients who experienced
a serious CV thromboembolic adverse event with
parecoxib/valdecoxib compared with placebo.18 As this
study was insufficiently powered to properly discern the
risk of serious CV thromboembolic adverse events, a
second CABG study was conducted using a list of
predefined, adjudicated CRAEs created by an independent panel of experts.19 This study showed a statistically
significant increase in the incidence of CV thromboembolic CRAEs in the parecoxib/valdecoxib treatment
group compared with the placebo group.
Some researchers have suggested that the increased
incidence of CV thromboembolic events was caused
by an imbalance in the pro- and antiplatelet aggregation influences through the selective inhibition of
COX-2 production of prostacyclin while sparing
COX-1 production of thromboxanes.16,38 Proponents
of this imbalance hypothesis have suggested that the
CABG, involving patients with the highest CV risk

Table 4. Parecoxib: Incidence of Any CV Thromboembolic Event (WHOART) in 17 Noncardiac Surgery Combined Studies With
Parecoxib 20 80 mg TDD
Body system adverse event
(WHOART), n (%)*
Any
Any
Any
Any
Any

Parecoxib 2080 mg TDD

(n " 2966)

Placebo
(n " 1915)

Relative risk
(95% CI)

13 (0.44)
4 (0.13)
3 (0.10)
3 (0.10)
4 (0.13)

7 (0.37)
2 (0.10)
1 (0.05)
3 (0.16)
1 (0.05)

1.230 (0.4783.165)
1.662 (0.27310.104)
1.454 (0.15114.014)
0.579 (0.0973.456)
2.472 (0.36116.941)

CV thromboembolic event
myocardial event
cerebrovascular event
vascular thrombosis event
pulmonary embolic event

If a patient had more than one adverse event within a body system, that patient is counted once in the overall incidence for that body system.
WHOART " World Health Organization Adverse Reaction Terminology; TDD " total daily dose; CI " confidence interval; CV " cardiovascular.
* P ! 0.20 for all comparisons.
P values from Fishers exact test.

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ANESTHESIA & ANALGESIA

Table 5. Incidence of CV Events per Number of CV Risk Factors, Following Treatment With Parecoxib 20 80 mg TDD or Valdecoxib
20 80 mg TDD for Noncardiac Surgery
Parecoxib versus placebo (17 studies)

Adverse event, n (%)*

With 0 CV risk factorsa
Treated patients
Any CV thromboembolic event
Any myocardial event
Any cerebrovascular event
Any vascular thrombosis event
Any pulmonary embolic event
With 1 CV risk factora
Treated patients
Any CV thromboembolic event
Any myocardial event
Any cerebrovascular event
Any vascular thrombosis event
Any pulmonary embolic event
With !2 CV risk factorsa
Treated patients
Any CV thromboembolic event
Any myocardial event
Any cerebrovascular event
Any vascular thrombosis event
Any pulmonary embolic event

Parecoxib
2080 mg Placebo
TDD n (%) n (%)

Relative risk
(95% CI)

Valdecoxib versus placebo

(15 studies)
Valdecoxib
2080 mg Placebo
TDD n (%) n (%)

Relative risk
(95% CI)

1873
5 (0.3)
0 (0.0)
1 (#0.1)
1 (#0.1)
3 (0.2)

1217
1 (#0.1) 4.041 (0.46934.804)
1 (#0.1)
NA
0 (0.0)
NA
0 (0.0)
NA
0 (0.0)
NA

1584
2 (0.1)
0 (0.0)
0 (0.0)
2 (0.1)
2 (0.1)

927
1 (0.1)
0 (0.0)
0 (0.0)
1 (0.1)
0 (0.0)

1.272 (0.08020.172)
NA
NA
1.272 (0.08020.172)
NA

679
5 (0.7)
3 (0.4)
1 (0.1)
1 (0.1)
1 (0.1)

445
5 (1.1)
1 (0.2)
1 (0.2)
2 (0.4)
1 (0.2)

0.598 (0.1782.015)
2.431 (0.22126.767)
0.459 (0.0316.801)
0.283 (0.0253.203)
0.455 (0.0375.522)

494
1 (0.2)
0 (0.0)
1 (0.2)
0 (0.0)
0 (0.0)

263
2 (0.8)
0 (0.0)
0 (0.0)
1 (0.4)
1 (0.4)

0.290 (0.0223.894)
NA
NA
NA
NA

414
3 (0.7)
1 (0.2)
1 (0.2)
1 (0.2)
0 (0.0)

253
1 (0.4)
0 (0.0)
0 (0.0)
1 (0.4)
0 (0.0)

1.904 (0.15223.837)
NA
NA
0.467 (0.01316.642)
NA

241
1 (0.4)
1 (0.4)
0 (0.0)
0 (0.0)
0 (0.0)

121
2 (1.7)
1 (0.8)
1 (0.8)
0 (0.0)
0 (0.0)

0.266 (0.0282.552)
0.516 (0.0357.599)
NA
NA
NA

TDD " total daily dose; CI " confidence intervals; CV " cardiovascular; NA " not applicable.
a
Angina, coronary atherosclerosis, myocardial infarction, hypertension, peripheral vascular disease, diabetes, hyperlipidemia, or peripheral edema.
* P ! 0.2 for all comparisons of parecoxib or valdecoxib versus placebo.
P value from Fishers exact test.

undergoing a high-risk procedure, was the canary in

the coal mine and that a similar increase in risk, albeit
smaller, must be assumed for non-CABG surgery.21
Because surgical stress and trauma increase circulating thromboxane levels, under the imbalance hypothesis, COX-2 selective inhibition would also increase
CV thromboembolic risk of non-CABG surgery patients. The results of this pooled analysis do not
support the imbalance hypothesis because the rates of
CV thromboembolic events were comparable between
patients treated with the COX-2 selective inhibitor
parecoxib and those who received placebo.
Furthermore, the imbalance hypothesis does not
hold in the CABG studies either, since all patients
received low-dose aspirin to inhibit COX-1.18,19 That
is, the CV thromboembolic risk in these CABG patients was increased even in the presence of COX-1
inhibition alongside COX-2 inhibition. In the first
study, aspirin was started by the time of study drug
administration and in the second study it was started
well before administration of study drugs. Therefore,
patients treated with parecoxib and/or valdecoxib in
these studies had reduced COX-1 and COX-2 activity
due to the presence of low-dose aspirin. This suggests
that the increased risk of CV thromboembolic events
after CABG surgery would extend to the nonselective
COX inhibitors.
Since the imbalance hypothesis is not consistent
with the results of this study, we present here an
Vol. 108, No. 1, January 2009

alternative, based on a recent study by Borgdorff et

al.39 We believe that the use of cardiopulmonary
bypass in the CABG studies is largely responsible for
the increase in CV thromboembolic risk associated
with the use of parecoxib. Borgdorff et al. showed that
in the presence of arterial stenosis, the high shear
stress associated with pump-assisted extracorporeal
circulation increased platelet aggregation.39 In this
experiment, continuous measurement of platelet aggregation in an extracorporeal shunt between a carotid
and femoral artery in rats showed that pretreatment
with parecoxib (selective inhibition of COX-2) and
high-dose aspirin (nonselective inhibition of both
COX-1 and COX-2) significantly increased shear
stress-induced platelet aggregation. In contrast, lowdose aspirin significantly reduced shear stressinduced platelet aggregation. However, enhancement
of pump-induced platelet aggregation by parecoxib
was not significantly altered by co-administration of
low-dose aspirin but was neutralized with a low dose
(1 mg/kg) of clopidogrel; higher doses of clopidogrel
progressively reduced (5 and 25 mg/kg) or completely prevented (50 mg/kg) platelet aggregation.
Borgdorff et al. proposed shear stress activation of von
Willebrand factor as the underlying mechanism for
increased platelet aggregation, which is consistent
with previous findings.40 Shear stress changes the
tertiary structure of von Willebrand factor, exposing
binding sites for glycoprotein Ib receptors in platelets.
2008 International Anesthesia Research Society

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Von Willebrand factor binding to these glycoprotein

Ib receptors results in platelet activation and increased
aggregation that are mediated by adenosine phosphate release and can be abolished by clopidogrel.
Co-administration of low-dose clopidogrel might
therefore enable patients with CV disease to benefit
from COX-2 inhibition without augmenting CV risk.
Most patients in the first CABG study (89%), and all
patients in the second study, used a cardiopulmonary
bypass pump. The high shear stress of the cardiopulmonary bypass pump probably resulted in increased
platelet aggregation when both COX-1 and COX-2
were inhibited (i.e., parecoxib administered in addition to low-dose aspirin).
Clearly, the imbalance hypothesis is untenable as
an explanation for the increased CV thromboembolic
risk seen in the CABG studies. Taken together, these
results suggest that the increased CV thromboembolic
risk in CABG patients extends to nonselective
NSAIDs, supporting the decision by the United States
Food and Drug Administration to contraindicate all
NSAIDs after this type of surgery.
This pooled analysis provides evidence that parecoxib and its active moiety, valdecoxib, administered
perioperatively, do not significantly increase the risk
of CV thromboembolic events, compared with placebo, in patients undergoing non-CABG surgery.
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