Novel Anticoagulants PHYSICIANS UPDATE 2014

Novel Anticoagulants PHYSICIANS UPDATE 2014 Farouk Mookadam MD FRCPC FACC MSc Professor College of Medicine Mayo Consultant Cardiovascular Diseases Medical Director Anticoagulation Clinic Assoc Programme Director Internal Medicine Residency Medical Director Cardio-Oncology Programme 2013 MFMER 3263885-1

Novel Anticoagulants Learning Objectives Appreciate the pharmacokinetic differences between novel anticoagulants Tailoring anticoagulation therapy to patient needs Define management strategy for patients receiving novel anticoagulant therapy in specific clinical scenarios 2013 MFMER 3263885-2

How Many Prescribe? A. Dabigatran? B. Rivaroxaban? C. Apixaban? D. Edoxaban? 2013 MFMER 3263885-3

What is the #1 Drug Responsible for Emergency Department Admissions Due to Adverse Events? A. Insulin B. Oral hypoglycemic agents C. Dabigatran D. Rivaroxaban E. Warfarin 2013 MFMER 3263885-4

Emergency Hospitalizations for Adverse Drug Events Annual National estimate of hospitalizations (n=99,628) Proportion of emergency department visits resulting in hospitalization Medication No. % (95% CI) % Most commonly implicated medications Warfarin 33,171 33.3 (28.0-38.5) 46.2 Insulins 13,854 13.9 (9.8-18.0) 40.6 Oral antiplatelet agents 13,263 13.3 (7.5-19.1) 41.5 Oral hypoglycemic agents 10,656 10.7 (8.1-13.3) 51.8 Opioid analgesics 4,778 4.8 (3.5-6.1) 32.4 Antibiotics 4,205 4.2 (2.9-5.5) 18.3 Digoxin 3,465 3.5 (1.9-5.0) 80.5 Budnitz DS et al. NEJM 365:2002, 2011 2013 MFMER 3263885-5

Odds ratio Therapeutic Range for Warfarin INR Values at Stroke or ICH Stroke Intracranial bleed 1 INR Fuster et al. JACC 38:1231, 2001 2013 MFMER 3263885-6

Why Search for New Anticoagulants? Warfarin Often not prescribed when indicated 35% of ideal AFib candidates not offered warfarin Especially true for Blacks and Hispanics Rates of discontinuation are high Stroke 37:1070, 2006 At 1 year, >25% of patients will stop warfarin despite an ongoing indication Circulation 115:2689, 2007 2013 MFMER 3263885-7

Alternatives to Warfarin At least same anti-thrombotic effect Lower risk of bleeding especially intracranial bleeding Oral bioavailability once or twice daily No food or drug interactions Broad therapeutic window at standard dosing Stable anticoagulation without laboratory monitoring Good patient acceptability and long-term tolerance 2013 MFMER 3263885-8

Novel Oral Anticoagulants Dabigatran Oral DTI Renal clearance(80%) Twice daily Rivaroxaban Direct factor Xa inhibitor Hepatic clearance (67%) Once daily Apixaban Direct factor Xa inhibitor Hepatic clearance (75%) Twice daily Edoxaban Direct factor Xa inhibitor Hepatic clearance(65%) Once daily Circulation 121: 1523, 2010 2013 MFMER 3263885-9

New Oral Anticoagulants vs. Warfarin Characteristics Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban Target Synthesis of II, VII, IX, X IIa (thrombin) Xa Xa Xa Dose Variable 110, 150 mg 20 (15) mg 5 (2.5) mg 30, 60 mg Frequency OD BID OD BID OD Interactions CYP2C9/ 3A4/1A2 P-gP CYP3A4/2J2 P-gP CYP3A4 P-gP P-gP Renal elimination <1%* 80% 33% 25% 35% CYP = cytochrome P450; P-gP = P-glycoprotein *Caution and more frequent INR monitoring in moderate to severe renal dysfunction; contraindicated if CrCl <15 ml/min (SPC) 2013 MFMER 3263885-10

Non-valvular Atrial Fibrillation Where approved Dabigatran Rivaroxaban Apixaban Edoxaban EU, Canada, US EU, Canada, US EU, Canada, US Under evaluation 2013 MFMER 3263885-11

VTE Prevention Ortho: THR, TKR, Hip Fracture Where approved Dabigatran Rivaroxaban Apixaban Edoxaban EU, Canada EU, Canada, US EU Japan 2013 MFMER 3263885-12

DVT and/or PE Treatment Approved Rivaroxaban Not approved Dabigatran Apixaban Edoxaban 2013 MFMER 3263885-13

Stroke rate (%/yr) Nonvalvular Atrial Fibrillation Stroke Rates without Anticoagulation by risk factor Prior stroke/tia Age > 75 yr Hypertension Female Diabetes Heart failure ± LVEF Hart RG et al. Neurology 69:546, 2007 2013 MFMER 3263885-14

The CHADS 2 Index Stroke Risk Score for Atrial Fibrillation Score (points) Prevalence (%)* Congestive heart failure 1 32 Hypertension 1 65 Age >75 years 1 28 Diabetes mellitus 1 18 Stroke or TIA 2 10 Moderate high-risk 2 50-60 Low-intermediate risk 0-1 40-50 VanWalraven C et al. Arch Intern Med 163:936, 2003 (Nieuwlaat R et al. (EuroHeart survey) Eur Heart J (e-published), 2006 2013 MFMER 3263885-15

Dabigatran FDA approval October, 2010 First oral anticoagulant approved in > 50 years Approved indication Non-valvular atrial fibrillation No dosing information CrCl < 15 ml/min Pregnancy, nursing mothers Pediatric patients Hematol 37:259, 2008 2013 MFMER 3263885-16

Laboratory Monitoring Generally not indicated Not suitable for efficacy May be useful in bleeding patients PT-INR aptt aptt 2 x control after 1-2 hours 1.5 x control at 12 hours Thrombin time Ecarin time Dabigatran J Thromb Haemost 7(1):107, 2009 2013 MFMER 3263885-17

Event rates/year (%) Dabigatran in AF RE-LY Study Outcomes Warfarin Dabigatran 110 bid Dabigatran 150 bid TTR RELY 64% AC Clinics 66% Community 57% P=0.10 P=0.04 P=0.003 P=0.031 P<0.001 P<0.001 P<0.001 Stroke/ embolism ICH Major bleed Minor bleed *CVE, TE, PE, MI, death, MB for 1 net clinical benefit Connolly SJ et al. NEJM 361:1139, 2009 2013 MFMER 3263885-18

In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. 2013 MFMER 3263885-19

Dabigatran Indications for lower dose Dabigatran (110 mg bid) > 80 years of age On P-gP inhibitors (specifically verapamil) Poor renal function (CR CI < 50 ml/min) 75-80y with bleeding risk or low thromboembolic risk Gastritis, esophagitis, etc. Contraindication: Renal dysfunction (<15 ml/min) Not recommended with dronedarone 2013 MFMER 3263885-20

Rivaroxiban Study Design Rivaroxaban 20 mg daily 15 mg for CrCI 30-49 ml/min Atrial Fibrillation Randomize double blind/ double dummy (n ~ 14,000) Risk factors CHF Hypertension Age 75 At least 2 or Diabetes 3 required* or Stroke, TIA or systemic embolus Warfarin INR target 2.5 (2.0-3.0 inclusive) Monthly monitoring Adherence to standard of care guidelines Primary endpoint: Stroke or non-cns systemic embolism *Enrollment of patients without prior stroke, TIA or systemic embolism and only 2 factors capped at 10% 2013 MFMER 3263885-21

Cumulative event rate (%) Cumulative event rate (%) Cumulative Rates of the Primary End Point (Stroke or Systemic Embolism) Events in Per-Protocol Population Events in Intention-to-Treat Population Warfarin Warfarin Rivaroxaban Rivaroxaban Days since randomization No. at risk Rivaroxaban 6958 6211 5786 5468 4406 3407 2472 1496 Warfarin 7004 6327 5911 5542 4461 3478 2539 1538 Days since continuation No. at risk Rivaroxaban 7081 6879 6683 6470 5264 4105 2951 1785 Warfarin 7090 6871 6656 6440 5225 4087 2944 1783 Patel et al. N Engl J Med 365:883, 2001 2013 MFMER 3263885-22

In patients with atrial fibrillation, rivaroxaban was non-inferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. 2013 MFMER 3263885-23

Summary Efficacy Rivaroxaban was noninferior to warfarin for prevention of stroke and non-cns embolism Safety Similar rates of bleeding and adverse events Less ICH and fatal bleeding with rivaroxaban Conclusion Rivaroxaban is a proven alternative to warfarin for moderate or high risk patients with AF 2013 MFMER 3263885-24

VTE EINSTEIN Studies I DVT and II PE 2013 MFMER 3263885-25

Rivaroxiban DVT Enoxaparin 15mg BID 3 weeks 20 mg daily 3, 6, 9 months SC Warfarin daily 3, 6, 9 2013 MFMER 3263885-26

Rivaroxaban offers a simple, single-drug approach to the short-term and continued treatment of venous thrombosis that may improve the benefit-to-risk profile of anticoagulation 2013 MFMER 3263885-27

A fixed-dose regimen of rivaroxaban alone was non-inferior to standard therapy for the initial and long-term treatment of pulmonary embolism and had a potentially improved benefitrisk profile 2013 MFMER 3263885-28

ACS 2013 MFMER 3263885-29

In patients with a recent acute coronary syndrome, rivaroxaban reduced the risk of the composite end point of death from cardiovascular causes, myocardial infarction, or stroke. Rivaroxaban increased the risk of major bleeding and intracranial hemorrhage but not the risk of fatal bleeding. 2013 MFMER 3263885-30

Apixaban 2013 MFMER 3263885-31

Atrial Fibrillation with at Least One Additional risk Factor for Stroke Inclusion risk factors Age 75 years Prior stroke, TIA, or SE HF or LVEF 40% Diabetes mellitus Hypertension Randomize double blind/ double dummy (n=18,201) Major exclusion criteria Mechanical prosthetic valve Severe renal insufficiency Need for aspirin plus thienopyridine Apixaban 5 mg oral twice daily 2.5 mg bid in selected patients Warfarin Target INR 2-3 Primary endpoint: Stroke or non-cns systemic embolism Hierarchical testing: Noninferiorty for primary outcome, superiority for primary outcome, major bleeding, death 2013 MFMER 3263885-32

Event (%) Primary Outcome Stroke (Ischemic/Hemorrhagic) or Systemic Embolism P (noninferiority) <0.001 Warfarin 21% RRR Apixaban Apixaban 212 pt 1.27%/yr Warfarin 265 pt 1.60/year HR 0.79 (95% CI 0.66-0.95) P (superiority) = 0.011 Months No. at risk Apixaban 9,120 8,726 8,440 6,051 3,464 1,751 Warfarin 9,081 8,620 8,301 5,972 3,405 1,768 2013 MFMER 3263885-33

Event (%) Major Bleeding ISTH Definition Apixaban 327 pt 2.13%/yr Warfarin 462 pt 3.09/year HR 0.79 (95% CI 0.60-0.80) P (superiority) <0.001 Warfarin 31% RRR Apixaban Months No. at risk Apixaban 9,088 8,103 7,564 5,365 3,048 1,515 Warfarin 9,052 7,910 7,335 5,196 2,956 1,491 2013 MFMER 3263885-34

In patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality. 2013 MFMER 3263885-35

Conclusions Upsides with Xa-Inhibition Compared to warfarin, Apixaban Reduces stroke and systemic embolism by 21% (P =.01) Reduces major bleeding by 31% (P<.001) Reduces mortality by 11% (P=.047) Consistency across subgroups including quality of warfarin treatment Apixiban better tolerated treatment than warfarin 2013 MFMER 3263885-36

Apixiban in VTE 2013 MFMER 3263885-37

Extended anticoagulation with apixaban at either a treatment dose (5 mg) or a thromboprophylactic dose (2.5 mg) reduced the risk of recurrent venous thromboembolism without increasing the rate of major bleeding 2013 MFMER 3263885-38

A fixed-dose regimen of apixaban alone was non-inferior to conventional therapy for the treatment of acute venous thromboembolism and was associated with significantly less bleeding 2013 MFMER 3263885-39

Stroke Prevention Anticoagulant Effect Meta-analysis of stroke or systemic embolism Category W vs placebo W vs W low dose W vs aspirin W vs aspirin + clop W vs ximelagatran W vs dabigatran 110 W vs rivaroxaban W vs dabigatran 150 W vs apixaban 5 0 Relative HR (95% CI) 0.3 Favors warfarin 0.6 0.9 1.2 1.5 1.8 2.0 Favors other Rx W vs dabigatran 110 W vs rivaroxaban W vs dabigatran 150 W vs apixaban 5 0 0.3 0.6 0.9 1.2 1.5 1.8 2.0 0 0.3 Favors warfarin ICH Major Bleeding W vs dabigatran 110 W vs rivaroxaban W vs dabigatran 150 W vs apixaban 5 0.6 0.9 1.2 1.5 1.8 2.0 Favors other Rx Camm AJ. EHJ 30:2554, 2009 2013 MFMER 3263885-40

Atrial Fibrillation CCS Recommendations Assess thromboembolic risk (CHADS 2 ) and bleeding risk (HAS-BLED) CHADS 2 = 0 CHADS 2 = 1 CHADS 2 2 Increasing stroke risk None ASA OAC OAC OAC No RF Female or vascular disease Age 65 female + vascular disease ASA is a reasonable alternative in some as indicated by risk-benefit Dabigatran, rivaroxaban or apixaban is preferred OAC over warfarin in most pt Skanes AC et al. Can J Cardiol 28:125, 2012 2013 MFMER 3263885-41

Proposed Use of Anticoagulants in AF Needs Warfarin based on CHADS2 Score 7 out 10 INR >2 Avoid Dabigatran in patient's with CAD < 7 out 10 INR>2 High dose PPI may inhibit absorption of Dabigatran Renal failure patients warfarin may be safer CHADS 2 2-3 Age <75 Age >75 CHADS 2 >3 Continue Warfarin Dabigatran Apixaban Rivaroxaban Non compliant patients better off with warfarin longer acting Skanes AC et al. Can J Cardiol 28:125, 2012 2013 MFMER 3263885-42

NOAC Peri-procedural Management 2013 MFMER 3263885-43

Pre-Procedural Recommendations How do we do it? Define the surgical date Define the creatinine clearance If 50, stop 2-4 days prior If < 50, stop 5-7 days prior If high risk of hemorrhage, check preoperative thrombin time to ensure complete elimination 2013 MFMER 3263885-44

Last Intake of Drug Before Elective Surgical Intervention 2013 MFMER 3263885-45

Bleeding While Using a NOAC Mild Bleeding Moderate Severe Bleeding Life-Threatening Bleeding Delay or discontinue next dose Reconsider concomitant medication + Supportive Measures Mechanical compression Surgical hemostasis Fluid replacement (colloids if needed) RBC substitution if needed Fresh frozen plasma (as plasma expander) Platelet substitution (if platelet count 60 x 10 9 /L) For Dabigatran Maintain adequate diuresis Consider hemodialysis (Charcoal hemoperfusion? Await more data) + Consider PCC (e.g., CoFact ) 25 U/kg; repeat 1x/2x if indicated apcc (Feiba ) 50 IE/kg; max 200 IE/kg/day ((rfviia (NovoSeven ) 90 µg/kg no data about additional benefit) 2013 MFMER 3263885-46

Case 60-year-old with diabetes, HTN and atrial fibrillation Home meds includes: Lisinopril 10 mg daily Metoprolol 50 mg Bid, Rivaroxaban 20 mg daily, Atrovastatin 10 mg daily Admitted for chest pain Coronary angiogram showed ~ 80% stenosis in the LAD What would be your recommendations for anticoagulation? 2013 MFMER 3263885-47

A. Proceed with bare metal stent; stop Rivaroxaban (ASA 81 mg, Clopidogrel 75 mg and warfarin combination for 1 month) B. Proceed with bare metal stent; continue Rivaroxaban add ASA and Clopidogrel C. Proceed with drug eluting stent; continue Rivaroxaban add ASA and Clopidogrel 2013 MFMER 3263885-48

What if he had no Diabetes or HTN? A. Proceed with bare metal stent; stop Rivaroxaban (ASA 81 mg, Clopidogrel 75 mg and warfarin combination for 1 month) B. Proceed with bare metal stent; continue Rivaroxaban add ASA and Clopidogrel C. Proceed with drug eluting stent; continue Rivaroxaban add ASA and Clopidogrel 2013 MFMER 3263885-49

85-F mild dementia, HTN and atrial fibrillation She had few falls over the past year What would be your choice for anticoagulation? 2013 MFMER 3263885-50

Warfarin (INR 2-3) Rivaroxaban 20 mg once daily Rivaroxaban 15 mg one daily Apixaban 5 mg BID 2013 MFMER 3263885-51

What if she has Cr of 1.7? Warfarin (INR 2-3) Rivaroxaban 20 mg once daily Rivaroxaban 15 mg one daily Apixaban 5 mg BID 2013 MFMER 3263885-52

What if she has used Warfarin for 7 Years? Warfarin (INR 2-3) Rivaroxaban 20 mg once daily Rivaroxaban 15 mg one daily Apixaban 5 mg BID 2013 MFMER 3263885-53

Thank You Questions 2013 MFMER 3263885-54

Management of NOAC Therapy for AFib Following PCI 2011 MFMER slide-55 2013 MFMER 3263885-55

75 yr M, Acute anterior (STEMI) AF on rivaroxaban (20mg OD), DMII, HTN Rx 325mg ASA and 600mg of clopidogrel; Rivaroxaban held and UF heparin started (PCI) performed, DES proximal LAD lesion. Creatinine clearance is >60 ml/min and liver enzymes are normal 2011 MFMER slide-56 2013 MFMER 3263885-56

QUESTION A. Resume rivaroxaban 20 mg daily and continue single antiplatelet therapy with aspirin 81 mg only. B. Resume rivaroxaban 20 mg daily and continue dual antiplatelet therapy with aspirin 81 mg and clopidogrel 75 mg. C. Switch rivaroxaban to warfarin (target INR 2.0) and continue single antiplatelet therapy with aspirin 81 mg only. D. Switch rivaroxaban to warfarin (target INR 2.0) and continue single antiplatelet therapy with clopidogrel 75 mg only. 2011 MFMER slide-57 2013 MFMER 3263885-57

QUESTION A. Resume rivaroxaban 20 mg daily and continue single antiplatelet therapy with aspirin 81 mg only. B. Resume rivaroxaban 20 mg daily and continue dual antiplatelet therapy with aspirin 81 mg and clopidogrel 75 mg. C. Switch rivaroxaban to warfarin (target INR 2.0) and continue single antiplatelet therapy with aspirin 81 mg only. D. Switch rivaroxaban to warfarin (target INR 2.0) and continue single antiplatelet therapy with clopidogrel 75 mg only. 2011 MFMER slide-58 2013 MFMER 3263885-58

Post PCI on NOAC 5% of patients undergoing PCI have a preexisting indication for anticoagulant Post PCI, dual antiplatelet Rx (DAPT) for a minimum 1 to 12 months to prevent stent thrombosis with bare metal stents (BMS) and drug-eluting stents (DES) respectively 2011 MFMER slide-59 2013 MFMER 3263885-59

Current consensus gravitates towards triple therapy with aspirin, clopidogrel, and warfarin with an INR target of 2.0 2.5. However this therapy has been associated with significant increase in risk of major bleeding. Further, the role of new oral anticoagulants (NOACs) as well as newer antiplatelet agents, such as prasugrel and ticagrelor, with regard to triple therapy remains unclear due to lack of clinical trial data. 2011 MFMER slide-60 2013 MFMER 3263885-60

Questions & Discussion 2013 MFMER 3263885-61