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UA/NSTEMI Guidelines Dr. Sajeer K.T Senior Resident Dept. of Cardiology Definition UA/NSTEMI Electrocardiographic ST segment depression or prominent T wave inversion and/or Positive biomarkers of necrosis (troponin ) In the absence of ST segment elevation In an appropriate clinical setting ( chest discomfort or anginal equivalent) ACC/AHA Task force on practice guidelines • 2007 • 2011 focused updates Risk stratification Early hospital care Conservative management strategy Invasive management strategy Risk stratification • Diagnostic evaluation: • Assesses the risk that a pt with UA/NSTEMI has for MI or death during next few weeks. • Focuses on history Physical findings ECG findings Biomarkers of cardiac injury (Cardiac specificTroponin) TIMI score 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 •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. 8 TIMI Risk Score TIMI Risk Score All-Cause Mortality, New or Recurrent MI, or Severe Recurrent Ischemia Requiring Urgent Revascularization Through 14 Days After Randomization % 0-1 4.7 2 8.3 3 13.2 4 19.9 5 26.2 6-7 40.9 9 Early Hospital care 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 - persistent ischemia - HF - hypertension Anti ischemic therapy contd.. class 1 - Oral beta-blocker therapy ( 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). 4) increased risk for cardiogenic shock Risk factors for increased cardiogenic shock • • • • • • Older age Female sex Time delay Higher killip class SBP<120 HR>110 or <60 If Beta blockers are contra indicated Nondihdropyridine calcium channel blockers - Verapamil - Diltiazem Contraindications for CCBs: Severe LV dysfunction COMMIT Trial •45,852 patients within 24 h acute MI ― 93% STEMI or LBBB, 7% had NSTEMI •Up to 15 mg IV → 50 mg po metoprolol daily v/s placebo • composite primary outcomes ― death, reinfarction, or cardiac arrest •No decrease of com-primary outcome by metoprolol - modest reduction in reinfarctions and VF • Risk cardiogenic shock especially with initial hemodynamic instability •Recommend: start -blocker po when hemodynamically stable 15 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 ACEIs ARBs: if intolerance to ACEI (class IIa) IV morphine IV beta blocker : in HTN with UA/NSTEMI ( with no CI for Beta Blocker) Oral long acting non-DHP CCBs : for recurrent ischemia if no CI ( after nitrates and beta blockers) Oral ACEI - in pts with out - pulmonary congestion - LVEF≤ 40% Intra aortic balloon counter pulsations (IABP) • For continuing severe ischemia • For hemodynamic unstability Class IIa Nitrates : - SBP<90 or ≥ 30mm Hg below the baseline. - with in 24 hr of PDEIs ( sildenafil& tadalafil) IV ACEI : ↑ ed risk of hypotension IV beta blockers : with CI to Beta blockade NSAIDs ( except ASA): a/w ↑ mortality, reinfarction, HTN, HF, myocardial rupture Class III Antiplatelet therapy Antiplatelet therapy class 1 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. 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 noninterventional approach is intended. • Useful approach in hospitals that do not have a routine policy about early invasive procedures Use of Proton pump inhibitors Interfere with the metabolism of clopidogrel - Lansoprazole inhibits CYP450 2C19 - Rabeprazole Omeprazole : significantly decrease the inhibitory effect of clopidogrel on platelet aggregation. Pantoprazole lacks inhibition of CYP450 2C19 -- Deleted recommendation 2011 Anti coagulant therapy recommendations Class I Invasive strategy: - UFH - Enoxaparin - Bivalirudin 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 UFH dosage • ACC/AHA Guidelines recommend weight-adjusted dose of UFH : 60 units/kg bolus and : 12 units/kg/hr infusion. Select Management Strategy: Initial Conservative Strategy Versus Initial Invasive strategy UA/NSTEMI Conservative strategy Anticoagulant therapy: Enoxaparin or UFH Fondaparinux Initiate clopidogrel ASA ( Clopidogrel if ASA intolerance) Invasive strategy Anticoagulant therapy: Enoxaparin or UFH Bivalirudin Pre cath: Add second antiplatelet agent: -Clopidogrel -GPIIb/IIIA inhibtor (IV eptifibatide or tirofiban) Next step per triage decision at angiography CABG: Maintenance ASA PCI: Clopidogrel (if not begun precath) Or Prasugrel Or GPIIB/IIIA inhibitor (if not begun precath Medical therapy: -D/C GPIIb/IIIainhibitor and give clopidogrel as per conservative strategy Initial Conservative management Strategy UA/NSTEMI Conservative strategy ASA + Anticoagulant therapy Clpidogrel (30-600 mg→→ 75mg) -ASA continued indefinitely -Clpidogrel continued for at least 1 month and ideally up to 1 year UA/NSTEMI- conservative strategy Class 1 No subsequent features that necessitates CAG EF<40% LV EF EF>40% Stress testing Low risk High Risk CAG -ASA indefinitely -Clopidogrel – 1 month (ideally up to 1 year) -Discontinue IV GPIIb/IIIa inhibitor if started previously -Continue UFH for 48 hrs or administer enoxaparin or fondaparinux max up to 8days or duration of hospitalization ACC/AHA noninvasive risk stratfication: high risk (>3% annual mortality rate) • • • • • • severe resting LV dysfunction (LVEF<35%) High risk TMT score (score≤ -11) Severe exercise LV dysfunction (LVEF<35%) Stress induced large perfusion defect (if ant.) Stress induced multiple perfusion defects Large fixed perfusion defect with LV dialatation or increased lung uptake (thallium 201) • Stress induced moderate perfusion defect with LV dialatation or increased lung uptake (thallium 201) • Echo wall motion abn.at low dose dobutamine • Stress echo evidence of extensive ischemia UA/NSTEMI- Conservative Strategy Class IIa Recurrent ischemic discomfort with ASA+ Clopidogrel+Anticoagulant treatment Add a GPIIb/IIIa inhibitor before diagnostic CAG Omit GPIIB/IIIa inhibitors if bivalirudin is selected as the anticoagulant & 300-600 mg clopidogrel was administered 6 hours earlier than planned CAG or PCI Management after Diagnostic Angiography in Patients with UA/NSTEMI Dx Angiography Select Post Angiography Management Strategy CABG • Cont ASA . • DC clopidogrel 5 to 7 d prior to PCI • Cont ASA • LD of clopidogrel if not given elective CABG. • DC IV GP IIb/IIIa 4 h prior to CABG • Cont UFH • DC enoxaparin 12 to 24 h prior to CABG; • DC fondaparinux 24 h prior to CABG; • DC bivalirudin 3 h prior to CABG. Dose with UFH per institutional practice pre angio Medical therapy No significant obstructive CAD on angiography & CAD on angiography • Cont ASA • LD of clopidogrel if not • IV GP IIb/IIIa if not started given pre angio pre angio • DC ACT after PCI for uncomplicated cases Antiplatelet and ACT at physician’s discretion (Class I, LOE: C) • DC IV GP IIb/IIIa after at least 12 h if started pre angio • Cont IV UFH for at least 48 h • or enoxaparin or fondaparinux for dur of hosp ; either DC bivalirudin or cont at a dose of 0.25 mg/kg/hr for up to 72 h at physician‘s discretion . 34 UA/NSTEMI- CABG selected as post angiography management Class 1 - -Continue ASA -Discontinue clopidogrel - 5 days prior to CABG -(discontinue prasugrel - 7 days prior to CABG) -Discontinue IV GPIIb/IIIa inhibitor (eptifibatide or tirofiban) 4 hrs before CABG. -Continue UFH - Discontinue enoxaparin & fondaparinux 12-24 hrs bfore CABG and dose with UFH per institutional practice -Discontinue bivalirudin 3 hours before CABG and dose with UFH as per institutional practice UA/NSTEMI- PCI has been selected as post angiography management Class 1A -Continue ASA - loading dose of thienopyridines if not given before CAG – - clopidogrel 300-600 mg - prasugrel 60 mg -IV GPIIa/IIIa inhibitor (abciximab, eptifibatide, tirofiban ) if not started before CAG (in troponin-positive and /or high risk patients) - Class IIa -Discontinue anticoagulant therapy after PCI for uncomplicated cases UA/NSTEMI –medical therapy is selected as management strategy + obstructive CAD -ASA -clopidogrel -discontinue IV GPIIb/IIIa inhibitor if started previously Anti coagulant therapy Continue intravenous UFH for at least 48 h or until discharge if given before diagnostic angiography Continue enoxaparin or fondaparinux for duration of hospitalization or up to 8 days. Discontinue Bivalirudin UA/NSTEMI –medical therapy is selected as management strategy -No significant obstructive CAD- Antiplatelet and anticoagulant therapy at the discretion of physician Luminal irregularities with out flow limiting lesions –long term ASA UA/NSTEMI – conservative strategy -who do not undergo CAG or stress testing -ASA indefinitely -Clopidogrel for at least 1 month ( ideally up to 1 year) -Discontinue GPIIb/IIIa inhibitor if started previously -Continue UFH for 48 hrs or -Enoxaparin or fondaparinux ( 8 days or dur.hosp.) Initial Invasive management strategy Relative Risk of All-Cause Mortality for Early Invasive Therapy Compared With Conservative Therapy at a Mean Follow-Up of 2 y Bavry AA, et al. J Am Coll Cardiol 2006;48:1319–1325. Reprinted with permission from Elsevier. CI = confidence interval; RR = relative risk. 41 Relative Risk of Recurrent Nonfatal MI for Early Invasive Therapy Compared With Conservative Therapy at a Mean Follow-Up of 2 y Bavry AA, et al. J Am Coll Cardiol 2006; 48:1319–1325. CI = confidence interval; RR = relative risk. Reprinted with permission from Elsevier. 42 Relative Risk of Recurrent UA Resulting in Rehospitalisation for Early Invasive Therapy Compared With Conservative Therapy at a Mean Follow-Up of 13 Months Bavry AA, et al. J Am Coll Cardiol 2006; 48:1319–1325. Reprinted with permission from Elsevier. CI = confidence interval; RR = relative risk; UA = unstable angina. 43 Recommendations for initial invasive strategies Class I - refractory angina - hemodynamic instability - arrhythmias - Elevated risk of clinical events Initially stabilized high risk patients –reasonable to choose early invasive strategy (With in 12-12 hrs) Class IIa 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%) UA/NSTEMI Invasive strategy Dual –antiplatelet on presentation Initiate anticoagulant therapy : Enoxaparin or UFH Bivalirudin Before PCIclopidogrel or IV GpIIb/IIIainhibitor-tirofiban or eptifibatide At the time of PCIclopidogrel (if not started) or Prasugrel IV GpIIb/IIIa-tirofiban or eptifibatide (if not begun pre catheterization) Recommendations in whom PCI is planned (2011) Class 1 Clopidogrel loading 300-600 mg should be given as early as possible before or at the time of PCI Or Prasugrel 60 mg should be given promptly and not later than 1 hour after PCI once coronary artery anatomy is defined. Class III No Abciximab to patients in whom PCI is not planned. Upstream GPIIa/IIIa inhibitors are not recommended in -TIMI score ≤ 2( low risk for ischemic events) - at high risk of bleeding Prasugrel contraindicated in -Prior h/o TIA or stroke Duration and maintenance of thienopyridine therapy (2011) Class 1 Clopidogrel 75 mg daily or Prasugrel 10 mg daily Duration : Up to 12 months If the risk of morbidity because of bleeding outweighs the benefit by thienopyridine therapy earlier discontinuation can be considered Long term Antiplatelet therapy Class I Medical therapy ASA 75-162 mg/d indefinitely & Clopidogrel 75 mg/d for at least 1 month and ideally up to 1 year BMS group 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) DES group 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 2011 new recommendation class IIb • Continuation of clopidogrel /prasugrel beyond 15 months may be considered in patients following DES placement Revascularization Strategy in UA/NSTEMI Cardiac cath CAD No Discharge from protocol Yes CABG Yes Left main disease No 1- or 2Vessel Disease Medial Therapy, PCI or CABG 3- or 2-vessel disease with proximal LAD involvement LV dysfunction or treated diabetes* No PCI or CABG Yes CABG *There is conflicting information about these patients. Most consider CABG to be preferable to PCI. Anderson JL, et al. J Am Coll Cardiol 2007;50:e1–e157, Figure 20. 52 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) Lipid Management contd.. Dietary therapy : -Reduced intake of saturated fats to < 7% of total calories -cholesterol to < 200 mg per d - trans fat (to < 1% of energy). Promoting daily physical activity and weight management are recommended Lipid Management If TG are ≥ 500 mg per dL: - Fibrate or niacin LDL-C be treated to goal after TG-lowering therapy. High dose statin+ fibrate can increase the risk of severe myopathy Statin doses kept low in this combination Blood Pressure Control Blood pressure control according to JNC 7 guidelines is recommended (i.e., BP < 140/90 mm Hg or < 130/80 mm Hg if the patient has diabetes mellitus or chronic kidney disease). Diabetes mellitus • Use insulin infusion to control hypeglycemia • control blood glucose from a more stringent to a more moderate target range . • Recommend treatment for hyperglycemia>180 mg/dl while avoiding hypogylcemia • NICE-SUGAR trial: ADA RECOMMENDATION “ Although hyperglycemia is associated with adverse outcomes after acute MI, reduction of glycemia per se and necessarily the use of insulin is a/w improved outcomes” Chronic Kidney Disease Creatinine clearance should be estimated in UA/NSTEMI patients. Doses of renally cleared drugs should be adjusted according to the pharmacokinetic data of specific medications. Chronic Kidney Disease contd… Patients undergoing CAG with receipt of contrast media should receive adequate preparatory hydration. Calculation of the contrast volume to Cr Cl ratio is useful to predict the maximum volume of contrast media that can be given with out significantly increasing the risk of contrast associated nephropathy TIME IS PRECIOUS • Creatinine clearance( an approximation of GFR) • is measured from plasma and urinary creatinine excretion rates for a defined time period (usually 24 h) • is expressed in milliliters per minute: • CrCl = (Uvol x UCr)/(PCr x Tmin). • Cockcroft-Gault: • CrCl (mL/min) = (140 – age (years) x weight (kg) x [0.85 if female])/(72 x sCr (mg/dL) Fragmin during Instability in Coronary Artery Disease (FRISC-2) • Patients within 48 h UA/NSTEMI • Early inv vs conserv & dalteparin vs placebo • 3048 patients → dalteparin for 5–7 d → 2457 continued dalteparin/placebo & received either inv or conserv rx strategy • Meds: ASA, β-blockers unless contraindicated • No ↓ death/MI @ 3 mo by dalteparin • ↓ Death/MI @ 6 mo, 1 y & 5 y for inv strategy ― Benefit confined to men, nonsmokers, and patients with ≥ 2 risk factors Wallentin L, et al. Lancet 2000;356:9–16 (1-year results). Lagerqvist B, et al. J Am Coll Cardiol 2001;38:41–8 (women vs men). Lagerqvist B, et al. Lancet 2006;368:998–1004 (5-yr follow-up). 76 Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS-TIMI-18) • • • • 2,220 patients within 24 h UA/NSTEMI Early inv or conserv (selective invasive) strategy Meds: ASA, heparin and tirofiban ↓ Death, MI, and rehosp for an ACS @ 6 mo for inv strategy ― Benefit in medium and high-risk patients (TnT ↑ of > 0.01 ng/mL, ST-segment deviation, TIMI risk score > 3) ― No high-risk features, outcomes ↔ ― ↓ Death/MI @ 6 mo for older adults with early inv strategy ― Benefit of early inv strategy for high-risk women (↑ TnT); low-risk women tended to have worse outcomes, incl ↑ risk of major bleeding Cannon CP, et al. N Engl J Med 2001;344:1879–87. 77 Third Randomized Intervention Treatment of Angina (RITA-3) • 1,810 moderate-risk ACS patients • Early inv or conserv (ischemia-driven) strategy • Exclusions: CK-MB > 2X ULN @ randomization, new Q-waves, MI w/in 1 mo, PCI w/in 1 y, any prior CABG • ↓ Death, MI, & refractory angina for inv strategy ― Benefit driven primarily by ↓ in refractory angina • ↓ Death/MI @ 5 y for early inv arm • No benefit of early inv strategy in women Fox KA, et al. Lancet 2002;360:743–51. Fox KA, et al. Lancet 2005;366:914–20 (5-y results). 78 Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) •12,562 patients within 24 h UA/NSTEMI •Placebo vs clopidogrel (LD 300 mg → 75 mg qd) •Other meds: ASA •↓ CV death, MI, or stroke, rate of recurrent ischemia & revasc with clopidogrel •↑ Major (non–life-threatening) bleeding with clopidogrel •No routine inv strategy, 23% revasc during initial admission •Although well tolerated, < 10% GP IIb/IIIa + ASA + clopidogrel + heparin use in study patients Yusuf S, et al. N Engl J Med 2001;345:494–502. 79 Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISMPLUS) •1,915 patients within 12 h UA/NSTEMI •Tirofiban alone, UFH alone, or both for 48–108 h. •Tirofiban-alone arm discontinued d/t ↑ mortality rate. •↓ Death, MI, or refractory ischemia at 7 d, 30 d & 6 mo by tirofiban + heparin •High rate of angio could have contributed to important ↓ in event rates •Recommend: Tirofiban + heparin for medical rx or during PCI PRISM-PLUS Study Investigators. N Engl J Med 1998;338:1488–97. 80 Relative Risk of All-Cause Mortality for Early Invasive Therapy Compared With Conservative Therapy at a Mean Follow-Up of 2 y Bavry AA, et al. J Am Coll Cardiol 2006;48:1319–1325. Reprinted with permission from Elsevier. CI = confidence interval; RR = relative risk. 82 Relative Risk of Recurrent Nonfatal MI for Early Invasive Therapy Compared With Conservative Therapy at a Mean Follow-Up of 2 y Bavry AA, et al. J Am Coll Cardiol 2006; 48:1319–1325. CI = confidence interval; RR = relative risk. Reprinted with permission from Elsevier. 83 Relative Risk of Recurrent UA Resulting in Rehospitalisation for Early Invasive Therapy Compared With Conservative Therapy at a Mean Follow-Up of 13 Months Bavry AA, et al. J Am Coll Cardiol 2006; 48:1319–1325. Reprinted with permission from Elsevier. CI = confidence interval; RR = relative risk; UA = unstable angina. 84 SYMPTOMS SUGGESTIVE OF ACS Noncardiac Diagnosis Chronic Stable Angina Definite ACS Possible ACS No ST-Elevation Treatment as indicated by alternative diagnosis ACC/AHA Chronic Stable Angina Guidelines Nondiagnostic ECG Normal initial serum cardiac biomarkers Observe ST and/or T wave changes Ongoing pain Positive cardiac biomarkers Hemodynamic abnormalities ≥ 12 h from symptom onset No recurrent pain; negative follow-up studies Recurrent ischemic pain or positive follow-up studies Stress study to provoke ischemia Diagnosis of ACS confirmed Consider evaluation of LV function if ischemia is present (tests may be performed either prior to discharge or as outpatient) Evaluate for reperfusion therapy ACC/AHA STEMI Guidelines Negative Positive Admit to hospital Potential diagnoses: nonischemic discomfort; lowrisk ACS Diagnosis of ACS confirmed or highly likely Manage via acute ischemia pathway Arrangements for outpatient follow-up ST-Elevation 85