Response to Letter Regarding Article, “Stent Thrombosis With Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes: An Analysis From the Prospective, Randomized PLATO Trial”
Authors: P. Gabriel Steg, Robert A. Harrington, Håkan Emanuelsson, Hugo A. Katus, Kenneth W. Mahaffey, Bernhard Meier, Robert F. Storey, Daniel M. Wojdyla, Basil S. Lewis, Gerald Maurer, Lars Wallentin, Stefan K. James
Journal: Circulation (2014)

We thank Drs Roguin and Musallam for their thoughtful comments on our article. 1They suggest that stent thrombosis rates may be higher than reported in the main Platelet Inhibition and Patient Outcomes (PLATO) article (1.3% versus 1.9% for ticagrelor versus clopidogrel) when patients with stents implanted before enrollment are excluded. 2Our article provided both types of analyses (in Figure 1 and Table 5).Excluding patients with stents placed before trial enrollment has no material impact on stent thrombosis rates, which are then 1.2% versus 1.9% for ticagrelor versus clopidogrel (Although the denominator for calculating stent thrombosis rates is smaller, the numerator is also lower because some stent thromboses occurred during the trial in stents placed before entry in the trial).Their second comment pertains to the rate of prior drug discontinuation among patients experiencing stent thrombosis.A substantial fraction of patients who experienced stent thrombosis were no longer on study drug, although the vast majority of these patients (79% [52 of 66] for ticagrelor and 72% [46 of 64] for clopidogrel) had discontinued study drug for <30 days.This is not "problematic" but merely reflects the very strong relation between the discontinuation of antiplatelet therapy and the risk of stent thrombosis.In a recent international registry, the risk of stent thrombosis was tripled when dual antiplatelet therapy was "disrupted" (ie, stopped because of bleeding or noncompliance), 3 but the risk was increased 18-fold in the first 7 days after disruption and >4-fold 8 to 30 days after disruption.The rates of premature discontinuation of study drug in the PLATO stent thrombosis analysis were 17.3% and 16.3% in the ticagrelor and clopidogrel groups, respectively, and compliance was similar between the 2 study arms.Therefore, the difference in stent thrombosis rates is not a reflection of greater discontinuation rates or worse compliance with clopidogrel but rather a reflection of the greater protection against stent thrombosis afforded by ticagrelor.Indeed, Table III in the online-only Data Supplement shows that adjusting for compliance does not modify the lower relative risk of stent thrombosis with ticagrelor (unadjusted hazard ratio, 0.67: hazard ratio when adjusted for compliance, 0.66).Finally, Drs Roguin and Musallam suggest that the adjudication of suspected stent thromboses was not consistent with the Academic Research Consortium definition because it did not involve core laboratory review of angiograms.In fact, the Academic Research Consortium defined definite stent thrombosis as requiring angiographic or pathological confirmation of stent thrombosis, 4 but because both are often unavailable, the consortium created the broader definitions of probable and possible stent thrombosis.The stent thrombosis events in PLATO were all adjudicated according to these exact Academic Research Consortium definitions and categories, and even though there was no core laboratory review of angiograms, whenever angiographic information was available from catheterization laboratory or hospital reports, it was made available to the clinical event committee, which was blinded to treatment assignment.Ticagrelor reduced the risk of stent thrombosis across all categories, and if anything, the more specific the definition was, the greater the reduction was relative to clopidogrel (relative reduction: 33% for definite stent thrombosis, 25% for definite or probable thrombosis, and 23% for any stent thrombosis).