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Dr. Doni Firman , SpJP (K)

Translating Evidence into Clinical Practice : Role of More Potent Antiplatelet in Acute Coronary Syndrome. Dr. Doni Firman , SpJP (K). CASE 1. Usia : 63 tahun

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Dr. Doni Firman , SpJP (K)

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  1. Translating Evidence into Clinical Practice : Role of More Potent Antiplatelet in Acute Coronary Syndrome Dr. Doni Firman, SpJP(K)

  2. CASE 1 Usia : 63 tahun Pasienmasukdengankeluhannyeri dada sejak 2 jam SMRS, terusmenerussepertiditekanbendaberat, tidakmenjalar, muntah (-)keringatdingin (+) hinggabasahkuyup. Keluhantimbulsaatsedangmenunggudibandara ,sesak (-), jantungberdebar (-) Pasienbarupertama kali mengalamihalini, riwayatmudahlelahsaataktivitas Faktorrisiko Hipertensi Kolesteroltinggi Merokok (-) DM (-) FH (-)

  3. Physical Examination and ECG • KU nyeri dada • TD 134/78 mmHg • Nadi 90 x / menit • RR 16 x / menit Lab • Hb 13.6 mg/dl • Lekosit 11.450 • Hs Trop T 32 • GDS 173

  4. Case 2 • Laki-laki 73 tahun • Dikirimdarisejawatdenganriwayat NSTEMI, DM ,CKD CABG 1996 • EF 63 % • DiagnostikAngio RCA distal CTO stent patent, LM stenosis 95%, LAD CTO, LCx CTO. LIMA Patent, SVG-RCA total oklusi, SVG-LCx total oklusi, LIMA patent

  5. Atherothrombosis: A Generalized and Progressive Disease Atherothrombosis Unstable angina MI Ischemic stroke/TIA Critical leg ischemia Intermittent claudication CV death ACS Atherosclerosis Stable angina/Intermittent claudication From first decade From fourth decade From third decade Thrombosis, haematoma Smooth muscle and collagen Growth mainly by lipid accumulation Adapted from Libby P. Circulation 2001; 104: 365–372

  6. Activated platelets are central to thrombus formation in ACS Platelets do 3 things that promote thrombus formation : • Adhesion • Activation • Aggregation Activated platelets aggregate and assemble a critical mass of activated, pro-thrombotic platelet membrane at the site of injury 3 Plaque rupture leads to platelet adhesion to the exposed subendothelium Adherent platelet become activated 2 1 Vorchheimer DA, et al. Mayo Clin Proc. 2006;81:59-68; Davies MJ. Heart. 2000;83:361-366.

  7. ACS with persistent ST segment elevation ACS without persistent ST segment elevation Troponin Elevated Troponin Elevated or not

  8. ACS with persistent ST segment elevation ACS without persistent ST segment elevation Management : Risk Stratification Optimal DAPT Early invasive Management : Primary PCI Fibrinolytic

  9. GRACE RISK SCORENon-ST elevation acute coronary syndrome Khalill R et al. Exp Clin Cardiol.2009; 14(2): e25 – e30

  10. GRACE RISK SCORE Khalill R et al. Exp Clin Cardiol.2009; 14(2): e25 – e30

  11. Importance of Primary Care Physician role in ACS management Play a major role in the early care of acute myocardial infarction Often the first to be contacted by patients What GP should do • Can perform and interpret the ECG • Alert EMS • Administer opioids and antithrombotic drugs (including fibrinolytic) • Undertake defibrillation if needed EARLY DIAGNOSIS AND TREATMENT Steg PG, et al. European Heart Journal. 2012;33:2569-2619

  12. 10-questions strategy in selecting oral antiplatelet in ACS Q#1:ACS Diagnosis doubtful Q#1:Definite ACS Admit to ICCU Continue diagnostic tests No antiplatelet therapy Aspirin : oral 150-300 or IV 80-150 mg Q#4 : Invasive strategy for NSTE-ACS ? Q#2 : STEMI ? Q#3 : Reperfusion ? Probable non Invasive Definite Invasive First Medical Contact No Reperfusion Reperfusion Ticagrelor 180 mg Or clopidogrel 75 mg if high bleeding risk Ticagrelor 180 mg Or Clopidogrel 600 mg if high bleeding risk Clopidogrel 75 mg Thrombolysis Primary PCI Ticagrelor 180 mg Or Clopidogrel 600 mg if high bleeding risk Age ≤ 75 : Clopidogrel 300 mg Age > 75 : Clopidogrel 75 mg Confirmed non invasive Switch to invasive Q#8 : normal coronary arteries? Q#5 : Large thrombus burden? Q#7 : Adequate antiplatelet Rx for PCI ? Q#6 : Surgery ? Clopidogrel pre Rx No Clopidogrel Stop P2Y12 : Clopidogrel or ticagrelor 5 days before. Resume DAPT after CABG Yes : Thrombectomy Cath Laboratory Clopidogrel or switch to Ticagrelor Discuss Tirofiban or Eptifibatide Ticagrelor or Clopidogrel Discuss Tirofiban or Eptifibatide Confirmed ACS ? If not, stop DAPT Low Bleeding Risk ? If yes, then GPIIb/IIIa inhibitor according to renal function Q#10 : Stent Thombosis Risk ? Q#9 : Low Bleeding Risk ? ICU and Long Term If yes, continue Ticagrelor 90 mg/12h if ongoing OR switch from clopidogrel to ticagrelor 90 mg/12h. If no, Clopidogrel 75 mg/d if ongoing OR discuss switch from Prasugrel to Clopidogrel Francois Schiele and Nicolas Meneveau. European Heart Journal: Acute Cardiovascular Care 1(2) 170–176

  13. Dual Antiplatelet Therapy is the STANDARD for ACS

  14. 0.04 0.03 HR 0.96 (0.85-1.08)P = 0.489 Cumulative Hazard 0.02 0.01 ASA 81-100 mg ASA 300-325 mg 0.0 0 3 6 9 12 15 18 21 24 27 30 Days Mehta SR et al. N Engl J Med. 2010;10:930-42

  15. ESC STEMI GUIDELINES : P2Y12 Inhibitor Aspirin oral or iv (if unable to swallow) is recommended P2Y12 inhibitor is recommended in addition to aspirin : Ticagrelor Clopidogrel, preferably when prasugrel or ticagrelor are either not available or contraindicated Steg GS et al. doi:10.1093/eurheartj/ehs215

  16. NSTEMI ACS Guidelines : P2Y12 Inhibitor Ticagrelor (180-mg loading dose, 90 mg twice daily) is recommended for all patients at moderate-to-high risk of ischaemic events (e.g. elevated troponins) , regardless of initial treatment strategy and including those pre-treated with clopidogrel (which should be discontinued when ticagrelor is commenced). Clopidogrel (300-mg loading dose, 75-mg daily dose) is recommended for patients who cannot receive ticagrelor or prasugrel. A 600-mg loading dose of clopidogrel (or a supplementary 300-mg dose at PCI following an initial 300-mg loading dose) is recommended for patients scheduled for an invasive strategy when ticagrelor or prasugrel is not an option. Hamm CW, et al. European Heart Journal (2011) 32, 2999–3054

  17. Limitation of clopidogrel Dual antiplatelet therapy (DAPT) with aspirin & clopidogrel is the current standard treatment in patients with ACS1 • With or without ST segment elevation1 Poor platelet inhibition response to clopidogrel is seen in approximately 15% - 40% of patients2 • Contribute to residual high risk of recurrent results Clopidogrel has slow onset of action1 • Prodrug that requires conversion to active metabolite1 Variable metabolism results in interindividual variability in inhibition of platelet agregation1 1. Bassand JP . European Heart Journal Supplements (2008) 10 (Supplement D), D3–D11; 2. Gurbel PA, Tantry US. Thrombosis Research. 2007;120: 311–321

  18. GRAVITAS Study (clopidogrel low responders) : No improve in CV outcome with increase dose of clopidogrel Observed event rates are listed; P value by log rank test.

  19. DISPERSE: Greater and more consistent IPA with ticagrelor than with clopidogrel (final extent) 100 80 60 40 20 0 Clopidogrel 75 mg od Ticagrelor 100 mg bd 100 80 DAY 1 60 40 20 0 Mean Inhibition, % Mean Inhibition, % 0 2 4 8 12 12 0 2 4 8 100 100 80 80 60 60 DAY 14 40 40 20 20  2nd dose 0 0 0 2 4 8 12 24 0 2 4 8 12 24 Time, h Time, h IPA = inhibition of platelet aggregation; od = once daily; bd = twice daily. Adapted from Husted SE, et al. Presented at: European Society of Cardiology Annual Congress 2005; 3-7 September, 2005; Stockholm, Sweden.

  20. P2Y12 inhibitor

  21. Ticagrelor is direct acting whereas all thienopyridines are pro-drugs No in vivobiotransformation Active compound Intermediate metabolite Pro-drug CYP-dependentoxidationCYP3A4/5 CYP2B6CYP2C19CYP2C9CYP2D6 Ticagrelor Binding Hydrolysisby esterase Platelet Prasugrel P2Y12 Clopidogrel CYP-dependentoxidationCYP1A2CYP2B6CYP2C19 CYP-dependentoxidationCYP2C19CYP3A4/5CYP2B6 Figure adapted from Schömig A (2009). CYP, cytochrome P450.Schömig A. N Engl J Med 2009;361:1108–1111.

  22. Last Maintenance Dose 90 mg bid Loading Dose 100 Ticagrelor (n=54) 75 mg qd * * * * * † 90 180 mg * * Clopidogrel (n=50) 600 mg  * 80 70 60 IPA %  * 50 40 ‡ 30 † 20 10  0 0 0.5 1 2 4 8 24 6 weeks 0 2 4 8 24 48 72 120 168 240 Onset Maintenance Offset Time (Hours) ONSET/OFFSET STUDY :TICAGRELOR FASTER ONSET and FASTER OFFSET VS HIGH DOSE CLOPIDOGREL *P<0.0001†P<0.005‡P<0.05 Time (Hours) Gurbel PA et al. Circulation 2009;120:2577-2585

  23. All OAP proven to reduce CV event (CV death, MI danStroke ) Rate of composite CV event (CV death, MI atau Stroke)%) P < 0.001 P < 0.001 P < 0.001 n = 12.562 n = 13.608 n = 18.624 1.Yusuf S et al. N Engl J Med 2001;345; Wiviott SD e tal. N Engl J Med 2007;357:2001-15; Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

  24. Only ticagrelor proven to have mortality benefit vsclopidogrel P = N/A Rate of CV death (%) Rate of composite CV death (%) n = 12.562 NNT = 250 n = 13.608 NNT = 333 n = 18.624 NNT = 91 1.Yusuf S et al. N Engl J Med 2001;345; Wiviott SD e tal. N Engl J Med 2007;357:2001-15; Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

  25. PLATO: Bleeding No difference in major bleeding as primary safety endpoint P = 0.008 NS NS K-M Estimated Rate (% Per Year) NS P = 0.03 NS CABG-Major Bleeding Non-CABG-Major Bleeding Major and Minor Bleeding Major Bleeding Fatal Bleeding Life-threatening/Fatal Bleeding All values presented by PLATO criteria. Both groups included aspirin. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

  26. ESC NSTEMI – Management Bleeding Complication Interruption and/or neutralization of both anticoagulant and antiplatelet therapies is indicated in case of major bleeding, unless it can be adequately controlled by specific haemostatic measures Minor bleeding should preferably be managed without interruption of active treatments. Co-medication of PPI and antithrombotic agents is recommended in patients at increased risk of GI haemorrhage. Hamm CW et al. Eur Heart J 2011;32:2999 – 3054

  27. Consistent result of ticagrelor in efficacy primary endpoint despite of PPI treatment Proton Pump Inhibitors (Rand.) P value interaction 0.69 KM % atMonth 12 Hazard Ratio(95% CI) HR (95% CI) Ti. Cl. No 9.2 11.0 0.83 (0.74, 0.93) n = 12,249 Yes 11.0 12.9 0.86 (0.75, 1.00) n = 6375 0.2 0.5 1.0 2.0 Ticagrelor better Clopidogrel better KM : Kaplan–Meier Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. + supplement

  28. Clinical Case

  29. CASE 1 Q#1:Definite ACS Aspirin : oral 150-300 or IV 80-150 mg Q#2 : STEMI ? Q#3 : Reperfusion ? First Medical Contact Reperfusion Primary PCI Which P2Y12 inhibitor preferred for this case ? Faster onset Low inter individual variability No issue with low responders Ticagrelor 180 mg Or Clopidogrel 600 mg if high bleeding risk Q#5 : Large thrombus burden? Yes : Thrombectomy Cath Laboratory Low Bleeding Risk ? If yes, then GPIIb/IIIa inhibitor according to renal function • Reduced risk of stent thrombosis • Reduced CV mortality Q#10 : Stent Thombosis Risk ? Q#9 : Low Bleeding Risk ? ICU and Long Term If yes, continue Ticagrelor 90 mg/12h if ongoing OR switch from clopidogrel to ticagrelor 90 mg/12h. If no, Clopidogrel 75 mg/d if ongoing OR discuss switch from Prasugrel to Clopidogrel Francois Schiele and Nicolas Meneveau. European Heart Journal: Acute Cardiovascular Care 1(2) 170–176

  30. Case 2 Q#1:Definite ACS Aspirin : oral 150-300 or IV 80-150 mg Q#4 : Invasive strategy for NSTE-ACS ? Check GRACE RISK Score Definite Invasive Age : 73 years old CKD, Elevated CardiACS maker, ST segment deviation Moderate – high risk patients Guidelines Ticagrelor Mod – high risk NSTEMI patient Pre treated with clopi or naïve PCI or MM Clopidogrel If ticagrelor or prasugrel not available First Medical Contact Ticagrelor 180 mg Or Clopidogrel 600 mg if high bleeding risk Q#7 : Adequate antiplatelet Rx for PCI ? 1 B Clopidogrel pre Rx No Clopidogrel Cath Laboratory Clopidogrel or switch to Ticagrelor Discuss Tirofiban or Eptifibatide Ticagrelor or Clopidogrel Discuss Tirofiban or Eptifibatide 1 A Q#10 : Stent Thombosis Risk ? Q#9 : Low Bleeding Risk ? ICU and Long Term If yes, continue Ticagrelor 90 mg/12h if ongoing OR switch from clopidogrel to ticagrelor 90 mg/12h. If no, Clopidogrel 75 mg/d if ongoing OR discuss switch from Prasugrel to Clopidogrel Francois Schiele and Nicolas Meneveau. European Heart Journal: Acute Cardiovascular Care 1(2) 170–176

  31. Duration of OAP for ACS Patient ESC STEMI Guidelines 2012 • DAPT and antithrombotic combination therapies after STEMI • Primary PCI and Fibrinolytic is up to 12 months • No reperfusion at least 1 month up to 12 months NTEMI Guidelines 2012 Continue for 12 months (unless at high risk of bleeding) Cessation of DAPT in Surgery patients • The risk of bleeding related to surgery must be balanced against the risk of recurrent ischaemic events related to discontinuation of therapy • it is reasonable to restart DAPT as soon as considered safe in relation to bleeding risk Steg GS et al. doi:10.1093/eurheartj/ehs215; Hamm CW, et al. European Heart Journal (2011) 32, 2999–3054

  32. Summary Antiplatelet therapy key to reducing thrombus burden and plaque stabilisation during ACS In STEMI patients, a loading dose of P2Y12 receptor inhibitor should be given as early as possible or at time of primary PCI In NSTEMI patients, a strategy of risk stratification, optimal potent dual antiplatelet therapy (including the new oral P2Y12 inhibitors and early invasive approach is appropriate Ticagrelor + aspirin has recommended in ESC and AHA guidelines as first line treatment in ACS and proven to reduced CV mortality

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