New Strategies in the World of Anticoagulant Therapy. October 13, 2012 Elaine M. Hylek, MD, MPH Boston University Medical Center

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1 New Strategies in the World of Anticoagulant Therapy October 13, 2012 Elaine M. Hylek, MD, MPH Boston University Medical Center

2 Presenter Disclosure Information Elaine M. Hylek, MD, MPH Research: NIH/NINDS, NIH/NHLBI Bristol-Myers Squibb-Executive Steering Committee ARISTOTLE trial, Ortho-McNeil-Executive Steering Committee ORBIT-AF Registry Advisory Boards: Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, Pfizer UNLABELED/UNAPPROVED USES DISCLOSURE: This presentation discusses the unapproved use of apixaban for stroke prevention in atrial fibrillation.

3 Projected number of persons with AF in the U.S. between 2000 and 2050 Assumes no further increase in age-adjusted AF incidence (solid curve) and assumes a continued increase in incidence rate as evident in 1980 to 2000 (dotted curve) Miyasaka, Y. et al. Circulation 2006;114:

4 TEE depicting a large LAA thrombus attached to the lateral wall Hesse, B. et al. Circulation 2006;113:e e

5 Efficacy of Warfarin in Atrial Fibrillation Five Randomized Trials in Non-Rheumatic AF Study Warfarin (#) Cont. (#) INR RR p-value AFASAK % SPAF % 0.01 BAATAF % <0.05 CAFA* % 0.25 SPINAF % *Stopped early due to published positive results 66% overall risk reduction for stroke

6 HAZARDS OF WARFARIN Budnitz D, et al. NEJM 2012

7 HAZARDS OF WARFARIN Budnitz D, et al. NEJM 2012

8 Warfarin dosing is complex Factors that correlate with warfarin dose Age Body surface area or weight Amiodarone Other drugs (e.g. acetaminophen) Race Sex Plasma vitamin K level Decompensated CHF Active malignancy Genetic status CYP2C9 (up to 15%) VKORC1 (up to 25%) Age, sex, weight (10 20%) Other factors (up to 40%) CHF = congestive heart failure; CYP2C9 = cytochrome P450 2C9; INR = international normalized ratio; VKORC1 = vitamin K epoxide reductase complex subunit 1

9 Hylek, EM. J Cardiovasc Med 2009;10:605-09

10 INTRACRANIAL HEMORRHAGE ON WARFARIN OR 80 years of age 2.8 (1.3 to 5.8) p< /3 occur with an INR in range 46% mortality 17% major deficit Hylek EM, Singer DE. Ann Intern Med 1994

11 Transitions and Fragmentation of Care 86 year old male admitted to hospital with decompensated heart failure. Maintenance weekly warfarin dose prior to admission: 50 mg: 5 mg tablet: 1 ½ tablets per day M-Sat M and 1 tablet on Sun. Discharged on 7.5 mg tablet. Patient continued to take 1 ½ tablets per day. Readmitted with INR=9.2

12 Optimizing Benefit and Reducing Risk Hemorrhage Thrombosis

13 Novel Anticoagulants TF/VIIa X IX Rivaroxaban Apixaban Edoxaban IXa VIIIa Xa Va II Dabigatran IIa Fibrinogen Fibrin Adapted from Turpie and Weitz & Bates, J Thromb Haemost 2007

14 RE-LY study design open-label Atrial fibrillation with 1 risk factor Absence of contraindications R Warfarin 1 mg, 3 mg, 5 mg (INR ) N=6000 Dabigatran etexilate 110 mg bid N=6000 Dabigatran etexilate 150 mg bid N=6000 Primary objective: To establish the non-inferiority of dabigatran etexilate to warfarin Ezekowitz MD, et al. Am Heart J 2009;157: Connolly SJ., et al. NEJM published online on Aug 30th DOI /NEJMoa

15 RE-LY Time to first stroke / SEE 0.05 RR 0.91 (95% CI: ) p<0.001 (noninferiority) p=0.34 (superiority) Cumulative hazard rates Warfarin Dabigatran etexilate 110 mg Dabigatran etexilate 150 mg 1.69% 1.53% 1.11% RRR 34% RR 0.66 (95% CI: ) p<0.001 (noninferiority) p<0.001 (superiority) Years Connolly SJ., et al. NEJM Aug 30th DOI /NEJMoa

16 Hemorrhagic stroke 50 RR 0.31 (95% CI: ) p<0.001 (sup) RR 0.26 (95% CI: ) p<0.001 (sup) Number of events % RRR 69% % RRR 74% % D110 mg BID D150 mg BID Warfarin 6,015 6,076 6,022 Connolly SJ., et al. NEJM published online on Aug 30th DOI /NEJMoa

17 Incidence of Major Hemorrhage Dabigatran vs Warfarin (RE-LY) Rate RR P Dabigatran 150 mg BID 3.11% Warfarin 3.36% (superiority) More GI bleeds with 150 mg dose compared to warfarin.

18 Discontinuations and Adverse Effects Dabigatran 110 Dabigatran 150 Warfarin DYSPEPSIA 11.8%* 11.3%* 5.8% *p<0.001 MYOCARDIAL 0.82% 0.81% 0.64% INFARCTION

19 Dabigatran Trials Meta-analysis: Mortality Uchino, K. et al. Arch Intern Med 2012;0:archinternmed v1-6.

20 ROCKET AF Protocol Schema Atrial Fibrillation Rivaroxaban 20 mg daily 15 mg for Cr Cl Randomize Double blind / Double Dummy (n ~ 14,000) Warfarin INR target ( inclusive) At least 2 of: CHF Hypertension Age 75 Diabetes AND/OR Stroke, TIA or Systemic Embolus Monthly Monitoring and adherence to standard of care guidelines Primary Endpoint: Stroke or non-cns Systemic Embolism Statistics: non-inferiority, >95% power, 2.3% warfarin event rate From Califf, DCRI

21 ROCKET-AF Primary Efficacy Outcome Stroke and non-cns Embolism On Treatment N= 14,143 Rivaroxaban Event Rate Warfarin Event Rate HR (95% CI) 0.79 (0.65,0.95) P-value ITT N= 14, (0.74,1.03) Rivaroxaban better Warfarin better Event Rates are per 100 patient-years Based on Safety on Treatment or Intention-to-Treat thru Site Notification populations

22 Key Secondary Efficacy Outcomes Rivaroxaban Warfarin Event Rate Event Rate HR (95% CI) P-value Vascular Death, Stroke, Embolism (0.74, 0.99) Stroke Type Hemorrhagic (0.37, 0.93) Ischemic (0.75, 1.17) Unknown Type (0.25, 1.67) Non-CNS Embolism (0.09, 0.61) Myocardial Infarction (0.63, 1.06) All Cause Mortality (0.70, 1.02) Vascular (0.73, 1.10) Non-vascular (0.36, 1.08) Unknown Cause (0.40, 1.41) 0.370

23 Primary Safety Outcomes Rivaroxaban Warfarin Event Rate or N (Rate) Event Rate or N (Rate) HR (95% CI) P-value Major (0.90, 1.20) >2 g/dl Hgb drop (1.03, 1.44) Transfusion (> 2 units) (1.01, 1.55) Critical organ bleeding (0.53, 0.91) Bleeding causing death (0.31, 0.79) Intracranial Hemorrhage 55 (0.49) 84 (0.74) 0.67 (0.47, 0.94) Intraparenchymal 37 (0.33) 56 (0.49) 0.67 (0.44, 1.02) Intraventricular 2 (0.02) 4 (0.04) Subdural 14 (0.13) 27 (0.27) 0.53 (0.28, 1.00) Subarachnoid 4 (0.04) 1 (0.01) Event Rates are per 100 patient-years Based on Safety on Treatment Population

24 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) 2 Warfarin/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

25 Primary Outcome Stroke (ischemic or hemorrhagic) or systemic embolism P (non-inferiority)< % RRR Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per year HR 0.79 (95% CI, ); P (superiority)=0.011 No. at Risk Apixaban Warfarin

26 Efficacy Outcomes Outcome Apixaban (N=9120) Event Rate (%/yr) Warfarin (N=9081) Event Rate (%/yr) HR (95% CI) P Value Stroke or systemic embolism* (0.66, 0.95) Stroke (0.65, 0.95) Ischemic or uncertain (0.74, 1.13) 0.42 Hemorrhagic (0.35, 0.75) <0.001 Systemic embolism (SE) (0.44, 1.75) 0.70 All-cause death* (0.80, 0.998) Stroke, SE, or all-cause death (0.81, 0.98) Myocardial infarction (0.66, 1.17) 0.37 * Part of sequential testing sequence preserving the overall type I error

27 Bleeding Outcomes Outcome Primary safety outcome: ISTH major bleeding* Apixaban (N=9088) Event Rate (%/yr) Warfarin (N=9052) Event Rate (%/yr) HR (95% CI) P Value (0.60, 0.80) <0.001 Intracranial (0.30, 0.58) <0.001 Gastrointestinal (0.70, 1.15) 0.37 Major or clinically relevant non-major bleeding (0.61, 0.75) <0.001 GUSTO severe bleeding (0.35, 0.60) <0.001 TIMI major bleeding (0.46, 0.70) <0.001 Any bleeding (0.68, 0.75) <0.001 * Part of sequential testing sequence preserving the overall type I error

28 New Oral Anticoagulants: Summary Property Dabigatran Rivaroxaban Apixaban Edoxaban Route of admin Oral Oral Oral Oral Target Thrombin FXa FXa FXa Dosing Twice daily Once daily Twice daily Once daily Monitoring required No No No No Half-life life (hrs) Mode of elimination Renal 80% Renal ~ 36% Renal ~ 25% Renal ~ 35%

29 Practical Considerations Translation across indication Atrial fibrillation and valvular heart disease Atrial fibrillation and ACS Atrial fibrillation and DVT or PE Reversibility-trauma, hemorrhage, surgery Select situations in which monitoring would be desirable Renal function PGP and CYP interactions

30 Case

31 Gender: Age: Indication for OAC: Associated diseases: Medications: Habits: Male 73 years old Paroxysmal non-valvular AF Hypertension, peripheral arterial disease, chronic kidney disease Stage III, GFR 48 ACEI, metoprolol, hydrochlorothiazide, atorvastatin Smoker, very active lifestyle, doesn t like doctors or taking medications

32 Camm AJ et al. Eur Heart J 2010;31: CHA 2 DS 2 VASc score= 3

33 Self monitors warfarin. He is not interested in switching to a new oral anticoagulant. He thinks he is doing fine with self management. Average INR monitoring frequency: Weekly Average TTR: 62% Previous major bleeding: Diverticular bleed 5 years ago

34 2011 ACCF/AHA/HRS Focused Update Selection of patients with AF and 1 risk factor for stroke who could benefit from treatment with dabigatran as opposed to warfarin should consider individual clinical features, including the ability to comply with twice-daily dosing, availability of an anticoagulation management program, patient preferences, cost, and other factors Because of the twice-daily dosing and greater risk of non-hemorrhagic side effects with dabigatran, patients already taking warfarin with excellent INR control may have little to gain by switching to dabigatran. Wann LS, et al. Heart Rhythm March 2011

35 Effect of TTR on Primary Endpoints In RELY Wallentin, et al. Lancet 2010

36 He presents to your office with symptoms concerning for TIA. Sudden onset of right-sided visual disturbance 10 days ago. Thinks the symptoms lasted 20 minutes. When his vision spontaneously recovered, he decided to wait to seek medical advice. VS: BP=138/72, HR=70 Cardiac: RRR, S1S2 no m/r/g Vascular: carotids 2+ no bruits Neuro exam: CN intact, motor 5/5 all muscle groups, no sensory deficit, cerebellar testing intact INR today: 2.1

37 What would you do now? 1. Continue warfarin with INR target range Add ASA 81mg and continue warfarin INR range Switch to dabigatran 150 mg twice daily 4. Switch to rivaroxaban 20 mg per day 5. Switch to rivaroxaban 15 mg per day

38 AGE RENAL FUNCTION BLEEDING HISTORY ADHERENCE COST PATIENT PREFERENCE

39 RE-LY: Prior stroke subgroup analysis - stroke or systemic embolism Warfarin D 110 mg BID D 150 mg BID Overall study population Annual rate (%) RR vs. warfarin P value 0.34 <0.001 Prior stroke/tia Annual rate (%) RR vs. warfarin P value Diener HC et al. ISC 2010; abstr 195

40 RE-LY: Prior stroke subgroup analysis - haemorrhagic stroke Warfarin D 110 mg BID D 150 mg BID Overall study population Annual rate (%) RR vs warfarin P value <0.001 <0.001 Prior stroke/tia Annual rate (%) RR vs. warfarin P value Diener HC et al. ISC 2010; abstr 195

41 How would you perform the transition after stopping warfarin? 1. Start dabigatran the same day 2. Start dabigatran after 48 hrs 3. Check INR after 48 hrs and start dabigatran when INR < Start rivaroxaban when INR < 3.0

42 Stroke/systemic embolism: no Bleeding: no Compliance: Side effect: full no He states he doesn t like the new medication. Wants to go back to warfarin. He feels more secure knowing how thin his blood is with selftesting.

43 If you decide to switch back to warfarin, would you: 1. Stop rivaroxaban and start warfarin the same day with his previous maintenance dose 2. Transition to LMWH and overlap with warfarin until INR > Continue rivaroxaban while initiating warfarin, overlap treatment for 2-3 days. CAUTION re: reliance on INR in this setting.

44 Gender: Female Age: 74 years old Indication for OAC: Paroxysmal non-valvular AF Associated diseases: Medications: Hypertension, peripheral arterial disease, chronic kidney disease Stage III, GFR 40, osteoarthritis ACEI, metoprolol, hydrochlorothiazide, atorvastatin, occasional NSAID

45 Hylek, EM. J Cardiovasc Med 2009;10:605-09

46 Gallagher AM et al. Thromb Haemost 2011;106:968-77

47 Patients on warfarin with: TTR < 50-55% Grade of recommendation A history of cerebral bleeding A time-demanding work schedule/important logistic problems - concomitant treatment with interfering drugs (INR fluctuations) - strong wish to take new OAC/unwillingness to frequent blood testing - Pengo V et al. Thromb Haemost 2011:106:868-76

48 The HAS BLED score is: whereby a score of 3 indicates high risk, and some caution and regular review of the patient is needed following the initiation of antithrombotic therapy, Camm AJ et al. Eur Heart J 2010;31:

49 HAS BLED score performed better than the HEMORR2HAGES and ATRIA scores, as reflected by ROC analysis, reclassification analysis, and decision curve analysis. HAS BLED was the only score that demonstrated a significant predictive performance for intracranial hemorrhage (c index: 0.75; p=0.03). An ATRIA score>3 was not significantly associated with the risk for any clinically relevant bleeding on Cox regression or on ROC analysis (c index: 0.50; p=0.87).

50 Polypharmacy and Non-adherence Strongest predictor of non-adherence is the # of medications Non-adherence rates estimated 25-50% Intentional about 75% of the time Changes in regimen made by patients to: -increase convenience -reduce adverse effects or -decrease refill expense

51 Medication Adherence by Dose Frequency (systematic review: 76 studies ) AJ Claxton et al. Clinical Therapeutics :

52 What agent would you choose for this patient? 1. Dabigatran 150 mg BID 2. Dabigatran 75 mg BID 3. Rivaroxaban 20 mg QD 4. Rivaroxaban 15 mg QD 5. Continue warfarin with closer follow-up; engage family in care

53 Presents to emergency department with complaints of dizziness. States hasn t felt well, arthritis giving her problems. Increased NSAIDS. Also notes decreased oral intake due to summer heat. Hasn t missed any medications after extended office discussion 3 months ago. VS: BP=102/62, HR=120, appears volume depleted Lungs-clear Cardiac: Tachy, S1S2 no m/r/g Abd: soft, mild tenderness midepigastric area Rectal: FOB+, melena Hemoglobin: egfr: 7.6 mg/dl 24 ml/min

54 Pharmacokinetics with Varying Levels of Renal Dysfunction Elimination half life with CrCl > 80 ml/min Elimination half life with CrCl ml/min Elimination half life with CrCl ml/min Elimination half life with CrCl < 30 ml/min Apixaban Dabigatran Rivaroxaban 15.1 hr 13.8 hr 8.3 hr 14.6 hr 16.6 hr 8.7 hr 17.6 hr 18.7 hr 9.0 hr 17.3 hr 27.5 hr 9.5 hr Kaatz S, et al. Am J Hematol May;87 Suppl 1:S PMID:

55 Guide to the Management of Bleeding in Patients Taking NOAC Patients with bleeding on NOAC therapy Mild bleeding Moderate-Severe bleeding Life-threatening bleeding Delay next dose or discontinue treatment as appropriate Mechanical compression Surgical intervention Fluid replacement and hemodynamic support Blood product transfusion Oral charcoal Hemodialysis? Prothrombin Complex Concentrate? (Circulation 2011;124:1573-9) Consideration of rfviia or PCC Charcoal filtration? Prothrombin Complex Concentrate (Circulation 2011;124:1573-9) Hankey GJ and Eikelboom JW. Circulation. 2011; 123:

56 Novel anticoagulants may be safer in the elderly population due to their wider therapeutic index, shorter t 1/2, lack of dietary interference, and fewer drug interactions. Older individuals with AF are at the highest risk of stroke, the highest risk of hemorrhage, and the highest risk of stopping therapy. Further research is needed to inform commonly encountered clinical situations to optimize the effectiveness of these novel agents in routine practice.