Risk stratification and medical management of NSTE-ACS

(UA/NSTEMI )
Dr Sajeer K T

Pathophysiology - 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)

Stable plaque v/s unstable plaque

Non occlusive thrombus UA/NSTEMI

occlusive thrombus STEMI

UA/NSTEMI definition
Electrocardiographic ST-segment depression or prominent Twave 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:e1157

3 principal presentations of UA

NonST-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.

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

P= 0.057

P= 0.001

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

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 Risk of Mortality in Acute Coronary Syndromes

Biomarkers contd
Markers of hemodynamic stress:

Inflammation:

- CRP - BNP& NT- proBNP

- 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

Variables Used in the TIMI Risk Score

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

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;284:83542
23

The TIMI risk score for unstable angina/nonST elevation MI: A method for prognostication and therapeutic decisionmaking. 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

class 1 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

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..

class 1

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).

COMMIT Trial (Lancet 2005;366:162232.)

- 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
38

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 Diltiazem Reinfarction Study - ( Eur Heart J 1984; 5: 516-28) - ( 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).

class 1

-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.

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

PRAUGREL
-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

Prasugrel

TRITON TIMII 38 Trial

Comparison of efficacy (top) and safety (bottom) in the TRITONTIMI 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.

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

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

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

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.

Class I

Anti coagulant therapy recommendations

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.)

UFH v/s Enoxaparin

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)

Fondaparinux
OASIS- 5 trial: The rate of major bleeding was reduced significantly almost by halfin 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.

ACUITY TRIAL
UFH+ GPIIb/IIa

Bivalirudin alone

Composite ischemia end point at 30d

Ischemia end point by clopidogrel loading before PCI at 30d

Ischemia end point by No clopidogrel loading before PCI at 30d

Major bleeding at 30 days

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 STsegment 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.

Long term Antiplatelet therapy

Class I

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

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 ITTIMI 22 trial. A significant reduction in events is seen in the first 30 days.
J Am Coll Cardiol 46:1405, 2005.)

summary

Patients with UA/NSTEMI

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

High risk
+Troponin, STs, TIMI score3 Recurrent Ischemia, CHF, Prior Revascularization

Low risk
Normal ECG Negative Markers TIMI score 0- 2

Invasive strategy

Conservative strategy

GpIIb/IIIa inhibitor

Hope you are not confused !