Update on the Medical Management of Acute Coronary Syndrome

Worldwide Statistics Each year: > 4 million patients are admitted with unstable angina and acute MI > 900,000 patients undergo PTCA with or without stent

Myocardial Ischemia Spectrum of presentation –silent ischemia –exertion-induced angina –unstable angina –acute myocardial infarction

Cumulative 6-month mortality from ischemic heart disease Months after hospital admission Deaths / 100 pts / month Acute MI Unstable angina Stable angina Duke Cardiovascular Database N = 21,761; Diagnosis on adm to hosp

Ischemic Heart Disease evaluation Based on the patient’s –history / physical exam –electrocardiogram Patients are categorized into 3 groups –non-cardiac chest pain –unstable angina –myocardial infarction

Acute Coronary Syndrome Ischemic Discomfort Unstable Symptoms No ST-segment elevation ST-segment elevation Unstable Non-QQ-Wave angina AMI AMI ECG Acute Reperfusion History Physical Exam

Acute Coronary Syndrome The spectrum of clinical conditions ranging from: –unstable angina –non-Q wave MI –Q-wave MI characterized by the common pathophysiology of a disrupted atheroslerotic plaque

Unstable Angina Anti-platelet Therapy Abciximab –EPIC Trial effective in preventing death, MI, and abrupt closure associated with coronary angioplasty (see also EPIC slides) –EPISTENT Trial

Unstable Angina Anti-platelet Therapy Abciximab –CAPTURE –At 30 days, there was a 29% reduction in the primary composite endpoint of death, MI, or urgent revascularization in the abciximab group –At 6 months, this benefit was not evident Lancet 1997;349:

Unstable Angina Anti-platelet Therapy Tirofiban –PRISM (Platelet Receptor Inhibition for Ischemic Syndrome Management) –3,200 patients with unstable angina were treated with either heparin or tirofiban –At 48 hours, there was significant risk reduction (5.9% to 3.6%) in the rate of death, MI, or refractory ischemia. The benefit was lost at 30 days. N Engl J Med 1998;338:

Unstable Angina Anti-platelet Therapy Tirofiban –PRISM -PLUS (Platelet Receptor Inhibition for Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms) –randomized 1,915 patients with UA and non- Q-MI to tirofiban alone, heparin alone, or a combination of the two (all received aspirin) N Engl J Med 1998;338:

Unstable Angina Anti-platelet Therapy Eptifibatide –PURSUIT (Platelet IIb/IIIa Underpinning the Receptor for Suppression of Unstable Ischemia Trial) –~11,000 patients admitted with unstable angina or non-Q-wave myocardial infarction –a broad-based trial encompassing a variety of clinical practices and practice styles NEJM 1998;339:

Unstable Angina Anti-platelet Therapy Eptifibatide PURSUIT –randomized to eptifibatide or placebo; all patients received aspirin and heparin –significantly reduced the risk of death and MI at 30 days from 15.7% to 14.2%, a 9% risk reduction NEJM 1998;339:

Platelet Inhibition and Bleeding Time IMPACT IIPURSUIT 135 / / 2.0 Inhibition of platelet aggregation 15 minutes after bolus 69% 84% at steady state 40-50% >90% 4h after infusion discontinuation <30% <50% Bleeding-time prolongation at steady state <5x <5x 6h after infusion discontinuation 1x 1.4x

Fiban incidence of intracranial bleeding Treatment (%) StudyCompound Placebo ActiveHeparin RESTORETirofiban EPICAbciximab EPILOGAbciximab IMPACT IIIntegrelin The EXCITE Trial Investigators Bolus Low dose High dose Bolus + Infusion

Unstable Angina Anti-platelet Therapy Summary –the four “P trials” (PRISM, PRISM-PLUS, PARAGON, PURSUIT) –all show reduction of death rate between 1.3% and 3.4% - in addition to the benefit of aspirin –useful in the management of patients with unstable angina and MI without ST elevation

Unstable Angina Anti-coagulant Therapy Heparin –recommendation is based on documented efficacy in many trials of moderate size –meta-analyses (1,2) of six trials showed a 33% risk reduction in MI and death, but with a two fold increase in major bleeding –titrate PTT to 2x the upper limits of normal 1. Circulation 1994;89: JAMA 1996;276:

Unstable Angina Anti-coagulant Therapy Low-molecular-weight heparin advantages over heparin: –better bio-availability –higher ratio (3:1) of anti-Xa to anti-IIa activity –longer anti-Xa activity, avoid rebound –induces less platelet activation –ease of use (subcutaneous - qd or bid) –no need for monitoring

ESSENCE Trial incidence of death, MI, or recurrent angina N Eng J Med 1997;337: heparin Lovenox n=1564 n= % 16.6% P= % 19.8% P=0.016 Day 14 Day 30