New Treatments for Stroke Prevention in Atrial Fibrillation. John C. Andrefsky, MD, FAHA NEOMED Internal Medicine Review course May 5 th, 2013

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1 New Treatments for Stroke Prevention in Atrial Fibrillation John C. Andrefsky, MD, FAHA NEOMED Internal Medicine Review course May 5 th, 2013

2 Classification Paroxysmal atrial fibrillation (AF) Last < 7 days Persistent AF Last > 7 days Permanent AF Failed or futile attempts at cardioversion

3 Epidemiology 2.2 to 5 million Americans Prevalence is 0.4% <50 years old (yo) < 0.5 % yo 2 % yo 4.6 % yo 8.8 %

4 Symptoms Palpitations Anxiety Dizziness Dyspnea Chest pain Fatigue Cerebral embolism

5 EKG Echocardiogram Holter monitor Diagnosis Temporary long term monitoring devices Pacemakers ICDs CXR Thyroid function tests

6 Risk of Thromboembolism Cerebral infarction (CI) is most common embolic event 36 % of CI in yo CI from AF in elderly are more severe AF patients have a differential CI risk

7 Risk of Thromboembolism CHADS 2 risk criteria score Prior stroke 2 Age > 75 yo 1 Hypertension 1 Diabetes mellitus 1 Congestive heart failure 1

8 Adjusted CI Rate CHADS 2 score CI rate

9 Neuroradiology

10 Neuroradiology

11 Basilar Case Study 31 year old male Baseline NIHSS Score 10 Symptom Onset to Treatment 4h 30min

12 Basilar Case Study NIHSSS 24 hours 0 30 days 0 mrs 90 days 0

13 Neuroradiology

14 Neuroradiology

15 Antithrombotic therapy Aspirin versus placebo trials for risk of CI 5 randomized and controlled studies Aspirin reduces reduces CI risk Pooled analysis 22 % risk reduction with a (p<.001)

16 Antithrombotic therapy

17 Antithrombotic therapy Warfarin versus placebo trials for risk of CI 6 randomized and controlled studies Warfarin significantly reduces CI risk Pooled analysis 68 % risk reduction with a (p<.001) INR

18 Antithrombotic therapy

19 INR and CI risk

20 Antithrombotic therapy Warfarin versus aspirin trials for risk of CI 5 randomized and controlled studies INR Warfarin significantly reduces CI risk Severity of CI Risk of death Annual risk of bleeding Coumadin 1.3 % Aspirin and placebo 1.0 %

21 Antithrombotic therapy

22 Antithrombotic therapy AHA/ASA guidelines for prevention of first stroke Warfarin (INR ) High and moderate risk Aspirin 325 mg po daily Low and some mod risk Increased bleeding risk Aspirin and clopidogrel daily If unsuitable for anticoagulation

23 Antithrombotic therapy AHA/ASA guidelines for prevention of stroke with history of transient ischemic attack (TIA) or CI Warfarin (INR ) Paroxysmal or permanent AF Aspirin daily Unable to take anticoagulants

24 Newer agents Dabigatran Direct inhibitor of thrombin Half-life is hours No monitoring 80 % excreted renally Not metabolized by cytochrome P450 system

25 Newer agents Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Warfarin vs. 110 or 150 mg dabigatran BID AF and 1 additional stroke risk factor Primary outcome CI or systemic embolism 18,113 patients 2 year follow up

26 Newer agents Dabigatran 150 mg vs. Warfarin Was superior for primary endpoint Similar for major bleeding (3.11 % vs %) Increased GI bleeding (1.51 % VS %) Lower intracranial bleeding (0.74 % vs. 1.8 %) No antidote Follow appt, TT, ECT

27 Newer agents Rivaroxaban Direct inhibitor of factor Xa Half-life is 5-9 hours No monitoring 36 % excreted renally and 7 % fecally Is metabolized by cytochrome P450 system

28 Newer agents Rivaroxaban vs. Warfarin in Nonvalvular Atrial Fibrillation (ROCKET AF) trial Warfarin vs. Rivaroxaban 20 mg daily AF and 2 additional stroke risk factor Primary outcome CI, hemorrhagic CI or systemic embolism 14,264 patients Median follow up was 707 days

29 Newer agents Rivaroxaban 20 mg vs. Warfarin Was noninferior for primary endpoint Similar for major bleeding (14.9 % vs %) Lower intracranial bleeding (0.5 % vs. 0.7 %) No antidote Follow PT and endogenous thrombin potential

30 Newer agents Apixaban Direct and competitive inhibitor of factor Xa Half-life is 8-15 hours No monitoring 25 % excreted renally and 50 % fecally Is metabolized by cytochrome P450 system

31 Newer agents Apixaban vs. Warfarin in Patients Atrial Fibrillation (ARISTOTLE) trial Warfarin vs. apixaban 5mg BID AF and 1 additional stroke risk factor Primary outcome CI or systemic embolism 18,201 patients Median follow up was 1.8 years

32 Newer agents Apixaban 5 mg vs. Warfarin Was superior for primary endpoint Hemorrhagic CI (0.24 vs. 0.47) CI ( 0.97 % vs %) Similar for major bleeding (2.13 % vs %) Lower intracranial bleeding (0.33 % vs. 0.8 %)

33 Newer agents Meta-analysis of Nonvitamin-K-antagonist oral anticoagulants compared to coumadin Efficacy outcomes CI or systemic embolism Relative risk reduction (RRR) of 14 % Hemorrhagic stroke RRR of 12 % Unknown stroke or cardiovascular death No significant different Myocardial infarction Trend toward more Dabigatran and rivaroxaban No data for apixaban

34 Newer agents Safety outcomes Major bleeding Significant RRR of 14 % Intracranial bleeding Significant RRR of 53.9 % Gastrointestinal bleeding Trend toward more Apixaban and dabigatran No data for rivaroxaban

35 Advantages Newer agents More effective than coumadin Safer than coumadin No monitoring No dose adjustment No dietary restrictions Less travel time for patients Disadvantages Higher cost Lower compliance Twice a day dosing Excreted via kidneys

36 New AHA/ASA Guidelines Warfarin, Apixaban and dabigatran and rivaroxaban all indicated for prevention of first and recurrent CI in patients with AF. Dabigatran 150 mg BID for patients with Creatinine clearance > 30 ml/min Dabigatran 75 mg BID for patients with Creatinine clearance (CrCl) ml/min Dabigatran not recommended for patients with CrCl < 15 ml/min

37 New AHA/ASA Guidelines Apixaban 5 mg po BID is an alternative to warfarin Apixaban should not be used if CrCl < 25 ml/min Rivaroxaban 20 mg po daily is an alternative to warfarin Consider rivaroxaban 15 mg po daily for CrCl of ml/min Rivaroxaban should not be used if CrCl < 15 ml/min

38 Summary AF is a significant health problem Significant mortality and morbidity Prevention of CI Multiple meds Individualized approach to patient management