Why Do Cyclo-Oxygenase-2 Inhibitors Cause Cardiovascular Events? Richard J

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Journal of the American College of Cardiology Vol. 39, No. 3, 2002 © 2002 by the American College of Cardiology ISSN 0735-1097/02/$22.00 Published by Elsevier Science Inc. PII S0735-1097(01)01749-1 PERSPECTIVE Why Do Cyclo-Oxygenase-2 Inhibitors Cause Cardiovascular Events? Richard J. Bing, MD, Magdalena Lomnicka Pasadena, California

This report conﬁrms evidence that selective nonsteroidal anti-inﬂammatory drugs (NSAIDs), such as celecoxib, can lead to thrombotic cardiovascular events. Aspirin, a nonselective COX-1 (cyclo-oxygenase) and COX-2 inhibitor may result in gastric toxicity. For this reason, selective COX-2 inhibitors have been developed to reduce erosion of the gastric mucosa. Both selective and nonselective NSAIDs reduce prostacyclin formation in the infarcted heart; they accomplish this by tipping the balance of prostacyclin/thromboxane in favor of thromboxane, a prothrombotic eicosanoid. The relative increase in thromboxane, coupled with a diminution in prostacyclin in infarcted heart muscle, can lead to the development of thrombotic cardiovascular events. This may be prevented by the addition of a nitric oxide donor to NSAIDs. (J Am Coll Cardiol 2002;39:521–2) © 2002 by the American College of Cardiology

Cyclo-oxygenase (COX) or prostaglandin endoperoxidase on one of the clinical trials (Vioxx Gastrointestinal Out- H synthase inhibitors are important contributors to the comes Research), they showed that the relative risk of treatment of arthritis and other inﬂammatory conditions. developing thrombotic cardiovascular events such as myo- Cyclo-oxygenases catalyze the conversion of arachidonic cardial infarction or unstable angina was high as compared

acid and O2 to PGH2, the committed step in prostanoid to naproxen, a nonselective COX inhibitor (5). The inves- synthesis (1). The two isoenzymes, COX-1 and COX-2, are tigators conclude that COX-2 inhibition favors prothrom- encoded by separate genes located on different chromo- botic events by tipping the balance of prostacyclin/ somes. The COX-2 expression can be induced through thromboxane in favor of thromboxane, a prethrombotic multiple signaling pathways involving protein kinases A and eicosanoid (5). Experimental data have confirmed these C, tyrosine kinases and bacterial endotoxin, among others conclusions. (1). Both isoenzymes are homodimeric, heme-containing The release of prostaglandins from ischemic tissue was glycosylated proteins with two catalytic sites (1). They are first demonstrated by McGiff et al. (6). The heart metabo- targets of nonselective nonsteroidal anti-inflammatory drugs lizes arachidonic acid into different prostaglandins (7), (NSAIDs); aspirin, a nonselective NSAID, acts via COX-1 particularly prostacyclin (8). An increase in prostaglandins to inhibit platelet thromboxane A2 formation and, there- in canine coronary venous blood occurs during postocclusive fore, lowers mortality from ischemic heart disease (1). reactive hyperemia (9). Acute myocardial ischemia not only Inhibition of COX-2 reduces inflammation, fever and increases prostacyclin but also thromboxane in coronary vein probably colon cancer (2,3). Covalent modifications of blood (10). Prostacyclin increases in microsomes prepared COX enzymes by aspirin cause permanent inactivation of from infarcted myocardium (10). It is likely that macro- the enzyme (1). Because of their anti-inflammatory action, phages are the main source of prostaglandins and throm- COX inhibitors have been selected for long-term treatment boxane (11). Production of prostacyclin and thromboxane of inflammatory conditions. The COX-2 inhibitors predis- by the infarcted heart in situ occurs in conjunction with pose to erosion of the gastric mucosa with subsequent increased activation of the inducible form of nitric oxide- hemorrhage. Both COX-2 selective and nonselective COX synthase (iNOS) (12). The induction of iNOS in the inhibitors cause renal toxicity with papillary necrosis and ischemic rabbit and human heart increases the coronary

interstitial nephritis (4). arterial-venous coronary difference of NO2 and NO3 (NOx). Recently, Mukherjee et al. (5) analyzed clinical trials Activation of iNOS occurs primarily by activated macro- dealing with the effect of celecoxib and rofecoxib, two phages during the inﬂammatory phase (12). selective COX-2 inhibitors, on cardiovascular events. They Both nitric oxide (NO) and prostaglandins play an concluded that these two inhibitors are responsible for a important role in the infarcted heart (2). Prostacyclin is a signiﬁcant risk of cardiovascular thrombotic events. Based vasodilator that prevents cardiac arrhythmias and platelet aggregation; thromboxane, in contrast, promotes platelet From the Huntington Medical Research Institutes, Department of Experimental aggregation, acts as a vasoconstrictor and initiates ventric- Cardiology, Pasadena, California. This work was supported by grants from the ular arrhythmias (2). Nitric oxide counteracts thromboxane, Charles S. and Carmen DeMora Hale Foundation, the Patron Saint Foundation and the Ann Peppers Foundation. inhibits platelet aggregation and compensates for the Manuscript received October 11, 2001; accepted November 2, 2001. NSAIDs’ induced reduction of prostacyclin (2). Production 522 Bing and Lomnicka JACC Vol. 39, No. 3, 2002 Cardiovascular Events February 6, 2002:521–2

B-NOD has already been used to prevent renal depletion of Abbreviations and Acronyms prostacyclin in situ following administration of aspirin (18). COX ϭ cyclo-oxygenase It is realized that re-evaluation of a commercially success- iNOS ϭ inducible form of nitric oxide-synthase ful compound is not a desirable course. Conversely, science ϭ NO nitric oxide should not be hampered by a matter of expediency. Progress NSAID ϭ nonsteroidal anti-inflammatory drug depends on re-evaluation of known facts; there are no immovable objects in either science or medicine. of thromboxane and prostacyclin in the infarcted rabbit Acknowledgment heart has been confirmed together with increased upgrading The authors appreciate the excellent secretarial help of Ms. of iNOS (9). The interaction between COX and iNOS is Susanna Kim. due to an iron-heme center as the active site of COX (9). Exogenous NO, together with cytokine-induced NO, en- Reprint requests and correspondence: Dr. Richard J. Bing, hances both COX isoenzymes (9). Upgrading of COX-2 Huntington Medical Research Institutes, 99 North El Molino protein by cytokines is also accomplished by NSAIDs. This Ave., Pasadena, California 91101. E-mail: [email protected]. action differs from upgrading by inflammatory cytokines, REFERENCES which increase COX at the transcriptional levels (13). Recently, we obtained evidence of changes in the pros- 1. Smith WL, Garavito RM, DeWitt DL. Prostaglandin endoperoxide-h tacyclin/thromboxane ratio after celecoxib, which lowers synthases (cyclooxygenases)-1 and -2. J Biol Chem 1996;271:33157–60. myocardial prostacyclin production in infarcted heart mus- 2. Bing RJ, Yamamoto T, Yamamoto M, Kakar NR, Cohen AM. A new look at myocardial infarction toward a better aspirin. Cardiovasc Res cle, but fails to inhibit thromboxane (14). Therefore, cele- 1999;43:25–31. coxib (5 mg/kg) tips the balance of prostacyclin/ 3. Bing RJ, Miyataka M, Rich KA, et al. 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