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