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PRIMARY CARE: Marie Hudson, Hugues Richard, and Louise Pilote Differences in outcomes of patients with congestive heart failure prescribed celecoxib, rofecoxib, or non-steroidal anti-inflammatory drugs: population based study BMJ 2005; 330: 1370 [Abstract] [Full text]

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Celecoxib is not a safer alternative in heart failure

Juan-Carlos Maldonado   (24 June 2005)

Variations in frequency of concomitant prescriptions of coumarine anticoagulants and NSAIDs

Michal R. Pijak, Frantisek Gazdik, Igor Huzicka   (5 July 2005)

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

Michal R. Pijak, Igor Huzicka, Frantisek Gazdik   (6 July 2005)

Celecoxib is not a safer alternative in heart failure 24 June 2005
Juan-Carlos Maldonado, Clinical Research Fellow. Pharmacology Unit. Biomedical Center. Central University of Ecuador. POBox: 17-11-6120. Quito-Ecuador. Send response to journal: Re: Celecoxib is not a safer alternative in heart failure	Editor.- Hudson and colleagues (1) reported that 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. Moreover, they conclude that celecoxib seems to be a safer alternative in elderly patients with congestive heart failure. Nevertheless, a critical appraisal of this recent retrospective cohort study shows some methodological problems. Selection bias and another confounding factors can explain the results. In this study (1) patients were eligible if they were discharged with a diagnosis of congestive heart failure. This takes no account the stages of heart failure or NYHA class symptoms, which can influence the study outcome because patients with a worse clinical condition are at a higher risk of developing complications and recurrent congestive heart failure. Baseline characteristics of studied patients shows that digoxin prescriptions significantly differed between NSAIDs and celecoxib groups (39.6% vs. 33.0%; p=0.04). Digoxin is an additional therapy for symptomatic patients with stage C or stage D heart failure (2). It is thus feasible that a higher number of patients in the NSAIDs group were in a higher risk. Although many confounding factors were included in the analysis, another variables as left ventricular ejection fraction, atrial fibrillation -as an specific subtype of cardiac arrhythmias-, and obesity are also related with heart failure. Moreover, modifications of lifestyle can be helpful in controlling the symptoms of heart failure (2), but these variables were not measured and were not included as confounding factors. In an observational study a crucial question concerns the appropriateness of the control group. In this study (1) the reference group received celecoxib (unknown prescribed dose) and this is inadequate to know the real risk profile. Furthermore the paper does not have information about some relevant outcome measures. Why patients died? An outcome of all cause death includes fatal myocardial infarction, which is probably the main cardiovascular adverse drug reaction of COX-2 inhibitors. We must remember that in the APC trial (3) frequency of non- fatal myocardial infarction and non-fatal heart failure were higher in celecoxib –400 mg twice daily– group than in placebo group (1.3% vs 0.4% and 0.6% vs 0.3%, respectively). Rofecoxib was withdrawn from the market after the APPROVe trial reported a higher incidence of cardiovascular events in treatment group (4). Cardiovascular adverse effects have been reported for other cyclo- oxygenase-2 inhibitors as celecoxib (3) and valdecoxib (5). The findings of this recent observational study (1) supports some evidence of differences among COX-2 inhibitors, but this does not mean celecoxib could be safer. In addition, when risk of recurrent congestive heart failure was assessed separately NSAIDs and celecoxib did not differ significantly (hazard ratio=1,21; CI95%=0,92-1,60). Nevertheless, pharmaceutical industry now can use the published paper for celecoxib promotional activities, presenting the drug as a good alternative for elderly patients. REFERENCES: 1- Hudson M, Richard H, Pilote L. Differences in outcomes of patients with congestive heart failure prescribed celecoxib, rofecoxib, or non- steroidal anti-inflammatory drugs: population based study. BMJ 2005; 330: 1370-3. 2- Jessup M, Brozena S. Heart Failure. N Engl J Med 2003; 348: 2007- 18. 3- Solomon SD, McMurray JJV, Pfeffer MA, et.al., for the Adenoma Prevention with Celecoxib (APC) Study Investigators. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005; 352: 1071-80. 4- Bresalier RS, Sandler RS, Quan H, et.al., for the Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005; 352: 1092-102. 5- Nussmeier NA, Whelton AA, Brown MT, et.al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 2005; 352: 1081-91. Competing interests: None declared
Variations in frequency of concomitant prescriptions of coumarine anticoagulants and NSAIDs 5 July 2005
Michal R. Pijak, Consultant in Internal Medicine, Rheumatology and and Clinical Immunology 1 Department of Internal Medicine, University Hospital, Limbova 5, 83305 Bratislava, Slovakia, Frantisek Gazdik, Igor Huzicka Send response to journal: Re: Variations in frequency of concomitant prescriptions of coumarine anticoagulants and NSAIDs	In their population based retrospective cohort study Hudson et al.(1) aimed to compare the risk of death and recurrent congestive heart failure (CHF) in patients over 65 years old with a history of CHF who were given one or more prescription for celecoxib, rofecoxib, or any non- selective non-steroidal anti-inflammatory drug (NSAID). We were surprised that about one-third of patients in each study group used warfarin before the first prescription of a study drug. We consider this frequency to be extremely high in the light of compelling evidence that the combination of a NSAID and warfarin can dramatically increase bleeding risk. (2,3) A recent study even suggested that such a combination, coxibs not excluded, may be contraindicated.(4) Our search of the literature revealed that the frequency of concomitant prescriptions of anticoagulants in NSAID users in the study of Hudson et al. is much higher than in other comparable observational studies (2, 5). For example, in a recent Canadian study concomitant prescriptions of coumarin anticoagulants were given only to 5% of NSAID users aged 65 years or older, a frequency that was similar to a cohort that did not use NSAIDs.(5) The reason for such a marked difference between the studies remains to be determined. Several plausible explanations include differences in the severity of heart disease and/or the quality of medication use reporting in the source databases. The availability of appropriate therapeutic guidelines and their implementation in clinical practice might also play an important role. Taken together, these data underscore the need for an improvement of physicians’ awareness of this important drug interaction. 1. Hudson M, Richard H, Pilote L. Differences in outcomes of patients with congestive heart failure prescribed celecoxib, rofecoxib, or non- steroidal anti-inflammatory drugs: population based study. BMJ 2005;330:1370. 2. Shorr RI, Ray WA, Daugherty JR, Griffin MR. Concurrent use of nonsteroidal anti-inflammatory drugs and oral anticoagulants places elderly persons at high risk for hemorrhagic peptic ulcer disease. Arch Intern Med 1993;153:1665–70. 3. Knijff-Dutmer EAJ, Schut GA, van de Laar MAFJ: Concomitant coumarin-NSAID therapy and risk for bleeding. Ann Pharmacother 2003;37:12–16. 4. Battistella M, Mamdami MM, Juurlink DN, Rabeneck L, Laupacis A. Risk of upper gastrointestinal hemorrhage in warfarin users treated with nonselective NSAIDs or COX-2 inhibitors. Arch Intern Med 2005;165:189-92. 5. Mamdani M, Rochon PA, Juurlink DN, Kopp A, Anderson GM, Naglie G, et al. Observational study of upper gastrointestinal haemorrhage in elderly patients given selective cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs. BMJ 2002;325:624-7. Competing interests: Dr. Pijak has served as a paid speaker and consultant for the local branches of the following manufacturers of NSAIDs: Pfizer, Merck Sharp & Dohme (MSD) and Fournier Slovakia.
Differences in the cardiovascular risk between NSAIDs and coxibs: the neglected role of pharmacokinetics and drug interactions 6 July 2005
Michal R. Pijak, Consultant in Internal Medicine, Rheumatology and and Clinical Immunology University Hospital Bratislava, Slovakia, Igor Huzicka, Frantisek Gazdik Send response to journal: Re: Differences in the cardiovascular risk between NSAIDs and coxibs: the neglected role of pharmacokinetics and drug interactions	The study by Hudson et al (1) indicates that celecoxib might be safer than rofecoxib and non-steroidal anti-inflammatory drugs (NSAIDs) in elderly patients with congestive heart failure (CHF). This is of great importance in a view of the evidence that NSAIDs could account for approximately 20% of hospitalizations for CHF. (2) The authors rightly point out that inhibition of renal COX-2 may contribute to increased cardiovascular mortality associated with specific COX-2 inhibitors (coxibs). However, they fail to mention that differences in cardiorenal effects between individual coxibs and NSAIDs could be related to pharmacokinetics of a particular drug and their interactions with other cardiovascular drugs. Indeed, results from many studies suggest that COX-2 rather than COX- 1 inhibition accounts for the renal effects of NSAIDs. Consequently, coxibs may be expected to have a similar renal adverse event profile as NSAIDs. The lower risk of celecoxib compared with rofecoxib corresponds with lower potency of celecoxib to inhibit COX-2. The dose-response relationship also suggests that this association may be causal. The pharmacodynamic effect is determined by the drug concentration at a receptor site. Accumulation of conventional NSAIDs occurs particularly in acidic environment (in the stomach, kidneys and in inflamed tissues) which is where these drugs exert their therapeutic as well as adverse effects. In contrast, non-acidic coxibs are equally distributed throughout the body. The lower risk of celecoxib may be explained by its large distribution volume, which is several times higher then that of rofecoxib. Other pharmacokinetic differences that may contribute to higher cardiorenal toxicity of rofecoxib are longer half-life and non-linear kinetics. Both NSAIDs and coxibs, in addition to the attenuation of therapeutic effects of many cardiovascular drugs, may also increase cardiovascular mortality due to potentiation of their side effects. For example, such interactions may increase the risk of bleeding in patients taking oral anticoagulants (3) or potentiate serious hyperkalemia associated with the use of spironolactone or an ACE inhibitor. (4) Finally, some NSAIDs my increase cardiovascular mortality by causing elevation of serum digoxin concentration. (5) 1. Hudson M, Richard H, Pilote L. Differences in outcomes of patients with congestive heart failure prescribed celecoxib, rofecoxib, or non-steroidal anti-inflammatory drugs: population based study. BMJ 2005;330:1370. 2. 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;160:777-84. 3. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709-17. 4. Battistella M, Mamdami MM, Juurlink DN, Rabeneck L, Laupacis A. Risk of upper gastrointestinal hemorrhage in warfarin users treated with nonselective NSAIDs or COX-2 inhibitors. Arch Intern Med 2005;165:189-92. 5. Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA 2003;289:871–8. Competing interests: Dr. Pijak has served as a paid speaker and consultant for the local branches of the following manufacturers of NSAIDs: Pfizer, Merck Sharp & Dohme (MSD) and Fournier Slovakia.