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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
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Oral antithrombotic agents
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Different mechanisms
Tissue Factor
Plasma ClottingCascade
Prothrombin
Thrombin
Fibrinogen Fibrin
Thrombus
Platelet Aggregation
Conformational Activation of GPIIb/IIIa
Collagen
Thromboxane A2
ADP
Aspirin
Thienopyridines
Direct Thrombin Inhibitors
FactorXa
Factor Xa Inhibitors
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Different indications
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•Major bleeding
•Fatal bleeding
•Intracranial bleeding
•Clinical Relevant
bleeding
•Stroke/TIA
•TIA
•Fatal Stroke
•Disabling stroke
Differences in bleeding risk
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Differences in bleeding risk
Aspirin:
Aspirin in the primary and secondary prevention of vasculardisease: collaborative meta-analysis of individual participantdata 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.
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Differences in bleeding risk
Antithrombotic Trialists Lancet. 2009; 373(9678):1849-60.
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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
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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]
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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. 2009 ;360:2066-78
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Differences in bleeding risk
Active Investigators N Engl J Med. 2009 ;360:2066-78
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Clopidogrel plus aspirin versus oral anticoagulation for atrialfibrillation in the Atrial fibrillation Clopidogrel Trial withIrbesartan 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
Aspirin plus clopidogrel:
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Differences in bleeding risk
ACTIVE Writing Group of the ACTIVE Investigators. Lancet.2006; 367: 1903-12.
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Summarizing bleeding risk in “old” antithrombotic agents
No antithrombotic therapy ASA Clopidogrel ASA+Clopidogrel VKAs VKAs+antiplatelets
1.2-1.5%
2-2.4% 2.2-3.4%
1.2-1.5%
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Why the number of anticoagulated patients is expected to increase?
Current practice:
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Implications of CHA2DS2VASc Score
BMJ 2011; 342: 1-9
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Phase Ι Phase ΙΙ Phase ΙΙΙ Approval
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
Betrixaban
The New Oral Anticoagulants
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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
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What is new about them: Better pharmacological properties
WARFARIN DABIGATRAN RIVAROXABAN APIXABAN
TargetVKA (VCORC1)
FII (thrombin); inhibits both clot-bound and free thrombin
Factor Xa;direct inhibitor
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)
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What is new about them: Better efficacy
Trial RE-LYNumber of patients 18 113Design Open-labeled, non-inferiorityMean patients’ age 71.5 years
Mean CHADS2 2.1
Previous stroke/TIA 20%TTR 64%Warfarin naïve 50.4%Median follow-up 2.0 yearsDrug and doses Dabigatran110mg twice
daily vs. warfarinDabigatran150mg
twice daily vs. warfarin
Str
oke
or s
yste
mic
em
bolis
m
N Engl J Med 2009;361:1139-51.
34%
RR
red
uctio
n
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What is new about them: Better efficacy
Trial ROCKET-AFNumber of patients 14 000Design Double-blind, double-dummy,
non-inferiorityMean patients’ age 73 years
Mean CHADS2 3.5
Previous stroke/TIA 55%TTR 57.8%Warfarin naïve 37.5%Median follow-up 1.9 yearsDrug and doses Rivaroxaban 20mg once daily
vs. warfarin
Inte
ntio
n to
tre
at p
opul
atio
nP
er p
roto
col p
opu
latio
n
Str
oke
or s
yste
mic
em
bolis
m
N Engl J Med 2011;365:883-91.
12.5
% R
R r
educ
tion
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What is new about them: Better efficacy
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
Str
oke
or s
yste
mic
em
bolis
m
21%
RR
red
uctio
n
N Engl J Med 2011;365:981-92.
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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
What is new about them: Better safety
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Are all new oral anticoagulants the same: insights from clinical trials
Trial RE-LY ROCKET-AF ARISTOTLENumber of patients 18 113 14 000 18 201Design Open-labeled, non-inferiority Double-blind,
double-dummy,non-inferiority
Double-blind, double-dummy,non-inferiority
Mean patients’ age 71.5 years 73 years 70 years
Mean CHADS2 2.1 3.5 2.1
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 yearsDrug and doses Dabigatran110mg
twice daily vs. warfarin
Dabigatran150mg twice daily vs.
warfarin
Rivaroxaban 20mg once daily
vs. warfarin
Apixaban 5mg twice daily vs.
warfarinPrimary 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;
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Effect on outcome event, vs warfarin Dabigatran150
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
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Are all new oral anticoagulants the same: insights from clinical trials
Trial RE-LY ROCKET-AF ARISTOTLENumber of patients 18 113 14 000 18 201Design Open-labeled, non-inferiority Double-blind,
double-dummy,non-inferiority
Double-blind, double-dummy,non-inferiority
Mean patients’ age 71.5 years 73 years 70 years
Mean CHADS2 2.1 3.5 2.1
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 yearsDrug and doses Dabigatran110mg
twice daily vs. warfarin
Dabigatran150mg twice daily vs.
warfarin
Rivaroxaban 20mg once daily
vs. warfarin
Apixaban 5mg twice daily vs.
warfarinPrimary 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;
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Effect on outcome event, vs warfarin Dabigatran150
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
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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.
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van Ryn et al Thromb Haemost 2010; 103: 1116-27
PCC = prothrombin complex concentrates (non-activated or activated).rFVIIa = recombinant activated factor VII.
Management of new oral anticoagulant-related bleeding
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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;138:1093-1100.
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Can we predict bleeding risk?
Apostolakis et al J Am Coll Cardiol. 2012;60:861-7.
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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.
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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.
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Aspirin or Clopidogrel,
No medication-related restrictions on duties
Conclusion: Guidance for patients on aspirin or clopidogrel
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Aspirin and Clopidogrel,
Advice should be obtained from the treating physician on the risks of bleeding.
Conclusion: Guidance for patients on aspirin and clopidogrel
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Oral Anticoagulants
(VKAs with INR range 2-3 or new OACs)
Conclusions: Guidance for patients on oral anticoagulants
HAS-BLED<3 HAS-BLED≥3
May be considered fit for work Consider permanent unfitness
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Questions?