Antiplatelet Therapy for Acute Coronary Syndrome

Orlando, FL—Antiplatelet and anticoagulant therapies are crucial in the management of patients with acute coronary syndrome (ACS). Platelet activation remains a major pathophysiological issue in ACS. Platelets upregulate the expression of receptors promoting aggregation and thrombosis during ACS, according to R. Scott Wright, MD, FACC, FESC, FAHA, professor of medicine, Mayo Clinic College of Medicine, who discussed antiplatelet therapy at NAMCP.

ACS refers to a spectrum of conditions compatible with acute myocardial ischemia and/or infarction due to an abrupt reduction in blood supplied to the heart muscle. ACS encompasses unstable angina, non–ST-elevation myocardial infarction (NSTEMI), and ST-elevation myocardial infarction (STEMI). Non–ST-elevation acute coronary syndrome includes unstable angina and NSTEMI. 

Guidelines stress the importance of these therapies with initial stabilization and long-term management of ACS patients, Dr Wright said, noting that the role of aspirin in the acute and long-term management of patients with ACS is well understood and established. The American College of Cardiology/American Heart Association and European Society of Cardiology guidelines for the management of ACS (STEMI and NSTEMI) are unified in their recommendation that all patients should receive a second oral antiplatelet agent—a P2Y12 inhibitor. Additionally, dual antiplatelet therapy (DAPT) is now a Class I indication.

Dr Wright reviewed the P2Y12 inhibitors approved for use in ACS: clopidogrel, prasugrel, and ticagrelor. He said the use of a P2Y12 inhibitor at the time of initiation of fibrinolytic therapy is established and currently limited to clopidogrel in the United States. Use of clopidogrel pre-junctively with fibrinolysis is strongly supported in STEMI for patients <75 years of age. Clopidogrel in STEMI has demonstrated a superiority to aspirin alone in pivotal clinical trials. Multiple studies have also demonstrated a benefit prior to percutaneous coronary intervention (PCI), explained Dr Wright. However, “other P2Y12 agents have tested superior in post-PCI populations with STEMI and represent dilemmas for formulary committees,” he said.

Clopidogrel has several weaknesses that have led to the development of alternative P2Y12 agents:

• Onset of action is 3 to 6 to 9 hours depending on loading dose—this makes acute loading tricky as there is a window of single antiplatelet coverage

• Some patients demonstrate “clopidogrel resistance”

Prasugrel, a third generation thienopyridine, is a P2Y12 receptor antagonist with potential antiplatelet effects. Characteristics include increased inhibition of platelet aggregation (IPA), rapid onset of IPA activity, and more consistent IPA response. Dr Wright cited a study by Wiviott et al [N Engl J Med. 2007;257(20):2001-2015] that compared prasugrel and clopidogrel in 13,608 patients with moderate-to-high-risk ACS with scheduled PCI. The primary efficacy endpoint was cardiovascular causes, nonfatal MI, or nonfatal stroke. The primary endpoint occurred in 12.1% of patients receiving clopidogrel and in 9.9% of patients receiving prasugrel.

Ticagrelor is a reversible and direct-acting oral antagonist of the adenosine diphosphate receptor P2Y12. Because it is a prodrug, it does not require metabolic activation, said Dr Wright, highlighting results from a multicenter, double-blind, randomized PLATO (Platelet Inhibition and Patient Outcomes) trial that compared ticagrelor to clopidogrel for the prevention of major cardiovascular events in 18,624 patients with ACS, with or without ST-segment elevation [N Engl J Med. 2009;361(11):1045-1047]. At 12 months, researchers found that treatment with ticagrelor plus aspirin led to a significantly greater reduction in the primary endpoint—a composite of cardiovascular death, MI, or stroke—compared with clopidogrel plus aspirin treatment (9.8% vs 11.7%, respectively) and lower rate of all-cause mortality (4.5% vs 5.9%, respectively).

Dr Wright also touched on vorapaxar—the first in a new class of drug called a protease-activated receptor-1 antagonist. The FDA approved vorapaxar, an antiplatelet agent designed to decrease the tendency of platelets to clump together to form a blood clot, in May 2014. A study by Morrow et al [N Engl J Med. 2012;366(15):1401-1413] found composite of death from cardiovascular causes, MI, or stroke in 9.3% of patients in the vorapaxar group and 10.5% in the placebo group. Cardiovascular death, MI, stroke, or recurrent ischemia leading to revascularization occurred in 11.2% of patients in the vorapaxar group and 12.4% of patients in the placebo group. Vorapaxar also increased the risk of moderate or severe bleeding, with the latter occurring most frequently in patients with a history of stroke.

Dr Wright said that DAPT therapy for 1 year in post-ACS patients is the gold standard. Evidence suggests that clopidogrel works well and that other PY212 inhibitors are slightly better with higher bleeding risks. Patient adherence to DAPT for the first year after ACS is critical. The use of aspirin after year 1 is the guideline-based expectation. —Eileen Koutnik-Fotopoulos