Disclosure. Objectives. New Anticoagulants 6/5/2014 GHASSAN HADDAD M.D FHM. South Miami hospital Director of the Anticoagulation clinic.

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1 /5/1 New Anticoagulants: Opportunities, Challenges and Practical Considerations GHASSAN HADDAD M.D FHM. Chief of Hospital Medicine i South Miami hospital Director of the Anticoagulation clinic. Financial Interest/ Affiliation Grant/Research Support Consultant Disclosure Commercial Organization(s) Portela None Objectives New Anticoagulants 1. Outline approved indications and opportunities for the new anticoagulants using the evidence from clinical trials. Highlight common clinical scenarios surrounding the use of these new drugs 3. Describe limitations and practical considerations when using these anticoagulants Indications Opportunities Evidence-base Challenges Practical Considerations 1

2 /5/1 New Anticoagulants Current Anticoagulants XIIa Vitamin K Antagonist XIa IXa VIIa Unfractionated Thrombin Inhibitors heparins Low molecular Bivalirudin weight heparins Lepirudin Enoxaparin Argatroban Tinzaparin Dalteparin Xa VIIIa IIa (thrombin) Factor Xa Inhibitors Fondaparinux Va FIBRIN VTE=venous thromboembolism. Walenga JM, et al. Thromb Res ;:1-3. New and Emerging Anticoagulants XIIa Factor Xa Inhibitors Idraparinux Apixaban Edoxaban Otamixaban Betrixaban YM15 LY AVE5 Thrombin Inhibitors Dabigatran Etexilate XIa IXa Walenga JM, et al. Thromb Res ;:1-3. Xa IIa (thrombin) FIBRIN VIIa VIIIa Va Pharmacodynamics & Pharmacokinetics of Old and New Anticoagulants Parameter Apixaban Dabigatran Enoxaparin Fondaparinux Route Oral Oral Subcutaneous Subcutaneous Oral Oral Bioavailability (%) Time to peak concentration (h) Clotting factors inhibited Xa IIa IIa, Xa Xa Xa II, VII, IX, X Route of Primarily Renal Primarily Primarily Primarily Primarily elimination (%) fecal (5), () renal renal renal () bile renal (5) bile () Half life (h) Routine None None None None None INR/PT, coagulation (plasma (Ecarin clotting (plasma (plasma (plasma frequently monitoring antifactor Time optional) antifactor antifactor antifactor Xa optional) Xa optional) Xa optional) Xa optional) Farley et al. Orthopedics 9;3(1):35.

3 /5/1 CHADS -> CHA DS VASc HAS-BLED CHADS Risk Score CHADS- Score VASc Risk CHF 1 CHF or LVEF < 1 % Hypertension 1 Hypertension 1 Age > 75 1 Age > 75 Diabetes 1 Diabetes 1 Stroke/TIA/ Thromboembolism Stroke or TIA Vascular Disease 1 From ESC AF Guidelines Age guidelines/guidelines Documents/guidelines-afib-FT.pdf Female 1 Clinical Points Risk Factors / Bleeds/ Letter Characteristic Awarded Score 1 Pt years 1.13 H Hypertension A Abnormal renal & 1 or 1. liver function (1 point each) S Stroke 1.7 B Bleeding L Labile INRs 1 E Elderly 1 7 D Drugs or alcohol 1 or (1 point each) 9 Pisters et al. Chest 1; 13: Epidemiology of Atrial Fibrillation Estimated to affect >. million Americans Prevalence increasing as population ages Presence of AF confers a 5-fold higher risk for ischemic stroke Most common arrhythmia requiring hospitalization 1, hospital discharges/year Associated with >9, deaths/year Risk for recurrent severe stroke is increased.-fold in patients not treated with anticoagulants Lloyd-Jones D, et al. Circulation. 1;11:e-e15. AF=atrial fibrillation. Millions) Adults With AF ( Future of Atrial Fibrillation: ATRIA Study Projected Number of Adults With AF in the US From 1995 to Year Go AS, et al. JAMA. 1;5; AF=atrial fibrillation. 3

4 /5/1 Unmet Needs in Clinical Practice Surrounding Atrial Fibrillation Numerous food and drug interactions, narrow therapeutic index, requires monitoring, has a slow onset of action and has an unpredictable dose response Guidelines is recommended for stroke prevention in most patients with AF but it is underused Many physicians do not adhere to the guidelines Stroke risk stratification has had little effect on warfarin use Patient Management Elderly patients benefit most from an anticoagulant, but are less likely to receive it, largely because of their perceived risk of falling or bleeding Only ~5% of patients treated with warfarin are in the therapeutic range Ansell et al. Chest. 1;119:S-3S. Waldo et al. J Am Coll Cardiol. 5;:1793. RCTs of the New Anticoagulants RE-LY ROCKET-AF ARISTOTLE ENGAGE AF Drug Dabigatran Apixaban Endoxaban Dose 15, 11 (15) 5 (.5), 3 Investigated (mg) Dose Frequency Twice daily Once daily Twice daily Once daily Drug Target Factor Iia Factor Xa Factor Xa Factor Xa Subjects (n) 1,113 1, ~15, ~1, Trial Design Open label Double blind Double blind Double blind Blind dose Double dummy Double dummy Double dummy Primary Efficacy Endpoint Stroke/SEE Stroke/SEE Stroke/SEE Stroke/SEE Dose Adjustment for No Yes Yes Yes Drug Clearance (mg) Non-inferiority Hazard Ratio Margin RE-LY: A Non-inferiority Trial 1 efficacy outcome=stroke or systemic embolism 1 safety outcome=major bleeding Non-inferiority margin=1. Open (INR.-3.) N= Atrial fibrillation 1 Risk Factor Absence of contra-indications 951 centers in countries R Dabigatran Etexilate 11mg BID N= Blinded Dabigatran Etexilate 15mg BID N= RE-LY: 1 Outcome Superiority Analysis D 11mg vs D 15mg vs D 11mg D 15mg Annual Annual Annual RR P- RR P- Rate Rate Rate 95% CI value 95% CI value Stroke or 1.5% 1.1% 1.7% <.1 Systemic Embolism Stroke 1.% 1.% 1.%.9.1. < PROBE=Prospective Randomized Open Trial With Blinded Adjudication of Events. INR=international normalized ratio. Connolly SJ, et al. N Engl J Med. 9;31: RE-LY=Randomized Evaluation of Long-Term Anticoagulation Therapy. BID=two times per day.

5 t /5/1 Dabigatran 11 mg (D11) vs in Atrial Fibrillation Dabigatran vs 15 mg (D15) vs in Atrial Fibrillation Percent 1 D Percent 1 t D Stroke or SE RRR 9% (-11 to ) Major hemorrhage Stroke RRR % (7 to 31) RRR % (-13 to ) NNT 7 (9 to 17) Outcomes (At median y) Death RRR 9% (-3 to ) Stroke or SE RRR 3% (1 to 7) NNT 9 (5 to 19) Major hemorrhage Stroke RRR 7% (-7 to 19) RRR 3% (19 to 9) NNT 9 ( to 17) Outcomes (At median y) Death RRR 1% ( to 3) Connolly et al. N Engl J Med 9;31: Connolly et al. N Engl J Med 9;31: Dabigatran 15 mg (D15) vs 11 mg (D11) in Atrial Fibrillation Higher-dose Dabigatran Reduced Stroke but not Major Hemorrhage Compared to Percent 1 t D15 D Stroke or SE RRR 7% (9 to ) NNT 1 ( to 371) Stroke Death RRR 3% (11 to ) RRR 3% (-11 to 15) NNT 1 ( to 35) Outcomes (At median y). 5. Major hemorrhage RRR 1% ( to 3) Conclusion In patients with Afib, D15 twice daily reduced risk for stroke and systemic embolism more than warfarin and had similar rates of major hemorrhage Impact on Practice First oral anticoagulant in > 5 years. Dabigatran has no food or drug interactions. Now endorsed by the AHA/ACCF/HRS Guidelines Connolly et al. N Engl J Med 9;31:

6 /5/1 Nonvalvular AF, history of stroke, TIA, or embolism, or of the following: HF, HTN, age 75 years, or diabetes mellitus ROCKET-AF Trial: Treatment period 1-3 months mg once daily 15 mg once daily (creatinine clearance 3-9 ml/min at entry) R N=1, target INR,.5 (INR range:.-3.) Day 1 Day 3 after last dose In AF patients with a moderate to high risk of stroke, does rivaroxaban reduce the risk of major vascular events compared with warfarin? 1 study endpoint: composite of all-cause stroke and non-cns systemic embolism endpoints: composite of TIA, all-cause death, vascular death, and MI 1 safety endpoint: composite of major and clinically relevant non-major bleeding events Randomization completed in June 9; follow-up completed 1 Follow-up: up to years (until 5 primary outcome events have been observed) TIA=transient ischemic attack. HF=heart failure. HTN=hypertension INR=international normalized ratio. Patel et al. N Engl J Med 11; 35:3-91. End of treatment Follow-up Rocket-AF: Baseline Demographics CHADS Score (mean) (%) 3 (%) (%) 5 (%) (%) (N=71) (N=79) Prior VKA Use (%) 3 Congestive Heart Failure (%) 3 Hypertension (%) 9 91 Diabetes Mellitus (%) 39 Prior Stroke/TIA/Embolism (%) Prior Myocardial Infarction (%) 17 1 CHADS =a score that estimates the risk of stroke in patients with AF and AF=atrial fibrillation. includes Congestive heart failure, Hypertension, Age 75, Diabetes VKA=vitamin K antagonists. mellitus, and prior incidence of Stroke or Transient Ischemic Attack. TIA=transient ischemic attack. Patel et al. N Engl J Med 11; 35:3-91. Event Rates Are per 1 Patient-Years Based on Protocol Compliant on Treatment Population Primary Efficacy Outcome Stroke and Non-CNS Embolism Event Rate (%) Cumulative E Event Rate HR (95% CI):.79 (.,.9) P-value Non-inferiority: < Days From Randomization No. at risk: Patel et al. N Engl J Med 11; 35:3-91. ROCKET-AF: Primary Efficacy Outcome Stroke and Non-CNS Embolism Better Event Rate Event Rate HR (95% CI) On.79 Treatment (.5,.95) N=1,13 ITT N=1,171 Better.1. Event rates are per 1 patient-years. Based on safety on treatment or ITT through site notification populations. Patel et al. N Engl J Med 11; 35:3-91. TTR 57.%. (.7,1.3) ITT=intention to treat. P-value

7 /5/1 ROCKET-AF: Major and Non-Major Bleeding Hazard Ratio Outcome (n=71) (n=79) (95% CI) P-value Major and Non-major Bleeding ( ) Major Bleeding (.9-1.) > g/dl hemoglobin drop (1.3-1.) Transfusion ( ) Critical organ bleeding ( ) Bleeding causing death ( ) Intracranial hemorrhage (.7-.9) Patel et al. N Engl J Med 11; 35:3-91. Rocket-AF: Summary Efficacy: was noninferior to warfarin for prevention of stroke and non-cns embolism was superior to warfarin while patients were taking study drug By intention-to-treat, rivaroxaban was non-inferior to warfarin but did not achieve superiority Safety: Similar rates of bleeding and adverse events Less ICH and fatal bleeding with rivaroxaban Conclusion: is a proven alternative to warfarin for moderate- or high-risk patients with AF Patel et al. N Engl J Med 11; 35:3-91. CNS=central nervous system. ICH=intracranial hemorrhage. CHADS Scores: RE-LY and ROCKET-AF RE-LY 1 ROCKET-AF CHADS Dabigatran Dabigatran Score 11mg 15mg Mean % 3.% 1.% 3.7% 35.% 37.% 13% 13% 3-3.7% 3.% 3.1% 7% 7% 1. Connolly SJ, et al. N Engl J Med. 9;31: Patel et al. N Engl J Med 11; 35:3-91. Atrial Fibrillation with at Least One Additional Risk Factor for Stroke Inclusion risk factors Randomize Age 75 years double blind, Prior stroke, TIA, or SE double dummy HF or LVEF % Diabetes mellitus (n = 1,1) Hypertension Apixaban 5 mg oral twice daily (.5 mg BID in selected patients) Major exclusion criteria Mechanical prosthetic valve Severe renal insufficiency Need for aspirin plus thienopyridine (target INR -3) /warfarin placebo adjusted by INR/sham INR based on encrypted point-of-care testing device Primary outcome: stroke or systemic embolism Hierarchical testing: non-inferiority for primary outcome, superiority for primary outcome, major bleeding, death 7

8 /5/1 Primary Outcome Stroke (ischemic or hemorrhagic) or systemic embolism P (non-inferiority)<.1 1% RRR Apixaban 1 patients, 1.7% per year 5 patients, 1.% per year HR.79 (95% CI,..95); P (superiority)=.11 No. at Risk Apixaban Efficacy Outcomes Apixaban Outcome (N=91) (N=91) P HR (95% CI) Event Rate Event Rate Value (%/yr) (%/yr) Stroke or systemic embolism* (.,.95).11 Stroke (.5,.95).1 Ischemic or uncertain (.7, 1.13). Hemorrhagic (.35,.75) <.1 Systemic embolism (SE) (., 1.75).7 All-cause death* (.,.99).7 Stroke, SE, or all-cause death (.1,.9).19 Myocardial infarction (., 1.17).37 * Part of sequential testing sequence preserving the overall type I error Major Bleeding ISTH definition 31% RRR Bleeding Outcomes Outcome Apixaban (N=9) Event Rate (%/yr) (N=95) Event Rate (%/yr) HR (95% CI) P Value Primary safety outcome: ISTH major bleeding* (.,.) <.1 Intracranial.33.. (.3,.5) <.1 Apixaban 37 patients,.13% per year patients, 3.9% per year HR.9 (95% CI,..); P<.1 No. at Risk Apixaban Gastrointestinal (.9 (.7, 1.15) 15) Major or clinically relevant non-major bleeding.7.1. (.1,.75) <.1 GUSTO severe bleeding (.35,.) <.1 TIMI major bleeding (.,.7) <.1 Any bleeding (.,.75) <.1 * Part of sequential testing sequence preserving the overall type I error

9 /5/1 Summary 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 1% (p=.1) Reduces major bleeding by 31% (p<.1) Reduces mortality by 11% (p=.7) 7) with consistent effects across all major subgroups and with fewer study drug discontinuations on apixaban than on warfarin, consistent with good tolerability. Einstein DVT: Study Design Randomized, open-label, event-driven, non-inferiority study Up to hours heparins / fondaparinux treatment permitted before study entry 99 primary efficacy outcomes needed Confirmed symptomatic DVT without symptomatic PE N=3,9 R Treatment period: 3, or 1 months 15 mg bid x 3 wks followed by mg po qd Enoxaparin 1. mg/kg bid 5 days, followed by VKA INR range -3 Day 1 Day 1 3-day observation period EINSTEIN Investigators. N Engl J Med. 1 Dec 3;33(): Primary Efficacy Outcome Analysis Enoxaparin / VKA (n=1,731) (n=1,71) n (%) n (%) First symptomatic recurrent VTE 3 (.1) 51 (3.) Recurrent DVT 1 (.) (1.) Recurrent DVT + PE 1 (<.1) () Non-fatal PE (1.) 1 (1.) Fatal PE / unexplained death where (.) (.3) PE cannot be ruled out Hazard ratio superior non-inferior inferior p=.7 for superiority (two-sided) p=.1 for non-superiority (one-sided) ITT population EINSTEIN Investigators. N Engl J Med. 1 Dec 3;33(): Principal Safety Outcome Analysis Enox / VKA HR (n=1,71) (n=1,711) (95% CI) n (%) n (%) p value First major or clinically relevant 139 (.1) 13 (.1).97 (.7-1.) Non-major bleeding p=.77 Major bleeding 1 (.) (1.) Contributing to death 1 (<.1) 5 (.3) In a critical site 3 (.) 3 (.) Associated with fall in Hb g/dl 1 (.) 1 (.7) and/or transfusion of units Clinically relevant non-major 19 (7.5) 1 (7.1) bleeding Safety population EINSTEIN Investigators. N Engl J Med. 1 Dec 3;33():

10 /5/1 Eighth ACCP Recommendations: Total Knee or Hip Replacement LMWH (grade 1A) Adjusted-dose warfarin (grade 1A) Fondaparinux (grade 1A) IPC (grade 1B-Only for TKA) LDUH, ASA, dextran, GCS, VFP not recommended (1A) Optimal duration of prophylaxis after THR and TKR: at least 7-1 days of LMWH (grade 1A) Extended out-of-hospital prophylaxis for THR or HFS for upto -35 days (grade 1A) Geerts et al. CHEST ; 31S-53S ents % of patie : Prophylaxis in Major Orthopedic Surgery VTE/Death * P <.1 ** P =.1 * * Record 1 Record Record 3 Record Eriksson B, et al. N Engl J Med. ;35: Kakkar AK, et al. Lancet. ;37: Lassen MR, et al. N Engl J Med. ;35:77-7. Turpie AG, et al. Lancet. 9;373(97): * ** tients % of pa Major Bleeding Record 1 Enoxaparin Record Record 3 Record 1, = total hip replacement Record 3, = total knee replacement Record Pharmacokinetic Properties of New Anticoagulants Preoperative Interruption of New Oral Anticoagulants: An Empiric Formulation New Anticoagulants Dabigatran Apixaban Direct factor Mode of IIa (thrombin) Direct factor Direct factor action inhibitor Xa inhibitor Xa inhibitor Bioavailability (F wt ).5% % % Peak action (t max ) 1-3 hrs 1-3 hrs 1-3 hrs Elimination half-life (t 1/ ) 1-17 hrs 9-15 hrs 9-1 hrs Route of clearance 1% renal 5% renal 5% renal Involvement of CYP minor minor minor Douketis. Current Pharmaceutical Design, 1, Vol 1, No 31 Aim for No or Minimal Aim for Mild-moderate Residual Anticoagulant Residual Anticoagulant Effect at Surgery (-5 Drug Effect at Surgery (-3 Drug Half-Lives Separate Half Lives Separate Drug (Half-Life) Renal Function Last Dose & Surgery) Last dose & Surgery) Dabigatran Normal or Mild Last dose: Day -3 Last dose: Day - t 1/ = 1 hrs Impairment before surgery before surgery (CrCl >5 ml/min) (skip doses) (skip doses) t 1/ = 15-1 hrs Moderate Impairment Last dose: Day - to Last dose: Day -3 (CrCl 3-5 ml/min) Day -5 before surgery before surgery (skip - doses) (skip doses) Normal or Mild Last dose: Day -3 Last dose: Day -3 t 1/ = 9 hrs Impairment before surgery before surgery (CrCl >5 ml/min) (skip doses) (skip doses) Apixaban as with rivaroxaban as with rivaroxaban as with rivaroxaban t 1/ = 9 hrs Douketis. Current Pharmaceutical Design, 1, Vol 1, No 31 1

11 /5/1 Postoperative Resumption of New Oral Anticoagulants: An Empiric Formulation Minor surgery or Procedure (low bleeding risk) Major surgery (high bleeding risk) Dabigatran resume on day after surgery resume days after surgery ( hrs postoperatively), ( hrs postoperatively), 15 mg twice-daily 15 mg twice-daily* resume on day after surgery resume days after surgery ( hrs postoperatively), ( hrs postoperatively), 1 mg daily 1 mg daily Apixaban as with rivaroxaban as with rivaroxaban *for patients at high risk for thromboembolism, consider administering a reduced dose of dabigatran eg., mg once-daily) on evening after surgery and on the first postoperative day. Douketis. Current Pharmaceutical Design, 1, Vol 1, No 31 11