1. Mind the Gap: AF and Evolving Strategies in Anticoagulation
Fred M. Kusumoto, MD, FACC
Mayo Clinic
Tracy Y. Wang, MD, MHS, FACC Duke Clinical Research Institute
Duke University Medical Center

2. Faculty Disclosures Fred M. Kusumoto, MD, FACC Nothing to disclose
Tracy Y. Wang, MD, FACC Consultant Fees/Honoraria: AstraZeneca; Medco Health Solutions
Research/Research Grants: Gilead; Canyon Pharmaceuticals; Daiichi Sankyo, Inc./Eli Lilly and Company; The Medicines Company

3. Acknowledgement
This activity is sponsored by Boehringer Ingelheim Pharmaceuticals, Inc. and Janssen Pharmaceuticals, Inc.

4. Course Objectives
Upon completion of this session, attendees should be able to:
Implement evidence-based anticoagulation regimens for atrial fibrillation patients based on individual risks and patients’ preferences
Recognize common barriers associated with managing chronic anticoagulation in atrial fibrillation patients

5. The Anticoagulation Initiative
A multidisciplinary effort to identify and address gaps in the quality of anticoagulation care
Purpose is to facilitate a greater understanding of AF treatments and practice patterns, particularly with the introduction of several new anticoagulants into the marketplace
This initiative is building on existing resources (i.e., the AFib Toolkit) and creating new resources (i.e., anticoagulation mobile app)

6. AnticoagEvaluator: An ACC Risk Assessment Tool
Tool for estimating risk of stroke and benefits and risks of antithrombotic therapy in patients with chronic atrial fibrillation
Combination risk calculator using CHADS2, CHA2DS2-VASc and HAS-BLED
Enter patient characteristics and get individualized annual risk of ischemic stroke and thromboembolism with concurrent annual risk of major bleed

7. AnticoagEvaluator: An ACC Risk Assessment Tool
Output presents antithrombotic therapy options including novel oral anticoagulants based on clinical trials (RE-LY, ROCKET-AF, ARISTOTLE)
individual patient results after completing risk calculator tool
Based on the SPARCtool (

8. AnticoagEvaluator: Calculators
Enter patient characteristics into single screen to calculate risk of stroke and major bleed:

9. AnticoagEvaluator: Results Screen
Review risk assessment for each antithrombotic therapy option based on individual patient characteristics entered:

10. Instructions to Download
Search “AnticoagEvaluator” in your app store or visit
Available on iPad, iPhone and Android devices

11. The Anticoagulation Initiative: Coming Soon
Anticoagulation Management Clinical Community
Will feature relevant news articles, case challenges, hot topics, basics of anticoagulation, videos, interactive discussion, and more
Launch in July 2013

12. The Anticoagulation Initiative: Coming Soon
Atrial Fibrillation Shared Decision Making Tool
Patient-centered decision aid being developed in partnership with the Informed Medical Decisions Foundation
Launching in Fall 2013
Visit for more information

13. Question 1
How many patients with atrial fibrillation do you typically see each week?
Fewer than 5
5-10
10-20
More than 20
Question designed to point out the prevalence of the problem and for the speaker to gauge the knowledge base of audience.

14. Question 2
What anticoagulants/antiplatelet agents do you most frequently use to prevent thromboembolic complications?
Aspirin
Aspirin/clopidogrel
Clopidogrel alone
NOACs (novel oral anticoagulant)
Warfarin
Other
REVISED SLIDE AS PER DR. STROBEL’S 1/23
Assess familiarity of audience with various agents

15. Question 3
Over the last nine months, when appropriate for your atrial fibrillation patients, have you found yourself making any of the following changes?
Switching some patients’ medication to a newer agent
Switching most patients from existing medication to a newer agent
No change in prescribing pattern, current medication successful in treatment
No change in prescribing pattern, waiting for more data on newer agents
Assess comfort level of audience with newer agents

16. Question 4
What is the primary thing you might do differently in treating your AF patients?
Increase my utilization of long-term anticoagulation in my at- risk atrial fibrillation patients
Work to better assess the thromboembolic risk in my atrial fibrillation patients
Explain to my patients the pros and cons of different anticoagulation agents
Better communicate the risk of stroke to my atrial fibrillation patients and the importance of anticoagulation
Nothing – I feel my level of patient care is appropriate
Is there a treatment gap in care of AF patients?

17. Question 5 What might impede you most from making this change?
Time constraints
Low priority compared to other patient management issues
Difficulty in changing patient behavior
Difficulty in getting patients to accept the benefits of long-term anticoagulation
Cost of medication
Cost of monitoring (blood tests, dosage adjustments) for patients on anticoagulation
Lack of data on or experience with newer agents
No change necessary
Barriers to therapy

18. Question 6
A 72-year-old male with a history of persistent atrial fibrillation for the past five (5) years is currently being treated with warfarin anticoagulation and a beta blocker for rate control. He comes to you to ask about switching to a new anticoagulant drug that does not require INR monitoring.
This and next slide: assess knowledge base in audience. Can be revisited later to assess retention.

19. Question 6 (Cont.)
Given the following patient characteristics, in which setting would switching from warfarin to a Novel Oral Anticoagulant (NOAC) be appropriate and supported by clinical data?
Ejection fraction of 30% with Class II heart failure
Normal functioning mechanical MVR
LVH with EF 55%; chronic renal insufficiency with creatinine clearance 10 ml/min

20. Atrial Fibrillation (AF) in the U.S.
2.2 million people have AF
3.3 million in 2020; 5.6 million by 2050
Above age 70: 10% incidence
Lifetime risk: 25%
Risk increases with increasing age
Epidemiology of problem, stressing importance 20

21. Prevalence
Ann Int Med 1995
Benjamin EJ JAMA 1994; Framingham Heart Study

22. Atrial Fibrillation and Stroke
15% of ischemic strokes are due to cardioemboli => 75,000 events/year
45% of cardioemboli are due to atrial fibrillation
Risk of stroke 5-7x increased in patients with atrial fibrillation
1. Fuster V, et al. Circulation. 2006;114:e
2. Benjamin EJ, et al. Circulation. 1998;98:
3. Lloyd-Jones D, et al. Circulation. 2009;119:e

23. Atrial Fibrillation and Stroke (Cont.)
Risk of stroke increases with age1
Ischemic stroke associated with AF is often more severe than stroke of other etiologies4
Stroke risk persists even in asymptomatic AF5
Asymptomatic AF implicated as a cause of cryptogenic stroke6
4. Dulli DA, et al. Neuroepidemiology. 2003;22:118-23
5. Page RL, et al. Circulation. 2003;107:1141-5
6. Bhatt A, et al. Stroke Res Treat. 2011; 2011: 1-5

24. CHADS2 Congestive heart failure Hypertension Age >75 years
Diabetes mellitus
Prior Stroke or TIA (*2 points)
Is the putative risk high and how good is the data for factors not included?
A general schema for assessing stroke risk but should be modified as needed by clinical judgement
CHADS score did not include all risk factors
Of those other risk factors ( female gender, thyrotoxicosis, LA size, etc. ) How compelling is the data for each of them.
CHADS2 score may not tell the whole story in each patient and clinical judgment comes into play and may need to be emphasized.
Gage, BF, et al. JAMA. 2001;285:

25. *Expected rate of stroke per 100 patient-years
Stroke Risk in AF ACP/AAFP Guidelines
*Expected rate of stroke per 100 patient-years
Snow V, et al. Ann Intern Med. 2003;139:

26. CHA2DS2-VASc
A refinement of CHADS2

27. ESC Guidelines for Antithrombotic Therapy
Slide 21 & 81 EDITED SLIDE PER DR. STROBEL’S 1/23
Could give example of a 70 y.o. woman without other risk factors who by CHADS2 would get ASA but by CHA2DS2VAS2 would get warfarin.
Europace 2010; 12:
European Heart Journal (2012) 33, 2719–2747

28. Stroke Prevention: Coumadin
Warfarin
AFASAK
BAATAF
SPAF
CAFA
SPINAF
Warfarin/ASA
EAFT
SPAF II
Foundation of current treatment recs.

29. Warfarin: Risk-Benefit Profile
Fuster V, et al. Circulation. 2006;114:e

30. Warfarin and Drug Interactions
Warfarin is metabolized by the hepatic P450 enzyme CYP2C9
Warfarin concentration (and therefore INR) is increased by drugs that inhibit CYP2C9. INR must be closely followed and warfarin dosage decreased
CYP2C9 inhibitors include:
Amiodarone
Statins simvastatin and rosuvastatin (not atorvastatin, pravastatin)
Fibrates (fenofibrate, gemfibrozil)
Antibiotics (sulfamethoxazole/trimethoprim, metronidazole)
Azole antifungals (fluconazole, miconazole, voriconazole)
Might also mention dietary factors.

31. Quality of Warfarin Control in AF Patients on Chronic Anticoagulation
Our meta-analysis assessed 8 studies including a total of 14 groups involving 22,237 warfarin-treated AF patients with 41,199 years of follow-up. Atrial fibrillation patients in the 14 groups spent 55% (95% CI = 51%-58%) of their time within the therapeutic INR range.
Of the 8 studies, 13 groups could be evaluated by setting: warfarin dosing was managed by anticoagulation clinics for 4 (31%) groups and by community (physician) practice, defined as usual care, for 9 (69%). Patients in anticoagulation clinics spent on average 63% (95% CI = 58%-68%) of their time in the therapeutic range versus 51% (95% CI = 47%-55%) for patients in community practice. Compared with an anticoagulation clinic, patients treated in the usual care (community) setting spent 11% (95% CI = 2%-20%, n = 6 studies) less time in therapeutic INR range.
Only 48% of eligible patients in this analysis received warfarin
Baker WL, et al. J Manag Care Pharm. 2009;15: 31

32. Time Spent in Therapeutic INR Range and Clinical Outcomes
Morgan CL, et al. Thromb Res. 2009;124:37-41.

33. Warfarin and Novel Anticoagulant Mechanisms of Action
Courtesy of David Garcia, MD
*This information includes a use that has not been approved by the U.S. FDA

34. Case 1 67-year-old Female with Dyspnea
USE SPARCTOOL APP FOR THIS CASE
Chronic paroxysmal AF patient managed by a primary care physician with a moderately-high bleeding risk. The patient is currently only on aspirin.

35. HPI
Shortness of breath and DOE for several months
Denies palpitations, chest pain or dizziness
PMH
Obesity, carotid artery disease s/p CEA, hyperlipidemia, DJD
Does not smoke or drink
Meds: diltiazem, celecoxib, pravastatin, aspirin

36. PE
VS: BP 134/72, HR 94
CV: irregularly irregular, no murmurs
Data
ECG: atrial fibrillation with controlled VR
BUN/Cr: 36/2.1, GFR 23 ml/min, other labs incl LFTs nl
CXR: mild cardiomegaly, o/w normal
Stress echo: nl LV function, mild LVH, no sig valve dz, no ischemia

37. Question What is her risk of stroke? High (~8-18%) Medium (~4-6%)
Low (~2-3%)

38. *Expected rate of stroke per 100 patient-years
Stroke Risk in AF ACP/AAFP Guidelines
*Expected rate of stroke per 100 patient-years
Snow V, et al. Ann Intern Med. 2003;139:

39. CHA2DS2-VASc

40. ESC Guidelines for Antithrombotic Therapy
Slide 21 & 81 - PER DR. STROBEL’S , REPLACED OLD SLIDE WITH THIS UPDATED SLIDE
changed the slide and the reference to reflect the new recommendations from the ESC.
Could give example of a 70 y.o. woman without other risk factors who by CHADS2 would get ASA but by CHA2DS2VAS2 would get warfarin.
Europace 2010; 12:
European Heart Journal (2012) 33, 2719–2747

41. Question What is her risk of bleeding with anticoagulation? High
Medium
Low

42. HAS-BLED Score
Clinically tied to CHADS-VASC, but not exernally validated.
HAS-BLED score ≥3 indicates increased one year risk of intracranial bleed, bleed requiring hospitalization, or drop in hemoglobin ≥2gm/L or requiring transfusion.

43. Impact of the CHA2DS2-VASc Score on
Anticoagulation Recommendations for Atrial Fibrillation
Pamela K. Mason, MD, Douglas E. Lake, PhD, John P. DiMarco, MD, PhD, John D. Ferguson, MBChB, MD, J. Michael Mangrum, MD, Kenneth Bilchick, MD, Liza P. Moorman, RN, ACNP-BC, J. Randall Moorman, MD University of Virginia Health System, Charlottesville.
Figure 2 Anticoagulation recommendations by CHADS2 and CHA2-DS2-VASc scores in women (A) and men (B).
The American Journal of Medicine , 603.e4

44. What is her risk of stroke/bleeding?
Question
What is her risk of stroke/bleeding?
CHADS2 score = 0 (annual stroke risk = 1.9%)
CHA2DS2VASc = 3 (annual stroke risk = 3.2%)
HASBLED score = 3 (annual bleeding risk = 5.6%)

45. Question Which anticoagulation regimen is most appropriate for her?
Aspirin
Warfarin
NOAC
Aspirin/clopidogrel

46. Which Anticoagulation Regimen Is Most Appropriate for Her?

47. Which Anticoagulation Regimen to Use?

48. Which Anticoagulation Regimen to Use?

49. Case 1 Teaching Points
When using oral anticoagulants, balancing the risks of bleeding vs. the risks of stroke can be difficult
Scoring systems that predict risk (CHADS2, CHA2DS2-VASc, HAS-BLED) can help with decision making

50. Practice Innovation and Clinical Excellence (PINNACLE) Registry
9,113 patients from 20 practices in 51 office locations
Mean CHADS2 score: 2.5 (moderate-to-high risk)
All eligible for warfarin
ADDED FROM TEAM A SLIDE DECK AS PER DR. DOHERTY’S 1/28
PINNACLE: Office-based cardiac quality improvement registry
Note that national guidelines call for anticoagulation with anticoagulation beyond aspirin for patients with moderate-to-high risk of stroke
Chan PS, et al. Am J Cardiol. 2011;108:

51. PINNACLE Results
55.1% treated with warfarin regardless of CHADS2 score
44.9% not treated with warfarin:
50.8% treated with aspirin only
4.4% treated with thienopyridine alone
10.1% treated with aspirin and thienopyridine
34.7% received no antithrombotic treatment
ADDED FROM TEAM A SLIDE DECK AS PER DR. DOHERTY’S 1/28
Chan PS, et al. Am J Cardiol. 2011;108:

52. PINNACLE: Percent of Patients on Warfarin (Practice Level)
ADDED FROM TEAM A SLIDE DECK AS PER DR. DOHERTY’S 1/28
Key Points: Median practice rate for warfarin treatment: 61%
Significant variation, ranging from 25% to 80%
Chan PS, et al. Am J Cardiol. 2011;108:

53. PINNACLE Coverage by Zip Code
US Population Density
Records from 1,000+ physicians at 280+ sites

54. Overall representation
Florida practice performance varies with national averages
7,618 patients with non-valvular AF documented in most recently available 12 months
53.8% performance on anticoagulation for afib patients (compared with 49.5% nationally)
Overall representation
8 data-submitting practices
17 clinical care locations
69 providers
Record type

55. Questions and Answers

56. ACTIVE-W: Warfarin vs. Dual Antiplatelet Therapy
for Prevention of Cardiovascular Events
Cumulative risk of primary composite endpointa
aStroke, MI, non-CNS systemic embolism or vascular death
ACTIVE Investigators. Lancet.
2006;367:

57. ACTIVE-A: Dual Antiplatelet Therapy Reduces the Incidence of Vascular Events in AF When Warfarin Therapy Is “Unsuitable”
aStroke, I, non-CNS systemic embolism or vascular death
ACTIVE Investigators. N Engl J Med. 2009;360:

58. ACTIVE-A: Dual Antiplatelet Therapy Increases the Risk of Bleeding

59. 2011 Focused Update Recommendation
Class IIb (New Recommendation)
The addition of clopidogrel to aspirin (ASA) to reduce the risk of major vascular events, including stroke, might be considered in patients with AF in whom oral anticoagulation with warfarin is considered unsuitable due to patient preference or the physician’s assessment of the patient’s ability to safely sustain anticoagulation. (Level of Evidence: B)
Single reference: ACTIVE-A
2011 ACCF/AHA/HRS Focused Update on the Management of Patients with Atrial Fibrillation (Updating the 2006 Guideline). Circulation 2011;123:

60. New Pharmacologic Approaches for Stroke Reduction in AF
Oral direct thrombin inhibitors
Fixed-dose, no monitoring
Dabigatran
Oral factor Xa inhibitors
Apixaban
Rivaroxaban
(Edoxaban)
Dabigatran, a long-acting oral direct thrombin inhibitor that requires no monitoring, The oral factor Xa inhibitors, apixaban and rivaroxaban, can also be administered as a fixed-dose with no monitoring required. 60

61. RE-LY: Randomized Evaluation of Long-Term Anticoagulation Therapy
18,113 patients with atrial fibrillation randomized to dabigatran (110 mg or 150 mg twice daily) versus warfarin (INR target )
Mean CHADS2 score = 2.1
By intention-to-treat analysis dabigatran 110 mg was non- inferior (p < 0.001) while dabigatran 150 mg was superior (p <0.001) to warfarin
INR was in the therapeutic range 64% of the time
NEJM

62. RE-LY AF Patients with at least one of: Prior CVA or TIA
LVEF < 40%;
NYHA Class I or greater CHF
Age >75 yrs
Age and on of: DM
HTN
CAD
Exclusions: “severe valve disease;” CVA <14 days or “severe CVA” <6 months; increased bleeding risk; active liver disease; CrCl <30; pregnancy

63. Cumulative Hazard Rate
RE-LY: Dabigatran Reduces the Risk of Stroke in AF Patients
Cumulative Hazard Rate
Time (months)
Connolly SJ, et al. N Engl J Med. 2009;361:

64. RE-LY: Safety Outcomes with Dabigatran
Modified from Connolly SJ, et al. N Engl J Med. 2009;361:

65. FDA Approval for Dabigatran:
Dabigatran 150 was superior to warfarin and dabigatran 110 mg for stroke prevention
Dabigatran 150 mg was similar to warfarin for bleeding risk but inferior to dabigatran 110 mg
Among the elderly (40% of RE-LY patients over age 75), thromboembolism risk was lower with dabi-150 than with dabi-110, but bleeding risk was higher. Because bleeding is “less undesirable” than stroke, dabi-110 not felt to be advantageous
Discuss QOL issues re. warfarin vs. dabigatran
Beasley BN, Unger EF, Temple R. Anticoagulant Options –
Why the FDA Approved a Higher but Not a Lower Dose of Dabigatran. NEJM 2011 (online first).

66. FDA Approval for Dabigatran: 75 mg q12h
Among pts with impaired renal function (CrCl 30-50), stroke risk for dabi-150 was 1/2 that of dabi-110 but bleeding risk was not higher
==> dabi-110 was not felt to offer any advantage, and it was felt that most patients should receive the higher dosage
The decision to approve the 75 mg q12h dose was based on pharmacokinetic and pharmacodynamic modeling; there is no safety or efficacy data
Beasley BN, Unger EF, Temple R. Anticoagulant Options –
Why the FDA Approved a Higher but Not a Lower Dose of Dabigatran. NEJM 2011 (online first).

67. 2011 ACCF/AHA/HRS Focused Update
on the Management of Patients with Atrial Fibrillation (Update on Dabigatran)
Emphasize contraindication for prosthetic valves and renal and liver failure

68. ROCKET-AF: Rivaroxaban for the Prevention of Stroke and Non-CNS Embolism
14,264 patients with atrial fibrillation randomized to rivaroxaban (20mg once daily) versus warfarin (INR target 2.5)
Mean CHADS2 score = 3.5
By intention-to-treat analysis rivaroxaban was non-inferior (p < ) but not superior (p = 0.12) to warfarin
Once daily dosing with half-life 5-13 hours and no monitoring
Clearance: 1/3 renal, 2/3 by P450 enzymes
Could point out the non-inferiority vs. superiority issue. Rivaroxaban was non-inferior by intention-to-treat and per protocol analysis. By per protocol without protocol violations it was superior. Intention-to-treat considered gold standard and therefore non-inferior.
Factor Xa inhibition
Do NOT discuss using these agents during the cases as they would not be applicable and would be off label!!
NEJM

69. Cumulative Rates of the Primary End Point
(Stroke or Systemic Embolism) in the Intention-to-Treat Population

70. ROCKET-AF: Rivaroxaban for the Prevention of Stroke and Non-CNS Embolism
INR was in the therapeutic range only 55 percent of the time
Approved by FDA
Safety: overall similar bleeding rates with less life- threatening (fatal or intracranial) hemorrhage

71. ARISTOTLE Phase III randomized, double-blind trial
Apixaban 5 mg bid vs warfarin for stroke prevention in 18,201 patients with AF and at least 1 additional risk factor for stroke
Randomized to apixaban 5 mg bid (n = 9120) or warfarin (target INR ) (n = 9081)
Primary efficacy outcome – stroke or systemic embolism
Primary safety outcome – major bleeding
Granger CB et al. N Engl J Med 2011 Aug 27. [Epub ahead of print]
ARISTOTLE = Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation
The key secondary efficacy outcome was death from any cause.
The rate of myocardial infarction was also assessed as a secondary efficacy outcome.
ARISTOTLE tested for noninferiority of study; key secondary objectives of testing for superiority with respect to the primary outcome and to the rates of major bleeding and death from any cause.
Granger CB et al. N Engl J Med 2011 Aug 27. [Epub ahead of print]

72. Primary Outcome Stroke (ischemic or hemorrhagic) or systemic embolism
No. at Risk
Apixaban
Warfarin
Granger CB et al. N Engl J Me 2011 Aug 27. [Epub ahead of print]
Duke Clinical Research Institute and Uppsala Clinical Research Center

73. Efficacy Outcomes
* Part of sequential testing sequence preserving the overall type I error
Granger CB et al. N Engl J Med 2011 Aug 27. [Epub ahead of print]
Duke Clinical Research Institute and Uppsala Clinical Research Center

74. Major Bleeding ISTH definition
No. at Risk
Apixaban
Warfarin
Granger CB et al. N Engl J Med 2011 Aug 27. [Epub ahead of print]
Duke Clinical Research Institute and Uppsala Clinical Research Center

75. Bleeding Outcomes
* Part of sequential testing sequence preserving the overall type I error
Granger CB et al. N Engl J Med 2011 Aug 27. [Epub ahead of print]
Duke Clinical Research Institute and Uppsala Clinical Research Center

76. Conclusions
Treatment with apixaban as compared to warfarin in patients with AF and at least one additional risk factor for stroke:
Reduces stroke and systemic embolism by 21% (p=0.01)
Reduces major bleeding by 31% (p<0.001)
Reduces mortality by 11% (p=0.047)
with consistent effects across all major subgroups and with fewer study drug discontinuations on apixaban than on warfarin, consistent with good tolerability.
Granger CB et al. N Engl J Med 2011 Aug 27. [Epub ahead of print]
Duke Clinical Research Institute and Uppsala Clinical Research Center

77. Summary of Clinical Trials
Note – this slide should be interpreted with caution. Different patients with different trials.
Intracranial bleeding is lower across the board.

78. New Anticoagulant Therapies Compared to Warfarin Stroke or Systemic Embolism
Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger CB et al NEJM 2011

79. New Anticoagulant Therapies Compared to Warfarin Major Bleeding
Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger CB et al NEJM 2011

80. New Anticoagulant Therapies Compared to Warfarin Intracranial Hemorrhage
Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger CB et al NEJM 2011

81. Conclusion
Compared to warfarin, the novel oral anticoagulants are at least as good at preventing stroke, have half the rate of ICH, appear to have 10% lower mortality and are easier to use
But many practical issues are important in their safe use, including
Adjusting for renal dysfunction
Understanding how to measure their effect
Understanding how to manage procedures
Understanding how to manage bleeding
Avoiding aspirin without clear indication
Having protocols in place to guide rationale use of the novel drugs is a high priority

82. European Society of Cardiology Recommendations
European Heart Journal 2012; 33: – doi: /eurheartj/ehs253

83. Case 2 80-year-old Male with Cholelithiasis
Bridging in afib patients Peri-operative management
Who do we bridge and how do we bridge? What INR do you go to? What’s an appropriate level of anticoagulation? What should be your target INR? What kinds of procedures need bridges? Bleeding complications?

84. HPI Cholelithiasis recently diagnosed Cholecystectomy is planned Surgeon requests peri-op cardiac management PMH Permanent atrial fibrillation for > 5 years, managed with metoprolol and dabigatran Meds: metoprolol, dabigatran, lisinopril, pravastatin

85. Physical Exam
VS: BP 134/68, HR 78 irreg irreg CV: irregularly irregular, no murmurs ECG: atrial fibrillation with controlled VR BUN/Cr – 34/1.2 (estimated creatinine clearance = 70)

86. What are the risks of thromboembolism if heparin is not administered?
Question
In preparation for surgery, you should:
Admit the patient to the hospital, stop dabigatran and administer IV heparin until the morning of surgery
Stop dabigatran 7 days prior to surgery and check INR on the morning of surgery
Stop dabigatran 2 days prior to surgery and check aPTT on the morning of surgery
Following discontinuation of warfarin, should the patient’s anticoagulation be bridged with heparin?
What are the risks of thromboembolism if heparin is not administered?
What are the risks of bleeding if heparin is administered?
Is it appropriate to use enoxaparin?
What if he were taking dabigatran instead?

87. Pharmacokinetics of Dabigatran
Disappearance curve of drug depends upon CrCl
When CrCl >80 ml/min drug effect mostly gone at 24 hours with 150 mg dose as reflected by PTT
When CrCl <30 ml/min drug effect about 50% at 48 hours at 75mg dose
Disappearance of drug can be followed by aPTT
Time for discontinuation depends upon nature of surgery
Can be dialysed with removal of 60% of drug in 2-3 hours
No specific antidote

88. Average Time Course for Effects of Dabigatran on Activated Partial Thromboplastin Time (aPTT), Following Dabigatran Dosing Regimens in Patients with Normal Renal Function and Various Degrees of Renal Impairment
Average time course for effects of dabigatran on activated partial thromboplastin time (aPTT), following dabigatran dosing regimens in patients with normal renal function and various degrees of renal impairment.*6 *Simulations are based on pharmacokinetic (PK) data from a study in subjects with renal impairment and PK/aPTT relationships derived from the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) study; aPTT prolongation in RE-LY was measured centrally in citrate plasma using partial thromboplastin time (PTT) reagent (Roche Diagnostics GmbH, Mannheim, Germany). There may be quantitative differences between various established methods for aPTT assessment. Simulations are based on patients receiving dabigatran 150 mg twice daily if creatinine clearance is >30 mL/min and 75 mg twice daily if creatinine clearance is ≤30 mL/min. The horizontal dotted line represents the upper limit of normal. Data were extracted from the US product information file and reprinted with the permission of Boehringer Ingelheim.
Copyright American Heart Association
Weitz J I et al. Circulation 2012;126:

89. Proposed Algorithm for Periprocedural Management of Dabigatran
* In some countries, dabigatran is contraindicated in patients with CrCl <30 mL/min
Copyright © American Heart Association
Weitz J I et al. Circulation 2012;126:

90. Now let’s assume that the patient is taking warfarin instead of dabigatran…

91. What are the risks of thromboembolism if heparin is not administered?
Question
In preparation for surgery, you should:
Admit the patient to the hospital, stop warfarin and administer IV heparin until the morning of surgery
Stop warfarin 5 days prior to surgery and initiate LMWH until the morning of surgery
Stop warfarin 5 days prior to surgery without bridging anticoagulation
Following discontinuation of warfarin, should the patient’s anticoagulation be bridged with heparin?
What are the risks of thromboembolism if heparin is not administered?
What are the risks of bleeding if heparin is administered?
Is it appropriate to use enoxaparin?
What if he were taking dabigatran instead?

92. Risks Associated with Temporary Discontinuation of Warfarin
After warfarin is stopped, it takes about 4 days for the INR to reach 1.5
Once the INR is 1.5 surgery can be safely performed
Therefore, if warfarin is held 4 days before surgery and treatment is started as soon as possible after surgery, patients can be expected to have a subtherapeautic INR for two days before and two days after surgery

93. Outcomes of Temporary
Interruptions

94. Adverse Events Caused or Prevented by Intravenous Heparin
Kearon C, Hirsh J. N Engl J Med 1997;336:

95. ACC/AHA/ESC 2006 Guidelines for Perioperative Management of Atrial Fibrillation
Anticoagulation may be interrupted for a period of up to one week for surgery
In high risk patients (prior stroke, TIA or systemic embolism) unfractionated or low-molecular-weight heparin may be used

96. Case 2 Teaching Points Warfarin
Most patients, unless they have had prior stroke, TIA or systemic embolism do not require bridging of anticoagulation
Warfarin can be stopped for 5 days prior to surgery
Teaching points warfarin

97. Case 2 Teaching Points Dabigatran
With normal kidney function, omit 2-3 doses for low risk surgery and 4-5 doses for higher risk surgery
With GFR 30-50, omit for days (3-4 doses) for low risk surgery
With GFR 30-50, omit for 3-4 days (6-8 doses) for higher risk surgery
Teaching points dabigatran

98. Guide to the Management of Bleeding in Patients Taking NOAC
Hankey GJ and Eikelboom JW. Circulation. 2011; 123:

99. Rivaroxaban
Dabigatran
Circulation. 2011;124:

100. Questions and Answers

101. Question 6 - Post Test Question
A 72-year-old male with a history of persistent atrial fibrillation for the past five (5) years is currently being treated with warfarin anticoagulation and a beta blocker for rate control. He comes to you to ask about switching to a new anticoagulant drug that does not require INR monitoring.
This is a reiteration of question asked earlier. Following slides demonstrate concepts stressed in didactic portion of presentation.

102. Question 6 (Cont.)
Given the following patient characteristics, in which setting would switching from warfarin to dabigatran, rivaroxaban or apixaban be appropriate and supported by clinical data?
Ejection fraction of 30% with Class II heart failure
Normal functioning mechanical MVR
LVH with EF 55%; chronic renal insufficiency with creatinine clearance 10 ml/min

103. Rationale The RE-LY trial showed that:
dabigatran 150 mg BID was superior to warfarin in terms of embolic events
dabigatran 110 mg BID dose was superior to warfarin in terms of major bleeding
The Rocket-AF trial showed that:
rivaroxaban was non-inferior to warfarin by intention-to-treat and superior by on treatment analysis in preventing embolic events
bleeding risk was similar
ARISTOTLE showed that:
apixaban was superior to warfarin in preventing embolic events with a reduced bleeding risk

104. Rationale
ANSWER A: Ejection fraction of 30% with Class II heart failure is the correct answer
Patients in the three trials included those with a low ejection fraction and heart failure
Patients with a mechanical MVR were excluded and thus efficacy of novel anti-coagulants is not known in these patients
Patients with a creatinine clearance of 10 ml/min should not have these drugs since they are excreted by the kidney
Patients with liver dysfunction and an elevated prothrombin time should not be given these agents due to high risk of bleeding

105. Questions and Answers

106. Case 2 80-year-old Male with Cholelithiasis
Bridging in afib patients Peri-operative management
Who do we bridge and how do we bridge? What INR do you go to? What’s an appropriate level of anticoagulation? What should be your target INR? What kinds of procedures need bridges? Bleeding complications?

107. HPI Cholelithiasis recently diagnosed Cholecystectomy is planned Surgeon requests peri-op cardiac management PMH Permanent atrial fibrillation for > 5 years, managed with metoprolol and dabigatran Meds: metoprolol, dabigatran, lisinopril, pravastatin

108. Physical Exam
VS: BP 134/68, HR 78 irreg irreg CV: irregularly irregular, no murmurs ECG: atrial fibrillation with controlled VR BUN/Cr – 34/1.2 (estimated creatinine clearance = 70)

109. What are the risks of thromboembolism if heparin is not administered?
Question
In preparation for surgery, you should:
Admit the patient to the hospital, stop dabigatran and administer IV heparin until the morning of surgery
Stop dabigatran 7 days prior to surgery and check INR on the morning of surgery
Stop dabigatran 2 days prior to surgery and check aPTT on the morning of surgery
Following discontinuation of warfarin, should the patient’s anticoagulation be bridged with heparin?
What are the risks of thromboembolism if heparin is not administered?
What are the risks of bleeding if heparin is administered?
Is it appropriate to use enoxaparin?
What if he were taking dabigatran instead?

110. Pharmacokinetics of Dabigatran
Disappearance curve of drug depends upon CrCl
When CrCl >80 ml/min drug effect mostly gone at 24 hours with 150 mg dose as reflected by PTT
When CrCl <30 ml/min drug effect about 50% at 48 hours at 75mg dose
Disappearance of drug can be followed by aPTT
Time for discontinuation depends upon nature of surgery
Can be dialysed with removal of 60% of drug in 2-3 hours
No specific antidote

111. Average Time Course for Effects of Dabigatran on Activated Partial Thromboplastin Time (aPTT), Following Dabigatran Dosing Regimens in Patients with Normal Renal Function and Various Degrees of Renal Impairment
Average time course for effects of dabigatran on activated partial thromboplastin time (aPTT), following dabigatran dosing regimens in patients with normal renal function and various degrees of renal impairment.*6 *Simulations are based on pharmacokinetic (PK) data from a study in subjects with renal impairment and PK/aPTT relationships derived from the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) study; aPTT prolongation in RE-LY was measured centrally in citrate plasma using partial thromboplastin time (PTT) reagent (Roche Diagnostics GmbH, Mannheim, Germany). There may be quantitative differences between various established methods for aPTT assessment. Simulations are based on patients receiving dabigatran 150 mg twice daily if creatinine clearance is >30 mL/min and 75 mg twice daily if creatinine clearance is ≤30 mL/min. The horizontal dotted line represents the upper limit of normal. Data were extracted from the US product information file and reprinted with the permission of Boehringer Ingelheim.
Copyright American Heart Association
Weitz J I et al. Circulation 2012;126:

112. Proposed Algorithm for Periprocedural Management of Dabigatran
* In some countries, dabigatran is contraindicated in patients with CrCl <30 mL/min
Copyright © American Heart Association
Weitz J I et al. Circulation 2012;126:

113. Bridging Algorithm for New Oral Anticoagulants
Should we delete this slide? The recommendations conflict with those from the Weitz article.
Copyright © American Heart Association
Gallego P et al. Circulation 2012;126:

114. Now let’s assume that the patient is taking warfarin instead of dabigatran…

115. What are the risks of thromboembolism if heparin is not administered?
Question
In preparation for surgery, you should:
Admit the patient to the hospital, stop warfarin and administer IV heparin until the morning of surgery
Stop warfarin 5 days prior to surgery and initiate LMWH until the morning of surgery
Stop warfarin 5 days prior to surgery without bridging anticoagulation
Following discontinuation of warfarin, should the patient’s anticoagulation be bridged with heparin?
What are the risks of thromboembolism if heparin is not administered?
What are the risks of bleeding if heparin is administered?
Is it appropriate to use enoxaparin?
What if he were taking dabigatran instead?

116. Risks Associated with Temporary Discontinuation of Warfarin
After warfarin is stopped, it takes about 4 days for the INR to reach 1.5
Once the INR is 1.5 surgery can be safely performed
Therefore, if warfarin is held 4 days before surgery and treatment is started as soon as possible after surgery, patients can be expected to have a subtherapeautic INR for two days before and two days after surgery

117. Outcomes of Temporary
Interruptions

118. Adverse Events Caused or Prevented by Intravenous Heparin
Kearon C, Hirsh J. N Engl J Med 1997;336:

119. ACC/AHA/ESC 2006 Guidelines for Perioperative Management of Atrial Fibrillation
Anticoagulation may be interrupted for a period of up to one week for surgery
In high risk patients (prior stroke, TIA or systemic embolism) unfractionated or low-molecular-weight heparin may be used

120. ACCP 8th Edition Evidence-Based Clinical Practice Guidelines: Managing Non-Therapeutic INRs
For patients with INRs of ≥ 5.0 but < 9.0 and no significant bleeding:
Omit the next one or two doses of warfarin
Monitor more frequently
Resume therapy at an appropriately adjusted dose when the INR is at a therapeutic level (Grade 1C)
Alternatively, omit a dose and administer 1 to 2.5 mg oral vitamin K, particularly if the patient is at increased risk of bleeding (Grade 2A)
Barriers to anticoagulation – difficulty maintaining therapeutic inr (too low or too high)
Ansell J, et al. Chest. 2008;133:160S-98S.

121. Bridging Algorithm for Vitamin K Antagonists
Bridging algorithm for vitamin K antagonists and new oral anticoagulants. Adapted from Wysokinski et al.8 AF indicates atrial fibrillation; INR, International Normalized Ratio; LMWH, low-molecular-weight heparin; MHV, mechanic heart valve; OAC, oral anticoagulants; VKA, vitamin K antagonist; and VTE, venous thromboembolism.
Copyright © American Heart Association
Gallego P et al. Circulation 2012;126:

122. Case 2 Teaching Points Warfarin
Most patients, unless they have had prior stroke, TIA or systemic embolism do not require bridging of anticoagulation
Warfarin can be stopped for 5 days prior to surgery
Teaching points warfarin

123. Case 2 Teaching Points Dabigatran
With normal kidney function, omit 2-3 doses for low risk surgery and 4-5 doses for higher risk surgery
With GFR 30-50, omit for days (3-4 doses) for low risk surgery
With GFR 30-50, omit for 3-4 days (6-8 doses) for higher risk surgery
Teaching points dabigatran

124. Guide to the Management of Bleeding in Patients Taking NOAC
Hankey GJ and Eikelboom JW. Circulation. 2011; 123:

125. Rivaroxaban
Dabigatran
Circulation. 2011;124:

126. Proposed Algorithm for Management of Moderate-to-Severe Bleeding and Life-Threatening Bleeding Episodes in Patients Treated with Dabigatran
Proposed algorithm for management of moderate-to-severe bleeding and life-threatening bleeding episodes in patients treated with dabigatran. *Recommendations are based on limited nonclinical data only. PCC indicates prothrombin complex concentrates (nonactivated); rFVIIa, recombinant activated factor VII. Moderate-to-severe bleeding indicates a reduction in hemoglobin ≥2 gd/L, transfusion of ≥2 U of red cells, or symptomatic bleeding in critical area (ie, intraocular, intracranial, intraspinal, intramuscular with compartment syndrome, retroperitoneal, intraarticular, or pericardial bleeding). Life-threatening bleeding indicates symptomatic intracranial bleed, reduction in hemoglobin ≥5 gd/L, transfusion of ≥4 U of red cells, hypotension requiring inotropic agents, or bleeding requiring surgical intervention.
*Recommendations are based on limited nonclinical data only.
Weitz J I et al. Circulation 2012;126:

127. Questions and Answers

129. Case 3 55-year-old Man with Hypertension and NIDDM Who Presents with Palpitations
A recently ablated (8 months post-procedure) AF patient with no detected recurrence of arrhythmia. Pressing physician to discontinue warfarin since “being cured”.
Tie in with data of post pvi patients and asymptomatic patients.
Discussion on discontinuation of anticoagulants or patient’s belief they are “cured” and no longer need the anticoagulant - if a patient is at risk of stroke before procedure, he will still be at risk after and needs to continue anticoagulants.
There are a number of referrals for afib ablation to discontinue anticoagulants but ablation doesn’t equate to ending anticoagulants.
Review data from the EP community regarding patients that have been referred for ablation.

130. Noted to Have AF with Rapid Rate
Echo – mildly dilated LA
Mild LVH
Mild diastolic dysfunction
Patient cardioverted to NSR after TEE demonstrated no thrombus
Started on warfarin, switched from amlodipine to metoprolol for BP control and AF suppression

131. 3 Months Later, Patients with Rapid AF
Cardioverted and begun on Sotalol 80 mg q/12
Metoprolol stopped, Amlodipine restarted
One month f/u admitted with recurrent atrial fibrillation and in retrospect complains of severe fatigue
After weighing options, patient underwent Pulmonary Vein Isolation for atrial fibrillation
Remained on Sotalol for 2 months which was then stopped
He returns to your office and wishes to be taken off warfarin

132. Question What would you do?
Do a 24 hr Holter and if negative for atrial fibrillation stop warfarin
Do a 2 week ambulatory telemetry monitor and if negative stop warfarin
Urge him strongly to continue warfarin
Substitute newer agent
Rhythm control does not equal anticoagulation/stroke prevention

133. Rhythm Control ≠ Anticoagulation/Stroke Prevention
Bridging in afib patients Peri-operative management
Who do we bridge and how do we bridge? What INR do you go to? What’s an appropriate level of anticoagulation? What should be your target INR? What kinds of procedures need bridges? Bleeding complications?

134. Case 3 Teaching Points
Discontinuation of warfarin is potentially hazardous in such patients since they may be minimally symptomatic or asymptomatic and remain at risk of stroke

135. Questions and Answers

136. Case 4 55-year-old Woman with 3-year History of Atrial Fibrillation
An otherwise healthy, middle-aged chronic paroxysmal AF patient with well monitored and managed warfarin therapy.
AFFIRM Trial
Calculation of CHADS2 score for the case
Assuming too much about AF burden from short term moitoring
Patient lives 45 minutes from nearest Coumadin clinic, with attendant convenience issues.
Perhaps change this to not focus on a patient living 45 minutes from a Coumadin clinic but maybe on a patient that is non-compliant vs. one that is compliant but still faces issues
Compliant patient maybe has INRs all over the map.
Pull in studies where anticoagulation is poor.
Possibly discuss home monitoring devices

137. 3 Years Ago Presented with TIA Noted to Be in NSR
Echo – normal
Not hypertensive, diabetic, pft’s normal
Discharged with ambulatory cardiac telemetry device
Noted to have multiple episodes of asymptomatic atrial fibrillation up to 4 hours in duration
Atrial fibrillation burden 20% of monitoring period

138. a) Initiate a rhythm control drug b) Discharge on beta-blocker alone
Question
What would you do?
a) Initiate a rhythm control drug b) Discharge on beta-blocker alone

139. Question
Patient begun on beta-blocker, warfarin, no symptomatic episode, 24-hour Holter showed no atrial fibrillation What would you do? a) Stop anticoagulation b) Stop beta-blocker c) Continue regimen

140. Question
In reviewing INR’s – they vary widely and she complains that blood tests are inconvenient and generally shows up once a month for INR’s What would you do? a) Attempt rhythm control drug and eliminate A/C b) Recommend a point of service monitor c) Stop A/C since she had no current TIA’s d) Consider dabigatran, rivaroxaban or apixaban

141. Question
What do you think the barriers are to regular INR testing? a) Fear of testing b) Remembering c) Understanding importance d) Inconvenience e) Cost f) Other

142. What Do You Think the Barriers Are to Regular INR Testing?

143. Warfarin Control Is Improved with the Use of an Internet-Based Patient Self-Testing System
Ryan F, et al. J Thromb Haemost. 2009;7:

144. Case 4 Teaching Points
24 Hour Holter Monitor is hardly adequate to assure she’s free of AF
AF was asymptomatic to begin with
Rhythm control drug doesn’t assure stroke risk has been eliminated nor does the lack of recurrent TIAs

145. Questions and Answers