Triple Anti-platelet Therapy

Role of platelets in acute coronary syndromes (ACS) is well established. Anti-platelet agents are standard of care for the prevention of ACS. However, due to the high risk of bleeding, anti-platelet agents except aspirin are not indicated for the prevention of ACS in primary prevention population as the risk of an ACS event is low. However, individuals with established CAD are at an increased risk of subsequent events and aspirin is indicated for such patients. In addition, those who has had a stent placed, usually get dual anti-platelet therapy (aspirin + either clopidogrel, prasugrel, or ticagrelor). One would imagine that in a very high-risk population, inhibition of an additional pathway may provide additional benefit. However, the TRACER trial, found that addition of vorapaxar, an oral protease-activated-receptor 1 (PAR 1) antagonist that inhibits thrombin-induced platelet activation, had no additional benefit in patient with acute coronary syndrome. In stead, addition of vorapaxar to the standard dual anti-platelet regiment was associated with increase risk of major bleeding. This study, suggested that perhaps too much of platelet inhibition may not be beneficial for ACS prevention but increases risk of bleeding.

More recently, a meta-analysis found that adding cilostazol, another anti-platelet agent that acts by inhibiting phosphodiestrase, to standard dual anti-platelet therapy was associated with 36% reduction in major adverse cardiac events (MACE; odds ratio (OR) = 0.64; 95% confidence interval (CI) = 0.51-0.81, P < .01), a 40% reduction (OR = 0.60, 95% CI = 0.44-0.80; P < .01) in target vessel revascularization (TVR), a 44% reduction (OR = 0.56, 95% CI = 0.34-0.91; P = .02) in target lesion revascularization (TLR) and a 47%/44% reduction in in-segment/in-stent restenosis (P < .01) and lower in-segment/in-stent late loss (P < .01). The effect sizes are large showing that the addition of cilostazol is very effective in reducing events. Cilostazol also inhibits smooth muscle contraction resulting in peripheral arterial dilatation. It is possible that the beneficial effect may be due to a combination of these two effects.