Real-world Evidence on Stroke Prevention in Patients with Atrial Fibrillation in the United States

1. Craig I. Coleman, Matthias Antz, Edgar Simard, Thomas Evers, Kevin Bowrin, Hendrik Bonnemeier, Riccardo Cappato University 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; HumanitasClinical and Research Centre, Rozzano, Italy Real-world EVIdence on Stroke prevention In patients with aTrial Fibrillation in the United States

2. Disclosures • I have received grant funding and/or consultancy fees from: • Bayer Pharma AG, Berlin, Germany • Janssen Scientific Affairs, LLC, Raritan, NJ, USA • Boehringer-Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA • Portola Pharmaceuticals, South San Francisco, CA, USA • Pfizer, Groton, CT, USA

3. Background • Phase III clinical trial data (ROCKET AF1and 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

4. Objective • To assess the real-world effectiveness and safety of newly-initiated rivaroxaban or apixaban compared to warfarin in NVAF patients

5. Methods • Retrospective analysis performed using US MarketScan claims data from 1/1/2012-10/31/2014 • Inclusion: • Adult patients newly initiated on rivaroxaban, apixaban or warfarin • Baseline CHA2DS2-VASC score≥2, • ≥2 ICD-9 diagnosis codes for NVAF, and • ≥180 days of continuous medical and prescription coverage • Exclusion: • Patients with a prior history of stroke, systemic embolism or ICH

6. Methods • Utilized validated FDA Mini-Sentinel1coding 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 study • Propensity-score matched each FXaI patient to a warfarin patient (during the same time period) to reduce differences between baseline characteristics • Cox 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.pdf

7. Considerations When Performing NOAC/NVAF Claims Database Studies • Claims databases have little, if any, data on vital signs or laboratory results • Not possible to assess whether prescribing is consistent with labeling in MarketScan • Time lag in data availability • Data through 10/2014 = limited apixaban usage and decreased power • NOACs were approved for NVAF at different times • Experience with NOACs likely grows over time, changing benefit/risk • All claims databases subject to potential misclassification bias • Some endpoints easier to detect accurately than others

8. Our Approach • Design study to optimize “internal validity” • Show consistency between HRs in Phase III trials and real-world analyses, not head-to-head NOAC comparisons • Selected 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 events • Included rivaroxaban and apixaban patients starting on their individual FDA approval dates and only matched them to warfarin patients initiated during the same time frame

9. 38,831 Patients Met Selection Criteria (Rivaroxaban vs. Warfarin) 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 *PY=Patient-years

10. 18,591 Patients Met Selection Criteria (Apixaban vs. Warfarin) 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 *PY=Patient-years

11. 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 andischemic stroke vs. warfarin *p<0.05 Favorsrivaroxaban Favors warfarin

12. Apixaban vs. Warfarin • Apixaban was associated with a significant* 62% reduction in ICH vs. warfarin • 13% non-significant increase in ischemic stroke vs. warfarin • Non-significant 37% reduction in the combined endpoint of ICH and ischemic stroke vs. warfarin *p<0.05 Favorsapixaban Favors warfarin

13. Conclusion • This study was designed to optimize internal validity (obtain the most unbiased HR estimates), however caution is warranted when comparing these results to Phase III trials • It provides reassurance that both oral agents have lower ICH rates vs. warfarin in routine practice • Rivaroxaban significantly reduced the combined endpoint of ischemic stroke and ICH • These 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. ClinCardiol. 2015;38:63-8; 4. N Engl J Med 2011; 365:981-992

14. Thank You! Questions?

15. Back Up Slides

16. Over-Use of the Reduce Doses of FXaIs in the US?1 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 IMS LifeLinkdata for apixaban and rivaroxaban from 9/19/2014–9/11/2015 1. CurrMed Res Opin. 2016 24:1-13. [Epub ahead of print]

17. Apixaban and Rivaroxban Prescription Data • 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 LifeLinkdata for apixaban and rivaroxaban Q2 2015

18. Impact of Lower Intensity Anticoagulation 1. N Engl J Med 2013;369:2093-104; 2. N Engl J Med 2003;349:1019-26

19. od dosing is associated with higher adherence than bid dosing: adherence to chronic cardiovascular disease medication1 −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<0.01 Dosing frequency Adherence (%) 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. CurrMed Res Opin. 2012;28:669-80.

20. Are differences in NOAC adherence clinically-relevant? Non-adherence is associated with worse outcomes during NVAF NOAC treatment 1.13 95%CI, 1.08–1.19 1.13 95%CI, 0.97–1.33 1.04 95%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 Am Heart J. 2014;167:810-7.