Warfarin and Direct-Acting Oral Anticoagulants for Primary and Secondary Stroke Prevention Click here for title Click here for subtitle Emmanuel Markakis, Pharm.D., BCPS Clinical Pharmacy Program Manager PGY1 Residency Director Boca Raton Regional Hospital

Objectives Review the vitamin K and non-vitamin K depending anticoagulants Identify patients at risk for stroke with atrial fibrillation Compare and contrast the oral anticoagulants used in primary and secondary stroke prevention Provide strategies in choosing the optimal anticoagulant in patients

Timeline and Approval of Oral Anticoagulants for NVAF Edoxaban 2015 Apixaban 2012 Rivaroxaban 2011 Dabigatran 2010 Warfarin 1954

What’s in a Name? What will they be called next? Warfarin Warfarin (VKA) Warfarin NOACS (Novel Anticoagulants) DOACS (Direct-Acting Anticoagulants) What will they be called next?

Let’s Begin with a Poll A 58 year old male patient with a PMH of atrial fibrillation is referred to your clinic by a PCP. The patient is deemed a candidate for anticoagulation. Which oral anticoagulant class would you recommend? Factor Xa Inhibitors (rivaroxaban, edoxaban, apixaban) Direct Thrombin Inhibitor (dabigatran) Warfarin I have no idea, I’ll text Dr. Espinosa

Oral Anticoagulants and the Clotting Cascade

The Oral Anticoagulants Generic Brand Dose in Afib Potential Clinical Benefits Downside Warfarin Coumadin Depends on INR Defined INR Range Defined INR range Expensive to reverse Physician Visits/Lab Draws Not at true dose until 2 weeks (Need to understand which factors are being inhibited) Dabigatran Pradaxa 150mg PO BID, if Cl 15-49ml/min, then 75mg PO daily No lab monitoring Cannot use Cl<15ml/min BID dosing?? Rivaroxaban Xarelto 20mg PO Daily with Food, if Cl 15-49ml/min, then 15mg PO daily, <15ml/min avoid use Once a day dosing MUST be given with food Apixaban Eliquis 5mg PO BID unless: SCr>1.5: >80 OR <60kg SCr <1.5: >80yo AND <60kg, then 2.5mg PO BID Complex Dosing – needs creatinine level to be accurate Edoxaban Savaysa 60mg PO Daily, if Cl15-49ml/min, then 30mg PO daily, <15ml/min avoid use Avoid if Cl>95ml/min Lack of familiarity

Pre-Assessment Question Which statement is true regarding how the DOACs compare to warfarin in primary prevention of stroke in literature in patients with NVAF? Warfarin is superior to DOACs in ischemic stroke prevention DOACs are superior to warfarin in preventing both ischemic strokes and hemorrhagic strokes In independent trials vs warfarin, DOACs have shown both noninferiority and superiority in various end points compared to warfarin I have no idea, I’ll text Dr. Espinosa

Primary Prevention

Primary Prevention .Vasc Health Risk Management, 2015: 11; 437-450

DOACs In Primary Prevention

Assessment Question Which statement is true regarding how the DOACs compare to warfarin in primary prevention of stroke in literature in patients with NVAF? Warfarin is superior to DOACs in ischemic stroke prevention DOACs are superior to warfarin in preventing both ischemic strokes and hemorrhagic strokes In independent trials vs warfarin, DOACs have shown both noninferiority and superiority in various end points compared to warfarin I have no idea, I’ll text Dr. Espinosa

Assess Primary Prevention CHA2DS2-VASc Score Congestive heart failure Hypertension Age >75 years (2) Diabetes mellitus Stroke or transient ischemic attack (2) Vascular disease Age 65-74 years Sex category Assign 1 point each for CHF, HTN, age 65-74 years, diabetes, vascular disease, female sex Assign 2 points for previous Stroke or TIA or Age ≥ 75 years If total=0, no therapy If total=1, give oral anticoagulant, aspirin, or no therapy If total ≥ 2, give oral anticoagulant

Real World Primary Prevention in Medicare Patients

DOACs vs Warfarin for Primary Prevention in Medicare Registry Amin et al; Current Medical Research and Opinion; June, 2017

DOACs vs DOACs in Insurance Registry Data Noseworthy et al, CHEST, Vol 150, Dec 2016

Another Assessment Which statement is true regarding how the DOACs compare to warfarin in primary prevention of ischemic and hemorrhagic stroke in literature in patients with NVAF? Warfarin is superior to DOACs in ischemic stroke prevention In Insurance registry patients, no DOAC has been shown more efficacious than another In CMS registry patients, only apixaban has been shown superiority compared to warfarin I have no idea, I’ll text Dr. Espinosa

Back to Our Question Which statement is true regarding how the DOACs compare to warfarin in primary prevention of ischemic and hemorrhagic stroke in literature in patients with NVAF? Warfarin is superior to DOACs in ischemic stroke prevention In Insurance registry patients, no DOAC has been shown more efficacious than another In CMS registry patients, only apixaban has been shown superiority compared to warfarin I have no idea, I’ll text Dr. Espinosa

Accurate Dosing Matters in Primary Prevention! Yao et al; Non-Vitamin K Antagonist Oral Anticoagulant Dosing in Patients with A-Fib and Renal Dysfunction; Journal of American Cardiology; Vol 69 (23) 2017

Secondary Prevention

2018 Stroke Guidelines for Secondary Prevention 14 Days Only AHA/ASA 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke; Stroke; March 2018

Secondary Prevention Tsivgoulis et al; Ther Adv Neurol Disord; 2016, Vol. 9(5) 359–368 Abstract Printed in STROKE; 2016:47:A37, presented at the International Stroke Conference

Results: Secondary Prevention The surface under the cumulative ranking curve (SUCRA) is a numeric presentation of the overall ranking and presents a single number associated with each treatment.SUCRA values range from 0 to 100%. Tsivgoulis et al; Ther Adv Neurol Disord; 2016, Vol. 9(5) 359–368 Abstract Printed in STROKE; 2016:47:A37, presented at the International Stroke Conference

Take Home Points

Summary-Primary Prevention DOACs vs Warfarin CMS Registry Efficacy vs Warfarin Combined Stroke/SE Ischemic Stroke Hemorrhagic Stroke Dabigatran No Difference Superior Rivaroxaban Apixaban CMS Registry Efficacy vs Warfarin Major Bleeding GI Bleeding Intracranial Bleeding Dabigatran Superior No Difference Rivaroxaban Inferior Apixaban

Summary-Primary Prevention DOACs vs DOACs No randomized controlled trials….yet Based on insurance report registry, none are more efficacious than the other Apixaban has had less overall less MAJOR bleeding, but no better than the others in preventing ICH Dosing is important!

Summary-Secondary Prevention Little data published in literature Meta-analysis shows dabigatran is best at preventing second hemorrhagic stroke, but worst at preventing second ischemic stroke Rivaroxaban is right in the middle regarding safety and preventing second strokes/systemic embolism Apixaban is more consistent preventing second stoke/systemic embolism and bleeding events

Poll Question When a patient has a CHA2DS2-VASc Score of >2, which oral anticoagulant would you initiate a patient <65