2013 Colombia Dabigatran Practical Issues OkPDF

7/28/2019 2013 Colombia Dabigatran Practical Issues OkPDF

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Dabigatran EtexilateAdequate use

CartagenaFebruary 22-23, 2013

1st International Forum in Oral

Anticoagulation and Atrial Fibrillation


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Question 1

The results of the randomized controlledtrials indicate that new OAC compared withwarfarin are associated with:

1. Similar or lower rate of stroke

2. Similar or lower rate of major bleeding

3. Consistent pattern of reduced mortality

4. All of the above

5. 1 and 2 only


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Question 2

Regarding anticoagulant therapy in AFpatients with renal impairment:

1. Warfarin is the anticoagulant of choice if eGFR


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Question 3

The absence of an antidote with Dabigatrancompared with warfarin is associated with:

1. Higher incidence of serious bleeding

2. More bleeding in patients requiring treatmentinterruption for urgent surgery

3. A higher case-fatality in patients with lifethreatening bleeding

4. 2 and 3 only

5. None of the above


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Question 4

Management of dabigatran around the timeof major surgery:

1. Hold dabigatran for 3 days before surgery

2. Bridge with LMWH on the day before surgery

3. A normal thrombin clotting time before surgeryindicates absence of drug

4. None of the above


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Questions

1. Which patients should I consider fortreatment with dabigatran?

2. How do I choose the dose of dabigatran?

3. How do I manage treatment interruption forsurgery?

4.

How should I manage bleeding?


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AHA/ASA and ESC Guidelines 2012

AHA/ASA 2012Warfarin (1A), dabigatran (1B), apixaban (1B)and rivaroxaban (IIaB) areindicated for the

prevention ofstroke innon-valvular AF

ESC 2012

One of the new OACs, either a DTI or an oralfXa inhibitor should be considered rather thandose-adjusted VKAfor most patients (IIaA)

Camm AJ , et al. Eur Heart J 2012Furie KL, et al. Stroke 2012


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Ischemic stroke prevention

should the acute ischaemic stroke occurwhilst the patient is taking rivaroxaban or

apixaban (neither of which significantly

reduced ischaemic stroke, compared withwarfarin, in their respective trials), the

clinician may consider the use of dabigatran

150 mg b.i.d. instead.

Camm AJ , et al. Eur Heart J 2012


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Canadian and ACCP Guidelines 2012

CCS 2012

we suggestthatmost patients shouldreceive dabigatran, rivaroxaban or apixaban in

preference to warfarin...

ACCP 2012

we suggest dabigatran 150 mg bid ratherthan adjusted-dose VKA therapy(2B).

You J J , et al. Chest 2012; 141: e531S-575SSkanes AC, et al. Can J Cardiol 2012; 28: 125-136


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CCS AF Guidelines 2012 Update


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Who should be considered for

dabigatran treatment?

Newly diagnosed (previously untreated)patients

Patients poorly controlled on warfarin or withstroke during warfarin therapy

Patients well controlled on warfarin


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Who should sti ll be considered for

warfarin therapy?

Severe renal dysfunction (eGFR 15-29)

Interacting drugs that preclude dabigatranuse (e.g., ketoconazole, quinidine, rifampicin)

Cannot afford the cost of the new oralanticoagulants


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How do I start dabigatran?

Check renal function Check liver function

Review medication history

In patients currently taking warfarin:

Start dabigatran when INR is below 2 (or on

the third day after stopping warfarin)


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Questions




4. How should I manage bleeding?


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Patients at increased risk of bleeding

Elderly (over 75 years)

Renal impairment (eGFR


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Definition and importance of CKD

Kidney damage or decreased function

for 3 months

Affects 10% of adults

Associated with increased risk of stroke andbleeding

30% of AF patients have moderate (or

severe/end stage disease)

Severe CKD and ESRD excluded from trialsHart RG, et al. Nat Rev Nephrol 2012 (on line)Herzog CA, et al. Kidney Int 2011; 80: 572-586

GrandMaison A, et al. Am J Cardiovasc Drugs 2005; 5: 291-305LeveyA, Coresh J . Chronic kidney disease. Lancet 2012; 379: 165-180


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New OAC vs. warfarin in moderate CKD

(eGFR


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New OAC vs. warfarin in moderate CKD

(eGFR


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Dabigatran in CKD

Longer half life of the drug

Increased frequency of renal functionmonitoring

Some guideline panels & regulatorsrecommend new OAC in severe CKD (eGFR15-29 ml/min)

Hart RG, et al. Nat Rev Nephrol 2012

Ri k f bl di ith i l d d l


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Risk of bleeding with single and dualantiplatelet therapy in RE-LY

Dans AL, et al. Presented at European Heart Society Meeting, August 28, 2012

P i f l l


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Patient fol low-up

Why:Adherence

Interacting drugs

Renal function (creatinine clearance) Interruption

When:

3 to 6 months; then 6 to 12 monthly (more oftenif eGFR


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Questions

1.Which patients should I consider fortreatment with dabigatran?




D bi t f i d bl di t


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Dabigatran vs. warfarin and bleeding rates

after treatment interruption

4,591 patients at least 1 invasive procedure

Procedures (>7,600)

First procedure for each patient

Major: >1 hour

Outcomes: 7 d before to 30 d after stopping

Major bleedingThromboembolism

Subgroups: urgency, surgery type, timing

Healey J S, et al. Circulation 2012; 126: 343-8.

D bi t f i


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Dabigatran vs. warfarin

Similar rates of thrombosis & CV death

Timing ofprocedure

Dabigatran110, %

Dabigatran150, %

Warfarin%

CV Death 0.6% 0.5% 0.5%

Stroke 0.5% 0.5% 0.6%

Embolism 0.1% 0.1% 0.1%

MI 0.1% 0.5% 0.3%PE 0.1% 0.1% 0.2%

Composite 1.2% 1.5% 1.2%


D bi t f i


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Lower rates of major bleeding within 24 hrs

Timing ofprocedure

Dabigatran110, %

Dabigatran150, %

Warfarin,%

< 24 hrs 2.8% 6.8% 15.4%

24 48 hrs 3.2% 3.3% 9.0%

48 72 hrs 4.5% 4.5% 5.7%

> 72 hrs 4.7% 6.2% 3.6%

P-trend 0.15 0.40


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Less bleeding in urgent / major surgery

SurgeryDabigatran

110, %Dabigatran

150, %Warfarin,

%

Urgent 17.8% 17.7% 21.6%

Elective 2.8% 3.8% 3.3%

Major 6.1% 6.5% 7.8%

Minor 1.9% 3.2% 1.8%


Management of interruption


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Management of interruption

Determine

renal function

Assess proceduralbleeding risk

Standard High

Hold2-3 drug half-lives

Hold4-5 drug half-lives

(pre-op aPTT)

aPTT and drug levels


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aPTT and drug levels

Van Ryn J , et al. Thromb Haemost2010

TCT (Hemoclot) and drug levels


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TCT (Hemoclot) and drug levels

Van Ryn J , et al. Thromb Haemost2010

M t f I t ti


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Management of Interruption

Rivaroxaban and apixaban half life (25-35%renal clearance)

Approximately 12 hours

Relatively unaffected by renal function

Dabigatran half life (80% renal clearance)

>80 ml/min: T 1/2 = 12 hours

50 to 80 ml/min: T 1/2 = 15 hours30 to 50 ml/min: T 1/2 = 18 hours


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Questions





Bleeding summary


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Bleeding summary

Bleeding is the most common complication ofantithrombotic therapy

Prevention is better than cure

Careful management of interruption andgeneral measures are foundation

Hemostatic agents, charcoal and dialysismay be considered but will be rarely needed

Reports of bleeding with dabigatran


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Reports of bleeding with dabigatran

need to be interpreted in context

Eikelboom J W, et al. J Thromb Hemost 2012


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Weitz J I, et al. Circulation 2012

What general hemostatic agents


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What general hemostatic agents

might be considered?

Antifibrinolytic agents (e.g., tranexamic acid)

Prothrombin complex concentrates

II, VII, IX, X, C, S, small amounts of heparin

25-50 units per kg

Activated prothrombin complex concentrates

FEIBA

Recombinant factor VIIa Novoseven

Dabigatran blood levels


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Dabigatran blood levels

Clemens A, et al. CurrMed Res Op 2012; 28: 195-201

Dabigatran antidote


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Dabigatran antidote

Human

MouseVL

CLCH

VH

Humanized

Fab

Specific high affinity binding to dabigatran

No homology of dabigatran to otherendogenous receptors/ligandsFab has shorter half life than full mAb (hrs vsdays for a full mAb)

van Ryn et al, J ACC 2011; 57 (Suppl 1) abstr 1142-367van Ryn et al, J TH 2011; 9 (suppl 2), 110, abstr P-MO-166

Summary


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Summary

New oral anticoagulants have the potential toreplace warfarin for majority of AF patients atrisk for stroke

Key to optimal use is appropriate patient anddose selection, careful follow up and safemanagement of interruption


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Warfarin and MI


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Warfarin and MI

Lip G, et al,Am J Med 2010.

Dabigatran and MI in RE LY


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Dabigatran and MI in RE-LY

Years of Follow-up

CumulativeHazardRates

0.0

0.0

5

0.1

0

0.1

5

0.2

0

0.2

5

0 0.5 1.0 1.5 2.0 2.5

MI

Stroke/SEE/MI/UA/PCI/CABG/Cardiac arrest/Cardiac death

Net clin ical benefit

Dabigatran 110Dabigatran 150Warfarin

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