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Annals of Internal Medicine
Dear Sir,
We agree with the commentaries of Kim et al. that while celecoxib appears less cardiotoxic than rofecoxib in several observation studies (1- 4) there is nevertheless reason for concern, particularly at higher doses as in the APC trial or in the largely unstudied group of patients with previous myocardial infarction. We also agree that any cardio-protective benefits of aspirin in rofecoxib users may be offset by a significant reduction in gastro-protection. As Pijak and colleagues point out the exact cardio-protective mechanism of aspirin and its potential interaction with Cox-2 inhibitors is far from established and a fertile ground for further research regarding the role of inflammation. Similarly, Shimmura and colleagues also have proposed another interesting new mechanism to explain the detrimental effects of Cox-2 inhibitors that again goes beyond the simple pro-thrombotic theory currently in vogue. These interesting and novel hypotheses will need further experimental confirmation.
Reference: 1. Levesque LE, Brophy JM, Zhang B. The risk for myocardial infarction with cyclooxygenase-2 inhibitors: a population study of elderly adults. Ann Intern Med 2005;142:481-489. 2. Graham DJ, Campen D, Hui R, 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;365:475-481. 3. Solomon DH, Schneeweiss S, Glynn RJ, et al. Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation 2004;109:2068-2073. 4. 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;359:118-123.
Conflict of Interest:
None declared
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Considering cyclooxygenase-2 inhibitor in other point of view
Submit responseI read Levesque and colleagues' article on the risk for myocardial infarction with cyclooxygenase-2 (COX-2) inhibitors (1) with interest. The article described myocardial infarction risk not increased with celecoxib. One recent study, Prevention of Spontaneous Adenomatous Polyps (PreSAP) (2), also showed celecoxib does not increase the risk of cardiovascular event. However, we should consider the result of Adenoma Prevention with Celebrex (APC) trial (3). In APC trial, celecoxib use was associated with a dose related increase in serious cardiovascular events and they thought this observation supported the hypothesis that sustained inhibition of prostacyclin with COX-2 inhibitors in twice daily dose may increase cardiovascular risk compared with once daily dose in PreSAP study. Therefore, we should not easily conclude celecoxib is not related to cardiovascular complications even though the risk may be lower than rofecoxib and the dosing schedule as well as the dosage should be considered.
This study also stated only 25% of current users of celecoxib received dosages greater than 200 mg/d. However, for prevention of adenomatous polyposis, higher doses need to be considered. So, the effect and complication of high dose celecoxib should not be disregarded.
This study also highlighted concomitant aspirin use attenuating the nefarious cardiovascular effects of rofecoxib. However, we should keep in mind why we consider COX-2 inhibitors. COX-2 inhibitors are usually considered in patients who have upper gastrointestinal (GI) intolerability. Goldstein and colleagues study (4) showed significant GI intolerability in the rofecoxib 25 mg once daily treatment group receiving concomitant low dose aspirin. While the difference of GI intolerability between NSAID only and concomitant use of aspirin and rofecoxib need to be ascertained, such concomitant use of aspirin and rofecoxib can be recommended only if its GI complication is less than NSAID only use. It is important to consider both GI intolerability and cardiovascular complications in the decision as to whether to use a COX-2-selective inhibitor.
1. Levesque LE, Brophy JM, Zhang B. The risk for myocardial infarction with cyclooxygenase-2 inhibitors: a population study of elderly adults. Ann Intern Med. 2005;142(7):481-9. 2. Sporadic Adenomatous Polyposis Trial: PreSAP and APC. Celecoxib & Valdecoxib cardiovascular Safety. Pfizer inc. 2005. 3. Solomon SD, McMurray JJ, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med. 2005;352(11):1071-80. 4. Goldstein JL, Bello AE, Spalding W, Suh S, Fort JG. Cyclooxygenase-2 specific inhibitors and upper gastrointestinal tolerability in patients with osteoarthritis receiving concomitant low dose aspirin: pooled analysis of 2 trials. J Rheumatol. 2005;32(1):111-7.
Conflict of Interest:
None declared
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The Risk of Myocardial Infarction with Cyclooxygenase-2 Inhibitors
Submit responseTO THE EDITOR: The population-based cohort study by Levesque and colleagues (1) has shown that aspirin eliminated the excess risk of myocardial infarction in persons receiving low doses of rofecoxib. This finding adds further support to the hypothesis that aspirin might mitigate the cardiovascular risk associated with the use of selective cyclooxygenase (COX)-2 inhibitors (2) The authors, however, fail to explain why this risk-modifying effect of aspirin was not seen at higher doses of rofecoxib and why no increase in risk was observed with celecoxib. Experimental and clinical data suggest that a competitive interaction between these drugs and aspirin on both COX-1 and COX-2 enzymes may play the most important role.
According to the experimental data, drugs with high affinity for COX-2 better preserved aspirin inhibition of platelet COX-1 activity (3), consistent with the results of clinical studies (2). Vice-versa, weakly selective COX-2 inhibitors, which show significant potency for COX-1 such as celecoxib, might have a greater ability to antagonize the antiplatelet effects of aspirin (3). Nevertheless, cardiovascular risk in clinical studies was lower among celecoxib users than with highly selective COX-2 inhibitors. We hypothesize that higher doses of the latter drugs interfere with other cardioprotective benefits of aspirin, in particular its anti-inflammatory effects.
The suggestion that cardioprotective properties of low-dose aspirin may reflect its anti-inflammatory rather than antiplatelet effects first came from the demonstration of the positive correlation between the reduction of cardiovascular risk by aspirin and the level of C- reactive protein (4). Consistent with this observation, numerous pharmacological studies have provided evidence that aspirin at low doses may exert the anti-inflammatory action by means of novel anti-inflammatory mediators generated at the leukocyte-endothelial cell interface (5).
In contrast to its action on COX-1, aspirin does not totally inhibit the oxidation of arachidonic acid by COX-2 but rather alters the enzyme in such a way that the acetylated form of COX-2 produces 15R- hydroxyeicosatetraenoic acid (15R-HETE) (5). This ASA-COX-2-triggered 15R -HETE is further transformed by leukocyte 5-lipoxygenase and subsequent reactions to a series of 15-epimer lipoxins, also termed the aspirin- triggered lipoxins (ATL). Generation of these mediators was recently documented in a randomized clinical trial of healthy volunteers on low- dose aspirin (6). Since COX-2 inhibition completely suppressed ATL formation caused by aspirin (5) monitoring of their levels might be useful in further studies investigating cardiovascular risk of COX-2 inhibitors.
Michal R. Pijak, M.D. Igor Huzicka, M.D. Frantisek Gazdik, M.D., Ph.D. University Hospital, 833 05 Bratislava, Slovakia
References
1. Levesque LE, Brophy JM, Zhang B. The risk for myocardial infarction with cyclooxygenase-2 inhibitors: a population study of elderly adults. Ann Intern Med. 2005;142:481-9.
2. Catella-Lawson F, Reilly MP, Kapoor SC, Cucchiara AJ, DeMarco S, Tournier B, et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med. 2001;345:1809-17.
3. Ouellet M, Riendeau D, Percival MD. A high level of cyclooxygenase -2 inhibitor selectivity is associated with a reduced interference of platelet cyclooxygenase-1 inactivation by aspirin. Proc Natl Acad Sci U S A. 2001;98:14583-8.
4. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336:973-9.
5. Fiorucci S, Distrutti E, Mencarelli A, Morelli A, Laufor SA, Cirino G, Wallace JL. Evidence that 5-lipoxygenase and acetylated cyclooxygenase 2-derived eicosanoids regulate leukocyte-endothelial adherence in response to aspirin. Br J Pharmacol. 2003;139:1351-9.
6. Chiang N, Bermudez EA, Ridker PM, Hurwitz S, Serhan CN . Aspirin triggers antiinflammatory 15-epi-lipoxin A4 and inhibits thromboxane in a randomized human trial. Proc Natl Acad Sci U S A. 2004;101:15178-83.
Conflict of Interest:
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), Fournier Slovakia
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A new hypothesis for the adverse effects of COX-2 inhibitors
Submit responseTO THE EDITORS:The reason for the propensity of COX-2 inhibitors to facilitate cardiovascular events remains unclear. A commonly postulated mechanism is an imbalance between prostacyclin (antithrombotic) and thromboxane (prothrombotic) since prostacyclin production depends on COX-2 activity in humans (1). However, Levesque et al. have reported that low-dose aspirin mitigates the cardiovascular risk associated with low-dose but not high- dose rofecoxib in elderly population. Similarly, Nussmeier et al. have demonstrated that the use of parecoxib and valdecoxib after CABG was associated with increased cardiovascular events despite co-administration of low-dose aspirin (2). Co-administration of aspirin with a COX-2 inhibitor should restore the balance between prostacyclin and thromboxane because low-dose aspirin selectively inhibits thromboxane production in platelets. Thus, the failure of low-dose aspirin to attenuate the cardiovascular risk associated with a COX-2 inhibitor implies that the COX -2 inhibitor increases the risk of cardiovascular events, at least in part, by mechanisms unrelated to thromboxane production.
The heart has a remarkable ability to adapt to various stresses, such as ischemia, hypoxia, and oxidative stress. This is exemplified by ischemic preconditioning, the phenomenon whereby a sublethal ischemic stress greatly enhances the tolerance of the myocardium to subsequent ischemia (3). The occurrence of ischemic preconditioning has been shown in almost all mammalian tissues and has also been confirmed in humans, where it may play an important role in protecting the heart from coronary artery disease (3). In 2000, we reported that induction of COX-2 plays an obligatory role in the development of ischemic preconditioning, most likely via the production of cardioprotective prostanoids such PGI2 and PGE2 (4). Since then, mounting evidence has accumulated which supports the concept that COX-2 is a cardioprotective protein that alleviates myocardial ischemia/reperfusion injury (5). We have suggested that induction of COX-2 is a fundamental mechanism whereby the heart adapts to stress. Importantly, low-dose aspirin does not interfere either with COX-2 or with ischemic preconditioning (5).
Thus, we propose a new mechanism for the detrimental effects of COX-2 inhibitors, namely, that, in addition to their prothrombotic actions, these drugs may deprive the heart of its natural ability to adapt to ischemic stress (i.e., preconditioning), thereby increasing the susceptibility of the myocardium to infarction and stunning. We suggest that the biological effects of COX-2 may differ depending on the cellular types where it is expressed (e.g., cancer cells vs. cardiac myocytes), the pathophysiological setting, and the ability of cells to metabolize COX-2-derived PGH2 into cytoprotective prostanoids.
References:
1. McAdam BF, Catella-Lawson F, Mardini IA, Kapoor S, Lawson JA, FitzGerald GA. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci U S A 1999;96(1):272-7.
2. 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(11):1081-91.
3. Yellon DM, Downey JM. Preconditioning the myocardium: from cellular physiology to clinical cardiology. Physiol Rev 2003;83(4):1113- 51.
4. Shinmura K, Tang XL, Wang Y, et al. Cyclooxygenase-2 mediates the cardioprotective effects of the late phase of ischemic preconditioning in conscious rabbits. Proc Natl Acad Sci U S A 2000;97(18):10197-202.
5. Bolli R, Shinmura K, Tang XL, et al. Discovery of a new function of cyclooxygenase (COX)-2: COX-2 is a cardioprotective protein that alleviates ischemia/reperfusion injury and mediates the late phase of preconditioning. Cardiovasc Res 2002;55(3):506-19.
Conflict of Interest:
None declared