vs. 35% inhibition of platelet aggregation) and have a faster onset of antiplatelet activity (30 min for onset, 2 hours for peak effect), without the interindividual response variability and the 30% hypo-responsiveness seen with clopidogrel. These agents have only been studied in ACS (ACS receiving PCI for prasugrel, ACS receiving PCI or medical therapy for ticagrelor).156,157 In comparison with clopidogrel, both have shown further reduction of combined death/MI at the expense of a higher major bleeding risk. Their superiority is particularly marked in the three highest-risk patient groups (STEMI, diabetes, and recurrent ACS).158,159 On the other hand, three subsets of patients have a marked bleeding risk with prasugrel without any net benefit, and these are contraindications to prasugrel use: (i) history of stroke/TIA, (ii) age > 75, (iii) weight < 60 kg (the latter two are relative contraindications). ESC guidelines give a class I preference to ticagrelor or prasugrel over clopidogrel in ACS. Yet, one should consider the ischemic risk as well as the age; in patients older than 70, clopidogrel compared favorably to ticagrelor, with less bleeding and similar ischemic outcomes (POPular age trial).Compared with prasugrel, ticagrelor has the following features: (i) reversible ADP receptor binding which allows reversal of the antiplatelet effect at 3–4 days (vs. 5 days with clopidogrel and 7 days with prasugrel); (ii) ticagrelor increases the release of adenosine, which may improve coronary flow but may also increase the risk of bronchospasm or asymptomatic pauses; (iii) ticagrelor did not increase fatal bleeding and did not specifically harm patients with a prior stroke or patients older than 75, yet both ticagrelor and prasugrel should be used carefully, if at all, in patients deemed at a high bleeding risk; (iv) ticagrelor is indicated not only in patients managed with PCI but also in high-risk ACS patients managed conservatively or not deemed appropriate for revascularization. In the latter patients, ticagrelor strikingly reduced death/MI in comparison to clopidogrel; conversely, prasugrel has not shown any benefit in patients not receiving PCI (TRILOGY-ACS trial); (v) ticagrelor or clopidogrel may be administered on admission, upstream of coronary angiography, whereas prasugrel should only be administered after coronary angiography is performed and the need for CABG ruled out (in the event CABG is needed, its performance within 7 days of prasugrel therapy drastically increases the bleeding risk).160Table 1.7 Comparison of the three oral ADP-receptor antagonists.ClopidogrelPrasugrel (60 mg load, 10 mg maintenance)Ticagrelor (180 mg load, 90 mg BID maintenance)Inhibition of platelet activation35–40%75%75%Activation*Prodrug becomes active metabolite *Inefficient metabolization by CYP2C19 explains 30% clopidogrel hyporesponsiveness*Prodrug becomes active metabolite *~Always efficiently metabolized by cytochromesActive drug and active metaboliteOnset of action (i.e., time to 30% platelet inhibition)600 mg: 2 h 300 mg: 6–24 h30 min30 minPeak effect (hours)600 mg: 6–8 h2–42–4Offset of action (days)a573–4Population studied and indicationsNon-ST elevation or ST elevation ACS managed conservatively or invasively Any PCI (stable or unstable)Non-ST elevation or ST elevation ACS managed by PCI (not conservatively) Not superior to clopidogrel in stable PCINon-ST elevation or ST elevation ACS managed conservatively or invasivelyAbsolute reduction of death/MI/stroke in comparison to clopidogrel (at 1 yr)—2%2%Mortality reduction in comparison to clopidogrel (at 1 yr)—None, except in the STEMI subgroup1%Stent thrombosis reduction in comparison to clopidogrel—1.3%0.7%BleedingAbsolute increase in TIMI major bleeding compared to clopidogrel (non-CABG related)Increase in CABG-related bleedingIncrease in fatal bleeding 0.6% 4 times Yes 0.6% No No (but increases intracranial bleeding)High-risk subgroups where it should be avoided—Prior stroke/TIA (absolute contraindication) Weight < 60 kg Age > 75No specific subgroupsaNote that the duration of effect is related to both the pharmacokinetic half-life and the reversibility of receptor binding. Aspirin, clopidogrel, and prasugrel have a relatively short half-life yet a very prolonged duration of action, as they irreversibly affect their target. Ticagrelor reversibly binds to ADP receptor but has a long half-life of ~15 h, accounting for both ticagrelor and its metabolite, which translates into a duration of action of 3–4 days. Cangrelor reversibly binds to ADP receptor and has a very short half-life, translating into a duration of action of 1 hour.Despite those features, one head-to-head ACS trial of upstream ticagrelor vs downstream prasugrel, ISAR-REACT-5, showed superiority of downstream prasugrel on MI/death reduction; in a way, this also adds to the evidence that only downstream ADP-receptor antagonist therapy is needed.69
4 Cangrelor is a very potent intravenous ADP-receptor antagonist (90% inhibition of platelet aggregation), reversible, and has a very short half-life. It is infused for the total duration of PCI (and for a total duration of at least 2 hours) and has a very short onset and offset of action (1 hour). It has been studied in stable and unstable CAD patients who have not received clopidogrel upstream of PCI, where it has allowed a quick and potent onset of an ADP antagonist effect during PCI.161 It reduces acute stent thrombosis and intraprocedural complications, and increases minor but not major bleeding, with no overall mortality benefit (Champion trials). Clopidogrel or prasugrel must be started at the end of the infusion; if given during the infusion, cangrelor would prevent ADP-receptor binding of their short-lived metabolite, which would be eliminated by the end of the infusion. On the other hand, ticagrelor may be given during cangrelor infusion, as its plasma half-life is longer. Cangrelor is considered in ADP-receptor antagonist-naïve patients undergoing PCI, in the setting of ACS or stable CAD (class IIb).4 It may be particularly useful in shock states, wherein the absorption of oral agents is limited, and in high-risk PCI.
5 Glycoprotein IIb-IIIa inhibitors (GPIs). GPIs are potent IV antiplatelet drugs that block the final common pathway of platelet aggregation (inhibit 95% of platelet aggregation). This comes at the expense of an absolute 2–4% increase in major bleeding risk.38 In particular, GPI therapy upstream of coronary angiography was associated with an increase in bleeding without a significant reduction in ischemic events (EARLY ACS trial).60 Thus, those drugs are typically used during PCI in some patients with elevated troponin, specifically those with heavy thrombus burden or PCI complications.36,162 The bleeding risk associated with GPI drastically increases in patients older than 70, women, and patients with CKD.
Upstream ADP-receptor antagonist therapy, before coronary angiography, theoretically serves to: (i) reduce ischemic events pre-PCI (CURE trial), (ii) optimize PCI outcomes and reduce thrombotic complications during PCI and early afterwards. However, ACCOAST trial (using prasugrel), ISAR-REACT-5 trial, and the large SCAAR registry have shown that this upstream initiation rather increases bleeding and does not reduce peri-PCI ischemic events, particularly when catheterization is performed within a few hours of presentation and a potent and fast ADP-receptor antagonist is used. In SCAAR, clopidogrel was used in half the patients and mean time to catheterization was 1.9 days, yet despite that, preloading was not beneficial. Based on those trials, aspirin and an anticoagulant appear sufficient before a timely PCI, and ESC guidelines recommend against upstream ADP-receptor antagonist (class III).69,70
Upstream ADP-receptor antagonist is more readily avoided when extensive CAD requiring CABG seems probable, e.g., a man with elevated troponin and PAD, HF, or insulin-dependent diabetes; or a patient with extensive ST segment depressions in ≥ 6 leads or ST elevation in aVR.
B. Clopidogrel resistance is seen in ~30% of patients
Clopidogrel resistance is defined as < 30% inhibition of ADP-induced platelet aggregation; or as an absolute platelet reactivity to ADP of < 208–230 platelet reactivity units (using a quick point-of-care assay, VerifyNow assay). Clopidogrel resistance is related to impaired clopidogrel activation and is at least partly genetic, determined by mutations of the cytochrome genes (particularly CYP2C19). Other factors, such as ACS presentation, obesity, and CKD may contribute.
Poor clopidogrel response is associated with an increased risk of coronary events and stent thrombosis. However, in hyporesponsive patients undergoing PCI for stable CAD, the tailored use of prasugrel or a higher clopidogrel maintenance (150 mg) did not translate into a clinical benefit (TRIGGER-PCI).163 In fact, stable CAD PCI is associated with a low risk of stent thrombosis and adverse outcomes even in poor clopidogrel responders, reducing the benefit of more potent antiplatelet