INR as a Biomarker: Anticoagulation in Atrial Fib, Heart Failure, and Cardiovascular Disease Daniel Blanchard, MD, FACC, FAHA

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1 INR as a Biomarker: Anticoagulation in Atrial Fib, Heart Failure, and Cardiovascular Disease Daniel Blanchard, MD, FACC, FAHA Professor of Medicine Director, Cardiology Fellowship Program Sulpizio Cardiovascular Center UC San Diego

2 The INR: Why Have We Needed It? Metabolism of warfarin varies considerably between patients Vitamin K consumption varies, and affects coagulation TTR is critically important to prevent embolism/bleed TTR in the best anticoagulation clinics is ~65%

3 The NOACS, chronologically Dabigatran: Pradaxa Rivaroxaban: Xarelto Apixaban: Eliquis Edoxaban: Savaysa Betrixaban: Bevyxxa For prevention of DVT/PE during and after acute hospitalization

4 NOACs Compared to Warfarin Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) Edoxaban (Savaysa) Trial RE-LY ROCKET AF ARISTOTLE ENGAGE AF # of Patients 18,113 14,264 18,201 21,105 Follow-up (y) S/SE Fewer Same Fewer Same Hemorrhagic CVA, ICH Fewer Fewer Fewer Fewer Major Bleeds Same Same Fewer Fewer GI Bleeds More More Same More C-Vascular Mortality Less Same Same Less

5 NOACs Compared to Warfarin All have similar or lower risk of stroke vs warfarin All have similar or lower risk of major bleeding Most have HIGHER risk of GI Bleed All have a LOWER risk of Intracranial Hemorrhage (!!)

6 Efficacy (Stroke/Systemic Embolus) (Data from a large US insurance [Optum] database, ) Noseworthy, et al. CHEST 2016;150:

7 Safety (Major Bleeding) Noseworthy, et al. CHEST 2016;150:

8 Questions: Warfarin vs NOACs Do we want blood tests to monitor drug levels? It would be good to have a NOAC INR TEG 6s and anti-xa assays detect presence of NOAC very accurately, but don t yet have therapeutic ranges What about use in valvular disease, CHF, and CAD? Is aspirin safer in patients with high bleeding risk? What about antidotes?

9 NOACs and Valvular Disease: Stroke & Bleeding

10 NOACs and Valvular Disease : ICH

11 NOACs for AFib with Valvular Disease NOACs appear safe in valvular heart disease EXCEPT Mechanical valve replacement, moderate-to-severe MS

12 NOACs for AFib with Heart Failure Meta-analysis of all 4 Phase III clinical trials of NOACs (55,000 pts) 48% of pts with HF, 52% without HF RR of stroke/se: 0.98 RR of major bleeding: 0.95 Savarese, et al. JACC HF 2016;4:

13 NOACs for AFib with Heart Failure: HF patients NOACs generally superior to warfarin in HF patients Savarese, et al. JACC HF 2016;4:

14 NOACs for AFib with Heart Failure: All patients Increased risk of all-cause and CV death in HF pts Savarese, et al. JACC HF 2016;4:

15 NOACs in Patients with Stable CAD The COMPASS Trial N=27,395 pts, stable ischemic coronary or PAD ASA 100mg monotherapy vs low-dose rivaroxaban 5mb bid monotherapy vs very-low-dose rivaroxaban 2.5mg bid + ASA 100mg clear winner, trial stopped early for overwhelming efficacy 1p endpoints: CV death, MI, stroke; bleeding Next step: ASA + very-low-dose NOAC vs ASA + P2Y12 Adding low-dose NOAC to ASA in stable CAD pts Eikelboom JW et al. NEJM 2017;377(14)

16 NOACs in Patients with Stable CAD The COMPASS Trial Eikelboom JW et al. NEJM 2017;377(14)

17 Dual vs Triple Therapy for Afib after PCI Low-dose NOAC Lower bleed risk with low-dose NOAC vs warfarin Bleeding Risk PIONEER AF-PCI N=2124 pts with AF after PCI Dual therapy: Low-dose rivaroxaban 15mg daily + P2Y12 (group 1) Triple therapy: Very-low-dose rivaroxaban 2.5mg bid + DAPT (group 2) Triple therapy: Warfarin + DAPT (group 3) *Both rivaroxaban arms lower risk of TIMI major + minor bleeding vs warfarin Gibson CM et al. NEJM 2016;375.

18 Summary of Dual vs Triple Therapy after PCI Odds of MACE (death, MI, revasc, stent thrombosis) not higher with dual therapy (NOAC) than with triple therapy (warfarin) Risk of bleeding clearly lower with dual therapy OR 0.49 (95% CI , p<0.001) Piccini JP, NEJM 2017;377(16)

19 What about patients prone to falling and bleeding? Should they be on aspirin instead of a NOAC?

20 AVERROES Substudy: Apixaban vs. ASA in older pts thought not to be good warfarin candidates Risk of Major Bleeding Similar Major Bleed Risk Risk of Stroke Increased risk of Stroke with ASA! Ng K et al. Age & Ageing 2015;0:1-7

21 NOAC Antidotes: For Major Bleeding Dabigatran: Idarucizumab (Praxbind) IV antibody fragment with very high affinity for dabigatran. Reverses anticoag effect in minutes, decreases hemorrhage in bleeding pts & those needing urgent surgery REVERSE-AD: n=503 with uncontrolled bleeding or about to undergo urgent procedure * Pollack CV et al. NEJM 2015;373. Pollack CV et al. NEJM 2017;377(5).

22 NOAC Antidotes: For Major Bleeding FXa inhibitors: (apixaban, rivaroxaban, edoxaban) PCC (K-centra, prothrombin complex concentrate) reverses hematologic effects, but has not been tested in bleeding patients. Only for severe bleeding because of prothrombotic risk Factor Xa protein decoys Andexanet (Andexxa) effective in preliminary studies, now FDA approved. Finally. Currently expensive

23 Do we still need warfarin? For now, yes Today, warfarin is still the anticoagulant of choice for patients with: Mechanical heart valve replacement Mitral stenosis Chronic well-managed warfarin therapy (??) Severe renal dysfunction/renal failure (??) What about a new patient with Afib at high risk for stroke?

24 New ACCP CHEST Recommendations for AFib Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel Report. Chest 2018;Aug 21:[Epub ahead of print]. When selecting an oral anticoagulant, recommend using a non-vka oral anticoagulant (NOAC) rather than dose-adjusted vitamin K antagonist therapy for eligible patients. For patients with prior unprovoked bleeding, bleeding on warfarin therapy, or at high risk for bleeding, recommend apixaban, edoxaban, or dabigatran 110 mg (where available).

25 NOACs in End-Stage Renal Disease Siontis, et al. Circulation. 2018;138:

26 NOACs in End-Stage Renal Disease Siontis, et al. Circulation. 2018;138:

27 NOACs vs Warfarin in End-Stage Renal Disease Siontis, et al. Circulation. 2018;138:

28 Conclusions NOACs associated with less intracranial bleeding Equivalent or lower MACE than warfarin Not for mechanical heart valves/mod-severe MS May be part of new regimens post-pci and in stable CAD (?)?? Apixaban in ESRD

29 (Prescribes warfarin) Prescribes NOACs

30 42

31 Lopes, et al. Am J Med 2018;131:

32 Lopes, et al. Am J Med 2018;131:

33 Lopes, et al. Am J Med 2018;131: