Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 116, Issue 1, Pages 4-15Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI27291
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Funding
- NCRR NIH HHS [M01 RR000040, M01RR00040] Funding Source: Medline
- NHLBI NIH HHS [P50 HL054500, HL 54500, HL 62250, P50 HL070128, HL70128, P01 HL062250] Funding Source: Medline
- NATIONAL CENTER FOR RESEARCH RESOURCES [M01RR000040] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [P50HL054500, P50HL070128, P01HL062250] Funding Source: NIH RePORTER
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Inhibitors selective for prostaglandin G/H synthase-2 (PGHS-2) (known colloquially as COX-2) were W designed to minimize gastrointestinal complications of traditional NSAIDs - adverse effects attributed to suppression of COX-1-derived PGE(2) and prostacyclin (PGI(2)). Evidence from 2 randomized controlled-outcome trials (RCTs) of 2 structurally distinct selective inhibitors of COX-2 supports this hypothesis. However, 5 RCTs of 3 structurally distinct inhibitors also indicate that such compounds elevate the risk of myocardial infarction and stroke. The clinical information is biologically plausible, as it is compatible with evidence that inhibition of COX-2-derived PGI(2) removes a protective constraint on thrombogenesis, hypertension, and atherogenesis in vivo. However, the concept of simply tipping a balance between COX-2-derived PGI(2) and COX-1-derived platelet thromboxane is misplaced. Among the questions that remain to be addressed are the following: (a) whether this hazard extends to all or some of the traditional NSAIDs; (b) whether adjuvant therapies, such as low-dose aspirin, will mitigate the hazard and if so, at what cost; (c) whether COX-2 inhibitors result in cardiovascular risk transformation during chronic dosing; and (d) how we might identify individuals most likely to benefit or suffer from such drugs in the future.
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