1. 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 1

2. Disclosures Drs. Bansilal, Castellano, Sanz and Fuster have no relevant disclosures. Ms. Garrido and Dr. Garcia-Alonso are employees of Grupo Ferrer. Drs. Wei, Steinberg, Spettell and Ms. Freeman are employees of Aetna.

3. 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). 3

4. Study Aims 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. 4

5. Methods Data Collection 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 5

6. Methods 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

7. Methods 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 1. Smolina K etal. Circ Cardiovascular Qual. Outcomes 2012 2. Ho PM etal.- Arch. Int Med 2006 ; Am Heart J 2008; Circulation 2009 3. Jackevicius CA etal. Circulation 2008 4. Choudhry NK etal. Am Heart J 2014

8. Methods Adherence 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’).

9. Statistical Analyses 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.

10. Covariates included for adjustment 10

11. Consort Diagram 11 n=1263 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/delive ry 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/delive ry 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%)

12. Baseline Characteristics 12

13. Time to Major cardiac Event by Adherence Levels 13

14. Primary Outcome Measures 14 Fully adherent (High PDC) group showed statistically significant lower events across the board when compared with partially adherent and non-adherent groups. Outcomes were not statistically different for the partially adherent and non-adherent groups. 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

15. Secondary Outcome Measures 15 Other than All cause ER visits, none of the other outcomes were statistically significant Event Low PDC (N=1031) Mid PDC (N=1263) High PDC (N=1721) PDC group comparison Ratiop value Hospitalization related to angina and CV atherosclerosis 7.6 (118)8.1 (154)5.8 (149) High v. Low 0.820.14 High v. Mid 0.790.06 Mid v. Low 1.040.78 All-Cause ER Visits39.4 (406)37.3 (471)31.3 (539) High v. Low 0.71<0.001 High v. Mid 0.890.08 Mid v. Low 0.800.002 Cardiac-Related ER visits3.0 (47)2.6 (50)2.7 (70) High v. Low 0.890.64 High v. Mid 1.070.78 Mid v. Low 0.830.49

16. Secondary Outcome Measures Event Low PDC (N=1031) Mid PDC (N=1263) High PDC (N=1721) PDC group comparison Ratiop value OP Cardiologist visits with CV testing 49.9 (777)49.4 (944)51.5 (1320) High v. Low 1.00 High v. Mid 1.010.80 Mid v. Low 0.990.83 General OP Cardiologist office visits 297 (4622)305.4 (5832)299.7 (7687) High v. Low 1.020.63 High v. Mid 1.010.71 Mid v. Low 1.000.90

17. Discussion The Challenge of poor adherence Ho etal. –VA database MI-FREEE-Randomized trial Novel strategies to enhance adherence Polypill 17

18. 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 18

19. 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. 19

20. Clinical Trial Update Hotline: Infarction, interventions and outcomes September 2 nd, 2014 Barcelona-Central Village 17:42- FOCUS - Fixed dose combination drug for secondary prevention Valentin Fuster, M.D, PhD

21. Thank you Aetna patients!