stavros apostolakis, md, phd university of birmingham centre for cardiovascular sciences, city...

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

Oral antithrombotic agents

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

Different indications

•Major bleeding

•Fatal bleeding

•Intracranial bleeding

•Clinical Relevant

bleeding

•Stroke/TIA

•TIA

•Fatal Stroke

•Disabling stroke

Differences in bleeding risk

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.

Differences in bleeding risk

Antithrombotic Trialists Lancet. 2009; 373(9678):1849-60.

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

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:

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

Differences in bleeding risk

Active Investigators N Engl J Med. 2009 ;360:2066-78

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:

Differences in bleeding risk

ACTIVE Writing Group of the ACTIVE Investigators. Lancet.2006; 367: 1903-12.

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%

Why the number of anticoagulated patients is expected to increase?

Current practice:

Implications of CHA2DS2VASc Score

BMJ 2011; 342: 1-9

Phase Ι Phase ΙΙ Phase ΙΙΙ Approval

Dabigatran

Rivaroxaban

Apixaban

Edoxaban

Betrixaban

The New Oral Anticoagulants

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

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)

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

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N Engl J Med 2009;361:1139-51.

34%

RR

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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

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N Engl J Med 2011;365:883-91.

12.5

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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

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21%

RR

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N Engl J Med 2011;365:981-92.

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

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;

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

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;

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

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.

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

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.

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.

Aspirin or Clopidogrel,

No medication-related restrictions on duties

Conclusion: Guidance for patients on aspirin or clopidogrel

Aspirin and Clopidogrel,

Advice should be obtained from the treating physician on the risks of bleeding.

Conclusion: Guidance for patients on aspirin and clopidogrel

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

Questions?