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The current state of antiplatelet therapy in acute coronary syndromes: The data and the real world

April 1, 2009|Cleveland Clinic Journal of Medicine
John H. Alexander, MD, MHSc
Author and Disclosure Information

John H. Alexander, MD, MHSc
Associate Professor of Medicine, Duke Clinical Research Institute, Duke University Medical Center, Durham, NC

Correspondence: John H. Alexander, MD, MHSc, Duke University Medical Center, Duke Clinical Research Institute, DUMC Box 3850, Durham, NC 27715; john.h.alexander@duke.edu

Dr. Alexander reported financial relationships with Adolor (consulting), Bristol-Myers Squibb (research support), Daiichi Sankyo (consulting), Medicure (consulting and research support), Medtronic Japan (research support), Millennium Pharmaceuticals (equity interest and research support), Momenta Pharmaceuticals (research support), the National Institutes of Health (consulting and research support), Novartis (consulting), Pfizer (consulting), Regado Biosciences (research support), and Schering-Plough (research support).

This article was developed from an audio transcript of Dr. Alexander’s lecture at the CME course that formed the basis of this supplement. The transcript was edited and formatted by the Cleveland Clinic Journal of Medicine staff for clarity and conciseness, and was then reviewed, revised, and approved by Dr. Alexander.

Dr. Alexander received honoraria for contributing to this supplement and the CME course on which it was based. The honoraria were paid by the Cleveland Clinic Center for Continuing Education from the educational grant from Daiichi Sankyo, Inc., and Eli Lilly and Co. that supported the course and this supplement. These grantors had no input on the content of the course or this supplement.

ABSTRACT

Managing antiplatelet therapy for patients with acute coronary syndromes (ACS) is complex, and current therapy options and approaches for these patients are suboptimal. Despite the use of available antiplatelet therapies—aspirin, clopidogrel, and the parenteral glycoprotein IIb/IIIa inhibitors—recurrence of ischemic events in patients with ACS continues to rise over time. Moreover, bleeding remains an important—and often underappreciated—risk with these therapies, and national registries demonstrate that dosing of antiplatelet therapies frequently strays from evidence-based guidelines. Recent quality-improvement initiatives developed in conjunction with national registries of patients with ACS promise to improve adherence to guidelines through hospital-specific performance reports. More evidence-based use of existing and emerging antiplatelet agents has the potential to improve both ischemic and bleeding outcomes in patients with ACS.

KEY POINTS

  • Recurrent ischemic events have been observed in all antiplatelet trials to date, in spite of the addition of more potent antiplatelet regimens.
  • There appears to be a gradient of benefit from dual antiplatelet therapy depending on patients’ risk of thrombotic events (the greater the risk, the greater the benefit).
  • Local practice patterns in interventional therapy for ACS should be taken into consideration when applying results from clinical trials to clinical practice.
  • ACS patients who stand to benefit most from antiplatelet therapies also are at the greatest risk of bleeding from those therapies.
  • The importance of a tailored approach to antiplatelet therapy and dosing is becoming more widely recognized.

Initial conservative strategy

  • In patients being managed conservatively (ie, non­invasively), clopidogrel should be given as a loading dose of at least 300 mg followed by a maintenance dosage of at least 75 mg/day, in addition to aspirin and anticoagulant therapy as soon as possible, and continued for at least 1 month (class I, level A) and, ideally, up to 1 year (class I, level B).
  • If patients who undergo an initial conservative management strategy have recurrent symptoms/ischemia, or if heart failure or serious arrhythmias develop, diagnostic angiography is recommended (class I, level A). Either a glycoprotein IIb/IIIa inhibitor (class I, level A) or clopidogrel (class I, level A) should be added to aspirin and anticoagulant therapy upstream (before angiography) in these patients (class I, level C).
  • Patients classified as low risk based on stress testing should continue aspirin indefinitely (class I, level A). Clopido­grel should be continued for at least 1 month (class I, level A) and, ideally, up to 1 year (class I, level B). If a glycoprotein IIb/IIIa inhibitor had been started previously, it should be discontinued (class I, level A).
  • Patients with coronary artery disease confirmed by angiography in whom a medical management strategy (rather than PCI) is selected should be continued on aspirin indefinitely (class I, level A). If clopidogrel has not already been started, a loading dose should be given (class I, level A). If started previously, glycoprotein IIb/IIIa inhibitor therapy should be discontinued (class I, level B).
  • For patients managed medically without stenting, 75 to 162 mg/day of aspirin should be prescribed indefinitely (class I, level A), along with 75 mg/day of clopidogrel for at least 1 month (class I, level A) and, ideally, for up to 1 year (class I, level B).

Antiplatelet guidelines for stenting

Antiplatelet therapy is more complicated in the setting of stenting.

  • For patients in whom bare metal stents are implanted, aspirin should be prescribed at a dosage of 162 to 325 mg/day for at least 1 month (class I, level B) and then continued indefinitely at 75 to 162 mg/day (class I, level A). In addition, 75 mg/day of clopidogrel should be continued for at least 1 month and, ideally, up to 1 year unless the patient is at increased risk of bleeding (in which case it should be given for at least 2 weeks) (class I, level B).
  • For patients receiving drug-eluting stents, aspirin is recommended at a dosage of 162 to 325 mg/day for at least 3 months in those with a sirolimus-eluting stent and at least 6 months in those with a paclitaxel-eluting stent, after which it should be continued indefinitely at 75 to 162 mg/day (class I, level B). In addition, clopidogrel 75 mg/day is recommended for at least 12 months regardless of the type of drug-eluting stent (class I, level B).

No mention is made of dual antiplatelet therapy beyond 1 year.

At my institution, Duke University Medical Center, patients are assessed carefully for their ability and willingness to adhere to extended antiplatelet therapy before drug-eluting stents are implanted. This assessment includes an evaluation of their insurance status, their history of adherence to other prescribed drug regimens, their education level, and the dispenser of their medications.

No guidance on concomitant anticoagulation

One omission in the current ACC/AHA guidelines is the lack of guidance for patients who require concomitant antiplatelet therapy and anticoagulation. Such guidance is needed, as many patients with ACS also have indications for long-term anti­coagulation, such as atrial fibrillation or valvular heart disease requiring prosthetic valves. The ACC/AHA guidelines recommend simply that anticoagulation be added to patients’ antiplatelet regimens.

HOW ARE WE DOING? APPLICATION OF GUIDELINES IN PRACTICE

No discussion of guidelines is complete without consideration of their implementation. Those interested in the use of antiplatelet therapy in ACS are fortunate to have the Acute Coronary Treatment and Intervention Outcomes Network (ACTION) Registry, a collaborative voluntary surveillance system launched in January 2007 to assess patient characteristics, treatment, and short-term outcomes in patients with ACS (MI with and without ST-segment elevation). In addition to the registry, ACTION offers guidance on measuring ACS outcomes and establishing programs for implementing evidence-based guideline recommendations in clinical practice, improving the quality and safety of ACS care, and potentially investigating novel quality-improvement methods.20

Findings from ACTION’s first 12 months

In its first 12 months (January–December 2007), the ACTION Registry captured data from 31,036 ACS cases from several hundred US hospitals, according to the ACTION National Cardio­vascular Data Registry Annual Report (personal communication from Matthew T. Roe, MD, September 2008). Data were collected at two time points: acutely (during the first 24 hours after presentation) and at hospital discharge. One caveat to interpreting data from the ACTION Registry is the voluntary and retrospective reporting system on which it relies.

Intervention rates. Among patients with non-ST-segment MI in whom catheterization was not contraindicated, 85% underwent catheterization and 70% did so within 48 hours of presentation; 53% underwent PCI and 45% did so within 48 hours of presentation; and 13% underwent CABG. The median time to catheterization was 21 hours, and the median time to PCI was 19 hours.

Although many patients who go to the catheterization laboratory are managed invasively, many do not undergo PCI and are managed medically or with CABG following coronary angiography. The message, therefore, is that local practice patterns should be taken into consideration when results from clinical trials are applied to clinical practice.

Acute antiplatelet therapy. The 2007 ACTION Registry data showed that aspirin was used acutely (< 24 hours) in almost all patients in whom it was not contraindicated (97%), clopidogrel was used in 59%, and glycoprotein IIb/IIIa inhibitors were used in 44%. Given the ACC/AHA guidelines’ strong endorsement (class I, level A) of clo­pidogrel in this setting, one would expect wider use of clopidogrel in this context. Moreover, this relatively low rate of clopidogrel use (59%) cannot be explained by use of glycoprotein IIb/IIIa inhibitors instead, since this rate comprises patients who received clopidogrel either with or without a concomitant glycoprotein IIb/IIIa inhibitor; only 12% of patients received a glycoprotein IIb/IIIa inhibitor without clopidogrel. In contrast, a full 28% of patients received neither clopidogrel nor a glycoprotein IIb/IIIa inhibitor, contrary to current ACC/AHA guideline recommendations.

Antiplatelet therapy at discharge. At discharge, 97% of ACTION Registry patients were being treated with aspirin and 73% with clopidogrel. Notably, the use of clopidogrel at discharge was highly correlated with overall management strategy: whereas it was used in 97% of patients undergoing PCI, it was used in only 53% of patients being managed medically and in 31% of those undergoing CABG. These findings are somewhat reassuring since they generally mirror the strength of evidence supporting clopidogrel use in these different settings.

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