Akute Koronarsyndrome

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1 12. Berner Notfall-Symposium, 17. Oktober 2013 Akute Koronarsyndrome Risikostratifizierung, Netzwerkstrategie und Medikamenten-Update Stephan Windecker Department of Cardiology Swiss Cardiovascular Center and Clinical Trials Unit Bern Bern University Hospital, Switzerland

2 ST-Elevation ACS Non ST-Elevation ACS

3 Admission Working diagnosis Chest Pain Suspicion of Acute Coronary Syndrome ECG Persistent ST elevation ST/T Abnormalities Normal or Undetermined ECG Biochemistry Risk stratification Troponin positive High Risk Troponin 2 x Negative Low Risk Diagnosis STEMI NSTEMI Unstable Angina Treatment Reperfusion Invasive Non-invasive

4 Risk Stratification in NSTE-ACS Update on Prehospital Medications Acute Myocardial Infarction Patient and System Delay in STEMI

5 Death by 42 days (%) Relationship of Troponin Level to Early Mortality in ACS Antman EM et al. NEJM 1996;335: p < < < < < <9.0 9 ctnl at baseline (ng/ml) Risk ratio

6 Accuracy of Cardiac Troponin Assays According to Time of Onset of Chest Pain Reichlin T et al. N Engl J Med 2009;361:858-67

7 High-Sensitivity Troponin Improves Risk Assessment in ACS Patients Lindahl B et al. Am Heart J 2010;160:224-9 GUSTO IV Trial -7,800 patients with NSTE-ACS enrolled between 1999 to random selection of serum samples in 1,452 patiens Cardiac biomarkers -hs-troponin T (Roche) -3rd gen Troponin T (Roche) measured at 48 hours Troponin Status -hstrop neg/trop T neg: 24% -hs Trop pos/trop T neg: 16% -hs Trop pos/trop T pos: 60%

8 Risk Stratification High-Sensitivity Troponin Assays

9 Differential Diagnosis Non-Cardiac Causes of Troponin Elevation - Myocardial Injury Hamm C et al. Eur Heart J 2011

10 Multidetector CT Parameters Compared With Coronary Angiography 4-Row CT 16-Row CT 64-Row CT 320-Row CT Angiography Temporal resolution 250 ms 210 ms 165 ms 175 ms 8 ms Spatial resolution 1.25 mm 1 mm 0.4 mm 0.4 mm mm Volume coverage cm 1-2 cm 2-4 cm 15 cm - Breath-hold 40 sec 20 sec 10 sec 2 sec no CT has Inferior Temporal and Spatial Resolution Compared With Invasive Angiography

11 Diagnostic Performance of Multi- Slice CT According to Patient Risk Meijboom WB et al. J Am Coll Card 2007 Pre-test probability N Sensitivity Specificity PPV NPV High % 74% 93% 89% Intermediate % 84% 80% 100% Low % 93% 75% 100%

12 Low Risk Patient Populations Litt HI et al. NEJM 2012 Clinical 30 days ROMICAT-II NEJM 2012 Discharge Diagnosis 5 % 100 % Death MI Death or MI 2.2 Revasc MI Unstable angina Coronary pain NO ACS Noncoronary pain N=1,370 N=1,000

13 2012 ESC Guidelines for NSTE-ACS ECG Hamm C et al. Eur Heart J 2011 Recommendation for Risk Stratification Biomarkers Stress test Coronary CT

14 High-Risk Indicators Early Invasive Strategy Warranted Class IA Indication for Early Invasive Strategy (ESC) Primary Relevant rise or fall in troponin Dynamic ST- or T-wave changes Secondary Diabetes mellitus Renal insufficiency (egfr < 60 ml/min) Reduced LV function (LVEF <40%) Early post infarction angina Recent PCI Prior CABG Intermediate to high GRACE risk score

15 GRACE Risk Score In-hospital Mortality and at 6 Months

16 Conservative versus Routine Invasive Strategy in Patients With High Risk NSTE-ACS Fox K et al. J Am Coll Cardiol 2010 An IPD Meta-Analysis of FRISC-II, ICTUS, and RITA-3 Trials Cardiac Death or 5 Years Cardiac Death HR 0.81 (95% CI 0.71 to 0.93) P=0.002 Myocardial Infarction

17 Invasive Angiography in NSTE-ACS NSTE-ACS ESC Guidelines - Hamm C et al. Eur Heart J 2011 High-Risk Criteria

18 Risk Stratification Update on Prehospital Medications Acute Myocardial Infarction Patient and System Delay

19 Benefits of Primary PCI Over Thrombolysis Higher IRA Patency Risk of Reocclusion (Reinfarction) Infarct Size ST Resolution TIMI Flow and MBG Lange RA. NEJM 2002;346:945

20 Patient S.V, male, 51 YO Strong, persistend retrosternal chest pain Lävo LAD Occlusion

21 Patient S.V, male, 51 YO Strong, persistend retrosternal chest pain Aspiration

22 Patient S.V, male, 51 YO Strong, persistend retrosternal chest pain Stent before Result

23 Primary PCI versus Thrombolysis in AMI Keeley EC et al. Lancet 2003;361: % P< Death, MI, Stroke 22% 57% P= Death Reinfarction Stroke ICH PCI P<0.001 Meta-Analysis -N=7739 patients -23 randomized trials -8x:streptokinase vs PCI -15x: tpa vs PCI 50% P<0.008 Thrombolysis 95% P< death prevented and 44 MI s and 11 strokes avoided for every 1000 pts treated with primary PCI instead of thrombolysis

24 Relationship Between Time to Reperfusion, Myocardial Salvage, and Mortality Reduction Gersh B et al. JAMA 2005;293: Windecker S et al. Lancet 2013; 382:644-57

25 Number of Deaths Associated With Increases in Door-to-Balloon Time Nallamothu BK et al. N Engl J Med 2007

26 Systems of Care for Patients With STEMI % Danchin N. J Am Coll Cardiol Intv 2009; 2: Days Mortality According to Number of Medical Parties Involved Before Admission Median Time From 1st Call to Reperfusion (range) 0 or 1 Party 2 Parties 3 Parties 100 min (50-170) 122 min (60-201) 155 min (80-270)

27 Optimizing Delays in The Management of STEMI Windecker S et al. Lancet 2013; 382:644-57

28 Network: Logistics of Pre-Hospital Care

29 Risk Stratification Update on Prehospital Medications Acute Myocardial Infarction Patient and System Delay

30 Targets for Antithrombotic Therapy Curzen N et al. Lancet 2013; 382:633-43

31 Platelet Inhibition Competing Risks ASA - 22% ASA + Clopidogrel ASA + Prasugrel/Ticagrelor - 20% - 19% Reduction in Ischemic Events + 60% + 38% + 32% Placebo APTC CURE TRITON-TIMI 38 Single Dual Higher Antiplatelet Rx Antiplatelet Rx IPA Increase in Major Bleeds

32 Assessment of Bleeding-Risk Hamm C et al. ESC Guidelines NSTEM-ACS Eur Heart J 2011 Age (>75) Renal failure Low body weight (<60kg) Female gender Anemia High dose antithrombotic agents Duration of antithrombotic Rx Combination of several antithrombotic agents Change between various antithrombotic agents

33 ST-Elevation ACS Non ST-Elevation ACS

34 Death and MI (%) Benefit of Aspirin in NSTE-ACS: Four Randomized Trials 20 P= P=0.012 P=0.008 P< Lewis et al Cairns et al Theroux et al RISC group NEJM 1983 (N=333) NEJM 1985 (N=555) NEJM 1988 (N=239) Lancet 1990 (N=796) Aspirin Placebo Note: mg oral LD = mg i.v. LD

35 CURRENT OASIS 7 Acute Coronary Syndromes Aspirin Double Dosage Mehta SR et al. N Engl J Med 2010;363: Primary outcome: CV death, MI or stroke at 30 days High dose ( mg) versus QuickTime are decompressor needed to and see athis picture. low dose ( mg) Aspirin Major GI Bleeding: 0.4% (high dose) vs 0.2% (low dose), P=0.04

36 Mode of Action of P 2 Y 12 Inhibitors: Clopidogrel, Prasugrel, Ticagrelor Schömig A. N Engl J Med 2009;361: Limitations of Clopidogrel 1. Delayed onset of action 2. Large interindividual variability in platelet response 3. Irreversibility of inhibitory action

37 Novel Oral P2Y12 Inhibitors in ACS Primary Endpoint: CV Death, MI or Stroke TIMI-TRITON 38 Wiviott SD et al. N Engl J Med 2007 PLATO Wallentin L al. N Engl J Med % 9.8%

38 Ticagrelor vs. Clopidogrel for ACS in Patients Intended to Treat Non-Invasive James SK et al. BMJ 2011, 342:d3527. doi: /bmj.d3527 NON INVASIVE INVASIVE CARDIOVASCULAR DEATH, MI OR STROKE (%) NON - INVASIVE STRATEGY HR 0.85, 95%CI 0.73 to 1.00

39 ACCOAST design NSTEMI + Troponin 1.5 times ULN local lab value Clopidogrel naive or on long term clopidogrel 75 mg Randomize 1:1 Double-blind n~4100 (event driven) Prasugrel 30 mg Placebo CABG or Medical Management (no more prasugrel) Coronary Angiography Prasugrel 30 mg Coronary Angiography Prasugrel 60 mg CABG or Medical Management (no prasugrel) PCI PCI Prasugrel 10 mg or 5 mg (based on weight and age) for 30 days 1 Endpoint: CV Death, MI, Stroke, Urg Revasc, GP IIb/IIIa bailout, at 7 days Montalescot G et al. Am Heart J 2011;161:

40 Pretreatment With Prasugrel in NSTE-ACS ACCOAST Trial - Montalescot G et al. N Eng J Med 2013; 369: Primary Efficacy Endpoint CV Death, MI, Stroke, Urgent Revasc, or GP IIb/IIIa Bailout Key Safety Endpoint TIMI Major Bleeding

41 Comparison of Fondaparinux and Enoxaparin in Patients With NSTE-ACS Yusuf S et al. NEJM EP: Death, MI, or Refractory 9 days Safety EP: Major 9 days

42 Checklist of Antithrombotic Treatments in NSTE-ACS Antithrombotic Drug Class and Level of Evidence Aspirin P2Y12 Inhibitor Aspirin mg po ( mg i.v.) loading, mg qd maintenance Ticagrelor 180 mg po loading dose, 90 mg BID maintenance IA IB Anticoagulation Fondaparinux 2.5 mg sc qd IA

43 ST-Elevation ACS Non ST-Elevation ACS

44 Cumulative number of vascular deaths Cumulative number of vascular deaths Cumulative number of vascular deaths Randomised Trial of Intravenous Streptokinase, Oral Aspirin, Both, or Neither among Cases of Suspected Acute Myocardial Infarction: ISIS Placebo infusion: 1029 vascular deaths (12.0%) 1000 Placebo tablets: 1016 vascular deaths (11.8%) 500 Placebo infusion and tablets: 568 vascular deaths (13.2%) Streptokinase: 791 vascular deaths (9.2%) Aspirin: 804 vascular deaths (9.4%) Streptokinase and Aspirin: 343 vascular deaths (8.0%) Days of randomisation Days of randomisation Days of randomisation ISIS-2 Collaborative Group, Lancet 1988; II:

45 Novel Oral P2Y12 Inhibitors in STEMI Primary Endpoint: CV Death, MI or Stroke TIMI-TRITON 38 PLATO Montalescot G et al. Lancet 2009;373: Steg PG et al. Circulation 2010;122: HR=0.87, 95% CI , P=0.07

46 Novel Oral P2Y12 Inhibitors in STEMI Primary Safety Endpoint: Major Bleeding TIMI-TRITON 38 PLATO Montalescot G et al. Lancet 2009;373: Steg PG et al. Circulation 2010;122:

47 Checklist of Antithrombotic Treatments in STEMI Antithrombotic Drug Class and Level of Evidence Aspirin P2Y12 Inhibitor Aspirin mg po ( mg i.v.) loading, mg qd maintenance Ticagrelor 180 mg po loading, 90 mg BID maintenance dose OR Prasugrel 60 mg loading, 10 mg maintenance dose in clopidogrel-naive pts, age <75 years, without prior stroke IA IB IB Anticoagulation Unfractionated Heparin OR Bivalirudin IC IB

48 KONTRAINDIKATIONEN WARNHINWEISE Kontraindikationen und Warnhinweise für Thrombozyten-Aggregationshemmer Clopidogrel - Aktive Blutung - Schwere Leberinsuffizienz Prasugrel - Aktive Blutung - Schwere Leberinsuffizienz - St.n. TIA/CVI Ticagrelor - Aktive Blutung - Schwere Leberinsuffizienz - St.n. intrakranieller Blutung - Co-Administration von CYP3A4 Inhibitoren (Ketokonazol, Clarithromcycin) - Thrombotischthrombozytopenische Purpura - CVI <7 Tage - Omeprazol, Esomeprazol, Fluoxetin, Ciprofloxacin, Carbamazepin - Alter 75 Jahre - Körpergewicht <60 kg - Thrombotischthrombozytopenische Purpura - Galactose-Intoleranz - Orale Antikoagulation - Sick-Sinus-Syndrom, AV- Block II und III - Asthma, COPD - Hyperurikämie/Gicht - Rifampicin, Dexamethason, Phenytoin, Carbamazepin, Phenobarbital, Digoxin - Orale Antikoagulation