International comparison of outcomes among 140 887 survivors

International comparison of outcomes among 140 887 survivors after acute myocardial infarction: real-world evidence from electronic health and administrative records Professor Harry Hemingway on behalf of the APOLLO investigators European Society of Cardiology Congress 2014 Registry Hot Line Session: Atrial fibrillation and myocardial infarction

Authors Eleni Rapsomaniki 1, Magnus Janzon 2, David J. Cohen 3, Tomas Jernberg 4, Nicholas Moore 5, Marcus Thuresson 6, Erru Yang 7, Patrick Blin 5, Saga Johansson 8, Harry Hemingway 1 1 Farr Institute of Health Informatics Research, University College London, UK 2 Linkoping University, Sweden 3 Saint Luke’s Mid America Heart Institute, Kansas City, USA 4 Karolinska University Hospital, Sweden 5 Department of Pharmacoepidemiology, University of Bordeaux, France 6 Statisticon AB, Uppsala, Sweden 7 Health Economics & Epidemiology, Evidera, Lexington, USA 8 Observational Research Center, Astra. Zeneca R&D, Mölndal, Sweden

Conflicts Astra. Zeneca funded the APOLLO Programme alongside the PEGASUS-TIMI 54 study which is aimed at determining the clinical efficacy and safety of long-term dual antiplatelet therapy with ticagrelor plus aspirin for the prevention of secondary cardiovascular events in patients with a recent myocardial infarction and additional atherothrombotic risk factors

Motivation • Importance • Uncertainty • Novel opportunity – MI survivors – International comparisons – Unselected populations – Long-term follow-up – Non-fatal and fatal – Benefits and harms – Electronic health and administrative records

Objective • To compare atherothrombotic events, death and bleeding risks in 1 -year post-MI survivors across Sweden, the USA, England France over 3 years of follow-up

Methods: electronic health records and administrative data sources in APOLLO Programme Countries Sweden Record sources Details USA National registries • • • Nationwide Longitudinal data Hospital discharge data linked to prescribed data register and death registry England • Age >65 years Demographics and health insurance claims Linked to death registry EGB, PMSI CPRD, MINAP, HES Medicare • • France • • • Four linked datasets Longitudinal data Primary and secondary care, and disease registry and death registry • • Sample of national healthcare insurance data Hospital discharge data linked to death registry CPRD, Clinical Practice Research Datalink; EGB, Echantillon Généraliste des Bénéficiaires; HES, Hospital Episodes Statistics; MINAP, Myocardial Ischaemia National Audit Project; PMSI, Programme de médicalisation des systèmes d'information

Methods: study population, disease definitions and statistics • • Patients entered the study 1 year after the most recent discharge for MI (study period: 2002– 2011) Disease definitions were harmonised using ICD 9/ICD 10 diagnostic codes Data from each country were analysed using a common protocol Cox models were utilised to estimate adjusted risks and relative risks, using Sweden as reference ICD, International Classification of Diseases

Age- and sex-standardised prevalence of comorbidities and secondary prevention treatments Baseline comorbidities (%) Treatments prescribed at 1 year post-MI (%) 63. 9% Hypertension 69. 1% 68. 7% 29. 0% History of heart failure 24. 2% 29. 6% 25. 4% Diabetes 23. 2% 28. 0% 79. 0% 40. 7% 38. 5% 22. 0% 24. 2% 20. 8% 16. 9% History of atrial fibrillation 81. 3% 68. 5% 73. 5% ACEI/ARBs 71. 4% 80. 1% 71. 3% ADP-receptor blockers History of cancer 13. 0% 7. 9% 8. 0% 15. 2% Dual antiplatelet 11. 9% 11. 2% 9. 1% History of hospitalised bleeding 7. 5% 3. 8% 0 41. 0% 54. 4% 8. 9% 8. 4% 9. 8% 20 40 60 Sweden, n=77 798 PCI USA, n=53 909 38. 7% England, n=7238 10. 5% 7. 2% 20 65. 0% 80 100 Revascularisation (%) 16. 1% 4. 2% 0. 4% 49. 7% Percentage 11. 2% 7. 8% History of PAD 22. 9% 0 28. 6% 5. 4% History of renal disease 26. 4% Vitamin K antagonists 11. 3% 6. 4% 8. 3% 3. 7% 10. 8% 82. 3% 79. 4% 80. 0% Aspirin 14. 4% 11. 7% 12. 2% 13. 5% History of COPD 86. 7% 80. 4% b-blockers History of >1 MI History of stroke 76. 1% Statins 40 60 Percentage 80 100 61. 6% 14. 1% 19. 7% CABG France, n=1764 54. 9% 48. 1% 11. 4% 7. 1% 0 20 40 Percentage 60 80 ACEI, angiotensin-converting enzyme inhibitor; ADP, adenosine diphosphate; ARB, angiotensin receptor blocker; CABG, coronary artery bypass graft; COPD, chronic obstructive pulmonary disease; MI, myocardial infarction; PAD, peripheral arterial disease; PCI, percutaneous coronary intervention

Prognostic validity: adjusted HRs of all-cause death CABG, no vs yes Sweden USA England France Overall mean Number of events % in study HR 95% CI 15 233 22 498 659 222 12. 6 16. 9 10. 4 5. 6 1. 67 2. 21 2. 00 1. 75 1. 92 (1. 58– 1. 78) (2. 12– 2. 31) (1. 42– 2. 83) (0. 95– 3. 22) (1. 54– 2. 40) 2. 15 1. 79 1. 69 1. 79 1. 85 (2. 11– 2. 20) (1. 75– 1. 82) (1. 55– 1. 84) (1. 57– 2. 04) (1. 63– 2. 11) Age per 10 years Sweden USA England France Overall mean 15 233 22 498 659 222 PCI, no vs yes Sweden USA England France Overall mean 15 233 22 498 659 222 55. 8 42. 9 41. 8 65. 0 1. 90 1. 71 1. 87 1. 85 1. 81 (1. 83– 1. 98) (1. 65– 1. 76) (1. 50– 2. 32) (1. 39– 2. 46) (1. 66– 1. 98) History of renal disease Sweden USA England France Overall mean 15 233 22 498 659 222 5. 0 3. 4 7. 0 6. 9 1. 85 1. 56 1. 92 1. 76 1. 73 (1. 72– 1. 92) (1. 50– 1. 62) (1. 57– 2. 34) (1. 22– 2. 54) (1. 53– 1. 96) History of heart failure Sweden USA England France Overall mean 15 233 22 498 659 222 27. 7 45. 0 21. 0 23. 2 1. 68 1. 72 1. 56 1. 45 1. 70 (1. 63– 1. 74) (1. 67– 1. 77) (1. 32– 1. 85) (1. 07– 1. 06) (1. 66– 1. 74) 0. 5 1 2 3 4 5 6 HR CABG, coronary artery bypass graft; CI, confidence interval; HR, hazard ratio; PCI, percutaneous coronary intervention

3 -year cumulative absolute risks All-cause death MI/stroke/all-cause death Observed risk (%) 50 Sweden 20. 1 (19. 7– 20. 4) USA 30. 2 (29. 8– 30. 7) England 13. 7 (12. 6– 14. 8) France 14. 3 (12. 5– 16. 1) 40 30 20 20 10 10 0 0 0. 5 1. 0 1. 5 2. 0 Sweden 26. 9 (26. 5– 27. 2) USA 36. 2 (35. 7– 36. 6) England 24. 1 (22. 7– 25. 5) France 17. 9 (16. 0– 19. 8) 2. 5 3. 0 0. 5 Follow-up (years) 1. 0 2. 5 3. 0 Follow-up (years) Adjusted risk (%) 20 30 Sweden 11. 2 (10. 9– 11. 5) USA 12. 8 (12. 3– 13. 4) England 8. 7 (6. 9– 10. 5) France 12. 4 (10. 1– 14. 7) 15 1. 5 Sweden 19. 8 (19. 4– 20. 2) USA 18. 2 (17. 6– 18. 9) England 21. 3 (18. 2– 24. 2) France 16. 7 (14. 3– 19. 2) 25 20 15 10 10 5 5 0 0 0. 5 1. 0 1. 5 2. 0 2. 5 3. 0 Follow-up (years) Shaded areas correspond to 95% confidence intervals MI, myocardial infarction 0. 0 0. 5 1. 0 1. 5 2. 0 Follow-up (years)

Relative risks vs Sweden All-cause death RR 95% CI MI/stroke/ all-cause death RR 95% CI USA Unadjusted (KM) 1. 55 (1. 50– 1. 61) 1. 33 (1. 29– 1. 37) Age and sex 1. 46 (1. 39– 1. 53) 1. 09 (1. 05– 1. 13) 1. 11 1. 17 (1. 05– 1. 18) (1. 11– 1. 24) 0. 83 0. 88 (0. 80– 0. 87) (0. 84– 0. 92) Unadjusted (KM) 0. 77 (0. 66– 0. 90) 0. 89 (0. 79– 1. 00) Age and sex 1. 04 (0. 86– 1. 26) 1. 12 (0. 98– 1. 28) 1. 04 0. 90 (0. 85– 1. 28) (0. 73– 1. 12) 1. 12 1. 04 (0. 98– 1. 30) (0. 90– 1. 20) Unadjusted (KM) 0. 69 (0. 56– 0. 84) 0. 60 (0. 50– 0. 72) Age and sex 1. 14 (0. 93– 1. 41) 0. 83 (0. 70– 0. 99) 1. 11 1. 09 (0. 88– 1. 39) (0. 86– 1. 37) 0. 82 0. 78 (0. 68– 0. 98) (0. 64– 0. 94) comorbiditiesa + + PCI/CABG England comorbiditiesa + + PCI/CABG France comorbiditiesa + + PCI/CABG 0. 75 1 RR 1. 5 0. 75 1 1. 5 RR a. Comorbidities adjusted for history of >1 MI, hypertension, renal disease, heart failure, PAD, stroke, atrial fibrillation, hospitalised bleeding, cancer and COPD. French group adjusted only for age, sex, and year of index MI. All models were additionally adjusted for year of index MI CABG, coronary artery bypass graft; CI, confidence interval; COPD, chronic obstructive pulmonary disease; KM, Kaplan– Meier; MI, myocardial infarction; PAD, peripheral arterial disease; PCI, percutaneous coronary intervention; RR, relative risk

3 -year cumulative risks of hospitalised bleeding events Observed risk (%) 6 Adjusted risk (%) 6 Sweden 2. 5 (2. 3– 2. 6) USA 5. 3 (5. 1– 5. 5) England 3. 6 (2. 9– 4. 3) France 2. 2 (1. 4– 3. 0) 5 4 3 3 2 2 1 1 0 0 0. 5 1. 0 1. 5 2. 0 Sweden 2. 0 (1. 9– 2. 1) USA 3. 6 (3. 2– 4. 0) England 4. 9 (2. 7– 7. 0) France 2. 2 (1. 5– 3. 4) 5 4 2. 5 Follow-up (years) 3. 0 RR (vs Sweden) 0. 0 0. 5 1. 0 1. 5 2. 0 2. 5 Follow-up (years) 3. 0 USA Unadjusted (KM) Age and sex + comorbiditiesa + PCI/CABG RR 95% CI 2. 12 2. 14 1. 69 (1. 92– 2. 34) (1. 92– 2. 38) (1. 45– 1. 84) (1. 51– 1. 90) England Unadjusted (KM) Age and sex + comorbiditiesa + PCI/CABG 1. 35 2. 07 1. 94 (0. 91– 2. 01) (1. 40– 3. 07) (1. 28– 2. 93) France Unadjusted (KM) Age and sex + comorbiditiesa + PCI/CABG 0. 75 0. 99 1. 06 (0. 42– 1. 33) (0. 58– 1. 69) (0. 62– 1. 81) 0. 5 1 2 RR Shaded areas correspond to 95% CIs a. Comorbidities adjusted for history of >1 MI, hypertension, renal disease, heart failure, PAD, stroke, atrial fibrillation, hospitalised bleeding, cancer and COPD. French group adjusted only for age, sex, and year of index MI. All models additionally adjusted for year of index MI CABG, coronary artery bypass graft; CI, confidence interval; COPD, chronic obstructive pulmonary disease; KM, Kaplan– Meier; MI, myocardial infarction; PAD, peripheral arterial disease; PCI, percutaneous coronary intervention; RR, relative risk

Limitations • Medication information – • Data on cause-specific mortality – • Lacking for USA, France Socioeconomic data – • Lacking for USA Lacking for Sweden, USA, France Patient age – USA >65 years only

Main results summary • Among 140 887 1 -year post-MI survivors drawn from unselected electronic health and administrative records populations: – – – High-risk state (>3% annual all-cause death risk 1, 2) About half of deaths are non-cardiovascular Compared with European populations, US patients had • • – – higher (age and sex-standardised) prevalence of comorbidities higher adjusted all-cause mortality Risk of further MI, stroke or death remained high (about 1 in 5) across the 3 years and across the 4 countries studied, with fairly constant annual risks Difference in risk of hospitalised bleeding in the USA and England vs Sweden remained substantial 1 Montalescot G et 2 Fihn SD et al. Eur Heart J 2013; 34: 2949– 3003 al. J Am Coll Cardiol 2012; 60: e 44–e 164

Clinical implications • Guidelines 1, 2 – • Policy – • Need for a generalist approach Evidence for regulators and clinicians – • Impetus to improve quality of healthcare systems Primary care – • Definition of ‘high risk’ needs to be considered New interventions and generalisability of trial results National electronic health record resources – Quality, scope and comparability 1 Montalescot G et 2 Fihn SD et al. Eur Heart J 2013; 34: 2949– 3003 al. J Am Coll Cardiol 2012; 60: e 44–e 164

Acknowledgements • Editorial support was provided by Oxford Pharma. Genesis™ Ltd