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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
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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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?
2. How do I choose the dose of dabigatran?
3. How do I manage treatment interruption forsurgery?
4. How should I manage bleeding?
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%
Healey J S, et al. Circulation 2012; 126: 343-8.
D bi t f i
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Dabigatran vs. warfarin
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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Dabigatran vs. warfarin
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%
Healey J S, et al. Circulation 2012; 126: 343-8.
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
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?
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