RoleofNOACsinAFManagement.FromEvidencetoRealWorldData

FocusonCardioversion

John Rickard MD, MPH Staff Electrophysiologist

Cleveland Clinic

Agenda

� NOACs: Update on Real World Data � NOAC reversal: DabigatranàPraxbind � NOACs and Cardioversion

Introduc>on�  Afib is associated with increased risk of stroke.

� Warfarin ◦  67% reduction in risk of stroke ◦  26% reduction in total mortality

Unpredictable response

Routine coagulation monitoring

Slow onset/offset of action

TTR <70%

VKA therapy has several limitations

that make it difficult to

use in practice

Numerous drug-drug interactions

Numerous food-drug interactions

Frequent dose adjustments

Narrow therapeutic window

(INR range 2-3)

Limitations of Vitamin K Antagonist

NewOralAn>coagulants:50yearslater

Dabigatran Rivaroxaban Apixaban Edoxaban

Target Factor IIa Factor Xa Factor Xa Factor Xa

Dosing twice daily once daily twice daily once daily

Clinical Trial RELY ROCKET-AF ARISTOTLE ENGAGE

NOACs are increasingly used in AF patients

Pivotal controlled trials IDEAL setting

•  Gold Standard •  Highly controlled environment •  Comorbidities often excluded •  selected patient population •  Good compliance

Practice-based evidence USUAL daily setting

•  Less controlled environment •  Represents the ‘real world’ •  Not on selected patient population •  Compliance may be poor •  Confirms effectiveness and safety in

wider patient sample

Clinical Trials vs. Registries

Real-world data can confirm whether the results of an RCT are observed in everyday clinical practice

Independent FDA study of Medicare patients mirrors the favourable benefit–risk profile of dabigatran from RE-LY®

7

MORTALITY

RE-LY®1–4 Warfarin D150 BID

MEDICARE*5 Warfarin D150 & D75 BID combined

EV

EN

T R

ATE

(% P

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) IN

CID

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ER

10

0 P

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N-Y

EA

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ISCHAEMIC STROKE

ICH MAJOR BLEEDING

GI BLEEDING

MI

HR: 0.76 P=0.04

HR: 0.80 P=0.02

RR: 0.41 P<0.001

HR: 0.34 P<0.001

RR: 0.94 P=0.41

HR: 0.97 P=0.50

RR: 1.48 P=0.001

HR: 1.28 P<0.001

RR: 1.27 P=0.12

HR: 0.92 P=0.29

RR: 0.88 P=0.05

HR: 0.86 P=0.006

1. Connolly et al. NEJM 2009; 2. Connolly et al. NEJM 2010; 3. Pradaxa®: EU SPC, 2015; 4. Graham et al. Circulation 2014l; 5. Connolly S et al. NEJM 2014

Only standard doses of NOACs were compared in this study.

Dabigatran and apixaban were associated with a statistically significantly lower risk of any bleeding, major bleeding, and death compared with rivaroxaban or

warfarin

0

1

2

3

4

5

6

D A R W

Wei

gh

ted

eve

nt

rate

(

1 y

ear

follo

w-u

p)*

Major bleeding

HR 0.58 (0.47–0.71)

HR 0.61 (0.49–0.75)

HR 1.06 (0.91–1.23)

Apixaban Dabigatran Rivaroxaban Warfarin

Adjusted HR (95% CI) vs warfarin All-cause mortality

0

2

4

6

8

10

D A R W W

eig

hte

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ven

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te

(1 y

ear

follo

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HR 0.63 (0.48–0.82)

HR 0.65 (0.56–0.75)

HR 0.92 (0.82–1.03)

Apixaban Dabigatran Rivaroxaban Warfarin

Adjusted HR (95% CI) vs warfarin

Larsen et al. BMJ 2016;353:i3189

Compara>veEffec>venessandSafetyofNOACsandwarfarininpa>entswithAF:propensityweightedna>onwidecohortstudy

N=61,678

AnindependentFDAstudyof>118000Medicarepa>entscomparedDabigatran150mgBIDwithRivaroxaban20mgOD

�  Graham et al. JAMA Intern Med 2016

If warfarin was fighting the battle against the newer agents Lower efficacy

Higher bleeding Need for bridging

Slow onset and offset Need for INR monitoring

Significant food and drug interactions

MAY NEVER HAVE BEEN APPROVED BY A REGULATORY AGENCY

Pa>ent’sMainConcern…

� What if I bleed, have an accident or need urgent surgery?

� Role of Reversal Agents

IdarucizumabReversalagentforDabigatran

Schiele et al. Blood 2013; Glund et al. Thromb Haemost 2015

Humanized Fab: binds free dabigatran and dabigatran bound to thrombin

No known off-target effects; does not reverse heparins or any other anticoagulants

Binding affinity for dabigatran ~350× higher than dabigatran for thrombin

IV administration, immediate onset of action

Short half-life

No intrinsic procoagulant or anticoagulant activity

IdarucizumabWhenDoYouNeedit?

•  Emergency surgery or urgent intervention •  Open fractures •  Vascular Surgeries •  Abdominal surgeries…

•  Life-threatening or uncontrolled bleeding •  Intracranial Hemorrhage •  GI bleeding

AndexanetAlfa

AndexanetAlfa

Introduc>onCardioversionforAF�  First performed in the mid-1950s

�  Increased risk of thromboembolic complications*. ◦  5–7% without adequate anticoagulation

�  Clot/ Atrial Stunning ◦ ↓ 0.8% by adequate anticoagulation#

�  Guidelines recommend anticoagulation before (3 weeks) and after cardioversion (4 weeks).

�  The “Early” route ◦  TEE as an alternative to 3 week OAC pre DCC ◦  Does not Preclude post DCC anticoagualtion

*Reneskov et al 1967 Br H J # Bjerkelund et al, AJC 1969)

Recommenda>onsforan>coagula>onforCVESC/EHRAFocusedUpdate2010

Dabigatran Rivaroxaban Apixaban Edoxaban

Post HOC Analysis

RELY ROCKET-AF ARISTOTLE ENGAGE

Prospective RCT

… X-Vert EMANATE ENSURE-AF

NOACsandCardioversion

Questions: �  Efficacy � Safety

ThromboembolicComplica>onsDuringPeri-Cardioversion

*** composite of TE and death in CV/ablation

�  Retrospective analysis �  DCC was a not a predefined variable �  Small number of patients

X-VERT:Rivaroxabanvs.VKAFirstProspec3veRandomizedClinicalTrial

1504 pts

Cappato R et al, Eur Heart J 2014;35:3346–3355�

X-VERTPrimaryEfficacy&SafetyOutcome

Efficacy: Composite of stroke, TIA, peripheral embolism, MI,CV death Safety: Major bleeding

Cappato R et al, Eur Heart J 2014;35:3346–3355�

ENSURE-AF:PrimaryEfficacyOutcome

Composite of : Stroke, SEE, MI, and CV Death

Edoxaban vs Enoxaparin/Warfarin in Subjects Undergoing Cardioversion of Atrial Fibrillation

EMANATE:Apixabanvs.Warfarin

Conclusion

�  Usage of the NOACs is expected to increase as clinicians gain more experience and reassurance with data from the real world studies which are generally consistent with that from clinical trials.

�  The availability of antidote to certain drugs will add more reassurance and acceptance from physicians and patients to use newer anticoagulant therapy.

�  All 4 currently available NOACS appear to be as effective and safe as warfarin in patients with NVAF undergoing DCC.

WhatwedoCardioversioninPa>entstreatedwithNOACS

�  In patients with AF of >48 h duration, OACs should be given for ≥3 weeks before cardioversion

�  It is essential to ask patients about compliance over the past weeks. Document in medical records. ◦  If compliance can reliably be confirmed, cardioversion seems

acceptably safe ◦  If doubts exist about compliance, consider prior TEE

�  Continuous oral anticoagulation for 4 weeks after cardioversion is also mandatory

�  Anticoagulation beyond 4 weeks as clinically indicated (CHADS2VASC2 score)

Thank You

MAKINGACHOICE

�  Largest RRR of ischemic stroke: dabigatran �  Largest renal elimination: dabigatran �  Once daily dosing: Rivaroxaban, edoxaban �  Most significant reduction in major bleeding: Apixaban �  Least expensive: Warfarin