NOACs Update 2016 · L.CH.MKT.HC.04.2016.0867-DE Rivaroxaban was associated with a Significant 47% reduction in ICH vs. VKA Comparable rate of ischemic stroke vs. VKA Significant

NOACs – Update 2016

PD Dr. Jan Steffel

Leitender Arzt, Klinik für KardiologieCo-Leiter Rhythmologie

Universitätsspital Zürich

Conflict of Interest Statement

o Consulting: Amgen, Astra Zeneca, AtriCure, Bayer, Biosense Webster,

Biotronik, BMS, Boehringer Ingelheim, Boston Scientific, Daiichi-Sankyo,

Medtronic, Pfizer, Sanofi-Aventis, SJM

o Speaker honoraria: Astra Zeneca, Bayer, Biosense Webster, Biotronik, BMS,

Boehringer Ingelheim, Daiichi-Sankyo, Medtronic, Novartis, Pfizer, Roche,

Sanofi-Aventis, SJM, Sorin, Zoll

o Grants (through institution): Bayer, Biotronik, Boston Scientific, Daiichi-

Sankyo, Medtronic, St. Jude Medical

o Co-president CorXL

o Collaboration with TIMI study group (ENGAGE AF-TIMI 48)

Relative Hazard Ratio (95% CI)

Favors NOAC Favors warfarin0.4 0.6 1.00.2 0.8 1.4 1.61.2 1.8

RE-LY: 110 mg BIDRE-LY: 150 mg BID

Dabigatran

ROCKET-AF: 20 mg QD

Rivaroxaban (safety AT)

ARISTOTLE: 5 mg BID

Apixaban

ENGAGE-AF: 30 mg QDENGAGE-AF: 60 mg QD

Edoxaban

P=0.13

P=0.051

P=0.073

P=0.047

P=0.006P=0.08

0.91

0.88

0.85

0.89

0.87

0.92

1. Connolly et al. N Engl J Med 2009;361:1139–1151; 2. Patel et al. N Engl J Med 2011;365:883–8913. Granger et al. N Engl J Med 2011;365:981–992; 4. Giugliano et al. N Engl J Med 2013; e-pub ahead of print

Phase III AF trials: All-cause mortality

For illustrative purpose only! No head-to-head comparisons!

‘Real Life’ Data aims to complement

Clinical Trial Data

Clinical trial RLE study

• Patients are selected by stringent

protocol criteria

• Treatment / observation is defined

in the protocol

• Methodology aims for reducing

bias when a randomized design is

used

• Patients are selected by the

treating physician

• Over- and under-reporting

of events possible

• Observation of real-life subgroups

possible

FDA Study on Medicare Patients

FDA, Mai 2014 - http://www.fda.gov/drugs/drugsafety/ucm396470.htm

XANTUS: Study Objective and Design

• Objective: Prospective Real world study on the safety profile of rivaroxaban

in patients wit nvAF

Final visit:

1 year#

Data collection at initial visit, hospital

discharge (if applicable) and quarterly*Population: Consecutively enrolled adult patients with NVAF receiving rivaroxaban for stroke/non-CNS SE prevention

Rivaroxaban: treatment

duration and dose at

physician’s discretion

Prospective, single-arm, observational, non-interventional phase IV study

Statistical analyses were descriptive and exploratory in nature

1 year

N=6,784

1. Camm AJ, et al, Vasc Health Risk Manag 2014.

2. Camm AJ, et al, Eur Heart J 2015.

* Exact referral dates for follow-up visits not defined (every 3 months recommended)

# For rivaroxaban discontinuation ≤1 year, observation period ends 30 days after last dose.

Observational design means no interference with clinical practice was allowed

• Primary outcomes: major bleeding (ISTH definition), all-cause mortality,

any other adverse events

• Secondary outcomes: symptomatic thromboembolic events (stroke, SE, TIA)

and MI, non-major bleeding events (all adjudicated centrally by an independent committee

(CAC ) blinded to individual patient data)

L.CH.MKT.HC.04.2016.0867-DE

Rivaroxaban was associated with a

Significant 47% reduction in ICH vs. VKA

Comparable rate of ischemic stroke vs. VKA

Significant 39% reduction in the combined endpoint of ICH

and ischemic stroke vs. VKA

REVISIT-US - Significant Reduction in the

Combined Endpoint for Rivaroxaban vs. VKA

Rivaroxaban VKA HR (95% CI)

Rivaroxaban vs.

VKA

HR (95% CI)

Rivaroxaban vs. VKARate

(%/year)

Rate

(%/year)

ICH 0.49 0.96 0.53 (0.35–0.79)*

Ischemic stroke 0.54 0.83 0.71 (0.47–1.07)

Combined 0.95 1.6 0.61 (0.45–0.82)*

FavorsRivaroxaban

Favors VKA

0,125 0,25 0,5 1 2 4*p<0.05 vs. VKA

Coleman CI et al. Real-world EVIdence on Stroke prevention In patients with aTrial Fibrillation in the United States (REVISIT-US) [Presentation at

ECAS 2016] Available at: http://clinicaltrialresults.org/Slides/REVISIT_US_Slides.pptx

http://clinicaltrialresults.org/Slides/REVISIT_US_Slides.pptx

US retrospective real-world database research (MarketScan® commercial & Medicare supplemental database)

Unadjusted incidence rates of major bleeding (in-patient bleeding per 100 person-year) and adjusted HR1* for apixaban vs warfarin

4.66%

2.35%

0

1

2

3

4

5

Warfarin(n=12,713)

Apixaban(n=2,402)

Adjusted HR=0.52(95% CI: 0.30-0.89)

Un

adju

sted

maj

or

ble

edin

g in

cid

ence

(%

/ y

ear)

Adapted from Lip et al. 2015

*Cox-proportional hazards model was used to assess the risk of first major bleed across index OAC prescription categories, adjusted for age, gender, region, embolic or primary ischaemic stroke, dyspepsia or stomach discomfort, congestive heart failure, coronary artery disease, diabetes, hypertension, renal disease, myocardial infarction, history of stroke or transient ischaemic attack, history of bleeding, Charlsoncomorbidity index, and co-medications at baseline.

Of the 2,402 apixaban patients, 85.6% received apixaban 5 mg BD

Lip GYH et al. Real world comparison of major bleeding risk among non-valvular atrial fibrillation patients newly initiated on apixaban, dabigatran, rivaroxaban or warfarin. Poster presented at: ESC Congress; 29 August–2 September, 2015: London, UK. Poster P6217.

Data from retrospective real-world research, not a randomisedcontrolled trial

Net clinical benefit: CHADS-VASC vs. HAS-BLED

Banerjee et al., Thromb & Hemost 2012

• Event rates / 100 pys for ischemic stroke and intracranial

hemorrhage were calculated using data from the Danish

study population for patients on no treatment and on warfarin

• Using data from recent trials of the new OACs, the event

rates for ischemic stroke and intracranial hemorrhage were

estimated for the Danish population





Idarucizumab

Enriquez et al., Europace 2014

REVERSE-AD

Pollack et al., NEJM 2015

REVERSE-AD

Pollack et al., NEJM 2015

Andexanet Alfa

Reversal of anticoagulation by factor Xa inhibitors1

1. Lu G, et al. Nature Medicine 2013;19(4):446-51

Recombinant engineered version of human factor Xa

• Acts as a factor Xa decoy

• High affinity for all direct factor Xa inhibitors

• Changed in a way that catalytic activity is eliminated (serine alanine) and

prothrombin cleavage is prevented

• GLA domain removed to prevent anticoagulation effect

GLA

S419

S S

Factor Xa

GLA

A419

S S

Andexanet Alfa

Factor Xa Inhibitor

Catalytic Domain

Factor Xa Inhibitor

ANNEXA-A / ANNEXA-R

Siegal et al., NEJM 2015

PROTECT-AF long-term data

Reddy et al., JAMA 2014

PROTECT-AF long-term data

Reddy et al., JAMA 2014

PREVAIL over time

Waksman and Pendyala. AJC 2015

Summary and Take Home Message

NOACs are standard therapy for stroke

prevention in AF

Real World data very consistent

Net Clinical Benefit matters for patients!

Direct antagonists are available (idarucizumab)

or just around the corner (for Xa inhibitors)

LAA occluder: Good option for special patient

populations (esp contraindicated for

anticoagulation)

NOACs – Update 2016

PD Dr. Jan Steffel

Leitender Arzt, Klinik für KardiologieCo-Leiter Rhythmologie

Universitätsspital Zürich

LAAOs vs. NOACs

NOACs in real world vs. LAAO in real world (efficacy and safety)

Not all AF is created equal

o Valvular vs. non-valvular

o "Paroxysmal" vs. "Persistent" many shortcomings!

Careful in extrapolating "off-label" use of NOACs and LAAOs

o No data for patients with contraindication for anticoagulation

(PROTECT-AF vs. ASAP)

Careful in extrapolating (rather) small scale trials to the entire AF

population, and combining trial results

LAAOs vs. NOACs

NOACs in real world vs. LAAO in real world (efficacy and safety)

Not all AF is created equal

o Valvular vs. non-valvular

o "Paroxysmal" vs. "Persistent" many shortcomings!

Careful in extrapolating "off-label" use of NOACs and LAAOs

o No data for patients with contraindication for anticoagulation

(PROTECT-AF vs. ASAP)

Careful in extrapolating (rather) small scale trials to the entire AF

population, and combining trial results

Only a well-designed RCT will answer this question!

All strokes from LAA…?

How does LAAO compare with NOACs ?

o Beware of cross-trial comparisons…

ENGAGE-AF: "Increased Risk of Falls"

In ENGAGE-AF, investigators prospectively categorizedpatients as having an increased risk of falling particularly ifthey had any of the following 8 criteria at randomization:

• A prior history of falls

• Lower extremity weakness

• Poor balance

• Cognitive impairment

• Orthostatic hypotension

• Use of psychotropic drugs

• Severe arthritis

• Dizziness

Steffel et al., submitted (presented at AHA 2015)

Edoxaban versus Warfarin in Patients with an Increased Risk of Falls


Fall Risk (n = 900, 4%)

No Fall Risk (n = 20205, 96%)

p-value

Male gender 51% 62% <0.001Age (years) 77 72 <0.001CHADS2 score (mean) 3.3 2.8 <0.001CHA2DS2VASc score (mean) 5.1 4.3 <0.001CHADS2 score >3 39% 22% <0.001History of Stroke (incl. TIA) 41% 28% <0.001CrCl (ml/min, median) 58 71 <0.001TTR (warfarin arm, median) 67 69 0.15

2,7

9,1

7,1

4,7

0,9

4,7

1,8

5,1

3,9

2,7

0,5

1,7

0

2

4

6

8

10

12

Stroke/SEE All cause death/ Stroke / SEE

All-causedeath

Major bleed ICH Bone Fracturedue to Fall

At risk Not at risk

aHR 1.2

(0.9-1.5)

aHR 1.4

(1.2-1.7)aHR 1.5

(1.2-1.7)

aHR 1.3

(1.0-1.6)

aHR 1.4

(0.8-2.4)

aHR 1.9

(1.5-2.4)

***

***

***

*



2,8

9,3

7,1

5,4

2,8

10,0

7,8

5,6

1,5

4,83,9

1,8

5,44,2

0

2

4

6

8

10

12

Stroke/SEE All cause death/Stroke/SEE All-cause death Major bleed

HDE At risk

Warfarin At risk

HDE Not at risk

Warfarin Not at risk





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NOACs Update 2016 · L.CH.MKT.HC.04.2016.0867-DE Rivaroxaban was associated with a Significant 47% reduction in ICH vs. VKA Comparable rate of ischemic stroke vs. VKA Significant