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Published Online, 27 June 2006, www.theannals.com, DOI 10.1345/aph.1G733.
 The Annals of Pharmacotherapy: Vol. 40, No. 7, pp. 1241-1247. DOI 10.1345/aph.1G733
© 2006 Harvey Whitney Books Company.
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ANTICOAGULATION

Does Celecoxib Potentiate the Anticoagulant Effect of Warfarin? A Randomized, Double-Blind, Controlled Trial

Francesco Dentali, MD

Research Fellow, Department of Medicine, McMaster University, Hamilton, ON, Canada

James D Douketis, MD FRCP(C)

Associate Professor, Department of Medicine, McMaster University

Karen Woods, RN

Nurse Coordinator, Department of Medicine, McMaster University

Lehana Thabane, PhD

Assistant Professor, Department of Clinical Epidemiology and Biostatistics and the Centre for Evaluation of Medicines, McMaster University

Gary Foster, PhD

Biostatistician, Department of Clinical Epidemiology and Biostatistics and the Centre for Evaluation of Medicines, McMaster University

Anne Holbrook, MD PharmD MSc FRCP(C)

Associate Professor, Departments of Medicine and Clinical Epidemiology and Biostatistics and the Centre for Evaluation of Medicines, McMaster University

Mark Crowther, MD MSc FRCP(C)

Associate Professor, Department of Medicine, McMaster University

Reprints: Dr. Douketis, St. Joseph's Healthcare, Room F-541, 50 Charlton Ave. East, Hamilton, ON L8N 4A6, Canada, fax 905/521-6068, jdouket{at}mcmaster.ca


   Abstract
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 Abstract
Methods
 Results
 Discussion
 Conclusions
 References
 
BACKGROUND: The management of patients who are receiving warfarin therapy and have musculoskeletal problems that require treatment with a nonsteroidal antiinflammatory drug (NSAID) is problematic because NSAID use may increase the risk for bleeding. Cyclooxygenase-2 selective NSAIDs such as celecoxib may be less likely to promote gastrointestinal bleeding; however, there are concerns that they could potentiate the anticoagulation effect of warfarin.

OBJECTIVE: To determine whether celecoxib potentiates the anticoagulant effect of warfarin, as measured by the international normalized ratio (INR).

METHODS: We performed a randomized, controlled, crossover trial to assess the effect on INR of celecoxib versus codeine (control treatment) in 15 patients who were receiving warfarin therapy and required analgesic treatment for osteoarthritis. During Phase 1 of the study, patients were randomly allocated to receive celecoxib 200 mg/day or codeine phosphate 7-15 mg 3-4 times daily for 5 weeks. During Phase 2 of the study, patients stopped the first study medication and started the other study medication; there was no drug-free interval between phases. Weekly INR testing was performed during the 10 week study period. Adopting the intent-to-treat principle, we used generalized estimating equations to analyze the data.

RESULTS: There was no significant difference in the mean INR values during each 5 week treatment period when patients received either celecoxib or codeine. There was, therefore, insufficient evidence to reject the hypothesis that these 2 treatments had an equal effect on the INR (mean difference [95% CI] 0.10 [-0.04 to 0.24]; p = 0.16) based on mean imputation. This finding was confirmed after we repeated the analysis with multiple imputations (mean difference [95% CI] 0.093 [-0.16 to 0.35]; p = 0.47).

CONCLUSIONS: Our results suggest that treatment with celecoxib does not potentiate the INR when taken with warfarin. Larger randomized trials are warranted to address the effects of coadministered warfarin and celecoxib on clinical outcomes.

Key Words: anticoagulant effect, celecoxib, warfarin

Published Online, June 27, 2006. www.theannals.com, DOI 10.1345/aph.1G733

The clinical management of patients who are receiving oral anticoagulants such as warfarin and who have musculoskeletal problems that require treatment with a nonsteroidal antiinflammatory drug (NSAID) is a common and challenging clinical scenario. Long-term warfarin therapy is widely used in approximately 2 million patients in North America, most frequently to prevent stroke in chronic atrial fibrillation.1,2 It is estimated that 15-30% of such patients also have musculoskeletal disease and may benefit from treatment with an NSAID.3,4

In patients taking warfarin, treatment with a nonselective NSAID such as naproxen or indomethacin is usually avoided because coadministration of a nonselective NSAID and warfarin confers an increased risk for life-threatening gastrointestinal bleeding.5 Treatment with acetaminophen may be only partially effective in alleviating joint pain, and acetaminophen may potentiate the anticoagulant effect of warfarin, although the mechanism is not clear and such potentiation appears to occur only with high doses.6,7 An alternative treatment is a cyclooxygenase-2 (COX-2) selective NSAID such as celecoxib, which has efficacy comparable to that of nonselective NSAIDs in alleviating joint pain and appears to be associated with a lower risk for gastrointestinal ulceration.8-10 However, celecoxib may potentiate the anticoagulant effect of warfarin, possibly through protein-binding interactions and because both drugs are metabolized in the liver by the CYP2C9 isoenzyme.11,12 Furthermore, there have been reports of excessive anticoagulation, bleeding complications, and death in patients receiving warfarin and celecoxib.13-16

We therefore conducted a randomized, controlled pilot trial in warfarin users with a painful musculoskeletal disease to determine whether celecoxib potentiates the anticoagulant effect of warfarin, as measured by the international normalized ratio (INR).


   Methods
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Results
 Discussion
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PATIENTS
We studied patients who were receiving long-term warfarin therapy and also required treatment for osteoarthritis. Patients were included in this study if they satisfied the following criteria: (1) age over 18 years; (2) use of warfarin therapy for at least 3 months with a dose administered to achieve a target INR of 2.0-3.0 or 2.5-3.5; (3) stable anticoagulation, defined as the last 2 consecutive INR measurements between 2.0 and 3.0 (± 0.2) or between 2.5 and 3.5 (± 0.2) during the preceding 1 month period; and (4) diagnosis of osteoarthritis of the knee, hand, hip, or spine for at least 3 months, requiring treatment with an NSAID or a non-NSAID analgesic for at least 10 weeks. Patients were excluded if they had one or more of the following: (1) active peptic ulcer disease; (2) gastrointestinal, intracranial, or body cavity bleeding in the last 6 months; (3) elevated liver enzymes (aspartate aminotransferase or alanine aminotransferase more than 3 times the upper limit of normal); (4) renal insufficiency (creatinine >150 µmol/L); or (5) cognitive impairment or uncontrolled psychiatric disorder. No concomitant antiinflammatory or other analgesic treatment was allowed during this study.

STUDY DESIGN
We undertook a randomized, double-blind, controlled, 2 phase crossover trial. In this pilot study, we originally planned to study 25 patients who would undergo 50 phases of treatment. The study took place at St. Joseph's Healthcare, Hamilton, Ontario, Canada, from January 2001 to June 2003 and was approved by the St. Joseph's Healthcare Research Ethics Board. All patients provided written informed consent. We compared celecoxib (experimental arm) with codeine (control arm). Codeine was chosen as the control intervention because it is an effective analgesic, does not potentiate the anticoagulant effect of warfarin, and is metabolized by mechanisms independent of warfarin.17,18 An alternative design comparing celecoxib and placebo was rejected because the use of a placebo in patients with symptomatic osteoarthritis, in whom analgesic treatment was required, was considered unethical.

Randomization was by a computer-generated random number sequence, and treatment allocation was by research personnel who were independent of the study. During the 2 phases of the trial, patients were randomly allocated to receive either celecoxib 200 mg daily or codeine phosphate 7-15 mg 3 or 4 times daily (titrated until pain was controlled) for each 5 week period, with INR testing performed weekly. An INR monitor, blinded to patients' treatment allocation, documented INR results and adjusted patients' warfarin dose according to a standardized nomogram (Appendix I). After the first 5 week treatment period, patients stopped the first study medication and started the second study medication, with no drug-free interval between the phases. During the second 5 week treatment period, INR testing was performed weekly and warfarin doses were adjusted according to a standardized warfarin nomogram. In all patients, venipuncture was used to obtain a blood sample for INR testing; all INR tests were performed in an accredited laboratory facility.

Treatment allocation was double-blinded by providing patients with 2 color-coded study medications (yellow and blue) during each 5 week treatment period. Neither the patient nor the study personnel administering the study drug were aware of whether the patient was receiving celecoxib or codeine. In each treatment period, the yellow agent (celecoxib or placebo) was taken as a fixed dose, and the blue medication (codeine or placebo) was taken as a variable dose as required to achieve pain control. Patients randomized to receive celecoxib took the fixed-dose (active yellow pill) and variable-dose (placebo blue pill) medication. Patients assigned to receive codeine took the fixed-dose (placebo yellow pill) and the variable-dose (active blue pill) medication up to 8 times daily to achieve pain control. Subjects underwent clinical monitoring by a nurse who dispensed the study drugs, performed weekly INR testing, and arranged clinic visits for the crossover phase of the trial. Pill counts ensured adherence to the fixed-dose agent and documented the amount of variable-dose study medication that was taken.

Patients were monitored for bleeding or adverse effects that might be related to the study medication. Factors that might influence the INR independent of those, such as new drug therapy, excessive alcohol intake, or acute illness, were monitored during the study. Use of drugs that might influence the INR was discouraged. All new drugs introduced during the study period were monitored closely for their effect on the INR.

STUDY OUTCOMES
For the primary outcomes, we planned to compare the mean INR values and the proportion of patients with excessive anticoagulation, defined by an INR higher than 4.5, during each 5 week treatment period while patients were receiving either celecoxib or codeine. For the secondary outcomes, we planned to determine the incidence of symptomatic thromboembolism, bleeding, or other adverse events that occurred during each 5 week treatment period with celecoxib or codeine. All outcomes were assessed by an investigator who was blinded to the treatment.

STATISTICAL ANALYSIS
Treatment allocation and flow throughout the study was summarized using a flow-diagram. The results of patient demographics and outcomes were summarized using descriptive summary measures expressed as mean ± SD for continuous variables and number and percent for categorical variables. All analyses and comparisons used the intent-to-treat (ITT) principle and, therefore, all patients who received at least one dose of assigned study medication were used in statistical analyses. All statistical tests were performed using 2 sided tests at the 0.05 level of significance.

To take advantage of multiple observations obtained over each 5 week treatment phase per patient, we used generalized estimating equations (GEE) assuming a first-order autoregressive correlation structure, which allows incorporation of the possible correlation between successive INR measurements within each patient.19 In accordance with the ITT principle, we used mean imputation to impute the missing INR values for each phase based on the mean treatment group INR. For comparative purposes, we also used the multiple imputation approach, which accounts for variability due to imputation in the results, to assess the robustness of the results to different methods of imputation.20 In all analyses, treatment group (celecoxib vs codeine) and treatment phase (1 vs 2) were considered fixed factors. The GEE results were expressed as coefficients, standard errors, corresponding 2 sided 95% confidence intervals, and associated p values (reported to 3 decimal places, with values <0.001 reported as <0.001). Goodness-of-fit was assessed by examining the model residuals using the {chi}2 test. All statistical analyses were performed using SAS software, Version 9.


   Results
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 Results
Discussion
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 References
 
PATIENT CHARACTERISTICS
Fifteen patients were eligible for data analysis (Figure 1). Our original target sample size of 25 patients was not attained because of a slower than anticipated rate of recruitment and funding limitations. In the 15 patients (8 men) studied, the mean age was 70.0 ± 13.5 years, and the mean baseline INR was 2.43 ± 0.45. Baseline patient characteristics are presented in Table 1. Weekly INR values for each patient are presented in Table 2 and mean INR values during each phase of treatment are presented in Figure 2.


Figure 1
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  		Figure 1. Patient enrollment and randomization.

 

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  		Table 1. Baseline Patient Characteristics

 

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  		Table 2. INR Values for Each Patienta

 

Figure 2
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  		Figure 2. Mean international normalized ratio (INR) values during each phase of treatment (black bars = celecoxib; white bars = codeine; lines connect medians).

 

STUDY OUTCOMES
Primary Outcomes
Based on the GEE results with mean imputation, there was no significant difference in the mean INR values during each 5 week treatment period when patients received either warfarin plus celecoxib or warfarin plus codeine. There was, therefore, insufficient evidence to reject the hypothesis that these 2 treatments had an equal effect on the INR (mean difference [95% CI] 0.10 [-0.04 to 0.24]; p = 0.16; goodness of fit {chi}2[146] 37.4; p > 0.999). This finding was consistent with the analysis using a generalized estimating equation on 10 data sets using multiple imputation (mean difference [95% CI] 0.088 [-0.15 to 0.32]; p = 0.46; average goodness of fit [across all 10 models] {chi}2[146] 48.73; p > 0.999). In terms of the proportion of patients with excessive anticoagulation, there was only one such outcome (INR 4.9), which occurred in a patient during treatment with celecoxib.

Secondary Outcomes
One patient had a cardiac arrest due to a myocardial infarction during treatment with codeine (INR 2.3 at the time of event). There were no episodes of bleeding during the study. Four patients discontinued the study medication prematurely: one developed dyspepsia during treatment with celecoxib, one developed constipation during treatment with codeine, and one experienced excessive anticoagulation. One patient was removed from the study at the end of Phase 1 because of poor adherence to the study protocol.


   Discussion
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 Abstract
 Methods
 Results
 Discussion
Conclusions
 References
 
The principal finding of this study is that, in patients receiving long-term warfarin therapy, coadministration of celecoxib for the treatment of osteoarthritis does not appear to have a significant effect on the stability of anticoagulation as measured by INR. Despite the small size of our trial, the INR values in celecoxib- and codeine-treated patients of 2.5 ± 0.58 and 2.4 ± 0.44, respectively, were remarkably similar and, statistically, it is unlikely that the results differed significantly (p = 0.95). Furthermore, if we disregard the order of treatments and consider the difference in the mean INR of the celecoxib and codeine phases of the trial, it is evident that this difference in INR values of 0.10 ± 0.29 is not clinically important in terms of altering the risk for thromboembolic or bleeding complications.21,22

We believe our findings are valid based on the following considerations. First, the study was a randomized and double-blind in which patients were their own control, thereby minimizing between-patient variability in the effect of treatment on the INR. Second, the primary outcome, namely, the INR measured during the celecoxib and codeine phases of treatment, was objective and determined without prior knowledge of treatment allocation. Third, our choice of control treatment (codeine) is unlikely to have any effect on INR stability during warfarin therapy and, in this regard, would be comparable to placebo. Further, we believe our findings are generalizable to clinical practice; we recruited consecutive, real-world patients who were comparable to those assessed in everyday clinical practice, were receiving warfarin therapy, and in whom there was a clinical indication for NSAID therapy.

Two other studies have assessed the effects of COX-2 NSAIDs on anticoagulation stability in patients receiving warfarin. One assessed the effects of coadministered celecoxib and warfarin in healthy volunteers.11 In this randomized trial, which involved 24 healthy adults (mean age 32.5 y; range 19-50), celecoxib did not significantly alter the steady-state pharmacokinetics of warfarin when administered to achieve a target prothrombin time of 1.2-1.7 times the prewarfarin prothrombin time (comparable to an INR range of 2.0-3.0). Another study was a randomized crossover trial assessing the effects of celecoxib 200 mg daily and rofecoxib 25 mg daily in 16 patients receiving warfarin.23 Celecoxib therapy was associated with a statistically significant 13% increase in the INR after one week of treatment, although the maximal difference in mean INR values ± SD before and after celecoxib treatment (2.5 ± 0.3 vs 2.8 ± 0.5, respectively) may not be clinically important. Furthermore, this study was limited by the lack of a control group of patients who were not using a COX-2 NSAID.

Limitations of our study should be addressed. First, we acknowledge that the small size, while allowing an assessment of celecoxib on an important predictor for bleeding (INR), was not designed to assess the effect of coadministered celecoxib and warfarin on bleeding and thromboembolic outcomes. Second, we cannot exclude a possible potentiating effect of celecoxib on INR stability with warfarin therapy if assessed in a larger population, although this outcome is unlikely based on finding that the 2 treatments had comparable effects on the INR (p = 0.95). Third, we acknowledge that there were a number of missing data points, due to missed INR tests. However, the results remained robust when assessed with statistical methods used in handling missing data. Finally, our small patient sample cannot exclude the possibility that celecoxib use could potentiate the INR through a pharmacogenetic drug interaction involving a CYP2C variant. However, such genetic polymorphisms, which may explain sporadic reports of warfarin-celecoxib drug interaction, are considered rare.13-16

We believe that our findings are relevant to patients receiving long-term warfarin therapy who also require treatment for osteoarthritis or other musculoskeletal disease.1,24 There are few management options available for such patients. Nonselective NSAIDs might be avoided because several agents can potentiate the anticoagulant effect of warfarin and coadministration of warfarin and a nonselective NSAID is associated with a 3- to 13-fold increased risk of gastrointestinal bleeding.5,25-31 Even treatment with a short, 5- to 10-day course of a nonselective NSAID is problematic because gastroduodenal ulceration can occur within days after starting treatment and is often clinically silent in elderly patients. In addition, the initial clinical manifestation may be life-threatening bleeding.32-35 Although acetaminophen is first-line treatment for degenerative osteoarthritis, it may have limited benefit in patients with inflammatory arthritis, gout, or bursitis.36,37

Our findings suggest that celecoxib may be considered as a treatment alternative to nonselective NSAIDs, as it is the only COX-2 selective NSAID available for clinical use in North America. However, clinicians should be cognizant that, despite our finding that the coadministration of celecoxib and warfarin does not potentiate the INR, this drug combination was found in one retrospective administrative database study to confer a 1.7-fold increased risk of upper gastrointestinal bleeding, which was comparable to the 1.9-fold increased risk of such bleeding with coadministered nonselective NSAIDs and warfarin.38 Furthermore, the administration of celecoxib 400 mg/day is associated with a 2.3-fold increased risk for myocardial infarction and other cardiovascular events; this risk is increased by 3.4-fold with a dose of 800 mg/day, thereby suggesting a dose-related risk.39 However, the risk for cardiovascular events with a 200 mg dose of celecoxib, which was used in this study and is the recommended dose for osteoarthritis, is not clear and may be less than the risk with higher doses.10,40 Overall, the potential therapeutic benefits of celecoxib should be weighed against the potential risks of gastrointestinal bleeding and cardiovascular events when considering treatment options in patients who are receiving warfarin and in whom there is an indication for treatment with an NSAID.40,41


   Conclusions
Top
 Abstract
 Methods
 Results
 Discussion
 Conclusions
References
 
Our results suggest that treatment with celecoxib does not potentiate the anticoagulant effect of warfarin. Larger randomized trials are warranted to address the effects of coadministered warfarin and celecoxib on clinical outcomes.


Appendix I. Warfarin Dosing Nomogram

INR
Action (warfarin dose)
Repeat INR
≤1.3 increase dose by 50% 1 wk
1.4 increase dose by 33% 1 wk
1.5–1.8 increase dose by 25% 1 wk
1.9 increase dose by 10% 1 wk
2.0–2.8 no change in dose 1 wk
2.9–3.1 decrease dose by 10% 1 wk
3.2–3.5 decrease dose by 25% 1 wk
3.6–3.7 decrease dose by 33% 1 wk
3.8–4.4 withhold warfarin for 1 day; decrease dose by 33% 1 wk
4.5–5.0 withhold warfarin for 2 days; decrease dose by 33% 3 days
5.1–6.0 withhold warfarin for 3 days; decrease dose by 33% 3 days
≥6.1
 determined by unblinded study physician
 1 day

INR = international normalized ratio


   Footnotes
 
Drs. Holbrook and Crowther hold Career Investigator Awards from the Canadian Institutes for Health Research.

We thank Terri Schnurr RN, Research Nurse, for her assistance with the randomization process.


   References
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 Results
 Discussion
 Conclusions
 References
 

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