Non st elevation myocardial infarction and unstable angina

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Non st elevation myocardial infarction and unstable angina

  1. 1. Grerk Sutamtewagul, M.D. June 2012
  2. 2. Outline  Definition  Pathophysiology  Clinical Presentation  Risk Stratification  Early Hospital Care  Medical treatment  Treatment strategy  Long Term Management
  3. 3. Unstable angina and Non-ST Elevation Myocardial Infarction
  4. 4. Unstable angina  Angina pectoris or equivalent type of ischemic discomfort with at least 1/3 of the following 1. Occurring at rest and lasting > 20 mins 2. New onset, severe symptom 3. Crescendo pattern (increasing in severity, duration, or frequency)
  5. 5. NSTEMI  Approximately 2/3 of patient with UA have elevated cardiac serum markers – thus the diagnosis of NSTEMI
  6. 6. Unstable angina and Non-ST Elevation Myocardial Infarction
  7. 7. Pathophysiologic process 1. Plaque rupture or erosion with superimposed thrombus* 2. Dynamic obstruction  Spasm of epicardial artery (Prinzmetal)  Constriction of small intramural arteries  Local vasoconstrictors (e.g. TXA2) released from platelets  Dysfunction of coronary endothelium  Adrenergic stimuli (cold, cocaine)
  8. 8. Pathophysiologic process 3. Severe coronary luminal narrowing  Atherosclerosis  Post-PCI restenosis 4. Inflammation 5. Secondary unstable angina to tachycardia, fever, hypotension, anemia
  9. 9. Plaque rupture and thrombosis  Platelet activation and aggregation  Exposure to subendothelial matrix (tissue factor, collagen)  Platelet adhesion (GP Ib-vWF and GP VI- collagen)  Platelet activation: ○ Morphology change (smooth  spiculated) ○ Degranulation (TXA2, serotonin, etc.) ○ GP IIb/IIIa receptor expression and enhancement  Platelet aggregation (GP IIb/IIIa – fibrinogen)  Secondary hemostasis
  10. 10. Plaque rupture and thrombosis  Platelet activation and aggregation  Secondary hemostasis  Initiation  Amplification  Propagation
  11. 11. Unstable angina and Non-ST Elevation Myocardial Infarction
  12. 12. Clinical Examination  Largely unremarkable  Signs of large fraction ischemia:  Diaphoresis  Pale, cool skin  Sinus tachycardia  Third or forth heart sound  Basilar rales  Hypotension
  13. 13. Electrocardiography  EKG abnormality found in 50% of patients with UA/NSTEMI  ST depression (>0.1 mV or >0.05 mV if prior EKG available)  Transient ST elevation (10%, poor prognosis)  T wave change (sensitive but not specific unless > 0.3 mV)
  14. 14. ST segment
  15. 15. 51 yo F with CP+SOB
  16. 16. 5 hrs later
  17. 17. Markers of Cardiac Necrosis  CK-MB  Troponin T, Troponin I  Higher level associates with worse prognosis.  Patients with UA/NSTEMI and troponin elevation but no apparent CAD on angiography had significantly worse prognosis than those who have troponin negative1. 1. Braunwald E, Lakkis N; TACTICS-TIMI-18 Investigators. Prognostic implications of elevated troponin in patients with suspected acute coronary syndrome but no critical epicardial coronary disease: a TACTICS-TIMI-18 substudy. J Am Coll Cardiol. 2005 Jan 4;45(1):19-24. Erratum in: J Am Coll Cardiol. 2005 Jun 7;45(11):1911.
  18. 18. Laboratory testing  Serum lipid panel – treatable risk factor  Total Cholesterol and HDL-C fall by as much as 30-40% in 24 hrs after UA/NSTEMI or STEMI.
  19. 19. Unstable angina and Non-ST Elevation Myocardial Infarction
  20. 20. High-risk clinical subgroups  Age  PURSUIT trial: univariate relationship between age and 30-day mortality was curvilinear with reflection at around 65 years in UA/NSTEMI. Boersma E et al. Predictors of outcome in patients with acute coronary syndromes without persistent ST-segment elevation. Results from an international trial of 9461 patients. The PURSUIT Investigators. Circulation. 2000 Jun 6;101(22):2557-67.
  21. 21. High-risk clinical subgroups  Gender  Women with ACS tend to have more traditional risk factors  confounded  Women usually presents with more atypical features  delay in diagnosis  Women with presumed ACS have less severe epicardial CAD.  Multivariate model: gender was not associated with cardiovascular outcomes2. 2 Hochman JS, et al. Outcome and profile of women and men presenting with acute coronary syndromes: a report from TIMI IIIB. TIMI Investigators. Thrombolysis in Myocardial Infarction. J Am Coll Cardiol. 1997 Jul;30(1):141-8.
  22. 22. High-risk clinical subgroups  Diabetes  Potent risk indicator  Increase in oxidative stress  proatherogenic  Risk of first MI in diabetics without prior MI is approximately equal to recurrent MI in non- diabetics who had prior MI*. * Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998 Jul 23;339(4):229-34.
  23. 23. Mortality comparison Haffner SM, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998 Jul 23;339(4):229-34.
  24. 24. High-risk clinical subgroups  Diabetes  1.5 to 2.0-fold higher rate of death and cardiac ischemic events for patients with NSTEMI (GUSTO IIb, PRISM-PLUS, FRISC II, TACTIC-TIMI 18, GUSTO IV-ACS)  Data across 11 TIMI trials: ○ 30-day mortality adj OR 1.78 [1.24-2.56] ○ 1-yr mortality adj HR 1.65 [1.30-2.10]
  25. 25. High-risk clinical subgroups  Smoking  Smoker‟s Paradox ○ Current smokers tend to have lower rates of death and ischemic events than nonsmokers.  Multivariate analysis: smoking is not a significant independent prognostic factor.* * Barbash GI, et al. Evaluation of paradoxic beneficial effects of smoking in patients receiving thrombolytic therapy for acute myocardial infarction: mechanism of the "smoker's paradox" from the GUSTO-I trial, with angiographic insights. Global Utilization of Streptokinase and Tissue- Plasminogen Activator for Occluded Coronary Arteries. J Am Coll Cardiol. 1995 Nov 1;26(5):1222- 9.
  26. 26. High-risk clinical subgroups  Peripheral vascular disease  Independent risk factor for death and ischemic complications in patients with UA- NSTEMI even after adjustment for traditional risk factors. (OPUS-TIMI 16, PURSUIT study)
  27. 27. High-risk clinical subgroups  Prior aspirin use  Multiple studies have confirmed that patients with prior aspirin use are at increased risk.  Present of aspirin-resistant platelet-rish thrombi.  Aspirin resistance may be associated with increased risk of death and cardiovascular complications.
  28. 28. High-risk clinical subgroups  Severity of angina  Worse prognosis with ○ Multiple episodes of angina in the past 24 hrs ○ Angina at rest ○ Post-infarction angina
  29. 29. High-risk clinical subgroups  Physical examination  Physical exam suggestive of LV dysfunction is more commonly seen in STEMI.  Higher Killip class (≥2)  significant underlying CAD  higher mortality
  30. 30. Holmes DR Jr et al. Cardiogenic shock in patients with acute ischemic syndromes with and without ST-segment elevation. Circulation. 1999 Nov 16;100(20):2067-73.
  31. 31. High-risk clinical subgroups  Electrocardiogram  Admission ECG is one of the most useful and powerful predictors of adverse outcomes.  ST depression is associated with ○ Worse in-hospital prognosis ○ Greater complexity and extent of the lesion  ST depression as little as 0.05 mV had ≈ 2 fold death or MI at 30 days and 1 year [TIMI III Registry]  T wave inversion is generally not assoc with worse prognosis (except deep TWI lateral leads)
  32. 32. High-risk clinical subgroups  Markers of necrosis  Blood samples should be obtained at least 6 to 9 hours after the onset of symptoms  There is a quantitative relationship between the magnitude of CK-MB, Troponin I and risk of death [PURSUIT, TIMI IIIb].
  33. 33. Troponin I and mortality Antman EM, et al. Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med. 1996 Oct 31;335(18):1342-9.
  34. 34. What should be the appropriate cut point of troponin assay?  Consensus panels recommend cut point at 99th percentile from a cohort of healthy individuals and coefficient of variation less than 10% (for study precision).  Trials of UA-NSTEMI supported the prognostic importance of “low-level” troponin elevation even below such cut point [data from TACTIC-TIMI 18]
  35. 35. Death, MI, ACS vs Troponin Morrow DA, et al; TACTICS-TIMI 18 Investigators. Ability of minor elevations of troponins I and T to predict benefit from an early invasive strategy in patients with unstable angina and non- ST elevation myocardial infarction: results from a randomized trial. JAMA. 2001 Nov 21;286(19):2405-12.
  36. 36. Emerging Biomarkers in ACS
  37. 37. Integrated Approach  TIMI risk score  GRACE risk score  Prognostic tools with high discriminatory ability using baseline variables which are parts of routine medical evaluation.
  38. 38. TIMI Risk Score for UA/NSTEMI  Data from 1957 patients who were randomized to the UFH arm of TIMI 11B trial (UA/NSTEMI only)  Multivariated logistic regression analysis  7 independent predictors.  TRS for UA/NSTEMI has been validated in many cohorts, including ESSENCE and TACTICS-TIMI 18.
  39. 39. TIMI Risk Score for UA/NSTEMI Antman EM et al. The TIMI risk score for unstable angina/non-ST elevation MI: A method for prognostication and therapeutic decision making. JAMA. 2000 Aug 16;284(7):835-42.
  40. 40. TIMI Risk Score for UA/NSTEMI Antman EM et al. The TIMI risk score for unstable angina/non-ST elevation MI: A method for prognostication and therapeutic decision making. JAMA. 2000 Aug 16;284(7):835-42.
  41. 41. TIMI Risk Score for UA/NSTEMI Antman EM et al. The TIMI risk score for unstable angina/non-ST elevation MI: A method for prognostication and therapeutic decision making. JAMA. 2000 Aug 16;284(7):835-42.
  42. 42. GRACE risk score  Data from Global Registry of Acute Coronary Events (GRACE) with 15,007 subjects across the spectrum of ACS  9 predictive variables.
  43. 43. Comparison of TRS for UA/NSTEMI and GRACE score  Retrospective analysis and prospective observational studies suggest that GRACE score has greater prognostic discrimination compared to TRS for UA/NSTEMI.  One retrospective analysis found no difference between GRACE score and TRS for STEMI.
  44. 44. TRS vs GRACE score Ramsay G, Podogrodzka M, McClure C, Fox KA. Risk prediction in patients presenting with suspected cardiac pain: the GRACE and TIMI risk scores versus clinical evaluation. QJM. 2007 Jan;100(1):11-8. Epub 2006 Dec 15.
  45. 45. Unstable angina and Non-ST Elevation Myocardial Infarction
  46. 46. Early hospital care  General and anti-ischemic therapy  Antiplatelet therapy  Anticoagulant therapy  ACEI or ARB  Treatment strategies: initial conservative vs early invasive
  47. 47. General Measures  Patient at medium-high risk should be admitted to intensive or intermediate cardiac care unit + ECG monitoring  Bed rest  Oxygen for SaO2 less than 90%, respiratory distress, other high-risk features for hypoxemia (Class I),  or all patient with UA/NSTEMI in the first 6 hours (Class IIa)  Anti-ischemic therapy: Nitrate, beta-blocker  Intravenous Morphine  for uncontrolled CP despite NTG. (Class IIa)
  48. 48. Anti-ischemic therapy  NITRATES  Endothelium-independent vasodilators (via G protein and cAMP)  Coronary vasodilation  Arteriolar and venous dilation  reduced myocardial afterload, preload, and wall stress
  49. 49. Anti-ischemic therapy  NITRATES  0.4 mg NTG Sublingual q5mins x 3  0.3-0.6 mg NTG Buccal spray q5mins x 3  If symptoms persist, IV NTG start at 5-10 μg/min, increase by 10 μg/min q3-5mins until relief of symptoms.
  50. 50. Anti-ischemic therapy  NITRATES  IV NTG should not be increased if it will preclude the use of beta-blocker or ACEI.  Contraindications: Hypotension, use of sidenafil or related phosphodiesterase-5 inhibitors within previous 12-48 hours, HR<50, or HR >100 in the absence of symptomatic HF or RV infarction  8-10 hours of nitrate-free interval to avoid the development of tolerance  No effect on mortality [ISIS-4]
  51. 51. Beta-blockers  Reduce subsequent MI or recurrent ischemia† and rate of VF‡, reduction in mortality in early placebo-controlled trials  Reduction in mortality in 21st century is less clear.  Chen et al∏. 45,852 subjects - Metoprolol vs Placebo in MI: Death OR 0.99, [0.92-1.05] [COMMIT trial] † Gottlieb SO, et al. Effect of the addition of propranolol to therapy with nifedipine for unstable angina pectoris: a randomized, double-blind, placebo-controlled trial. Circulation. 1986 Feb;73(2):331-7. ‡ Yusuf S, et al. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis. 1985 Mar-Apr;27(5):335-71. ∏ Chen ZM, et al; COMMIT collaborative group. Early intravenous then oral metoprolol in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005 Nov 5;366(9497):1622-32.
  52. 52. Beta-blockers  Oral beta-blocker should be initiated within the first 24 hours (Class I) for pt without contraindication and ≥ 1 of the following:  Signs of HF  Low output state  At risk for cardiogenic shock ○ Age>70, SBP<120mmHg, HR<60 or >110  Relative contraindications: PR >240ms, 2nd or 3rd degree heart block, active asthma, Reactive airway
  53. 53. Calcium channel blocker  Calcium channel blockers  vasodilatory effects, reduce blood pressure, slow heart rate and reduce myocardial contractility  Reduce recurrent MI in early studies  Non-dihydropyridine (Verapamil, Diltiazem) should be used.  Short-acting dihydropyridine CCB (e.g. Nifedipine), which accelerate HR, has been shown to be harmful when it is not coadministered with beta-blocker.  Long-acting dihydropyridine CCB is safe for stable CAD.
  54. 54. Calcium channel blocker  In whom beta blockers are contraindicated, a nondihydropyridine CCB should be given as initial therapy. (Class I)  in the absence of significant LV dysfunction  For recurrent ischemia after beta blocker and nitrates have been fully used, oral long-acting nondihydropyridine CCB can be used (Class IIa)
  55. 55. Antiplatelet Therapy  Platelets play a major role in pathogenesis of UA/NSTEMI.  Accordingly, antiplatelet therapy plays a central role in management.  Antiplatelets:  Aspirin  ADP receptor (P2Y12) antagonist  Glycoprotein IIb/IIIa (αIIbβ3) inhibitor
  56. 56. Antiplatelets
  57. 57. Aspirin  Irreversibly acetylates platelet cyclooxygenase 1 (COX-1)  decrease synthesis and release of Thromboxane A2 (TXA2), a major platelet activator.  Antiplatelet effect lasts for lifetime of the platelets (7-10 days).
  58. 58. Aspirin  Several trials have demonstrated clear beneficial effects of ASA in UA/NSTEMI.  Approximately 25% reduction in death or MI  Efficacy is not dose-dependent.  CURRENT-OASIS 7 compared high-dose (300-325 mg) versus low-dose (75-100 mg) aspirin daily after a loading dose  No difference in death, MI, stroke, major bleeding in 30 days.† † Mehta SR, et al. CURRENT-OASIS 7 Investigators. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med. 2010 Sep 2;363(10):930-42. Erratum in: N Engl J Med. 2010 Oct 14;363(16):1585.
  59. 59. Aspirin
  60. 60. Aspirin  Aspirin resistance  2-8% of patients have limited anti-platelet effect  Lead to worse cardiovascular outcome  Often related to poor compliance  Concomitant use of ibuprofen (reversible COX-1 inhibitor – competitively bound to COX-1)
  61. 61. Aspirin  ASA should be administered to patients with UA/NSTEMI as soon as possible after hospital presentation and continued indefinitely in patients who tolerate it. (Class I, LOE A)  Clopidogrel can be used if the patients who are unable to take aspirin. (Class I, LOE B)
  62. 62. ADP antagonist  Thienopyridines  Ticlopidine  Clopidogrel  Prasugrel  Elinogrel  Non-thienopyridines  Tigagrelor  Cangrelor
  63. 63. ADP antagonist Cattaneo M. New P2Y(12) inhibitors. Circulation. 2010 Jan 5;121(1):171-9.
  64. 64. Thienopyridines  Prodrugs  Oxidation by P-450 system in the liver  Active metabolites irreversibly inhibit the binding of ADP to platelet P2Y12 receptor  inhibit platelet aggregation.  Ticlopidine is the first thienopyridines. Its use was limited by bleeding complication, neutropenia, and risk of TTP.
  65. 65. ADP antagonist
  66. 66. Clopidogrel  Absorption  85% Hydrolyzed  P-450 oxidation (mainly cytochrome 2C19)  As effective as ticlopidine for prevention of stent thrombosis but less bleeding complication.  CURE trial: 12,562 UA/NSTEMI patients ASA + heparin + clopidogrel or placebo  20% reduction in cardiovascular death, MI or stroke in all groups (high-low risk, PCI- medical-CABG). Benefit seen from first 24 hours and extended through the 1-year period of the study.
  67. 67. Figure 1. Cardiovascular death, MI, or stroke for entire study. Fox K A et al. Circulation 2004;110:1202-1208 Copyright © American Heart Association
  68. 68. Clopidogrel before PCI  Clopidogrel given before PCI  29% reduction in cardiovascular death or MI  Benefit even without concomitant GP IIb/IIIa inhibitor Sabatine MS,et al; Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)-Thrombolysis in Myocardial Infarction (TIMI) 28 Investigators. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. JAMA. 2005 Sep 14;294(10):1224-32. Epub 2005 Sep 4.
  69. 69. CLARITY-TIMI 28 Sabatine MS,et al; Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)-Thrombolysis in Myocardial Infarction (TIMI) 28 Investigators. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. JAMA. 2005 Sep 14;294(10):1224-32. Epub 2005 Sep 4.
  70. 70. Clopidogrel before CABG  In patient undergoing CABG, clopidogrel given within 5 days before surgery is associated with major bleeding complication and longer hospital stay (not statistically significant).
  71. 71. Figure 3. Major bleeding (point estimates and CIs) for study as a whole. Fox K A et al. Circulation 2004;110:1202-1208 Copyright © American Heart Association
  72. 72. TABLE 4 The time interval between study drug discontinuation and early CABG surgery in relation to bleeding frequency Life threatenting or other major bleeds within 7 days of CABG surgery Placebo Clopidogrel RR 95% CI % % Day of CABG 6/119 5 9/110 8.2 1.62 0.60-4.41 1 day prior to CABG 11/139 7.9 11/99 11.1 1.4 0.63-3.11 2 days prior to CABG 7/95 7.4 12/118 10.2 1.38 0.57-3.37 3 days prior to CABG 3/73 4.1 5/54 9.3 2.25 0.56-9.02 4 days prior to CABG 3/50 6.0 5/55 9.1 1.52 0.38-6.02 ≥5 days prior to CABG 24/454 5.3 20/456 4.4 0.83 0.46-1.48 Fox K A et al. Circulation 2004;110:1202-1208
  73. 73. Strategies for initiation of clopidogrel therapy  Start at presentation  Start immediately after PCI
  74. 74. Strategies for initiation of clopidogrel therapy  Start at presentation  Reducing ischemic event before PCI  Increase bleeding in pt who undergo CABG  Start immediately after PCI  Decrease bleeding, blood transfusion, immediate post-op death
  75. 75. Strategies for initiation of clopidogrel therapy  Overall benefit-to-risk ratio from major randomized studies favors early initiation of clopidogrel. Biancari, et al. J Thorac Cardiovasc Surg, Mar 2012
  76. 76. Loading dose  Initial loading dose decrease the time achieving target level.  Clopidogrel 75 mg/day  3-5 days  Clopidogrel 300 mg loading  4-6 hrs  Clopidogrel 600 mg loading  2 hrs
  77. 77. Loading dose  Clopidogrel 600 mg vs 300 mg loading  Lower rate of major cardiovascular event [ARMYDA-2]  No difference in cardiovascular death, MI, or stroke [CURRENT-OASIS 7]  Review of literature:  Decrease major adverse cardiovascular events  Marginally decrease all-cause mortality  Slightly increase bleeding risk
  78. 78. Nijjer SS, et al. Quantitative comparison of clopidogrel 600mg, prasugrel and ticagrelor, against clopidogrel300mg on major adverse cardiovascular events and bleeding in coronary stenting: Synthesis of CURRENT-OASIS-7, TRITON- TIMI-38 and PLATO. Int J Cardiol. 2012 Jul 12;158(2):181-5. Epub 2012 Jan 10.
  79. 79. Clopidogrel hyporesponsiveness  Common among  Diabetics  Obesity  Advanced age  Genetic polymorphism in cytochrome P450 (esp. CYP2C19 - *C2 allele) ○ 1/3 of Whites, more frequent in Asians ○ Related with adverse outcome and in stent thrombosis
  80. 80. Clopidogrel and PPI  Proton-pump inhibitors (PPI) are often prescribed prophylactically to prevent GI bleeding due to dual-antiplatelet therapy.  Some PPIs inhibit CYP2C19: omeprazole, lansoprazole, rabeprazole but not pantoprazole  Some observational studies reported adverse cardiovascular outcome with PPI-clopidogrel-ASA.
  81. 81. Clopidogrel and PPI  2 randomized trials: PRINCIPLE TIMI-44 and TRITON TIMI-38  PPI treatment attenuated the pharmacodynamic effect of clopidogrel.  PPI treatment did not affect the clinical outcome. The finding was true for all PPIs including omeprazole and pantoprazole.  COGENT study: omeprazole vs placebo  No difference cardiovascular events HR 0.99 [0.68-1.44] but obvious benefit in GIB
  82. 82. Clopidogrel and PPI Bhatt DL, COGENT Investigators. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med. 2010 Nov 11;363(20):1909-17. Epub 2010 Oct 6.
  83. 83. Prasugrel  Prodrug  Active metabolite is an irreversible inhibitor of the platelet P2Y12 receptor.  CYP2C19 is not the major enzyme   Decrease interaction with PPI  Can be use in clopidogrel hyporesponders
  84. 84. ADP antagonist
  85. 85. Prasugrel  TRITON-TIMI 38 trial  13,608 pts with ACS (10,074 with UA/NSTEMI) in whom PCI was planned.  Loading 60 mg  10 mg daily  Compared to clopidogrel 300  75 mg  Reduce cardiovascular death, MI, and stroke by 19% HR 0.81 [0.73-0.90]  Decrease in stent thrombosis by 52% HR 0.48 p<0.0001
  86. 86. Prasugrel
  87. 87. Prasugrel  TRITON-TIMI 38 trial  More common in serious bleeding  Risk of bleeding was especially higher in ○ Elderly (>75 yo) ○ Body weight < 60 kg  Prasugrel is contraindicated in patient with history of stroke or TIA.  Prasugrel use should be strictly followed the study protocol of TRITON-TIMI 38 design.  Diagnostic catheterization first  planned PCI
  88. 88. Ticagrelor  Non-thienopyridine  Not require P450 for activation  Reversibly block P2Y12 platelet receptor  Ticagrelor and its active metabolite are excreted into the bile.  Rapid onset (30 mins)  Shorter half-life
  89. 89. Ticagrelor  PLATO trial  18,624 pts;15,381 (62%) had UA/NSTEMI  Compare Ticagrelor (90 mg BID) with Clopidogrel (300 or 600  75 mg daily)  16% Reduction in composite cardiovascular death, MI, and stroke  22% Reduction in total mortality
  90. 90. Ticagrelor
  91. 91. Ticagrelor  PLATO trial  No difference in total major bleeding but significantly higher non-CABG major bleeding  Should be started at ER  If necessary, it could be stopped and CABG could be carried out 48-72 hrs later.
  92. 92. Glycoprotein IIb/IIIa inhibitors  Abciximab (ReoPro) mAb – only prior PCI  Eptifibatide (Integrilin)  Tirofiban (Aggrastat)  Bind GP IIb/IIIa (αIIbβ3) thus prevent platelet aggregation caused by all types of stimuli.
  93. 93. Glycoprotein IIb/IIIa inhibitors  Intravenous bolus followed by continuous infusion  Receptor blocking activity and associated bleeding risk subside promptly after discontinuation.  Several trials confirm the benefit for cardiovascular death, MI  Also benefit even on the background of clopidogrel pretreatment
  94. 94. Glycoprotein IIb/IIIa inhibitors  Abciximab in UA/NSTEMI pts whom early conservative strategy was planned  no benefit and higher early mortality
  95. 95. Glycoprotein IIb/IIIa inhibitors  Timing of GP IIb/IIIa inhibition  Starting at the time of presentation or  Use just before or during PCI  No difference in benefit  Risk of major bleeding is higher with longer infusion group. [EARLY ACS trial]
  96. 96. Other antiplatelets
  97. 97. Early hospital care antiplatelet therapy  Pts with definite UA/NSTEMI at medium or high risk, initial invasive strategy  ASA plus one of the following  Before PCI ○ Clopidogrel (Class I, LOE B) ○ An IV GPIIb/IIIa inhibitor (Class I, LOE A)  At PCI ○ Clopidogrel if not started ○ Prasugrel (Class I, LOE B) ○ An IV GPIIb/IIIa inhibitor (Class I, LOE A)
  98. 98. Early hospital care antiplatelet therapy  Pts with initial conservative strategy  Clopidogrel loading dose followed by daily maintenance dose [added to ASA and anticoagulant therapy]  Administered for at least 1 month  Ideally up to 1 year (Class I, LOE B)
  99. 99. Early hospital care antiplatelet therapy  Loading dose of thienopyridines:  Clopidogrel 300-600 mg as early as possible before or at the time of PCI (Class I, LOE A)  Prasugrel 60 mg no later than 1 hr after PCI once coronary anatomy is defined, decide to do PCI (Class I, LOE B)  Maintenance dose at least 12 months  Clopidogrel 75 mg daily  Prasugrel 10 mg daily (Class I, LOE B)
  100. 100. Early hospital care antiplatelet therapy  UA/NSTEMI, early invasive;  Clopidogrel 600 mg loading dose  Followed by 150 mg daily for 6 days  Then 75 mg daily  In patient not high risk of bleeding (Class IIb, LOE B)
  101. 101. Anticoagulants  Heparin  Low-molecular-weight heparin  Fondaparinux  Direct thrombin inhibitors  Direct Xa inhibitors
  102. 102. Heparin  Activating Antithrombin (previously known as antithrombin III)  Accelerate the inhibition of Thrombin and FXa
  103. 103. Heparin
  104. 104. Heparin  Unfractionated heparin (UFH) has been a cornerstone of therapy for patients with UA/NSTEMI.  Goal aPTT of 50-75 sec or 1.5-2.5x  33% reduction in death or MI comparing UFH+ASA vs ASA alone
  105. 105. Low-Molecular-Weight Heparin  Compare to UFH  LMWH has greater anti-FXa activity  more effective in decreasing synthesis of thrombin  Lower rate of thrombocytopenia  Higher bioavailability  subcut admin  Less binding to plasma protein  more consistent effect  no need for monitoring aPTT  In case of bleeding, reversal of protamine is less effective.  Need renal adjustment
  106. 106. Low-Molecular-Weight Heparin
  107. 107. Low-Molecular-Weight Heparin  LMWH was found to be non-inferior to UFH.  Enoxaparin provides significant benefit over UFH in patients with UA/NSTEMI who are managed conservatively and receive at least 48 hrs of anticoagulation but not in patients managed invasively.
  108. 108. Fondaparinux  Synthetic analogue of the antithrombin- binding sequence found in heparin and LMWH.  Indirectly inhibit FXa via antithrombin
  109. 109. Fondaparinux  OASIS-5 trial  20,078 pts with high-risk UA/NSTEMI  Low dose fondaparinux (2.5 mg sc daily) vs standard dose enoxaparin  No difference in 9-day death, MI  Lower 30-day mortality (2.9% vs 3.5%)  Significantly reduce the rate of major bleeding  3x increase in catheter related thrombi
  110. 110. Direct thrombin inhibitors  Univalent DTI  Agatroban  Apixaban  Dabigatran  Bivalent DTI  Hirudin (leech)  Lepirudin  Bivalirudin (Angiomax)
  111. 111. Direct thrombin inhibitors  Not require antithrombin  Able to inhibit clot-bound thrombin  Not interact with plasma protein  Not cause thrombocytopenia  FDA approved for treatment of HIT (lepirudin and agatroban)  Recent FDA approval of bivalirudin for PCI (but not approved for HIT).
  112. 112. Bivalirudin  Angiomax  Binds reversibly to thrombin, cleaved by thrombin  No need to monitor ACT except in case of renal insufficiency  ACUITY trial  13,819 pts with UA/NSTEMI, managed with early invasive strategy  UFH or enoxaparin / GPIIb/IIIa / bivalirudin  No difference in efficacy (death, MI)  Lower rate of bleeding in bivalirudin alone
  113. 113. Additional Management of antiplatelet and anticoagulation  UA/NSTEMI; initial conservative; low risk stress test  Indefinite ASA (Class I, LOE A)  Clopidogrel at least 1 month, ideally 1 yr (Class I, LOE B)  UFH for 48 hrs (Class I, LOE A)  Enoxaparin or Fondaparinux for the duration of hospitalization, up to 8 days, then discontinue.
  114. 114. Unstable angina and Non-ST Elevation Myocardial Infarction
  115. 115. Treatment Strategies  Early invasive strategy  Conservative approach
  116. 116. Treatment Strategies  Early invasive strategy  Routine early cardiac catheterization followed by PCI, CABG, or continuing medical therapy  Conservative approach  Initial medical management and catheterization reserved for patients with recurrent ischemia either at rest or on a non- invasive test
  117. 117. Treatment Strategies  To date, comparisons of these 2 strategies have been studied in 10 randomized trials.  4 trials – no difference  6 trials – favor invasive strategies
  118. 118. Treatment Strategies
  119. 119. Indications for invasive vs conservative management  Early invasive strategy has been shown to benefit in patients with  ST-segment changes  Positive troponin  Recurrent ischemia  Evidence of CHF  All men and high-risk women
  120. 120. Initial invasive vs initial conservative  Early invasive strategy is indicated in patients with  Refractory angina  Hemodynamic or electrical instability (Class I, LOE B)  Elevated risk for clinical events* (Class I, LOE A)
  121. 121. Diagnosis of UA/NSTEMI is Likely or Definite ASA (Class I, LOE: A) Clopidogrel if ASA intolerant (Class I, LOE: B) Select Management Strategy Initial Conservative Strategy or Unknown Invasive Strategy† Initiate anticoagulant therapy (Class I, LOE: A) Acceptable options include • Enoxaparin or UFH (Class I, LOE: A) • Fondaparinux (Class I, LOE: B)* • Enoxaparin or fondaparinux preferred over UFH (Class IIa, LOE: B) Initiate clopidogrel (Class I, LOE: B) Initiate anticoagulant therapy (Class I, LOE: A)* Acceptable options include • Enoxaparin or UFH (Class I, LOE: A) • Bivalirudin (Class I, LOE: B) CABG: Maintenance ASA (Class I, LOE: A) Medical Therapy: D/C GP IIb/IIIa inhibitors if begun and give clopidogrel per conservative strategy Precatheterization: Add second antiplatelet agent (Class I, LOE: A)‡ • Clopidogrel (Class I, LOE: B) or • GP IIb/IIIa inhibitor (Class I, LOE: A) • (IV eptifibatide or tirofiban preferred) Next step per triage decision at angiography PCI: Class I: • Clopidogrel (if not begun precatheterization) (LOE: A) or • Prasugrel (LOE: B) or • Selectively, a GP IIb/IIIa inhibitor (if not begun precatheterization) (LOE: A) Wright RS, et al. J Am Coll Cardiol. 2011;57(19):1920-59. *If fondaparinux is used with an invasive strategy (Class I, LOE: B), it must be coadministered with another anticoagulant with Factor IIa activity, i.e., UFH.) †Timing of invasive strategy generally is assumed to be 4 to 48 hours. If immediate angiography is selected, see STEMI guidelines. ‡Precatheterization triple antiplatelet therapy (ASA, clopidogrel, GP inhibitors) is a Class IIb, LOE: B rec for selected high- risk patients.
  122. 122. • Cont aspirin (Class I, LOE: A) • DC clopidogrel 5 to 7 d prior to elective CABG (Class I, LOE: B) • DC IV GP IIb/IIIa 4 h prior to CABG (Class I, LOE: B) • Cont UFH (Class I, LOE: B); 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 (Class I, LOE: B) • Cont aspirin (Class I, LOE A) • LD of clopidogrel if not given pre angio (Class I, LOE: A) & • IV GP IIb/IIIa if not started pre angio (Class I, LOE: A) • DC ACT after PCI for uncomplicated cases (Class I, LOE: B) • Cont aspirin (Class I, LOE: A) • LD of clopidogrel if not given pre angio (Class I, LOE A)* • DC IV GP IIb/IIIa after at least 12 h if started pre angio (Class I, LOE: B) • Cont IV UFH for at least 48 h (Class I, LOE: A) or enoxaparin or fondaparinux for dur of hosp (LOE: A); either DC bivalirudin or cont at a dose of 0.25 mg/kg/hr for up to 72 h at physician„s discretion (Class I, LOE: B) Antiplatelet and ACT at physician‟s discretion (Class I, LOE: C) No significant obstructive CAD on angiography CAD on angiography Medical therapyPCICABG Select Post Angiography Management Strategy Dx Angiography Management after Diagnostic Angiography in Patients with UA/NSTEMI Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1-e157, Figure 9. ACT = anticoagulation therapy; LOE = level of evidence. G H I J F
  123. 123. Cardiac cath CAD No Discharge from protocol Yes Left main disease Yes CABG No 1- or 2- Vessel Disease 3- or 2-vessel disease with proximal LAD involvement LV dysfunction or treated diabetes* No PCI or CABG Medial Therapy, 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. Revascularization Strategy in UA/NSTEMI
  124. 124. Other therapies  Inhibition of Renin-Angiotensin- Aldosterone System  Angiotensin-converting enzyme inhibitors  Angiotensin receptor blockers  Lipid-lowering therapy  Hydroxymethylglutaryl coA reductase inhibitors (statins)
  125. 125. ACEI/ARB  Large trials have shown a 0.5% absolute mortality benefit of early ACEI (within 24 hours) in acute MI.  No benefit in patients without ST elevation. [ISIS-4]  Long-term use prevents ischemic events and mortality.  ARB can be used in pts who cannot tolerate ACEI.
  126. 126. ACEI/ARB  An ACE inhibitor should be administered orally within the first 24 h to UA/NSTEMI patients with  Pulmonary congestion or  LV ejection fraction (LVEF) less than or equal to 0.40  Not or known contraindications (class I, LOE A)  ARB can be used instead in pts who are intolerant to ACEI. (class I, LOE A)  ACE inhibitor (or ARB if not tolerate ACEI) is reasonable in pts without LV dysfunction. (class IIa, LOE A)
  127. 127. Lipid-lowering therapy  Long-term treatment with statin has shown benefit in pts after acute MI and UA/NSTEMI.  PROVE IT-TIMI 22  Intensive lipid-lowering therapy with Atorvastatin 80 mg resulted in 16% reduction in MI, death or rehospitalization for ACS compared with moderate dose of pravastatin (40 mg).  Suggest Early initiation of statin.
  128. 128. Unstable angina and Non-ST Elevation Myocardial Infarction
  129. 129. Long-term secondary prevention  Six classes of therapies that have improved outcomes after UA/NSTEMI in large randomized trials:  Intensive LDL-C reduction with high dose statins  ACEI or ARB  Beta blocker  Low dose ASA plus a P2Y12 inhibitor for at least a year  Smoking cessation programs  Exercise-based cardiac rehabilitation
  130. 130. Long-Term Antithrombotic Therapy at Hospital Discharge after UA/NSTEMI Medical Therapy without Stent Bare Metal Stent Group Drug Eluting Stent Group aspirin 162 to 325 mg/d for at least 1 month, then 75 to 162 mg/d indefinitely (Class I, LOE: A) & Clopidogrel 75 mg/d for at least 1 month and up to 1 year (Class I, LOE:B) Add: Warfarin (INR 2.0 to 2.5) (Class IIb, LOE: B) Continue with dual antiplatelet therapy as above Ye s No Indication for Anticoagulation? aspirin 75 to 162 mg/d indefinitely (Class I, LOE: A) & Clopidogrel 75 mg/d at least 1 month (Class I, LOE: A) and up to 1 year (Class I, LOE: B) aspirin 162 to 325 mg/d for at least 3 to 6 months, then 75 to 162 mg/d indefinitely (Class I, LOE: A) & Clopidogrel 75 mg/d for at least 1 year (Class I, LOE: B) Anderson JL, et al. J Am Coll Cardiol 2007;50:e1–e157, Figure 11. INR = international normalized ratio; LOE = level of evidence. UA/NSTEMI Patient Groups at Discharge
  131. 131. Statins  Statins should be given in pts post- UA/NSTEMI before discharge, regardless of baseline LDL-C. (class I, LOE A)
  132. 132. Unstable angina and Non-ST Elevation Myocardial Infarction
  133. 133. ESC 2011 vs ACC/AHA 2011  Antiplatelets (Class I)  Ticagrelor (180  90 mg BID) for all mod- high risk regardless of treatment strategy.  Prasugrel (60  10 mg daily) is recommended for P2Y12 naïve patients (esp DM) in whom coronary anatomy is known.  Clopidogrel (300 (or 600 if invasive)  75 mg daily) is recommended for pts who cannot receive ticagrelor or prasugrel.
  134. 134. ESC 2011 vs ACC/AHA 2011  Anticoagulants (Class I)  Fondaparinux (2.5 mg sc daily) is recommended as having the most favourable efficacy-safety profile. ○ Single bolus UFH at PCI  Enoxaparin (1mg/kg BID) is recommended when fondaparinux is not available.
  135. 135. ESC 2011 vs ACC/AHA 2011 Indication for invasive strategy
  136. 136. Key Reference  Bonow, RO. Braunwald’s Heart Disease: A textbook of cardiovascular medicine: Chapter 56 Unstable angina and Non-ST elevation myocardial infarction. 9th edition. Mar 2011.  Wright RS, et al. 2011 ACCF/AHA focused update incorporated into the ACC/AHA2007 Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction. J Am Coll Cardiol. 2011 May 10;57(19):e215-367.  Updated ESC Guidelines for managing patients with suspected non-ST-elevation acute coronary syndromes. Eur Heart J. 2011 Dec;32(23):2909-10.

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