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Eduardo S. Caguioa , MD., FPCP, FPCC, FACC

Acute Coronary Syndrome: Antiplatelets and Antithrombotics. Eduardo S. Caguioa , MD., FPCP, FPCC, FACC Asst. Professor, UST Faculty of Medicine and Surgery, Dept of Medicine, Section of Cardiology Medical Director, UST Hospital. Member of Advisory Board: Astra-Zeneca MSD Pfizer Servier

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Eduardo S. Caguioa , MD., FPCP, FPCC, FACC

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  1. Acute Coronary Syndrome: Antiplatelets and Antithrombotics Eduardo S. Caguioa, MD., FPCP, FPCC, FACC Asst. Professor, UST Faculty of Medicine and Surgery, Dept of Medicine, Section of Cardiology Medical Director, UST Hospital

  2. Member of Advisory Board: • Astra-Zeneca • MSD • Pfizer • Servier Receives honorarium for lectures or drug trials Have no financial interest in any drug company. Disclosures

  3. Anti-Thrombin Rx Heparin LMWH Bivalirudin [ Fondaparinux ] Anti-Platelet Rx GP IIb/IIIa blockers Aspirin Clopidogrel Treatment Strategy Conservative Early invasive PRISM-PLUS REPLACE 2 OASIS-5 PURSUIT CURE ESSENCE TACTICS TIMI-18 PCI ~ 5% stents ~85% stents Drug-eluting stents Milestones in ACS Management ICTUS ISAR-REACT 2 ACUITY SYNERGY 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 Ischemic risk Bleeding risk Adapted from and with the courtesy of Steven Manoukian, MD

  4. 1990 1996 1997 2000 2001 2005 2007 2008 Evolution of ACS Therapies CLOPIDOGREL IIb/IIIa receptor antagonist Atorvastatin Low molecular weight heparin Fondaparinux DABIGATRAN Bivalirudin Aspirin Heparin Integrated strategy Early invasive management Year Adapted from White HD et al. Lancet 2008; 372: 570–84

  5. Proportional effects of antiplatelet therapy on Vascular events in five main high risk categories Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.

  6. Absolute effects of antiplatelet therapy on vascular events in five main high risk categories Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.

  7. Clopidogrel in NSTE ACS: CURE 12,563 Pts, GP IIb/IIIa & early invasive approach discouraged 0.14 Placebo (11.4%) 0.12 0.10 Clopidogrel (9.3%) 0.08 CV Death, MI, Stroke 0.06 RR 0.80, p<0.001 0.04 0.02 0.0 0 3 6 9 12 Months of follow-up CURE. NEJM 2001;345:494-502

  8. CURE: Very Early Efficacy of Clopidogrel in NSTE ACS CV Death, MI, Stroke, Severe Ischemia Within First 24 Hours 0.025 34% Relative RiskReduction 0.020 Placebo + Aspirin (n=6303) 0.015 Cumulative Hazard Rate 0.010 P=.003 Clopidogrel + Aspirin (n=6259) 0.005 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 Hours After Randomization Yusuf S et al. Circulation 2003;107:966-972

  9. Clopidogrel in STEMI Double-blind, randomized, placebo-controlled trial in3491 patients, age 18-75 yrs with STEMI < 12 hours Fibrinolytic, ASA, Heparin randomize Clopidogrel 300 mg + 75 mg qd Placebo Study Drug Primary endpoint: Occludedartery (TIMI Flow Grade 0/1) or D/MI by timeof angio Coronary Angiogram (2-8 days) Open-label clopidogrel per MD inboth groups 30-day clinical follow-up

  10. Clopidogrel in STEMI 15 36%  P<0.0001 Placebo 20% Clopidogrel 10 CV Death, MI, or Urg Revasc (%) 5 Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 0 Clopidogrel Placebo 0 5 10 15 20 25 30 days Sabatine MS et al. NEJM 2005; 352: 1179

  11. PCI-CLARITY Design 3491 Patients Randomized into CLARITY-TIMI 28 1739 assigned placebo 1752 assigned clopidogrel 300 mg  75 mg/d (NO PRETREATMENT) (CLOPIDOGREL PRETREATMENT) Open-label clopidogrel w/ loading dose recommended A n g i o g r a p h y 930 underwent PCI during index hosp. 933 underwent PCI during index hosp. 30-day clinical follow-up

  12. 46% Clopidogrel – 3.6% Pretreatment CV Death, MI, or StrokefollowingPCI 8 Odds Ratio 0.54 (95% CI 0.35-0.85) P=0.008 No Pretreatment – 6.2% 6 Percentage with outcome (%) 4 2 Sabatine MS et al. JAMA 2005;294:1224-32 0 10 20 0 30 Days post PCI

  13. Meta-Analysis of Clopidogrel Pretreatment MI before PCI (%) ClopidogrelNo TrialPretreatmentPretreatment PCI-CURE 3.65.1 CREDO n/an/a PCI-CLARITY 4.06.1 Overall 3.75.5 ClopidogrelNo TrialPretreatmentPretreatment PCI-CURE 2.9 4.4 CREDO 6.0 7.1 PCI-CLARITY 3.3 5.4 Overall 3.9 5.5 Favors Pretreatment Favors No Pretreatment OR 0.67 P=0.005 CV Death or MI after PCI (%) 0.25 0.5 1.0 2.0 OR (95% CI) OR 0.71 P=0.004 0.25 0.5 1.0 2.0 Sabatine MS et al. JAMA 2005;294:1224-32 OR (95% CI)

  14. Variable and Unpredictable Response to Clopidogrel 24 hrs after 300 mg Clopidogrel N = 96, Elective PCI “Resistance” = 31% 20 Patients (%) 10 ≤ -30 (-20,-10) (0,10) (20,30) (40,50) >60 (-30,-20) (-10,0) (10,20) (30,40) (50,60)  Platelet aggregation before and after Clopidogrel (%) “Resistance” = ≤ 10%  platelet aggregation Gurbel PA et al. Circulation 2003; 107: 2908-2913 2015.01

  15. 5 µM ADP induced plt agg Death/ACS/CVA by 6 m Clop resist 40 120 40 100 Q1 P = 0.007 30 80 Q2 Baseline (%) 60 Percent 20 Q3 40 Q4 6.7 10 20 Quartiles of response 0 0 0 0 1 2 3 4 5 6 Q1 Q2 Q3 Q4 Days Clopidogrel Response Variability andIncreased Risk of Ischemic EventsPrimary PCI for STEMI (N = 60) Matetzky S, et al. Circulation. 2004;109:3171-3175. Wiviott SD, Antman EM. Circulation. 2004 109:3064-3067. 3116.01

  16. PRASUGREL 1990 1996 1997 2000 2001 2005 2007 2008 Evolution of ACS Therapies CLOPIDOGREL IIb/IIIa receptor antagonist Atorvastatin Low molecular weight heparin Fondaparinux Bivalirudin Aspirin Heparin Integrated strategy Early invasive management Year Adapted from White HD et al. Lancet 2008; 372: 570–84

  17. Prasugrel CYP1A2, 2B6, 2C19 hCE1 Gut hCE2 85% Inactive Metabolite Intermediate Intermediate Gut CYP3A, 2B6,2C9, 2C19 CYP3A, 2B6,2C9, 2C19 Liver and Liver Active Metabolite Active Metabolite Prasugrel has no clinically relevant interactions with CYP2C19 variants or inhibitors More Efficient and Less Variable Activation of Prasugrel Compared to Clopidogrel Clopidogrel Liver CYP2C19 variants and inhibitors affect the PK and PD of clopidogrel

  18. Clopidogrel 300 mg LD Clopidogrel 600 mg LD Prasugrel 60 mg LD Higher Active Metabolite Concentrations of Prasugrel After Loading Dose 600 Cmax and Tmax influence onset of platelet inhibition • Relevant for loading dose but not maintenance dose AUC influences extent of platelet inhibition • Relevant for loading and maintenance dose 500 400 Active Metabolite Concentration (ng/mL) 300 100 0 0 2 4 6 8 Time (Hrs)

  19. Prasugrel 60 mg LD with 10 mg MD Demonstrates Superior Response Compared to Clopidogrel 60 52% 50 45% Loading dose Maintenance dose 40 36% Non Responders (%) 30 - - 21% 20 10 3% 3% 0% 0% 0 Pras 60 mg Clop 300 mg Pras 40 mg Pras 5 mg Pras 7.5 mg Pras 10 mg Pras 15 mg Clop 75 mg Day 1 (4 hr) Day 28 (0 hr) Jernberg et al., Eur Heart J 2006; 27:1166-1173

  20. TRITON-TIMI 38 Study Design ACS (STEMI or UA/NSTEMI) & Planned PCI ASA N = 13,608 Double-blind CLOPIDOGREL 300 mg LD/ 75 mg MD PRASUGREL 60 mg LD/ 10 mg MD Median duration of therapy - 12 months 1o endpoint: CV death, MI, stroke 2o endpoints: CV death, MI, stroke, rehosp-Rec Isch CV death, MI, UTVR Stent thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, life-threatening bleedsKey substudies: Pharmacokinetic, genomic

  21. Balance of Efficacy and Safety: All ACS 15 138 events Clopidogrel 12.1% CV death / MI / stroke HR 0.81(0.73 - 0.90)P = 0.0004 9.9% 10 Prasugrel NNT = 46 Endpoint (%) 5 35 events TIMI major Non-CABG bleeds Prasugrel HR 1.32(1.03 - 1.68)P = 0.03 2.4% 1.8% Clopidogrel 0 NNH = 167 0 30 60 90 180 270 360 450 Days Wiviott SD et al. NEJM 2007; 357: 2001-2015

  22. Antiplatelet Therapy in ACS ASA ASA +Clopidogrel 100 ASA + Prasugrel - 22% Reduction inIschemicEvents - 20% - 19% Ischemic events Increase in Major Bleeds + 32% + 38% + 60% 0 Placebo APTC CURE TRITON-TIMI 38 Single Antiplatelet Rx Dual Antiplatelet Rx Higher IPA Wiviott SD et al. NEJM 2007; 357: 2001-2015

  23. Net Clinical Benefit in Subgroups: Death / MI / CVA / Major BleedPost-Hoc Analysis Risk (%) + 54 Yes PriorTIA / stroke -16 No Pint = 0.006 -1 ≥ 75 yrs Age -16 Pint = 0.18 < 75 yrs < 60 kg +3 Weight ≥ 60 kg Pint = 0.36 -14 -13 OVERALL 0.5 1 2 Favors Clopidogrel Favors Prasugrel HR Wiviott SD et al. NEJM 2007; 357: 2001-2015

  24. Balance of Efficacy and Safety in Patients < 75 Yrs, ≥ 60 kg, and without Prior TIA/Stroke 16 CV death, NF MI, or NF stroke 14 Clopidogrel 11.0% 12 Hazard Ratio, 0.75 (95% CI, 0.66 - 0.84) P < 0.001 10 Endpoint (%) 8 Prasugrel 8.3% 6 TIMI major bleeding 4 Hazard Ratio, 1.240 (95% CI, 0.91 - 1.69) P = 0.17 Prasugrel 2.0% 2 Clopidogrel 1.50% 0 0 30 90 180 270 360 450 Days Modified from Wiviott SD et al. NEJM 2007; 357: 2001-2015

  25. Kaplan-Meier estimates of the incidence of the primary composite endpoint and of non-CABG related TIMI Major bleeding for All ACS patients with diabetes. All ACS Patients with Diabetes 20 Clopidogrel 17.0% Hazard Ratio, 0.705 (95% CI, 0.58-0.85) p<0.001 CV Death, NF MI , or NF Stroke 15 Prasugrel 12.2% 10 KM Estimates of Event Rate (%) 5 Prasugrel 2.6% Hazard Ratio, 1.06 (95% CI, 0.66-1.69) p=0.81 TIMI Major Bleeding Clopidogrel 2.5% 0 0 30 90 180 270 360 450 Days From Randomization or First Dose

  26. Therapeutic Considerations Recommend Reduced MD Guided PKWt < 60 kgAge > 75 y Avoid PrasugrelPrior CVA/TIA 16% 4% Significant Net Clinical Benefit with Prasugrel80% MD 10 mg Wiviott SD et al. NEJM 2007; 357: 2001-2015

  27. August 30, 2009

  28. TICAGRELOR: First and Only Approved CPTP • TICAGRELOR, a new chemical class, is a cyclo-pentyl-triazolo-pyrimidine (CPTP) • Ticagrelor is direct acting (not a pro-drug and does not require metabolic activation) • It binds directly to P2Y12 receptors and reversibly interacts with the receptor, to prevent platelet activation and aggregation • Thienopyridines bind covalently to P2Y12 ADP binding site for the life of the platelet ADP binding site Ticagrelor P2Y12 receptor on platelet Husted S, et al. Eur Heart J. 2006;27:1038–1047. Gurbel PA, et al. Expert Opin Drug Metab Toxicol. 2009;5(8):989–1004. Van Giezen JJ, et al. J ThrombHaemost. 2009;7:1556-1565.

  29. Inhibition of Platelet Aggregation: Onset Ticagrelor (n=54) * * * * * Clopidogrel (n=50) Inhibition of Platelet Aggregation * Placebo (n=12) Time (Hours) Loading Dose Ticagrelor 180-mg loading dose in Stable CAD patients Clopidogrel 600-mg loading dose in Stable CAD patients *P<0.0001Ticgrelor vs Clopidogrel Adapted from Gurbel PA, et al. Circulation. 2009;120:2577–2585.

  30. PLATO: Study Design 18,624 patients with ACS (UA, NSTEMI, or STEMI*) randomized within 24 hours of symptom onset Initial treatment approaches • Medically managed (n=5,216 — 28.0%) • Invasively managed (n=13,408 — 72.0%) Patients could be taking clopidogrel at time of randomization Ticagrelor (n=9,333) Clopidogrel (n=9,293) 300-mg loading dose† 75 mg qd + ASA Maintenance dose 180-mg loading dose 90 mg bid + ASA Maintenance dose 6–12 months of double-blind treatment Primary efficacy endpoint: Primary safety endpoint: Composite of CV death, MI (excluding silent MI), or stroke Total PLATO major bleeding‡ *STEMI patients scheduled for primary PCI were randomized; however, they may not have received PCI. †A loading dose of 300-mg clopidogrel was permitted in patients not previously treated with clopidogrel, with an additional 300 mg allowed at the discretion of the investigator. ‡The PLATO study expanded the definition of major bleeding to be more inclusive compared with previous studies in ACS patients. The primary safety endpoint was the first occurrence of any major bleeding event. 1. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. 2. James S, et al. Am Heart J. 2009;157:599–605.

  31. PLATO Main: Inclusion Criteria • Hospitalisation for STEMI or NSTEMI/UA ACS, with onset during previous 24 hours • With STEMI, the following 2 inclusion criteria were required • Persistent ST elevation of at least 0.1 mV in ≥2 contiguous leads or new LBBB • Primary PCI planned • With NSTEMI, at least 2 of the following 3 were required • ST changes on ECG indicating ischaemia • Positive biomarker indicating myocardial necrosis • One of the following risk indicators • ≥60 years of age • Previous MI or CABG • CAD with ≥50% stenosis in ≥2 vessels • Previous ischaemic stroke, TIA, carotid stenosis (≥50%), or cerebral revascularisation • Diabetes mellitus • Peripheral artery disease • Chronic renal dysfunction (creatinine clearance <60 mL/min) James S, et al. Am Heart J. 2009;157:599–605.

  32. PLATO: Baseline Characteristics Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

  33. 8,628 8,460 8,219 6,743 5,161 4,147 8,521 8,362 8,124 6,650 5,096 4,047 PLATO: Primary Efficacy Endpoint(Composite of CV Death, MI, or Stroke) 0–30 Days 0–12 Months 13 12 11.7 Clopidogrel 11 10 TICAGRELOR 9.8 9 Clopidogrel 8 5.4 7 Cumulative Incidence (%) 6 5 ARR=1.9% RRR=16% NNT=54* P<0.001 HR: 0.84 (95% CI, 0.77–0.92) ARR=0.6% RRR=12% P=0.045 HR: 0.88 (95% CI, 0.77−1.00) 4 4.8 3 TICAGRELOR 2 1 0 0 2 4 6 8 10 12 No. at risk Months After Randomization 9,333 TICAGRELOR Clopidogrel 9,291 Both groups included aspirin. *NNT at one year. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

  34. PLATO: Predefined Testing of Primary and Major Secondary Efficacy Endpoints * Patients could have had more than one type of endpoint. Death from CV causes and fatal bleeding, as only traumatic fatal bleeds were excluded from the CV death category. ** By Cox regression analysis using treatment as factor; †Excluding silent MI; ‡Death from any cause was tested after stroke, which was non-significant, so the results should be considered nominally significant. Both groups included aspirin. The percentages presented are Kaplan-Meier estimates of the rate of the endpoint at 12 months. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

  35. PLATO: Secondary Efficacy Endpoints Cardiovascular Death Myocardial Infarction 6.9 7 7 Clopidogrel 6 6 5.8 Clopidogrel 5.1 TICAGRELOR 5 5 4.0 4 4 Cumulative Incidence (%) Cumulative Incidence (%) TICAGRELOR 3 3 ARR=1.1% RRR=16% Calculated NNT=91 P=0.005 HR: 0.84 (95% CI, 0.75–0.95) ARR=1.1% RRR=21% NNT=91 P=0.001 HR: 0.79 (95% CI, 0.69–0.91) 2 2 1 1 0 0 0 2 4 6 8 10 12 0 2 4 6 8 10 12 Months After Randomisation Months After Randomisation Rate of stroke for TICAGRELOR was not different from clopidogrel (1.3% vs 1.1% ), P=0.225. Both groups included aspirin. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. Supplement.BRILIQUE: Summary of Product Characteristics, 2010.

  36. No. at risk 9,235 TICAGRELOR 7,246 6,826 6,545 5,129 3,783 3,433 Clopidogrel 9,186 7,305 6,930 6,670 5,209 3,841 3,479 PLATO: Primary Safety Endpoint 15 TICAGRELOR 11.6% P=NS 11.2% Clopidogrel 10 PLATO-defined Total Major Bleeding (%) 5 P=0.43 HR: 1.04 (95% CI, 0.95–1.13) 0 0 60 120 180 240 300 360 Days From First Dose Both groups included aspirin. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

  37. PLATO: Bleeding 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 Life-threatening/Fatal Bleeding Fatal Bleeding All values presented by PLATO criteria. Both groups included aspirin. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

  38. PLATO: Dyspnea • Ticagrelor-associated dyspnea was mostly mild to moderate in severity and did not reduce efficacy • Most events were reported as single episode occurring early after starting treatment • Not associated with new or worsening heart or lung disease • In 2.2% of patients, investigators considered dyspnoea causally related to treatment with Ticagrelor • Label precautions and warnings: use with caution in patients with history of asthma and COPD Ticagrelor: Summary of Product Characteristics, 2010.; Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.Storey R, et al. J Am Coll Cardio. 2010;55(Suppl 1):A108.E1007.

  39. PLATO: Bradycardia-related Events • Ventricular pauses ≥3 seconds occurred in 5.8% of ticagrelor-treated patients vs 3.6% of clopidogrel-treated patients in the acute phase, and 2.1% and 1.7% after 1 month, respectively • There were no differences in adverse clinical consequences (ie, pacemaker insertion, syncope, bradycardia, and heart block) • Label precautions and warnings: Ticagrelor should be used with caution in patients at risk of bradycardic events Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.; Ticagrelor: Summary of Product Characteristics, 2010.

  40. PLATO: Laboratory Parameters • Creatinine levels may increase during treatment with ticagrelor; renal function should be checked after 1 month and thereafter according to medical practice • Label precautions and warnings: as a precautionary measure, the use of ticagrelor in patients with uric acid nephropathy is discouraged Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.; Ticagrelor: Summary of Product Characteristics, 2010.

  41. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind studyChristopher P. Cannon, Robert A. Harrington, Stefan James, et al.for the PLATelet inhibition and patient Outcomes (PLATO) investigators • Presented at ESC 2009 as an oral presentation • Subsequently published in Lancet, January 2010 • A pre-specified objective of PLATO was to compare outcomes of Ticagrelol versus clopidogrel in patients with planned invasive strategy at randomization • For all patients, the intention for early invasive management had to be indicated by the investigator before patients were randomized Cannon CP, et al. Lancet.2010;375:283−293.

  42. PLATO Primary Endpoint: Initial Invasive vs Initial Non-Invasive Management Initial Invasive72% of patients in PLATO Initial Non-Invasive28% of patients in PLATO 14.3% Clopidogrel 12% 10.7% Clopidogrel Ticagrelor 9% K-M Estimated Rate Primary Composite of CV Death/MI/Stroke (%) K-M Estimated Rate Primary Composite of CV Death/MI/Stroke (%) Ticagrelor P<0.0025 HR: 0.84 (95% CI, 0.75–0.94) P<0.045 HR: 0.85 (95% CI, 0.73–1.00) Days After Randomisation Days After Randomisation No. at risk Ticagrelor 6,732 6,236 6,134 5,972 4,889 3,735 3,048 Ticagrelor 2,601 2,392 2,326 2,247 1,854 1,426 1,099 Clopidogrel 6,676 6,129 6,034 5,881 4,815 3,680 2,965 Clopidogrel 2,615 2,392 2,328 2,243 1,835 1,416 1,109 James S, et al. ESC 2010; Poster #1353.; Cannon C, et al. Lancet. 2010;375:283–293.

  43. Clinical Implications • In ACS patients with planned invasive management at randomisation in PLATO, compared with clopidogrel, ticagrelor significantly reduced the incidence of • CV death/MI/stroke (primary efficacy endpoint) • Ticagrelol: 9.0% vs clopidogrel: 10.7% • CV death • Ticagrelol: 3.4% vs clopidogrel: 4.3% • Consistent with the overall study, ticaggrelor had an increase in dyspnea in this patient population compared to clopidogrel • In PLATO, in ACS patients with a planned invasive management strategy, Ticagrelol was shown to be more effective than clopidogrel for the prevention of CV and total death without any significant increase in major bleeding* • Invasive study was consistent with the overall results from PLATO * No overall increase in major bleeding in this sub-study, however there was an increase in the PLATO main non-CABG bleeding (Ticagrelor: 4.5% vs. clopidogrel 3.8%); and major and minor bleeding (Ticagrelor16.1% vs. clopidogrel 14.6%). European Association for Percutaneous Cardiovascular Intervention, et al. Eur Heart J. 2010;31:2501–2555. Canadian Cardiovascular Society Anti Platelet Guidelines published online at http://www.ccs.ca.Accessed February 12, 2011. Adapted form Cannon CP, et al. Lancet.2010;375:283−293.

  44. TICAGRELOR Indication • Ticagrelor, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in adult patients with acute coronary syndromes (unstable angina, non–ST-elevation myocardial infarction [NSTEMI] or ST-elevation myocardial infarction [STEMI]); including patients managed medically, and those who are managed with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) If clinically indicated, Ticagrelor should be used with caution in the following patient groups: Patients with concomitant administration of medicinal products that may increase the risk of bleeding (eg, non-steroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants and/or fibrinolytics) within 24 hours of ticagrelor dosing Ticagrelor: Summary of Product Characteristics, 2010.

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