1. Risk stratification and medical management of NSTE-ACS (UA/NSTEMI )
Dr Sajeer K T

2. - Plaque rupture or erosion with super imposed non-occlusive thrombus
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)

3. Stable plaque v/s unstable plaque Non –occlusive thrombus
UA/NSTEMI
occlusive thrombus
STEMI

4. 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

5. 3 principal presentations of UA
Non–ST-elevation MI
- presents as prolonged, more intense
rest angina or angina equivalent

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

7. Early Risk stratification

8. 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

9. Clinical Indicators of Increased Risk in UA/NSTEMI

10. 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

11. Tools for Risk Stratification

12. ECG Indicators of Increased Risk
Transient (i.e., <20 minutes) ST elevation, (10% of patients), portends a high risk of future cardiac events

13. 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)

14. 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

15. Risk assessment by cardiac Biomarkers
Troponins - preferred marker

16. Troponin I Levels to Predict the Risk of Mortality in Acute Coronary Syndromes

17. Markers of hemodynamic stress:
Biomarkers contd…
Markers of hemodynamic stress:
Inflammation:
- CRP
- Myeloperoxidase
- PAPP-A
- Soluble CD-40 ligand
- IL-6
- BNP& NT- proBNP

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

19. 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= )
Patients with both elevated CRP and Troponin level
had highest mortality rates ( 9.1%)
Topol hand book
FRISC II sub study
CRP >10 mg/L : increased risk of cardiac vascular
death at all troponin levels.

20. Cardiac markers Clinical Indicators of Increased Risk in UA/NSTEMI

22. Combined risk assessment scores
TIMI
PURSUIT
GRACE

23. 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;284:835–42

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

27. 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

30. 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

31. - in patients with resting STD (≥0.1 mV) - LV hypertrophy
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).

32. ACC/AHAA Recommendations for Non-invasive Risk Stratification

33. Medical Management of NSTE-ACS (UA/NSTEMI )

34. Algorithm for management of NSTEACS

35. 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

36. 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

37. 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).

38. 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

39. 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: )
Diltiazem Reinfarction Study ( N Engl J Med 1986; 315: 423-9)

40. 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

41. Antiplatelet therapy

42. Antiplatelet therapy class 1
Aspirin : as soon as possible ( 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.
Meta-analysis pooled data from 195 trials
Involving more than 143,000 patients
22% reduction in the odds of vascular death, MI, or stroke with antiplatelet therapy
An analysis from the CURE trial suggested that there was no difference in the rate of thrombotic events according to ASA dose, but there was a dose-dependent increase in bleeding in patients receiving ASA (plus placebo): the major bleeding
rate was 2.0% in patients taking less than 100 mg of ASA,
2.3% with 100 to 200 mg, and 4.0% with greater than 200
mg per d (243,376). Therefore, maintenance doses of 75 to
162 mg of ASA are preferred.

43. ISIS-2) trial led to the recommendation that ASA be initiated immediately in the ED once the diagnosis of ACS is made or suspected.
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.)

44. 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.

45. CURE trial :
12,562 patients with UA/NSTEMI presenting with in 24 hrs
Clopidogrel 300mg loading >>>75mg/d v/s placebo
All patients received ASA
Significant reductions in the rate of in-hospital severe ischemia and revascularization and need for IV GPIIb/IIIa inhibitors.
Strong evidence for addition of clopidogrel to ASA on admission in management of patients in whom a non-interventional approach is intended.
Useful approach in hospitals that do not have a routine policy about early invasive procedures
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

46. 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

47. Prasugrel TRITON TIMII 38 Trial
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.

48. 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

49. 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.

50. Anti coagulant therapy recommendations
Class 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

51. 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.)

52. UFH v/s Enoxaparin
Systematic overview of death/MI at 30 days including 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)

53. 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

54. Bivalirudin. ACUITY TRIAL
UFH+ GPIIb/IIa
Bivalirudin alone
Ischemia
end point by
No clopidogrel loading before PCI at 30d
Major bleeding at 30 days
Composite ischemia end point at 30d
Ischemia
end point by clopidogrel loading before PCI at 30d
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

55. 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

56. 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%)

57. 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.

58. Long term Antiplatelet therapy
Class I
Medical therapy
BMS group
DES group
ASA mg/d indefinitely
&
Clopidogrel 75 mg/d for at least 1 month and ideally up to 1 year
ASA mg/d
(1 month) ↓
mg/d
(indefinitely)
&
Clopidogrel 75 mg/d or Prasugrel 10 mg/d (for at least 1 year)
ASA mg/d (SES-3months)
(PES-6months) ↓
mg/d
(indefinitely)
&
Clopidogrel 75 mg/d Or
prasugrel 10mg for at least 1 year

59. 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)

60. 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)

61. 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.)

62. Patients with UA/NSTEMI
summary
Patients with UA/NSTEMI
Aspirin, clopidogrel, UFH/enoxaparin, beta blocker, nitrates.
High risk
+Troponin, ST▲’s,
TIMI score≥3
Recurrent Ischemia, CHF, Prior Revascularization
Low risk
Normal ECG
Negative Markers
TIMI score 0- 2
Conservative strategy
Invasive strategy
GpIIb/IIIa inhibitor

63. Hope you are not confused !
Thank you
Hope you are not confused !