APIXABAN : FROM THE CLINICAL TRIALS

TO THE REAL LIFE EXPERIENCES

XII International Meeting

Atrial Fibrillation and Heart Failure

Bologna, February 16, 2017

Giuseppe Di Pasquale, MD, FESC, FACC

Director Department of Medicine

Director Division of Cardiology

Maggiore Hospital, Bologna, Italy

Giuseppe Di Pasquale Disclosures

• Member of the Steering Committee of the RELY, PALLAS, and

GLORIA AF

• Member of Advisory Board of Dabigatran,

Rivaroxaban, Apixaban, Dronedarone, Edoxaban

• Consulting fees / honoraria

Boehringer Ingelheim, Bayer AG, Sanofi Aventis

BMS / Pfizer, Daiichi Sankyo

Why do we need real world data?

To assess the applicability of Evidence Based

Medicine

To determine the application of guidelines

To determine areas in which treatment practices

are suboptimal

To indicate where current guidelines might be

lacking

To indicate areas where education is necessary

To analyze high risk subgroups

Real World versus RCTs

RCTs

Spontaneous registries

Administrative Databases

RCTs vs Observational Studies

Institutional registries

Sel

ecti

on

Bia

s

Extent of the Population

Apixaban and real world

Int J Clin Pract 2016;70:752-763

Cumulative incidence of major bleeding

requiring hospitalisation for anticoagulant initiation

Lip GYH et al, Int J Clin Pract 2016;70:752-763

BMJ 2016;353:i3189

Methods

Data from three Danish nationwide databases:

• The Danish national prescription registry, 8which holds

information on purchase date, Anatomical Therapeutic

Chemical (ATC) classification code, and package size for

every prescription claimed since 1994

• The Danish national patient register established in 1977,

which includes admission and discharge dates, and

discharge diagnoses (international classification of

diseases) for more than 99% of hospital admissions

• The Danish civil registration system, with information on

sex, date of birth, and vital and emigration status

Larsen TB et al, BMJ 2016;353:i3189

Larsen TB et al, BMJ 2016;353:i3189

Study population

• PSM variables: - age (continuous); gender; ischaemic stroke or systemic embolism or

transient ischaemic attack; vascular disease; hypertension; diabetes; cancer; recent prescription of aspirin, β blockers, NSAIDs or statins; CHA2DS2-VASc score; HAS-BLED score

Final study population

Apixaban

(n)

Dabigatran

(n)

Rivaroxaban

(n)

Warfarin

(n)

Total

(n)

6,349

12,701

7,192

35,436

61,678

Endpoints cumulative incidence according to initiated treatment

Larsen TB et al. BMJ 2016;353:i3189

J Am Heart Assoc 2016;5:e003725 doi: 10.1161

March 2014

Final sample

Apixaban vs. warfarin

(N=15,390)

Dabigatran vs. warfarin

(N=28,614)

Rivaroxaban vs.

warfarin (N=32,350)

Study population - Cohort Creation

OAC initiation (Oct 2010 to Jun 2015) and

at least 12-month continuous enrollment

N=339,606

Patients with AF at baseline

N=176,723

Exclude: valvular heart disease, ESRD/dialysis,

kidney transplant, VTE at baseline or joint

replacement within 6 wks prior the index date

N=160,328

Three 1:1 propensity

score matched cohorts Xiaoxi Yao et al. J Am Heart Assoc. 2016;5:e003725 - doi: 10.1161/JAHA.116.003725

Adult patients who had valid demographic data,

were not admitted for primary outcomes or died on the

index date, and the index medication was not edoxaban

N=125,243

Baseline Characteristics in Propensity

Score-Matched NOAC or Warfarin Users

Apixaban

(n=7695)

Warfarin

(n=7695)

Dabigatran

(n=14 307)

Warfarin

(n=14 307)

Rivaroxaban

(n=16 175)

Warfarin

(n=16 175)

Age, y

Median (IQR) 73 (66–81) 73 (66–81) 70 (62–78) 70 (61–78) 72 (64–79) 72 (64–80)

18–64 22.7 23.0 34.1 35.0 25.3 25.8

65–74 30.9 30.9 31.5 30.4 32.9 32.8

≥75 46.4 46.1 34.4 34.6 41.8 41.4

Female 46.9 46.8 39.7 40.4 43.2 43.7

Bleeding history or predisposition 31.4 31.8 29.4 30.1 30.7 31.5

Antiplatelets/NSAID 12.1 12.5 10.3 10.2 11.6 11.6

CHA2DS2-VASc

Median (IQR) 4 (3–5) 4 (3–5) 3 (2–5) 3 (2–5) 4 (2–5) 4 (2–5)

0–1 9.9 10.0 15.9 16.6 12.2 12.1

2–3 33.2 33.0 38.2 36.9 35.6 35.6

≥4 56.8 57.0 45.9 46.5 52.2 52.3

HAS-BLED

Median (IQR) 2 (2–3) 2 (2–3) 2 (1–3) 2 (1–3) 2 (2–3) 2 (2–3)

≥3 41.5 41.9 33.7 33.9 38.6 39.1

Charlson index

Median (IQR) 2 (1–4) 2 (1–4) 2 (1–3) 2 (1–3) 2 (1–4) 2 (1–4)

0–1 37.7 37.9 45.5 45.3 41.3 40.6

2–3 32.0 32.1 30.4 30.4 30.8 30.5

≥4 30.3 30.0 24.1 24.3 27.9 28.9

SAMe-TT2R2

Median (IQR) 2 (1–3) 2 (1–3) 2 (1–3) 2 (1–3) 2 (1–3) 2 (1–3)

≥3 30.7 31.1 26.1 26.4 28.8 30.5

Warfarin experienced 20.2 20.4 37.8 38.6 24.4 25.0

Reduced-dose NOAC 18.1 NA 8.8 NA 21.5 NA

Yao X et al. J Am Heart Assoc. 2016;5:e003725 - doi: 10.1161/JAHA.116.003725

Yao X et al. J Am Heart Assoc 2016;5:e003725 doi: 10.1161

Yao X et al. J Am Heart Assoc 2016;5:e003725 doi: 10.1161

Apixaban: efficacy and safety

1. Granger CB et al. N Engl J Med. 2011 Sep 15;365(11):981-92

2.Xiaoxi Yao et al. J Am Heart Assoc. 2016;5:e003725 - doi: 10.1161/JAHA.116.003725

Endpoint primario di efficacia Ictus/Embolia sistemica

Endpoint primario di sicurezza Sanguinamenti maggiori

Endpoint primario di efficacia Ictus/Embolia sistemica

Endpoint primario di sicurezza Sanguinamenti maggiori

1,27

n=212

2,13

n=327 1,33 2,33

ARISTOTLE1 RWD (Yao X et al.)2

21% 33%

31%

55%

Warfarin (n=9.081)

Apixaban (n=9.120)

Warfarin (n=9.052)

Apixaban (n=9.088)

Warfarin (n=7.695)

Apixaban (n=7.695)

Warfarin (n=7.695)

Apixaban (n=7.695)

Elaborazione grafica da ref. 1 Elaborazione grafica da ref. 2

Eur Heart J Cardiovasc Pharmacother 2017; 3: 28-36

Methods

• Nationwide registries: Norwegian Patient Registry and Norwegian

Prescription Database

• AF patients with a first prescription of oral anticoagulants

between January 2013 and June 2015 (N. 32,675).

• VKA: 11,427 pts; DAB: 7,925 pts; RIVA: 6,817 pts, APIX: 6,506 pts

• Patients followed until discontinuation or switching of oral

anticoagulants, death, or end of follow-up.

• Primary endpoint: major or clinically relevant non-major bleeding

(CRNM).

Eur Heart J Cardiovasc Pharmacother 2017; 3: 28-36

Risk of major or CRNM bleeding for the reduced

and standard dose of NOACs vs warfarin

Halvorsen S et al, Eur Heart J Cardiovasc Pharmacother 2017; 3: 28-36

«A high proportion of patients (27-35%) initiated NOAC on the reduced dose .

Due to lack of information on creatinine levels, weight and bleeding diathesis, we do not know

how many of these patients that fulfilled the criteria for dose reduction for stroke prevention for

the different NOACs. However, 82% of these patients were ≥75 years, and also had a high

baseline risk profile with respect to bleeding.»

GI bleeding

NOACs vs. warfarin: Major gastrointestinal bleeding

1. Granger et al. N Engl J Med 2011;365:981-92; 2. Connolly et al. N Engl J

Med 2010;363:1875-6, suppl app; 3. Giugliano et al. N Engl J Med

2013;369:2093-104; 4. Patel et al. N Engl J Med 2011;365:883-91, suppl app.

105 (0.76) 119 (0.86)

224 (3.15) 154 (2.16)

NOAC Warfarin

0.5 1.0

Favours NOAC Favours warfarin

HR 95% CI

0.70–1.15 0.89

1.19–1.78 1.46

137 (1.15) 126 (1.07) 0.85–1.38 1.08

1.5

188 (1.56) 126 (1.07) 1.18–1.85 1.48

No. of events (%/yr)

2.0

Dabigatran 110 mg2

Rivaroxaban4 †

Apixaban1

Dabigatran 150 mg2

232 (1.51) 190 (1.23) Edoxaban high dose3 *

129 (0.82) Edoxaban low dose3 * 190 (1.23)

1.23 1.02–1.50

0.67

* Data are from the safety cohort during the treatment period (which began when the first dose of study drug was administered), with interval censoring

of events during study-drug interruptions that lasted more than 3 days, except for net clinical outcomes, which are presented for the overall treatment

period (which began at the time of randomisation). † % and not %/yr are reported; RR, not reported, was calculated: http://www.spc.univ-lyon1.fr/mfcalc

0.53–0.83

Head-to-head studies do not exist, and direct comparisons between agents may not be made

Abraham NS et al. Gastroenterology. December 2016. DOI: 10.1053/j.gastro.2016.12.018

Study population - Cohort Creation

Abraham NS et al. Gastroenterology.

December 2016. DOI: 10.1053/j.gastro.2016.12.018

Absolute Risk Reduction (ARR) and Number Needed to

Harm (NNH)

Abraham NS et al. Gastroenterology. December 2016. DOI: 10.1053/j.gastro.2016.12.018

Adherence & persistence with Apixaban

Thromb Haemost 2016; 115: 31-39

Therapy Persistence: Warfarin vs NOACs

27,514 anticoagulant-naïve patients with incident non-valvular AF

between January 2011 and May 2014 in the UK primary care Clinical Practice Research Datalink

Martinez C et al. Thromb Haemost 2016; 115: 31–39

Unadjusted persistence with anticoagulant treatment

in NVAF patients with CHA2DS2VASc scores 2-9

Forslund T et al, Eur J Clin Pharmacol 2016; 72(3):329-38

AEGEAN study: Objectives

Primary Objective:

• To assess the impact of an educational program on implementation

phase adherence in patients taking apixaban for SPAF. Assessed at 24

weeks after initiation using an EMD, Helping Hand®

Secondary Objectives:

• To assess the impact of an educational program on persistence at 24

weeks in patients taking apixaban

• To identify predictive risk factors linked to non-adherence in patients

treated with apixaban

• To evaluate impact of an educational program on efficacy/safety profile

of apixaban

EMD, electronic monitoring device;

SPAF, stroke prevention in atrial fibrillation Montalescot et al. Poster presentation at ESC Aug/Sept 2015; London, UK Poster/oral poster no.2191

For medical non-promotional reactive use only

Adherence (primary endpoint) A

dhere

nce (

%)

Week 24

P=0.89

Montalescot et al. Poster presentation at ESC Aug/Sept 2015; London, UK Poster/oral poster no.2191

For medical non-promotional reactive use only

Persistence (secondary endpoint)

75 0

80

85

90

95

100

20 40 60 80 100 120 140 160 180

Days

556

554

541

541

523

526

523

519

513

513

486

488

484

485

481

480

466

464

Pe

rsis

ten

t p

ati

en

ts (

%)

Number of patients still persistent

AEP

SOC

Additional Educational Program (AEP)

Standard Of Care (SOC)

Persistence at 24

weeks:

Overall: 90.8%

SOC: 90.5%

AEP: 91.1% P=0.76

Montalescot et al. Poster presentation at ESC Aug/Sept 2015; London, UK Poster/oral poster no.2191

The issue of dose reduction

Current Medical Research & Opinion 2016;32:1277-1279

Current Medical Research & Opinion 2016;32:1277-1279

Comparison of the percentage

of apixaban and rivaroxaban

prescriptions filled for a reduced

dose vs. the proportion of patients

requiring a reduced dose in

corresponding registration trials.

Percentage of apixaban

and rivaroxaban

prescriptions written for

the reduced dose in routine

cardiology practice.

Steinberg BA et al. J Am Coll Cardiol 2016;68:2597- 604

Steinberg BA et al. JACC 2016;68:2597- 604

ORBIT-AF: Rates of NOAC prescription, according to the U.S.

FDA-approved labeling

Steinberg BA et al.

JACC 2016;68:2597- 604

NOAC over- and underdosing are associated with

increased risk for adverse events

Thromb Haemost 2016; 116: 975–986

J Am Heart Assoc. 2016;5:e003725

BMJ 2016;353:i3189

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