1. 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;

2. 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

3. 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

4. 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

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

6. 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, 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. 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]

9. 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]

10. 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 ;360:

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

12. 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:

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

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

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

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

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

18. What would we expect from a new oral anticoagulant18
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
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)

20. 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:

21. 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:

22. 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:

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

24. 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;

25. 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

26. 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;

27. 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

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. 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:

30. 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:

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

35. 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.

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

37. Questions?