BMJ  2005;330:1370 (11 June), doi:10.1136/bmj.330.7504.1370

Primary care

Differences in outcomes of patients with congestive heart failure prescribed celecoxib, rofecoxib, or non-steroidal anti-inflammatory drugs: population based study

¹ Division of Clinical Epidemiology, Research Institute of McGill University Health Center, 1650 Cedar Avenue, Montreal, QC, H3G 1A4 Canada

Abstract

Objectives To compare the risk of death and recurrent congestive heart failure in elderly patients prescribed celecoxib, rofecoxib, or non-steroidal anti-inflammatory drugs (NSAIDs) and to determine whether there are class differences between celecoxib and rofecoxib.

Design Population based retrospective cohort study.

Setting Databases of hospital discharge summaries and prescription drug claims in Quebec.

Participants 2256 patients aged 66 or more prescribed celecoxib, rofecoxib, or a NSAID after an index admission for congestive heart failure between April 2000 and March 2002.

Main outcome measures Time to all cause death and recurrent congestive heart failure, combined and separately.

Results The risk of death and recurrent congestive heart failure combined was higher in patients prescribed NSAIDs or rofexocib than in those prescribed celecoxib (hazard ratio 1.26, 95% confidence interval 1.00 to 1.57 and 1.27, 1.09 to 1.49, respectively). The findings were similar when the outcomes were assessed separately. In pairwise analysis, the risks of death and recurrent congestive heart failure, combined and separate, were similar between patients prescribed NSAIDs and rofecoxib.

Conclusions Celecoxib seems safer than rofecoxib and NSAIDs in elderly patients with congestive heart failure. Differences were found among cyclo-oxygenase-2 inhibitors.

Introduction

The cardiovascular effects of non-steroidal anti-inflammatory drugs (NSAIDs) and cyclo-oxygenase-2 inhibitors have been the subject of much controversy. Rofecoxib has been consistently associated with an increased risk of myocardial infarction.^{1 2-5} Although most of the evidence to date shows no association between celecoxib and an increased risk of myocardial infarction,^{3 6-9} a meta-analysis² and a recent study¹⁰ have cast doubt. Whether cyclo-oxygenas-2 inhibitors have similar or different cardiovascular toxicities remains debatable.^{11 12}

Both NSAIDs and cyclo-oxygenase-2 inhibitors have renovascular side effects, all of which can exacerbate heart failure.^13-16 The cyclo-oxygenase-2 enzyme, however, is induced in the myocardium of the failing heart and is associated with myocardial scarring.^{17 18} Selective cyclo-oxygenase-2 inhibitors can therefore be cardioprotective at the level of the failing myocardium.

Clinically, NSAIDs have been associated with the onset and exacerbation of congestive heart failure.^19-21 Clinical information on the association between cyclo-oxygenase-2 inhibitors and heart failure is however, scarce.^22-25

Elderly patients are likely to be given cyclo-oxygenase-2 inhibitors for pain and inflammation as these drugs are thought to have fewer gastrointestinal side effects than NSAIDs.^{26 27} Yet the risk of cardiovascular disease increases with age. We assessed the effects of celecoxib, rofecoxib, and NSAIDs on the risk of death and recurrent congestive heart failure in elderly patients with known congestive heart failure and we determined whether there are class differences between celecoxib and rofecoxib.

Methods

Our cohort was derived from the database of discharge summaries for Quebec. Patients were eligible for inclusion if they were discharged with a diagnosis of congestive heart failure (code 428.x; international classification of diseases, 9th revision) between 1 April 2000 and 31 March 2002 (the index admission), they had been prescribed celecoxib, rofecoxib, or a NSAID during that time, and they were aged 66 or more at the time of discharge from the index admission. Celecoxib became available on the market in late 1999 and rofecoxib on 1 April 2000. We chose the starting date of 1 April 2000 to ensure the availability of both drugs. The age cut-off point ensured that all participants had at least one full year of observation in the database before entry into the study.

We used the Quebec database for claims for prescription drugs claims to determine exposure to drugs. This database contains information on all drug prescriptions for outpatients aged 65 or more.

The study groups consisted of patients exclusively given one or more prescriptions for celecoxib, rofecoxib, or any non-selective NSAID after the index admission. Patients in the NSAID group could have been dispensed more than one different non-selective NSAID during the study.

The primary outcome was the combined outcome of time to all cause death or to recurrent congestive heart failure. The secondary outcomes were time to all cause death and time to recurrent congestive heart failure assessed separately.

Patients were followed from the time of their first prescription to death, recurrent congestive heart failure, or end of the study (31 December 2002).

Statistical analysis
We generated descriptive statistics to compare patient characteristics according to exposure groups. To compare time to outcome we carried out Cox proportional hazards modelling. We adjusted the models for possible confounders, including age, sex, comorbidities, other drugs prescribed before the first prescription for a study drug, characteristics of the treating doctor or hospital, length of stay, year of exposure, acute myocardial infarction in the previous three years, time to first prescription, and episodes of congestive heart failure after the index admission but before the first prescription.

View larger version (28K): [in this window] [in a new window]   Fig 1 Kaplan-Meier analysis of time to recurrent congestive heart failure or death in patients prescribed celecoxib, rofecoxib, or non-steroidal anti-inflammatory drugs

 

Results

We identified 2256 patients admitted with a diagnosis of congestive heart failure between 1 April 2000 and 31 March 2002 (the index admission) who were given one or more prescriptions for a coxib or NSAID during that time. Of these, 717 (31.8%) received celecoxib, 869 (38.5%) received rofecoxib, and 280 (12.4%) received NSAIDs. Patient characteristics at the index date and prescribing patterns were well balanced between the groups (see bmj.com). Overall, 492 patients had recurrent congestive heart failure and 473 died (table).

View this table: [in this window] [in a new window]   Unadjusted rates of study events in patients with congestive heart failure who were prescribed celecoxib, rofecoxib, or non-steroidal anti-inflammatory drugs (NSAIDs)

 

The most commonly used NSAIDs were diclofenac (4.3%), naproxen (2.6%), indomethacin (1.8%), and ibuprofen (1.0%).

Significantly more patients prescribed celecoxib survived or remained free of recurrent congestive heart failure than those prescribed rofecoxib or NSAIDs (fig 1). The point of divergence occurred early and persisted over time. The difference in survival was persistently significant when assessed as a single end point (see bmj.com), and the trend was towards those prescribed celecoxib remaining free of recurrent congestive heart failure compared with those prescribed rofecoxib or NSAIDs (see bmj.com).

In adjusted analysis, we found a significantly higher risk of death or recurrent congestive heart failure in patients prescribed NSAIDs or rofecoxib than in those prescribed celecoxib (hazard ratio 1.26, 95% confidence interval 1.00 to 1.57 and 1.27, 1.09 to 1.49, respectively; fig 2). These increased risks persisted when death was assessed as a separate outcome (NSAIDs, 1.54, 1.17 to 2.04; rofecoxib, 1.44, 1.17 to 1.78). When recurrent congestive heart failure was assessed separately, the trend was towards an increase in risk (NSAIDs, 1.21, 0.92 to 1.60; rofecoxib, 1.17, 0.96 to 1.42).

View larger version (24K): [in this window] [in a new window]   Fig 2 Adjusted hazard ratios (95% confidence intervals) for death and recurrent congestive heart failure, combined and alone, according to exposure group

 
In pairwise analysis, the risk of death and recurrent congestive heart failure, combined and separate, was similar between patients prescribed NSAIDs and those prescribed rofecoxib (combined 0.99, 0.80 to 1.22, death only 1.07, 0.82 to 1.39, recurrent congestive heart failure only 1.04, 0.80 to 1.36; fig 2).

Discussion

The risk of death and recurrent congestive heart failure was higher in elderly patients prescribed non-steroidal anti-inflammatory drugs (NSAIDs) or rofecoxib than in those prescribed celecoxib. In pairwise analysis, we found similar risks of death and recurrent congestive heart failure in patients prescribed rofecoxib or NSAIDs.

An association between cyclo-oxygenase-2 inhibitors and congestive heart failure is emerging, but there seem to be intraclass differences. Data from a small prospective database for disease management suggests that patients who are prescribed a cyclo-oxygenase-2 inhibitor on discharge are more likely to be readmitted for congestive heart failure within a year compared with those not prescribed a cyclo-oxygenase-2 inhibitor (32.5% versus 22.0%, respectively, P < 0.05).²⁸ In that study, the risk of recurrent congestive heart failure differed between rofecoxib and celecoxib. In a drug safety database, rofecoxib was associated with significantly more reports of cardiac failure than celecoxib.²⁹ Finally, in a recent population based study of cyclo-oxygenase-2 inhibitors and congestive heart failure, users of rofecoxib and NSAIDs, but not celecoxib, had a higher risk of admission for congestive heart failure than controls not receiving NSAIDs.³⁰ In pairwise comparisons, they found a significantly higher risk of admission for congestive heart failure in patients prescribed rofecoxib than in those prescribed celecoxib or NSAIDs (adjusted rate ratio 1.8, 95% confidence interval 1.4 to 2.4 and 1.5, 1.1 to 2.1).

Our findings are consistent with these data and are unique because we studied high risk patients with known congestive heart failure and we found a lower risk of death, assessed alone and in combination with recurrent congestive heart failure, in patients prescribed celecoxib compared with those prescribed NSAIDs or rofecoxib. Celecoxib may be safer than NSAIDs in high risk patients and there may be important differences between cyclo-oxygenase-2 inhibitors. Differences in selectivity³¹ may, at least in part, explain the different results observed in patients prescribed celecoxib compared with those prescribed rofecoxib.

Our study has several limitations. Firstly, patients who were classified as not taking drugs may have been using over the counter aminosalicylic acid or ibuprofen. Such non-differential misclassification would, however, tend to bias the results towards the null. Secondly, by starting the study on the date that rofecoxib became available (1 April 2000), we included only incident users of rofecoxib but incident and prevalent users of celecoxib. We carried out a sensitivity analysis in which we included only new users of celecoxib (and excluded those with a prescription before 1 April 2000). Time to all cause death or recurrent congestive heart failure was similar to that reported in the main analysis (hazard ratio 1.27, 95% confidence interval 1.07 to 1.52 versus 1.27, 1.09 to 1.49).

No head to head comparisons in randomised trials are available to determine the relative risks between NSAIDs and cyclo-oxygenase-2 inhibitors. We used an observational design and compared a cohort of patients with congestive heart failure who used NSAIDs or cyclo-oxygenase-2 inhibitors, and we found that celecoxib was associated with a lower risk of death and recurrent congestive heart failure than were NSAIDs and rofecoxib. Since we had no unexposed group, we were unable to estimate whether, and by how much, celecoxib increases the risk of recurrent congestive heart failure and death compared with non-users of NSAIDs and cyclo-oxygenase-2 inhibitors.

What is already known on this topic Non-steroidal anti-inflammatory drugs (NSAIDs) increase the risk of congestive heart failure Little is known about the safety of cyclo-oxygenase-2 inhibitors in patients with congestive heart failure What this study adds Celecoxib seems to be a safer alternative to rofecoxib and NSAIDs in elderly patients with congestive heart failure Class differences seem to exist between NSAIDs and cyclo-oxygenase-2 inhibitors and between cyclo-oxygenase-2 inhibitors

---

This is the abridged version; the full version is on bmj.com

Editorial by Jüni et al and p 1366

Contributors: See bmj.com

Funding: MH and LP are funded by the Canadian Institutes of Health Research. LP is a William Dawson professor of medicine at McGill University. This study was funded by a grant from the Canadian Institutes of Health Research (No 122882).

Competing interests: None declared.

Ethical approval: Not required.

References

1. Graham DJ, Campen D, Hui R, Spence M, Cheetham C, Levy G, et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet 2005;365: 4996.
2. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001;286: 954-9.[Abstract/Free Full Text]
3. Ray WA, Stein CM, Daugherty JR, Hall K, Arbogast PG, Griffin MR. COX-2 selective non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease. Lancet 2002;360: 1071-3.[CrossRef][ISI][Medline]
4. Juni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA, Egger M. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet 2004;364: 2021-9.[CrossRef][ISI][Medline]
5. Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005;352: 1092-102.[Abstract/Free Full Text]
6. Konstam MA, Weir MR, Reicin A, Shapiro D, Sperling RS, Barr E, et al. Cardiovascular thrombotic events in controlled, clinical trials of rofecoxib. Circulation 2001;104: 2280-8.[Abstract/Free Full Text]
7. Reicin A, Shapiro D, Sperling RS, Barr E, Yu Q. Comparison of cardiovascular thrombotic events in patients with osteoarthritis treated with rofecoxib versus nonselective nonsteroidal anti-inflammatory drugs (ibuprofen, diclofenac, and nabumetone). Am J Cardiol 2002;89: 204-9.[CrossRef][ISI][Medline]
8. White WB, Faich G, Whelton A, Maurath C, Ridge NJ, Verburg KM, et al. Comparison of the thromboembolic events in patients treated with celecoxib, a cyclo-oxygenase-2 specific inhibitor, versus ibuprofen and diclofenac. Am J Cardiol 2002;89: 425-30.[CrossRef][ISI][Medline]
9. Mamdani M, Rochon P, Juurlink DN, Anderson GM, Kopp A, Naglie G, et al. Effect of selective cyclooxygenase 2 inhibitors and naproxen on short-term risk of acute myocardial infarction in the elderly. Arch Intern Med 2003;163: 481-6.[Abstract/Free Full Text]
10. Solomon SD, McMurray JJ, Pfeffer MA, Wittes J, Fowler R, Finn P, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005;352: 1071-80.[Abstract/Free Full Text]
11. Topol EJ. Failing the public health—rofecoxib, Merck, and the FDA. N Engl J Med 2004;351: 1707-9.[Free Full Text]
12. Fitzgerald GA. Coxibs and cardiovascular disease. N Engl J Med 2004;351: 1709-11.[Free Full Text]
13. Pope JE, Anderson JJ, Felson DT. A meta-analysis of the effects of nonsteroidal anti-inflammatory drugs on blood pressure. Arch Intern Med 1993;153: 477-83.[Abstract]
14. Johnson AJ, Nguyen TV, Day RO. Do nonsteroidal anti-inflammatory drugs affect blood pressure? A meta-analysis. Ann Intern Med 1994;121: 289-300.[Abstract/Free Full Text]
15. Brater DC, Harris C, Redfern JS, Gertz BJ. Renal effects of selective COX-2 inhibitors. Am J Nephrol 2001;21: 1-15.[CrossRef][ISI][Medline]
16. Perazella MA, Tray K. Selective cyclooxygenase-2 inhibitors: a pattern of nephrotoxicity similar to traditional nonsteroidal anti-inflammatory drugs. Am J Med 2001;111: 64-7.[ISI][Medline]
17. Wong SC, Fukuchi M, Melnyk P, Rodger I, Giaid A. Induction of cyclooxygenase-2 and activation of nuclear factor- in myocardium of patients with congestive heart failure. Circulation 1998;98: 100-3.[Abstract/Free Full Text]
18. Zhang Z, Vezza R, Plappert T, McNamara P, Lawson JA, Austin S, et al. COX-2-dependent cardiac failure in Gh/tTG transgenic mice. Circ Res 2003;92: 1153-61.[Abstract/Free Full Text]
19. Feenstra J, Heerdink ER, Grobbee DE, Stricker BH. Association of nonsteroidal anti-inflammatory drugs with first occurrence of heart failure and with relapsing heart failure: the Rotterdam Study. Arch Intern Med 2002;162: 265-70.[Abstract/Free Full Text]
20. Rodriguez LA, Hernandez-Diaz S. Nonsteroidal anti-inflammatory drugs as a trigger of clinical heart failure. Epidemiology 2003;14: 240-6.[CrossRef][ISI][Medline]
21. Page J, Henry D. Consumption of NSAIDs and the development of congestive heart failure in elderly patients: an underrecognized public health problem. Arch Intern Med 2000; 777-84.
22. Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib long-term arthritis safety study. JAMA 2000;284: 1247-55.[Abstract/Free Full Text]
23. Data presented to the FDA arthritis advisory committee, Feb 2001. www.fda.gov/ohrms/dockets/ac/01/briefing/3677b1_03_med.pdf (accessed 13 Apr 2005).
24. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;343: 1520-8.[Abstract/Free Full Text]
25. Data presented to the FDA arthritis advisory committee, Feb 2001. www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_01_merck.pdf (accessed 13 Apr 2005).
26. Lipsky PE, Abramson SB, Breedveld FC, Brook P, Burmester R, Buttgereit F, et al. Analysis of the effect of COX-2 specific inhibitors and recommendations for their use in clinical practice. J Rheumatol 2000;27: 1338-40.[ISI][Medline]
27. Tannenbaum H, Peloso PM, Russell AS, Marlow B. An evidence-based approach to prescribing NSAIDs in the treatment of osteoarthritis and rheumatoid arthritis: the second Canadian consensus conference. Can J Clin Phamacol 2000;7(Suppl A); A4-16.
28. Jassal DS, Howlett J, Cox JL. Are COX-2 inhibitors safe in congestive heart failure? American Heart Association: scientific sessions. Orlando, FL: Nov 9-12, 2003. Circulation 2003;108: 665.
29. Zhao SZ, Reynolds MW, Lejkowith J, Whelton A, Arellano FM. A comparison of renal-related adverse drug reactions between rofecoxib and celecoxib, based on the World Health Organization/Uppsala Monitoring Centre safety database. Clin Ther 2001;23: 1478-91.[CrossRef][ISI][Medline]
30. Mamdani M, Juurlink DN, Lee DS, Rochon PA, Kopp A, Naglie G, et al. Cyclo-oxygenase-2 inhibitors versus non-selective non-steroidal anti-inflammatory drugs and congestive heart failure outcomes in elderly patients: a population-based cohort study. Lancet 2004;363: 1751-6.[CrossRef][ISI][Medline]
31. FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001;345: 433-42.[Free Full Text]

(Accepted 29 April 2005)

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

Relevant Articles

Celecoxib seems to be the choice for congestive heart failure
BMJ 2005 330: 0. [Full Text]

COX 2 inhibitors, traditional NSAIDs, and the heart

Peter Jüni, Stephan Reichenbach, and Matthias Egger
BMJ 2005 330: 1342-1343. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

• Aneja, A., Farkouh, M. E. (2008). Review: Adverse cardiovascular effects of NSAIDs: driven by blood pressure, or edema?. Therapeutic Advances in Cardiovascular Disease 2: 53-66 [Abstract]  
• Zarraga, I. G. E., Schwarz, E. R. (2007). Coxibs and Heart Disease: What We Have Learned and What Else We Need to Know. J Am Coll Cardiol 49: 1-14 [Abstract] [Full text]  
• Luyten, F P, Geusens, P, Malaise, M, De Clerck, L, Westhovens, R, Raeman, F, Vander Mijnsbrugge, D, Mathy, L, Hauzeur, J P, De Keyser, F, Van den Bosch, F (2007). A prospective randomised multicentre study comparing continuous and intermittent treatment with celecoxib in patients with osteoarthritis of the knee or hip. Ann Rheum Dis 66: 99-106 [Abstract] [Full text]  
• Anning, P. B., Coles, B., Morton, J., Wang, H., Uddin, J., Morrow, J. D., Dey, S. K., Marnett, L. J., O'Donnell, V. B. (2006). Nitric oxide deficiency promotes vascular side effects of cyclooxygenase inhibitors. Blood 108: 4059-4062 [Abstract] [Full text]  
• Chaiamnuay, S., Allison, J. J., Curtis, J. R. (2006). Risks versus benefits of cyclooxygenase-2-selective nonsteroidal antiinflammatory drugs.. Am J Health Syst Pharm 63: 1837-1851 [Abstract] [Full text]  
• Gislason, G. H., Jacobsen, S., Rasmussen, J. N., Rasmussen, S., Buch, P., Friberg, J., Schramm, T. K., Abildstrom, S. Z., Kober, L., Madsen, M., Torp-Pedersen, C. (2006). Risk of Death or Reinfarction Associated With the Use of Selective Cyclooxygenase-2 Inhibitors and Nonselective Nonsteroidal Antiinflammatory Drugs After Acute Myocardial Infarction. Circulation 113: 2906-2913 [Abstract] [Full text]  
• Sooriakumaran, P (2006). COX-2 inhibitors and the heart: are all coxibs the same?. Postgrad. Med. J. 82: 242-245 [Abstract] [Full text]  
• Chan, A. T., Manson, J. E., Albert, C. M., Chae, C. U., Rexrode, K. M., Curhan, G. C., Rimm, E. B., Willett, W. C., Fuchs, C. S. (2006). Nonsteroidal Antiinflammatory Drugs, Acetaminophen, and the Risk of Cardiovascular Events. Circulation 113: 1578-1587 [Abstract] [Full text]  

Rapid Responses:

Read all Rapid Responses

Celecoxib is not a safer alternative in heart failure

Juan-Carlos Maldonado
bmj.com, 24 Jun 2005 [Full text]

Variations in frequency of concomitant prescriptions of coumarine anticoagulants and NSAIDs

Michal R. Pijak, et al.
bmj.com, 5 Jul 2005 [Full text]

Differences in the cardiovascular risk between NSAIDs and coxibs: the neglected role of pharmacokinetics and drug interactions

Michal R. Pijak, et al.
bmj.com, 6 Jul 2005 [Full text]