State of art in

anticoagulation in non

valvular Atrial

Fibrillation: the

additional value of

Rivaroxaban real life

data

Massimo Grimaldi

Ospedale “F. Miulli”

Acquaviva delle Fonti - Bari

Disclosure

Biosense Webster (J&J):

Patent licensing agreement

Ospedale “F. Miulli”

Acquaviva delle Fonti - Bari

Randomized clinical trial Vs. Real life data

RCT

Prospective, non-

interventional study

Prospective Registry

Retrospective databases

US PMSS 5

RELIEF6

REVISIT US7

Dresden

NOAC

Registry4

Xantus2

Xapass3

Rocket AF1

Independent Central

Adjudication

Committee (CAC)

Highest

quality

1) Patel MR et al, N Engl J Med 2011;365:883–891 2) Camm AJ et al. Eur Heart J 2016;37:1145-53 3) Abstract presented at ESC congress 2016 4) Hecker J et al, Thromb Haemost

2016;115:939-49 5) Tamayo S et al, Clin Cardiol 2015;38:63–68 6) Coleman CI et al. Int J Cardiol 2016;203:882-4 7)Coleman CI et al, Curr Med Res Opin 2016;Sep 20:1-7

Rivaroxaban Dataset

XANTUS: Study Objective and Design

Primary outcomes: major bleeding, all-cause mortality, any other adverse events

Final visit: 1 year#

Data collection at initial visit/hospital discharge

and quarterly*

Population: 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

Objective: to collect real world data on NVAF patients treated with rivaroxaban

*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

Camm AJ et al. Eur Heart J 2016;37:1145-53

XANTUS1 Baseline ROCKET AF2

2.0 CHADS2 3.5

0–1

2

≥3

Heart failure

Hypertension

Age >75 years

Diabetes

Prior stroke#

Prior MI

87%

13%

Rivaroxaban:

Randomized Clinical Trial and the Real World

41%

30%

29%

19%

75%

37%

20%

19%

10%

0%

13%

87%

63%

91

% 44%

40%

55%

17%

*Events per 100 patient-years; #includes prior stroke, SE or TIA

Adapted from

1. Camm AJ et al. Eur Heart J 2016;37:1145-53

2. Patel MR et al, N Engl J Med 2011;365:883–891

≤1 2 3–6 CHADS2 score

Rivaroxaban2

29%

30%

41%

Rivaroxaban1

and

{1. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466}

*Includes prior stroke, SE or TIA.

1,7

3,6

1,91,7

0,5

2,0

0,8

2,11,9

0,70,4

0,9

0,0

1,0

2,0

3,0

4,0

Stroke/SE Major bleeding Death All strokes ICH GI bleeding

Inci

de

nce

rat

eEv

en

t p

er

10

0 p

atie

nt-

year

s

ROCKET AF XANTUS

CHADS2 Prior stroke*

ROCKET AF 3.5 55%

XANTUS 2.0 19%

XAPASS

Objective: To confirm the safety and effectiveness profile of rivaroxaban across NVAF patients in Japanese real- world clinical practice.

Primary outcomes: adverse events (AEs) including bleeding events (eg, major bleeding) and efficacy events (stroke, systemic embolism [SE], and myocardial infarction [MI])

Study population: patients with NVAF in Japan who start treatment with rivaroxaban for stroke/non-CNS SE prevention

Rivaroxaban; treatment duration and dose (15/10 mg) at the attending physician’s discretion

Data collection at visit, 6-month, 1-year, and 2-year

Enrolment: from April 2012 to

June 2014

Standard observation period

Once a year

Maximum 5 years

Follow-up investigation

Prospective, single-arm, observational study Statistical analyses were descriptive and exploratory in nature

Ogawa et al., J Stroke Cerebrovasc Dis, 2014;23:2520-6

2 years

XAPASS: Results

Hori M. et al: Circ J 2012;76:2104–2111 Abstract presented at ESC congress 2016 Results are not intended for direct comparison

XAPASS mean CHADS2 score= 2,2

J-ROCKET AF mean CHADS2 score=3.3

RCT

Prospective, non-interventional

study

Prospective Registry

Retrospective databases

US PMSS 5

RELIEF6

REVISIT US7

Dresden NOAC

Registry4

Xantus2

Xapass3

Rocket AF1

Independent Central

Adjudication

Committee (CAC)

Highest

quality

1) Patel MR et al, N Engl J Med 2011;365:883–891 2) Camm AJ et al. Eur Heart J 2016;37:1145-53 3) Abstract presented at ESC congress 2016 4) Hecker J et al, Thromb Haemost

2016;115:939-49 5) Tamayo S et al, Clin Cardiol 2015;38:63–68 6) Coleman CI et al. Int J Cardiol 2016;203:882-4 7)Coleman CI et al, Curr Med Res Opin 2016;Sep 20:1-7

Rivaroxaban Provides a Consistent and Unique

Dataset Covering the Full Patient-Risk Spectrum

0 1 2 3 4

Stroke/TIA/SE

Major bleeding

ROCKET AF (n=7111)

All rivaroxaban SPAFpatients Dresden registry(n=1204)

1

Dresden NOAC Registry

Effectiveness and Safety of Rivaroxaban for AF

1. Patel MR et al, N Engl J Med 2011;365:883–891

2. Adapted from Hecker J et al, Thromb Haemost 2016;115:939-49

Using data from the Dresden NOAC Registry, a large multicentric registry, we prospectively evaluated the management and outcome of patients with SPAF treated with rivaroxaban

Results are not intended for direct comparison

(mean CHADS2=2,4)

(mean CHADS2=3,5)

2

Outcome of VKA treated patients with AF not

switched to NOACs-Dresden NOAC Registry

1. Adapted from Michalski et al, Thromb Haemost 2015;114:1076-84.

2. Adapted from Hecker J et al, Thromb Haemost 2016;115:939-49

% p

ts/y

ear

1.0

2.0

3.0

4.0

5.0

1.3

Stroke

TIA/SE

4.1

MB

VKA, median TTR 75.5%1

1.7 3.0

Stroke

TIA/SE

MB

Rivaroxaban2

RCT

Prospective, non-interventional

study

Prospective Registry

Retrospective databases

US PMSS 5

RELIEF6

REVISIT US7

Dresden NOAC

Registry4

Xantus2

Xapass3

Rocket AF1

Independent Central

Adjudication

Committee (CAC)

Highest

quality

1) Patel MR et al, N Engl J Med 2011;365:883–891 2) Camm AJ et al. Eur Heart J 2016;37:1145-53 3) Abstract presented at ESC congress 2016 4) Hecker J et al, Thromb Haemost

2016;115:939-49 5) Tamayo S et al, Clin Cardiol 2015;38:63–68 6) Coleman CI et al. Int J Cardiol 2016;203:882-4 7)Coleman CI et al, Curr Med Res Opin 2016;Sep 20:1-7

Rivaroxaban Provides a Consistent and Unique

Dataset Covering the Full Patient-Risk Spectrum

Major Bleedig (MB) in patients with NVAF:

pharmacovigilance of 27.467 patients taking rivaroxaban

Adapted from Tamayo S. et al, Clin Cardiol 2015;38:63-8

Patients characteristics MB n=478 No MB n=26.989

Age, y, mean (SD) 78,4 (7,7) 75,7 (9,7)

Comorbid condition, % 100,0 87,0

CHADS2 score, mean (SD) 3,0 (1,2) 2,2 (1,3)

CHA2DS2-VASc score, mean (SD) 4,8 (1,5) 3,7 (1,7)

MB characteristics* MB n=478

MB cases with fatal outcome 14

MB incidence rate %person-years (95% CI) 2,86 (2,61-3,13)

Bleeding cases with fatal outcome (95% CI) 0,08 (0,05-0,14)

*MB classified using the Cunningham et al. defintion including: GI bleeding, hemorragic Strokes and other intracranial bleeds, genitourinarybleeding and bleeding at other sites.

Real World Evidence: Major Bleeding in Patients

with Renal Disease Taking Rivaroxaban (US DoD)

• Analysis of electronic records from the DoD over a 2-year period

• Of 39,052 rivaroxaban users, 15.5% had renal disease

4,52

2,59

0

1

2

3

4

5

6

Renal disease No renal disease

Majo

r b

leed

ing

even

ts

(%/y

ear)

Mean

CHA2DS2-

VASc 5.2

Mean

CHA2DS2

VASc 4.7

Error bars indicate 95% CI

Tamayo et al, Circulation 2015;132: abstract A15905

Major bleeding rates were higher in patients with renal disease than those without, and

CHA2DS2-VASc scores were also higher in patients with renal disease

Major bleeding in patients taking rivaroxaban

Real World Evidence for Patients with

Renal Impairment

Major bleeding Fatal bleeding

1. Adapted from Fox et al, Eur Heart J 2011;32:2387-94 2. adapted from Tamayo Poster presentation at AHA 2015

Rivaroxaban

%/year

Warfarin

%/year

Rivaroxaban

%/year

Rivaroxaban

%/year

Warfarin

%/year

Rivaroxaban

%/year

ROCKET AF

RENAL

IMPAIRMENT

TAMAYO

RENAL

IMPAIRMENT

4,49 4,70

4,52

0,28

0,74

0,09

ROCKET AF

RENAL

IMPAIRMENT

TAMAYO

RENAL

IMPAIRMENT

Adapted from:

1.Bansilal S et al, Am Heart J 2015;170:675–682.e8;

2.Patel M et al. Major bleeding among rivaroxaban users with non-valvular atrial fbrillation and diabetes. Poster presentation at the American College of

Cardiology 65th Annual Scientifc Session. Chicago, Illinois, 2016

Real World Evidence for Patients with

Diabetes Mellitus

Major bleeding Intracranial

hemorrhage

Rivaroxaban

%/year

Warfarin

%/year

Rivaroxaban

%/year

Rivaroxaban

%/year

Warfarin

%/year

Rivaroxaban

%/year

ROCKET AF

DIABETES

TAMAYO

DIABETES ROCKET AF

DIABETES

TAMAYO

DIABETES

3,79 3,90 3,68

0,50 0,82

0,19

The RELIEF Study Demonstrated Favourable Effectiveness

of Rivaroxaban in NVAF Patients in Real-World Practice

RELIEF: retrospective study of German outpatients newly initiated on

rivaroxaban or VKA using data from an electronic medical record database %

/ye

ar

Composite

endpoint

Rivaroxaban (n=1039) VKA (n=1039)

3.7

2.0

1.6

0.7

1.1

0.6

0.3 0.1 0.1

0

0.7 0.6

Other non-

traumatic

ICH

Ischaemic

stroke

TIA ICH MI

*Not otherwise specified

Coleman C et al, Int J Card Med 2015;203:882–884

Combined Endpoint of Ischemic Stroke and ICH

– Most likely to be coded accurately and with less variability in

claims data and of equal importance to allow for benefit/risk

assessment

– Used validated ICD-9 coding algorithms and restricted codes to

the primary diagnosis code position

– May miss cases, but greater robustness in those identified

REVISIT-US

Study Design to Optimize “Internal Validity”

Coleman CI et al. Curr Med Res Opin 2016;20:1-7

REVISIT-US Baseline characteristics

Parameters Rivaroxaban

(n=11,411)

VKA

(n=11,411)

Apixaban

(n=4083)

VKA

(n=4083)

Age, years, mean (DS) 70.7 (11.0) 70.7 (11.4) 71.2 (11.3) 71.0 (11.3)

Gender, % (n) male 53.6 (6115) 53.9 (6145) 53.2 (2217) 53.6 (2189)

CHADS2 score,

mean (DS)

1.92 (1.08) 1.94 (1.08) 1.93 (1.07) 1.92 (1.07)

CHA2DS2-VASc score,

mean (DS)

3.46 (1.37) 3.48 (1.35) 3.47 (1.38) 3.47 (1.35)

HAS-BLED score,

mean (DS)

1.62 (0.69) 1.62 (0.71) 1.66 (0.72) 1.65 (0.69)

NAOC low dose 15 mg od;

17.3%

N/A 2.5 mg bid;

15.5%

N/A

Modifed from:

Coleman Cl et al,Curr Med Res Opin 2016 Sep 15

Coleman CI et al, presented at ESC 2016

Rivaroxaban was associated vs warfarin with a

Significant 47% reduction in ICH

Non-significant 29% decrease in ischemic stroke

Significant 39% reduction in the combined endpoint of ICH

and ischemic stroke

REVISIT US - Significant Reduction in the

Combined Endpoint for Rivaroxaban vs warfarin

Rivaroxaban Warfarin HR (95% CI)

rivaroxaban vs.

warfarin

HR (95% CI)

rivaroxaban vs. warfarin

Rate

(%/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)*

Favors rivaroxaban

Favors warfarin

0,125 0,25 0,5 1 2 4

*p<0.05

Coleman CI et al. Curr Med Res Opin 2016;20:1-7

ICHs and Ischaemic Strokes of NOACs Compared with

VKA in Large Retrospective Observational Analysis

Adapted from Coleman CI et al. Curr Med Res Opin 2016;20:1-7;

Staerk L. et al. Eur Heart J 2016.pii:ehw496.[Epub ahead of print];

Larsen TB et al. BMJ 2016;353:i3189 Results are not intended for direct comparison

0,53 0,66

0,56

0,71

0,37 0,3

0,38

0,53

0,71

0

0,2

0,4

0,6

0,8

1

Coleman CMRO 2016 Staerk EHJ 2016 Larsen BMJ 2016

ICH

Rivaroxaban Dabigatran Apixaban

HR

vs

Wa

rfari

n

0,71 0,89 0,82

0,87 0,89

1,22 1,13

0,98 1,11

0

0,2

0,4

0,6

0,8

1

1,2

1,4

Coleman CMRO 2016 Staerk EHJ 2016 Larsen BMJ 2016

Ischaemic Stroke

Rivaroxaban Dabigatran Apixaban

Warfarin

HR

vs

Wa

rfari

n

Warfarin

Safety Profile of Rivaroxaban Confirmed Through

Real-World Evidence Regardless of Data Source6

Mean CHADS2

score

Major bleeding

event

rate/year§

Randomized

clinical trial

ROCKET AF1*

n=7111

3.6% 3.1% 2.9%

2.1%

Results are not intended for direct comparison

Prospective

registry Dresden NOAC2#

n=1200

3.5

2.2**

3,0*** 2.4

2.0

Retrospective

database

US DoD PMSS3‡

n=27,467

Observational

study

XANTUS4*

n=6784

2.0% 1.2% 0.9% Major GI bleeding

event rate/year† 1.5%

*Major bleeding definition according to ISTH; #modified ISTH definition (additionally included surgical revision from bleeding); ‡major bleeding defined by the Cunningham algorithm5; § Warfarin MB 3,4% †Warfarin MB-GI 1,24

1. Patel MR et al, N Engl J Med 2011;365:883–891; 2. Hecker J et al, Thromb Haemost 2016 Jan 21;115(5) ];

3. Tamayo S et al, Clin Cardiol 2015;38:63–68; 4 ; Camm AJ et al, Eur Heart J 2016;37(4):1145-53

5. Cunningham A et al, Pharmacoepidemiol Drug Saf 2011;20:560–566

6. Modified from Beyer-Westendorf J et al Thromb Hemost 2016:116:S13-S23

** Referred to patient population with no major bleeding cohort ( representative of > 98% of the patient population)

*** Referred to pts with major bleeding ( Beyer-Westendorf et Al. Thromb and Haemost Suppl 2/2016)

Adherence and Persistence

Cramer JA et al. Value Health 2008;11(1):44-47

Percentage of doses taken

as prescribed

Days taking medication

(without exceeding

permissible gap)

Start

medication or

observation

Stop

medication or

end

observation

Persistence Adherence

Non optimal adherence (PDC <80%) and

ischemic stroke

M.J. Alberts et al. / International Journal of Cardiology 215 (2016) 11–13

Treatment Persistence and Discontinuation with Rivaroxaban,

Dabigatran, and warfarin for Stroke Prevention in Patients with

Non-Valvular Atrial Fibrillation in the United States

PLOS ONE | DOI:10.1371/journal.pone.0157769 Coleman, et al.,

Retrospective cohort analysis of the US MarketScan

Comparison of Adherence to Rivaroxaban vs.

Apixaban Among Patients with AF

McHorney CA et al. Clin Ther 2016;doi: 10.1016/j.clinthera.2016.09.014. [Epub ahead of print]

Objective: to compare adherence with rivaroxaban and apixaban among patients with NVAF in routine clinical practice.

• PDC: number of days of supply divided by 90 and 180 days respectively.

85,3% 79,9%

75,8% 72,2%

78,8%

70,7%

61,9% 54,9%

PDC at 90 days PDC at 180 days PDC at 90 days PDC at 180 days

Percentage Point Difference:

5,4; p < 0.001 Percentage Point

Difference: 3,6; p = 0.001

Percentage Point Difference:

8,1; p < 0.001 Percentage Point Difference:

7,0; p < 0.001

Proportion of days covered (PDC) ≥ 0.80-matched analysis of apixaban and rivaroxaban users (n=2992 per cohort)

Proportion of days covered (PDC) ≥ 0.90-matched analysis of apixaban and rivaroxaban users (n=2992 per cohort)

Rivaroxaban

Apixaban

McHorney CA, Crivera C, et al. Curr Med Res Opin. 2015 Sep 22:1-16

Pharmacy quality alliance measure: adherence

to non-warfarin oral anticoagulant medications

rivaroxaban: n = 4194, dabigatran: n = 5489, apixaban: n = 265

Association between OD and BID DOAC adherence

in NVAF patients and rates of ischemic stroke

Adapted from Alberts MJ et al, Int J Cardiol 2016;215:11-3

CI= confidence interval; HR= hazard ratio; N= sample size; DOAC= direct oral anticoagulant; PDC= proportion of days covered; Pys = person years. a PDC < 80% represents suboptimal adherence. b p < 0.001 compared to once-daily DOAC use.

Patients prescribed DOACs requiring twice-daily dosing were less adherent than once-daily users. These results did not support the hypothesis that twice-daily dosing of a DOAC is “more forgiving” in the presence of suboptimal adherence

0

0,5

1

1,5

Ad

just

ed

HR

(6

5%

CI)

fo

r is

che

mic

str

oke

wh

en

P

DC

* <

80

%

All DOAC users

Once-daily users

Twice-daily users

Suboptimal adherence to DOACs was found to be associated with an increased hazard of ischemic stroke

+50

%

+47

%

+50

%

One-Third of Twice-Daily Prescribed

Medications Were Being Taken Once Daily

Therapy adherence

Self-reported patient survey (N=266)

Taking OAC once daily Taking OAC twice daily

94% 6% Rivaroxaban

27% 73% Dabigatran

30% 70% Apixaban

86% 14% Warfarin

Andrade JG et al, Can J Cardiol 2016;32:747-53

Conclusions

Real world data confirm the safety and effectiveness

profile of rivaroxaban when compared to randomized

clinical trial data

The adherence and persistence are poor in warfarin

users but are also not optimal in direct oral

anticoagulants

Adherence and persistence are higher in Rivaroxaban

users when compared to warfarin and twice day direct

oral anticoagulants users