NSAIDS
Nonselective NSAIDS, such as ibuprofen, inhibit both cyclooxygenase1 and 2, and thus alter thromboxane A2 synthesis and platelet aggregation (Figure 1). However, unlike aspirin, the effects of these drugs are reversible and last for a shorter period of time, based upon the half-life of the individual drug.27 When the drug is removed from the body, platelet function is restored. A recent study demonstrated that platelet function returned to normal within 24 hours of discontinuation of ibuprofen use in healthy individuals.76 Many professionals continue to recommend discontinuing the use of NSAIDS at least 7 days prior to surgery, when in fact, a much shorter timeframe may suffice. Practitioners should look up the half-life of the NSAID to determine how long it will take for the drug to clear from the body.
The degree of platelet inhibition seems to vary among different nonselective NSAIDS, but for most drugs, this effect does not appear to last throughout the length of the dosing period. For example, taking naproxen 500 mg twice daily inhibits platelet aggregation throughout the dosing period, versus ibuprofen, which achieves adequate platelet inhibition at peak levels, but is not sustained, given the short half-life of the drug. Further, data suggests that the antiplatelet effects of naproxen are significant and comparable to those produced by aspirin, but are less with ibuprofen and diclofenac.77 This suggests that naproxen may have greater cardioprotective properties than other NSAIDS. The variance in effect on platelet inhibition is among the many reasons why NSAIDS are not used for cardioprotective therapy.
A large epidemiologic study found no evidence of cardioprotective effects of traditional NSAIDS.78 Several studies concluded that current use of NSAIDS does not substantially reduce the risk of acute myocardial infarction (MI).79,80,81,82 Given the effects of naproxen, several investigations examined whether naproxen therapy could reduce the risk for MI; study results were inconclusive.80,81,83,84,85,86,87,88 There is also increasing evidence that concurrent use of NSAIDS with aspirin may decrease the cardioprotective effects of aspirin.89,90,91
A recent retrospective case-control analysis of 8688 case patients with first-time acute MI revealed that current use of NSAIDS does not alter the risk of acute MI. Further, the risk for acute MI was higher among subjects who stopped taking NSAIDS within 2 months before the MI occurred. The authors hypothesize that current NSAID use does offer some protective effect, such as reducing MI risk related to chronic inflammation, but that this effect only occurs while the drug is being taken.92
Selective NSAIDS, known as the COX-2 inhibitors (eg, Celebrex®, Vioxx®, Bextra®), inhibit cyclooxygenase 2 without affecting cyclooxygenase 1. Thus, their effects predominantly alter prostacyclin versus thromboxane A2 (Figure 1). Studies in healthy volunteers show that treatment with COX-2 inhibitors decreases systemic production of prostacyclin with no effects on platelet-derived thromboxane A2 synthesis.79,93
Expression of cyclooxygenase 2 is increased during ischemia, which is thought to be a protective mechanism against vascular injury, causing increased prostacyclin synthesis, resulting in vasodilation and decreased platelet aggregation to facilitate blood flow. Inhibition of the COX-2 enzyme blocks these protective effects, and because platelet thromboxane A2 is unaffected, the balance of the equilibrium maintained between these 2 prostanoids becomes disrupted. This allows the influence of thromboxane to predominate, increasing vasoconstriction and clotting. This is the mechanism thought to underlie the adverse hypertension and stroke events found with long-term use of COX-2 inhibitors (eg, Vioxx®)
