NOAC Therapy for CV Disease:
AFib and Beyond
Daniel G. Blanchard, MD, FACC, FAHA
Professor of Medicine
Director, Cardiology Fellowship Program
Sulpizio Cardiovascular Center
UC San Diego
• Dabigatran: Pradaxa
• Rivaroxaban: Xarelto
• Apixaban: Eliquis
• Edoxaban: Savaysa
The NOACS, chronologically
Currently Available NOACs for AFibDabigatran
(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) 2 1.6 1.7 2.8
CHADS2 2.1 3.5 2.1 2.8
Age >75 (%) 40 38 31 40
Dosing based
on renal fx
Yes Yes Yes Yes
Frequency BID QD BID QD
Class DTI FXa inhibitor FXa inhibitor FXa inhibitor
NOACs Compared to WarfarinDabigatran
(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) 2 1.6 1.7 2.8
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
NOACs Compared to Warfarin
All have similar or lower
risk of stroke vs warfarin
All have similar or lower
risk of major bleeding
All have a LOWER risk of
Intracranial Hemorrhage (!!)
Most have HIGHER risk of
GI Bleed
• Better major bleeding outcomes
• Especially intracranial
• Increased GI bleeding with some agents
• At least as (or more) effective at preventing stroke
Summary of NOACs vs Warfarin: Stroke Prevention in AFib
• 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?
• Is aspirin safer in patients with high bleeding risk?
• What about antidotes?
Questions: Warfarin vs NOACs
• ARISTOTLE & ENGAGE-AF had pts with
• Moderate valvular disease (except mitral stenosis)
• Aortic bioprosthetic valve
• ROCKET and RE-LY had pts with:
• Mod-severe valvular disease
• (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
NOACs & Valvular Disease: Definition of “Valvular AF”
Renda et al. JACC 2017
NOACs and Valvular Disease: Stroke & Bleeding
NOACs and Valvular Disease: All-cause Mortality
• NOACs appear safe in valvular heart disease EXCEPT
• Mechanical valve replacement
• Moderate-to-severe MS (??)
• Early registry data from Korea suggests no increase in events with NOAC
NOACs and Valvular Disease
What about patients prone to falling and bleeding?
Should they be on aspirin instead of a NOAC?
AVERROES Substudy: Apixaban vs. ASA in older pts
thought not to be good warfarin candidates
Risk of
Major
Bleeding
Risk of
Stroke
Ng K et al. Age & Ageing
2015;0:1-7
Similar Major
Bleed Risk…
Increased risk
of Stroke with
ASA!
• 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
NOAC Antidotes: For Major Bleeding
* Pollack CV et al. NEJM 2015;373.
Pollack CV et al. NEJM 2017;377(5).
• 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.
• Currently expensive
NOAC Antidotes: For Major Bleeding
• For now, yes
• Today, warfarin is still the anticoagulant of choice for patients with:
• Mechanical heart valve replacement
• One bad European study
• Mitral stenosis
• Recent favorable data for NOACs from Korea
• Severe renal dysfunction/renal failure (??) (Apixaban OK?)
• Chronic well-managed warfarin therapy (??)
Do we still need warfarin?
• Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel Report. Chest 2018;Aug 21.
• When selecting an oral anticoagulant, recommend using a direct oral anticoagulant (DOAC) rather than dose-adjusted vitamin K antagonist therapy for eligible patients.
ACCP CHEST Recommendations for AFib
PCI in Afib:Summary of Dual vs Triple Therapy After PCI
Piccini JP, NEJM 2017;377(16)
• Risk of bleeding clearly lower with dual therapy (NOAC + Plavix) vs triple therapy (add ASA)
• OR 0.49 (95% CI 0.34-0.72, p<0.001)
• Current recommendation: triple therapy for a month after PCI, then stop ASA. Consider stopping Plavix after 6-12 months.
Summary of Dual vs Triple Therapy for Afib after PCI
• N=27,395 pts, stable ischemic CAD or PAD
• ASA 100 mg monotherapy vs low-dose rivaroxaban 5 mg bid monotherapy vs very-low-dose rivaroxaban 2.5 mg bid + ASA 100mg → clear winner, trial stopped early for “overwhelming efficacy”
• 1⁰ endpoints: CV death, MI, stroke; bleeding
COMPASS: Use of NOACs in Stable CAD, without AFib
Eikelboom JW et al. NEJM 2017;377(14)
Adding low-dose NOAC to
ASA in stable CAD pts
COMPASS: Effect of
NOACs in CAD on Bleeding
• N=2236 pts with stable CAD, h/o PCI or CABG (>1 yr prior)
• Randomized to Rivaroxaban alone vs. Riva + ASA or Plavix
• 1⁰ efficacy endpoints: CV death, MI, stroke, CVA, revasc.
• 1⁰ safety endpoint: major bleeding
AFIRE Study: Effect of NOAC With vs. Without ASA in Pts with AFib and Stable CAD
Yasuda S, et al. NEJM 2019;381:1103
AFib in Patients with stable
CAD: Is a NOAC enough,
or is ASA necessary?
• Primary Efficacy Endpoint: Noninferior
35
AFIRE Results
• Primary Safety Endpoint: Superior for NOAC alone.
• (So why use ASA?)
• N=4614 pts with ACS and AFib, treated medically or with PCI
• Randomized to Apixaban + Plavix alone, compared to patients also on ASA and/or warfarin.
AUGUSTUS Results: Effect of NOAC + Plavix with or without ASA or Warfarin in Pts with AFib and ACS
Windecker S, et al. Circulation 2019;140:1921.
AFib in Patients with ACS:
Is a NOAC enough, or is
ASA necessary?
• N=4614 pts with ACS and AFib, treated medically or with PCI
• Apixaban vs. warfarin
AUGUSTUS Study: NOAC + Plavix With or Without ASA or Warfarin in Pts with AFib and ACS
Windecker S, et al. Circulation 2019;140:1921
Windecker S, et al. Circulation 2019;140:1921
• Apixaban with or without ASA
NOACs: Treatment for PE and VTE
NOACs in End-Stage Renal Disease
Siontis, et al. Circulation. 2018;138:1519-29.
• NOACs associated with less intracranial bleeding
• Equivalent or lower MACE than warfarin
• Not for mechanical heart valves/mod-severe MS (at this time)
• New and evolving regimens
• post-PCI and stable CAD (rivaroxaban)
• post-PCI with ACS and AFib (apixaban)
Conclusions
54
“I suppose, stranger, that flying for a major airline makes
you think you’re something special”
(Takes warfarin)
On a NOAC