Appendix Table 1

Supplementary material: Statin adherence and risk of acute cardiovascular events among women: a cohort study accounting for time-dependent confounding affected by previous adherence Piia Lavikainen1,2*, Arja Helin-Salmivaara1,3, Mervi Eerola4, Gang Fang5, Juha Hartikainen6,7, Risto 1,8 1,5 Huupponen and Maarit Jaana Korhonen 1Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland 2Drug Research Doctoral Programme, University of Turku, Turku, Finland 3Unit of Primary Health Care, Hospital District of Helsinki and Uusimaa, Helsinki, Finland 4The Center of Statistics, University of Turku, Turku, Finland 5Division of Pharmaceutical Outcomes and Policy, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA 6Heart Center, Kuopio University Hospital, Kuopio, Finland 7School of Medicine, University of Eastern Finland, Kuopio, Finland 8Department of Clinical Pharmacology, Tykslab, Turku University Hospital, Turku, Finland Table of Contents: Table S1. Definitions of exclusion criteria……………………………..…………..…............... 2 Table S2. Definitions of outcomes……………………………………………………………... 3 Table S3. Definitions and classifications of baseline characteristics……................................... 4 Table S4. Definitions and classifications of potential time-dependent confounders…………… 8 Table S5. Distributions of baseline characteristics………………………................................... 12 Table S6. Follow-up year specific un-weighted and stabilized inverse probability of treatment weighted (model 3) standardized differences of the means comparing distributions of baseline characteristics and time-dependent confounders between the adherers and non-adherers..…………………………………………………………………… 14 Appendix 1. Inverse probability weights and marginal structural model…..……………………... 19 Appendix 2. Sensitivity analyses………………………………………….…................................. 22 Figure S1. Directed acyclic graphs for time-dependent adherence and confounding…………… 22 Table S7. Effect of statin adherence on acute cardiovascular events…………………………... 23 Figure S2. Flow of patients according to statin refills………………….....…………….............. 24 Table S8. Effect of statin refill on acute cardiovascular events………………………………… 24 1 Table S1. Definitions of exclusion criteria. Definition ATC codes Reimbursement ICD-10 code in Other code Data Time of code primary or secondary Source measurement diagnosis Treatment initiation with cerivastatin C10AA06 SII t0 Evidence of atherosclerotic cardiovascular disease Coronary heart disease I20–I25 FCR t-3 - t0 206, 213, 280 SII ≤ t0 CABG/PTCA FNA, FNB, FNC, FND, FNE, FCR t-3 - t0 FN1AT, FN1BT, FN1YT, TFN40, TFN50 Clopidogrel 315 SII ≤ t0 Nitrates C01DA SII t-3 - t0 Cerebrovascular diseases and TIA I60–I66, I68–I69, FCR t-3 - t0 G45–G46 Carotid endarterectomy or thrombolytic therapy PAF, AAL120 FCR t-3 - t0 Atherosclerosis I70 FCR t-3 - t0 Peripheral arterial disease PFH, PDQ, PEQ, PFQ, FCR t-3 - t0 PF1AT, PF1BT, PE1AT, PE1BT Aneurysm I71 Use of other lipid lowering medications C10A SII t-3 - t0 (excl. C10AA) Long-term institutionalization date of decision SII ≤ t1 Death SII t0 - t1 Acute cardiovascular event Acute coronary syndrome I20.0, I21, I22 as a FCR t0 - t1 primary diagnosis Acute ischemic stroke I63 as a primary FCR t0 - t1 diagnosis Abbreviations: ATC, Anatomical Therapeutic Chemical; CABG, coronary artery bypass graft; FCR, Finnish Care Register; ICD, International Classification of Diseases; PTCA, percutaneous transluminal coronary angioplasty; SII, Social Insurance Institution; TIA, transient ischemic attack. t0 = date of the cohort entry = date of the first statin dispensation, t-3= three years prior to statin initiation, t1 = one year since statin initiation 2 Table S2. Definitions of outcomes. Definition ICD-10 code/Medical procedure code Data Source MAIN OUTCOME Acute cardiovascular event As a primary diagnosis: Acute coronary syndrome I20.0, I21, I22 FCR Acute ischemic stroke I63 FCR OUTCOMES IN SENSITIVITY ANALYSES Composite outcome Acute coronary syndrome I20.0, I21, I22 FCR Acute ischemic stroke I63 FCR CABG/PTCA FNA, FNB, FNC, FND, FNE, FN1AT, FN1BT, FN1YT, FCR TFN40, TFN50 Death from any cause SII Low-energy fracture As a primary or secondary diagnosis: FCR Hip fracture S32.1−S32.4, S72.0−S72.8 FCR Wrist fracture S52.0, S62.4 FCR Ankle fracture S82.1−S82.7, S92.0, S92.3 FCR Forearm fracture S42.2−S42.4 FCR Abbreviations: CABG, coronary artery bypass graft; FCR, Finnish Care Register; ICD, International Classification of Diseases; PTCA, percutaneous transluminal coronary angioplasty; SII, Social Insurance Institution. 3 Table S3. Definitions and classifications of baseline characteristics. Definition ATC code Special ICD-10 code Other Data source Time of reimbursement in primary or specifications measurement code secondary diagnoses SOCIO-DEMOGRAPHIC FACTORS Age, years SII t0 45–49 50–54 55–59 60–64 University hospital catchment area SF t0 Helsinki Turku Tampere Kuopio Oulu Marital status SF t0 Married, partner in a registered partnership, separated Divorced or widowed Unmarried SOCIO-ECONOMIC FACTORS Quartiles of income, euros SF t0 ≤11,200 11,300–18,700 18,800–25,400 ≥25,500 Educational level SF t0 Basic level Secondary level Higher-degree level Labor market status SF t0 Employed labor force Unemployed Pensioner or unemployment pensioner Others outside the labor force Table continues 4 Table S3. Continued Definition ATC code Special ICD-10 code Other Data source Time of reimbursement in primary or specifications measurement code secondary diagnoses FACTORS DESCRIBING STATIN THERAPY Statin at baseline t0 Simvastatin C10AA01 SII Lovastatin C10AA02 SII Pravastatin C10AA03 SII Fluvastatin C10AA04 SII Atrovastatin C10AA05 SII Rosuvastatin C10AA07 SII Year of statin initiation C10AA SII t0 2001 2002 2003 2004 a Intensity of statin therapy Strength and type SII t0 of statin Low Moderate High CARDIAC COMORBIDITY FACTORS Diabetes (yes/no) E10– E14 FCR t-3 – t0 103 SII ≤t0 A10A or A10B SII t-1 – t0 Insulin (yes/no) A10A SII t-1 – t0 Hypertensive diseases (yes/no) I10– I15 FCR t-3 – t0 205 SII ≤t0 Heart failure or chronic cardiac I50 FCR t-3 – t0 insufficiency (yes/no) 201 SII ≤ t0 Cardiac arrhythmia (yes/no) I46–I49 FCR t-3 – t0 207 SII ≤t0 Dysfunctions of lipid metabolism (yes/no) E78 FCR t-3 – t0 211 SII ≤t0 Table continues 5 Table S3. Continued Definition ATC code Special ICD-10 code Other Data source Time of reimbursement in primary or specifications measurement code secondary diagnoses Number of concurrent CVD medications Total number of SII t-1 – t0 0 different ATC codes 1 related to CVD (B01, 2 C01, C02, C03, C07, 3–6 C08, C09) Charlson Comorbidity Index FCR t-1 – t0 0 ≥1 NON-CARDIAC COMORBIDITY FACTORS Rheumatoid arthritis (yes/no) M05, M06 or M45 FCR t-3 – t0 202 SII ≤t0 Cancer (yes/no) C00–C99 or D00–D09 FCR t-3 – t0 115–117, 128, SII ≤t0 130, 180, 184, 185, 189, 311, 312, 316 L01 SII t-1 – t0 Mental disorders (yes/no) F20–F31 FCR t-3 – t0 112, 188 SII ≤t0 N05A SII t-1 – t0 Depression (yes/no) F32–F34 FCR t-3 – t0 N06A SII t-1 – t0 Respiratory diseases (yes/no) J44–J46 FCR t-3 – t0 203 SII ≤t0 R03 SII t-1 – t0 Alcohol-related diseases (yes/no) F10, Z50.2, Z71.4, FCR t-3 – t0 G31.2, G40.51, G62.1, G72.1, K29.2, K85.2, K86.0, K86.01, K86.08, I42.6, R78.0, T51.0, Y91.1, Y91.2, Y91.3, Y91.9, E24.4, K70.4, K70 Table continues 6 Table S3. Continued Definition ATC code Special ICD-10 code Other Data source Time of reimbursement in primary or secondary specifications measurement code diagnoses NSAID (yes/no) M01A excluding M01AX05 SII t-1 – t0 Anxiolytics, hypnotics and sedatives (yes/no) N05B or N05C SII t-1 – t0 Corticosteroids for systemic use (yes/no) H02A SII t-1 – t0 Hormone therapy (yes/no) G03C or G03F SII t-1 – t0 Total number of concurrent medications Total number of SII 120 days before 1–2 different ATC codes t0 – t0 3–5 6–31 Number of in-hospital days FCR t-1 – t0 0 1–2 3–7 8–321 Abbreviations: ATC, Anatomical Therapeutic Chemical; CHD, coronary heart disease; CVD, cardiovascular diseases; FCR, Finnish Care Register; ICD, International Classification of Diseases; NSAID, nonsteroidal anti-inflammatory medications; SII, Social Insurance Institution; SF, Statistics Finland. t-3 = three years prior to statin initiation t-1 = one year prior to statin initiation t0 = date of statin initiation a Intensity of statin therapy: Low: Fluvastatin 20–40mg, lovastatin 20mg, pravastatin 10–20mg, simvastatin 5–10mg. Moderate: Atorvastatin 10–20mg, fluvastatin 80mg, lovastatin 40mg, pravastatin 40mg, rosuvastatin 10mg, simvastatin 20–40mg. High: Atorvastatin 40–80mg, rosuvastatin 20–40mg, simvastatin 80mg. 7 Table S4. Definitions and classifications of potential time-dependent confounders at time ti, i=1,2,3. Definition ATC code Special ICD-10 code in Other Data source Time of reimbursement primary or secondary specifications measurement code diagnoses SOCIO-DEMOGRAPHIC FACTORS Marital status SF ti Married, partner in a registered partnership, separated Divorced or widowed Unmarried SOCIO-ECONOMIC FACTORS Quartiles of income SF ti Labor market status SF ti Employed labor force Unemployed Pensioner or unemployment pensioner Others outside the labor force FACTORS DESCRIBING STATIN THERAPY Increase in intensity of statin therapya (yes/no) Strength and type SII latest of statin prescription in ti-1 – ti vs. latest prescription in ti-2 – ti-1 CARDIAC COMORBIDITY FACTORS Diabetes (yes/no) E10–E14 FCR ≤ti 103 SII ≤ti A10A or SII ≤ti A10B Insulin (yes/no) A10A SII ti-1 – ti

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