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

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

Different mechanisms Tissue Factor Collagen Aspirin Factor Xa Inhibitors Plasma Clotting Cascade ADP Thromboxane A2 Thienopyridines Prothrombin Factor Xa Conformational Activation of GPIIb/IIIa Thrombin Platelet Aggregation Direct Thrombin Inhibitors Fibrinogen Fibrin Thrombus

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

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

Differences in bleeding risk 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, 660000 person- years, 3554 serious vascular events) and 16 secondary prevention trials (17000 individuals at high average risk, 43000 person-years). Antithrombotic Trialists Lancet. 2009; 373(9678):1849-60.

Differences in bleeding risk Antithrombotic Trialists Lancet. 2009; 373(9678):1849-60.

Differences in bleeding risk Aspirin: 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. Flaker et al. Stroke 2012 Oct 2. [Epub ahead of print]

Differences in bleeding risk 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]

Differences in bleeding risk Aspirin plus clopidogrel: Effect of clopidogrel added to aspirin in patients with atrial fibrillation. 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. Active Investigators N Engl J Med. 2009 ;360:2066-78

Differences in bleeding risk Active Investigators N Engl J Med. 2009 ;360:2066-78

Differences in bleeding risk Aspirin plus clopidogrel: 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: 1903-12.

Differences in bleeding risk ACTIVE Writing Group of the ACTIVE Investigators. Lancet.2006; 367: 1903-12.

Summarizing bleeding risk in “old” antithrombotic agents 2-2.4% 2.2-3.4% 1.2-1.5% 1.2-1.5% No antithrombotic therapy ASA Clopidogrel ASA+Clopidogrel VKAs VKAs+antiplatelets

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

Implications of CHA2DS2VASc Score BMJ 2011; 342: 1-9

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

What would we expect from a new oral anticoagulant 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

What is new about them: Better pharmacological properties WARFARIN DABIGATRAN RIVAROXABAN APIXABAN Target VKA (VCORC1) FII (thrombin); inhibits both clot-bound and free thrombin Factor Xa; direct inhibitor Bioavailability >95% ~6% >80% >50% (66%) Tmax variable 2 h 2.5-4 h 1-3 h Half-life 35-45 ha 12-17 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 inhibitorsb(verapamil-reduce dose, dronedarone-avoid, amiodarone-no dose adjustment) Potent P-gp inducersc (to be avoided) Potent CYP3A4dand P-gp inhibitors (to be avoided) Potent CYP3A4eand P-gp inducers (to be used with caution) Potent CYP3A4d and P-gp inhibitors (to be avoided) Potent CYP3A4e and P-gp inducers (caution needed)

What is new about them: Better efficacy 34% RR reduction Stroke or systemic embolism Trial RE-LY Number of patients 18 113 Design Open-labeled, non-inferiority Mean patients’ age 71.5 years Mean CHADS2 2.1 Previous stroke/TIA 20% TTR 64% Warfarin naïve 50.4% Median follow-up 2.0 years Drug and doses Dabigatran110mg twice daily vs. warfarin Dabigatran150mg twice daily vs. warfarin N Engl J Med 2009;361:1139-51.

What is new about them: Better efficacy Per protocol population Stroke or systemic embolism Trial ROCKET-AF Number of patients 14 000 Design Double-blind, double-dummy, non-inferiority Mean patients’ age 73 years Mean CHADS2 3.5 Previous stroke/TIA 55% TTR 57.8% Warfarin naïve 37.5% Median follow-up 1.9 years Drug and doses Rivaroxaban 20mg once daily vs. warfarin 12.5% RR reduction Intention to treat population N Engl J Med 2011;365:883-91.

What is new about them: Better efficacy 21% RR reduction Stroke or systemic embolism Trial ARISTOTLE Number of patients 18 201 Design Double-blind, double-dummy, non-inferiority Mean patients’ age 70 years Mean CHADS2 2.1 Previous stroke/TIA 19% TTR 62.2% Warfarin naïve 43% Median follow-up 1.8 years Drug and doses Apixaban 5mg twice daily vs. warfarin N Engl J Med 2011;365:981-92.

What is new about them: Better safety Trial RE-LY ROCKET-AF ARISTOTLE Intracranial haemorrhage 0.23% vs. 0.74%; 0.31; 0.20-0.47; p<0.001 0.30% vs. 0.74%; 0.40; 0.27-0.60; p<0.001 0.49% vs. 0.74%; 0.67; 0.47-0.93; p=0.019 0.33% vs. 0.80%; 0.42; 0.30-0.58; p<0.001 Major bleeding 2.71% vs. 3.36%; 0.80; 0.69-0.93; p=0.003 3.11% vs. 3.36%; 0.93; 0.81-1.07; p=0.31 3.6% vs. 3.45% not specified; p=0.576 2.13% vs. 3.09%; 0.69; 0.60-0.80; p<0.001 Gastrointestinal bleedings 1.12% vs. 1.02%; 1.10; 0.86-1.41; p=0.43 1.51% vs. 1.02%; 1.50; 1.19-1.89; p<0.001 3.15% vs. 2.16%; not specified; p<0.001 0.76% vs. 0.86%; 0.89; 0.70-1.15; p=0.37 No statistically significant difference New OAC better Warfarin better

Are all new oral anticoagulants the same: insights from clinical trials RE-LY ROCKET-AF ARISTOTLE Number of patients 18 113 14 000 18 201 Design Open-labeled, non-inferiority Double-blind, double-dummy, non-inferiority Mean patients’ age 71.5 years 73 years 70 years Mean CHADS2 2.1 3.5 Previous stroke/TIA 20% 55% 19% TTR 64% 57.8% 62.2% Warfarin naïve 50.4% 37.5% 43% Median follow-up 2.0 years 1.9 years 1.8 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;

Are all new oral anticoagulants the same: insights from clinical trials Effect on outcome event, vs warfarin Dabigatran 150 Dabigatran 110 Rivaroxaban Apixaban 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 RE-LY ROCKET-AF ARISTOTLE Number of patients 18 113 14 000 18 201 Design Open-labeled, non-inferiority Double-blind, double-dummy, non-inferiority Mean patients’ age 71.5 years 73 years 70 years Mean CHADS2 2.1 3.5 Previous stroke/TIA 20% 55% 19% TTR 64% 57.8% 62.2% Warfarin naïve 50.4% 37.5% 43% Median follow-up 2.0 years 1.9 years 1.8 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;

Are all new oral anticoagulants the same: insights from clinical trials Effect on outcome event, vs warfarin Dabigatran 150 Dabigatran 110 Rivaroxaban Apixaban 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

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.

Management of new oral anticoagulant-related bleeding PCC = prothrombin complex concentrates (non-activated or activated). rFVIIa = recombinant activated factor VII. van Ryn et al Thromb Haemost 2010; 103: 1116-27

Can we predict bleeding risk? A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Pisters R et al. Chest 2010;138:1093-1100.

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

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.

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.

Conclusion: Guidance for patients on aspirin or clopidogrel No medication-related restrictions on duties

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

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

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