Risk stratification and medical management of NSTE-ACS

(UA/NSTEMI )

Dr Sajeer K T

- Plaque rupture or erosion with super imposed non-occlusive thrombus -most common cause of UA/NSTEMI

Other mechanism: - dynamic obstruction : spasm of epicardial coronary artery : dysfunction of coronary endothelium

- Restenosis : post PCI interventions

- Inflammation

- Secondary UA: ↑ed O2 demand or ↓ed O2 supply (tachycardia, fever, hypotension, or anemia)

Pathophysiology

Non –occlusive thrombus

UA/NSTEMI

occlusive thrombus

STEMI

Stable plaque

v/s unstable plaque

UA/NSTEMI definition

Electrocardiographic ST-segment depression or prominent T-wave inversion

and/or positive biomarkers of necrosis (e.g., Troponins)

in the absence of ST-segment elevation

and in an appropriate clinical setting (chest discomfort or anginal equivalent)

-Anderson et al. JACC Vol. 50, No. 7, 2007 ACC/AHA UA/NSTEMI Guideline Revision August 14, 2007:e1–157

3 principal presentations of UA

Non–ST-elevation MI - presents as prolonged, more intense rest angina or angina equivalent

Braunwald Clinical Classification of UA/NSTEMI - Braunwald E: Unstable angina: A classification. Circulation 80:410, 1989.

EARLY RISK STRATIFICATION

Rationale for Risk Stratification

1) selection of the site of care: - coronary care unit

- monitored step-down unit

- outpatient setting

2) selection of therapy: - GP IIb/IIIa inhibitors

- invasive management strategy

Estimation of the Level of Risk - Focuses on history - Physical findings - ECG findings - Biomarkers of cardiac injury (Cardiac specific Troponin) - TIMI score

Clinical Indicators of Increased Risk in UA/NSTEMI

Braunwald Clinical Classification of UA/NSTEMI

Data from TIMI III Registry: Scirica BM et al: Prognosis in the TIMI III Registry according to the Braunwald unstable angina pectoris classification. Am J Cardiol 90:821, 2002

P= 0.057

P= 0.001

Tools for Risk Stratification

ECG Indicators of Increased Risk

• Transient (i.e., <20 minutes) ST elevation, (10% of patients), portends a high risk of future cardiac events

Echocardiography

RWMA coupled with ECG changes - high risk indicator.

Echo identifies other parameters associated with adverse

prognosis

- LA dilatation

- mitral regurgitation

- diastolic dysfunction

Assessment of LV systolic function, even with Troponin negative

status is an important predictor of long term risk.

( class 1 recommendation)

Nuclear Cardiac Imaging

An abnormal rest myocardial imaging

indicates:

- high risk of MI

- cardiac death

- need for revascularization over next 12 months

Normal rest myocardial scan:

- low risk patients

Risk assessment by cardiac Biomarkers

Troponins - preferred marker

Troponin I Levels to Predict the Riskof Mortality in Acute Coronary Syndromes

Biomarkers contd…

Markers of hemodynamic stress:

- BNP& NT- proBNP

Inflammation:

- CRP

- Myeloperoxidase

- PAPP-A

- Soluble CD-40 ligand

- IL-6

Association between levels of BNP and mortality across the spectrum of acute coronary syndrome in the OPUS-TIMI 16

study.

C-Reactive protein (CRP)

TIMI 11 A trial : CRP level ≥ 1.55 mg/dL had higher mortality rate,

even those patients with negative troponin level

(5.8% v/s 0.36% , p= 0.006)

Patients with both elevated CRP and Troponin level• had highest mortality rates ( 9.1%)

• FRISC II sub study

CRP >10 mg/L : increased risk of cardiac vascular

death at all troponin levels.

Cardiac markers Clinical Indicators of Increased Risk in UA/NSTEMI

Combined risk assessment scores

• TIMI• PURSUIT• GRACE

•Age ≥ 65 years

•At least 3 risk factors for CAD

•Prior coronary stenosis of ≥ 50%

•ST-segment deviation on ECG presentation( ST deviation >0.5 mm)

•At least 2 anginal events in prior 24 hours

•Use of aspirin in prior 7 days

•Elevated serum cardiac biomarkers

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Variables Used in the TIMI Risk Score

The TIMI risk score is determined by the sum of the presence of the above 7 variables at admission. 1 point is given for each variable. Primary coronary stenosis of 50% or more remained relatively insensitive to missing information and remained a significant predictor of events.

- Antman EM, et al. JAMA 2000;284:835–42

The TIMI risk score for unstable angina/non–ST elevation MI: A method for prognostication and therapeutic decision-making. JAMA 284:835, 2000.

GRACE registry & GRACE score

• A global registry of ACS patients from 94 hospitals in 14 countries.

• GRACE score:

Can be used to predict the cumulative risk of death or

myocardial infarction in the period from admission to

hospital to six months after discharge

• The tool is simple and applicable to patients across the complete spectrum of acute coronary syndrome

Later Risk Stratification and Management

Low-risk patients:

- early stress testing is performed

( Exercise ECG -1st choice non-invasive test)

Intermediate risk patients:

managed with an early conservative strategy

(free of ischemia and heart failure for a minimum of 2 to 3 days)

stress testing

Sub maximal protocol

Target workload =5 METS, 70 % MPHR or symptom limited

• Stress echo

- in patients with resting STD (≥0.1 mV)

- LV hypertrophy

- Bundle branch block

- Intraventricular conduction defect

- Preexcitation, or digoxin.

Pharmacologic stress testing with imaging: ( when physical limitations preclude adequate exercise stress )(e.g., arthritis, amputation, severe peripheral vascular disease, severe chronic obstructive pulmonary disease, or general debility).

ACC/AHAA Recommendations for Non-invasive Risk Stratification

Medical Management of NSTE-ACS (UA/NSTEMI )

Algorithm for management of NSTEACS

Anti ischemic therapy and analgesic therapy

– Bed rest with continuous ECG monitoring– Supplemental oxygen ( if spo2<90% or respiratory

distress).– sublingual nitrate every 5 min for a total of 3 doses

.– IV NTG in first 48 hrs ( at the rate of 10 mcg/kg/min)

- persistent ischemia

- HF

- hypertension

class 1

Nitrates should not be administered to patients with:

Systolic pressure < 90 mm Hg or ≥ to 30 mm Hg

below baseline Severe bradycardia(< 50 bpm) Tachycardia (> 100 bpm) in the absence of

symptomatic heart failure Suspected RV infarction. Who have received a phosphodiesterase

Anti ischemic therapy contd..

Oral beta-blocker therapy when hemodynamically

stable ( within the 1st 24 h)

Contraindications: 1) signs of HF

2) low out put state( SBP<90,oliguria,HR<50)

3) other relative contraindications to beta blockade.

(PR > 0.24 s, 2nd or 3rd degree AV block,

active asthma or reactive airway disease).

class 1

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COMMIT Trial (Lancet 2005;366:1622–32.)

- 45,852 patients within 24 h acute MI

― 93% STEMI or LBBB, 7% had NSTEMI

- Utility of IV beta blockade followed by oral was tested (Up to 15 mg IV → 50 mg po metoprolol daily v/s placebo)

- No decrease of composite primary outcomes ― death, reinfarction, or cardiac arrest

- Modest reduction in re- infarctions and VF

Risk of cardiogenic shock especially with initial hemodynamic instability

Nondihdropyridine calcium channel blockers - Verapamil - Diltiazem

Contraindications for CCBs:Severe LV dysfunction

Summary :

definitive evidence for a benefit of CCBs in UA/NSTEMI is

predominantly limited to symptom control.

DAVIT STUDY - ( Eur Heart J 1984; 5: 516-28)

Diltiazem Reinfarction Study - ( N Engl J Med 1986; 315: 423-9)

ACEI & ARBs

ACE inhibitor (orally within 1st 24 h) in patients with

- pulmonary congestion

- LVEF ≤ 40%

contraindications:

- hypotension

(SBP < 100 mm Hg or < 30mm Hg below baseline)

- known contraindications to ACEIs

ARBs: if intolerance to ACEI

Antiplatelet therapy

Antiplatelet therapy

Aspirin : as soon as possible (165-325 mg)

- (non enteric formulation orally or chewed).

-Continued indefinitely(75-162mg/d ) in pts who

tolerate it.

Clopidogrel :

- loading dose -300mg

- daily maintenance dose 75mg

- Continued for at least 1 month and ideally up to 1 year.

class 1

Four randomized trials showing the benefit of aspirin in UA/NSTEMI, in which the incidence of death or MI was reduced by more than 50% in each of the four trials. The doses of aspirin in the four trials were 325 mg, 1300 mg, 650 mg, and 75 mg

daily, indicating no difference in efficacy for aspirin across these doses

(Data from Lewis HD, et al: N Engl J Med 309:396, 1983; Cairns JA, et al: N Engl J Med 313:1369, 1985; Theroux P, et al: N Engl J Med 319:1105, 1988; RISC Group: Lancet

349:827, 1990.)

Clopidogrel dosage:

initial loading dose of 300 to 600 mg clopidogrel is followed by a maintenance dose of 75 mg/day.

Initiation with only 75 mg daily will achieve the target level of platelet inhibition after 3 to 5 days.

Loading dose of 300 mg will achieve effective platelet inhibition within 4 to 6 hours.

Use of a 600-mg loading dose achieves a steady-state level of platelet inhibition after just 2 hours.

Benefit of clopidogrel in reducing cardiovascular death, MI, or stroke to 1 year in the CURE trial conducted in patients with UA/NSTEMI and in patients managed medically, with PCI or CABG. The Clopidogrel in Unstable angina to prevent Recurrent ischemic Events [CURE] Trial. Circulation 110:1202, 2004

-rapidly acting , more potent thienopyridine. -associated with less respose variability than clopidogrel

• Dosage :

Prasugrel 60 mg should be given promptly and not

later than 1 hour after PCI once coronary artery

anatomy is defined.

• Duration and maintenance dose :

Prasugrel 10 mg daily

Duration : Up to 12 months

• Contraindications :

Elderly ≥ 75 years,

Body weight <60 kg

Prior history of TIA or stroke

PRAUGREL

Prasugrel

Comparison of efficacy (top) and safety (bottom) in the TRITON–TIMI 38 trial,

which compared Prasugrel with clopidogrel in patients with ACS undergoing PCI.

Comparison of prasugrel and clopidogrel on the development of stent thrombosis.

ARC = Academic Research Consortium.

TRITON TIMII 38 Trial

GPIIb/IIIa Inhibitor

• Upstream strategy:

Eptifibatide or tirofiban is administered in the ED or

hospital for medical stabilization usually in an

anticipation for an early invasive approach.

• Adjunctive strategy: Use either Eptifibatide or Abciximab as adjunctive

therapy immediately before PCI

The routine upstream administration of GP IIb/IIIa inhibitors did not improve the primary outcome of death or myocardial infarction (MI) at 30 days and significantly increased bleeding.

EARLY ACS trial ( in 9492 pts with UA/NATEMI)

Upstream glycoprotein (GP) IIb/IIIa inhibitor V/S

Adjunctive strategy GP IIb/IIIa inhibitor

Anti coagulant therapy recommendationsClass I

Conservative strategy: - UFH or Enoxaparin

- Fondaparinux

( preferable in pts with increased risk of bleeding)

Enoxaparin or fondaparinux preferable to UFH unless CABG is planned with in 24 hrs Class IIa

Invasive strategy: - UFH - Enoxaparin - Bivalirudin

Unfractionated heparin (UFH)

- ACC/AHA Guidelines recommend weight adjusted dose

: 60 units/kg bolus (maximum 4000 u)

: 12 units/kg/hr infusion (1000 units/hour).

- Most of trials continued therapy for 2 to 5 days.

- (Optimal duration of anticoagulation remain

undefined.)

Systematic overview of death/MI at 30 days including 21946 patients enrolled in six trials comparing enoxaparin with UFH . Overall, a significant reduction in death or MI was observed (10.1% vs 11.0%)

(Petersen JL, et al. Efficacy and bleeding complications among patients randomized to enoxaparin or unfractionated heparin for antithrombin therapy Non STE ACS: a systematic overview. JAMA 2004;292:89, 96)

UFH v/s Enoxaparin

Fondaparinux

• OASIS- 5 trial:• The rate of major bleeding was reduced significantly—

almost by half—in the fondaparinux arm • (Fondaparinux arm 2.2%) versus (4.1% enoxaparin arm).

• In patients undergoing PCI, fondaparinux has associated with more than a 3 fold increased risk of catheter-related thrombi.

• It is recommended only in patients at a higher risk of bleeding who are managed conservatively

Bivalirudin.

Composite ischemia end point at 30d

Ischemiaend point by clopidogrel loading before PCI at 30d

Ischemiaend point by No clopidogrel loading before PCI at 30d

Major bleeding at 30 days

ACUITY TRIAL

Bivalirudin alone

UFH+ GPIIb/IIa

Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial was a complex trial performed in 13,819 patients with UA/NSTEMI, all of whom underwent cardiac catheterization within 72 hours

Treatment strategies and interventions

1. Early invasive strategy: Routine CAG

PCI, CABG, Medical Mx

2. Conservative approach: Medical Mx

Recurrent Ischemia (at rest /on noninvasive stress test)

Revasularization

High risk clinical events

Recurrent angina/ischemia at rest with low-level activities despite intensive medical therapy

Elevated cardiac TnT or TnI

New/presumably new ST- segment depression

Signs/symptoms of heart failure or new/worsening mitral regurgitation

High-risk findings from noninvasive testing

Hemodynamic instability

Sustained ventricular tachycardia

PCI within 6 months

Prior CABG

High risk score (e.g., TIMI, GRACE)

- LVEF < 40%)

Meta-analysis of the benefit of a routine invasive versus “selective” invasive (i.e., conservative) strategy for patients with unstable angina or NSTEMI on the rate of death, myocardial infarction, or rehospitalisation through follow-up. J Am Coll Cardiol  2006; 48:1319.

Medical therapy BMS group DES group

ASA 75-162 mg/d indefinitely

&Clopidogrel 75

mg/d for at least 1 month and

ideally up to 1 year

ASA 162-325 mg/d (1 month)

↓75-162 mg/d (indefinitely)

&Clopidogrel 75

mg/d or Prasugrel 10 mg/d (for at least 1 year)

ASA 162-325 mg/d (SES-3months)(PES-6months)

↓75-162 mg/d (indefinitely)

&Clopidogrel 75 mg/d

Or prasugrel 10mg for

at least 1 year

Long term Antiplatelet therapy

Class I

Lipid Management

Lipid management should include assessment of a fasting lipid profile for all patients, within 24 h of hospitalization.

High dose statins in the absence of contraindications, regardless of baseline LDL-C and diet modification, should be given to post-UA/NSTEMI patients, including post revascularization patients.

LDL goal: <100mg/dl

<70 mg/dl reasonable (classIIa)

Meta analysis of intensive v/s standard statin therapy, showing a highly significant 16% reduction in the risk of coronary death or

MI (p<0.0001)

The benefit of intensive statin therapy initiated early after acute coronary syndrome (ACS) in the PROVE IT–TIMI 22 trial. A significant reduction in events is seen in the first 30 days. J Am Coll Cardiol 46:1405, 2005.)

Patients with UA/NSTEMI

Aspirin, clopidogrel, UFH/enoxaparin, beta blocker, nitrates.

High risk

+Troponin, ST▲’s,TIMI score≥3Recurrent Ischemia, CHF, Prior Revascularization

Low risk

Normal ECG Negative Markers TIMI score 0- 2

GpIIb/IIIa inhibitor

Conservative strategyInvasive strategy

summary

THANK YOU

Hope you are not confused !