NSTEMI Acute Coronary Syndromes

Patrick Hildbrand

Trends and Prognosis in NSTEMI

Furman MI, JACC 2001, 37:1571-1580Hospital 1 year

Trends and Prognosis

Diagnosis and Risk assessment

Initial ManagementTreatment <

Long-Term Management

Summary of Treatment Approaches

NSTEMI Acute Coronary Syndromes

Chest Pain

ECG

Kaul P, JACC 2001, 38:64-71

Biochemistry

Risk Stratification

Summary Diagnosis and Risk assessment

Diagnosis and short-term risk stratification should be based on a combination of

Clinical history Symptoms ECG and (10 minutes, 6h, 24h and before hospital discharge) Biomarkers (admission and after 6-12 h) Risk score results

Echocardiography is recommended to rule out differential diagnosis

Patient without recurrence of pain, normal ECG findings and negative troponins tests > non invasive stress testing

Trends and Prognosis

Diagnosis and Risk assessment

Initial ManagementTreatment <

Long-Term Management

Summary of Treatment Approaches

NSTEMI Acute Coronary Syndromes

Therapeutic Options

Anti-ischemic agents

Anti-coagulants UFH or LMWH Factor-Xa inhibitors (Fondaparinux) Direct Thrombin inhibitors (Bivalirudin)

Anti-platelet agents ASA Clopidrogel GP IIb/IIIa Inhibitors

Revascularization

NSTEMI

Anti-Ischemic Agents

Aim: Decrease myocardial oxygen consumption and/or induce vasodilatation

Betablockers are recommended in absence of contraindications (hypertension and tachycardia; cave inferior MI, acute LV

dysfunction) (IB)

Nitrates are effective in symptom relief in the acute management of angina episodes (IC)

(Cave: Phospodiesterase-5-inhibitors, RV MI)

Calcium channel blockers provide symptom relief in patients already receiving betablockers and nitrates; patient with contraindication to betablockers; vasospastic angina (Ic)

Nifedipine or other dihydropyridine should not be used (IIIC) unless combined with betalockers (IIa-B)

Anti-ischemic agents

Anti-coagulants UFH or LMWH Factor-Xa inhibitors (Fondaparinux) Direct Thrombin inhibitors (Bivalirudin)

Anti-platelet agentsASAClopidrogelGP IIb/IIIa Inhibitors

Revascularization

NSTEMI

UFH

LMWH

UFH33% RR

Enoxaparin (©Clexane) vs UFH

NON REVASC.

GP IIb/IIIa Inhibitors

GP IIb/IIIa Inhibitors

Enoxaparin was non-inferior to UFH in Reducing death or MI in the Synergy Trial

Synergy 14% versus 14.5% p=n.s.

Factor-Xa inhibitors (Fondaparinux, © Arixtra)

Oasis 5 TrialDeath, MI or refractory ischemia through day 9

Oasisi 5: Major bleeding through d9

Relation between bleeding and mortality in OASIS 5

Bleeding carries a high risk of death

Prevention of bleeding is as important as prevention of ischemic events and results in a significant rate reduction of death

> Risk stratification of bleeding should be part of the decision making process

Direct thrombin inhibitors (Bivalirudin, ©Angiox) UFH/LMWH

Acuity Trial

Primary Endpoint Measures Net clinical outcome

Cave: hematoma > 5cm never used in any other definition

Summary Anti-coagulants

Anticoagulation is recommended for all Patient in addition to anti-platelet therapy

Anticoagulation should be selected to the risk of both ischemic and bleeding events

Choice of the anticoagulants (UFH, LMWH, fondaparinux and bivalirudin should depend on the strategy.

Urgent invasiv

UFH (I-C), Enoxaparin (IIa-B) or bivalirudin (I-B)

Non-urgent situation

Fondaparinux efficacy/safety profile (I-A)

Enoxaparin only if bleeding risk is low (IIa-B)

>> not LMWH (other then Enoxaparin) / UFH

Anti-ischemic agents

Anti-coagulants UFH or LMWH Factor-Xa inhibitors (Fondaparinux) Direct Thrombin inhibitors (Bivalirudin)

Anti-platelet agents ASA Clopidrogel GP IIb/IIIa Inhibitors

Revascularization

NSTEMI

Anti-platelet agents

ASA

GI intolerance 5-40%, bleeding >0.9% in CAPRIE

Primary End Point—MI/Stroke/CV Death

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

Cum

ulat

ive

Haz

ard

Rat

e

Clopidogrel + ASA*

3 6 9

Placebo + ASA*

Months of Follow-Up

P = 0.00009†

N = 12,562

0 12

20%Relative Risk

Reduction

CURE Study

The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

PCI-CURE Study: CV Death or MI

.00

.05

.10

.15

0 10 100 300 400200

Cu

mu

lati

ve H

aza

rd R

ate

Clopidogrel + Aspirin*(n=1313)

31% RelativeRisk Reduction

Placebo + Aspirin*(n=1345)Median

time to PCI

Days of Follow-Up

12.6%

8.8%

P=0.002

*In combination with standard therapy.Mehta SR, et al. Lancet. 2001;358:527-533.

GP IIb/IIIa Inhibitors

Tirofiban

Eptifibatide

Abciximab

Lamifibane

Lamifibane

Acuity timing

Summary GP IIb/IIIa Inhibitors

Intermediate to high risk (DM, ST segment depression and Troponin pos.) patients, either eptifibatide or tirofibane for initial early treatment is recommended in addition to oral antiplatelet agents (IIa-A)

Patient not pre-treated with GP IIb/IIIa inhibitors and proceeding to PCI; abciximab is recommended (IA)

GpIIb/IIIa inhibitors must be combined with anticoagulation I-A

Bivaluridin may be used as an alternative to GPIIb/IIIa inhibitors plus UFH/LMWH (IIa-B)

GPIIb/IIIa inhibitors only for invasive strategy

Anti-ischemic agents

Anti-coagulants UFH or LMWH Factor-Xa inhibitors (Fondaparinux) Direct Thrombin inhibitors (Bivalirudin)

Anti-platelet agents ASA Clopidrogel GP IIb/IIIa Inhibitors

Revascularization

NSTEMI

Coronary revascularization

Randomized trials comparing early invasive (dark bars)

vs. conservative strategy (open bars)

Summary Invasive vs. Conservative Strategies

New data coming from long-term follow up of RITA-3 and FRISC-2 and Mehta meta-analysis show significant risk reduction for death

and „death & MI“ at long-term follow up

Early hazard shown in ICTUS Trial

Early hazard shown in Mehta meta-analysis

ICTUS, Lancet 2007FRISC 2, Lancet 2000

RITA 3 Lancet 2005Metha JAMA 2005

Summary Therapeutic Options

Anti-ischemic agents

Anti-coagulants UFH or LMWH Factor-Xa inhibitors (Fondaparinux) Direct Thrombin inhibitors (Bivalirudin)

Anti-platelet agents ASA Clopidrogel GP IIb/IIIa Inhibitors

Revascularization

NSTEMI

Trends and Prognosis

Diagnosis and Risk assessment

Initial ManagementTreatment <

Long-Term Management

Summary of Treatment Approaches

NSTEMI Acute Coronary Syndromes

ATC 2002: Indirect Comparisons ASA Doses on Vascular Events in High Risk Patients

0 0.5 1.0 1.5 2.0

500-1500 mg 34 19%

160-325 mg 19 26%

75-150 mg 12 32%

<75 mg 3 13%

Overall 65 23%

Antiplatelet Better

Antiplatelet Worse

ASA Dose # Trials OR

Antithrombotic Trialists’ Collaboration BMJ 2002; 324:71-86

Primary End Point—MI/Stroke/CV Death

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

Cum

ulat

ive

Haz

ard

Rat

e

Clopidogrel + ASA*

3 6 9

Placebo + ASA*

Months of Follow-Up

P = 0.00009†

N = 12,562

0 12

20%Relative Risk

Reduction

CURE Study

The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

ACE-Inhibitors

HOPEHOPE

HOPE: N Engl J Med. 2000;342:145-153.

P<.001RRR=22%

0

5

10

15

20

0 500 1000 1500

Follow-Up (days)Pat

ien

ts R

each

ing

Co

mp

osi

te E

nd

Po

int

[MI,

Str

oke

, CV

Dea

th]

(%)

Ramipril

Placebo

CV

Dea

th, M

I, o

r C

ard

iac

Arr

est

(%)

Placebo annual event rate: 2.4%

Perindopril

Placebo

P=.0003RRR=20%

Years

0 1 2 3 4 5

N = 12,218

14

12

10

8

6

4

2

EUROPA:. Lancet. 2003;362:782-788.

PEACE:N Engl J Med. 2004;351:2058-2068. 0 1 2 3 4 5 6

30

25

20

15

10

5

0

Placebo

Trandolapril

Inci

den

ce o

f P

rim

ary

En

d P

oin

t (%

)

Years After Randomization

EUROPA

PEACE

Disease Modifying Drugs in Atherothrombosis

Statins

Prevent CV events

Prevent progression of CAD

Prevents development of DM

ACE-Inhibitors/ARB’s

Prevent CV events

Prevent renal dysfunction in DM

Clopidogrel

Prevents CV events

Non-ST-segment Elevation Acute Coronary Syndromes

Anti-ischemic agents

Anti-coagulants UFH or LMWH Factor-Xa inhibitors (Fondaparinux) Direct Thrombin inhibitors (Bivalirudin)

Anti-platelet agents ASA Clopidrogel GP IIb/IIIa Inhibitors

Revascularization

NSTEMI

?

Timing of Intervention Few studies have shown superiority of very early intervention vs. deferred intervention

ISAR-COOL (small sample size) JAMA 2003

Many trials have shown early hazard with early intervention vs. deferred intervention

ICTUS trial NEJM 2005

Mehta meta-analysis JAMA 2005

Grace and Crusade registries Heart 2007, Arch Intern Med 2006

> Timing of intervention recommended on the basis of risk stratification

Risk Stratification

Summary Management Strategy

Summary Long-Term Management

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