Differences in outcomes of patients with congestive heart failure pres
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《英国医生杂志》
1 Division of Clinical Epidemiology, Research Institute of McGill University Health Center, 1650 Cedar Avenue, Montreal, QC, H3G 1A4 Canada
Correspondence to: L Pilote louise.pilote@mcgill.ca
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 an 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.
The cardiovascular effects of non-steroidal anti-inflammatory drugs (NSAIDs) and cyclo-oxygenase-2 inhibitors have been the subject of much controversy. Studies of NSAIDs, in particular naproxen, have shown decreases, increases, or no effects on the risk of ischaemic heart disease.1-7 Rofecoxib has been consistently associated with an increased risk of myocardial infarction.5 8-10 It was withdrawn when data from a trial on benign sporadic colonic adenomas showed a significant increase in the incidence of cardiovascular events compared with placebo (relative risk 1.92, 95% confidence interval 1.19 to 3.11).11 Although most of the evidence to date shows no association between celecoxib and an increased risk of myocardial infarction,9 12-15 a meta-analysis8 and a recent study16 have cast doubt. Whether cyclo-oxygenase-2 inhibitors have similar or different cardiovascular toxicities remains debatable.17 18
The role of cyclo-oxygenase-2 inhibition in congestive heart failure is complex. On the one hand, both NSAIDs and cyclo-oxygenase-2 inhibitors have various renovascular side effects, which include increased volume retention, oedema, and blood pressure, all of which can exacerbate heart failure.19-22 Data, however, suggest that differences exist between the two types of drugs as well as between the cyclo-oxygenase-2 inhibitors themselves, with some,23-25 but not all,26 studies showing that rofecoxib is associated with more renovascular side effects, including increased oedema and blood pressure, than are NSAIDs and celecoxib. On the other hand, the cyclo-oxygenase-2 enzyme is induced in the myocardium of the failing heart and is associated with myocardial scarring.27 28 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.29-31 Clinical information on the association between cyclo-oxygenase-2 inhibitors and heart failure is, however, scarce.32-35 In a recent population based study, users of rofecoxib and NSAIDs, but not celecoxib, had a higher risk of admission for congestive heart failure than controls not taking NSAIDs.36
Elderly patients are likely to be given cyclo-oxygenase-2 inhibitors for the management of pain and inflammation as these drugs are thought to have fewer gastrointestinal side effects than NSAIDs.37 38 Yet the risk of cardiovascular disease increases with age. It is therefore important to ascertain the cardiovascular effects of cyclo-oxygenase-2 inhibitors in elderly people at both the patient and the population level. 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
Information for our population based, retrospective, observational cohort study was derived from the database of hospital discharge summaries for Quebec. The reliability of the coding for congestive heart failure in administrative databases has been shown to be high.39 40 A similar cohort of patients with congestive heart failure has been used in other pharmacoepidemiological studies.39 41 42
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 that both drugs were available throughout the study. Patients were excluded if they were admitted to hospital for congestive heart failure in the preceding three years. The age cut-off point was determined on the basis of the availability of prescription records, to ensure that all participants had at least one full year of observation in the database before entry into the study.
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
Exposure to drugs
We used the Quebec database for prescription drugs claims to determine exposure to drugs. This database contains information on all drug prescriptions for outpatients aged 65 or more. It has been validated for the accuracy of prescription claims.43 It also contains information on vital status.44
The study groups consisted of patients exclusively given one or more prescriptions for celecoxib, rofecoxib, or any non-selective NSAID after the index admission. Other cyclo-oxygenase-2 inhibitors were not available in Quebec during the study. The NSAIDs of interest were those included on the provincial drug formulary. Patients in the NSAID group could have been dispensed more than one different non-selective NSAID during the study.
Study outcomes and follow-up
The primary outcome was the combined outcome of time to all cause death or time to recurrent congestive heart failure. The secondary outcomes were time to all cause death and time to recurrent congestive heart failure assessed separately. We included episodes of congestive heart failure treated in the emergency room or that required admission. A patient treated in the emergency room and then admitted for the same episode of congestive heart failure was counted only once.
Patients were followed from the time of their first prescription to one of the following censorship times: 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 according to group we carried out Cox proportional hazards modelling. We adjusted the models for several possible confounders, including age, sex, comorbidities (diabetes mellitus, cerebrovascular disease, acute and chronic renal failure, cardiac arrhythmias, hypertension, malignancy, and chronic obstructive pulmonary disease), other drugs prescribed before the first prescription for a cyclo-oxygenase-2 inhibitor or a NSAID ( blockers, angiotensin converting enzyme inhibitors, calcium channel blockers, statins, diuretics, digoxin, aspirin, clopidogrel, and warfarin), characteristics of the treating doctor or hospital (cardiologist, internist or other specialist, general practitioner, volume of admissions for congestive heart failure, availability of a catheterisation laboratory), 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. All analyses were carried out using SAS version 8.2.
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 cyclo-oxygenase-2 inhibitor 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 (tables 1 and 2). Overall, 492 patients had recurrent congestive heart failure and 473 died (table 3).
Table 1 Baseline characteristics of patients with congestive heart failure prescribed celecoxib, rofecoxib, or non-steroidal anti-inflammatory drugs (NSAIDs). Values are numbers (percentages) unless stated otherwise
Table 2 Prescribing characteristics for patients given celecoxib, rofecoxib, or non-steroidal anti-inflammatory drugs (NSAIDs)
Table 3 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%). Other less commonly used NSAIDs included ketoprofen, sulindac, piroxicam, flurbiprofen, tiaprofenic acid, nabumetone, salsalate, and etodolac.
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 (fig 2), and the trend was towards those prescribed celecoxib remaining free of recurrent congestive heart failure compared with those prescribed rofecoxib or NSAIDs (fig 3).
Fig 2 Kaplan-Meier analysis of time to death in patients prescribed celecoxib, rofecoxib, or non-steroidal anti-inflammatory drugs
Fig 3 Kaplan-Meier analysis of time to recurrent congestive heart failure in patients prescribed celecoxib, rofecoxib, or non-steroidal anti-inflammatory drugs
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 4). 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).
Fig 4 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 4).
Discussion
Rahme E, Pilote L, LeLorier J. Association between naproxen use and protection against acute myocardial infarction. Arch Intern Med 2002;162: 1111-5.
Solomon DH, Glynn RJ, Levin R, Avorn J. Nonsteroidal anti-inflammatory drug use and acute myocardial infarction. Arch Intern Med 2002;162: 1099-104.
Watson DJ, Rhodes T, Cai B, Guess HA. Lower risk of thromboembolic cardiovascular events with naproxen among patients with rheumatoid arthritis. Arch Intern Med 2002;162: 1105-10.
Ko D, Wang Y, Berger AK, Radford MJ, Krumholz HM. Nonsteroidal anti-inflammatory drugs after acute myocardial infarction. Am Heart J 2002;143: 475-81.
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.
NIH News. Use of non-steroidal anti-inflammatory drugs suspended in large Alzheimer's disease prevention trial. Dec 20, 2004. www.nih.gov/news/pr/dec2004/od-20.htm (accessed 2 Feb 2005).
Ray WA, Stein CM, Hall K, Daugherty JR, Griffin MR. Non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease: an observational cohort study. Lancet 2002;359: 118-23.
Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001;286: 954-9.
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.
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.
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.
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.
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.
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.
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.
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.
Topol EJ. Failing the public health—rofecoxib, Merck, and the FDA. N Engl J Med 2004;351: 1707-9.
Fitzgerald GA. Coxibs and cardiovascular disease. N Engl J Med 2004;351: 1709-11.
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.
Johnson AJ, Nguyen TV, Day RO. Do nonsteroidal anti-inflammatory drugs affect blood pressure? A meta-analysis. Ann Intern Med 1994;121: 289-300.
Brater DC, Harris C, Redfern JS, Gertz BJ. Renal effects of selective COX-2 inhibitors. Am J Nephrol 2001;21: 1-15.
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.
Whelton A, White WB, Bello A, Puma JA, Fort JG, SUCCESS-VII Investigators. Effects of celecoxib and rofecoxib on blood pressure and edema in patients 65 years of age with systemic hypertension and osteoarthritis. Am J Cardiol 2002;90: 959-63.
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.
Wolfe F, Zhao S, Reynolds M, Pettitt D. Blood pressure destabilization and edema among 8538 users of celecoxib, rofecoxib, and nonselective nonsteroidal anti-inflammatory drugs (NSAID) and nonusers of NSAID receiving ordinary clinical care. J Rheumatol 2004;31: 1143-51.
Gertz BJ, Krupa D, Bolognese JA, Sperling RS, Reicin A. A comparison of adverse renovascular experiences among osteoarthritis patients treated with rofecoxib and comparator non-selective non-steroidal anti-inflammatory agents. Curr Med Res Opin 2002;18: 82-91.
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.
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.
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.
Rodriguez LA, Hernandez-Diaz S. Nonsteroidal anti-inflammatory drugs as a trigger of clinical heart failure. Epidemiology 2003;14: 240-6.
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.
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.
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).
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.
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).
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.
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.
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.
Jong P, Gong Y, Liu PP, Austin PC, Lee DS, Tu JV. Care and outcomes of patients newly hospitalized for heart failure in the community treated by cardiologists compared to other specialists. Circulation 2003;108: 184-91.
Goff DC, Pandey DK, Chan FA, Ortiz C, Nichaman MZ. Congestive heart failure in the United States—is there more than meets the I(CD code)? The Corpus Christi Heart Project. Arch Intern Med 2000;160: 197-202.
Lee DS, Austin PC, Rouleau JL, Liu PP, Naimark D, Tu JV. Predicting mortality among patients hospitalized for heart failure: derivation and validation of a clinical model. JAMA 2003;290: 2581-7.
Jong P, Vowinckel E, Liu PP, Gong Y, Tu JV. Prognosis and determinants of survival in patients newly hospitalized for heart failure: a population-based study. Arch Intern Med 2002;162: 1689-94.
Tamblyn R, Lavoie G, Petrella L, Monette J. The use of prescription claims databases in pharmacoepidemiological research: the accuracy and comprehensiveness of the prescription claims database in Quebec. J Clin Epidemiol 1995;48: 999-1009.
Pilote L, Lavoie F, Ho V, Eisenberg MJ. Changes in the treatment of acute myocardial infarction in Quebec, 1988-1995. Can Med Ass J 2000;163: 31-6.
Pitkala KH, Strandberg TE, Tilvis RS. Worsening heart failure associated with COX-2 inhibitors. Am J Med 2002;112: 424-6.
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.
Zhao SZ, Burke TA, Whelton A, von Allmen H, Henderson SC. Cost of heart failure among hypertensive users of nonspecific NSAIDs and COX-2-specific inhibitors. Am J Manag Care 2002;8(15 Suppl): S414-27.
FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001;345: 433-42.
Rahme E, Marentette MA, Kong SX, LeLorier J. Use of NSAIDs, COX-2 inhibitors, and acetaminophen and associated coprescriptions of gastroprotective agents in an elderly population. Arthritis Care Res 2002;47: 595-602.
Ray WA. Evaluating medication effects outside of clinical trials: new-user designs. Am J Epidemiol 2003;158: 915-20.(Marie Hudson, postdoctoral fellow in epi)
Correspondence to: L Pilote louise.pilote@mcgill.ca
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 an 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.
The cardiovascular effects of non-steroidal anti-inflammatory drugs (NSAIDs) and cyclo-oxygenase-2 inhibitors have been the subject of much controversy. Studies of NSAIDs, in particular naproxen, have shown decreases, increases, or no effects on the risk of ischaemic heart disease.1-7 Rofecoxib has been consistently associated with an increased risk of myocardial infarction.5 8-10 It was withdrawn when data from a trial on benign sporadic colonic adenomas showed a significant increase in the incidence of cardiovascular events compared with placebo (relative risk 1.92, 95% confidence interval 1.19 to 3.11).11 Although most of the evidence to date shows no association between celecoxib and an increased risk of myocardial infarction,9 12-15 a meta-analysis8 and a recent study16 have cast doubt. Whether cyclo-oxygenase-2 inhibitors have similar or different cardiovascular toxicities remains debatable.17 18
The role of cyclo-oxygenase-2 inhibition in congestive heart failure is complex. On the one hand, both NSAIDs and cyclo-oxygenase-2 inhibitors have various renovascular side effects, which include increased volume retention, oedema, and blood pressure, all of which can exacerbate heart failure.19-22 Data, however, suggest that differences exist between the two types of drugs as well as between the cyclo-oxygenase-2 inhibitors themselves, with some,23-25 but not all,26 studies showing that rofecoxib is associated with more renovascular side effects, including increased oedema and blood pressure, than are NSAIDs and celecoxib. On the other hand, the cyclo-oxygenase-2 enzyme is induced in the myocardium of the failing heart and is associated with myocardial scarring.27 28 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.29-31 Clinical information on the association between cyclo-oxygenase-2 inhibitors and heart failure is, however, scarce.32-35 In a recent population based study, users of rofecoxib and NSAIDs, but not celecoxib, had a higher risk of admission for congestive heart failure than controls not taking NSAIDs.36
Elderly patients are likely to be given cyclo-oxygenase-2 inhibitors for the management of pain and inflammation as these drugs are thought to have fewer gastrointestinal side effects than NSAIDs.37 38 Yet the risk of cardiovascular disease increases with age. It is therefore important to ascertain the cardiovascular effects of cyclo-oxygenase-2 inhibitors in elderly people at both the patient and the population level. 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
Information for our population based, retrospective, observational cohort study was derived from the database of hospital discharge summaries for Quebec. The reliability of the coding for congestive heart failure in administrative databases has been shown to be high.39 40 A similar cohort of patients with congestive heart failure has been used in other pharmacoepidemiological studies.39 41 42
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 that both drugs were available throughout the study. Patients were excluded if they were admitted to hospital for congestive heart failure in the preceding three years. The age cut-off point was determined on the basis of the availability of prescription records, to ensure that all participants had at least one full year of observation in the database before entry into the study.
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
Exposure to drugs
We used the Quebec database for prescription drugs claims to determine exposure to drugs. This database contains information on all drug prescriptions for outpatients aged 65 or more. It has been validated for the accuracy of prescription claims.43 It also contains information on vital status.44
The study groups consisted of patients exclusively given one or more prescriptions for celecoxib, rofecoxib, or any non-selective NSAID after the index admission. Other cyclo-oxygenase-2 inhibitors were not available in Quebec during the study. The NSAIDs of interest were those included on the provincial drug formulary. Patients in the NSAID group could have been dispensed more than one different non-selective NSAID during the study.
Study outcomes and follow-up
The primary outcome was the combined outcome of time to all cause death or time to recurrent congestive heart failure. The secondary outcomes were time to all cause death and time to recurrent congestive heart failure assessed separately. We included episodes of congestive heart failure treated in the emergency room or that required admission. A patient treated in the emergency room and then admitted for the same episode of congestive heart failure was counted only once.
Patients were followed from the time of their first prescription to one of the following censorship times: 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 according to group we carried out Cox proportional hazards modelling. We adjusted the models for several possible confounders, including age, sex, comorbidities (diabetes mellitus, cerebrovascular disease, acute and chronic renal failure, cardiac arrhythmias, hypertension, malignancy, and chronic obstructive pulmonary disease), other drugs prescribed before the first prescription for a cyclo-oxygenase-2 inhibitor or a NSAID ( blockers, angiotensin converting enzyme inhibitors, calcium channel blockers, statins, diuretics, digoxin, aspirin, clopidogrel, and warfarin), characteristics of the treating doctor or hospital (cardiologist, internist or other specialist, general practitioner, volume of admissions for congestive heart failure, availability of a catheterisation laboratory), 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. All analyses were carried out using SAS version 8.2.
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 cyclo-oxygenase-2 inhibitor 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 (tables 1 and 2). Overall, 492 patients had recurrent congestive heart failure and 473 died (table 3).
Table 1 Baseline characteristics of patients with congestive heart failure prescribed celecoxib, rofecoxib, or non-steroidal anti-inflammatory drugs (NSAIDs). Values are numbers (percentages) unless stated otherwise
Table 2 Prescribing characteristics for patients given celecoxib, rofecoxib, or non-steroidal anti-inflammatory drugs (NSAIDs)
Table 3 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%). Other less commonly used NSAIDs included ketoprofen, sulindac, piroxicam, flurbiprofen, tiaprofenic acid, nabumetone, salsalate, and etodolac.
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 (fig 2), and the trend was towards those prescribed celecoxib remaining free of recurrent congestive heart failure compared with those prescribed rofecoxib or NSAIDs (fig 3).
Fig 2 Kaplan-Meier analysis of time to death in patients prescribed celecoxib, rofecoxib, or non-steroidal anti-inflammatory drugs
Fig 3 Kaplan-Meier analysis of time to recurrent congestive heart failure in patients prescribed celecoxib, rofecoxib, or non-steroidal anti-inflammatory drugs
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 4). 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).
Fig 4 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 4).
Discussion
Rahme E, Pilote L, LeLorier J. Association between naproxen use and protection against acute myocardial infarction. Arch Intern Med 2002;162: 1111-5.
Solomon DH, Glynn RJ, Levin R, Avorn J. Nonsteroidal anti-inflammatory drug use and acute myocardial infarction. Arch Intern Med 2002;162: 1099-104.
Watson DJ, Rhodes T, Cai B, Guess HA. Lower risk of thromboembolic cardiovascular events with naproxen among patients with rheumatoid arthritis. Arch Intern Med 2002;162: 1105-10.
Ko D, Wang Y, Berger AK, Radford MJ, Krumholz HM. Nonsteroidal anti-inflammatory drugs after acute myocardial infarction. Am Heart J 2002;143: 475-81.
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.
NIH News. Use of non-steroidal anti-inflammatory drugs suspended in large Alzheimer's disease prevention trial. Dec 20, 2004. www.nih.gov/news/pr/dec2004/od-20.htm (accessed 2 Feb 2005).
Ray WA, Stein CM, Hall K, Daugherty JR, Griffin MR. Non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease: an observational cohort study. Lancet 2002;359: 118-23.
Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001;286: 954-9.
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.
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.
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.
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.
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.
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.
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.
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.
Topol EJ. Failing the public health—rofecoxib, Merck, and the FDA. N Engl J Med 2004;351: 1707-9.
Fitzgerald GA. Coxibs and cardiovascular disease. N Engl J Med 2004;351: 1709-11.
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.
Johnson AJ, Nguyen TV, Day RO. Do nonsteroidal anti-inflammatory drugs affect blood pressure? A meta-analysis. Ann Intern Med 1994;121: 289-300.
Brater DC, Harris C, Redfern JS, Gertz BJ. Renal effects of selective COX-2 inhibitors. Am J Nephrol 2001;21: 1-15.
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.
Whelton A, White WB, Bello A, Puma JA, Fort JG, SUCCESS-VII Investigators. Effects of celecoxib and rofecoxib on blood pressure and edema in patients 65 years of age with systemic hypertension and osteoarthritis. Am J Cardiol 2002;90: 959-63.
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.
Wolfe F, Zhao S, Reynolds M, Pettitt D. Blood pressure destabilization and edema among 8538 users of celecoxib, rofecoxib, and nonselective nonsteroidal anti-inflammatory drugs (NSAID) and nonusers of NSAID receiving ordinary clinical care. J Rheumatol 2004;31: 1143-51.
Gertz BJ, Krupa D, Bolognese JA, Sperling RS, Reicin A. A comparison of adverse renovascular experiences among osteoarthritis patients treated with rofecoxib and comparator non-selective non-steroidal anti-inflammatory agents. Curr Med Res Opin 2002;18: 82-91.
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.
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.
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.
Rodriguez LA, Hernandez-Diaz S. Nonsteroidal anti-inflammatory drugs as a trigger of clinical heart failure. Epidemiology 2003;14: 240-6.
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.
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.
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).
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.
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).
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.
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.
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.
Jong P, Gong Y, Liu PP, Austin PC, Lee DS, Tu JV. Care and outcomes of patients newly hospitalized for heart failure in the community treated by cardiologists compared to other specialists. Circulation 2003;108: 184-91.
Goff DC, Pandey DK, Chan FA, Ortiz C, Nichaman MZ. Congestive heart failure in the United States—is there more than meets the I(CD code)? The Corpus Christi Heart Project. Arch Intern Med 2000;160: 197-202.
Lee DS, Austin PC, Rouleau JL, Liu PP, Naimark D, Tu JV. Predicting mortality among patients hospitalized for heart failure: derivation and validation of a clinical model. JAMA 2003;290: 2581-7.
Jong P, Vowinckel E, Liu PP, Gong Y, Tu JV. Prognosis and determinants of survival in patients newly hospitalized for heart failure: a population-based study. Arch Intern Med 2002;162: 1689-94.
Tamblyn R, Lavoie G, Petrella L, Monette J. The use of prescription claims databases in pharmacoepidemiological research: the accuracy and comprehensiveness of the prescription claims database in Quebec. J Clin Epidemiol 1995;48: 999-1009.
Pilote L, Lavoie F, Ho V, Eisenberg MJ. Changes in the treatment of acute myocardial infarction in Quebec, 1988-1995. Can Med Ass J 2000;163: 31-6.
Pitkala KH, Strandberg TE, Tilvis RS. Worsening heart failure associated with COX-2 inhibitors. Am J Med 2002;112: 424-6.
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.
Zhao SZ, Burke TA, Whelton A, von Allmen H, Henderson SC. Cost of heart failure among hypertensive users of nonspecific NSAIDs and COX-2-specific inhibitors. Am J Manag Care 2002;8(15 Suppl): S414-27.
FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001;345: 433-42.
Rahme E, Marentette MA, Kong SX, LeLorier J. Use of NSAIDs, COX-2 inhibitors, and acetaminophen and associated coprescriptions of gastroprotective agents in an elderly population. Arthritis Care Res 2002;47: 595-602.
Ray WA. Evaluating medication effects outside of clinical trials: new-user designs. Am J Epidemiol 2003;158: 915-20.(Marie Hudson, postdoctoral fellow in epi)