Most important cause of cardioembolic stroke. Increases the relative risk of ischemic stroke 5 X.

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1 Atrial Fibrillation Karen Whalen, BS Pharm, BCPS St. Joseph s Hospital Syracuse, NY Most important cause of cardioembolic stroke. Increases the relative risk of ischemic stroke 5 X. Estimated age-specific prevalence based on 4 population-based surveys Fuster, V. et al. Circulation 2006;114:e257-e354

2 ACCP CHEST Guidelines 2008 CHADS 2 Risk Anti-thrombotic Choice 0 Low Aspirin mg 1 Intermediate Aspirin mg or Warfarin INR goal High Warfarin INR goal 2-3 Hx stroke, TIA or systemic Warfarin INR goal 2-3 embolism Mitral stenosis or prosthetic heart valve Post Cardiac Surgery ( 48 hours duration & when bleeding risk acceptable) Singer DE et al. CHEST 2008; 133:546S-592S G Warfarin INR goal 2-3 or Higher valve specific INR Warfarin INR goal 2-3 For 4 weeks following reversion to & maintenance of NSR Adjusted Stroke Rate per 100 patient years High risk 12.5 G CHADS2 Score CHF; LV dysfunction 1 Low risk Intermediate risk Singer DE et al. CHEST 2008; 133:546S-592S Hypertension 1 Age > 75 1 Diabetes 1 S 2 troke/tia 2

3 ACTIVE (A, W) Inclusion criteria AFib plus at least one RF Age 75yo Hypertension Hx stroke, TIA or systemic embolism LVEF < 45% Peripheral vascular disease Age plus diabetes or CAD Exclusion criteria Peptic ulcer disease < 6 months Hx ICH Thrombocytopenia (Platelets < 50 x10 9 /L) Ongoing alcohol abuse The ACTIVE Investigators NEJM 2009; 360: ACTIVE W Open label trial, blinded adjudication. Stopped early due to clear evidence that warfarin is superior to Plavix/ASA. Investigators notified to treat according to current guidelines (CHEST 2004). Combination anti-platelet therapy not listed as an option in CHEST Risk (%/year) Composite stroke, non CNS embolism, MI, vascular death Plavix + ASA N=3335 Warfarin N= % 3.93% Stroke 2.39% 1.4% RR (95% CI) 1.44 ( ) P ( ) P Ischemic 2.15% 1% 2.17 ( ) P< Hemorrhagic 0.12% 0.36% 0.34 ( ) P Net benefit for 1 o outcome, major bleed & death 8.32% 6.45% 1.31 ( ) P The ACTIVE Writing Group Lancet 2006; 367:

4 ACTIVE W Stratified by Stroke Risk CHADS2 C + A Warfarin Stroke rate per 100 pt years Healey JS et al. Stroke 2008; 39: ACTIVE A Unsuitable for VKA (warfarin) due to Specific risk of bleeding Physician judgment VKA is inappropriate Patient preference not to take VKA Randomized to ASA mg plus placebo PO qday OR ASA mg plus clopidogrel 75mg PO qday The ACTIVE Investigators NEJM 2009; 360:

5 Unsuitable for VKA Specific risk of bleeding 23.5% Predisposed to falls/head trauma 9.8% Persistent elevation BP > 160/ % Previous serious bleeding on anticoagulant 5.8% Hx severe alcohol abuse in prior 2 years 1.1% Peptic ulcer disease 6-12 months prior 0.7% Platelets x10 9 /L 2.2% Long-term NSAID (not COX-2 inhib) 1.6% Physician judgment VKA is inappropriate 50.4% Unable to comply with INR monitoring, MD assessment VKA inappropriate or both Patient unwillingness (only reason) 26.1% Patient unwillingness plus another reason above 48.9% The ACTIVE Investigators NEJM 2009; 360: ACTIVE A Results %/yr C + ASA N=3772 ASA N= o outcome 6.8% 7.6% Stroke 2.4% 3.3% Ischemic 1.9% 2.8% Hemorrhagic 0.2% 0.2% Nondisabling 0.9% 1.2% Disabling 1.6% 2.1% Major bleeding 2% 1.3% Minor bleeding 3.5% 1.4% RR (95% CI) 0.89 ( ) P ( ) P < ( ) 1.37 ( ) 0.70 ( ) P ( ) P ( ) P < ( ) P < The ACTIVE Investigators NEJM 2009; 360:

6 ACTIVE A Net Benefit vs Risk Benefit Nondisabling stroke 46 less Disabling or fatal 69 less Fatal 26 less, but 3 fatal hemorrhagic Net 23 less fatal Risk Major bleeding 83 more 62 severe Fatal bleeding 13 more The ACTIVE Investigators NEJM 2009; 360: Cardioversion, elective Conventional ( No TEE) < 48 hours duration (Grade 2C) No anticoagulation required but it is suggested if no contraindications exist. Immediate UFH IV (target aptt sec) or LMWH full DVT treatment dose. TEE is suggested if risk factors for stroke exist. 48 hours or unknown duration (Grade 1C) Warfarin target INR 2-3 for 3 weeks prior and a minimum of 4 weeks post. G

7 Cardioversion, elective TEE Guided (1B) < 48 hours duration TEE not required but suggested for patients with stroke risk. 48 hours or unknown duration Immediate UFH IV (target aptt sec) or Immediate LMWH full treatment dose or Warfarin target INR 2-3 begin minimum 5 days prior. No thrombus - Perform cardioversion Warfarin target INR 2-3 for a minimum of 4 weeks post. Thrombus - Postpone cardioversion Continue warfarin target INR 2-3 G Anticoagulation for AF ablation Post-procedure Management Calkins H, et al. Heart Rhythm 2007; Low molecular weight heparin or intravenous heparin should be used as a bridge to resumption of systemic anticoagulation following AF ablation. Warfarin is recommended for all patients for at least two months following an AF ablation procedure. Decisions regarding the use of warfarin more than two months following ablation should be based on the patient s risk factors for stroke & not on the presence or type of AF. Discontinuation of warfarin therapy post ablation is generally not recommended in patients who have a CHADS 2 score 2. Recently published observational data suggest more patients might be able to discontinue warfarin, but this should be confirmed with a prospective, randomized trial. Themistoclakis S, et al. J Am Coll Cardiol 2010;55:

8 Risk of bleeding on warfarin In AF patients, fatal or disabling bleeding events are largely due to ICH. Other major extracranial bleeding events (ie GI) should not be ignored, but weighed against the risk of fatal or disabling strokes, ICH is the greatest concern. Risk factors for ICH include increasing age, prior ischemic stroke and INR > 4, even though ICH may occur at any INR. HEMORR 2 HAGES 1 point for all except prior bleed Hepatic or renal disease Ethanol abuse Malignancy Older = Age > 75 yo Reduced platelet count or function Rebleeding risk (prior bleed) 2 points Hypertension (uncontrolled) Anemia Genetic factors Excessive fall risk Stroke Validated in Afib patients taking warfarin Bleeding requiring hospitalization Points Rate per 100 patient years ( ) ( ) ( ) ( ) ( ) ( ) Gage BF, et al. Am Heart J 2006; 151:

9 The Net Clinical Benefit of Warfarin in Atrial Fibrillation Mixed retrospective & prospective data (ATRIA). Arbitrary weight assigned to ischemic stroke & ICH. Singer DE, et al. Ann Intern Med. 2009;151: Benefit based on age group Singer DE, et al. Ann Intern Med. 2009;151:

10 Bleeding risk during the first year Elderly (>65yo) cohort with atrial fibrillation who started warfarin and followed for 1 year. N=472 patients, 32% were 80 yo 91% had 1 stroke risk factor Cumulative incidence of major hemorrhage: 80 yo: 13.1 per 100 person-years <80 yo: 4.7 per 100 person-years (P=0.009) During the 1 st 90 days, age 80 yo, & INR 4 were each associated with increased risk of hemorrhage. Within the 1 st year, 26% of patients 80 yo stopped taking warfarin; perceived safety issues accounted for 81% of these. Rates of major hemorrhage and warfarin termination were highest among patients with CHADS 2 scores of 3. Hylek EM, etal. Circulation. 2007;115: Bleeding Risk in Patients > 80yo N=783 consecutive patients; prospective INR within range 71% Due to length of follow-up & median age at enrollment (75yo), some patients started in < 80 yo age group, but ended up in 80 yo group. Bleeding Age < 80 Age 80 RR (CI) P N Rate N Rate Major ( ) Cerebral ( ) 0.1 GI (1-10.7) 0.03 Fatal (0.9-26) 0.04 Minor (1-3) 0.03 Poli D, et al. J Am Coll Cardiol 2009;54: )

11 Median warfarin doses Atrial Fibrillation patients Garcia D et al. CHEST 2005; 127: Garcia D et al. CHEST 2005; 127:

12 What is new for Atrial Fibrillation? New oral agents, pending FDA approval: Apixaban Rivaroxaban Dabigatran New European Society of Cardiology Guidelines New guidelines released at the ESC Congress 8/ Published in the European Heart Journal Stroke risk stratification: CHA 2 DS 2 VASc Bleeding risk stratification: HAS-BLED Sites of Action New Anticoagulants Steps in Coagulation Coagulation Cascade Drug Initiation Propagation Amplification X TF/VIIa IX IXa Xa Va II IIa Apixaban Rivaroxaban Dabigatran Fibrinogen Fibrin Weitz et al Chest 2001;119:95S 107S

13 Apixaban Direct Xa Inhibitor Bioavailability > 50% Peak plasma concentrations in 3 4 hours Half-life ~12 hours 25 % renal elimination Oxidative (CYP3A4) & non oxidative elimination Drug interactions: primarily strong 3A4 agents (ie ketoconazole) AVERROES (Apixaban vs ASA) Afib pts with at least 1 stroke risk factor and that have failed or are unsuitable for warfarin. Double blind, double dummy, superiority trial Apixiban 5mg bid vs ASA mg qday 2.5mg bid if 2 of the following: age 80; ABW 60kg; serum creatinine 1.5mg/dL Excluded pt with serum Cr 2.5mg/dL or calc CrCl < 25ml/min Trial stopped early when the safety board performed a prespecified analysis showing significant benefit over ASA. Data released at the ESC 2010 Congress 8/31/10 CHADS2 0-1 = 36% 2 = 37% 3 = 27% No data on dose breakdown for apixaban or ASA. No data on why warfarin was unsuitable. Trial design: Eikelboom KW et al. Am Heart J 2010; 159: e1 ESC announcement: Accessed 9/7/10.

14 AVERROES (Apixaban vs ASA) Apixaban N=2809 Aspirin N=2791 RR (95% CI) Stroke or systemic embolism 1.8% 3.6% 0.46 ( ) P XXX Stroke, embolism, MI, vascular death 4.1% 6.2% 0.66 ( ) P XXX MI 0.7% 0.8% 0.85 ( ) P XXX Vascular death 2.5% 2.9% 0.86 ( ) P XXX Cardio hospitalizations 11.8% 14.9% 0.79 ( ) P XXX Total death 3.4% 4.4% 0.79 ( ) P XXX Major Bleeding 1.4% 1.2% 1.14 ( ) P XXX ICH 0.4% 0.3% 1.09 ( ) P XXX Fatal bleeding 0.1% 0.1% 0.84 ( ) P XXX Minor Bleeding 5.2% 4.1% 1.27 ( ) P XXX ESC announcement: Accessed 9/7/10. ARISTOTLE (Apixaban vs Warfarin) Afib pts with at least 1 stroke risk factor Apixaban 5mg bid vs Warfarin (INR 2-3) Double blind, double dummy design with sham INRs 2.5mg bid if 2 of the following: age 80; ABW 60kg; serum creatinine 1.5mg/dL 1 o outcome: Combined endpoint of stroke (ischemic or hemorrhagic) and systemic embolism. All-cause death. If noninferiority met, then test for superiority will be performed. Exclusions Serum Cr 2.5mg/dL or calc CrCl < 25ml/min ASA required > 165mg/day Simultaneous ASA plus thienopyridine Results expected April 2011 Trial design: Am Heart J 2010; 159:

15 Rivaroxaban (Xarelto) Direct Xa Inhibitor Peak plasma concentration in ~2-3 hours Terminal half life 4-9 hours; longer in elderly patients Food delays but does not hinder absorption Bioavailabilty ~ 80% Strong 3A4 inhibitors/inducers & P-gp inhibitors significant. Predominantly renal elimination Contraindicated with Cr Cl < 30 ml/min FDA deferred action on the Advisory Committee recommendation to approve. FDA is requesting long term safety data LFTs/liver toxicity Cardiac events reported following cessation of rivaroxaban? DrugsAdvisoryCommittee/ucm htm (Accessed 9/20/2010) ROCKET AF (Rivaroxaban vs Warfarin) Moderate to high risk Afib pts (ie prior stroke/tia/systemic embolism or 2 or 3 traditional risk factors. Double blind, double dummy design with sham INRs Rivaroxaban 20mg qday vs Warfarin (INR 2-3) If calc CrCl 30-49ml/min: Rivaroxaban 15mg qday Exclusions calc CrCl < 30ml/min ASA required > 100mg/day Simultaneous ASA plus thienopyridine* Trial design: Am Heart J 2010; 159: e1.

16 Dabigatran etexilate (Pradaxa) Direct thrombin inhibitor Prodrug rapidly converted to dabigatran Peak plasma concentrations in 1.5 hours No P450 involvement Bioavailability 7.2% Absorption requires an acidic microenvironment Bioavailability 20-30% lower with Pantoprazole. T ½ at steady state is hours Active drug is renally eliminated Reduced dose with moderate renal dysfunction P-glycoprotein substrate Drug interactions with verapamil, quinidine, amiodarone RE-LY (Dabigatran vs Warfarin) Dabigatran 110mg or 150mg bid (blinded) vs warfarin (INR 2-3), unblinded. Blinded adjudication of endpoints Exclusion: Calc CrCl < 30ml/min, liver disease, quinidine (protocol amendment) Aspirin < 100mg qday or other antiplatelet allowed. CHADS2 0-1 = 30-32%; 2 = 34-37%; 3 = 32% INR in range 64% Connolly SJ et al. NEJM 2009;

17 RE-LY %/yr Stroke or systemic embolism Dabigatran 110mg N=6015 (Dabigatran vs warfarin) Dabigatran 150mg N=6076 Warfarin N= % 1.11% 1.69% Stroke 1.44% 1.01% 1.57% Hemorrhagic 0.12% 0.10% 0.38% Nondisabling (mrs 0-2) 0.5% 0.37% 0.58% Disabling or fatal 0.84% 0.66% 1% MI 0.72% 0.74% 0.53% Pulmonary embolism 0.12% 0.15% 0.09% Vascular death 2.43% 2.28% 2.69% Total death 3.75% 3.64% 4.13% Connolly SJ et al. NEJM 2009; RE-LY (Dabigatran vs warfarin) %/yr Dabigatran 110mg Dabigatran 150mg Warfarin Major bleeding 2.71% 3.11% 3.36% Life threatening 1.22% 1.45% 1.8% GI bleeding 1.12% 1.51% 1.02% Minor bleeding 13.16% 14.84% 16.37% Intracranial 0.23% 0.3% 0.74% % of pts Discontinuation 1yr 2yr 15% 21% 16% 21% 10% 17% d/t serious ADR 2.7% 2.7% 1.7% d/t GI symptoms 2.2% 2.1% 0.6% Dyspepsia (all pts) 11.8% 11.2% 5.8% Connolly SJ et al. NEJM 2009;

18 CHA 2 DS 2 VASc Risk factor Congestive heart failure/lv systolic dysfunction (ie LV EF 40%) Score Hypertension 1 Age 75 2 Diabetes 1 Stroke, TIA or systemic embolism 2 Vascular disease (prior MI, PAD, aortic plaque) 1 Age Sex category = Female 1 Maximum score 9 1 CHEST 2010; 137(2): HAS-BLED Clinical characteristic Points H Hypertension (systolic > 160mmHg) 1 A 1 or 2 Abnormal renal (dialysis, transplant, Cr 200mmol/L) or Abnormal liver (chronic hepatic, cirrhosis, bili > 2xULN & transaminase > 3xULN) S Stroke 1 B Bleeding 1 L Labile INRs (unstable/high INRs or in range < 60%) 1 E Elderly (age > 65yo) 1 D Drugs (antiplatelets, NSAIDs) or alcohol abuse 1 0r 2 Scores 3 indicates high risk. Chestjournal.chestpubs.org/content/early/2010/03/18/chest Accessed 9/7/10.

19 Case - JK JK is an 81yo F recently diagnosed with atrial fibrillation (duration unknown). Her PMH is negative for hypertension, heart failure, LV dysfunction, diabetes or prior stroke/tia. JK leads a very active lifestyle, exercising and traveling with friends and family. Question #1 Calculate the patient s CHADS2 score Unable to calculate due to insufficient information. Case - JK Question #2 Which option for stroke prevention should be selected? 1. Aspirin 81mg qday 2. Aspirin 81mg qday Plus Plavix 75mg qday 3. Warfarin dose adjusted to target INR The patient does not need stroke prevention. 5. Answer 1 or 2 is correct. 6. Answer 1 or 3 is correct. 7. Answer 1 or 2 or 3 is correct.

20 Case - JK The cardiologist plans a direct cardioversion for the patient in 4 weeks so warfarin is initiated in the office. The patient s baseline laboratory results are WNL, she is not taking amiodarone and she will be back in 6 days for her first INR. Question #3 Select an appropriate starting dose: 1.Warfarin 2.5mg qday 2.Warfarin 5mg qday 3.Warfarin 7.5mg qday 4.More than one of the above doses is correct. Case - JK JK does not show up for her INR visit because she is too busy for frequent appointments and with the exception of her racing heart annoying her, feels too good to see the doctor. She wants the cardioversion, but does not want to take warfarin. Question #4 What do you recommend? 1.Cancel the cardioversion. 2.ASA 81mg plus Plavix 75mg qday 3.Convince patient warfarin is mandatory. 4.Schedule patient for TEE guided cardioversion and administer wt/renal adjusted LMWH on that day. 5.More than one of the above answers is correct.

21 Case - JK The TEE does not show a thrombus and the cardioversion is successful. Question #5 Select the most appropriate follow-up medication(s). 1.Aspirin 325mg qday x 4 weeks 2.Aspirin 81mg qday plus Plavix 75mg qday x 4 weeks 3.Warfarin, dose adjusted to INR 2-3 x 4 weeks 4.More than one of the above answers is correct. 5.The patient does not need follow-up medication because she is in NSR.