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ACS-WRAP

ACS-WRAP. Charles V. Pollack, Jr., M.A., M.D., FACEP, FAHA Professor and Chairman Emergency Medicine, Pennsylvania Hospital University of Pennsylvania Health System Philadelphia. Non-ST-Segment-Elevation ACS. Inclusive of unstable angina and NSTEMI

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ACS-WRAP

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  1. ACS-WRAP Charles V. Pollack, Jr., M.A., M.D., FACEP, FAHA Professor and Chairman Emergency Medicine, Pennsylvania HospitalUniversity of Pennsylvania Health System Philadelphia

  2. Non-ST-Segment-Elevation ACS • Inclusive of unstable angina and NSTEMI • These are the same clinical syndrome, with the only distinction being the objective identification of myonecrosis with NSTEMI • Neither UA or NSTEMI are necessarily associated with ischemic ECG changes • Result from partial or intermittent obstruction of epicardial vessels, or complete obstruction of distal branches • In contradistinction, STEMI is complete obstruction of larger vessel, which is associated with ECG changes

  3. Non-ST-Segment-Elevation ACS • UA/NSTEMI typically result from fissure or frank rupture of an atherosclerotic plaque • Stimulates local activation of: • platelets • coagulation cascade • complement • Platelet aggregate forms over site of plaque injury . . . but remains unstable and subject to shear forces from passing blood flow • No obstruction in situ, but downstream embolization can occur • perhaps resulting in ST↓ or troponin leak

  4. Non-ST-Segment-Elevation ACS • Pharmacologic therapy in NSTE ACS is therefore directed at this triad of abnormal activity: • Platelet activation—anti-activation and anti-aggregation • ASA and clopidogrel • GPIs • Coagulation activation—anticoagulants • Complement activation—anti-inflammatories . . . ? statins

  5. Guidelines for NSTE-ACS diagnosis and management • Very complex disease state with broad ranges of risk and a multitude of therapeutic options • Many important and pertinent clinical studies • Information overload! • Need evidence-based guidelines to promote consistency of care and resulting better outcomes

  6. Guidelines for NSTE-ACS diagnosis and management • AHCPR guidelines 1994: first attempt • ACC/AHA Joint Task Force: Sep 2000 • Widely read, lots of interest • Clear evidence scoring, sensible recommendations, temporal sequencing • “soup to nuts” • Recapitulation, interpretation, and promulgation for upstream providers in Annals of Emergency Medicine

  7. Applying Classification of Recommendations

  8. “The Guidelines”Weighing the Evidence • Weight of evidence grades: = Data from many large, randomized trials = Data from fewer, smaller randomized trials, careful analyses of nonrandomized studies, observational registries = Expert consensus

  9. NSTE ACS: Optimal Therapy, 2002-07 • Braunwald E, Antman EM, Beasley JW, et al: ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). J Am Coll Cardiol 2000;36:970-1062 (2002 update at www.acc.org; summary in Circulation 2002;106:1893-1900) • Pollack CV, Roe MT, Peterson ED: 2002 Update to the ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: Implications for emergency department practice. Ann Emerg Med 2003;41:355-69.

  10. NSTE ACS: Optimal Therapy, 8/6/07 • Anderson JL, Adams CD, Antman EM, et al. 2007 guidelines for the management of patients with unstable angina/non-ST-segment-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2007;50:e1-e157, and Circulation 2007;116:e148-e304, and at www.acc.org and at www.americanheart.org. • Pollack CV, Braunwald E: 2007 Update to the ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: Implications for emergency department practice. Ann Emerg Med 2008, in press.

  11. CRUSADE: A National Quality Improvement Initiative Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the ACC/AHA Guidelines 2002-2007

  12. The CRUSADE Experience 443 Participating Sites 205,528 Patients WA (5) ME (0) VT (1) ND (1) MT (0) MI NH (1) MN (3) NY (34) OR (5) MA (10) WI (5) SD (3) RI (1) ID (0) MI (20) WY (0) CT (7) PA (36) IA (6) NJ (12) NE (3) OH (35) DE (3) NV (2) IL (17) IN (7) WV (2) MD (13) VA (17) UT (1) CO (9) KY (8) MO (8) KS (3) DC (1) CA (34) NC (14) TN (9) SC (7) OK (7) AR (2) AZ (8) NM (1) AL (9) GA (14) MS (6) LA (6) TX (13) FL (31) AK (0) HI (0) January 2007 Data on file, Duke Clinical Research Institute.

  13. Hospital Link Between Overall Guidelines Adherence and Mortality Every 10%  in guidelines adherence  10%  in mortality (OR=0.90, 95% CI: 0.84-0.97) Peterson et al, JAMA 2006;295:1863-1912

  14. I IIa IIb III Management Strategies: 2002 GuidelinesConservative vs. Invasive Strategies Early (within 48h) invasive strategy in high-risk patients with any of the following: - Recurrent ischemia, despite meds - Elevated Troponin I or T - New ST-segment depression - New CHF symptoms - High-risk stress test findings - LV dysfunction (EF < 40%) - Hemodynamic instability, sustained VT - PCI within 6 months, prior CABG

  15. Invasive Procedures 4Q 2006(among patients without contraindications to cath) • Median Times • Cath - 22 hrs • PCI - 21 hrs • CABG - 69 hrs

  16. Management Strategies: 2007Early Invasive vs Selectively Invasive • Early invasive: diagnostic angiography with intent to perform revascularization • cath anticipated within 4-24 hours • follows a foundation of risk-directed medical therapy • Selectively invasive (or early conservative): invasive evaluation only if optimal medical management fails • Note: from ED perspective, both strategies involve risk-directed, evidence-based medical therapy

  17. I IIa IIb III Management Strategies: 2007Early Invasive vs Selectively Invasive EIS is indicated in initially stabilized UA/NSTEMI patients (without contraindications) who have an elevated risk for clinical events EIS is indicated in UA/NSTEMI patients (without contraindications) who have refractory angina or hemodynamic or electrical instability SIS may be considered in initially stabilized patients who have an elevated risk for clinical events (including ↑Tn)

  18. Benefits of Early Catheterizationby Risk Group % Inhospital Mortality - Bhatt AHA 2002

  19. I IIa IIb III Medical Management: 2007 GuidelinesAnti-Ischemic Therapy: Independent of Strategy NTG Morphine Beta-Blockers: emphasis on oral dosing

  20. I IIa IIb III Medical Management: 2002 GuidelinesAnti-Thrombotic Therapy Immediate aspirin Clopidogrel, if aspirin contraindicated Heparin (IV unfractionated, LMW) with antiplatelet agents listed above Enoxaparin preferred over UFH unless CABG is planned within 24 hours

  21. I IIa IIb III Medical Management: 2007 GuidelinesAnti-Thrombotic Therapy Immediate ASA In EIS: • enoxaparin or UFH • bivalirudin* or fondaparinux In SIS: • enoxaparin or UFH • fondaparinux

  22. Medical Management: 2007 GuidelinesAnti-Thrombotic Therapy Relevant new studies for antithrombotic therapy: SYNERGY, JAMA 2004 • 10,027 patients with high-risk NSTE ACS, randomized to enox vs UFH, open-label, superiority OASIS-5, NEJM 2006 • 20,078 patients with high-risk NSTE ACS, randomized to fonda vs enox, double-blind, noninferiority ACUITY, NEJM 2006 • 13,819 patients with moderate or high-risk NSTE ACS, randomized to hep/GPI vs bival/GPI vs bival, open-label, noninferiority

  23. I IIa IIb III Anti-Aggregation Antiplatelet Tx: 2002Platelet GP IIb/IIIa Inhibitors Any GP IIb/IIIa inhibitor + ASA/Heparin for all patients, if cath/PCI planned Eptifibatide or tirofiban + ASA/Heparin for high-risk* patients in whom early cath/PCI is not planned Any GP IIb/IIIa inhibitor for patients already on ASA + Heparin + clopidogrel, if cath/PCI is planned * High-risk: Age > 75; prolonged, ongoing CP; hemodynamic instability; rest CP w/ ST ; VT; positive cardiac markers

  24. I IIa IIb III Ant-Aggregation Antiplatelet Tx: 2002Platelet GP IIb/IIIa Inhibitors Eptifibatide or tirofiban + ASA/Heparin for patients without continuing ischemia in whom PCI is not planned Abciximab for patients in whom PCI is not planned

  25. I IIa IIb III Anti-Activation Antiplatelet Therapy: 2002Clopidogrel Aspirin + clopidogrel, for up to 1 month* Aspirin + clopidogrel, for up to 9 months* Withhold clopidogrel for 5-7 days for CABG * For patients managed with an early conservative strategy, and those who are planned to undergo early PCI Guidelines do not specify initial timing of using clopidogrel when coronary anatomy is unknown

  26. I IIa IIb III Advanced Antiplatelet Tx: 2007 All patients receive ASA EIS: upstream clopidogrel or IIb/IIIa EIS: upstream IIb/IIIa should be small-molecule SIS: if medical management fails, add IIb/IIIa or clopidogrel . . . . . . upstream

  27. I IIa IIb III Advanced Antiplatelet Tx: 2007 SIS with recurrent ischemia on ASA, clopidogrel, and anticoag: add IIb/IIIa upstream EIS: it is reasonable to give both clopidogrel and IIb/IIIa upstream EIS: can omit IIb/IIIa if bivalirudin is anticoagulant + at least 300mg clopidogrel given > 6h prior to cath

  28. I IIa IIb III Anti-Activation Antiplatelet Tx: 2007More onClopidogrel Clopidogrel with full loading dose in ASA-allergic patients EIS: clopidogrel or IIb/IIIa administered upstream SIS: clopidogrel initiated “as soon as possible” and continued for at least one month . . . . . . and preferably for one year

  29. Antiplatelet Drug Targets Platelet Thrombin PAR-1 Platelet Fibrinogen PAR-4 Clopidogrel Prasugrel P2Y1 GP IIIa ADP GP IIb P2Y12 P2Y12 GP IIb Thromboxane A2 Aspirin TXA2-R GP IIIa Epinephrine Serotonin 5HT2A Gp IIb/IIIa inhibitors Anionic phospholipid surfaces GP VI Collagen GP Ia

  30. CURE Primary Results % 14 11.4% Placebo + ASA 12 9.3% 10 8 Clopidogrel + ASA Death, MI, or Stroke 20% RRR P < 0.001 N = 12,562 6 4 2 0 0 3 6 9 12 Months of Follow-Up N Engl J Med. 2001

  31. CURE: Ischemic Endpoints Were Reduced within 24h of Randomization 0.025 Placebo + ASA 0.020 33% RRR 0.015 Cumulative Hazard Rates Clopidogrel + ASA 0.010 0.005 RR = 0.67 P = 0.003 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 Hours After Randomization Adapted from Yusuf S, et al. Circulation. 2003;107:966-972.

  32. ACUITY Composite Ischemia at 1-Year 17.7% 16.4% 1.14 (0.99-1.30) 14.6% 16.1% 0.95 (0.80-1.14) 16.2% 17.2% 0.97 (0.86-1.11) 16.4% 14.3% 1.20 (1.01-1.44) 19.8% 19.2% 1.09 (0.96-1.23) 21.1% 20.7% 1.04 (0.79-1.36) 9.0% 9.6% 0.97 (0.76-1.24) UFH/Enoxaparin + GPIIb/IIIa vs. Bivalirudin alone 1 yr KM estimate UFH/Enox + IIb/IIIa Hazard ratio ±95% CI Bival alone HR (95% CI) Pint Biomarkers (CK/Trop) Elevated (n=5072) Normal (n=3402) 0.11 Pre Thienopyridine Yes (n=5751) No (n=3305) 0.07 Actual Treatment PCI (n=5179) CABG (n=1040) Medical (n=2994) 0.67 P value interaction only between subgroups Bivalirudin alone better UFH/Enox + IIb/IIIa better ACUITY 1-Year Data as presented at ACC 2007.

  33. Clopidogrel Dosing and Duration of Therapy • ordinarily given with ASA (established in CURE) • labeled loading dose 300mg • Many cardiologists prefer 600mg for faster onset of action, no apparent additional safety concerns • labeled maintenance dose 75mg • Some cardiologists prefer 150mg for first month after stenting • CURRENT (OASIS-7) trial currently studying 600 vs 300, 150 vs 75 (first month), and low- vs high-dose ASA • Results in 2009?

  34. Clopidogrel Dosing and Duration of Therapy • duration of therapy after ACS, whether or nor PCI performed with BMS, with 75-162mg ASA • 75mg daily for at least 1 month (I-A) • preferably 12 months (I-B) • duration of therapy after ACS and PCI performed with DES, with 162-325mg ASA for at least 3 months after sirolimus-eluting stent and 6 months after paclitaxel-eluting stent . . . then indefinitely thereafter • 75mg daily for at least 12 months (I-B) • CHARISMA showed no net benefit from long-term clopidogrel therapy to patients with cardiac risk factors but no objectively demonstrated CAD

  35. Optimal Management of NSTE ACS: ED to Cardiology — A Functional Model • Chest Pain or ACS Committee • Meets quarterly or PRN • PRN means after . . . • Pertinent, “practice-changing” new study published • ACC / AHA / TCT meetings • M & M or sentinel event • New guidelines published

  36. Optimal Management of NSTE ACS ED to Cardiology — A Functional Model • Chest Pain or ACS Committee comprised of: • Emergency physicians • Interventional cardiologists • Medical cardiologists • Hospitalists • CT surgeons • ED nursing • Cath lab nursing • CCU nursing • Lab • Imaging

  37. Optimal Management of NSTE ACS ED to Cardiology — A Functional Model • Chest Pain or ACS Committee discusses: • Protocols and standing orders • Practice variations versus evidence • Time to catheterization predictability • Reduction of medical errors in ACS care • DTB times • QI issues (CRUSADE / NRMI / ACTION) • Transfers in, transfers out • New data: How should it impact our protocols?

  38. Optimal Management of NSTE ACS ED to Cardiology — Summary and Game Plan • ED physicians should be using optimal, evidence-based, guideline-consistent medical therapy for NSTE ACS • ED physicians must work with their colleagues in cardiology to develop pathways and approaches (EDICT for ACS) for proper use of antithrombotic and antiplatelet therapy at all levels • ED physicians should facilitate early invasive management of ACS whenever feasible and appropriate • ED physicians should address issues related to bleeding risk as well as ischemic risk. • A seamless transition of care is most likely to result in good outcomes.

  39. Conclusion: NSTE ACS We should be using optimal medical therapy for NSTE ACS in the ED, just as in the CCU or the cath lab. There must be cross-disciplinary collaboration (EM, CD, IM, HM, CTS, nursing throughout all levels of care) to develop pathways for proper use of antithrombotic and antiplatelet therapy at all levels, to facilitate early invasive management whenever feasible, and to address issues related to bleeding risk as well as ischemic risk.

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