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].
Dual antiplatelet therapy duration
Optimal DAPT duration after PCI for NSTE‐ACS remains controversial. In the past extra‐long antiplatelet regiments were considered the norm to prevent thrombotic events, especially for ACS patients. In the era of new generation DES, shorter DAPT duration is being evaluated. Risk stratification tools, such as the PREdicting bleeding Complications In patients undergoing Stent implantation and subsEquent Dual Anti Platelet Therapy (PRECISE‐DAPT) score may help towards that direction [45]. The most recent guideline recommendations on DAPT duration from Europe and the United States are presented in Figure 12.3 [46,47].
Figure 12.3 American and European guidelines on optimal DAPT duration in ACS patients.
ACS, acute coronary syndrome; DAPT, dual antiplatelet therapy; HBR, high bleeding risk; MI, myocardial infarction.
In the Short and Optimal Duration of Dual Antiplatelet Therapy After Everolimus‐Eluting Cobalt‐Chromium Stent (STOPDAPT‐2) trial 1 month of DAPT followed by clopidogrel monotherapy compared to 12 months of DAPT demonstrated non‐inferiority as well as superiority for the primary endpoint of cardiovascular death, MI, ischemic or hemorrhagic stroke, definite stent thrombosis, or major or minor bleeding at 12 months. More importantly, the major secondary endpoint of cardiovascular death, MI, ischemic or hemorrhagic stroke, or definite stent thrombosis was not different between the two groups (1.96% vs 2.51%; p‐value=0.34, pnon‐inferiority= 0.005). However, of the 3045 patients enrolled in this trial, only 587 (19.5%) presented with an NSTE‐ACS [48]. Concurrently, the Smart Angioplasty Research Team: Comparison Between P2Y12 Antagonist Monotherapy vs Dual Antiplatelet Therapy in Patients Undergoing Implantation of Coronary Drug‐Eluting Stents (SMART‐CHOICE) trial randomized 2993 patients (47.7% NSTE‐ACS) to 3 months of DAPT and 9 months of P2Y12 inhibitor monotherapy versus the conventional 12 months of DAPT. The experimental arm achieved a statistically significant lower rate of bleeding type 2 to 5 according to Bleeding Academic Research Consortium (2.0% vs 3.4%; P = 0.02) and was non‐inferior for the primary endpoint of all‐cause death, myocardial infarction, or stroke at 1 year. (2.9% vs 2.5%; pnon‐inferiority= 0.007) [49]. The largest trial to date (n=7,487) the Clinical Study Comparing Two Forms of Anti‐platelet Therapy After Stent Implantation (GLOBAL LEADERS) failed to show that 1 month of aspirin plus ticagrelor followed by 23 months of ticagrelor monotherapy was superior to 1 year of dual antiplatelet therapy (DAPT) (aspirin plus either clopidogrel or ticagrelor) followed by 1 year of aspirin monotherapy for preventing adverse events among patients undergoing percutaneous coronary intervention (PCI) with a biolimus‐eluting stent [50].
The Ticagrelor with Aspirin or Alone in High‐Risk Patients after Coronary Intervention (TWILIGHT) trial enrolled 7119 high risk patients across 11 countries and randomized them to a conventional regiment of 12 months of DAPT with ticagrelor versus 3 months of DAPT followed by P2Y12 inhibitor monotherapy with ticagrelor. TWILIGHT reported lower bleeding (7.1% vs 4.0%; P<0.001) with no apparent ischemic harm (3.9% vs 3.9%; p for non‐inferiority <0.001) with monotherapy. The outcome was consistent across the stable CAD and NSTE‐ACS (35% of patients had unstable angina and 30% had NSTEMI ) subgroups [51]. In summary, a short DAPT regiment followed by P2Y12 monotherapy may be an appealing post‐PCI regiment, especially for patients at high bleeding risk [52].
Parenteral antiplatelet therapy
Intravenous (IV) antiplatelet medication include cangrelor and glycoprotein (GP) IIb/IIIa inhibitors. Cangrelor is a direct, quick onset and short acting IV P2Y12 inhibitor that was evaluated in the Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION) trials in ACS patients. A meta‐analysis of existing evidence published in 2013 reported fewer periprocedural ischemic complication at the cost of increased bleeding complications [53]. Moreover, the thrombotic benefit of cangrelor was attenuated in patients pretreated with clopidogrel during the CHAMPION PCI trial [54]. The most recent European guidelines give a class IIb recommendation for cangrelor administration only in P2Y12‐inhibitor naïve patients undergoing PCI [14]. Most of the evidence supporting GP IIb/ IIIa inhibitors (eptifibatide, or tirofiban) use in NSTE‐ACS patients was obtained in the era before routine use of DAPT. In a meta‐analysis by Boersma et al. GP IIb/ IIIa inhibitors were only beneficial in high risk patients with elevated troponin and in those who underwent revascularization within 30 days [55]. In a more contemporary setting, in the Early Glycoprotein IIb/IIIa Inhibition in Non–ST‐Segment Elevation Acute Coronary Syndrome (EARLY‐ACS) trial, routine upstream administration of eptifibatide did not benefit NSTE‐ACS patients, except patients at the highest risk for ischemic complications (such as those with troponin elevation, ST deviation, diabetes, recurrent ischemia) and low risk for bleeding (age <75 years). In addition, in the context of pre‐treatment with P2Y12 inhibitors, outcomes were favorable with use of bivalirudin alone versus unfractionated heparin and GPI during the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial. As a result, GP IIa/ IIIa inhibitors are currently primarily used for thrombotic bail out [14].