Novel Anticoagulants (NOACs) in Non Valvular Atrial Fibrillation Raj Chakka, M.D. Electrophysiologist CHI St. Vincent Heart Clinic Arkansas April 25, 2015

CHADS VASc

Warfarin  Warfarin is an extremely effective drug for stroke prevention in AF patients, reducing stroke by 68% and mortality by 26%. 60% of patients never get warfarin, around half of patients who do get it stop taking it, and of those who still take it only half are in therapeutic range. So only a small minority are well treated.

Warfarin Target INR 2-3 Absolute risk reduction with warfarin 31 ischemic strokes prevented each year per 1000 patients treated Warfarin superior to Aspirin alone Antiplatelet agents like Clopidogrel + Aspirin increased major bleeding and no net benefit over Aspirin alone TTR < 58% showed no benefit of warfarin over combination antiplatelet therapy.

NOACs superior or similar stroke rates to warfarin, with reduced intracranial hemorrhage Ease of use and no INR testing needed  "alternatives to warfarin," while Canadian guidelines and those by the ACCP have made the jump to the new agents being "preferred to warfarin."

Tials of NOACs Indication Dabigatran Rivoraxaban Apixaban Edoxaban Non valvular atrial fibrillation RE-LY Re-LYABLE ROCKET-AF AVERROES ARISTOTLE ENGAGE-AF ACS REDEEM (Phase II) ATLAS ACS 2-TIMI 51 APPRAISE-2 Discontinued due to increased bleeding THR, TKR, VTE Acute medical illness

Advantages of NOACs over Warfarin Real World Implications Rapid onset of action No need for bridging with IV Heparin etc Predictable anticoagulant effect No need to routinely monitor INR etc Specific coagulation enzyme target Low risk of off-target adverse effects Low food interactions Can eat greens/salads etc Lower risk of drug interactions Few restrictions in use of other drugs Lower adverse events Skin necrosis in protein C or S deficiency Risk of osteoporosis

Downside of NOACs Very short half-lives, which will be hazardous if patients are noncompliant. Lack of effect assay (we do not know if someone is compliant or not) Renal function needs to be monitored. No reversal agents at this time

4 NOACs Characteristic Dabigatran (Pradaxatm) Rivaroxaban (Xareltotm) Apixaban (Eliquistm) Edoxaban Target Thrombin Factor Xa Half-life (hours) 12-14 7-13 8-13 9-11 Renal Clearance 80% 66% ~25% 35% Dosing 150 mg BID 20 mg QD 5 mg PO BID Fixed, QD Drug interactions Rifampin, Quinidine, Amiodarone, P-gp inhibitors Potent CYP3A4 and Potent CYP3A4 inhibitors CYP involvement NO CYP3A4 (15%) CYP3A4 (32%) CYP3A4

Rivoraxaban vs Warfarin Risk-Benefit balance in ROCKET – AF 1000 patient treated with Rivoraxaban instead of Warfarin Rivoraxaban vs Warfarin Benefit 3 fewer hemorrhagic strokes 4 fewer ischemic strokes No monitoring/fixed dose Limited potential for drug and food interactions Risk 7 excessive bleeding 3 excess blood transfusions 5 excess hemoglobin drop > 2 g/dl 6 excess SAEs leadsing to Rx discontinuation Increased cost No antidote

Clinical Tid Bits! Some people prefer a once-daily dosage (ie, Rivaroxaban, Adoxaban). Dabigatran should be avoided in severe renal failure. Renal function is not so much of a problem with Rivaroxaban but it still needs to be considered. Apixaban least renally cleared and preferred. Avoid Adoxaban if craetinine clearance > 95 ml/min Only the low dose of Dabigatran should be used with the P-glycoprotein (Pgp) inhibitor Verapamil, and close clinical surveillance is recommended especially in patients with renal impairment with Quinidine and Amiodarone. Dabigatran dose should be decreased to 75 mg BID with Dronedarone or systemic Ketoconazole in patients with moderate renal impairment (CrCl 30- 50 ml/min). Dabigatran can be dialysed out of the system; Rivaroxaban cannot. For ACS patients, there is better data for Rivaroxaban (in low dose) from the ATLAS trial. There is concern over the higher dose of Dabigatran in the elderly.

Crcl < 15 do not use Dabigatran or Rivaroxaban Take Dabigatran with a full glass of water to reduce dyspepsia and GI side effects Apixaban is the only NOACs that can be used in ESRD and in those on hemodialysis Adjust dose of Apixaban based on age, weight, creatinine Decrease dose to 2.5 mg BID if ≥ 2 of the criteria – age ≥ 80, Weight ≤ 60 Kg, or serum creatinine ≥ 1.5 mg/dL Boxed warning on Rivaroxaban – premature discontinuation increases the risk of thromboembolic events. Keep all these medications in original bottles delivered by pharmacy

How do we decrease risk clinically? Treat BP well Avoid constipation in anticoagulation patients Be wary of using NOACs with dual anti platelet agents (eg: Aspirin + Plavix)

Management of bleeding* * based on non clinical data and volunteers Moderate to severe bleeding Life threatening bleeding Symptomatic treatment Mechanical compression Surgical intervention Fluid replacement Hemodynamic support Blood product treatment Hemodialysis (60%, < 2-3 hrs) Oral Charcoal (<2hrs) rFVIIa PCC Prohemostatic agents Aprotinin, ECSA Tranexaine acid Desmopressin Charcoal filtration aDabi-Fab, PRT 4445 Andexanet-Alfa (Annexa-R) – being studied as a reversal agent in Phase III trials

40% of patients who have indication for anticoagulation still do not receive anticoagulation Comparison with left atrial occlusion devices – NOACs superior in early data

What CHADS/CHADS-VASc don’t account for Echo parameters (LA size, LVH) Renal/Hepatic Pattern of AF Bleeding Risk

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