Warfarin and DirectActing Oral Anticoagulants for Primary and

Warfarin and Direct-Acting Oral Anticoagulants for Primary and Secondary Click here for title Stroke Prevention Click here for subtitle Emmanuel Markakis, Pharm. D. , BCPS Clinical Pharmacy Program Manager PGY 1 Residency Director Boca Raton Regional Hospital

Objectives 1. Review the vitamin K and non-vitamin K depending anticoagulants 2. Identify patients at risk for stroke with atrial fibrillation 3. Compare and contrast the oral anticoagulants used in primary and secondary stroke prevention 4. Provide strategies in choosing the optimal anticoagulant in patients

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

What’s in a Name? Warfarin NOACS (Novel Anticoagulants) Warfarin (VKA) 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? a. b. c. d. 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 Warfarin Brand Coumadin Dose in Afib Depends on INR Potential Clinical Benefits Defined INR Range Downside 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 150 mg PO BID, if Cl 15 - No lab monitoring Cannot use Cl<15 ml/min BID dosing? ? Rivaroxaban Xarelto 20 mg PO Daily with Food, if Cl 15 -49 ml/min, Once a day dosing No lab monitoring Cannot use Cl<15 ml/min MUST be given with food 49 ml/min, then 75 mg PO daily then 15 mg PO daily, <15 ml/min avoid use Apixaban Eliquis 5 mg PO BID unless: No lab monitoring Complex Dosing – needs creatinine level to be accurate BID dosing? ? Edoxaban Savaysa 60 mg PO Daily, if Cl 15 - Once a day dosing No lab monitoring Avoid if Cl>95 ml/min Lack of familiarity SCr>1. 5: >80 OR <60 kg SCr <1. 5: >80 yo AND <60 kg, then 2. 5 mg PO BID 49 ml/min, then 30 mg PO daily, <15 ml/min avoid use

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? a. Warfarin is superior to DOACs in ischemic stroke prevention b. DOACs are superior to warfarin in preventing both ischemic strokes and hemorrhagic strokes c. In independent trials vs warfarin, DOACs have shown both noninferiority and superiority in various end points compared to warfarin d. 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? a. Warfarin is superior to DOACs in ischemic stroke prevention b. DOACs are superior to warfarin in preventing both ischemic strokes and hemorrhagic strokes c. In independent trials vs warfarin, DOACs have shown both noninferiority and superiority in various end points compared to warfarin d. I have no idea, I’ll text Dr. Espinosa

Assess Primary Prevention CHA 2 DS 2 -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? a. Warfarin is superior to DOACs in ischemic stroke prevention b. In Insurance registry patients, no DOAC has been shown more efficacious than another c. In CMS registry patients, only apixaban has been shown superiority compared to warfarin d. 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? a. Warfarin is superior to DOACs in ischemic stroke prevention b. In Insurance registry patients, no DOAC has been shown more efficacious than another c. In CMS registry patients, only apixaban has been shown superiority compared to warfarin d. 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; March 2018

Secondary Prevention Tsivgoulis et al; Ther Adv Neurol Disord; 2016, Vol. 9(5) 359– 368 Abstract Printed in STROKE; 2016: 47: A 37, 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: A 37, 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 Superior No Difference Apixaban Superior CMS Registry Efficacy vs Warfarin Major Bleeding GI Bleeding Intracranial Bleeding Dabigatran Superior No Difference Superior Rivaroxaban Inferior Superior Apixaban Superior

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

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

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