Novel antiplatelet strategies in acute coronary syndromes

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Clopidogrel achieves about 30% inhibition of platelet aggregation to ADP at its current FDA-approved loading dose of 300 mg and about 40% inhibition when its dose is doubled to 600 mg. These levels of inhibition are increased to 75% to 80% by clopidogrel’s fellow thienopyridine prasugrel, and this increase is attributable to prasugrel’s more efficient metabolism from prodrug to active metabolite. The reversible P2Y 12 receptor antagonist AZD6140 achieves a comparable 75% to 80% inhibition of platelet aggregation. The parenterally administered P2Y 12 receptor antagonist cangrelor achieves greater than 90% inhibition, as does the oral thrombin receptor antagonist SCH 530348, although the latter agent’s inhibition is to the agonist TRAP rather than ADP.

Time to peak effect

The time to peak effect with clopidogrel is approximately 4 hours regardless of the loading dose used (300 mg or 600 mg); this is substantially reduced with all of the investigational agents except SCH 530348. The novel agents’ reduced time to peak effect can offer advantages in speeding patients’ readiness to undergo catheterization procedures. This is particularly true for the IV agent cangrelor, which achieves its peak effect within minutes, although the 1-hour to 2-hour time frame with oral agents prasugrel and AZD6140 also would usually obviate any need to delay catheterization.

Consistency of platelet response

Standard-dose clopidogrel has the least consistency of platelet response among the therapies reviewed. Although increasing the clopidogrel dose yields somewhat greater consistency in response, it is still lower than the very high degrees of consistency observed with all of the novel compounds, each of which appears to achieve the same degree of inhibition of aggregation in virtually all patients.

Offset of effect

Both of the thienopyridines—clopidogrel and prasugrel—have an offset of effect of about 5 days, which requires delay of surgery, if possible, for several days in patients taking these agents. This is not an issue for the reversible oral agent AZD6140, whose offset of action takes just 1 to 2 days. While this rapid wearing-off of effect translates to a potential advantage for AZD6140, it also poses the potential drawback that a missed dose or two may leave the patient exposed to the risk of a thrombotic event. Cangrelor’s rapid offset of 20 minutes promotes its envisioned use as a catheterization lab–based medication like the glycoprotein IIb/IIIa inhibitors that can be started right before a PCI procedure and stopped immediately afterward. Because SCH 530348 has a very long half-life and thus a weeks-long washout period, the practicality of its use may depend on the hypothesis that thrombin receptor antagonists do not interfere with primary hemostasis, which is supported by data to date but remains to be definitively confirmed.


Clopidogrel achieves modest platelet inhibition with wide variability in response. Higher doses of clopidogrel achieve modestly greater degrees of inhibition than standard doses, and appear to result in a decreased rate of ischemic events. Although higher doses of clopidogrel have been embraced by some clinicians, we await definitive phase 3 trial evidence of net benefit before making high-dose clopidogrel the new standard of care.

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