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

0 1 2 3 4 5 6

5

10

0

15

20

25

Months after hospital admission

Dea

ths

/ 100

pts

/ m

onth

Acute MIUnstable anginaStable angina

Duke Cardiovascular Database

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

Ischemic Heart Diseaseevaluation

• 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 DiscomfortUnstable Symptoms

No ST-segmentelevation

ST-segmentelevation

Unstable Non-Q Q-Waveangina AMI AMI

ECG

AcuteReperfusion

HistoryPhysical 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 AnginaAnti-platelet Therapy

• Abciximab – EPIC Trial

effective in preventing death, MI, and abrupt closure associated with coronary angioplasty (see also EPIC slides)

– EPISTENT Trial

Unstable AnginaAnti-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 AnginaAnti-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 AnginaAnti-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;338:1488-97

Unstable AnginaAnti-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 AnginaAnti-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 PURSUIT

135 / 0.5 180 / 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

Fibanincidence of intracranial bleeding

Treatment (%)

Study Compound Placebo Active Heparin

RESTORE Tirofiban 0.3 0.1

EPIC Abciximab 0.3 0.1

0.4

EPILOG Abciximab 0.0 0.1

IMPACT II Integrelin 0.07 0.07 0.15

The EXCITE Trial Investigators

Bolus

Low dose

High dose

Bolus + Infusion

Unstable AnginaAnti-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 AnginaAnti-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;89:81-882. JAMA 1996;276:811-815

Unstable AnginaAnti-coagulant Therapy

• Low-molecular-weight heparinadvantages 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 Trialincidence of death, MI, or recurrent angina

N Eng J Med 1997;337:447-452

0

5

10

15

20

25

0

5

10

15

20

25

heparin Lovenox heparin Lovenox

n=1564 n=1607 n=1564 n=1607

19.8%

16.6%P=0.019

23.3%

19.8%P=0.016

Day 14 Day 30