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Controversies in non-ST-elevation acute coronary syndromes and percutaneous coronary interventions

Cleveland Clinic Journal of Medicine. 2010 February;77(2):101-109 | 10.3949/ccjm.77gr.32009
February 1, 2010|Cleveland Clinic Journal of Medicine
Deepak L. Bhatt, MD, MPH
Author and Disclosure Information

Deepak L. Bhatt, MD, MPH
Chief of Cardiology, VA Boston Healthcare System; Director, Integrated Interventional Cardiovascular Program, Brigham and Women’s Hospital and the VA Boston Healthcare System; Senior Investigator, TIMI Study Group; Associate Professor of Medicine, Harvard Medical School, Boston, MA

Address: Deepak L. Bhatt, MD, MPH, VA Boston Healthcare System and Brigham and Women’s Hospital, Cardiovascular Division, 75 Francis Street, PBB-146 Boston, MA 02115; e-mail dlbhattmd@post.harvard.edu

Medical Grand Rounds articles are based on edited transcripts from Education Institute Department of Medicine Grand Rounds presentations at Cleveland Clinic. They are approved by the author but are not peer-reviewed.

Dr. Bhatt has disclosed that he has been the principal investigator in several potentially related studies. His institution has received research funding from Astra Zeneca, Bristol-Myers Squibb, Eisai, Ethicon, Heartscape, Sanofi-Aventis, and The Medicines Company. This paper discusses offlabel and investigational uses of various drugs and stents.

ABSTRACTNon-ST-elevation myocardial infarction (MI) and unstable angina represent the majority of acute coronary syndromes. Recent studies have helped clarify treatment strategies. Drug-eluting stents have reduced the problem of restenosis, but questions remain about the length of time patients need dual antiplatelet therapy.

KEY POINTS

  • The data favor an aggressive strategy of routine catheterization, rather than a conservative strategy of catheterization only if a patient develops recurrent, spontaneous, or stress-induced ischemia.
  • Early percutaneous intervention (within 24 hours) may be beneficial in patients at higher risk, but not necessarily in those at lower risk.
  • Drug-eluting stents appear safe, assuming dual antiplatelet therapy is used. It is unclear how long this therapy needs to be continued.
  • The choice of revascularization strategy—bypass surgery, bare-metal stent, or drug-eluting stent—should be individualized based on the risk of restenosis, thrombosis, and other factors.

Should nonresponders get higher doses of clopidogrel?

In vitro, response to clopidogrel shows a normal bell-shaped distribution.30 In theory, therefore, patients who are hyperresponders may be at higher risk of bleeding, and those who are hyporesponders may be at risk of ischemic events.

A clinical trial is under way to examine whether hyporesponders should get higher doses. Called GRAVITAS (Gauging Responsiveness With a VerifyNow Assay Impact on Thrombosis and Safety), it will use a point-of-care platelet assay and then allocate patients to receive either standard therapy or double the dose of clopidogrel. The primary end point will be the rate of cardiovascular death, nonfatal MI, or stent thrombosis at 6 months.

Is prasugrel better than clopidogrel?

Prasugrel (Effient) is a new drug of the same class as clopidogrel, ie, a thienopyridine, with its active metabolite binding to the same platelet receptor as clopidogrel and inhibiting platelet aggregation more rapidly, more consistently, and to a greater extent than clopidogrel. Prasugrel was recently approved by the Food and Drug Administration. But is it better?31

The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction (TRITON-TIMI 38) compared prasugrel and clopidogrel in 13,608 patients with moderate- to high-risk acute coronary syndromes who were scheduled to undergo percutaneous coronary intervention.32

Overall, prasugrel was better. At 15 months, the incidence of the primary end point (death from cardiovascular causes, nonfatal MI, or nonfatal stroke) was significantly lower with prasugrel therapy than with clopidogrel in the entire cohort (9.9% vs 12.1%, hazard ratio 0.81, 95% CI 0.73–0.90, P < .001), in the subgroup with ST-segment elevation MI, and in the subgroup with unstable angina or non-ST-elevation MI.

However, there was a price to pay. The rate of major bleeding was higher with prasugrel (2.4% vs 1.8%, hazard ratio 1.32, 95% CI 1.03–1.68, P = .03). Assessing the balance between the risk and the benefit, the investigators identified three subgroups who did not derive a net clinical benefit from prasugrel: patients who had had a previous stroke or transient ischemic attack (this group actually had a net harm from prasugrel), patients 75 years of age or older, and patients weighing less than 60 kg (132 pounds).

More work is needed to determine which patients are best served by standard-dose clopidogrel, higher doses of clopidogrel, platelet-assay-guided dosing of clopidogrel, or prasugrel.24

Short-acting, potent intravenous platelet blockade with an agent such as cangrelor is theoretically appealing, but further research is necessary.33,34 Ticagrelor, a reversible adenosine diphosphate receptor antagonist, provides yet another potential option in antiplatelet therapy for acute coronary syndromes. In the recent PLATO trial (Study of Platelet Inhibition and Patient Outcomes), compared with clopidogrel, ticagrelor reduced the risk of ischemic events, including death.35,36 Here, too, there was more major bleeding (unrelated to coronary artery bypass grafting) with ticagrelor.

Thus, clinical assessment of an individual patient’s ischemic and bleeding risks will continue to be critical as therapeutic strategies evolve.

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