Pearls in Thrombosis. Alan Bell, MD, FCFP

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1 Pearls in Thrombosis Alan Bell, MD, FCFP Staff Physician, Humber River Regional Hospital Assistant Professor, Department of Family and Community Medicine University of Toronto

2 Alan Bell MD, FCFP Disclosures Grants/Research Support: Amgen, Daiichi Sankyo, Takeda, Boehringer Ingelheim, AstraZeneca, Bristol Myers Squibb, Lilly, Janssen Speakers Bureau/Honoraria: Amgen, Bristol Myers Squibb, Janssen, Takeda, Tweed, AstraZeneca, Novartis, Pfizer, Bayer, Lilly, Boehringer Ingelheim, Sanofi, Valeant Consulting Fees: Amgen, Bristol Myers Squibb, Janssen, Takeda, AstraZeneca, Novartis, Pfizer, Bayer, Lilly, Boehringer Ingelheim, Tweed, Sanofi, Valeant Other: Thrombosis Canada, Hypertension Canada, Canadian Cardiovascular Society, Heart and Stroke Foundation of Canada

3 Disclosure of Financial Support This program has not received financial support from any commercial or non-commercial organizations Potential for conflict(s) of interest: Dr. Alan Bell is Vice President of Thrombosis Canada (non-profit, unpaid) Dr. Alan Bell is a member of the Canadian Cardiovascular Society Antiplatelet Guidelines primary panel (non-profit, unpaid) Atrial Fibrillation Guidelines primary panel (non-profit, unpaid)

4 Mitigating Potential Bias Bias has been mitigated by the following: All program content was developed by the speaker All clinical recommendations are based on clinical guidelines and peer-reviewed evidence. No commercial or other non-commercial organization has had any input to the content of this program

5 Learning Objectives After attending this session, participants will be more skilled at: Appropriate dosing of anticoagulants in atrial fibrillation Diagnosis and management of venous thromboembolic disorders (VTE) including deep vein thrombosis and pulmonary embolism Duration of therapy in VTE for secondary prevention Perioperative management of anticoagulants

7 Clinical Guides

8 Management Tools

10 ATRIAL FIBRILLATION

12 The Impact of Stroke Globally 1 : The 3 rd most common cause of death in developed countries 15 million strokes annually 5 million deaths 5 million people permanently disabled Each year in Canada 2 : 50,000 people have a stroke one every 10 minutes 14,000 people die from stroke the 3 rd leading cause of death Stroke costs the Canadian economy $2.7 billion annually 3 1. World Health Organization Heart and Stroke Foundation of Canada Press release. 3. Canadian Stroke Network.

13 Atrial fibrillation affects approximately 350,000 Canadians

14 Atrial Fibrillation: Major Risk Factor for Stroke Increases the risk of stroke by 5-fold 1,2,3 Accounts for approximately 1 in 5 strokes Risk of stroke in atrial fibrillation patients who do not receive anticoagulation averages ~ 5% per year Risk of stroke in atrial fibrillation patients increases sharply with age 1.5% in year olds 23.5% in year olds 1. Arch Intern Med 1994; 154(13): Wolf PA et al. Stroke 1991; 22(8): Savelieva I et al. Ann Med 2007; 39(5): Singer DE et al. Chest 2008; 133(6 Suppl):546S-592S.

Case-fatality rate Bedridden patients (%) Atrial Fibrillation Patients Have Increased Post-Stroke Mortality and Morbidity 60 50 Mortality With AF 49.5 Without AF 50 40 41.2% Morbidity 40 30 32.5 27.

15 Case-fatality rate Bedridden patients (%) Atrial Fibrillation Patients Have Increased Post-Stroke Mortality and Morbidity Mortality With AF 49.5 Without AF % Morbidity % days 1 year 0 With atrial fibrillation Without atrial fibrillation Dulli DA, et al. Neuroepidemiology. 2003;22(2):118-23; Marini C, et al. Stroke. 2005;36(6):

16 Atrial Fibrillation: Warfarin Benefit Warfarin reduces the risk of AF related stroke by about 2/3 1. Hart et al Ann Intern Med. 2007;146: ; 2. Connolly et al. Lancet. 2006;367:

17 Anticoagulants: Stroke or Systemic Embolism RE-LY [Dabigatran 150 mg vs warfarin] ROCKET AF [Rivaroxaban 20 mg vs warfarin] ARISTOTLE [Apixababan 5 mg vs warfarin] ENGAGE AF-TIMI 48 [Edoxaban 60 mg vs warfarin] Combined [Random Effects Model] Risk Ratio (95% CI) 0.66 ( ) p = ( ) p = ( ) p = ( ) p = ( ) p < Ruff CT, et al. Lancet. 2014;383(9921): N=71,683

18 ASA, Warfarin and NOACs: Efficacy in Atrial Fibrillation Reduction of stroke/systemic embolism ASA 19% vs. placebo 1 64% vs. placebo 2 Warfarin Further 19% vs. warfarin 3 NOACs Not intended as a cross trial comparison 1. Turagam MK et al. Expert Rev Cardiovasc Ther 2012;10(4):433-9; 2. Hart RG et al. Ann Intern Med 2007;146:857-67; 3. Ruff et al. The Lancet 2014;383:

Anticoagulants: Major Bleeding Events RE-LY [Dabigatran 150 mg vs warfarin] ROCKET AF [Rivaroxaban 20 mg vs warfarin] ARISTOTLE [Apixababan 5 mg vs warfarin] ENGAGE AF-TIMI 48 [Edoxaban 60 mg vs

19 Anticoagulants: Major Bleeding Events RE-LY [Dabigatran 150 mg vs warfarin] ROCKET AF [Rivaroxaban 20 mg vs warfarin] ARISTOTLE [Apixababan 5 mg vs warfarin] ENGAGE AF-TIMI 48 [Edoxaban 60 mg vs warfarin] Combined [Random Effects Model] Risk Ratio (95% CI) 0.94 ( ) p = ( ) p = ( ) p = < ( ) p = ( ) p = 0.06 Ruff CT, et al. Lancet. 2014;383(9921): N=71,683

0001 All Cause Mortality 0.90 (0.85-0.95) P=0.

20 Anticoagulants: Specific Events of Interest Risk Ratio (95% CI) ICH 0.48 ( ) p< All Cause Mortality 0.90 ( ) P= GI Bleeding 1.25 ( ) p=0.043 Ruff CT, et al. Lancet. 2014;383(9921):

bleeding is active or risk is extreme Ensure blood pressure controlled to target Correct anemia and determine cause

21 Address Reversible Risk Factors for Bleeding Co-prescribe PPI (if recurrent GI bleeding) Encourage alcohol abstinence Measure and monitor renal function Anticoagulation should not be withheld based on bleeding risk, unless bleeding is active or risk is extreme Ensure blood pressure controlled to target Correct anemia and determine cause Provide mobility aids Discontinue ASA and NSAIDs if possible Clinical Guides Olessin JB et al. Thromb Haemost 2011;106:

ASA + Anticoagulant: Risk of Bleeding 6 5.82 5.5 5 4.5 4 4.81 3.94 4.81 4.41 4.76 3.92 3.5 3 2.81 2.84 2.65 3.03 3.02 2.78 3.1 2.5 2.22 2 1.82 1.5 1 0.

22 ASA + Anticoagulant: Risk of Bleeding RELY- 110 NO ASA RELY ASA RELY- 150 NO ASA RELY ASA ROCKET- AF NO ASA ROCKET- AF + ASA ARISTOT LE NO ASA ARISTOT LE + ASA WARFARIN DOACs Connolly SJ, et al. N Engl J Med. 2009; 361: Patel MR, et al. N Engl J Med. 2011; 365: Granger C, et al. N Eng J Med. 2011; 365:

23 CCS AF Guidelines Stroke prevention in non-valvular Atrial Fibrillaliton 1. A NOAC is preferred over warfarin in non valvular atrial fibrillation Andrade JG et al Can J Cardiol Nov;34(11):

24 What is Non Valvular Atrial Fibrillation? Absolute contraindications for DOAC: 1. Mechanical heart valves in any position 2. Rheumatic mitral stenosis 3. Moderate and severe non-rheumatic mitral stenosis Other conditions: Bioprosthetic heart valves, valve repairs, unknown, but were allowed in some trials Can J Cardiol Oct;31(10):

25 Management of AF with CAD Andrade JG et al Can J Cardiol Nov;34(11):

26 Mr NG 79-year-old man with hypertension, diabetes, mild chronic kidney disease (serum creatinine 134 µmol/l), His weight is 99 kg Presents for diabetes follow up and noted to have an irregular pulse

27 ECG

28 Decision Case of asymptomatic AF in an elderly patient with mild CKD Which anticoagulant would you use? A) Warfarin, INR target 2-3 B) Full dose DOAC C) Reduced dose DOAC

Anticoagulant use in Canada 7,019 patients with nonvalvular atrial fibrillation (AF) from 735 primary care physician practices Over 90% of patients with CHADS2 >1 receiving oral anticoagulation.

29 Anticoagulant use in Canada 7,019 patients with nonvalvular atrial fibrillation (AF) from 735 primary care physician practices Over 90% of patients with CHADS2 >1 receiving oral anticoagulation. But Over 50% of patients on OAC taking warfarin 30.9% of patients on warfarin TTR < 65% Of the patients on NOACs, 11.7% were on the wrong dose 7.6% on OAC + ASA % had no history of ischemic vascular disease Bell AD, et al. Am J Cardiol Apr 1;117(7):

Canadian Dosing Recommendations for Stroke Prevention in AF Dabigatran Patient has risk factor for stroke Estimate CrCl Recommended dose Dose can be considered <30 ml/min 30 49 ml/min 50 ml/min

30 Canadian Dosing Recommendations for Stroke Prevention in AF Dabigatran Patient has risk factor for stroke Estimate CrCl Recommended dose Dose can be considered <30 ml/min ml/min 50 ml/min Contraindicated Elderly or risk factors for bleeding Age <75 Age Age >80 One other risk factor for bleeding 110 mg BID 150 mg BID 150 mg BID 110 mg BID 150 mg BID 110 mg BID Pradaxa Canada Product Monograph

ml/min 15 49 ml/min 50 ml/min Not recommended 15 mg OD* 20 mg OD*

31 Canadian Dosing Recommendations for Stroke Prevention in AF Rivaroxaban Patient has risk factor for stroke Recommended dose Estimate CrCl <15 ml/min ml/min 50 ml/min Not recommended 15 mg OD* 20 mg OD* *Rivaroxaban 15 mg and 20 mg should be taken with food Xarelto Canada Product Monograph

weight Check serum creatinine 80 years 60 kg 133 μmol/l 2.

32 Canadian Dosing Recommendations for Stroke Prevention in AF Apixaban Patient has risk factor for stroke Estimate CrCl Recommended dose <15 ml/min ml/min 25 ml/min Not recommended No dosing recommendation can be made* Check age Check weight Check serum creatinine 80 years 60 kg 133 μmol/l 2.5 mg BID If 2 features If 1 features 5 mg BID *In patients with CrCl ml//min, no dosing recommendation can be made as clinical data are very limited Eliquis Canada Product Monograph

33 Management Tools

35 Teaching Pearls Oral anticoagulation is indicated for patients with atrial fibrillation over 65 or any other CHADS 2 risk factor Strokes associated with AF are associated with excess morbidity and mortality Do not withhold anticoagulation unless bleeding risk extreme Address reversible bleeding risk factors NOACs are considered first line over warfarin, in most patients, but require appropriate dosing.

36 VENOUS THROMBOEMBOLISM

Migration Thrombus Pulmonary embolism (PE) Thromboemboli detach and travel through the

37 VTE: Clot Formation Within the Venous Circulation Deep vein thrombosis (DVT) Thrombi form predominantly in venous valve pockets and other sites of presumed stasis Embolus Migration Thrombus Pulmonary embolism (PE) Thromboemboli detach and travel through the right side of the heart to block vessels in the lungs Tapson VF. N Engl J Med. 2008;358:

38 Incidence of VTE in Canada An estimated 45,000 patients in Canada are affected by deep vein thrombosis (DVT) each year 1 There are approximately 1-2 cases per 1,000 persons annually 2 Despite adequate therapy, 1% to 8% of patients in whom pulmonary embolism develops will die 1 40% of DVT patients develop post phlebitic syndrome 1 4% of PE patients develop chronic thromboembolic pulmonary hypertension 1 1. Thrombosis Canada, 2013, Clinical Guides, Venous Thromboembolism; 2. Scarvelis et al, CMAJ 2006; 175(9)

39 Risk Stratification

40 How is DVT diagnosed?

41 D-Dimer Fibrin degradation product Sensitive but non-specific measure of thrombosis Useful to help rule out DVT when negative, but of no diagnostic value when positive Variety of assays available highly sensitive assays are of greatest value to r/o DVT

42 Ms TC Otherwise well, 31-year-old account executive Presents to family doctor with a 24-hour history of pain and swelling in right leg Just returned from a sales meeting in Paris yesterday (economy class) Current medications: Oral contraceptive Physical exam confirms swelling of right lower leg and foot, with slight pitting edema, no redness, minimal tenderness Normal BP, HR, RR, chest exam

43 Decision How do you manage this patient? A) Refer to ER B) Confirm DVT with US prior to starting anticoagulation C) Start anticoagulant empirically

44 ACCP Guidelines

45 Treat DC Rx Prepared by Pfizer-BMS alliance in response to an unsolicited request Not for further distribution

46 Treatment Options in 2016 Bridge Single agent (LMWH/rivaroxaban/apixaban) Switch (dabigatran/edoxaban*)

47 Published between n=27,075

48 The Bottom Line: Acute Treatment Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban Dosing Variable 150 mg BID* 15 mg BID x 3 weeks then 20 mg OD 10 mg BID x 7 days then 5 mg BID 60 mg OD (30 mg OD for CKD, wt <60) Initial LMWH Rx Required Required Not required Not required Required Efficacy v warfarin Same Same Same Same Safety v warf Major bleeds Same Less Less Same Clinically sig bleeds Same efficacy Less Same Less Less Less bleeding Health Canada Approved Approved Approved Approved Renal clearance 85% 33% 25% 35% *110 mg BID if age >80 or additional RF for bleeding)

49 CHEST 2016; 149(2):

50 Anticoagulant dosing: VTE Treatment Drug Initial Treatment Long Term (initial 3 months) Extended >6 months if indicated Apixaban 10 mg bid x 7 days 5 mg bid 2.5 mg bid indefinitely ASA Not indicated Not indicated mg daily Dabigatran LMWH for 5-10 days 150 mg bid * 150 mg bid * Rivaroxaban 15 mg bid x 21 days 20 mg daily 10 mg daily indefinitely Warfarin LMWH for 5 days & INR > 2 for 2 days Variable (INR 2-3) Variable (INR 2-3) Boehringer Ingelheim Canada Ltd. (2014). Pradaxa Product Monograph. Bayer Inc. (2014). Xarelto Product Monograph Pfizer Canada Inc. (2014). Eliquis Product Monograph Can J Cardiol 2014; 30: *(110 mg bid if CrCl ml/min, age >80, or higher risk of bleeding)

Home or Hospital? Home treatment VTE recurrence: 0.61 (0.42-0.

51 Home or Hospital? Home treatment VTE recurrence: 0.61 ( ) Mortality: 0.72 ( ) Major bleeding: 0.67 ( )

52 Patients who should be admitted Iliofemoral DVT Phlegmasia or venous ischemia Severe CKD (CrCl <30) Suspicion for high risk PE High bleeding risk Significant comorbid disease Douketis, JD.

53 Provoked vs non-provoked Provoked by a transient major risk factor Surgery Major trauma Hospitalization Lower extremity cast Immobilization > 3 days Pregnancy and puerperium Estrogen therapy Provoked by a minor risk factor Air travel Stuck in traffic Minor trauma Unprovoked or provoked by an irreversible risk factor Cancer Immobilization 5-10% 1% ACCP guidelines recommend at least 3 months anticoagulant therapy after provoked VTE with transient risk factors or longer after unprovoked (idiopathic) or VTE provoked by irreversible factors Annual recurrence risk off anticoagulation

54 Duration of Antithrombotic Therapy Clearly Provoked 3 months Clearly Unprovoked, Recurrent Low or moderate bleeding risk Indefinite High bleeding risk 3 months then re-evaluate Cancer associated with LMWH Low or moderate bleeding risk As long as cancer active or on chemotherapy High bleeding risk 3 months then re-evaluate

55 Ms TC Otherwise well, 31-year-old account executive Presents to family doctor with a 24-hour history of pain and swelling in right leg Just returned from a sales meeting in Paris yesterday (economy class) Current medications: Oral contraceptive Physical exam confirms swelling of right lower leg and foot, with slight pitting edema, no redness, minimal tenderness Normal BP, HR, RR, chest exam

56 Ms TC Oh no! This could be a DVT I have to get an ultrasound right now I have to start her on low molecular weight heparin I haven t used that stuff since residency I have no idea how to dose it I have to teach her how to do self injections I also have to start her on warfarin Just what I need, another patient on warfarin This may just be a swollen leg and not a DVT I hate this!

57 Ms TC Most primary care physicians Dump this patient on the ER

58 Ms TC Oh no! The ER is terrible I don t want to go to the ER. Last time I had to wait 7 hours to be seen with my 5-year-old, and he was really sick All I have is a swollen leg, they ll treat me as a very low priority I have no time for this, I have to pick up my kid at the daycare I hate this!

59 Ms TC Impact on Healthcare Oh no! Another patient going to the ER Our ER is already overcrowded This will require assessments by: Clerical persons Triage nurse Clinical nurse ER physician Specialist consultant Radiologist Radiology technician Pharmacist All this hospital assessment will cost a fortune This could be done at a fraction of the cost I hate this!

60 VTE NOAC Approach

61 Ms TC I can just start her on a NOAC I ll send her for an elective duplex ultrasound that can be done in the next 48 hours I ll see her back after the ultrasound and continue or stop I love this!

62 Ms TC Oh no! This could be serious I m so glad he knows how to handle it What a great doctor I have! I love this!

63 Ms TC Impact on Healthcare I love this!

64 Teaching Pearls Treat first ask questions later For most patients, NOACs are recommended first line therapy over warfarin Extended therapy should be considered for unprovoked and recurrent VTE Home therapy is appropriate for the vast majority of patients with DVT

65 PERI-PROCEDURAL ANTICOAGULANT MANAGEMENT

66 Mr. JF 75-year-old retired lawyer Referred for GI endoscopy to investigate altered bowel habit Non-valvular AF Apixaban 5 mg BID CHADS 2 = 3 (hypertension, diabetes, age) Serum creatinine 122 µmol/l Weight 92 kg

67 Decision GI endoscopy required in patient on NOAC How should the NOAC be managed? A) Continued throughout the procedure B) Hold for 5 days prior to the procedure and restart day following C) Hold for 2 days prior to the procedure and restart 2 days following D) Hold the NOAC for 5 days but provide LMWH bridging E) I don t know and I admit it

68 Does not yet address perioperative management of NOACs

69 Where Does this Leave the Clinician?

70 Management Tools

72 Teaching Pearls Periprocedural management of anticoagulants is a very common yet complex clinical issue often left to the family physician Correct management is critically important to prevent bleeding and thrombotic events Tools are available to ensure optimized dosing DON T GUESS

73 Date of preparation: December QUESTIONS?

74 Too bad we don t have time to talk about DOAC REVERSAL AGENTS

75 How to reverse NOACs Remove drug: Dialysis Yes for dabigatran (not highly protein bound) No for oral Xa inhibitors (highly protein bound) Neutralize drug: Antidote Idarucizumab: Humanized Fab fragment, attracts dabigatran with > 300-times affinity than thrombin Andexanet-α: Human rfxa variant, decoy molecule that competes with native fxa to bind oral Xa inhibitors Coagulation factors? 4-factor PCC or FEIBA 50 IU/kg Lauw M, et al. Can J Cardiol 2014; 30(4):381-4.

intrinsic procoagulant or anticoagulant activity IV dosing by bolus or

76 Idarucizumab Specific Dabigagran Reversal Agent Humanized Fab fragment Binding affinity ~350 higher than dabigatran to thrombin Dabigatran No intrinsic procoagulant or anticoagulant activity IV dosing by bolus or rapid infusion; immediate onset of action Idarucizumab Schiele et al. Blood 2013

77 Andexanet Alfa Specific Xa reversal agent Recombinant modified form of fxa Binds fxa inhibitors (Rivaroxaban, Apixaban) with similar affinity as endogenous fxa Cannot assemble into prothrombinase complex

78 RE-VERSE AD Trial 301 patients on dabigatran with acute bleeding (Group A) 202 patients on dabigatran requiring urgent surgery (Group B) All administered 5 g IV Idarucizumab N Engl J Med Jun 22. [Epub ahead of print]

79 RE-VERSE AD Trial Results The median maximum percentage reversal of dabigatran was 100% (95% confidence interval, 100 to 100) N Engl J Med 2017;377:431-41

80 RE-VERSE AD Clinical Outcomes 202 Patients evaluable for time to cessation of bleeding 197 patients who underwent urgent surgery Time to cessation of bleeding: 2.5 hours Intraoperative hemostasis normal: 93.4% Mildly abndormal: 5.1% Moderately abnormal: 1.5% N Engl J Med 2017;377:431-41

81 ANNEXA Phase 3 Studies: Andexanet Alfa Antidote to the Anticoagulant Effects of fxa Inhibitors in Healthy Volunteers Andexanet bolus only Apixaban Rivaroxaban R Apixaban 400 mg Andexanet Rivaroxaban 800 mg Andexanet Part 1 Placebo 5 mg BID Apixaban/ 20 mg OD Rivaroxaban administered over 3 days and morning of 4 th day prior to administration of Andexanet or Placebo Andexanet bolus + infusion Apixaban Rivaroxaban R Apixaban 400 mg + 4 mg/min Andexanet Rivaroxaban 800 mg + 8 mg/min Andexanet Part 2 Placebo Crowther M et al. Circulation. 2014;130:2116-7; Gold AM et al. J Am Coll Cardiol. 2015;65:A

82 N Engl J Med 2016; 375:

Atrial Fibrillation. Alan Bell, MD, CCFP. Staff Physician, Humber River Regional Hospital. University of Toronto

Atrial Fibrillation. Alan Bell, MD, CCFP. Staff Physician, Humber River Regional Hospital. University of Toronto Pearls in Thrombosis 1 Atrial Fibrillation Alan Bell, MD, CCFP Staff Physician, Humber River Regional Hospital Assistant tprofessor, Department tof Family and Community Mdii Medicine University of Toronto