1. Anticoagulation for Atrial Fibrillation: Who, When, and How?
August 17, 2013
Elaine M. Hylek, MD, MPH
Boston University School of Medicine

2. Disclosures Disclosures of Elaine Hylek Employment
No conflict of interest to disclose
Research support
NIH/NINDS, NIH/NHLBI; Bristol-Myers Squibb-Executive Steering Committee; ARISTOTLE trial; Janssen-Executive Steering Committee; ORBIT-AF Registry
Scientific advisory board
Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, Pfizer
Consultancy
Speakers bureau
Major stockholder
Patents
Honoraria
Bayer, Boehringer-Ingelheim, Pfizer
Travel support
Other

3. TEE depicting a large LAA thrombus attached to the lateral wall
Hesse, B. et al. Circulation 2006;113:e e

4. Stanford Stroke Center, Albers G

5. Stanford Stroke Center, Albers G

6. Prevalence of AF by Age
Feinberg WM. Arch Intern Med. 1995;155(5):469–473 6

7. Budnitz D et al. N Engl J Med 2011;365:2002–12
HAZARDS OF WARFARIN
Budnitz D et al. N Engl J Med 2011;365:2002–12

8. Budnitz D et al. N Engl J Med 2011;365:2002–12
HAZARDS OF WARFARIN
Budnitz D et al. N Engl J Med 2011;365:2002–12

9. Efficacy and Safety Data for Target-Specific Oral Anticoagulants

10. RE-LY: Time to First Stroke/SEE
RR 0.91
(95% CI: 0.74–1.11)
p<0.001 (noninferiority)
p= (superiority)
0.05
0.04
RRR
34%
1.69%
Warfarin
Dabigatran etexilate 110 mg
Dabigatran etexilate 150 mg
0.03
Cumulative hazard rates
1.53%
0.02
RR 0.66
(95% CI: 0.53–0.82)
p<0.001 (superiority)
1.11%
0.01
0.0
0.5
1.0
1.5
2.0
2.5
Years
Connolly SJ et al. N Engl J Med 2009; 361:1139–51

11. RE-LY Primary Efficacy Outcome Stroke and non-CNS Embolism
Connolly SJ., et al. NEJM Aug 30th DOI /NEJMoa

12. Hemorrhagic stroke 50 45 40 30 20 14 10 12 D110 mg BID D150 mg BID
RR 0.31 (95% CI: 0.17–0.56)
p<0.001 (sup)
RR 0.26 (95% CI: 0.14–0.49)
p<0.001 (sup) 50
Number of events 45 40
0.38%
RRR
69%
RRR
74% 30 20
Both dosages of dabigatran etexilate significantly reduced the incidence of hemorrhagic stroke (one element of the primary efficacy endpoint including stroke and systemic embolism) compared to warfarin: The relative risk reduction (RRR) for dabigatran etexilate 110mg BID compared to warfarin was 69%, RRR for dabigatran etexilate 150mg was 74%. 14 10 12
0.12%
0.10%
D110 mg BID
D150 mg BID
Warfarin
6,015
6,076
6,022
Connolly SJ., et al. NEJM published online on Aug 30th DOI /NEJMoa

13. Dabigatran Etexilate vs Warfarin (RE-LY)
October 19, 2010
FDA Approves Pradaxa to Reduce the Risk of Stroke in Patients with Non-Valvular Atrial Fibrillation
PRADAXA 150 mg BID-higher rate of major (GI) bleeds and any GI bleeds compared to warfarin.
In patients ≥75 years of age, the risk of major bleeding may be greater with PRADAXA than with warfarin.

14. ROCKET-AF Primary Efficacy Outcome Stroke and non-CNS Embolism
Rivaroxaban
Warfarin
Event Rate
HR (95% CI)
P-value
On Treatment
N= 14,143
1.70
2.15
0.79 (0.65,0.95)
0.015
ITT
N= 14,171
2.12
2.42
0.88 (0.74,1.03)
0.117
Rivaroxaban
better
Warfarin better
Event Rates are per 100 Patient-years
Based on Safety on Treatment or Intention-to-Treat thru Site Notification Populations
Patel et al. NEJM 2011;365:883-91

15. Key Secondary Efficacy Outcomes
Rivaroxaban
Warfarin
Event Rate
HR (95% CI)
P-value
Vascular Death, Stroke, Embolism
3.11
3.63
0.86 (0.74, 0.99)
0.034
Stroke Type Hemorrhagic Ischemic Unknown Type
0.59 (0.37, 0.93) 0.94 (0.75, 1.17) 0.65 (0.25, 1.67)
Non-CNS Embolism
0.04
0.19
0.23 (0.09, 0.61)
0.003
Myocardial Infarction
0.91
1.12
0.81 (0.63, 1.06)
0.121
All Cause Mortality Vascular Non-vascular Unknown Cause
0.85 (0.70, 1.02) 0.89 (0.73, 1.10) 0.63 (0.36, 1.08) 0.75 (0.40, 1.41)
Patel et al. NEJM 2011;365:883-91

16. Safety Outcomes Rivaroxaban
Warfarin
Event Rate or N (Rate)
HR (95% CI)
P-value
Major
>2 g/dL Hgb drop
Transfusion (> 2 units)
Critical organ bleeding
Bleeding causing death
3.60
2.77
1.65
0.82
0.24
3.45
2.26
1.32
1.18
0.48
1.04 (0.90, 1.20)
1.22 (1.03, 1.44)
1.25 (1.01, 1.55)
0.69 (0.53, 0.91)
0.50 (0.31, 0.79)
0.576
0.019
0.044
0.007
0.003
Intracranial Hemorrhage
55 (0.49)
84 (0.74)
0.67 (0.47, 0.94)
Intraparenchymal
37 (0.33)
56 (0.49)
0.67 (0.44, 1.02)
0.060
Intraventricular
2 (0.02)
4 (0.04)
Subdural
14 (0.13)
27 (0.27)
0.53 (0.28, 1.00)
0.051
Subarachnoid
1 (0.01)
Event Rates are per 100 patient-years Based on Safety on Treatment Population

17. Primary Outcome Stroke (ischemic or hemorrhagic) or systemic embolism
P (non-inferiority)<0.001
21% RRR
Apixaban 212 patients, 1.27% per year
Warfarin patients, 1.60% per year
HR 0.79 (95% CI, 0.66–0.95); P (superiority)=0.011
No. at Risk
Apixaban
Warfarin
Granger C et al. NEJM 2011;365:981–92

18. Efficacy Outcomes Outcome Apixaban (N=9120) Warfarin (N=9081)
HR (95% CI)
P Value
Event Rate
(%/yr)
Stroke or systemic embolism*
1.27
1.60
0.79 (0.66, 0.95)
0.011
Stroke
1.19
1.51
0.79 (0.65, 0.95)
0.012
Ischemic or uncertain
0.97
1.05
0.92 (0.74, 1.13)
0.42
Hemorrhagic
0.24
0.47
0.51 (0.35, 0.75)
<0.001
Systemic embolism (SE)
0.09
0.10
0.87 (0.44, 1.75)
0.70
All-cause death*
3.52
3.94
0.89 (0.80, 0.998)
0.047
Stroke, SE, or all-cause death
4.49
5.04
0.89 (0.81, 0.98)
0.019
Myocardial infarction
0.53
0.61
0.88 (0.66, 1.17)
0.37
* Part of sequential testing sequence preserving the overall type I error
Granger C et al. NEJM 2011;365:981–92

19. Bleeding Outcomes Outcome Apixaban (N=9088) Warfarin (N=9052)
HR (95% CI)
P Value
Event Rate
(%/yr)
Primary safety outcome: ISTH major bleeding*
2.13
3.09
0.69 (0.60, 0.80)
<0.001
Intracranial
0.33
0.80
0.42 (0.30, 0.58)
Gastrointestinal
0.76
0.86
0.89 (0.70, 1.15)
0.37
Major or clinically relevant non-major bleeding
4.07
6.01
0.68 (0.61, 0.75)
GUSTO severe bleeding
0.52
1.13
0.46 (0.35, 0.60)
TIMI major bleeding
0.96
1.69
0.57 (0.46, 0.70)
Any bleeding
18.1
25.8
0.71 (0.68, 0.75)
* Part of sequential testing sequence preserving the overall type I error

20. You JJ et al. Chest 2012;141(2 Suppl):e531S-75S. PMID: 22315271
ACCP Recommendations for Stroke Prevention Therapy
CHADS 2 score = 0 No therapy rather than antithrombotic therapy (Grade 2B) CHADS 2 score = 1 Oral anticoagulation rather than no therapy or antiplatelet therapy
(Grade 1B) CHADS 2 score = 2 Oral anticoagulation rather than no therapy or other therapies (Grade 1A) For recommendations in favor of oral AC, we
suggest dabigatran 150 mg twice daily rather than VKA therapy (Grade 2B)
You JJ et al. Chest 2012;141(2 Suppl):e531S-75S. PMID:

21. ESC 2012 UPDATE GUIDELINES For ATRIAL FIBRILLATION
Camm J et al. Eur Heart J 2012;33:2719–47

22. 2011 ACCF/AHA/HRS Focused Update
Dabigatran is useful as an alternative to warfarin for the
prevention of stroke in patients with AF.
Selection of patients with AF and ≥1 risk factor for stroke who could
benefit from treatment with dabigatran as opposed to warfarin should
consider individual clinical features, including the ability to comply with twice-daily dosing, availability of an anticoagulation management program, patient preferences, cost, and other factors
Because of the twice-daily dosing and greater risk of non-hemorrhagic side effects with dabigatran, patients already taking warfarin with excellent INR control may have little to gain by switching to dabigatran.
Wann LS et al. Heart Rhythm 2011;8:e1–e8

23. Hylek, EM. J Cardiovasc Med 2009;10:605-09

24. Effect of TTR on Primary Endpoints
In RELY
0.54
0.59
0.91
1.21
Wallentin, et al. Lancet 2010 24 24

25. 10% increase in center algorithm-consistent warfarin dosing predicted a 6.12% increase in TTR (95% CI %), and an 8% decrease in rate of the composite
clinical outcome (HR 0.92, 95% CI ).

26. Translating the Results of Clinical Trials into Clinical Practice
Patient selection
Therapeutic implementation      
Environment of the healthcare delivery system    
Nallamothu, et al. Circulation 2008;118:1294–303

27. Will we be able to translate trial results to real-world practice?
Revised Guidelines for the Management of Patients with Atrial Fibrillation were published in August 2006.

28. New Oral Anticoagulants: Summary
Property
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
Route of admin
Oral
Target
Thrombin
FXa
Dosing
Twice daily
Once daily
Monitoring required No
Half-life (hrs)
12–17
9–12
8–15
8–11
Mode of elimination
Renal 80%
Renal ~36%
Renal ~25%
Renal ~35%

29. Definitions: Chronic Kidney Disease and Renal Insufficiency
Kidney Disease Outcomes Quality Initiative (KDOQI) of the National Kidney Foundation
I MILD I MOD I SEVERE I
Renal Insufficiency Classification
Slide courtesy of C Cove

30. Randomized Trial Age Baseline CrCl Exclusion CrCl ARISTOTLE ROCKET AF
Apixaban 5 mg bid 70
83% ≥50
<25 ml/min
Warfarin
ROCKET AF
Rivaroxaban 20 mg qd 73
67 (median)
< 30 ml/min
RE-LY
Dabigatran 150 mg bid 72
68 (median)
<30 ml/min
69 (median)

31. Pharmacokinetics with Varying Levels of Renal Dysfunction
Apixaban
Dabigatran
Rivaroxaban
Elimination half life with
CrCl >80 ml/min
7.6 hr
13.8 hr
8.3 hr
CrCl 50–79 ml/min
7.3 hr
16.6 hr
8.7 hr
CrCl 30–49 ml/min
17.6 hr
18.7 hr
9.0 hr
CrCl <30 ml/min
17.3 hr
27.5 hr
9.5 hr
Am J Hematol. 2012 May;87 Suppl 1:S doi: /ajh Epub 2012 Apr 4.
Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors.
Kaatz S, Kouides PA, Garcia DA, Spyropolous AC, Crowther M, Douketis JD, Chan AK, James A, Moll S, Ortel TL, Van Cott EM, Ansell J.
Source
Department of Medicine, Henry Ford Hospital, Detroit, Michigan 48202, USA.
Abstract
The new oral anticoagulants dabigatran, rivaroxaban and apixaban have advantages over warfarin which include no need for laboratory monitoring, less drug-drug interactions and less food-drug interactions. However, there is no established antidote for patients who are bleeding or require emergent surgery and there is a paucity of evidence to guide the clinical care during these situations. Members of thrombosis and anticoagulation groups participating in the Thrombosis and Hemostasis Summit of North America formulated expert opinion guidance for reversing the anticoagulant effect of the new oral anticoagulants and suggest: routine supportive care, activated charcoal if drug ingestion was within a couple of hours, and hemodialysis if feasible for dabigatran. Also, the pros and cons of the possible use of four factor prothrombin complex concentrate are discussed.
Copyright © 2012 Wiley Periodicals, Inc.
PMID: 
Kaatz S et al. Am J Hematol 2012 Suppl 1:S PMID:

32. JANUARY 2012 UPDATE DABIGATRAN PACKAGE INSERT
Periodically assess renal function as clinically indicated (i.e., more frequently in clinical situations that may be associated with a decline in renal function) and adjust therapy accordingly.
Discontinue dabigatran in patients who develop acute renal failure and consider alternative therapy.
In patients with moderate renal impairment (CrCl 30–50 mL/min), concomitant use of the P-gp inhibitor dronedarone or systemic ketoconazole can be expected to produce drug exposure similar to that observed in severe renal impairment. Consider reducing the dose.

33. New Oral Anticoagulants: Summary
Property
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
Route of admin
Oral
Target
Thrombin
FXa
Dosing
Twice daily
Once daily
Monitoring required No
Half-life (hrs)
12–17
9–12
8–15
8–11
Mode of elimination
Renal 80%
Renal ~36%
Renal ~25%
Renal ~35%

34. Polypharmacy and Non-adherence
Strongest predictor of non-adherence is
the # of medications
Non-adherence rates estimated 25–50%
Intentional about 75% of the time
Changes in regimen made by patients to:
increase convenience
reduce adverse effects or
decrease refill expense

36. Recommended Structured Follow-up First month and subsequent 3 month intervals

37. Pradaxa (dabigatran etexilate mesylate): Drug Safety Communication – Safety Review of Post-Market Reports of Serious Bleeding Events UPDATED 11/02/ … bleeding rates associated with new use of Pradaxa do not appear to be higher than bleeding rates associated with new use of warfarin, which is consistent with observations from the large clinical trial used to approve Pradaxa (the RE-LY trial). FDA is continuing to evaluate multiple sources of data in the ongoing safety review of this issue.

38. HAS-BLED Bleeding Risk Score
Hypertension (SBP>160mmHg)
Abnormal renal/liver fxn (1 pt for each)
Stroke
Bleeding history or prone
Labile INR (if on warfarin)
Elderly (>65 years)
Drugs (ASA, NSAIDS)/alcohol
(1 pt for each)
Increasing score associated
with ISTH major bleeding
(C-index 0.72)
Based on 3978 patients in the EuroHeart Survey on AF with complete follow-up, all univariate bleeding risk factors in this cohort were used in a multivariate analyses along with ‘historic’ bleeding risk factors. A new bleeding risk score (acronym HAS-BLED: Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65), Drugs/alcohol concomitantly) was calculated, incorporating risk factors from the derivation cohort.Results: Fifty-three (1.5%) major bleeds occurred during 1-year follow-up. The annual bleeding rate rose with increasing risk factors. The predictive accuracy in the overall population using significant risk factors in the derivation cohort (c-statistic 0.72) was consistent when applied in several subgroups. Application of the new bleeding risk score (HAS-BLED) gave similar c-statistics except where patients were receiving antiplatelet agents alone or no antithrombotic therapy, with c-statistics of 0.91 and 0.85, respectively.
Pisters R et al. Chest 2010;138:1093–100

39. Optimizing Benefit and
Reducing Risk
Hemorrhage
Thrombosis
AF stroke associated with a 30-day mortality of 24%.

40. Swedish AF Cohort; Circulation 2011; 125: 2298-2307

41. Kirley K et al. Circ Cardiovasc Qual Outcomes 2012;5:615–21
Dabigatran visits,%
2010Q4
2011 Q1 Q2 Q3 Q4
Atrial fibrillation 92 72 75 71 63
Venous thromboembolism 4 8 3 5
Hypertensive heart disease 13 15 14
Coronary artery disease 9 6
CVA/TIA
Valvular disorders
Kirley K et al. Circ Cardiovasc Qual Outcomes 2012;5:615–21

42. Effective Use of TSOACs in Clinical Practice
1. Patient selection – ADHERENCE
Dose selection – creatinine clearance
Determine interval follow-up
Assess stability of renal function
Blood pressure control
Avoidance of concomitant antiplatelet therapy
Package insert – avoid potent drug interactions,
guidance on transitions

43. Procedural Management based on Bleeding Risk of Surgery
DABIGATRAN
APIXABAN/ RIVAROXABAN

44. Novel Anticoagulants Dabigatran 150 mg BID reduced ischemic stroke
Dabigatran 80% renal clearance
Dabigatran is associated with small risk of MI, but
reduced cardiovascular mortality
Dabigatran and rivaroxaban increase GI bleeding
Rivaroxaban is once per day and approved Rx for VTE
6. Apixaban reduced stroke, major hemorrhage, and mortality
7. Well-controlled warfarin is associated with low rate of adverse events

45. Gaps: Practical Considerations
Translation across indication
Atrial fibrillation and valvular heart disease
Atrial fibrillation and ACS
Atrial fibrillation and DVT or PE
Select situations in which monitoring would be desirable
Reversibility-trauma, urgent surgery, life-threatening hemorrhage

46. Guide to the Management of Bleeding in Patients Taking NOAC
Patients with bleeding on NOAC therapy
Mild bleeding
Moderate-Severe
bleeding
Life-threatening
bleeding
Delay next dose or discontinue treatment as appropriate
Mechanical compression
Surgical intervention
Fluid replacement and hemodynamic support
Blood product transfusion
Oral charcoal
Hemodialysis
? Prothrombin Complex Concentrate?
(Circulation 2011;124:1573-9)
Consideration of rFVIIa or PCC
Charcoal filtration
? Prothrombin Complex Concentrate
(Circulation 2011;124:1573-9)
Hankey GJ and Eikelboom JW. Circulation. 2011; 123:

47. WILL THERE BE A CONTINUING ROLE FOR WARFARIN?
1. Mechanical heart valves
Cost
Pregnancy
Severe renal impairment
Drug Interactions
Lack of acceptance of no monitoring
Reversal?
Nonadherence
9. Intolerant of novel anticoagulant drug 47

48. Novel anticoagulants may be safer in the elderly population due to their wider therapeutic index, shorter t1/2, lack of dietary interference, and fewer drug interactions.
Older individuals with AF are at the highest risk of stroke, the highest risk of hemorrhage, and the highest risk of stopping therapy.
Further research is needed to inform commonly encountered clinical situations to optimize the effectiveness of these novel agents in routine practice. . 48 48