R eal-world - PowerPoint Presentation

Slide1

Real-world EVIdence on Stroke prevention In patients with aTrial Fibrillation in the United States

Craig I. Coleman, Matthias Antz, Edgar Simard, Thomas Evers, Kevin Bowrin, Hendrik Bonnemeier, Riccardo CappatoUniversity of Connecticut School of Pharmacy, Storrs, CT, USA; Hospital Oldenburg, Department of Cardiology, Oldenburg, Germany; Aetion, Inc., New York, NY, USA,; Bayer Pharma AG, Wuppertal, Germany; Bayer Pharma AG, Berlin, Germany; University Medical Center of Schleswig-Holstein, Department of Electrophysiology and Rhythmology, Kiel, Germany; Humanitas Clinical and Research Centre, Rozzano, ItalySlide2

DisclosuresI have received grant funding and/or consultancy fees from:Bayer Pharma AG, Berlin, GermanyJanssen Scientific Affairs, LLC, Raritan, NJ, USA Boehringer-Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA Portola Pharmaceuticals, South San Francisco, CA, USAPfizer, Groton, CT, USASlide3

BackgroundPhase III clinical trial data (ROCKET AF1 and ARISTOTLE2) demonstrated the favorable efficacy and safety profiles of rivaroxaban and apixaban vs. vitamin K antagonists (VKAs)Real-world evidence is needed to confirm the magnitude of benefits and risks in routine clinical practice 1. N Engl J Med 2011; 365:883-891; 2. N Engl J Med 2011; 365:981-992 Slide4

ObjectiveTo assess the real-world effectiveness and safety of newly-initiated rivaroxaban or apixaban compared to warfarin in NVAF patientsSlide5

MethodsRetrospective analysis performed using US MarketScan claims data from 1/1/2012-10/31/2014Inclusion:Adult patients newly initiated on rivaroxaban, apixaban or warfarinBaseline CHA2DS2-VASC score≥2, ≥2 ICD-9 diagnosis codes for NVAF, and ≥180 days of continuous medical and prescription coverageExclusion:Patients with a prior history of stroke, systemic embolism or ICHSlide6

MethodsUtilized validated FDA Mini-Sentinel1 coding for ischemic stroke and ICH endpoints (primary ICD-9 code position only)Patients were followed until the occurrence of a primary event, discontinuation/switch of therapy, disenrollment, or end of the studyPropensity-score matched each FXaI patient to a warfarin patient (during the same time period) to reduce differences between baseline characteristicsCox regression was performed and reported as hazard ratios (HRs) and 95% confidence intervals (CIs)1. http://www.mini-sentinel.org/work_products/Assessments/Mini-Sentinel_Protocol-for-Assessment-of-Dabigatran.pdfSlide7

Considerations When Performing NOAC/NVAF Claims Database StudiesClaims databases have little, if any, data on vital signs or laboratory resultsNot possible to assess whether prescribing is consistent with labeling in MarketScanTime lag in data availability Data through 10/2014 = limited apixaban usage and decreased powerNOACs were approved for NVAF at different timesExperience with NOACs likely grows over time, changing benefit/riskAll claims databases subject to potential misclassification biasSome endpoints easier to detect accurately than othersSlide8

Our ApproachDesign study to optimize “internal validity”Show consistency between HRs in Phase III trials and real-world analyses, not head-to-head NOAC comparisonsSelected endpoints most likely to be coded accurately (and with less variability) in claims data and of equal importance to allow for benefit/risk assessment (ischemic stroke and ICH) Used validated ICD-9 coding algorithms and restricted codes to the primary diagnosis code position (may miss cases, but greater faith in those identified)Exclusion of patients with baseline eventsIncluded rivaroxaban and apixaban patients starting on their individual FDA approval dates and only matched them to warfarin patients initiated during the same time frameSlide9

Characteristics of included patients (matched cohorts)Parameter

Rivaroxaban(n=11,411)7,715 PYs*Warfarin (n=11,411)6,271 PYs*Age in years, mean (SD)70.7 (10.99)70.7 (11.35)

Male,

%

53.6

53.9

CHADS

2

score, 180 day;

mean (SD)

1.92 (1.08)

1.94 (1.08)

CHA

2

DS

2

-VASc score

, 180 day;

mean

(SD)

3.46 (1.37)

3.48 (1.35)

HAS-BLED Score, 180 day; mean (SD)1.62 (0.69)1.62 (0.71)Reduced dose, %17.3NA

Newly initiated on rivaroxaban or warfarin meeting selection criteriaN=38,831

Rivaroxabann=12,748

warfarinn=26,083

Following propensity-score matching

stratified by

exposure status. 11,411 rivaroxaban and 11,411 warfarin users were identified

38,831 Patients Met Selection Criteria (Rivaroxaban vs. Warfarin)

*

PY

=Patient-yearsSlide10

Characteristics of included patients (matched cohorts)Parameter

Apixaban (n=4,083)2,125 PYs*Warfarin(n=4,083)1,951 PYs*Age in years, mean (SD)71.15 (11.32)

71.00 (11.25)

Male, %

53.2

53.6

CHADS

2

score, 180 day;

mean (SD)

1.93 (1.07)

1.92 (1.07)

CHA

2

DS

2

-VASc score

, 180 day; mean

(SD)

3.47 (1.38)

3.47 (1.35)

HAS-BLED Score, 180 day;

mean (SD)1.65 (0.69)

1.66 (0.72)Reduced dose, %15.5

NA

Newly initiated on apixaban or warfarin meeting selection criteria

N=18,591

Apixaban n=4,332

Warfarinn=14,259

Following propensity-score matching,

stratified by exposure status

4,083 apixaban

and

4,083

warfarin

users

were

identified

18,591 Patients Met Selection Criteria

(Apixaban

vs. Warfarin)

*

PY

=Patient-yearsSlide11

RivaroxabanWarfarinHR (95% CI)rivaroxaban vs. warfarinHR (95% CI)rivaroxaban vs. warfarinRate (%/year)

Rate (%/year)ICH0.490.960.53 (0.35–0.79)Ischemic stroke0.540.830.71 (0.47–1.07)

Combined

0.95

1.6

0.61 (0.45–0.82)

Rivaroxaban vs. Warfarin

Rivaroxaban

was associated with a

significant* 47%

reduction in ICH vs

. warfarin

29%

non-significant

decrease

in ischaemic stroke vs.

warfarin

Significant* 39%

reduction in

the combined endpoint of ICH and

ischemic stroke vs

. warfarin*p<0.05Favorsrivaroxaban

Favors

warfarinSlide12

Apixaban vs. WarfarinApixaban was associated with a significant* 62% reduction in ICH vs. warfarin13% non-significant increase in ischemic stroke vs. warfarin Non-significant 37% reduction in the combined endpoint of ICH and ischemic stroke vs. warfarinApixabanWarfarinHR (95% CI)apixaban vs. warfarinHR (95% CI)

apixaban vs. warfarinRate (%/year)Rate (%/year)ICH0.380.970.38 (0.17–0.88)

Ischemic stroke

0.56

0.51

1.13 (0.49–2.63)

Combined

0.89

1.44

0.63 (0.35–1.12)

Favors

apixaban

Favors

warfarin

*p<0.05Slide13

ConclusionThis study was designed to optimize internal validity (obtain the most unbiased HR estimates), however caution is warranted when comparing these results to Phase III trialsIt provides reassurance that both oral agents have lower ICH rates vs. warfarin in routine practiceRivaroxaban significantly reduced the combined endpoint of ischemic stroke and ICHThese results are generally consistent with that of ROCKET AF1 and other real-world studies (XANTUS2, PMSS3)Observed apixaban HRs were less consistent with those seen in ARISTOTLE4 (particularly 13% increased hazard of ischemic stroke, p=NS)1. N Engl J Med 2011; 365:883-891; 2. Eur Heart J. 2015 Sep 1. pii: ehv466. [Epub ahead of print]; 3. Clin Cardiol.

2015;38:63-8; 4. N Engl J Med 2011; 365:981-992 Slide14

Thank You!Questions?Slide15

Back Up SlidesSlide16

Over-Use of the Reduce Doses of FXaIs in the US?1percentage of apixaban and rivaroxaban prescriptions filled for a reduced dose vs. the proportion of patients requiring a reduced dose in corresponding registration trialsPercentage of Apixaban and Rivaroxaban Prescriptions Written for the Reduced Dose in Routine Cardiology Practice IMS LifeLink data

for apixaban and rivaroxaban from 9/19/2014–9/11/20151. Curr Med Res Opin. 2016 24:1-13. [Epub ahead of print]Slide17

Apixaban and Rivaroxban Prescription DataNOAC Prescription DataApixabanRivaroxaban

Q2 2015Q2 2015Country2.5 MG5 MG

10 MG

15 MG

20 MG

UNITED

STATES

25%

75%

5%

20%

75%

JAPAN

60%

40%

55%

45%

0%

GERMANY

45%

55%

4%

34%

62%CANADA38%

62%5%

26%69%AUSTRALIA

40%60%

2%30%

68%UNITED KINGDOM39%61%

5%

22%

74%

SPAIN

38%

62%

5%

31%

64%

FRANCE

45%

55%

7%

36%

57%

BELGIUM

31%

69%

2%

42%

57%

ITALY

41%

59%

3%

37%

60%

Pivotal RCTs and labeling provide clear

recommendation for the use of

the reduced dose each agent

In routine practice, a high proportion of

FXaI

prescriptions are written for the reduced dose

IMS

LifeLink

data

for apixaban and rivaroxaban

Q2 2015Slide18

Impact of Lower Intensity AnticoagulationHigh Edox1%/year Low Edox1%/year Warfarin INR 2.6-3.02%/year Warfarin INR 1.5-1.92

%/year ICH0.390.260.5 0.3 Ischemic stroke1.251.770.9 1.9 1. N Engl J Med 2013;369:2093-104; 2. N Engl J Med 2003;349:1019-26Slide19

od dosing is associated with higher adherence than bid dosing: adherence to chronic cardiovascular disease medication1

Dosing frequencyAdherence (%)

Number of bottle cap openings divided by the prescribed number of doses

Percentage of days with the appropriate number of doses taken

Percentage of near optimal

inter-administration intervals

Less stringent

More stringent

1.

Curr

Med

Res

Opin

.

2012;28:669-80

.

−

6.9 (95% CI

−

11.2 to

−

2.6)

p

<0.01

−

14.0 (95% CI

−

19.9 to

−

8.1)

p

<0.01

−

22.9 (95% CI

−

33.1 to

−

12.7)

p

<0.01Slide20

Are differences in NOAC adherence clinically-relevant?1.1395%CI, 1.08–1.191.1395%CI, 0.97–1.331.0495%CI, 0.94–1.14

5376 US veterans with NVAF (71.3±9.7 years; 98.3% were men and mean CHADS2 score was 2.4±1.2; mean PDC 84%±22%; 27.8% with a PDC <80%; median follow-up of 244 days) initiated on dabigatran from October 2010 to September 2012

Non-adherence is associated with worse outcomes during NVAF NOAC treatment

Am Heart J. 2014;167:810-7.