Anticoagulation Strategies: Mind the Gap

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 CHADS 2 , CHA 2 DS 2 -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) Email individual patient results after completing risk calculator tool Based on the SPARCtool ( http://sparctool.com / )

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 http://CardioSource.org/apps Available on iPad, iPhone and Android devices

11. 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 The Anticoagulation Initiative: Coming Soon

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 http://CardioSource.org/anticoagulation for more information

13. How many patients with atrial fibrillation do you typically see each week? a) Fewer than 5 b) 5-10 c) 10-20 d) More than 20 Question 1

14. What anticoagulants/antiplatelet agents do you most frequently use to prevent thromboembolic complications? a) Aspirin b) Aspirin/clopidogrel c) Clopidogrel alone d) NOACs (novel oral anticoagulant) e) Warfarin f) Other Question 2

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

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

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

18. 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. Question 6

19. 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? a) Ejection fraction of 30% with Class II heart failure b) Normal functioning mechanical MVR c) LVH with EF 55%; chronic renal insufficiency with creatinine clearance 10 ml/min Question 6 ( Cont. )

20. 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 Atrial Fibrillation (AF) in the U.S.

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

22. 1. Fuster V, et al. Circulation . 2006;114:e257-354 . 2 . Benjamin EJ, et al. Circulation . 1998;98:946-52. 3. Lloyd-Jones D, et al. Circulation . 2009; 119:e21-181. 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

23. Risk of stroke increases with age 1 Ischemic stroke associated with AF is often more severe than stroke of other etiologies 4 Stroke risk persists even in asymptomatic AF 5 Asymptomatic AF implicated as a cause of cryptogenic stroke 6 Atrial Fibrillation and Stroke ( Cont. ) 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. CHADS 2 Congestive heart failure Hypertension Age >75 years Diabetes mellitus Prior Stroke or TIA (*2 points) Gage, BF, et al. JAMA . 2001;285:2864-70

25. Stroke Risk in AF ACP/AAFP Guidelines Snow V, et al. Ann Intern Med . 2003;139:1009-17 * Expected rate of stroke per 100 patient-years

26. CHA 2 DS 2 -VASc

27. ESC Guidelines for Antithrombotic Therapy Europace 2010; 12: 1360-1420 European Heart Journal (2012) 33, 27192747

28. Stroke Prevention: Coumadin Warfarin AFASAK BAATAF SPAF CAFA SPINAF Warfarin/ASA EAFT SPAF II AFASAK

29. Warfarin: Risk-Benefit Profile Fuster V, et al. Circulation . 2006;114:e257-354 .

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)

31. Quality of Warfarin Control in AF Patients on Chronic Anticoagulation Baker WL, et al. J Manag Care Pharm . 2009;15:244-52 . Only 48% of eligible patients in this analysis received warfarin

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

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

38. Stroke Risk in AF ACP/AAFP Guidelines * Expected rate of stroke per 100 patient-years Snow V, et al. Ann Intern Med . 2003;139:1009-17

39. CHA 2 DS 2 -VASc

40. ESC Guidelines for Antithrombotic Therapy Europace 2010; 12: 1360-1420 European Heart Journal (2012) 33, 27192747

41. a) High b) Medium c) Low What is her risk of bleeding with anticoagulation? Question

42. HAS-BLED Score 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 CHADS 2 and CHA 2 -DS 2 -VASc scores in women (A) and men (B). The American Journal of Medicine 2012 125, 603.e4

44. What is her risk of stroke/bleeding? a) CHADS 2 score = 0 (annual stroke risk = 1.9%) b) CHA 2 DS 2 VASc = 3 (annual stroke risk = 3.2%) c) HASBLED score = 3 (annual bleeding risk = 5.6%) Question

45. Which anticoagulation regimen is most appropriate for her? a) Aspirin b) Warfarin c) NOAC d) Aspirin/clopidogrel Question

46. Which Anticoagulation Regimen Is Most Appropriate for Her? http://www.vhpharmsci.com/sparc/

47. http://www.vhpharmsci.com/spar c/ Which Anticoagulation Regimen to Use?

48. http://www.vhpharmsci.com/spar c/ 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 (CHADS 2 , CHA 2 DS 2 -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 CHADS 2 score: 2.5 (moderate-to-high risk) All eligible for warfarin Chan PS, et al. Am J Cardiol . 2011;108:1136-1140.

51. PINNACLE Results 55.1% treated with warfarin regardless of CHADS 2 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 Chan PS, et al. Am J Cardiol . 2011;108:1136-1140.

52. PINNACLE: Percent of Patients on Warfarin (Practice Level) 52 Chan PS, et al. Am J Cardiol . 2011;108:1136-1140.

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

54. 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 endpoint a a Stroke, MI, non-CNS systemic embolism or vascular death ACTIVE Investigators. Lancet . 2006;367:1903-12 .

57. ACTIVE-A: Dual Antiplatelet Therapy Reduces the Incidence of Vascular Events in AF When Warfarin Therapy Is Unsuitable a Stroke, I, non-CNS systemic embolism or vascular death ACTIVE Investigators. N Engl J Med . 2009;360:2066-78

58. ACTIVE-A: Dual Antiplatelet Therapy Increases the Risk of Bleeding P<0.001

59. 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 physicians assessment of the patients 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;123:104-123. 2011 Focused Update Recommendation

60. New Pharmacologic Approaches for Stroke Reduction in AF Oral direct thrombin inhibitors Fixed-dose, no monitoring Dabigatran Oral factor Xa inhibitors Fixed-dose, no monitoring Apixaban Rivaroxaban (Edoxaban)

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 2.0-3.0) Mean CHADS 2 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 10.1056

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 65-74 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. RE-LY: Dabigatran Reduces the Risk of Stroke in AF Patients Time (months ) Cumulative Hazard Rate Connolly SJ, et al. N Engl J Med. 2009;361:1139-51 .

64. RE-LY: Safety Outcomes with Dabigatran Modified from Connolly SJ, et al. N Engl J Med. 2009;361:1139-51 .

65. FDA Approval for 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). 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

66. FDA Approval for Dabigatran: 75 mg q12h 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). 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

67. 2011 ACCF/AHA/HRS Focused Update on the Management of Patients with Atrial Fibrillation (Update on Dabigatran)

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 CHADS 2 score = 3.5 By intention-to-treat analysis rivaroxaban was non-inferior (p < 0.0001) but not superior (p = 0.12) to warfarin NEJM 10.1056

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. 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 2.0-3.0) (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

72. Primary Outcome Stroke (ischemic or hemorrhagic) or systemic embolism No. at Risk Apixaban 9120 8726 8440 6051 3464 1754 Warfarin 9081 8620 8301 5972 3405 1768 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 9088 8103 7564 5365 3048 1515 Warfarin 9052 7910 7335 5196 2956 1491 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

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. www.escardio.org/guidelines European Heart Journal 2012; 33:2719-2747 doi:10.1093/eurheartj/ehs253 European Society of Cardiology Recommendations

83. Case 2 80-year-old Male with Cholelithiasis

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. 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) Physical Exam

86. In preparation for surgery, you should: a) Admit the patient to the hospital, stop dabigatran and administer IV heparin until the morning of surgery b) Stop dabigatran 7 days prior to surgery and check INR on the morning of surgery c) Stop dabigatran 2 days prior to surgery and check aPTT on the morning of surgery Question

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. Copyright American Heart Association Weitz J I et al. Circulation 2012;126:2428-2432 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

89. Weitz J I et al. Circulation 2012;126:2428-2432 Copyright American Heart Association Proposed Algorithm for Periprocedural Management of Dabigatran * In some countries, dabigatran is contraindicated in patients with CrCl <30 mL/min

90. Now lets assume that the patient is taking warfarin instead of dabigatran

91. In preparation for surgery, you should: a) Admit the patient to the hospital, stop warfarin and administer IV heparin until the morning of surgery b) Stop warfarin 5 days prior to surgery and initiate LMWH until the morning of surgery c) Stop warfarin 5 days prior to surgery without bridging anticoagulation Question

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;336:1506-1511.

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

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 1.5-2 days (3-4 doses) for low risk surgery With GFR 30-50, omit for 3-4 days (6-8 doses) for higher risk surgery

98. Guide to the Management of Bleeding in Patients Taking NOAC Hankey GJ and Eikelboom JW. Circulation. 2011; 123: 1436-1450

99. Circulation. 2011;124:1573-1579 Rivaroxaban Dabigatran

100. Questions and Answers

101. 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. Question 6 - Post Test Question

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

103. 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 Rationale

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

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. 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) Physical Exam

109. In preparation for surgery, you should: a) Admit the patient to the hospital, stop dabigatran and administer IV heparin until the morning of surgery b) Stop dabigatran 7 days prior to surgery and check INR on the morning of surgery c) Stop dabigatran 2 days prior to surgery and check aPTT on the morning of surgery Question

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. Copyright American Heart Association Weitz J I et al. Circulation 2012;126:2428-2432 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

112. Weitz J I et al. Circulation 2012;126:2428-2432 Copyright American Heart Association Proposed Algorithm for Periprocedural Management of Dabigatran * In some countries, dabigatran is contraindicated in patients with CrCl <30 mL/min

113. Copyright American Heart Association Gallego P et al. Circulation 2012;126:1573-1576 Bridging Algorithm for New Oral Anticoagulants

114. Now lets assume that the patient is taking warfarin instead of dabigatran

115. In preparation for surgery, you should: a) Admit the patient to the hospital, stop warfarin and administer IV heparin until the morning of surgery b) Stop warfarin 5 days prior to surgery and initiate LMWH until the morning of surgery c) Stop warfarin 5 days prior to surgery without bridging anticoagulation Question

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;336:1506-1511.

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 8 th 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) Ansell J, et al. Chest. 2008;133:160S-98S .

121. Copyright American Heart Association Gallego P et al. Circulation 2012;126:1573-1576 Bridging Algorithm for Vitamin K Antagonists

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

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 1.5-2 days (3-4 doses) for low risk surgery With GFR 30-50, omit for 3-4 days (6-8 doses) for higher risk surgery

124. Guide to the Management of Bleeding in Patients Taking NOAC Hankey GJ and Eikelboom JW. Circulation. 2011; 123: 1436-1450

125. Circulation. 2011;124:1573-1579 Rivaroxaban Dabigatran

126. Weitz J I et al. Circulation 2012;126:2428-2432 *Recommendations are based on limited nonclinical data only. Proposed Algorithm for Management of Moderate-to-Severe Bleeding and Life-Threatening Bleeding Episodes in Patients Treated with Dabigatran

127. Questions and Answers

129. Case 3 55-year-old Man with Hypertension and NIDDM Who Presents with Palpitations

130. 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 Noted to Have AF with Rapid Rate

131. 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 3 Months Later, Patients with Rapid AF

132. a) Do a 24 hr Holter and if negative for atrial fibrillation stop warfarin b) Do a 2 week ambulatory telemetry monitor and if negative stop warfarin c) Urge him strongly to continue warfarin d) Substitute newer agent What would you do? Question

133. Rhythm Control Anticoagulation/Stroke Prevention

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

137. Echo normal Not hypertensive, diabetic, pfts 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 3 Years Ago Presented with TIA Noted to Be in NSR

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

139. 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 Question

140. In reviewing INRs they vary widely and she complains that blood tests are inconvenient and generally shows up once a month for INRs 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 TIAs d) Consider dabigatran, rivaroxaban or apixaban Question

141. 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 Question

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;7:1284-90 .

144. Case 4 Teaching Points 24 Hour Holter Monitor is hardly adequate to assure shes free of AF AF was asymptomatic to begin with Rhythm control drug doesnt assure stroke risk has been eliminated nor does the lack of recurrent TIAs

145. Questions and Answers