Update on the NOAC s: 2018 Daniel Blanchard, MD, FACC, FAHA

Transcription

1 Update on the NOAC s: 2018 Daniel Blanchard, MD, FACC, FAHA Professor of Medicine Director, Cardiology Fellowship Program Sulpizio Cardiovascular Center UC San Diego

2 The NOACS, chronologically Dabigatran: Pradaxa Rivaroxaban: Xarelto Apixaban: Eliquis Edoxaban: Savaysa Should not be used in patients with CrCl > 95 ml/min because of increased risk of ischemic stroke (about 20% of ENGAGE-AF study population) Betrexiban

3 Currently Available NOACs 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) CHADS Age >75 (%) Dosing based on renal fx Yes Yes Yes Yes Frequency BID QD BID QD Class DTI FXa inhibitor FXa inhibitor FXa inhibitor

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 Currently Available NOACs: stroke risk All have similar or lower risk of stroke vs warfarin Kovacs, et al. JACC 2015;65:

6 Currently Available NOACs: Major Bleeding All have similar or lower risk of major bleeding Kovacs, et al. JACC 2015;65:

7 Currently Available NOACs: ICH All have similar or LOWER risk of Intracranial Hemorrhage Kovacs, et al. JACC 2015;65:

8 Currently Available NOACs: GI Bleed All have HIGHER or similar risk of GI Bleed Kovacs, et al. JACC 2015;65:

9 Summary of NOACs vs Warfarin Better major bleeding outcomes Especially intracranial Increased GI bleeding with some agents At least as (or more) effective at preventing stroke

10 Questions about NOACs All of these results are from industry-sponsored clinical trials What about real-world results?

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

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

13 Questions: Warfarin vs NOACs Do we want blood tests to monitor drug levels? 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 and CKD? Is aspirin safer in patients with high bleeding risk? What about antidotes?

14 NOACs and Valvular Disease Definition of Valvular Afib a moving target For now: mechanical valve replacement, moderate-to-severe MS

15 NOACs and Valvular Disease Definition of Valvular AF ARISTOTLE & ENGAGE-AF had pts with Valvular disease unless requiring surgery (except mitral stenosis) Aortic bioprosthetic valve ROCKET and RE-LY had pts with: Mod-severe valvular disease unless requiring surgery (except mitral stenosis) (Excluded prosthetic valves and mitral stenosis) No evidence of any problems with NOAC s in these populations. Avoid use in pts with moderate-severe mitral stenosis or mechanical valves Renda et al. JACC 2017

16 NOACs and Valvular Disease: Stroke & Bleeding

17 NOACs and Valvular Disease : ICH

18 NOACs and Valvular Disease: All-cause Mortality

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, prothrombotic risk Antifibrinolytic agent (tranexamic acid, aminocaproic acid) Factor Xa protein decoys Andexanet (Annexa) effective in prelim studies, not yet approved Universal NOAC inhibitors: Ciraparantag, FXa I16L prelim studies only

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 Severe renal dysfunction/renal failure (??) Chronic well-managed warfarin therapy (??)

24 Other options besides anticoagulation Left atrial appendage exclusion Surgical ligation at time of CTS FDA-Approved device: WATCHMAN Self-expanding nitinol cage Trans-septal approach Endothelialized within 45 days Must be able to tolerate warfarin (+ASA) x 6 wks Then clopidogrel + ASA until 6m

25 Dual vs Triple Therapy for Afib after PCI Lower Low-dose bleed NOAC risk with low-dose NOAC vs warfarin PIONEER AF-PCI N=2124 pts with AF after PCI Dual therapy: Low-dose rivaroxaban 15mg daily + P2Y12 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 Not powered to detect differences in prevention of ischemic events but no excess risk noted Gibson CM et al. NEJM 2016;375. Bleeding Risk

26 Dual vs Triple Therapy for Afib after PCI RE-DUAL PCI 2725 pts with AF after PCI Triple therapy: Warfarin + P2Y12 (clopidogrel/ticagrelor) + ASA Dual therapy: Low-dose Dabigatran 110mg bid + P2Y12 Dual therapy: Dabigatran 150mg bid + P2Y12 Bleeding: Lower in dabigatran 110mg DAPT group (HR 0.52, p<0.001 noninferiority) and 150mg group (HR 0.72, p<0.001) compared to triple Rx Less intracranial bleeding vs triple Rx Efficacy: Dual Rx non-inferior vs triple Rx (death, MI, stroke, revasc) NOAC instead of warfarin, drop ASA? Cannon CP et al. NEJM 2017;377(16)

27 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)

28 Summary of Dual vs Triple Therapy After PCI Piccini JP, NEJM 2017;377(16)

29 New Study Data with NOACs: Stable CAD pts COMPASS 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 1⁰ 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)

30 New Study Data with NOACs: Stable CAD pts COMPASS Eikelboom JW et al. NEJM 2017;377(14)

31 Conclusions NOACs associated with less intracranial bleeding Equivalent MACE Not for mechanical heart valves/mod-severe MS May be part of new regimens post-pci and (??) stable CAD