Afib, Stroke, and DOAC. Albert Luo, MD. Cardiology Lindsey Frischmann, DO. Neurology Xiao Cai, MD. HBS

Afib, Stroke, and DOAC Albert Luo, MD. Cardiology Lindsey Frischmann, DO. Neurology Xiao Cai, MD. HBS

Disclosure of Relevant Financial Relationships I have no relevant financial relationships with commercial or industry organizations. The CME Department has reviewed disclosure information for the planner(s) and/or committee/faculty for this program and they do not have relationships that present a relevant conflict of interest. Under the ACCME Standards for Commercial Support, everyone who is in a position to control the content of an education activity must disclose all relevant financial relationships with any commercial interest. A commercial interest includes any proprietary entity producing health care goods or services, with the exemption of non-profit or government organizations and non-health care related companies. A financial relationship is relevant if it pertains to the activity s content matter including any related health care products or services to be discussed or presented.

Overall Purpose for Today s Education: At the conclusion of this day's meeting, participants will be able to: Use CHA 2 DS 2 VASc score to calculate stroke risk Familiar with the indication for starting anticoagulation in patients with Afib Select the appropriate patients for direct oral anticoagulants Familiar with the benefit and risk of direct oral anticoagulants

Case #1 68 yo woman with well-controlled HTN, otherwise healthy, who presents to your office with 1 week of palpitations and found to have new-onset atrial fibrillation (AF). What is her risk of stroke and systemic embolism? Should she be started on an oral anticoagulant medication for stroke prevention?

Risk-Based Antithrombotic Therapy: Class I Recommendation In patients with nonvalvular AF, the CHA2DS2-VASc score is recommended for assessment of stroke risk (164-166). (Level of Evidence: B) Selection of antithrombotic therapy should be based on the risk of thromboembolism irrespective of whether the AF pattern is paroxysmal, persistent, or permanent (160-163). (Level of Evidence:B)

Classification of Nonvalvular AF RE-LY (dabigatran) - Excluded patients with patients with prosthetic heart valves, significant mitral stenosis and valve disease requiring an intervention before study end - Included other valve disorders: mitral regurgitation, tricuspid regurgitation, aortic regurgitation, aortic stenosis, and mild mitral stenosis ROCKET AF (rivaroxaban) - Excluded patients with hemodynamically significant mitral valve stenosis, prosthetic heart valves, and planned invasive interventions with a major risk of uncontrolled bleeding - Included all other valvular heart disease conditions and/or annuloplasty with or without a prosthetic ring, commissurotomy, and valvuloplasty ARISTOTLE (apixaban) - Excluded patients with clinically significant moderate or severe mitral stenosis and prosthetic heart valves - Included all other valvular heart disease conditions and/or moderate mitral regurgitation, aortic regurgitation, aortic stenosis, tricuspid regurgitation, and valve surgery ENGAGE-AF-TIMI (edoxaban) - Excluded patients with moderate or severe mitral stenosis, unresected atrial myxoma, and mechanical heart valve - Included all other valvular heart disease conditions and/or bioprosthetic heart valves and valve repair

Risk factor- point-based scoring system - CHA 2 DS 2 VASc *Prior myocardial infarction, peripheral artery disease, aortic plaque. Actual rates of stroke in contemporary cohorts may vary from these estimates.

CHADS 2 vs CHA 2 DS 2 VASc ACC/AHA/ARS endorsed CHA2DS2VASc 2014 CHADS2 score Thromboembolism rate/year CHA2DS2-VASc score Thromboembolism rate/year 0 1.7 1 4.75 2 7.34 3 15.47 4 20.55 5 19.71 6 22.36 0 0.78 1 2.01 2 3.71 3 5.92 4 9.2 5 15.26 6 19.74 7 21.50 8 22.38 9 23.61 From ESC AF Guidelines: http://www.escardio.org/guidelines-surveys/escguidelines/guidelinesdocuments/guidelines-afib-ft.pdf

Back to our case What is the CHA 2 DS 2 VASc score for our patient? CHA 2 DS 2 VASc = 3 ( vs. CHADS 2 of 1) CHA 2 DS 2 VASc is better at predicting thromboembolic events among those with a lower risk score Which antiplatelet or oral anticoagulant will you start her on? Aspirin Warfarin DOAC

Thromboprophylaxis recommendation for NVAF ACC/AHA/ARS (Level of Evidence: B) AF = atrial fibrillation; CHA 2 DS 2 -VASc = cardiac failure, hypertension, age 75 (doubled), diabetes, stroke (doubled)-vascular disease, age 65 74 and sex category (female); INR = international normalized ratio; OAC = oral anticoagulation, such as a vitamin K antagonist (VKA) adjusted to an intensity range of INR 2.0 3.0 (target 2.5).

When is only warfarin indicated? Valvular AF (rheumatic MS, prosthetic or repaired valves) Mechanical heart valves: no safety data as yet; (phase 2, RE-ALIGN trial of dabigatran was terminated early owing to excess thrombosis) Impaired renal function (CrCl <30 ml/min) Severe hepatic disease or any hepatic dysfunction associated coagulopathies

Direct Oral Anticoagulants (DOAC) Dabigatran (Pradaxa ) first novel oral drug approved on Oct. 19, 2010. Rivaroxaban (Xarelto ) First oral FXa inhibitor approved in mid -2011 Apixaban (Eliquis ) Second oral factor Xa approved on Dec 2012 Edoxaban (Sayvasa ) Third oral factor Xa approved on Jan 2015

Mechanism of action Dabigatran: competitive direct thrombin inhibitor -inhibits the conversion of fibrinogen to fibrin Rivaroxaban, Apixaban & Edoxaban: reversible direct FX a inhibitor; Xa catalyzes the conversion of prothrombin to thrombin which, in turn converts fibrinogen to fibrin

Dabigatran On KP formulary FDA approved for prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation Praxbind (idarucizumab) reversal agent approved for KP formulary November 2015

Re-LY Outcome analysis in NVAF warfarin dabigatran Major bleeding 3.36% 3.11%/yr 150 mg (P=.31) 2.77%/yr 110 mg (P=.003) ICH 0.74%/yr 0.3%/yr (P=<.001) 0.23%/yr (P=<.001) GI bleeding 1.07%/yr 1.56%/yr (P= 0.001) 5.1% in Age >75yrs Dyspepsia 24%/yr 35%/yr (P= 0.001) MI 0.64%/yr 0.8%/yr (P= 0.12) Discontinuation rates 16% 21%

Back to our case What is the CHA 2 DS 2 VASc score for our patient? CHA 2 DS 2 VASc = 3 ( vs. CHADS 2 of 1) CHA 2 DS 2 VASc is better at predicting thromboembolic events among those with a lower risk score Which antiplatelet or oral anticoagulant will you start her on? Aspirin Warfarin Dabigatran (or other DOAC)

Case #2 83 yo man with hx of CAD sp CABG, HTN, PVD with chronic claudication, DM complicated by neuropathy, who presents to the ED with one day of new right LE weakness, and found to have new acute stroke. Telemetry monitoring showed afib. What is the CHA 2 DS 2 VASc for this patient? Which antiplatelet or oral anticoagulant will you start him on?

Afib and Ischemic Stroke AF is associated with more severe ischemic strokes than other causes of stroke Patients with AF who suffer an ischemic stroke appear to have a worse outcome (more disability, greater mortality) than those who have an ischemic stroke in the absence of AF AF is also associated with silent cerebral infarctions and TIAs Anticoagulated AF patients who experience ischemic stroke typically have smaller infarcts with a lower mortality rate compared with AF patients with strokes who are not anticoagulated UptoDate

Back to our case What is the CHA 2 DS 2 VASc for this patient? High! (CHA 2 DS 2 VASc =7) Which antiplatelet or oral anticoagulant will you start him on? 1. None. He is elderly and at an increased risk for fall 2. ASA, it has lower risk of bleeding if he falls 3. Warfarin, at least it s reversible if he bleeds after a fall 4. DOAC

AAN Recommendations 2014 Clinicians should routinely offer anticoagulation to patients with NVAF and a history of TIA or stroke, to reduce these patient s subsequent risk of ischemic stroke. (Level B)

AAN Recommendations 2014 Clinicians should routinely offer oral anticoagulants to elderly patients (age >75 years) with NVAF if there is no history of recent unprovoked bleeding or intracranial hemorrhage (Level B). Based on evidences that anticoagulation with warfarin is superior to that with asa for reducing the risk of ischemic stroke in patients >75 years with NVAF, whereas rate of major bleeding are comparable.

Intracranial Bleeding AAN Recommendations 2014 Clinicians might offer oral anticoagulation to patients with NVAF who have dementia or occasional falls. However, clinicians should counsel patients or their families that the risk-benefit ratio of oral anticoagulation is uncertain in patients with NVAF who have moderate to severe dementia or very frequent falls (Level B). One study estimated that an elderly patient would need to fall 295 times in 1 year to offset the stroke reduction benefit with anticoagulation.

Intracranial Bleeding AAN Recommendations 2014 Clinicians should administer dabigatran, rivaroxaban or apixaban to patients who have NVAF requiring anticoagulant medications and are at higher risk of intracranial bleeding (Level B). Based on the evidences that the new oral anticoagulants have a more favorable intracranial bleeding profile than warfarin.

Case #3 For case #1 and #2, you are planning to start Dabigatran, what are some of the risks and benefits you should be aware of prior to starting the medication?

Direct Oral Anticoagulants No lab monitoring no monitoring

DABIGATRAN(formulary): CAVEATS Antidote available Idarucizumab (Praxabind ) Available in rapid reversal order set Kinetics: Short half life with leading to rapid onset and offset BID dosing 80% renal elimination ties closely to GFR Bleeding risk increases with falling GFR Side Effects: Dyspepsia-related switch back to VKA (~20%) Interactions: P-gp inhibitors can increase bleeding risk e.g systemic ketoconazole P-gp inducers e.g Rifampin cuts exposure by 50% Cost compared to VKA to Member and Plan

Caution on Dabigatran Renal insufficiency Advanced liver disease Pregnancy and nursing mothers Dyspepsia (most common reported side effect) Hx of GI bleed? Severe Obesity (>120kg)? Hx of Gastric bypass? Noncompliance

Non valvular AF: Dabigatran dosing 150 mg bid if GFR is >30 75 mg bid if GFR is 15-30 (FDA recommendation, but not studied). Not approved for use in pts with CrCl <15 Smart Rx available for appropriate dosing

Econsult to Regional DOAC Pharmacy

DOAC Regional Pharmacy Phone 1-844-854-9342 Option 1 (Patients), Option 2 (Providers) Pool: P DOAC Pharmacy Service Best way to contact me 1. Cortext for nonurgent issues 2. KP Cell phone for urgent issues

Take Home Points USE CHA 2 DS 2 VASc score to calculate stroke risk Anticoagulation is indicated for CHA 2 DS 2 VASc 2 DOAC is associated with less intracranial bleeding than Warfarin DOAC still requires monitoring!

Thank You!