platelet ADP receptor eventually leads to conformational activation of the IIb/IIIa receptors. Clopidogrel and prasugrel (thienopyridines) are prodrugs that get metabolized into the same active metabolite. This active metabolite irreversibly binds to the P2Y12 ADP receptor, extending the pharmacodynamic effect of these drugs to 5–7 days despite a half-life of 6 h. The prodrugs are metabolized by cytochromes (CYP), particularly CYP2C19; only 15% of clopidogrel vs. 100% of prasugrel is actively metabolized. This explains why prasugrel is a much more potent inhibitor of platelet aggregation (~75% vs. ~35% inhibition of platelet aggregation).
Some patients have a CYP2C19 mutation that slows clopidogrel metabolism and preferentially increases its inactivation by esterases, translating into a poor or no response to clopidogrel. Prasugrel, on the other hand, has only one metabolic pathway, and will be metabolized by cytochromes regardless of how slow the metabolism is.
Ticagrelor directly binds to the P2Y12 ADP receptor and reversibly inhibits it (the effect clears as the drug clears from plasma). Despite being a reversible ADP antagonist, the very potent ADP blockade and the long half-life translate into an antiplatelet effect that lasts 3–4 days (half-life ~15 h). Since it directly acts on its receptor, the response to ticagrelor is consistent and potent (~75% platelet inhibition), including in clopidogrel non-responders.
Cangrelor is an intravenous ADP receptor antagonist that directly and reversibly binds to the ADP receptor. It inhibits 90% of the platelet aggregation. In contrast to ticagrelor, it has a short half-life of 5 min, which, in addition to the reversible receptor binding, leads to a very quick onset and offset of action.
Thrombin is also a potent activator of platelet aggregation. Vorapaxar blocks the thrombin receptor.
Cyclic AMP, promoted by cilostazol, inhibits platelet aggregation.
The IIb/IIIa receptor is the final common pathway of platelet aggregation and allows linking of the platelets through fibrinogen molecules.
C. Anticoagulant therapy (see Appendix 4 for a detailed discussion)
Four anticoagulants are considered in NSTE-ACS: (i) unfractionated heparin (UFH), (ii) enoxaparin, (iii) bivalirudin, and (iv) fondaparinux. Upon admission, anticoagulation with any one of these four drugs should be initiated (class I recommendation). During PCI, either UFH or bivalirudin is used (Figures 1.5, 1.6; Table 1.3).
In NSTEMI, the anticoagulant is not usually withheld before the catheterization procedure.
The dose of UFH used in NSTEMI is lower than the dose used in PE, with a PTT goal of 46–70 seconds. As cornerstone antiplatelet therapy is administered, moderate rather than high-level anticoagulation is appropriate for ischemic reduction in ACS and minimizes bleeding, which is a powerful prognostic marker in ACS.
Anticoagulants are typically stopped after the performance of PCI. If PCI is not performed, anticoagulants are typically administered for at least 48 hours (up to 8 days). Longer therapy reduces rebound ischemia, which mainly occurs with heparin.
In patients undergoing catheterization, upstream enoxaparin therapy is associated with a higher bleeding risk than UFH. Moreover, the switch between enoxaparin and UFH increases the bleeding risk and should be avoided. If the patient is going for an invasive strategy and the operator prefers not to use enoxaparin during PCI, the patient should receive UFH on admission, not enoxaparin.
During PCI, a switch from UFH to bivalirudin, or from fondaparinux to other anticoagulants has not shown harm.
Figure 1.5 Specific effects of the four anticoagulants.
A heparin derivative induces a conformational change in antithrombin III (AT III), which, according to the size of the heparin–AT III complex, predominantly inactivates Xa or the active thrombin. UFH inactivates thrombin preferentially, while low-molecular-weight heparin (LMWH) inactivates Xa preferentially. The smaller fondaparinux molecule inactivates Xa exclusively. The inactivation of Xa eventually inhibits thrombin generation rather than thrombin activity. Heparin activates platelets directly by binding to them, which also triggers antiplatelet antibodies (HIT).
The oral direct thrombin inhibitor (dabigatran) and the oral Xa antagonists (apixaban, rivaroxaban) are used to treat AF, not ACS.
Figure 1.6 Summary of anticoagulant use in NSTE-ACS, before catheterization and during PCI.
Operators who are not comfortable with performing PCI solely under the coverage of a prior subcutaneous dose of enoxaparin should avoid starting enoxaparin on admission and should use any of the other three agents upfront.
D. Anti-ischemic therapy and other therapies
Table 1.3 Summary of antithrombotic therapy in ACS.
| Antiplatelet therapy |
| 1.Aspirin 325mg on admission to all, then 81 mg daily (after a 325mg first dose) |
| 2.Clopidogrel 300mg or ticagrelor 180mg may be used on admission, but in the era of expedite catheterization <24 hours, ADP receptor antagonists are best reserved for downstream use, during PCI |
| 3. After coronary angiography, if PCI is to be performed: |
| Add 300 mg of clopidogrel if 300 mg has already been given |
| or load with 600 mg of clopidogrel in the lab if no clopidogrel has been given |
| or load with prasugrel 60 mg (even if clopidogrel has been given) |
| or load with ticagrelor 180 mg (even if clopidogrel has been given) |
| or infuse IV cangrelor for 2 hours, not if patient already received P2Y12-antagonist, then load with oral P2Y12-antagonist as infusion finishes |
| GPI if PCI complications or heavy thrombus burden (bailout use of GPI) |
| Anticoagulant therapy |
| UFH pre-catheterization and during PCI |
| or UFH pre-catheterization and switch to bivalirudin during PCI |
| or Fondaparinux 2.5mg SQ once daily pre-catheterization, with standard-dose UFH or bivalirudin during PCI |
|
or Enoxaparin pre-catheterization. If patient received 1 mg/kg SQ within 8h of PCI and has already received two doses of enoxaparin, no additional anticoagulation
|