Update on Anticoagulation & Atrial Fibrillation

Update on Anticoagulation & Atrial Fibrillation Review recent changes in guidelines for VTE prophylaxis Discuss risk benefit assessment for stroke prevention in atrial fibrillation Review recent updates to stroke prevention for atrial fibrillation Discuss new oral anticoagulants 1

Unit dose products and prefilled syringes preferred Use approved protocols to manage anticoagulation Implement a policy to address baseline risk and ongoing monitoring for anti coagulated patients Educate all providers and staff re: Monitoring, adherence, drug food interactions, ADRs Audit and improve safety practices AMDA, Joint Commission LTC Grade of recommendation Risk/Benefit Considerations 1A Strong recommendation, High quality evidence 1B Strong recommendation, Moderate quality evidence 1C Strong recommendation, Low/very low quality evidence 2A Weak recommendation, High quality evidence 2B Weak recommendation, Moderate quality evidence 2c Weak recommendation, Low/Very low quality evidence Benefits > burdens. Appropriate for most patients Benefits> burdens, but important study limitations OK for most patients Benefits>burdens, weaker studies. OK for most patients in many situations Benefits burdens. Strong studies. Patient circumstances and preferences important Benefits burdens. Study limitations. Patient circumstances and preferences important Uncertain benefit/burden balance. Weak studies. Other alternatives equally reasonable 2

Hospitalization increases VTE risk 8 fold Medical pts suffer 50 75% of hospital VTE events For 1,000 high risk patients, 34 fewer symptomatic VTE (CI 0 51) with prophylaxis No clear benefit with prophylaxis if low risk Patient preferences 1 bleeding event 1 symptomatic VTE averted 1 intracranial bleed 2.5 symptomatic VTE Kahn ST Chest 2012;141:e195S e226s Risk Factor Points Active CA 3 Prior VTE 3 Low mobility (Bed rest w BR privileges 3 days) 3 High Risk Known thrombophilic defect 3 4 points VTE rate 11% Trauma or surgery 1 month 2 Age 70 1 Heart or respiratory failure 1 Low Risk Acute MI or Acute stroke 1 VTE rate 0.3% Acute infection or rheumatologic disorder 1 BMI 30 Active hormonal treatment 1 1 Barbar S, J Thromb Haemost. 2010;8(11):2450 57 3

Risk Factor Points Risk Factor Points GFR 30 59 1 GFR<30 2.5 Male 1 INR>1.5 2.5 Score < 7 0.4% Major 1.5% Any Age 40 84 1.5 Age 85 3.5 bleeding Current CA 2 Platelets < 50 K 4 Rheumatic dz 2 Bleeding < 3 mo before Central vein catheter 2 Active UGI ulcer 4.5 4 Score 7 4.1 % Major 7.9% Any bleeding ICU/CCU 2.5 Decousus H, Chest High risk medical patients Prophylaxis with LDUH, LMWH or fondaparinux (1B) Low risk medical patients No anticoagulant or mechanical prophylaxis (1B) Stop anticoagulant when mobile or discharged (1B) Kahn ST Chest 2012;141:e195S e226s 4

High risk patients who are bleeding or at high risk of bleeding No anticoagulant prophylaxis (1B) Substitute Graded Compression Stockings (GCS) (2C) or Intermittent Pneumatic Compression (IPC) devices (2C) When bleeding stops or risk is low Substitute anticoagulant prophylaxis for mechanical (2B) Kahn ST Chest 2012;141:e195S e226s Baseline VTE risk s/p Hip Fracture Surgery (HFS) Before 1980 15 30% symptomatic VTE 1980 89 5% 1989 2001 1 2% Shorter LOS Quicker mobilization and ambulation Surgical technique 5

Symptomatic VTE on LMWH is 0.8% LMWH reduces DVT risk 50 60%, Off prophylaxis symptomatic DVT rate 1.8% Symptomatic PE on LMWH 0.35% LMWH reduce PE risk 66% Off prophylaxis symptomatic PE rate 1% 35 day off prophylaxis symptomatic VTE rate 4.3% Post op Prophylaxis Day 0 14 Post op Prophylaxis Day 15 35 Post op Prophylaxis Day o 35 No Prophylaxis VTE 2.8% PE 1% DVT 1.8% VTE 1.5% PE 0.5% DVT 1% VTE 4.3% PE 1.5% DVT 2.8% LMWH VTE 1.15% PE 0.35% DVT 0.8% VTE 0.65% PE 0.2% DVT 0.45% VTE 1.8% PE 0.55% DVT 1.25% Median off prophylaxis bleeding rate 1.5% Bleeding risk factor schema not well tested However, for major orthopedic surgery, the surgeryspecific risk far outweighs the contribution of the patient specific factors 6

Total Hip or Total Knee Arthroplasty Minimum 10 14 days of LMWH, Fondaparinux (1B) Apixaban, Dabigatran, Rivaroxaban (1B) LDUH (1B) Adjusted dose VKA (1B) Aspirin (1B) Intermitted Pneumatic Cuff device (1C) Total Hip or Total Knee Arthroplasty LMWH preferred agent over Fondaparinux (2B) Apixaban, Dabigatran, Rivaroxaban (2B) LDUH (2B) Adjusted dose VKA (2C) Aspirin (2C) 7

Hip Fracture Surgery Minimum of 10 14 days of; LMWH, Fondaparinux (1B) LDUH (1B) Adjusted dose VKA (1B) Aspirin (1B) IPCD (1C) 18 hours Hip Fracture Surgery LMWH preferred agent over; Fondaparinux, LDUH (2B) Adjusted dose VKA, aspirin (2C) (NO DATA on other oral anticoagulants) 35 days preferred over 14 days (2B) Major orthopedic surgery patients who decline or are uncooperative with injections or IPCD Recommended over other alternatives; Apixiban or dabigatran (1B) Rivaroxaban or adjusted dose VKA if API, DAB unavailable (1B) 8

Rivaroxaban approved for THA & TKA Not evaluated in HFS >10,000 pts in RCTs 10mg rivaroxaban/day vs enoxaparin 40mg/day LMWH wins out overall RIV reduces symptomatic DVT by 5/1,000 v ENOX RIV increases major bleeding by 9/1,000 v ENOX Dabigatran NOT approved for THA, TKA Not evaluated in HFS > 10,000 pts in RCTs DAB 200mg or 150 mg once daily vs ENOX 40 mg/day Overall, DAB similar to ENOX Quirky exceptions for the extremely curious Apixaban NOT approved for TKA, THA, HFS in US > 12,000 pts in RCT for TKA THA No HFS studies API 2.5 mg Q 12H v ENOX 40mg/day Overall, similar to LMWH Possibly 7 fewer DVT per 1,000 No difference in PE, mortality 9

ASA 160mg/day for 35 days (n=17,444) 43% got LMWH or LDUH!? 3 Fewer Non fatal PE per 1,000 over 35 days 15/1,000 vs 12/1,000 ( NS) 8 fewer symptomatic DVT per 1,000 over 35 days 20/1,000 vs 28/1,000 3 more major bleeding episodes 30/1,000 vs 27/1,000 2 fewer deaths 54/1,0o00 vs 52/1,000 (NS) Commonest sustained arrhythmia 1 Responsible for 15% of ischemic strokes Rhythm control strategies do not eliminate need for anticoagulation 2,3 Strokes occurring with therapeutic INR are less severe 4 Anticoagulation reduces A fib stroke risk by 66% 1 NNT 32 vs placebo 1.Singer DE Chest 2008:133:546S 592S 2. Wyse DG N Engl J Med 2002;347:1825 33 3. VanGelder IC N Engl J Med 2002;347:1834 40. 4. Hylek EM N Engl J Med 1996;349:1019 26 10

Simple heuristics fail complex decisions Many thought traps confound the anticoagulation decision Algorithmic, evidence based approach provides data that can then be adapted to patient s values, goals, functional and cognitive status Are you betting with the patient s nickel? Miles, RW JAMDA 2007;8:349 54) Don t overestimate bleeding risk Calculate it, then reduce it Don t overestimate fall risk Get the facts, then reduce fall risk Don t underestimate anticoagulant benefits Don t overestimate benefits of antiplatelet agents Benefits seen with warfarin will be similar with new approved oral anticoagulants Adverse effects seen with warfarin may be the same or less likely with new approved oral anticoagulants Similar assumptions and decision processes apply to warfarin and new approved oral anticoagulants 11

Patients rate non fatal stroke worse than 3 major bleeding episodes ACCP endorses only treatments that prevent 3 or more strokes for every major bleeding event For all cause mortality, no difference exists between current treatment options All options are better than no treatment You JJ. Chest 2012;141:e531 575. Median annual major bleeding risk 1.3% 0.8% above Baseline Risk of 0.5%/yr (not ALL major bleeding is due to anticoagulation) Fatality rates Extracranial bleeding 15% Hemorrhagic stroke 50% Ischemic stroke 25% Anticoagulant efficacy 66% fewer strokes 25% fewer deaths You JJ. Chest 2012;141:e531 575. 12

Score CVA per 10,000/yr 0 190 1 point each for 1 280 CHF or LVEF< 50% Hypertension 2 400 Age 75 3 590 Diabetes 4 850 2 points for 5 1,250 Stroke or TIA 6 1,820 Gage, BF JAMA 2001;285:2864-70 CHADS2 ACCP 2012 Stroke Risk Gage 2001 0 0.8% 1.9% 1 2.2% 2.8% 2 4.5% 4.0% 3 6 9.6% 5.9 18.2% You JJ. Chest 2012;141:e531 575. ACCP bases stroke risk on updated CHADS 2 Updated risks based on data from recent studies Predictive value of updated estimates untested CHADS has poor predictive value, but is best CHADS does not account for continuous increase in stroke risk with increasing age You JJ. Chest 2012;141:e531 575. 13

Oral anticoagulation (OAC) preferred to no therapy (1A) OAC preferred to aspirin (1B) OAC preferred to aspirin plus clopidogrel (1B) Aspirin plus clopidogrel preferred to aspirin alone, if unable or unwilling to take OAC (1B) You JJ. Chest 2012;141:e531 575. Educate patients that antiplatelet therapy is inferior to oral anticoagulant treatment for stroke prevention. Dabigatran 150 mg twice daily preferred to warfarin (2B) 2B Weak recommendation Benefits burdens. Moderate quality evidence Study limitations. Patient circumstances and preferences important You JJ. Chest 2012;141:e531 575. 2c Weak recommendation Uncertain benefit/burden balance Other alternatives equally reasonable Weak studies. Low/Very low quality evidence 14

Stable coronary artery disease (CAD) Warfarin (VKA) alone preferred to VKA plus aspirin (2C) S/P acute coronary syndrome (ACS), no PCI or stent VKA plus single antiplatelet agent for 12 months (2C) After 12 mo, VKA alone preferred to VKA +ASA (2C) You JJ. Chest 2012;141:e531 575. PCI with bare metal stent (BMS) VKA + ASA+ clopidogrel for 1 mo (2C) 12 mo triple therapy if high risk of late stent thrombosis VKA + single antiplatelet agent 2 12 mo (2C) After 12 mo, VKA alone preferred to VKA + ASA (2C) You JJ. Chest 2012;141:e531 575. PCI with paclitaxel DES VKA + ASA + Clopidogrel for 1 6 mo (2C) 12 mo triple therapy if high risk of late stent thrombosis VKA + single antiplatelet agent rest of year after triple tx (2C) After 12 mo, VKA alone preferred to VKA + ASA (2C) You JJ. Chest 2012;141:e531 575. 15

PCI with sirolimus, zotarolimus, everolimus DES VKA + ASA + Clopidogrel for 3 6 mo (2C) 12 mo triple therapy if high risk of late stent thrombosis VKA + single antiplatelet agent rest of year after triple tx (2C) After 12 mo, VKA alone preferred to VKA + ASA (2C) You JJ. Chest 2012;141:e531 575. SDH rate = 0.0004 per elderly pt/year 4 per 10,000 pt yrs 33% >65 fall at least once/year 10% of falls cause major injury 70% of elderly SDH have head trauma Half of these associated with a fall Man-Son- Hing Arch Intern Med 1999:159;677-685 16

70% of elderly SDH have head trauma 50% of SDH due to trauma are due to falls RR of SDH among those who fall = 1.4 1.4 X.0004 =.00056 SDH/pt year of fallers Net increase of 1 2 SDH per ten thousand patients among those who fall Man-Son- Hing Arch Intern Med 1999:159;677-685 Persons taking coumadin must fall approximately 295 times in 1 year before coumadin is no longer the optimal therapy Fracture more likely than SDH Man-Son- Hing Arch Intern Med 1999:159;677-685 Retrospective chart review hospital falls SDH, major bleeding 2664 falls in 1861 patients 50% on antithrombotic therapy 1.4% falls caused fracture 10% had major hemorrhagic injury warfarin 6%, no therapy 11% p0.01 OR: 1.6 female, 1.4 ASA, 2.2 clopidogrel No increased risk with warfarin, INR level 1 fatal SDH (ASA + warfarin with INR 4.3) Bond AJ Thrombosis Journal 2005;3:1 17

Treat AF with warfarin to INR 2 3 Falling raises SDH risk 1 2/10,000 If stroke rate 2%, fall rate 100%, warfarin still better than no treatment Bleeding and fall risk factors identifiable May be modifiable 8932 pts,15 randomized groups,12 studies A fib independently increases stroke risk 5 fold Overall stroke risk increases with age, so the influence of AF increased with age. OACS >AP > placebo to decrease the risk of ischemic stroke and CV events. van Walraven, C. et al. Stroke 2009;40:1410 1416 18

Hazard Ratios below 1 indicate that treatment decreased the risk When the confidence interval of the hazard Ratio excludes 1, the result is statistically significant (p <.05) van Walraven, C. et al. Stroke 2009;40:1410 1416 OAC Effectiveness Persists van Walraven, C. et al. Stroke 2009;40:1410 1416 Antiplatelet Effectiveness Wanes van Walraven, C. et al. Stroke 2009;40:1410 1416 19

OAC benefit persists with age AP benefit decreases with age Hemorrhagic risk similar OAC and AP Real world patients likely sicker than RCT patients Bleeding risk may be higher, INR control worse van Walraven, C. et al. Stroke 2009;40:1410 1416 Expected net clinical benefit...is highest among patients with the highest untreated risk for stroke, which includes the oldest age category. risk assessment that incorporates both risk of thromboembolism and risk for intracranial hemorrhage provides a more quantitatively informed basis for the decision. How much better and safer? 20

Dabigatran ( RE LY) Direct thrombin inhibitor Rivaroxaban ( Rocket AF) Factor Xa Inhibitor Apixaban (ARISTOTLE) Factor Xa Inhibitor Comparisons difficult due to different study populations Not very many patients like our LTC patients Age, GFR In general, equivalent or better than warfarin Less intracerebral hemorrhage Same or less hemorrhage Same or less overall negative outcomes RE LY Dabigatran ROCKET AF Rivaroxaban ARISTOTLE Apixaban CHADS2 DAB 150mg Warfarin RIV Warfarin APIX Warfarin Mean 2.1 2.1 3.48 3.46 2.1 2.1 0 1 32% 31% 0 0 34% 34% 2 35% 37% 13% 13% 36% 36% 3 6 33% 32% 87% 87% 30% 30% 21

RE LY Dabigatran ROCKET AF Rivaroxaban ARISTOTLE Apixaban DAB 150mg Warfarin RIV Warfarin APIX Warfarin Age 72 (63 80) 72 (62 80) 73 (65 78) 73 (65 78) 70 (63 76) 70 (63 76) CVA,TIA,V TE 20% 20% 55% 55% 19% 19% GFR 31 50 Median 67 (52 88) Median 67 (52 88) 15% 15% GFR < 30 Exclude Exclude 1.5% 1.55 RE LY Dabigatran ROCKET AF Rivaroxaban ARISTOTLE Apixaban DAB 150mg Warfarin RIV Warfarin APIX Warfarin CVA/VTE 1.11%/yr 1.6%/yr 2.1%/yr 2.4%/yr 1.27%/yr 1.6%/yr Ischemic 0.92%/yr 1.20%/yr 0.97%/yr 1..51%/yr Hemorrhagic 0.1%/yr 0.38%/yr 0.5%/yr 0.7%/yr 0.24%/yr 0.47%/yr CVA,VTE, MI, death 4.85%/yr 5.49%/yr RE LY Dabigatran ROCKET AF Rivaroxaban ARISTOTLE Apixaban DAB 150mg Warfarin RIV Warfarin APIX Warfarin Major bleed 1.45%/yr 1.8%/yr 3.6%/yr 3.4%/yr 4.07%/yr 6.01%/yr Minor bleed 14.8%/yr 16.4%/yr 11.8%/yr 16.2%/yr Bleed, MI, Vasc event, death 6.91%/yr 7.09%/yr 3.17%/yr 4.11%/yr 22

INR below 2.0 results in a higher risk of stroke Hylek EM, et al. NEJM 1996;335:540 546 Hylek EM, Singer DE, Ann Int Med 1994;120:897 902 23