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Preventing Stroke and Managing Atrial Fibrillation Patients

Which NOAC for Which Patient?

Amos Katz, M.D.

Grant/Research Support:

Pfizer, - Boehringer Ingelheim, - Bayer, - Daiichi Sankyo, - Cardio 3, - Sanofi, TIMI group, - Trevena, - Hamilton Health Sciences Corporation, Population Health Research Institute, - Novartis

Speaker’s Bureau:

Pfizer, - Bayer. - Boehringer Ingelheim, - BIOTRONIK, -Medtronic, - Sanofi, - Novartis

Consultant:

BIOTRONIK, - Spirocor

Disclosures

New / Novel Oral Anticoagulants (NOACs)

Non-warfarin Oral Anti Coagulants (NOACs)

Non-vitamin K antagonist oral anticoagulants (NOACs)

Target-Specific Oral anti Coagulants (TSOCs)

Direct Oral Anti Coagulants (DOACs)

Oral Direct Inhibitors (ODIs)

Non-monitored Oral Anti Coagulants (NOACs)

NOACs? - No longer new or novel

Most strokes associated with AF are ischaemic

Based on data collected in the Danish National Indicator Project for 39 484 patients hospitalized for stroke (80% of all stroke admissions in Denmark) including 6294 patients with AF); OAC use not recorded

Andersen KK et al. Stroke 2009;40:2068–72 4

Types of stroke in patients with AF

Ischaemic

92% (n=5810)

Haemorrhagic

8% (n=484)

NOAC Phase III Trials Timelines

• AVERROS

• Double blind

• Vs. Aspirin

NOAC

Europe Approved June 26, 2015

FDA Approved January 8, 2015

Pharmacological Characteristics and Rx dose of NOAC

in Phase III Trials

RELY (Dabigatran )

ROCKET (Rivaroxaban)

ARISTOTLE (Apixaban)

ENGAGE-AF (Edoxaban)

Mechanism of action

Selective direct FIIa inhibitor

Selective direct FXa inhibitor

Selective direct FXa inhibitor

Selective direct FXa inhibitor

Oral bioavailability, %

6.5 80-100 50 62

Half-life, h 12-17 5-13 8-15 6-11

Renal elimination % 85 66 (36 unchanged &30 inactive)

27 50

Time to maximal inhibition, h

0,5-2 1-4 1-4 1-2

Potential for drug–drug interactions

P-gp inhibitor CYP3A4 substrate and P-gp inhibitor

CYP3A4 substrate and P-gp inhibitor

Study treatment Dabigatran 110mg BID

Dabigatran 150mg BID

Rivaroxaban 20mg

(15 in pts with eFGR

30-49 ml/min)

QD

Apixaban 5mg

2.5 mg in age > 80 Y,

weight < 60 kg, creat < 1.5mg/dl

BID

Edoxaban 30mg QD

Edoxaban 60mg QD

Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011; ENGAGE- AF Study Investigators. AHJ 2010

CRNM-clinically relevant non-mjor

Baseline Characteristics

All NOACs; Stroke or Systemic Embolic Events

Secondary Efficacy Outcome

All NOACs; Major Bleeding

Safety outcomes of NOACs vs. warfarin: Data from RE-LY, ROCKET AF and ARISTOTLE

NA=not available; * Includes major and nonmajor clinically relevant bleeding events only

Based on an indirect comparison, where dabigatran , rivaroxaban and apixaban were all compared against the reference drug warfarin (target INR 2-3).

Connolly SJ et al. N Engl J Med 2009;361:1139–51; Connolly SJ et al. N Engl J Med 2010;363:1875–6 ; Patel MR et al. N Engl J Med 2011;365:883–91 ; Granger CB et al. N Engl J Med 2011;365:981–92

Apixaban 5mg BID

Rivaroxaban 20mg OD

Dabigatran 110mg BID

Dabigatran 150mg BID

Major bleeds

ICH

NA Life-threatening bleeds

Major GI bleeds

* Total bleeds

=

=

=

=

=

ROCKET AF Reveals Higher GI leeding Rates With

Rivaroxaban

• Retrospective analysis of the trial (14,236 patients in the safety-end-point population of trial)

• GI bleeding rates were 42% higher for rivaroxaban-treated patients (HR 1.42, 95% CI 1.22–1.66), than for warfarin

• 48% - upper-GI tract

• 23% - lower-GI tract

• 29% - rectum

Sherwood M,et al. J Am Coll Cardiol 2015; 66:2271-2281

NOACs: Absorption & Metabolism

H. Heidbuchel et al. Updated EHRA practical guide for use of the non-VKA oral anticoagulants. Europace 8/2015

Drug–drug interactions

H. Heidbuchel et al. Updated EHRA practical guide for use of the non-VKA oral anticoagulants. Europace 8/2015

Drug–drug interactions

H. Heidbuchel et al. Updated EHRA practical guide for use of the non-VKA oral anticoagulants. Europace 8/2015

Approved European labels for NOACs and

their dosing in CKD

H. Heidbuchel et al. Updated EHRA practical guide for use of the non-VKA oral anticoagulants. Europace 8/2015

תהיה בטוח שבחרת נכון

NOACs – Dose Reduction

• VKA is protective after an ACS, Warfarin plus aspirin reduces the risk

of recurrent ischaemic

• Triple therapy with DAPT and NOACs - doubles the risk of major

bleeding after an ACS.

• Studies evaluating combinations of NOAC or VKA + antiplatelets post

PCI & stenting

• PIONEER AF PCI – Rivaroxaban; ongoing

• RE-DUAL PCI – Dabigatran ; ongoing

• AUGUSTUS - Apixaban ; ongoing

• EVOLVE-AF-PCI – Edoxaban; to start

• Unknown whether SAPT/DAPT plus NOAC is safer than

SAPT/DAPT plus VKA or vice versa.

NOACS in Patient with Atrial Fibrillation & CAD

H. Heidbuchel et al. Updated EHRA practical guide for use of the non-VKA oral anticoagulants. Europace 8/2015

• Dabigatran and edoxaban have not been evaluated in a Phase III study of

patients with recent ACS.

• In a meta-analysis of dabigatran trials, there was a significantly higher rate of

MIs with dabigatran vs. VKA (odds ratio 1.33, 95% confidence interval1.03–

1.71, P ¼ 0.03)

• The absolute excess was very low (about 3 per 1000 patients)

• The net clinical benefit and mortality benefit of dabigatran over VKA was maintained in AF

patients with a previous MI,

• No excess of MI was observed in a Danish registry & in an FDA conducted US Medicare registry

• No trial with FXa inhibitors showed a statistically significant excess of MI.

• After ACS, DAPT on top of apixaban (5 mg BID) significantly increases major

and fatal bleeding risk, without reduction in ischaemic events (APPRAISE-2 )

• Phase II trial with dabigatran in combination with DAPT after ACS, showed a

dose-dependent increase in bleeding events

• Rivaroxaban (2.5 mg BID) on top of DAPT significantly improves ischaemic

outcome after ACS, but is associated with increased major and intracranial

bleeding (ATLAS ACS)

NOACS in Patient with Atrial Fibrillation & CAD

H. Heidbuchel et al. Updated EHRA practical guide for use of the non-VKA oral anticoagulants. Europace 8/2015

NOAC Antidotes – Clinical Trials

• Electrical cardioversion in patients treated with NOACs has a similar

(and very low) thrombo-embolic risk as under warfarin

• Subgroup analyses from:

• RE-LY (dabigatran)

• ROCKET-AF (rivaroxaban),

• ARISTOTLE (apixaban)

• The recently published X-VeRT trial confirmed the low peri-

cardioversion stroke risk in patients treated with rivaroxaban compared

with warfarin

• Ongoing Clinical Studies:

• ENAMATE – Rivaroxaban

• ENSURE – Adoxaban

NOACS & Cardioversion

H. Heidbuchel et al. Updated EHRA practical guide for use of the non-VKA oral anticoagulants. Europace 8/2015

Adherence

Discontinuation

Patients Preference vs. Safety

Pan X et al. ESC 2014, Barcelona, Spain. Oral poster presentation, ESC 2014. Accessible on congress365.escardio.org

% O

F PA

TIEN

TS W

ITH

DIS

CO

NTI

NU

ATI

ON

TIME FROM ANTICOAGULATION INITIATION (DAYS)

WARFARIN (n=14,339)

RIVAROXABAN (n=12,080)

DABIGATRAN (n=4,495)

APIXABAN (n=2,956)

Warfarin vs. Apixaban: Adjusted HR: 1.638 (95% Cl: 1.514–1.772) P<0.001 Rivaroxaban vs. Apixaban: Adjusted HR: 1.215 (95% Cl: 1.121–1.317) P<0.001 Dabigatran vs. Apixaban: Adjusted HR: 1.581 (95% Cl: 1.451–1.721) P<0.001

Analysis controlled for other variables including age, gender, onset of embolic or primary ischaemic stroke, dyspepsia or stomach discomfort, congestive heart failure, coronary artery disease, diabetes, hypertension, renal disease, myocardial infarction, history of TIA or stroke and history of bleeding

0

0

10

20

40

60

70

30 60 90 120 150 180 210 240 270 300 330 360 390

30

50

BMS/Pfizer confidential. For internal use only. Not for further distribution

Discontinuation Rates In USA NVAF Patients New To Anticoagulation (Jan 2013 – Dec 2013) (Marketscan Commercial and Medicare)

The proportion of patients who discontinued

during the follow-up period was:

• 23.32% for apixaban

• 46.96% for dabigatran

• 35.15% for rivaroxaban • 46.28% for warfarin

Conclusions:

• The twice-daily dosing regimen of NOACs appears to offer a more

balanced risk-benefit profile with respect to stroke prevention and

intracranial bleeding.

Real Life Data

FDA analysis on Dabigatran Jan 2014

Surveillance plan for rivaroxaban

Danish Registry

FDA study of Medicare patients finds risks lower for stroke and death but higher for gastrointestinal bleeding with Pradaxa

(dabigatran) compared to warfarin (13.5.2014)

Larsen TB, et al. J Am Coll Cardiol 2013; 61: 2264-73.

Real World Comparison Of Major Bleeding Risk Among Non-valvular

Atrial Fibrillation Patients Newly Initiated On Apixaban, Dabigatran,

Rivaroxaban Or Warfarin (poster ESC 2015 LIP)

Which NOACS for which patient?

Which is the est NOACS?

• No Head to head comparison

• CHADS2 score and more secondary prevention pts. In

ROCKET AF

• Ischemic Stroke reduction only with dabigatran 150 mg

BID

• GI bleeding in the trials: • Increased with:

• Dabigatran 150 mg

• Rivaroxaban

• Edoxaban 60 mg

• Not increased with:

• Apixaban

• Edoxaban 30 mg

• Decreased in total mortality:

• Rivaroxaban

• Edoxaban 30 mg

NOACs – Indirect Comparison

Double-blind study

VKA unsuitable

M F/U 1.1 years.

NEJM February 10, 2011

•DMC recommended early study termination at 1st analysis of efficacy – May 28, 2010

• 4 SD x 2 in favour of apixaban

•Long-term open-label apixaban follow-up*

•94% patients received apixaban 5 mg BID

•91% patients received aspirin ≤162 mg daily

•Median follow-up: 1.1 year

Which NOACS for which patient?

Adapted from Camm et al. Clinical Cardiology on line December 2013.

2015

A= Apixaban, D=dabigatran, E= edoxaban, R=rivaroxaban

Watchman LAA Closure Technology

The WATCHMAN LAA Closure Technology is designed to prevent embolization of thrombi that may form in the LAA.

The WATHCMAN Left Atrial Appendage Closure Technology is intended as an alternative to warfarin therapy for patients with non-valvular atrial fibrillation.

If all else fails - LAA Closure Device

39

Preventing Stroke and Managing Atrial Fibrillation Patients

Which NOAC for Which Patient?

Amos Katz, M.D.

41

A proposed algorithm to aid in the selection of

NOACs in the patients with non-valvular AF

Abhishek Maan. J Thorac Dis 2015;7(2):115-131

תהיה בטוח שבחרת נכון

ARISTOTLE:

Stroke/SE and Major Bleeding According to Renal Function