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Stavros Apostolakis, MD, PhD University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, United Kingdom; Antithrombotic therapy.

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Presentation on theme: "Stavros Apostolakis, MD, PhD University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, United Kingdom; Antithrombotic therapy."— Presentation transcript:

1 Stavros Apostolakis, MD, PhD University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, United Kingdom; Antithrombotic therapy and bleeding risk: Implications for work at sea

2 Oral antithrombotic agents Antiplatelets AspirinThienopyridines First generation Second generation Third generation Anticoagulants Vitamin K antagonists New oral anticoagulants Direct Thrombin Inhibitors Factor Xa Inhibitors

3 Different mechanisms Tissue Factor Plasma Clotting Cascade Prothrombin Thrombin FibrinogenFibrin Thrombus Platelet Aggregation Conformational Activation of GPIIb/IIIa Collagen Thromboxane A 2 ADP Aspirin Thienopyridines Direct Thrombin Inhibitors Factor Xa Factor Xa Inhibitors

4 Oral antithrombotic agents Antiplatelets Secondary prevention of cardiovascular events Secondary prevention of cerebrovascular events Primary prevention of cardiovascular/cerebrovascula r events Prevention of coronary stent thrombosis Anticoagulants Stroke prevention in AF Primary and secondary prevention of VTE Prosthetic Valve Disease Different indications

5 Major bleeding Fatal bleeding Intracranial bleeding Clinical Relevant bleeding Stroke/TIA TIA Fatal Stroke Disabling stroke Differences in bleeding risk

6 Aspirin: Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials Antithrombotic Trialists (ATT) Collaboration A meta-analyses of serious vascular events (myocardial infarction, stroke, or vascular death) and major bleeds in six primary prevention trials (95000 individuals at low average risk, person- years, 3554 serious vascular events) and 16 secondary prevention trials (17000 individuals at high average risk, person-years). Antithrombotic Trialists Lancet. 2009; 373(9678):

7 Differences in bleeding risk Antithrombotic Trialists Lancet. 2009; 373(9678):

8 Bleeding During Treatment With Aspirin Versus Apixaban in Patients With Atrial Fibrillation Unsuitable for Warfarin: The Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin k Antagonist Treatment (AVERROES) Trial The Apixaban versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin k Antagonist Treatment (AVERROES) trial randomized 5599 patients with atrial fibrillation and risk factors to receive either apixaban or aspirin. Bleeding events were defined as the first occurrence of either major bleeding or clinically relevant non-major bleeding. Aspirin: Flaker et al. Stroke 2012 Oct 2. [Epub ahead of print] Differences in bleeding risk

9 The annualized rate of major bleeding and any clinically relevant non major bleeding was 1.2% and 2.7% respectively. Flaker et al. Stroke 2012 Oct 2. [Epub ahead of print]

10 Differences in bleeding risk Aspirin plus clopidogrel: A total of 7554 patients with atrial fibrillation who had an increased risk of stroke and for whom vitamin K-antagonist therapy was unsuitable were randomly assigned to receive clopidogrel (75 mg) or placebo, once daily, in addition to aspirin. The primary outcome was the composite of stroke, myocardial infarction, non-central nervous system systemic embolism, or death from vascular causes. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. Active Investigators N Engl J Med ;360:

11 Differences in bleeding risk Active Investigators N Engl J Med ;360:

12 Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial Patients were enrolled if they had atrial fi brillation plus one or more risk factor for stroke, and were randomly allocated to receive oral anticoagulation therapy (target international normalised ratio of 2·0–3·0; n=3371) or clopidogrel (75 mg per day) plus aspirin (75–100 mg per day recommended; n=3335). ACTIVE Writing Group of the ACTIVE Investigators. Lancet.2006; 367: Differences in bleeding risk Aspirin plus clopidogrel:

13 Differences in bleeding risk ACTIVE Writing Group of the ACTIVE Investigators. Lancet.2006; 367:

14 Summarizing bleeding risk in old antithrombotic agents No antithrombotic therapy ASA Clopidogrel ASA+Clopidogrel VKAs VKAs+antiplatelets % 2-2.4% % %

15 Why the number of anticoagulated patients is expected to increase? Current practice:

16 Implications of CHA 2 DS 2 VASc Score BMJ 2011; 342: 1-9

17 Phase Ι Phase ΙΙ Phase ΙΙΙ Approval Dabigatran Rivaroxaban Apixaban Edoxaban Betrixaban The New Oral Anticoagulants

18 What would we expect from a new oral anticoagulant More effective (less strokes) Safer (less bleedings) Orally available Fixed dosing Minimal food and drug interactions No need for monitoring Rapid onset of action Rapid offset of action Reversible action 18

19 What is new about them: Better pharmacological properties WARFARINDABIGATRANRIVAROXABANAPIXABAN Target VKA (VCORC1) FII (thrombin); inhibits both clot-bound and free thrombin Factor Xa; direct inhibitor Factor Xa; direct inhibitor Bioavailability>95%~6%>80%>50% (66%) Tmaxvariable2 h2.5-4 h1-3 h Half-life35-45 h a h 5-9 h (healthy); 9-13 h (elderly) 8-15 h Renal clearance 0%80%66%25% Potential drug interactions CYP2C9, 3A4, 1A2 inhibitors, dietary vitamin K P-gp inhibitors b (verapamil- reduce dose, dronedarone- avoid, amiodarone-no dose adjustment) Potent P-gp inducers c (to be avoided) Potent CYP3A4 d and P-gp inhibitors (to be avoided) Potent CYP3A4 e and P-gp inducers (to be used with caution) Potent CYP3A4 d and P- gp inhibitors (to be avoided) Potent CYP3A4 e and P- gp inducers (caution needed)

20 What is new about them: Better efficacy TrialRE-LY Number of patients DesignOpen-labeled, non-inferiority Mean patients age71.5 years Mean CHADS Previous stroke/TIA20% TTR64% Warfarin naïve50.4% Median follow-up2.0 years Drug and dosesDabigatran110mg twice daily vs. warfarin Dabigatran150mg twice daily vs. warfarin Stroke or systemic embolism N Engl J Med 2009;361: % RR reduction

21 What is new about them: Better efficacy TrialROCKET-AF Number of patients Design Double-blind, double-dummy, non-inferiority Mean patients age73 years Mean CHADS Previous stroke/TIA55% TTR57.8% Warfarin naïve37.5% Median follow-up1.9 years Drug and dosesRivaroxaban 20mg once daily vs. warfarin Intention to treat population Per protocol population Stroke or systemic embolism N Engl J Med 2011;365: % RR reduction

22 What is new about them: Better efficacy TrialARISTOTLE Number of patients Design Double-blind, double-dummy, non-inferiority Mean patients age70 years Mean CHADS Previous stroke/TIA19% TTR62.2% Warfarin naïve43% Median follow-up1.8 years Drug and dosesApixaban 5mg twice daily vs. warfarin Stroke or systemic embolism 21% RR reduction N Engl J Med 2011;365:

23 TrialRE-LYROCKET-AFARISTOTLE Intracranial haemorrhage 0.23% vs. 0.74%; 0.31; ; p< % vs. 0.74%; 0.40; ; p< % vs. 0.74%; 0.67; ; p= % vs. 0.80%; 0.42; ; p<0.001 Major bleeding 2.71% vs. 3.36%; 0.80; ; p= % vs. 3.36%; 0.93; ; p= % vs. 3.45% not specified; p= % vs. 3.09%; 0.69; ; p<0.001 Gastrointestinal bleedings 1.12% vs. 1.02%; 1.10; ; p= % vs. 1.02%; 1.50; ; p< % vs. 2.16%; not specified; p< % vs. 0.86%; 0.89; ; p=0.37 No statistically significant difference New OAC better Warfarin better What is new about them: Better safety

24 Are all new oral anticoagulants the same: insights from clinical trials TrialRE-LYROCKET-AFARISTOTLE Number of patients DesignOpen-labeled, non-inferiority Double-blind, double-dummy, non-inferiority Double-blind, double-dummy, non-inferiority Mean patients age71.5 years73 years70 years Mean CHADS Previous stroke/TIA20%55%19% TTR64%57.8%62.2% Warfarin naïve50.4%37.5%43% Median follow-up2.0 years1.9 years1.8 years Drug and doses Dabigatran110mg twice daily vs. warfarin Dabigatran150mg twice daily vs. warfarin Rivaroxaban 20mg once daily vs. warfarin Apixaban 5mg twice daily vs. warfarin Primary end-point (%/year; RR;95%CI): stroke or systemic embolism 1.53% vs. 1.69%1.11% vs. 1.69%;2.12% vs. 2.42%;1.27% vs. 1.60;

25 Effect on outcome event, vs warfarin Dabigatran 150 Dabigatran 110 RivaroxabanApixaban Noninferiority stroke Reduction hemorrhagic stroke Reduction ischemic stroke Reduction mortality() Reduction in CV mortality Reduction major bleeding Reduced major & minor bleeds Increased gastrointestinal major bleeds Increased myocardial infarction?? Fewer treatment discontinuations Validation in a second randomized trial Are all new oral anticoagulants the same: insights from clinical trials

26 TrialRE-LYROCKET-AFARISTOTLE Number of patients DesignOpen-labeled, non-inferiority Double-blind, double-dummy, non-inferiority Double-blind, double-dummy, non-inferiority Mean patients age71.5 years73 years70 years Mean CHADS Previous stroke/TIA20%55%19% TTR64%57.8%62.2% Warfarin naïve50.4%37.5%43% Median follow-up2.0 years1.9 years1.8 years Drug and doses Dabigatran110mg twice daily vs. warfarin Dabigatran150mg twice daily vs. warfarin Rivaroxaban 20mg once daily vs. warfarin Apixaban 5mg twice daily vs. warfarin Primary end-point (%/year; RR;95%CI): stroke or systemic embolism 1.53% vs. 1.69%1.11% vs. 1.69%;2.12% vs. 2.42%;1.27% vs. 1.60;

27 Effect on outcome event, vs warfarin Dabigatran 150 Dabigatran 110 RivaroxabanApixaban Noninferiority stroke Reduction hemorrhagic stroke Reduction ischemic stroke Reduction mortality() Reduction in CV mortality Reduction major bleeding Reduced major & minor bleeds Increased gastrointestinal major bleeds Increased myocardial infarction?? Fewer treatment discontinuations Validation in a second randomized trial Are all new oral anticoagulants the same: insights from clinical trials

28 Pitfalls in the use of new oral anticoagulants It is important to remember when handling new oral anticoagulants: There is no specific antidote for all agents. Specific tests to measure these agents activity are not widely available.

29 van Ryn et al Thromb Haemost 2010; 103: PCC = prothrombin complex concentrates (non-activated or activated). rFVIIa = recombinant activated factor VII. Management of new oral anticoagulant-related bleeding

30 A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Can we predict bleeding risk? Pisters R et al. Chest 2010;138:

31 Can we predict bleeding risk? Apostolakis et al J Am Coll Cardiol. 2012;60:861-7.

32 Pitfalls in bleeding risk estimation Hypertension is defined as systolic blood pressure >160 mmHg. Abnormal kidney function is defined as the presence of chronic dialysis or renal transplantation or serum creatinine 200 mmol/L. Abnormal liver function is defined as chronic hepatic disease (e.g. cirrhosis) or biochemical evidence of significant hepatic derangement (e.g. bilirubin >2 x upper limit of normal, in association with aspartate aminotransferase/alanine aminotransferase/alkaline phosphatase >3 x upper limit normal, etc.). Bleeding refers to previous bleeding history and/or predisposition to bleeding, e.g. bleeding diathesis, anaemia, etc. Labile INRs refers to unstable/high INRs or poor time in therapeutic range (e.g. <60%). Drugs/alcohol use refers to concomitant use of drugs, such as antiplatelet agents, non-steroidal anti-inflammatory drugs, or alcohol abuse, etc.

33 Conclusions The number of patients treated with OAC is expected to significantly increase. Decisions on the ability to work at sea while on antithrombotic therapy should be based on the estimated bleeding risk. Bleeding risk related to antiplatelet therapy with either aspirin or clopidogrel can be considered low. Bleeding risk while on dual antiplatelet therapy is considerable high and comparable with the bleeding risk associated with OAC therapy. The HAS-BLED score is an easy way to estimate OAC-related bleeding risk. The new OACs are as effective and likely safer than VKAs, however they lack of specific antidote and their antithrombotic activity is not measurable in clinical practice.

34 Aspirin or Clopidogrel, No medication-related restrictions on duties Conclusion: Guidance for patients on aspirin or clopidogrel

35 Aspirin and Clopidogrel, Advice should be obtained from the treating physician on the risks of bleeding. Conclusion: Guidance for patients on aspirin and clopidogrel

36 Oral Anticoagulants (VKAs with INR range 2-3 or new OACs) Conclusions: Guidance for patients on oral anticoagulants HAS-BLED<3 HAS-BLED3 May be considered fit for work Consider permanent unfitness

37 Questions?


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