Which NOAC and When for Stroke Prevention in AF? Elaine M. Hylek MD MPH Boston University School of Medicine Professor of Medicine

Disclosures Research support Executive Steering Committees: BMS/Pfizer-ARISTOTLE trial; Janssen-ORBIT-AF Registry, QUANTUM AF; Boehringer Ingelheim-REVERSE-AD Consultant Bayer, Boehringer Ingelheim, BMS/Pfizer, Janssen, Medtronic, Portola, Roche Honoraria Boehringer Ingelheim, BMS/Pfizer Other Steering Committee American College of Cardiology/Medscape Center of Excellence on Atrial Fibrillation; HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation

2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation. Published on January 28, 2019, available at: Journal of the American College of Cardiology and Circulation. The full-text guidelines are also available on the following Web sites: ACC (www.acc.org) and AHA(professional.heart.org)

Anticoagulation Regimen – Balancing Risks and Benefits Recommendations for Selecting an Anticoagulant Regimen—Balancing Risks and Benefits COR LOE Recommendations I A For patients with AF and an elevated CHA2DS2-VASc score of 2 or greater in men or 3 or greater in women, oral anticoagulants are recommended. Options include: Warfarin (LOE: A) Dabigatran (LOE: B) Rivaroxaban (LOE: B) Apixaban (LOE: B) or Edoxaban (LOE: B-R) MODIFIED: This recommendation has been updated in response to the approval of edoxaban, a new factor Xa inhibitor. More precision in the use of CHA2DS2-VASc scores is specified in subsequent recommendations. The LOEs for warfarin, dabigatran, rivaroxaban, and apixaban have not been updated for greater granularity as per the new LOE system. (Section 4.1. in the 2014 AF Guideline) The original text can be found in Section 4.1 of the 2014 AF guideline. Additional information about the comparative effectiveness and bleeding risk of NOACs can be found in Section 4.2.2.2. B B-R

Anticoagulation Regimen – Balancing Risks and Benefits Recommendations for Selecting an Anticoagulant Regimen—Balancing Risks and Benefits COR LOE Recommendations I B-NR Renal function and hepatic function should be evaluated before initiation of a NOAC and should be reevaluated at least annually. MODIFIED: Evaluation of hepatic function was added. LOE was updated from B to B-NR. New evidence was added. (Section 4.1. in the 2014 AF Guideline)

Reversal COR LOE Recommendations I B-NR Idarucizumab is recommended for the reversal of dabigatran in the event of life-threatening bleeding or an urgent procedure. NEW: New evidence has been published about idarucizumab to support LOE B-NR. IIa Andexanet alfa can be useful for the reversal of rivaroxaban and apixaban in the event of life-threatening or uncontrolled bleeding. NEW: New evidence has been published about andexanet alfa to support LOE B-NR.

METHODS Retrospective new-user cohort study of US Medicare patients with AF using claims data Warfarin (n=183,318), or a standard dose of dabigatran (150 mg twice-daily; n=86,198), rivaroxaban (20 mg once-daily; n=106,389) or apixaban (5 mg twice-daily; n=73,039) Anticoagulation exposure: censored with >3-day gap in Rx Study Period: October 2010 and September 2015 Propensity score adjusted Cox proportional hazards regression to estimate adjusted HR 95% (CI) for TE stroke, ICH, major extracranial bleeding, and all-cause mortality, comparing each NOAC with warfarin, and with each other NOAC

>65 years of age

Retrospective cohort study of Medicare beneficiaries included in the U.S. Renal Data System (October 2010 to December 2015). Eligible patients: ESKD and AF undergoing dialysis who initiated Rx with OAC. (Outcomes were only assessed in patients treated with apixaban or warfarin).

2,351 patients on apixaban: 44% FDA dose 5 mg twice daily 23 ,172 patients on warfarin In matched cohorts 1:3, there was no difference in the risks of stroke/systemic embolism between apixaban and warfarin (HR, 0.88; 95% CI, 0.69–1.12; P=0.29) Stroke/SEE Death Apixaban 5 mg vs 2.5 mg HR, 0.61; 95% CI, 0.37–0.98 HR, 0.64; 95% CI, 0.45–0.92 vs. warfarin HR, 0.64; 95% CI, 0.42–0.97 HR, 0.63; 95% CI, 0.46–0.85

MAJOR BLEEDING NO DIFFERENCE in INTRACRANIAL OR GI BLEEDING Absolute rates of major bleeding higher than previously reported in this patient population—19.7% for apixaban and 22.9% for warfarin. (? related to definition) High discontinuation rates for both drugs apixaban 105 days, warfarin 157 days Apixaban was associated with a significantly lower risk of major bleeding (HR, 0.72; 95% CI, 0.59–0.87; P<0.001). NO DIFFERENCE in INTRACRANIAL OR GI BLEEDING

352 patients, mean age 77 years (apixaban or rivaroxaban) February 7, 2019. DOI: 10.1056 /NEJMoa1814051 352 patients, mean age 77 years (apixaban or rivaroxaban) ICH [64%] or GI [26%] Low or High bolus followed by 2 hour infusion: 92% reduction anti–factor Xa activity Excellent or good hemostasis occurred in 82% who could be evaluated. Within 30 days, death occurred in 49 patients (14%) and a thrombotic event in 34 (10%). SURGICAL patients were not studied Recurrence of activity at end of infusion Approx cost US $25K-50K

CONCLUSIONS NOACs preferred over warfarin for stroke prevention in AF AC recommended for CHA2DS2-VASc ≧2 for men; ≧3 for women Warfarin first line Rx for mechanical valves, mod-severe mitral stenosis To date, limited evidence for use of either VKA or apixaban in ESRD Sequelae of reversal in clinical practice warrants further study