Selective COX-2 inhibitors (coxibs) were associated with increased cardiovascular events. The biochemical explanation is best described as:

• A COX-2 inhibition selectively reduces prostacyclin (PGI2) synthesis in vascular endothelium while leaving COX-1-dependent platelet thromboxane A2 (TXA2) unopposed, tipping the balance toward thrombosis ✓
• B COX-2 inhibition increases leukotriene synthesis through shunting of arachidonic acid, promoting inflammation and plaque instability
• C Coxibs directly inhibit adenosine diphosphate receptors on platelets causing paradoxical aggregation
• D COX-2 inhibition prevents prostaglandin E2 synthesis in the kidney, causing sodium retention and hypertension exclusively

Explanation

Endothelial prostacyclin (PGI2) is produced largely via COX-2, while platelet TXA2 depends primarily on COX-1. Selective COX-2 inhibition reduces prostacyclin (anti-platelet, vasodilatory) without affecting platelet TXA2 (pro-aggregatory, vasoconstrictive), creating a prothrombotic imbalance. This mechanism, demonstrated with rofecoxib in the VIGOR trial and subsequently with other coxibs, led to withdrawal of some agents. Renal sodium retention also contributes to cardiovascular risk but is not the primary thrombotic mechanism.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.