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Anesth Analg 2009; 108:299-307
© 2009 International Anesthesia Research Society
doi: 10.1213/ane.0b013e31818ca3ac
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ANALGESIA

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*{dagger}, Girish P. Joshi, MBBS, MD, FFARCSI{ddagger}, Frederic Camu, MD, PhD§, Sharon Pan, PhD||, and Raymond Cheung, PhD||

From the *Pharmacology and Anaesthesiology Unit, University of Western Australia Perth, Australia; {dagger}Department of Pain Medicine, Royal Perth Hospital, Perth, Australia; {ddagger}University of Texas Southwestern Medical Center, Dallas, Texas; §University of Brussels, Brussels, Belgium; and ||Pfizer Inc, New York, New York.

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{at}uwa.edu.au.

Abstract

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.

Parecoxib sodium (parecoxib; the inactive water-soluble 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 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 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 Fisher’s 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):

  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.


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  		Table 1. Summary of Each of 17 Parecoxib Clinical Surgical Studies Included in Integrated Analysis
 

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  		Table 1. Continued
 

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  		Table 2. Summary of Each of 15 Valdecoxib Clinical Surgical Studies Included in Integrated Analysis
 
For all studies, institutional review board and ethics committee approvals were obtained, and patients provided written informed consent (data on file, Pfizer Inc).2–4,18,19,20,22–33,35,36 Patient inclusion/exclusion criteria and details of the interventions have been reported previously for 11 parecoxib2–4,18,19,20,22–30 and 5 valdecoxib31–33,35,36 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 using Fisher’s 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 Fisher’s 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.

RESULTS

Patients and Demographics
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).


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  		Table 3. Demographic and Baseline Characteristics for the 17 Parecoxib Studies, 15 Valdecoxib Studies, and 32 Total Parecoxib and/or Valdecoxib Studies

 

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).


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  		Table 4. Parecoxib: Incidence of Any CV Thromboembolic Event (WHOART) in 17 Noncardiac Surgery Combined Studies With Parecoxib 20–80 mg TDD

 

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.


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  		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

 

DISCUSSION

The analysis reported here, using data from 8511 patients in 17 parecoxib and 15 valdecoxib placebo-controlled 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 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 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 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, low-dose aspirin significantly reduced shear stress-induced 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. 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.

Footnotes

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.

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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2009 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press