Acute coronary syndrome

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  • Here the slide set introduces the evidence that the GpIIb/IIIa anti-platelet drugs are highly effective in minimizing those adverse outcomes for what are referred to as well defined outcomes, mortality or MI. They show the consistent studies of various drugs. Notably, they omit GUSTO IV, presumably because they consider it an outlier that is not valid. The slide clearly makes the case that the use of these drugs is highly effective.
  • This slide emphasizes that aspirin should be given liberally, but, one should reserve the use of Gpii//IIIa drugs for definitie ACS. Therein lies a tale! Troponin positivity, in the appropriate chest pain patient, is what makes the diagnosis “definite.” This is the essence of the newly revised definition of MI from the joint U.S. and European societies. As you can see, troponin is central to the decision to treat although this slide makes that an indirect connection.
  • Acute coronary syndrome

    1. 1. Acute Coronary Syndromes
    2. 2. ACS: Definition• A spectrum of clinical diagnoses comprising unstable angina, Non-STEMI, and STEMI that share similar pathological features involving intracoronary thrombosis
    3. 3. ACS: Definition From: Braunwald’s Heart Disease
    4. 4. Pathophysiology• atherosclerosis with superimposed coronary thrombosis• Slowly growing high-grade stenoses can progress to complete occlusion but do not usually precipitate acute STEMI d/t collateral circulation• During development of plaques, abrupt transition can occur, resulting in • Platelet activation • Thrombin generation • Thrombus formation• Blood flow occlusion leads to imbalance between supply and demand and could lead to myocardial necrosis• Pts with non-transmural infarction more likely to have more significan stenosis in IRA• Less severe stenosis with lipid-laden plaques and fragile caps more likely to rupture and causing thrombsis and STEMI
    5. 5. Stable Angina Pathophysiology•Progressivenarrowing of coronarylumen•Stable fibrous cap STEMI •Minimal priorUnstable narrowing of coronary lumenAngina •Acute rupture of thin•Progressive fibrous capnarrowing •Occlusive thrombus•Acute worsening of formationcoronary lumen due •Acute injury patternto thrombus •Myocardial necrosisformationNSTEMI•Acute worsening ofcoronary lumen due tothrombus formation•Sub-occlusive/transient coronarythrombus withmyocardial necrosis
    6. 6. ACS Evaluation
    7. 7. Angina• Definition: Discomfort in the chest/ “choking,” that characteristically comes on with exertion, relieved by rest and/or NTG Favors Ischemic Against Origin Ischemic Origin Character Constricting Squeezing Dull ache Knife-like, sharp Burning Jabs Heaviness Pleuritic Location Substernal Anterior thorax Left submammary area Left hemithorax Arms, shoulders Neck, teeth, Interscapular Provoking Exertion Pain after completion of exercise Excitement Factors Cold, meals, stress Pain with movement
    8. 8. Likelihood that signs & symptoms represent an ACS secondary to CADFeature High Intermediate LowHistory Chest or left arm pain or Chest or left arm pain or Probable ischemic discomfort as chief discomfort as chief symptoms in absence of symptom reproducing prior symptom the intermediate likelihood documented angina Age > 70 characteristics Known history of CAD, Male gender Recent cocaine use including MI Diabetes mellitusExam Transient MR, hypotension, Extracardiac vascular Chest discomfort diaphoresis, pulmonary disease reproduced by palpation or edema or rales respirationEKG New or presumably new, Fixed Q waves T wave flattening or transient ST segment Abnormal ST segments or inversion in leads with deviation (≥0.05mV) or T T waves not documented to dominant R wave wave inversion (≥0.2mV) be new Normal EKG with symptomsCardiac Elevated cardiac TnI, TnT Normal NormalMarker or CK-MB Braundwald 1994 AHCPR Publication No. 94-0602
    9. 9. Chest Pain Classification• Substernal• Exertional• Relieved with rest• Interpretation – Typical Angina: 3 criteria from above – Atypical Angina: 2 criteria from above – Non-Anginal Chest Pain: 1 or less criteria from above
    10. 10. Classification of Angina• STABLE vs UNSTABLE• CCS Classification for STABLE Angina – I: No symptoms, or angina with strenuous exertion – II: Slight limitation of ordinary physical activity • Walking more than two blocks, climbing more than one flight of stairs brings on angina – III: Marked limitation of ordinary physical activity • Walking less than two blocks, climbing less than one flight of stairs – IV: Any physical activity brings on angina; angina at rest
    11. 11. UA/NSTEMIUA/NSTEMI 9/00 THREE PRINCIPAL PRESENTATIONS Rest Angina* Angina occurring at rest and prolonged, usually > 20 minutes New-onset Angina New-onset angina of at least CCS Class III severity Increasing Angina Previously diagnosed angina that has become distinctly more frequent, longer in duration, or lower in threshold (i.e., increased by > 1 CCS) class to at least CCS Class III severity. * Pts with NSTEMI usually present with angina at rest. Braunwald Braunwald Circulation 80:410; 1989 Circulation 80:410; 1989
    12. 12. Pre-Test Likelihood of CAD Nonanginal pain Atypical angina Typical anginaAge (y.) Men Women Men Women Men Women 30-39 4 2 34 12 76 26 40-49 13 3 51 22 87 55 50-59 20 7 65 31 93 73 60-69 27 14 72 51 94 86 Diamond and Forrester, NEJM, 1979
    13. 13. Relationship of Rise in Biochemical Markers to Onset of AMI
    14. 14. Troponin• cTnT (33 kDa) binds to tropomyosin to complex molecule to thin filament• cTnI (24kDa) inhibits actin-myosin interactions• cTnC binds Ca2+• Generally not detectable in plasma of normal persons
    15. 15. Troponin• TnT and TnI have different amino acid sequence in cardiac vs. skeletal muscle – Permits development of cardiac specific antibodies• More sensitive and specific than CKMB – Detects minimal amounts of cardiac necrosis (neg. CKMB) • “minor myocardial damage/microinfarction” – Elevated in MI (pos. CKMB) – New guidelines suggest troponin is sufficient to dx MI• Other situations assoc. with increased troponin: • CHF • ICU • Renal failure • CVA • Myocarditis/other myocardial injury
    16. 16. TROPONIN I LEVELS PREDICT THEChanges in Focus onIN UA/NSTEMI RISK OF MORTALITY Heart Failure Mortality at 42 Days (% of patients) Mortality at 42 Days (% of patients) 7.5 7.5 8 8 6.0 6.0 6 6 3.7 3.7 4 3.4 3.4 4 1.7 1.7 2 2 1.0 1.0 831 174 148 134 50 67 0 0 0 to <0.4 0 to <0.4 0.4 to <1.0 0.4 to <1.0 1.0 to <2.0 1.0 to <2.0 2.0 to <5.0 2.0 to <5.0 5.0 to <9.0 5.0 to <9.0 >9.0 >9.0 Cardiac Troponin II (ng/ml) Cardiac Troponin (ng/ml)Risk RatioRisk Ratio 1. 1. 1. 1. 3.5 3.5 3.9 3.9 6.2 6.2 7.8 7.8Antman N Engl J Med. 335:1342, 1996Antman N Engl J Med. 335:1342, 1996
    17. 17. TROPONINS T AND I AS PREDICTORS OF MORTALITY Total Mortality Total Mortality Cardiac Mortality Cardiac Mortality 6.9 6.9 7 7 6.4 6.4 6 6 5.0 5.0 5 5 4 4 3.3 3.3 3 3 2.0 2.0 1.7 1.7 2 2 1 1 0 0 PTS 1993 PTS 1993 1057 1057 RR RR 1641 1641 792 792 RR RR Trop. Neg Trop. Neg Pos Pos Neg Neg Pos PosNo. TrialsNo. Trials 6 7
    18. 18. Prognostic Significance of Cardiac Troponin N Engl J Med 1997;337:1648-53
    19. 19. Risk Stratification of Patients with ACS in ER
    20. 20. US/NSTEMI Rx
    21. 21. Management of UA/NSTEMI• 8 medication• Oxygen• ASA , clopidogrel• Anticoagulant: UFH, LMWH• Nitrates for pain – Nitropatch 0.4 mg/hr x 12 hours daily – IV NTG• Beta-blocker – Metoprolol 25-50 mg PO BID• + Calcium channel blocker• ACEI for secondary prevention• Statin• Investigations: – Serial cardiac enzymes – Definitive in-hospital risk stratification.
    22. 22. Platelet Inhibitors in the ACS• “A platelet GpIIb/IIIa receptor antagonist should be administered, in addition to ASA and UFH, to patients with continuing ischemia or with other high risk features—”• “Level of the evidence: A”ACC/AHA Guideline Circulation 2000;102:1193-1209
    23. 23. DEATH OR MI AT 30 DAYS 18 16.7 Placebo GP IIb-IIIa Inhibitor 14.1 14 11.6Percent of Patients 10.9 10.1 10.2 9 10 5.9 6 4.8 3.9 3.6 1.8 2 0 EPIC CAPTURE EPILOG EPISTENT PRISM-PLUS PURSUIT ACC Slide
    24. 24. ANTIPLATELET RxClass I Definite ACS with continuingPossible ACS Likely/Definite ACS Ischemia or Other High-Risk Features or planned PCI Aspirin Aspirin Aspirin + + Subcutaneous LMWH IV heparin or + IV heparin IV platelet GP IIb/IIIa antagonist ACC Slide
    25. 25. Other Antiplatelet Agents: ClopidogrelPrimary efficacy endpoints in the CURE trialEndpoint Clopidogrel Placebo Relative p value riskCV 9.3% 11.4% 0.80 <0.001death/MI/strokeCV 16.4% 18.8% 0.86 <0.001death/MI/stroke/refractoryischemia The CURE Investigators. N Engl J Med 2001;345: 494-502. Role at this point in combination with 2b3a inhibitor . unclear: a useful option in ASA allergic pt’
    26. 26. Effect of Clopidogrel in ACS: the CURE trial Bleeding results Endpoint Clopidogrel Placebo p value Major bleeding 3.7% 2.7% 0.001 Life-threatening 2.1% 1.8% 0.13 bleeding The CURE Investigators. N Engl J Med 2001;345: 494-502.
    27. 27. In Hospital Risk Stratification with ACS: Principles• Spectrum of risk• Features associated with poor prognosis (high probability of short term MI, etc.) – EKG features: dynamic ST depression – Cardiac markers: increased troponin• Risk stratification refers to identifying patients at risk
    28. 28. Strategies for Risk Stratification• Non-invasive – EST • Sensitivity 70% • Specificity 70% – MIBI scan • Sensitivity 86-90% • Specificity 90%• Invasive – Diagnostic coronary angiography
    29. 29. Exercise Stress Testing– Positive response: horizontal 1mm ST depression and symptoms– High risk response: • Deep ST depression • Poor exercise tolerance: unable to exercise past stage 2 (<6 mins) • Exercise induced hypotension and dysrhythmias– Uninterpretable: • LBBB • Digoxin • LVH– Contra-indications: • Severe Aortic stenosis • Aortic dissection • MI/ACS within 24 h • PE
    30. 30. Angiography• Gold standard – Defines anatomy: 1VD, 2VD, 3VD, LM – Assesses LV function – Guides treatment: PCI, CABG or medical therapy• Indications – UA/post MI with ongoing pain, ST depresssion – Hemodynamic instability – CHF, ventricular arrhythmias – Previous PCI, CABG – High risk non-invasive test – Emerging as the strategy of choice for initial evaluation of most ACS with elevated troponins or EKG changes • Based on FRISC II, TACTICS trials• Strategy needs to be individualized.
    31. 31. Angiography
    32. 32. Indications for Invasive Risk Stratification Strategy in UA/NSTEMI• Class I – Recurrent ischemia at rest despite medical Rx – Elevated troponin I or T – New ST depression – High risk findings on non-invasive testing – Depressed LV function – Hemodynamic instability – Sustained VT – PCI within 6 months – Prior CABG• In the absence of the above, either non-invasive or invasive strategy can be followed. ACC/AHA Guidelines for Management of UA/NSTEMI 2002
    33. 33. SUMMARY: ER Evaluation of Patient with Chest Pain Symptoms Suggestive of Cardiac Origin? NO YES ConsiderAlternative Diagnosis Stable Unstable Early Risk Stratification in ER
    34. 34. SUMMARY: Management of UA/NSTEMI HIGH RISK INTERM. RISK LOW RISK (12-30%)* (4-8%) (<2%)•Prolonged CP (>20 minutes •No high risk features but >=1 •No high oror ongoing), plus:•EKG: of: intermediated features •Transient ST changes •Ongoing chest pain •Chest pain, single *30 day rate of death or MI •Sustained ST depr. •Crescendo angina episode, exertional •Deep T wave inv. (>5 •Borderline positive •EKG: normal or leads) troponin I (0.4-2.0) nonspecific or•Biochemical markers: •Previous intervention: unchanged •Troponin/CKMB PCI or CABG abnormal •Increased baseline risk •May include previous•Recurrent ischemia•AMI in last 4 weeks (DM, elderly) hx of CAD or risk•Hemodynamic compromise factors •ASA + heparin/LMWH •ASA + clopidogrel •ASA •GP IIb/IIIa •UFH or LMWH •No heparin •Early cardiac cath •Cardiac cath lab •Observe/outpt tests
    35. 35. STEMI• WHO defn: 2 of – characteristic chest pain – ECG changes – ST elevation – Biochemical changes• ACC + ESC – Rise and fall of biochemical marker (Tn, CK-MB) + one of • ischemic symptoms • development of pathological Q waves • ECG changes suggestive of ischemia • Coronary angiography
    36. 36. STEMI• More than 1 million MI’s per year in US• Fatal in 1/3 of pts, ½ of death occurs within 1 hr of symptoms (arrhythmias)
    37. 37. Symptoms• prolonged pain > 30 min usually• constricting, crushing, or compressing; heaviness or squeezing• can be choking, burning, knife-like• retrosternal, radiating to L>R side of chest, ulnar sides of arms L>R, shoulder, upper extremity, jaw, neck, interscapular region sometimes epigastric• pain usually implies ischemia• other sx – nausea/vomiting more common in inferior MI – weakness – dizziness – palpitation – cold perspiration – sense of impending doom
    38. 38. STEMI• Pre-hospital care – EMS • Dispatch, first response, EMS ambulance • AED to first responders • Relief of pain to reduce sympathetic tone • Rapid transfer to hospital – Prehosp fibrinolysis • Some evidence suggesting improved mortality
    39. 39. STEMI• ER Management – Early recognition • Ischemic type chest pain • ECG signs – ECG monitor rhythm – IV access – O2 – Reperfusion strategy will depend on • Time since symptoms • Risk assoc with STEMI • Risk of lytics • Time required for PCI
    40. 40. Time to Rx
    41. 41. STEMI - Acute Rx• ASA – Block formation of thromboxane A2 in platelets by blocking cox – Chew 160-325 mg to allow for buccal absorption• Pain control – Try to decrease sympathetic activity – Analgesics – Nitrates • Coronary vasodilation, decrease preload by increasing venous capacitance • Avoid if suspect RV infarct – Beta blockers • Reduce HR, decrease myocardial oxygen demand • Reduce pain • Reduce the need for analgesics • Reduce infarct size – Oxygen
    42. 42. STEMI - Reperfusion• “Time is muscle”• Increased mortality with delay in reperfusion regardless of strategy• Less time: – Recovery of LV systolic fxn – Improved diastolic dysfxn – Reduced mortality – Post ischemic contractile dysfxn can occur after reperfusion – Myocardial stunning
    43. 43. STEMI - Lytics• Benefits – Recanalize thrombotic occlusion – Restores coronary flow – Reduce infarct size – Improves myocardial function – Improves survival – May result in microvascualr damage and reperfusion injury – STR strong predictor of reperfusion
    44. 44. STEMI - lytics• GISSI first trial to demonstrate benefit of streptokinase• Other fibrinolytics – Alteplase (t-PA) • GUSTO I – Reteplace (rtPA) • GUSTO III (equivalence) – Tenecteplase (TNK) • ASSENT II (equiv with t-PA)
    45. 45. Evidence for Fibrinolysis: GISSI n >11,000 ARR: 2% RRR: 18% Circ. 1998
    46. 46. Comparison of Thrombolytics: GUSTO n=>41,000 ARR 0.9% RRR 12.5% NEJM, 1993
    47. 47. ASSENT 2 • N= 16949 • Design: non-inferiority • Trend toward decrease in bleeding • Improve ease of use with Bolus infusion • Combination with heparin IV Lancet 1999; 354: 716-22
    48. 48. Time to Rx
    49. 49. Efficacy of Thrombolysis: Subgroups n=56,800 Fibrinolytic Therapy Trialists’ Group. Lancet, 1988
    50. 50. Choosing a Fibrinolytic• Patients in whom t-PA is proven superior to SK: – Age < 75 – Anterior MI, presenting within 4 hours – High risk/extensive MI at other site within 4 hours – Cardiogenic shock – Previous SK exposure• TNK = rtPA > tPA – Easy administration – Lower chance of med error – Less non-cerebral bleeds• Patients in whom SK appears to be equivalent to t-PA: – Inferior, posterior or lateral MI – MI at any site after 6 hours – Age > 75 years
    51. 51. Bleeding complications with Lytics• Major bleeding 0.5-2%• Minor bleeding: 10-20 %• Intracranial hemorrhage: 0.5-2%• Management: – D/C thrombolytic – Cryoprecipitate (fibrinogen enriched) – If heparin, give protamine sulfate
    52. 52. Indications for Primary PCI• Class I – Alternative to thrombolytic if performed in a timely fashion by skilled individuals – Patients within 36 hours of AMI, with cardiogenic shock, <75 years• Class IIa – Contraindication to thrombolysis• Class IIb – NSTEMI within 12 hours, with less than TIMI II flow in infarct related artery• Class III – Elective PCI of non-IRA at time of AMI – Beyond 12 hours of symptoms, no evidence of ischemia – Successful thrombolysis From ACC/AHA Guidelines, 2000
    53. 53. STEMI -PCI• Meta analyis shows improved clinical endpoints favoring PCI – Factors to consider • Time to treatment • Risk of STEMI • Cardiogenic shock • Kilip class >= II • Risk of bleeding • Time to transport to skilled PCI center
    54. 54. STEMI – Other Rx• ASA – ISIS-2• Thienpyridines – Clopidogrel • CLARITY – Ticlopidine • Inhibit binding to adenosine diphosphate receptor• GPIIb/IIIa inhibitors – Abciximab – Tirofiban – Eptifibatide• GUSTO V – rtPA vs 1/2rtPA and abciximab – similar efficace endpoints but increased bleeds with IIb/IIIa
    55. 55. ASA: ISIS 2 n > 17, 000 Lancet, 1988
    56. 56. STEMI – Other Rx• Heparin – reduces reinfarction, stroke, PE – reduces mortality in pts receiving lytic• LMWH – ASSENT III showed benefit over UFH in pts receiving TNK• Others – Bivalirudin (HITT)
    57. 57. Post- STEMI Rx• BB• ACEi – Prevents ventricular remodeling – Improved hemodynamics – Reduces CHF – Selected population: (long-term, started day 3-16) • SAVE • AIRE • TRACE – Unselected pop (short term, started early) • GISSI 3 • SMILE • ISIS-4 • CCS-1
    58. 58. Post- STEMI Rx• ARB – OPTIMAAL (losartan) – VALIANT (valsartan)• Aldasterone antagonists – EPHESUS (acute MI, LV dysfxn, HF) – Reduction in mortality• Statins – PROVE-IT
    59. 59. Mechanical Complications of MIVariable VSD Free Wall Papillary Rupture Muscle RuptureAge 63 69 65Days, post MI 3-5 3-6 3-5Anterior MI 66% 50% 25%New Murmur 90% 25% 50%Thrill Yes No RarePrevious MI 25% 25% 30%Echo: VSD Pericardial Flail leaflet Effusion MRPA catheter: O2 step-up Equalization of Prominent V- RA-RV diastolic press. waveMortality: Medical 90% 90% 90% Surgical 50% ? 40-90%
    60. 60. Other Complications• Arrhythmias – Electrical instability • VPB • VT • VF • AIVR – Pump failure/inc symp drive • Sinus tachy • AFib/Flutter • SVT – Brady/conduction • Sinus brady • Junctional escape • AVB
    61. 61. Other Complications• Recurrent chest pain – Distinguish reinfarction from recurrent ischemia from non-ischemic chest pain• Pericarditis• LV aneurysm
    62. 62. Risk Stratification• survival after STEMI depends on – LV fxn • Stress/pharma Echo, PET – Residual potentially ischemic myocardium • Submaximal ETT – Susceptibility to vent arrhythmias
    63. 63. Risk Stratification
    64. 64. Discharge Planning• usually 5 days post STEMI• counseling – ambulation but avoid heavy lifting – graded activity (symptom limited) – Rehabilitation
    65. 65. Questions

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