Risk stratification and medical management of NSTE-ACS UA

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

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

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

9. Clinical Indicators of Increased Risk in UA/NSTEMI

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 Riskof Mortality in Acute Coronary Syndromes

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

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= 0.006) Patients with both elevated CRP and Troponin level had highest mortality rates ( 9.1%) Topol hand bookTopol hand book

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

22. Combined risk assessment scores TIMI PURSUIT GRACE

23. 23

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. Stress echo - in patients with resting STD (=0.1�mV) - LV hypertrophy - Bundle branch block - Intraventricular conduction defect - Preexcitation, or digoxin.

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

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

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.. 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. 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 - DiltiazemContraindications 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)

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

41. Antiplatelet therapy

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

44. Clopidogrel dosage:initial loading dose of 300 to 600�mg clopidogrel is followed by a maintenance dose of 75�mg/day.

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 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

46.  -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

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

50. 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

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.)

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. 

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

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.)