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Mind the DAP: Dual antiplatelet therapy as clopidogrel goes genericMay 21, 2012 11:45 EDT
With seven manufacturers just approved to produce generic clopidogrel in the US, Dr Seth Bilazarian ponders antiplatelet therapy in 2012.
What I think I know:
- Aspirin is critically important but dose is not critical (81–325 mg daily) for either efficacy or safety.
- Dual antiplatelet therapy (DAP) is useful in all ACS patients but critical in ACS patients treated with stents, especially with drug-eluting stents (DES).
- DAP=aspirin+one of three agents: generic clopidogrel, prasugrel (Effient), or ticagrelor (Brilinta)
- DAP reduced major adverse cardiac events (MACE) by 20% 11.4 to 9.3% in CURE with clopidogrel; NNT=47. Benefits extend out to one year.
- Clopidogrel 300 mg inhibits 80% of platelet aggregation in two hours and 60% at six hours. Better with 600 mg, not better than 900 mg. Better with 75 twice daily for seven days after PCI.
- Clopidogrel is a prodrug, has drug-drug interactions, has a later onset (six hours vs two hours) than newer therapies, and has resistance in the range of 15% to 63%, genetic variability in activation of prodrug.
- Variability with clopidogrel predicted by genetics or functional testing predicts clinical hazard.
- There is little variability in response to prasugrel or ticagrelor
- Effient (prasugrel) is more effective than clopidogrel, only studied in ACS with PCI, has three boxed warnings, and has higher rates of bleeding than clopidogrel 300/75. Benefits extend to a year.
- Ticagrelor (Brilinta), a cyclopentyl-triazolo-pyrimidine (CPTP), is more effective than clopidogrel, studied in ACS with and without PCI, does not have any boxed warnings, and has similar rates of bleeding as clopidogrel 300/75. Benefits extend to a year.
What I'm sure about:
- Some DAP is better than single antiplatelet therapy and no antiplatelet therapy. If a patient can't get a prescription for a new antiplatelet, clopidogrel is the best option. In cases of patient with higher risk or possible resistance, should dose be doubled?
- Door-to-balloon (DTB) times are shorter. Any delay in treatment or complexity in clinical pathway may contribute to delays (eg, boxed warning).
What I wish I knew now: Questions, uncertainty, inconvenience:
- What is the correct duration of DAP?
- What should be done about clopidogrel resistance?
- Is there a role for testing (genetic or functional)? Should testing be done in all patients or only those at high risk? Practically speaking, what is the best method for doing genetic or functional testing in the clinical setting?
- Is drug-drug interaction with proton-pump inhibitors (PPIs) real?
- How to get the pharmacy benefit managers (PBMs) to stop sending me letters about PPI and clopidogrel interaction?
- Are new agents preferred?
- Is prasugrel bleeding hazard worth the efficacy benefit?
- Does ticagrelor work in the US (PLATO trial)? Did the aspirin dose in PLATO explain the results? Is twice-daily compliance important? Is a CPTP agent beneficial in noncoronary vascular prevention?
- At discharge, can we switch post-ACS patients to generic clopidogrel?
- Is there a role for a third drug: rivaroxaban (Xarelto) or vorapaxar?
- If stent thrombosis occurs, should DAP choice be switched?
- Is switching from new agent to clopidogrel at discharge or at one month reasonable? (TRITON bleeding hazard after three days)
- How can we do a better job with medication adherence? Cardiac rehab, discharge planning, PBM policies?
- Will all seven generic manufacturers of clopidogrel produce a quality drug?
To download a PDF version of this list, click here.