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How Long Should Plavix be Used After Coronary Stenting?
Variability in Duration of Clopidogrel (Plavix) Therapy Following Percutaneous Coronary Intervention
Sarah A. Spinler, Pharm.D., FCCP
April 2004
The American College of Cardiology (ACC) and American Heart Association (AHA) first issued guidelines regarding antithrombotic therapy for percutaneous coronary intervention (PCI) with bare metal intracoronary stents in 1993 with revisions published in 2001. Specific guidelines stating that clopidogrel therapy (in addition to aspirin) should be administered for a minimum of 1 month and for up to 9 months in PCI patients were provided by the ACC/AHA in 2002. New guidelines are due to be released in mid-2004. Until that time, there are several clinical trials which differently impact the duration of clopidogrel therapy, used in combination with aspirin and often glycoprotein IIb/IIIa receptor blockers, for PCI.
There are several types of PCI procedures being performed in the U.S. at this time – most often, a drug-eluting intracoronary stent is inserted into the atheromatous coronary artery. In addition, bare metal intracoronary stents, balloon angioplasty and brachytherapy are also used. The rationale for different durations of clopidogrel therapy may relate to both the type of PCI and the clinical data supporting the use of clopidogrel for a particular duration of time for that type of PCI. The use of a thienopyridine (such as clopidogrel) in combination with aspirin reduces the rate of subacute stent thrombosis. The original STARS trial documented the benefit of ticlopidine, another type of thienopyridine, plus aspirin for one month over aspirin alone and aspirin plus clopidogrel at reducing sub-acute stent thrombosis. Clopidogrel has been shown to be safer than ticlopidine for intracoronary stent patients (CLASSICS). Therefore, the standard duration of clopidogrel therapy following implantation of a bare metal stent is one month. The PCI-CURE trial, a pre-planned subgroup analysis of the CURE trial, documented the benefit of a longer duration, 9 months and 1 year, respectively of the combination of clopidogrel plus aspirin following implantation of a bare metal stent at reducing the composite end point rate of death, myocardial infarction (MI), or stroke (CREDO) or death, MI or target vessel revascularization (TVR) in PCI-CURE in patients with a non-ST-segment elevation acute coronary syndrome (ACS) undergoing PCI with a bare metal stent. Therefore, some interventional cardiologists will chose to continue clopidogrel therapy for 9 months to a year following PCI. However, criticisms of the PCI-CURE trial were that few patients received a glycoprotein IIb/IIIa receptor blocker during the procedure and these agents have been shown to reduce the composite rate of death or MI for up to one year following bare metal stent placement (ESPRIT). In addition, there was no statistical benefit of clopidogrel over placebo seen between 30 days and 9 months, with 30 days being the standard duration of combination therapy post-PCI. The CREDO trial has been criticized in that the control group did not receive the standard 300 mg loading dose of clopidogrel prior to the procedure, but rather a dose of 75 mg which does not have significant early antiplatelet effects; and, again, glycoprotein IIb/IIIa receptor blockers were not used in the majority of patients.
Patients who receive a drug-eluting stent have mandated minimum durations of therapy with clopidogrel and aspirin following stent placement. Patients receiving a sirolimus-eluting stent need to receive clopidogrel plus aspirin for a minimum of 2 to 3 months following implantation, and those receiving a polymer-based paclitaxel-eluting intracoronary stent need to receive clopidogrel plus aspirin for a minimum of 6 months following stent implantation. All patients should receive aspirin therapy indefinitely. Patients undergoing Brachytherapy, or intracoronary radiation therapy, should receive clopidogrel in combination with aspirin for a minimum of 12 months based upon the 2001 ACC/AHA guidelines. Both the drug-eluting stents and Brachytherapy delay re-endothelialization of the artery following the procedure and extended duration of combination antiplatelet therapy is required to prevent late stent thrombosis.
Finally, evidence is available from retrospective analysis of the CPARIE trial with clopidogrel that patients who have atherosclerosis in other vascular beds, such as prior ischemic stroke or concurrent peripheral vascular disease, benefit from receiving clopidogrel over aspirin. Some cardiologists have concluded that these patients, who are at higher risk of a subsequent vascular event, would benefit from combined therapy. In addition, subgroup analysis from CAPRIE has documented that patients who have undergone coronary artery bypass surgery receive particular benefit from continuing combined antiplatelet therapy with clopidogrel and aspirin.
Thus the durations of clopidogrel therapy combined with aspirin that may be used range from one month to 3 months to 9 months to one year to life-long therapy! Further clarification and recommendations can be expected with publication of the 2004 ACC/AHA PCI guidelines.
References
1. Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, Jones RH, Kereiakes D, Kupersmith J, Levin TN, Pepine CJ, Schaeffer JW, Smith EE, 3rd, Steward DE, Theroux P, Gibbons RJ, Alpert JS, Faxon DP, Fuster V, Gregoratos G, Hiratzka LF, Jacobs AK, Smith SC, Jr. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction--summary article: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol 2002;40:1366-74.
2. Smith SC Jr., Dove JT, Jacobs AK, et al. ACC/AHA guidelines for percutaneous coronary intervention (revision of the 1993 PTCA guidelines). J Am Coll Cardiol 2001;37:2215-39.
3. Leon MB, Baim DS, Popma JJ, Gordon PC, Cutlip DE, Ho KK, et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med 1998;339:1665-7.
4. Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH, Investigators FT. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation 2000;102:624-9.
5. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK, Malmberg K, Rupprecht H, Zhao F, Chrolavicius S, Copland I, Fox KA. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358:527-33.
6. Steinhubl SR, Berger PB, Mann JT, 3rd, Fry ET, DeLago A, Wilmer C, Topol EJ. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;288:2411-20.
7. O’Shea JC, Buller CE, Cantor WJ, et al. Long-term efficacy of platelet glycoprotein IIb/IIIa integrin blockade with eptifibatide in coronary stent intervention. JAMA 2002;287:618-21.
8. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-39.
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