1. Collaborating for Impact National Forum for Heart Disease and Stroke Prevention 12th Annual Meeting October 22, 2014 Helene D. Clayton-Jeter, O.D.Fortunato Fred Senatore MD, PhD, FACC Director, Cardiovascular and Endocrine Liaison ProgramMedical Officer Commissioner’s Office of External AffairsDivision of Cardiovascular and Renal ProductsFood and Drug Administration 1

2. Presenter Disclosure The opinions and content in this presentation are based on personal views and do not reflect positions or policies of the FDA. 2

3. Million Hearts ® National initiative co-led by CDC and CMS In partnership with federal, state, and private organizations innovating and implementing To address the causes of 1.5M events and 800K deaths a year, $312.6 B in annual health care costs and lost productivity and major disparities in outcomes 3 Goal: Prevent 1 million heart attacks and strokes by 2017 Goal: Prevent 1 million heart attacks and strokes by 2017 From presentation by Janet Wright, MD, FACC, Executive Director, MH Initiative

4. Key Components of Million Hearts ® Keeping Us Healthy Changing the context Excelling in the ABCS Optimizing care Prioritizing the ABCS Health tools and technology Innovations in care delivery TRANS FAT Health Disparities From presentation by Janet Wright, MD, FACC, Executive Director, MH Initiative

5. Million Hearts Three things must happen to prevent 1 million heart attacks and stroke –6.3 million smokers quit –10 million more people control their hypertension –20% reduction in sodium intake Focus on populations with greatest burden and at greatest risk 5 From presentation by Janet Wright, MD, FACC, Executive Director, MH Initiative

6. Preventing a Million: Targets for Our Environment Intervention 2009-2010 Pre-Initiative Estimate 2017 Target Smoking prevalence26%10% reduction Sodium reduction3580 mg/day20% reduction Trans fat reduction0.6% of calories100% reduction National Survey on Drug Use and Health 2009-2010 National Health and Nutrition Examination Survey 2009-2010 From presentation by Janet Wright, MD, FACC, Executive Director, MH Initiative

7. Preventing a Million: Targets for the ABCS Intervention 2009-2010 Pre-Initiative Estimate 2017 Population- wide Target 2017 Clinical Target Aspirin when appropriate54%65%70% Blood pressure control52%65%70% Cholesterol management33%65%70% Smoking cessation22%65%70% National Ambulatory Medical Care Survey, National Health and Nutrition Examination Survey

8. 8 Partnering For Public Health Partnering For Public Health FDA Patients/Societies/Payers Government/ Academia Scientific Research Medication Adherence Strategies Improved Healthcare and Care Delivery

9. Collaborating for Impact 9 Assess, Address, and Reduce Health Disparities

10. FDA Action Items to support Million Hearts 10 Translate and Disseminate Knowledge Implement and Innovate for Population Health Research* Liaison program, newsletters, and webinars targeting CV health practitioners, patients, patient advocates, and consumers Nutritional Fact Label Campaign Label Youth Outreach Menu and Vending Enhanced adherence strategies for CV meds Link MH website with FDA’s CV webpage. Conduct “the real cost” tobacco cessation program Evidence synthesis focused on improved patient outcomes Publication: sodium levels for food partially hydrogenated oils are not generally recognized as safe* Response to the challenge to “push the envelope”

11. Adherence: Multifaceted faceted issue 11 Adherence TI TI = Therapeutic Index Patient Attitude and awareness Cost of drugs Pill Burden/Day PCP-Patient Relationship Symptom of Disease Test for Adherence Health Equity Rescue Therapy Convenience

12. 12 Evidence- synthesis on improved patient outcomes Increased public / sector awareness Strategy for enhanced adherence TIPill burden ACL and Administration on Aging TI = Therapeutic Index; ACL= Administration of Community Living Improved Care Delivery Professional Academies and Colleges Rescue Therapies Research Action Item-MH Outcome Metrics Alliance

13. Why is adherence important? Assessing the Impact of Medication Adherence on Long-term Outcomes Post Myocardial Infarction –Bansilal S, Castellano JM, Wei HG, Garrido E, Freeman E, Spettell CM, Garcia-Alonso F, Steinberg G, Sanz G, Fuster V; ESC Congress 2014 Outcome: Time to MACE (death, hospitalization for MI, stroke, coronary revascularization) by Adherence Levels (Portion of Days Covered for both statin and ACE-I as determined by prescription pattern x 6 months 13

14. Time to MACE by Adherence Levels 14

15. Collaborating for Impact Conclusion –Million Hearts promotes collaboration in CV risk modification involving ABCS –Million Hearts involves a multitude of government agencies each tasked with specific action items –Mechanisms to enhance medication adherence being examined 15

16. 16 For additional information, contact the Commissioner’s Office of External Affairs, Office of Health and Constituent Affairs, Million Hearts Liaison Helene Clayton-Jeter, O.D. at cardio.endocrine@fda.hhs.gov or 301.796.8452cardio.endocrine@fda.hhs.gov

17. Collaborating for Impact 17 Back-up

18. Assessing the Impact of Medication Adherence on Long-term Outcomes Post Myocardial Infarction S. Bansilal, JM. Castellano, HG. Wei, E. Garrido, A. Freeman, CM. Spettell, F. Garcia-Alonso, G. Steinberg, G. Sanz, V. Fuster European Society Of Cardiology Congress 2014 18 Bansilal et al, ESC 2014

19. Adherence Study-Background Evidence based medications for secondary prevention of cardiovascular disease (CVD) have led to a 50% reduction in mortality Nearly half of the patients are non adherent within the first year post event. Long-term studies linking adherence with outcomes are limited. We attempted to study the association between levels of medication adherence and long-term major adverse cardiovascular events in patients post myocardial infarction (MI). 19 Bansilal et al, ESC 2014

20. Adherence Study-Objectives Evaluate the association of levels of medication adherence with long-term major cardiovascular events- death, hospitalization for MI, stroke and coronary revascularization. Evaluate the association of levels of medication adherence with ‘softer’ cardiac outcomes – hospitalization for angina, All-cause and cardiac –related visited to ED. Evaluate the association of levels of medication adherence with resource utilization- outpatient visits to a cardiac specialist and cardiac testing. 20 Bansilal et al, ESC 2014

21. Adherence Study-Methods 2010-2013 data from Aetna Commercial & Medicare Advantage population databases Enrolment records, medical and pharmacy health insurance claims. Records linked for comprehensive tracking of individuals’ use of healthcare resources and clinical outcomes over time and across providers. Symmetry Episode Risk Groups (ERG®) Scores & publicly available data from the U.S. Census 2010 file used 21 Bansilal et al, ESC 2014

22. Adherence Study: Inclusion/Exclusion Inclusion Criteria: Adults who initiated both statin and ace-inhibitor (ACEI) medications following a hospitalization discharge for myocardial infarction (MI) based on ICD codes with a length of stay of more than 2 days, between January 1, 2010, and February 28, 2013. Continuous eligibility for both medical and prescription drug benefits from Aetna during 6 months before and after the MI. Exclusion Criteria: Pregnant Diagnosis codes indicating psychoses, dementia, bipolar disorder, major depressive disorder (severe with psychotic behaviours) or alcohol/substance abuse Living in a nursing home or in a hospice or respite care. Patients who had a refill for ARB medication within 6 months following the discharge date of the MI 22 Bansilal et al, ESC 2014

23. Adherence Study: Endpoint Selection Most recurrent events post MI occur within the first year Patients ‘reveal’ their adherence patterns as early as a month post MI, but their stable pattern is best apparent around 6 months and beyond Studies evaluating adherence have typically selected a 6-12 month exposure period We chose a 6 month adherence assessment period to optimize rigor while maintaining power 23 1. Smolina K et al. Circ Cardiovascular Qual. Outcomes 2012 2. Ho PM etal.- Arch. Int Med 2006 ; Am Heart J 2008; Circulation 2009 3. Jackevicius CA et al. Circulation 2008 4. Choudhry NK et al. Am Heart J 2014 Bansilal et al, ESC 2014

24. Adherence Study: Assessment Proportion of days covered (PDC) for both statin and ACEI during 6 months of follow-up after the index prescription. Patients were considered to be adherent if they were getting the refill of both ACEI and statin prescriptions. Based on their PDCs, we categorized patients into one of three groups using standard thresholds: ≥80% (‘fully adherent’), 40–79% (‘partially-adherent’), and <40% (‘non-adherent’). 24 Bansilal et al, ESC 2014

25. Adherence Study: Statistical Analysis Descriptive analyses were conducted to compare baseline characteristics between adherence exposure groups. Time to MACE for the three exposure groups was compared using Cox Proportional Hazards regression. Adjustment for significant confounders including those related to the “healthy adherer effect”. Event counts were compared using Negative Binomial regression with adjustment for confounders as above. 25 Bansilal et al, ESC 2014

26. Adherence Study: Covariates for adjustment 26 Bansilal et al, ESC 2014

27. Adherence Study: Disposition 27 Adults post- MI 1/10/10-2/28/13 N=14,119 Adults post- MI 1/10/10-2/28/13 N=14,119 7012 (49.6%) No fill of both ACEI and Statin during 6 months post MI Adults post MI with ACEI and Statin fill within 6 month post event N=7107 Adults post MI with ACEI and Statin fill within 6 month post event N=7107 Adults post MI with ACEI and Statin fill within 6 month post event, No exclusion N=5776 Adults post MI with ACEI and Statin fill within 6 month post event, No exclusion N=5776 1331 excluded 29% mental disorders 1% pregnant/deliv ery 10% Hospice 23% Nursing facility 33% ARB fill during 6 months post MI 4% MI was not index event 1331 excluded 29% mental disorders 1% pregnant/deliv ery 10% Hospice 23% Nursing facility 33% ARB fill during 6 months post MI 4% MI was not index event 1761 without 6 months pre-period Adults post MI with ACEI and Statin fill within 6 month post event, No exclusion, with 6 mth pre- period N=4015 Adults post MI with ACEI and Statin fill within 6 month post event, No exclusion, with 6 mth pre- period N=4015 Fully- Adherent (>80%) N=1721 (43%) Partially-Adherent (40-79%) N=1031 (31%) Non-Adherent (<40%) N=1263 (26%) Bansilal et al, ESC 2014

28. Adherence Study: Baseline Characteristics 28 Bansilal et al, ESC 2014

29. Adherence Study: Time to MACE by Adherence Level 29 Bansilal et al, ESC 2014

30. Adherence Study: Primary Outcome Measures 30 Event Low PDC (N=1031) Mid PDC (N=1263) High PDC (N=1721) PDC group comparison Ratiop value Composite Cardiac Events18.1 (281)17.2 (329)12.8 (328)High v. Low0.720.002 High v. Mid0.810.01 Mid v. Low0.900.18 Coronary/MI Hospitalization4.8 (74)4.4 (84)2.3 (58)High v. Low0.540.001 High v. Mid0.590.01 Mid v. Low0.900.57 Stroke Hospitalization1.2 (18)0.9 (17)0.6 (16)High v. Low0.540.09 High v. Mid0.940.86 Mid v. Low0.580.14 Revascularization Procedures (IP or OP) 14.4 (224)13.1 (249)10.8 (277)High v. Low0.780.01 High v. Mid0.860.12 Mid v. Low0.900.30 Bansilal et al, ESC 2014

31. Adherence Study: Limitations Insurance and pharmacy claims database Lack of benefit for secondary outcomes Overlap of outcomes with the adherence assessment period Unable to directly establish causality Confounding bias Treatment initiation 31 Bansilal et al, ESC 2014

32. Adherence Study: Conclusions High levels of adherence to guideline recommended therapies are associated with a lower rate of major cardiovascular events compared to partial or non- adherence. There appeared to be a threshold effect for this benefit at >80% adherence. Novel approaches to improve adherence such as a polypill that may enable >80% adherence with secondary preventive therapies may lead to a significant reduction in CV events post MI. 32 Bansilal et al, ESC 2014