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

25

Deaths / 100 pts / month

20 15 10 5 0 0 1 Acute MI Unstable angina Stable angina

N = 21,761; 1985-1992 Diagnosis on adm to hosp

2 3 4 5 Months after hospital admission

Duke Cardiovascular Database

Ischemic Heart Disease evaluation

Based on the patients
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
History Physical Exam

No ST-segment elevation

ST-segment elevation

ECG

Unstable angina

Non-Q AMI

Q-Wave AMI

Acute Reperfusion

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;349:1429-1435

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;338:1498-505

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 nonQ-MI to tirofiban alone, heparin alone, or a combination of the two (all received aspirin)
N Engl J Med 1998;338:1488-97

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;339:436-443

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;339:436-443

Platelet Inhibition and Bleeding Time

IMPACT II 135 / 0.5 Inhibition of platelet aggregation 15 minutes after bolus at steady state 4h after infusion discontinuation Bleeding-time prolongation at steady state 6h after infusion discontinuation PURSUIT 180 / 2.0

69% 40-50% <30% <5x 1x

84% >90% <50% <5x 1.4x

Fiban incidence of intracranial bleeding

Study RESTORE EPIC EPILOG IMPACT II Compound Tirofiban Abciximab Abciximab Integrelin Treatment (%) Placebo Active 0.3 0.3 0.0 0.07 0.1 0.1 0.4 0.1 0.07 0.15 Heparin

Bolus Bolus + Infusion

Low dose High dose

The EXCITE Trial Investigators

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;89:81-88 2. JAMA 1996;276:811-815

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
Day 14 Day 30

25 20 15 10 5
n=1564 n=1607

25 20
16.6%
P=0.019

23.3% 19.8%
P=0.016

19.8%

15 10 5 0

n=1564 n=1607

0
heparin Lovenox

heparin Lovenox

N Eng J Med 1997;337:447-452