Dabigatran may be used as an alternative to warfarin for anticoagulation during cardioversion for atrial fibrillation. A post-hoc analysis found similar rates of stroke, embolism, and major bleeding within 30 days of cardioversion for dabigatran 110mg and 150mg compared to warfarin. However, the 110mg dose was associated with higher bleeding in patients also taking antiplatelet therapy. For ablation, discontinuing dabigatran at least 24 hours prior may reduce bleeding risks compared to uninterrupted warfarin, but randomized controlled trials are still needed.
3. Patient Case
• Mr. W 64 y/o male
admitted with a chief
complaint of chest pain,
heart palpitations, and
DOE x 1 week
o EKG shows A. fib with RVR
Vitals
Temperature
98.06
Pulse
100
Respiration
18
Blood Pressure
120/82
• PMH: HTN, sleep apnea,
paroxysmal A. fib., and
obesity
• Medications:
o ASA 325 mg
o Lisinopril 40 mg daily
o Sotalol 160mg PO BID (HELD)
• CHADS2 = 1
• CrCl = 90mL/min
• Cardiology consult
o Diltiazem and heparin drip
started
o Plan for TEE and cardioversion
o Patient does not want warfarin,
was offered dabigatran and
wants it instead.
4. Clinical Question
• What is the role of dabigatran as an anticoagulant
during cardioversion or ablation for atrial fibrillation?
7. Atrial Fibrillation
Pathophysiology
Pulmonary vein reentry circuits
Reversible Causes
Cardiac surgery, pericarditis, myocardial infarction,
hyperthyroidism, pulmonary embolism, pulmonary
disease, and excessive alcohol ingestion
Symptoms
Common - palpitations, tachycardia, weakness,
dizziness, lightheadedness, reduced exercise
capacity, mild dyspnea
Severe - dyspnea at rest, angina, presyncope,
syncope, embolic event, right sided heart failure
Classification
Paroxysmal
≥ 2 episodes that terminates
spontaneously in 7 days or less
Persistent
AF that does NOT terminate after 7 days
Permanent
AF for which cardioversion has failed or not been
attempted
Cheng A, Kumar K. Overview of atrial fibrillation. In: UpToDate, Baslo, DS (Ed), Waltham, MS, 2013
8. Atrial Fibrillation
Treatment
• General
o
o
o
o
o
•
Treat any underlying reversible causes
Slow ventricular rate – beta blockers, non-DHP calcium channel blockers
Convert to normal sinus rhythm – direct current, pharmacologic
Prevent recurrences – ablation
Prevent stroke/improve survival – anticoagulation
Congestive Heart Failure, Hypertension, Age > 75, Diabetes, Stroke
CHADS2 Score
Events per 100 patient years OR % per year
0
0.49
1
1.52
2
2.50
3
5.27
4
6.02
5 or 6
6.88
Go AS, Hylek EM, Chang Y, et al. JAMA. 2003;290(20):2685-2692
Cheng A, Kumar K. Overview of atrial fibrillation. In: UpToDate, Baslo, DS (Ed), Waltham, MS, 2013
9. Cardioversion
• Direct current or antiarrhythmic to return to NSR
Reasons to Cardiovert
Reasons NOT to Cardiovert
Unstable hemodynamics or
worsening symptoms due to AF
Minimally symptomatic
First episode, irrespective of long
term control strategy
Multiple comorbidities OR
Overall poor prognosis
• Stroke risk post-cardioversion is 1-5% over 1 month
o Higher than baseline risk of 1-6% over 1 year
Duration of AF
Pre-Cardioversion
Post-Cardioversion
≤ 48 h
LMWH/UFH at therapeutic doses on
presentation
Oral Anticoagulation x 4 weeks
Stop/Continue based on rhythm
> 48h
TEE and/or
Oral Anticoagulation x 3 weeks
Oral Anticoagulation x 4 weeks
Stop/Continue based on rhythm
You JJ, Singer DE, Howard PA et al. Chest.2012;141(2 Suppl):e531S-75S.
Naccarelli G, Ganz L, Manning W. Restoration of sinus rhythm in atrial fibrillation.
In: UpToDate, Baslo, DS (Ed), Waltham, MS, 2013
10. Ablation
• Radiofrequency catheter ablation is applied to
pulmonary veins suspected of initiating AF.
o Success ranges from 50-80%
• Complications:
o Periprocedural Embolism (CVA/TIA) – 0.5 - 2.0%
o Cardiac tamponade > 1%
• Most frequent cause of death
o Pulmonary vein stenosis 1.0 - 3.0%
• No clear anticoagulation
strategy
o Continuous warfarin therapy shown to be
safe and effective
o Unclear safety and efficacy of dabigatran
Passman, R. Radiofrequency ablation to prevent recurrent atrial
fibrillation. In: UpToDate, Baslo, DS (Ed), Waltham, MS, 2013.
11. Dabigatran
Mechanism
Direct thrombin inhibitor
Pharmacokinetics
Time to peak – 1 hour
Excreted 80% in urine
Metabolized to active form by plasma/hepatic esterases
Dosage forms
75mg, 150mg
Renal dose adjustment
> 50 mL/min: no dose adjustment
30-50 mL/min adjust dose in concomitant interacting
medication that increases dabigatran concentrations
15-30 mL/min: 75 mg PO BID
< 15mL/min: avoid use
FDA-approved uses
Nonvalvular atrial fibrillation
Non FDA-approved uses
Postoperative thomboprophylaxis (knee/hip replacement)
Contraindications
Mechanical prosthetic heart valves
Active bleeding
*Severe renal impairment (CrCl <30 mL/min)
*Both Canadian labeling and ACCP list CrCl <30mL/min as a contraindication to dabigatran use.
Dabigatran: Lexicomp Drug information. In: UpToDate, Baslo, DS (Ed), Waltham, MS, 2013.
13. RE-LY
Design
Post-hoc analysis of a prospective, randomized, controlled, multi center study
Inclusion
• Documented AF (paroxysmal or persistent)
PLUS one of the following:
• History of previous stroke, TIA, or systemic embolism
• EF < 40%
• Symptomatic heart failure (≥ NYHA class II)
• Age 75 years
• Age 65 years and DM (on treatment), CAD, or HTN (on
treatment)
AND
• Underwent cardioversion during the RCT
Exclusion
Severe heart valve disorder
Stroke within 14 days OR severe stroke within last 6 months
Conditions that increased the risk of hemorrhage
CrCl < 30 mL/min
Reversible cause of A. fib.
Plan for ablation
Nagarakanti R, Ezekowitz MD, Oldgren J et al. Circulation. 2011;123(2):131-6.
Connolly SJ, Ezekowitz MD, Yusuf S et al. N Engl J Med. 2009;361(12):1139-51
14. RE-LY
Treatment
Warfarin titrated to an INR of 2.0-3.0
OR
Dabigatran 110 mg BID
OR
Dabigatran 150 mg BID
Major Outcomes
Stroke, systemic embolism, and major bleeding within 30 days of
cardioversion
Nagarakanti R, Ezekowitz MD, Oldgren J et al. Circulation. 2011;123(2):131-6.
Connolly SJ, Ezekowitz MD, Yusuf S et al. N Engl J Med. 2009;361(12):1139-51
15. Results
Outcome
Major
Bleeding
First
0.30%
0.60%
(N = 672)
(N = 664)
0.48%
0.48%
0.46%
(N = 421)
(N = 436)
1.7%
0.60%
0.60%
(N = 647)
All
0.77%
(N = 413)
First
Warfarin
(N = 647)
All
Dabigatran
150 mg
(N = 672)
(N = 664)
2.66%
0.48%
0.46%
(N = 413)
Stroke &
systemic
embolism
30 days
post
Cardioversion Dabigatran
110 mg
(N = 421)
P-value
(N = 436)
D110
vs. W
D150
vs. W
0.71
0.45
0.96
0.97
_
_
0.009
0.97
*6/11 (54%) of patients with major bleeding in the dabigatran 110 mg group were taking
concomitant aspirin and clopidogrel, no other groups has patients taking both.
Nagarakanti R, Ezekowitz MD, Oldgren J et al. Circulation. 2011;123(2):131-6.
16. Author’s Conclusions
• RE-LY was not powered to detect a difference in
stroke and systemic embolism among groups
undergoing cardioversion.
o At 80% power and 0.05 significance 15,000 – 40,000 cardioversions
assuming stroke and embolism rates of 0.6% in the warfarin arm and
between 0.3% and 0.4% in the D150 arm.
• Major bleeding rates were similar among all groups,
but highest in the D110 group.
• Warfarin and dabigatran are comparable in this
setting.
Nagarakanti R, Ezekowitz MD, Oldgren J et al. Circulation. 2011;123(2):131-6.
17. Analysis
Strengths
Limitations
• Large, randomized,
controlled trial
• Intention to treat
analysis
• Posthoc analysis
• Not powered to find
difference in stroke and
embolism
• Did not address lack of
reversal agent for
dabigatran
• Sponsored by
manufacturer
18. Lakkireddy et al.
Design
Multicenter, prospective, matched observational study
Patient population
Patients undergoing ablation for AF in 8 high volume US centers
Inclusion
Symptomatic AF
Scheduled AF ablation
Drug refractory
Exclusion
INR not between 2.0-3.5 on warfarin
Treatment
Warfarin titrated to an INR of 2.0-3.5 x at least 3 weeks prior then
continued uninterrupted throughout the procedure
OR
Dabigatran 150 mg BID x at least 3 weeks, held morning of, and
resumed 3 h post
Outcomes
Bleeding (Major and Minor)
Thromboembolic complications (CVA and TIA)
Lakkireddy D, Reddy YM, Di Biase L et al. J Am Coll Cardiol. 2012;59(13):1168-74.
19. Results
Outcome
Dabigatran
(N= 145)
Warfarin
(N = 145)
P-value
Major Bleeding Complications
9 (6)
1 (1)
0.019
Periprocedural pericardial
tamponade
6 (4)
1 (1)
0.12
Late pericardial tamponade
3 (2)
0 (0)
0.25
Minor Bleeding Complications
12 (8)
8 (6)
0.35
Groin hematoma
6 (4)
5 (3)
0.76
Pericardial hematoma without
tamponade
6 (4)
4 (3)
0.76
Embolic Complications
(CVA/TIA)
3 (2)
0 (0)
0.25
9 (6)
0.009
Composite bleeding and
23 (16)
thromboembolic complications
Values are n (%)
Note: Dabigatran use and age > 75 were the only univariable predictors of composite bleeding and
thromboembolic complications.
Lakkireddy D, Reddy YM, Di Biase L et al. J Am Coll Cardiol. 2012;59(13):1168-74.
20. Author’s Conclusions
• Use of dabigatran periprocedurally for AF ablation
was associated with an increased risk of bleeding.
o Discontinued dabigatran only the morning prior to the procedure
o Overlapped of dabigatran with UFH required during the procedure.
• Large randomized controlled trials are required to
confirm results and identify an optimal
periprocedural anticoagulation protocol.
Lakkireddy D, Reddy YM, Di Biase L et al. J Am Coll Cardiol. 2012;59(13):1168-74.
22. Kim et al.
Design
Case-control study
Inclusion
Symptomatic AF
Scheduled for ablation
Exclusion
Not specifically stated
Treatment
Warfarin titrated to an INR of 2.0-3.0 ≥ 4 weeks and continued during
ablation and continued ≥ 3 months post
OR
Dabigatran 110 mg BID ≥ 4 weeks, held 24-30 hours prior, resumed 4 h
post hemostasis and continued ≥ 3 months post
Outcomes
Thromboembolic complications (CVA, TIA, systemic embolism)
Major and minor bleeding
Kim JS, She F, Jongnarangsin K et al. Heart Rhythm. 2013;10(4):483-9.
23. Results
Outcome
Dabigatran
(N= 191)
Warfarin
(N = 572)
P-value
Major Bleeding
4 (2.1)
12 (2.1)*
1.0
Pericardial tamponade
2 (1.0)
7 (1.2)
1.0
Vascular complications
2 (1.0)
5 (0.9)
1.0
Minor Bleeding
5 (2.6)
19 (3.3)
0.81
Groin hematoma
4 (2.1)
19 (3.3)
0.47
Pericardial effusion without
tamponade
1 (0.5)
0 (0)
0.25
Embolic Complications
(CVA/TIA)
0 (0)
0 (0)
1.0
Values are n (%)
*INR, clopidogrel use, and CHADS2-VASc were the only things associated with major bleeding in
the warfarin group.
+Warfarin group had a higher number of patients with previous stroke and a higher number of
patients on statin medications.
#TEE performed in all dabigatran patients and at risk warfarin patients, no LAA thrombus in any
patients
Kim JS, She F, Jongnarangsin K et al. Heart Rhythm. 2013;10(4):483-9.
24. Author’s Conclusions
• When held 24 hours prior to ablation and resumed 4
hours post, dabigatran appears to be as safe and
effective as uninterrupted warfarin therapy
• There seems to be no risk of left atrial appendage
thrombus after holding dabigatran for 24-30 h prior
to ablation
Kim JS, She F, Jongnarangsin K et al. Heart Rhythm. 2013;10(4):483-9.
26. Summary
Cardioversion
• Dabigatran 110 mg was associated with a higher
incidence of bleeding in patients taking dual
antiplatelet therapy
• Difference in stroke rate between warfarin and
dabigatran in this setting will likely never be
determined
Ablation
• Discontinuation period prior to ablation can effect
bleeding rates, ideally discontinue at least 24 h prior
to ablation
27. Patient Case
• Mr. W 64 y/o male
admitted with a chief
complaint of chest pain,
heart palpitations, and
DOE x 1 week
o EKG shows A. fib with RVR
Vitals
Temperature
98.06
Pulse
100
Respiration
18
Blood Pressure
120/82
• PMH: HTN, sleep apnea,
paroxysmal A. fib., and
obesity
• Medications:
o ASA 325 mg
o Lisinopril 40 mg daily
o Sotalol 160mg PO BID (HELD)
• CHADS2 = 1
• CrCl = 90mL/min
• Cardiology consult
o Diltiazem and heparin drip
started
o Plan for TEE and cardioversion
o Patient does not want warfarin,
was offered dabigatran and
wants it instead.
28. Patient Case
• Given the RE-LY data we cannot be sure about the
difference in stroke or embolism rate of warfarin vs.
dabigatran in our patient
• The patient would be switched from ASA to warfarin
or dabigatran and is on no other antiplatelet agents
o Only difference in bleeding rates shown by RE-LY in patients on dual
antiplatelet therapy and dabigatran.
• No contraindications to use of warfarin or
dabigatran exist for this patient
• Cost is an issue and patient desire not sufficient
indication for dabigatran
29. Patient Update
• Per cardiology note:
o Patient was discharged on enoxaparin and warfarin for a total of 4 weeks
o After 4 weeks patient can switch to dabigatran for prevention of stroke
• 2 days after discharge patient was seen in the ED
complaining of pounding in his chest and a high
pulse
o EKG showed A. fib with a ventricular rate of 88
o ED physician and patient discussed the option of ablation
o Patient wants to postpone this until he returns from a 2 month vacation.
• If follows cardiology plan, he will be on dabigatran
at the time of ablation
o Should be okay if discontinued 24 hours prior to ablation
o Pre-procedural TEE is recommended
30. References
1. Cheng A, Kumar K. Overview of atrial fibrillation. In: UpToDate, Baslo, DS (Ed), Waltham, MS, 2013
2. Connolly SJ, Ezekowitz MD, Yusuf S et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl
J Med. 2009;361(12):1139-51.
3. Dabigatran: Lexicomp Drug information. In: UpToDate, Baslo, DS (Ed), Waltham, MS, 2013.
4. Go AS, Hylek EM, Chang Y, et al. Anticoagulation Therapy for Stroke Prevention in Atrial Fibrillation:
How Well Do Randomized Trials Translate Into Clinical Practice? JAMA. 2003;290(20):2685-2692
5. Kim JS, She F, Jongnarangsin K et al. Dabigatran vs warfarin for radiofrequency catheter ablation of atrial
fibrillation. Heart Rhythm. 2013;10(4):483-9.
6. Lakkireddy D, Reddy YM, Di Biase L et al. Feasibility and safety of dabigatran versus warfarin for
periprocedural anticoagulation in patients undergoing radiofrequency ablation for atrial fibrillation:
Results from a multicenter prospective registry. J Am Coll Cardiol. 2012;59(13):1168-74.
7. Naccarelli G, Ganz L, Manning W. Restoration of sinus rhythm in atrial fibrillation. In: UpToDate, Baslo, DS
(Ed), Waltham, MS, 2013
8. Nagarakanti R, Ezekowitz MD, Oldgren J et al. Dabigatran versus warfarin in patients with atrial fibrillation:
An analysis of patients undergoing cardioversion. Circulation. 2011;123(2):131-6.
9. Passman, R. Radiofrequency ablation to prevent recurrent atrial fibrillation. In: UpToDate, Baslo, DS (Ed),
Waltham, MS, 2013.
10. You JJ, Singer DE, Howard PA et al. Antithrombotic therapy for atrial fibrillation: Antithrombotic therapy
and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical
practice guidelines. Chest.2012;141(2 Suppl):e531S-75S.
Mr. W admitted with cc of CP, palpitations, and DOE x 1 weekEKG on admitPMH significant for HTN paroxysmalFor his A. fib he takesCardiology was consultedStartedPlan forPt does not want warfarin
Difference between NSR and a. fib. is a change in the initiation of cardiac conductionNSR – SA node is pacemakerfib. – abnormal pulmonary veins in atria take over as the pacemaker, bypassing the SA nodeResult = atria to not depolarize and contract normally to fill the ventricles adequatelyStasis of blood in the atria can lead to thrombus and if pushed systemically can lead to stroke
Reversible causes are listed hereSome common symptoms our patient experienced palpitations, tachycardia, dyspnea, and angina.
General treatment strategies are listed here; today we will focus on conversion to NSR with cardioversion and ablation as well as anticoagulation.Patients with AF have baseline risk for strokeStratified by CHADS2 score – Increased score = increased risk of stroke over the next year
Cardioversion is the conversion of a patient from A. fib into NSREither DCC or antiarrhythmic medications like amiodarone can be usedSome patients make good candidates while others don’tReasons to cardiovert or not are listed hereBut the reason we are talking about this in relation to dabigatran has to do with increase risk of stroke in the post-cardioversion periodRisk of stroke is increased from baseline in patients undergoing cardioversion, therefore specific guidelines exist for anticoagulationDepending upon the duration of a. fib. and presence of atrial thrombus dabigatran could potentially be used in either the pre or post cardioversion period. Unstable hemodynamics (RVR, decreased CO) or worsening symptoms due to AFMultiple comorbidities (LVH or mitral valve disease) OR Overall poor prognosis (> 80 y/o)DCC – unstable patients OR first/rare episode patientsPharmacologic (Amiodarone, Dofetilide, Ibutilide) – longstanding AF patients in whom a rhythm approach is planned. If failed then DCC an option
Radiofrequency ablation is done to eliminate pulmonary veins that are ectopicSuccess is fairly high, but ablation is invasive and complications do occurEmbolism surrounding a. fib is as high as 2% although some studies quote higherUse of anticoagulation in the periablation period can reduce this complication and dabigatran could be used in this settingUnlike cardioversion, there is no clear method for anticoagulation surrounding ablation. Continuous warfarin therapy effective, unclear safety and efficacy of dabigatran
Dabigatran is a DTI with quick onsetAccording to it’s labeling it should be renally dosed; however dosing in renal dysfunction is not well studied Canadian labeling, the ACCP, and the VA avoid dabigatran in renal imparimentApproved fro non-valvular AF
RE-LY was a prospective, randomized, controlled, multi-center study A posthoc analysis of this study was done to look at dabigatran in patients who underwent cardioversion while on study medicationInclusion criteria was documented AF and at least 1 other factor that would make the patient a candidate for anticoagulationPatients were excluded if they had a heart valve disorder, recent or severe stroke or poor renal function
Patients were treated with one of 3 regimens Warfarin titrated to an INR of 2-3 or Dabigatran at one of two doses (discontinued <12h prior in 50% of patients)Outcomes included stroke, systemic embolism and major bleeding.Major bleeding was defined as a reduction in the hemoglobin level of at least 2, transfusion of at least 2 U blood, or symptomatic bleeding in a critical area or organ.
Results showed no difference in stroke and systemic embolism 30 days post NO difference in major bleeding except for in the group receiving D110 whose rate was higher6/11 of these patients happened to have been receiving ASA and clopidogrel while no other treatment arms were exposed to this
Study not powered to detect a difference in stroke/embolismIn order to power a study like this would need 15,000-40,000 patients due to low rate of strokesMajor bleeding rates were similar in all groups,except D110 likely due to use of DAPT in this group. Concluded both agents were comparable in this setting
Strengths of this study that improved its internal validity were it’s large randomized and controlled nature as well as intention to treatLimitations include the unplanned posthoc analysis which was not powered to detect differences in stroke/embolismStudy did not address the lack of a reversal agentSponsored by manufacturer
Lakkireddy et al performed a multicenter, prospective, matched observational study in patients undergoing ablation in 8 high volume US centersPatient had to have drug refractory symptomatic AF and be scheduled for an ablationPatients on warfarin were kept on continuous therapy during the procedure with a goal INR or 2-3.5Patients on dabigatran were told to hold their AM dose and resumed it 3h post procedureOutcomes included bleeding, both major [bleeding requiring blood transfusion, hematomas requiring surgical intervention, and pericardial effusions requiring drainage (tamponade)] and minor small hematomas and pericardial effusions not requiring an intervention (nontamponade). Thromboembolic complications included stroke and TIA
NNH = 20 for major bleeding complicationsNNH for composite bleeding and thromboembolic complications = 10Most of the results showed no difference between groups with the exception of major bleeding complications in the dabigatran group in which cardiac tamponade requiring drainage was the most common event.Additionally the composite bleeding and thromboembolic complications were also significantly different between the groups for which dabigatran use and age>75 were the predictors for these events.
Concluded dabigatran increases risk of bleeding complications which they attributed to not enough time off dabigatran prior to ablation and overlapping dabigatran with UFH a practice that is not well studied.Overalll think a large randomized trial would be ideal to determine what regimen to use.
One of the strengths of this study was it’s multicenter nature which increases generalizability, However, it was limited by the fact that it was not randomized and had a matched control design limiting internal validity.
A study by Kim et al was also case-control for AF patients undergoing ablationPatients underwent a very similar protocol as the previous study, but dabigatran was held for a longer period prior to ablationOutcomes measured included thromboembolic complications and major and minor bleedingMajor bleeding complications included pericardial tamponade that requiring surgery, rehospitalization and/or longer hospital stay, or blood transfusion.Minor bleeding complications were defined as a small groin hematoma, any bleeding that did not require an intervention, or pericardial effusion without tamponade.
Results from this case control showed no difference in any of the measured outcomes; however, INR, clopidogrel use and CHADS-Vasc was associated with major bleeding in the warfarin groupNeither group had left atrial appendage thrombus on TEE
If withheld for 24 h dabigatran is as safe and effective as warfarin therapy in the periablation period, risk of thrombus is not increased during this holding period.
Although the data was collected prospectively the study was not randomized, had a case control design which limit internal validity. Also, the may not have powered their study adequately to detect a difference
Overall in cardioversionDabigatran was associated with increased bleeding in patients taking DAPTDifference in stroke rate will probably not be determined since the sample size needed is so highAblationKinetics matter, must give at least 24 hours between dabigatran and ablation procedure to maintain safety of dabigatran in the periablation periodNo study has looked at patients with severe renal impairment taking dabigatran.
Just a reminder of the patient case – Mr W is in A. fib. awaiting cardioversion and hoping to receive pradaxa afterwards
If we look at the data to support use of dabigatran in this patient we see that given the RE-LY data is is not clear if warfarin or dabigatran is better with regards to stroke risk. Additionally, this patient would be switched from ASA to warfarin or dabigatran meaning he would not be at the increased risk of bleeding seen when overlapping antiplatelets and dabigatran in the pericardioversion period. Generally this patient has no contraindications to either medication, but cost is an issue and a non-formulary consult just because the patient doesn’t want warfarin is not likely to get approved.
Per cardiology on discharge they were able to convince the patient to do warfarin for 4 weeks and then he could switch to dabigatran afterwards2 days after discharge the patient came to the ED with palpitations and a high pulseOn EKG he has A. fi and ventricular rate of 88The ED physician discussed the option of ablation with the patient who decided he would postpone this until after his planned vacationIf this were to happen per cardiology’s request he would be on dabigatran (assuming approval by pharmacy) prior to ablation. Based on the data we reviewed he would be okay to continue it as long as it was held 24h prior to the procedure.