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An oral P2Y12 inhibitor should be administered in addition to aspirin to all NSTE‐ACS patients. Three oral P2Y12 inhibitors are currently being used: clopidogrel, prasugrel, and ticagrelor (ticlopidine is seldom used because of potentially serious hematologic side effects).

The first P2Y12 inhibitor studied was clopidogrel, a prodrug that requires multistep activation in the liver. In the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial, dual antiplatelet therapy (DAPT) was shown to be superior to aspirin monotherapy in reducing the incidence of the composite of cardiovascular death, MI, or stroke (9.3% vs 11.4%; p<0.001) after nine months of follow‐up in NSTE‐ACS [34]. Optimal clopidogrel dosing was studied during the Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events−Seventh Organization to Assess Strategies in Ischemic Syndromes 7 (CURRENT–OASIS 7) trial, in which doubling clopidogrel dose early after the procedure was shown to lower the risk of stent thrombosis (1.6% vs 2.3%; p‐value < 0.001) at the cost of increased major bleeding (2.5% vs 2.0%; p = 0.01) while there was no difference in the primary outcome of 30‐day cardiovascular death, MI, or stroke (4.2% vs 4.4%; p = 0.30) [35]. One of the main limitations of clopidogrel is the large number of patients with inadequate response due to CYP 2C19 gene polymorphisms [36]. In the POPular Genetics trial that randomized 2488 STEMI patients undergoing primary PCI to a genotype‐guided strategy for selection of oral P2Y12 inhibitor or with standard therapy with ticagrelor or prasugrel. Approximately 40% were clopidogrel non‐respondents. At 12 months the incidence of death from any cause, myocardial infarction, definite stent thrombosis, stroke, or major bleeding was 5.1% in the genotype‐guided group vs 5.9% in the standard‐treatment group P<0.001 for noninferiority), with lower incidence of PLATO major or minor bleeding in the genotype‐guided group [37].

Prasugrel is another prodrug with potent antiplatelet properties but unlike clopidogrel has a very efficient conversion to its active metabolite. In the trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction 38 (TRITON–TIMI 38) 13,608 PCI patients (74% NSTE‐ACS) were randomized to prasugrel or clopidogrel (300 mg loading dose). During a median follow‐up of 14.5 months, compared with clopidogrel, prasugrel reduced the incidence of cardiovascular death, MI, or stroke (9.9% vs 12.1%; p <0.001), and the risk for stent thrombosis (of both bare metal and drug‐eluting stents) [38], but also increased the risk for TIMI major and fatal bleeding. Subgroup analyses showed that prasugrel was harmful in patients with prior transient ischemic attack or stroke and failed to provide net clinical benefit among patients ≥75 years old or with <60 kg body weight [39]. Pretreatment with prasugrel was not beneficial during a Comparison of Prasugrel at PCI or Time of Diagnosis of Non‐ST Elevation Myocardial Infarction (ACCOAST) trial [40] and it should be avoided in patients with medically treated NSTE‐ACS according to the results of the TRILOGY‐ACS trial [41].

The third oral antiplatelet agent currently in use is ticagrelor, a reversible, direct‐acting P2Y12 inhibitor. The Platelet Inhibition and Patient Outcomes (PLATO) trial, randomized 18 624 patients (62% of whom had NSTE‐ACS) to ticagrelor or clopidogrel. Compared with clopidogrel, ticagrelor reduced the 12‐month incidence of vascular death, MI, or stroke (9.8% vs 11.7%; p < 0.001) and also reduced all‐cause mortality (4.5% vs 5.9%; p < 0.001). However, ticagrelor‐treated patients had higher rate of non‐CABG related major bleeding, dyspnea, and ventricular pauses lasting ≥3 s (but not requiring specific treatment) [42]. North American patients did not derive benefit from ticagrelor administration, possibly due to co‐administration of ≥100 mg/day aspirin [43]. However, when compared with prasugrel in ACS patients in the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR‐REACT) 5 trial ticagrelor had a higher incidence of death, MI or stroke (6.9% vs 9.3%, P=0.006), while the two groups had comparable rates of major bleeding [44].