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Roberta Rossini Ospedali Riuniti di Bergamo

IV Convention delle UTIC Lombarde Varese 08 Aprile 2011. La tripla antiaggregazione: Linee Guida e pratica clinica. Roberta Rossini Ospedali Riuniti di Bergamo. Triple therapy: why?. Kuzniatsova N Int J Card. To improve effectiveness.

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Roberta Rossini Ospedali Riuniti di Bergamo

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  1. IV Convention delle UTIC Lombarde Varese 08 Aprile 2011 La tripla antiaggregazione: Linee Guida e pratica clinica Roberta Rossini Ospedali Riuniti di Bergamo

  2. Triple therapy: why? Kuzniatsova N Int J Card • To improve effectiveness • To treat comorbidities which require both antiplatelet therapy and anticoagulant therapy

  3. The Holy-Grail for antithrombotic therapy “The ‘holy grail’ for antithrombotic therapy — a drug that will prevent coagulation without promoting bleeding — has yet to be found. However, molecules that contribute to thrombosis continue to be identified, and these could be new targets for the next generation of antithrombotic therapy” Nigel Mackman, Nature. 2008 February 21; 451(7181): 914–918 “Treatment options are controversial because current guidelines are an evidence-based medicine-free zone” Gregory Lipp, GTF Barcelona, 19-20 March 2011tim

  4. Targets of antiplatelets drugs Nigel Mackman, Nature. 2008 February 21; 451(7181): 914–918

  5. Circulation published online Mar 28, 2011

  6. Circulation published online Mar 28, 2011

  7. Early ACS Primary Endpoint BleedingEarly Delayed eptifibatide TIMI major 2.6 1.8 0.015 TIMI major or minor 5.8 3.4 <0.001 PRBC transfusion 8.6 6.7 0.001 15 10% 10 9.3% Death, MI, RIUR or TBO (%) Delayed provisional eptifibatide P = 0.23 (stratified for intended early clopidogrel use) 5 Routine early eptifibatide 0 0 8 16 24 32 40 48 56 64 72 80 88 96 Time Since Randomization (Hours)

  8. Acuity Timing: Primary Endpoint Measures Routine Upstream IIb/IIIa vs. Deferred PCI IIb/IIIa PNI<0.0001 PSup=0.93 PNI=0.044 PSup=0.13 PNI<0.0001 PSup=0.009 30 day events JAMA 2007;297:591-602

  9. FINESSE: Endpoint Primario e Componenti % P NS Primary PCI con Abciximab In Lab (n=806) Abciximab PCI (n=818) Abciximab/Reteplase PCI (n=828) Ellis S, NEJM 2008; 358:2205-17

  10. Time of major bleeding and long-term outcome Bleeding and Long-Term Mortality 12-month Bleeding and Long-Term Mortality 30-day Log rank p < 0.001 Log rank p = 0.019 No major bleeding at 12 months Major bleeding at 12 months No major bleeding at 30 days Major bleeding at 30 days Rossini R, et al. ESC Congress 2010, Stockholm August 2010

  11. Major Bleeding and Antiplatelet Discontinuation % Major bleeding No major bleeding Antiplatelet Discontinuation Rossini R, et al. ESC Congress 2010, Stockholm August 2010

  12. Premature Discontinuation of Antiplatelet Therapy after DES Implantation • 1358 consecutive pts treated with DES, discharged on ASA (100 mg/day) and clopidogrel (75 mg/day) • Clopidogrel was to be maintained for 12 months • Pts were followed-up for 32.4±11.3 months Discontinuation Causes: • Surgery 34.5% • Bleeding 21% • Medical decision 17.6% • Dental interventions 7.6% • Economic/burocratic reasons 5.9% • Anticoagulant therapy 5.0% Rossini R et al. Am J Card 2011, 107: 186-194

  13. Discontinuation and Prognosis % MACE Rossini R et al. Am J Card 2011, 107: 186-194

  14. TRA (SCH 530348) Program Evaluation of Efficacy and Safety in Acute and Chronic Atherothrombosis TRA (SCH 530348-vorapaxar) Program (35,000 pts) 2º Prevention 25,000 pts NSTEACS 10,000 pts SCH 530348 Placebo SCH 530348 Placebo F/U: 30 days, 4,8,12 months,and 6 months thereafter F/U 1 yr minimum 1o EP: Composite of CV death, MI, Stroke, urgent revascularization and Recurrent Ischemia w/ Rehosp 1o EP: Composite of CV death, MI, Stroke, and urgent revascularization

  15. TRA•2P TIMI-50 "The DSMB has communicated to us that based on all of the data (safety and efficacy) available to them from both trials, they recommend that subjects with a history of stroke not receive vorapaxar. They have observed an increase in intracranial hemorrhage in patients with a history of stroke that is not outweighed by their considerations of potential benefit." "In contrast, on the basis of their risk/benefit assessment in patients without a history of stroke, the DSMB recommended to us that it is important that the trial continue to completion in the more than 20,000 subjects who qualified for the trial with myocardial infarction or peripheral arterial disease who have not had a stroke. On the basis of their recommendation, we and Merck remain committed to completing this important scientific investigation with a potential for a reduction in death and ischemic events in these patients." Eugene Braunwald, MD Commenting on TRA 2P-TIMI 50 January 2011

  16. Antithrombotic strategies following coronary stenting in patients with atrial fibrillation requiring oral anticoagulant therapy European Heart Journal (2010) 31, 1311–1318

  17. Rates of Major Cardiovascular Outcomes byOral Anticoagulant Intensity and Aspirin Use Oral Anticoagulants Control (Aspirin) High-to-Moderate Intensity OAT vs ASA Anand S et al. JAMA 1999;282:2058

  18. Safety and efficacy of combined antiplatelet-warfarin therapy after coronary stenting On prescribed regimen Off prescribed regimen Major Bleeding at 12 months FU Stroke at 12 months FU 8.8 11.8 11.1 6.6 6.1 3.0 2.8 0 Stent Thrombosis at 12 months FU Myocardial Infarction at 12 months FU 15.2 18.2 11.1 8.5 5.9 5.9 1.9 0 Karjalainen P, Porela P, Ylitalo A, et al. Eur Heart J 2007; 28:726–732

  19. Zhao HJ et al. CHEST 2011; 139(2):260–270 Risk of major adverse cardiovascular events in patients receiving TT or DT

  20. Risk of major bleeding at 6-month follow-up in patients receiving TT or DT Zhao HJ et al. CHEST 2011; 139(2):260–270

  21. Bleeding Cumulative Distribution “Double” vs “Triple” TX % 100 95.1 % 90 89.2 % P=0.13 80 Bleeding event free survival 70 Double therapy (ASA + Clopidogrel) 60 Triple therapy (ASA + Clopidogrel + Warfarin) 50 0 200 300 450 600 Days Rossini, et al. Am J Cardiol 2008

  22. Bleeding Cumulative Distribution by INR “Double” vs “Triple” TX % 100 95.1 % 95.1 % 90 80 Bleeding event free survival † 70 Double therapy 66.7 % ‡ 60 Triple therapy with INR < 2.6 Triple therapy with INR ≥ 2.6 50 0 200 300 450 600 Days † P<0.0001 vs Double therapy ‡ P<0.0001 vs Triple with INR <2.6 Rossini, et al. Am J Cardiol 2008

  23. Antithrombotic drug complexity in ACS • Anticoagulants • Unfractionated heparin • Enoxaparin • Dalteparin • Bivalirudin • Fondaparinux • Dicumarin • Apixaban • Dabigatran • Rivaroxaban • Otamixaban • Betrixaban • Dosing? • How soon? • How long? • Antiaplatelets • Aspirin • Clopidogrel • Ticlopidine • Abcximab • Tirofiban • Lamifiban • Prasugrel • Cangrelor • Ticagrelor • Rationale • Pathophysiology • Efficacy • Safety • Costs • Clinical setting • ST / non ST MI; UA • Clinical trial elegible or not • Age, Gender • Risk profile • Thrombolysis yes / no • PCI yes / no PCI • Stenting yes / no • Renal function • Other comorbidities • Prescriptors • Cardiologist • Internal Med, Interventional specialist • Emergency specialist • Mobile Units • Pharmacists

  24. Conclusions • Triple therapy may be advocated in order to further reduce ischemic events and/or treat comorbidities which require oral anticoagulation • Treatment options are still controversial • The treatment should be individualized on the basis of the balance between ischemic and bleeding risk

  25. One size doesn’t fit all!

  26. Criteri di scelta della terapia antitrombotica

  27. Karjalainen P, Porela P, Ylitalo A, et al. Safety and efficacy of combined antiplatelet-warfarin therapy after coronary stenting. Eur Heart J 2007; 28:726–732

  28. Early Discontinuation • in-hospital major bleeding (OR=9.00, p<0.001) • statins at discharge (OR=0.36, p<0.001) • oral anticoagulants at discharge (OR=8.21, p<0.001) Late Discontinuation • history of prior stroke (OR=5.21, p<0.001) Predictors of Discontinuation Rossini R et al. Am J Card 2011, 107: 186-194

  29. Overall death and discontinuation 100 90 Late discontinuation 80 No discontinuation Survival (%) 70 Earlydiscontinuation Log rank test Overall: p=0.001 No discontinuation vs early discontinuation: p=0.001 No discontinuation vs late discontinuation: p=0.223 Early discontinuation vs late discontinuation: p=0.011 No discontinuation vs early+late discontinuation: p=0.018 60 50 40 48 24 36 12 Months Rossini R et al. Am J Card 2011, 107: 186-194

  30. MACE and discontinuation 100 Late discontinuation No discontinuation 90 Earlydiscontinuation 80 Survival free from MACE (%) 70 Log rank test Overall: p=0.001 No discontinuation vs early discontinuation: p=0.001 No discontinuation vs late discontinuation: p=0.223 Early discontinuation vs late discontinuation: p=0.011 No discontinuation vs early+late discontinuation: p=0.018 60 50 40 Months 24 36 12 48 Rossini R et al. Am J Card 2011, 107: 186-194

  31. Stent Thrombosis and discontinuation 100 Late discontinuation 90 No discontinuation Earlydiscontinuation 80 Log rank test Overall: p=0.031 No discontinuation vs early discontinuation: p=0.015 No discontinuation vs late discontinuation: p=0.175 Early discontinuation vs late discontinuation: p=0.653 No discontinuation vs early+late discontinuation: p=0.009 70 Survival free from Stent Thrombosis (%) 60 50 40 Months 24 36 12 48 0 Rossini R et al. Am J Card 2011, 107: 186-194

  32. Death, MACE or stent thrombosis and time of discontinuation P for trend = 0.004 P=0.008 % P=0.02 P for trend = 0.004 P for trend = 0.004 P=0.10 P=0.008 P=0.008 P=0.02 P=0.02 P=0.10 P=0.10 Rossini R et al. Am J Card 2011, 107: 186-194

  33. Association between thienopyridine and/or aspirin discontinuation and MACE stratified by time intervals Discuntinuation of Thienopyridines Only Discuntinuation of Aspirin Only Discuntinuation of Both No Discontinuation % P = 0.07 P=0.001 P=0.11 P=0.002 P=0.08 P = 0.24 P = 0.20 P=1.00 P=0.001 P=0.88 P=0.26 P=1.0 Rossini R et al. Am J Card 2011, 107: 186-194

  34. The Holy-Grail for antithrombotic therapy

  35. Conclusions • Premature discontinuation of antiplatelet therapy is relatively common, especially within the first year, and strongly associated with increased cardiovascular events, including ST and death. • Early discontinuation of antiplatelet agents within the first year was predicted by in-hospital major bleeding, oral anticoagulant use at discharge, and the lack of statin prescription. • Strategies to improve compliance to antiplatelet therapy in patients with greater likelihood to interrupt treatment are warranted

  36. Triggers of arterial thrombosis Nigel Mackman, Nature 2008 February 21; 451(7181): 914–918

  37. Triggers of venous thrombosis Nigel Mackman, Nature. 2008 February 21; 451(7181): 914–918

  38. DECLARE-LONG II Trial ASA+Clopidogrel+Cilostazol ASA+Clopidogrel Late loss at 8 months FU Adverse events at 12 months FU mm P=0.045 P=0.07 P=0.042 P=0.006 Lee et al. J Am Coll C 2011;57:1264

  39. 29 August 2010

  40. p<0.001 p<0.001 p=0.008 p=0.025 p=0.006 p=0.547 p=0.025 p=0.141 p=0.127 FINESSE: Nonintracranial bleeding Ellis S, NEJM 2008; 358:2205-17

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