SUPPLEMENTAL MATERIALS Table S1: Variables included in the propensity-score matching Table S1.1: Components of the CHA 2DS 2Vasc score Table S2: Crude event rates in the compared AF patient cohorts Table S3: IRRs for CO1 (efficacy) and CO2 (safety) for the comparison of event rates in PSM-matched patients who received specific NOAC agents versus VKA patients Table S4: PSM-adjusted IRRs in the two sensitivity analyses considering (a) therapy-naïve patients (Cohort 1a / 2a) and (b) end of follow up if a 30 days gap was observed (Cohort 1 / 2) Figure S1a: Results of the multivariable Cox Regression analysis addressing composite outcome 3, based on Cohorts 1 and 2 Figure S1b: Results of the multivariable Cox Regression analysis addressing composite outcome 1 (effectiveness), based on Cohorts 1 and 2 Figure S1c: Results of the multivariable Cox Regression analysis addressing composite outcome 2 (safety), based on Cohorts 1 and 2 1
Table S1: Variables included in the propensity-score matching. The table outlines the definition of all 32 variables used for the PSM analysis that led to the PSM cohort. A backward elimination logistic regression using group exposition as dependent variable was applied. Please note that all independent variables included in the logistic regression estimates were based on the 12 months before index date. Variable Description Age per index year Gender CHA2DS2Vasc score CCI Highest level of nursing care: 0-4 (reference=0) Nb. of prescribed long-term medication Nb. of physician visits Prescription of antihypertensive agents Prescription of oral antidiabetic agents Prescription of insulin Prescription of antiarrhythmic agents Prescription of NSAIDs Prescription of antiplatelets Prescription of lipid lowering agents Prescription of antiulcerants Prescription of cardiac glycosides Prescription of oral corticosteroids Prescription of benzodiazepines Acute hosp. with ischaemic stroke Acute hosp. with haemorrhagic stroke Acute hosp. with non-specific stroke Acute hosp. with arterial embolism Acute hosp. with TIA Acute hosp. with myocardial infarction Acute hosp. with severe bleeding Acute hosp. due to other heart diseases (years) (male/female) Score (see description in table S1.1) Charlson Comorbidity Index (CCI) score Level of nursing care as documented in the database Number of prescribed medications (only those agents that had been prescribed at least twice in the 12 months baseline period, excluding VKAs, NOACs and antibiotics) Number of visits (yes/no; ATC: C02* and C06A*) (yes/no; ATC: A10B* and A10X*) (yes/no; ATC: A10A*) (yes/no; ATC: C08* and C01B* and C07AB* and C07AG*) Nonsteroidal anti-inflammatory drugs (yes/no; ATC: M01*) (yes/no; ATC: B01AC*) (yes/no; ATC: C10*) (yes/no; ATC: A02B*) (yes/no; ATC: C01A%) (yes/no; ATC: H02%) (yes/no; ATC: N05BA*) 2
Peripheral vascular disease Other cerebrovascular diseases Severe kidney disease/acute renal failure Mild to moderate kidney disease Dementia Alcohol abuse (yes/no; ICD-10 I70.-/I71.-/I72.-/I73.-) (yes/no; ICD-10 I65.-/I66.-/I67.-/I68.-/I69.-) (yes/no; at least one outpatient and/or inpatient diagnosis ICD-10 N17.-/ N18.4/N18.5) (yes/no; at least one outpatient and/or inpatient diagnosis ICD-10 N18.1-N18.3/N18.9/N19-) (yes/no; ICD-10 F00.-/F01.-/F02.-/F03.-) (yes/no; ICD-10 F10.-) Table S1.1: Components of the CHA2DS2Vasc score. The table contains the components of the calculated CHA2DS2Vasc score and describes the score methodology used based on observed outpatient/inpatient ICD-10 codes and sociodemographic information available in the database. All data was based on a 12 months baseline period before index date. Risk factor CHA 2DS 2- VASc-score value Used ICD-10 code (at least one documented outpatient or inpatient diagnosis) Heart failure 1 I50.- Hypertension 1 I10.- Age 65 74 years 1 - Age 75 years 2 - Diabetes mellitus 1 E11.-/E10.-/E12.- Stroke/TIA/embolism 2 Vascular disease (prior myocardial infarction/ peripheral artery disease/aortic plaque) I61.-/I63.-/I64.-/I69.-/ I82.-/G45.-/I74.-/ K55.0/N28.0/H34.- 1 I21.-/I22.-/I23.-/I73.- Female gender 1 - ICD-10: 10th revision of the International Statistical Classification of Diseases and Related Health Problems; TIA:transient ischaemic attack 3
Table S2: Crude event rates in the compared AF patient cohorts Observed outcome Event frequencies: number of observed events per 100 patient years in the followup period Cohort 1 (NOAC) N = 51,155 patients Cohort 2 (VKA) N = 128,274 patients IRR (95% CI) Cohort 1 vs. 2 Time to first event during the follow-up period Unadjusted HR (95% CI) Cohort 1 vs. 2 a: Death 13.93 7.23 1.93 (1.87-1.99)**** 1.88 (1.82-1.94)**** b: IS 2.55 0.98 2.59 (2.39-2.80)**** 2.59 (2.38-2.81)**** c: Non-specified stroke 0.13 0.04 3.03 (2.10-4.38)**** 2.85 (1.99-4.08)**** d: TIA 1.16 0.52 2.23 (1.99-2.49)**** 2.16 (1.92-2.43)**** e: MI 1.44 0.90 1.61 (1.46-1.77)**** 1.56 (1.41-1.73)**** f: AE 0.45 0.18 2.46 (2.04-2.97)**** 2.41(1.99-2.91)**** g: Haemorrhagic stroke 0.51 0.44 1.17 (1.01-1.36)* 1.19 (1.01-1.41)* h: Severe bleedings 2.74 1.12 2.44 (2.27-2.63)**** 2.36 (2.18-2.55)**** CO 1 (a-f) 19.66 9.85 1.99 (1.94-2.05)**** 1.95 (1.89-2.00)**** CO 2 (g and h) 3.25 1.56 2.09 (1.95-2.23)**** 2.08 (1.94-2.23)**** CO 3 (a-h) 22.91 11.41 2.01 (1.96-2.06)**** 1.97 (1.92-2.02)**** * p < 0.050; ** p < 0.010; *** p < 0.005; ****p < 0.001 AE: arterial embolism; CI: confidence interval 95%; CO1: effectiveness composite outcome 1; CO2: safety composite outcome 2; CO3: general composite outcome 3; HR: hazard ratio; IRR: incidence rate ratio; IS: ischaemic stroke; MI: myocardial infarction; NOAC: non-vitamin K antagonist oral anticoagulants; PSM: propensity score matched; TIA:transient ischaemic attack; VKA: vitamin-kantagonist Legend: The table lists results of the crude event rate analysis based on patient-specific follow-up periods. Results are reported as incidence rate ratios (IRRs) for events per 100 observed patient-years and unadjusted Hazard Ratios (HRs) for time to first event. 4
Table S3: IRRs for CO1 (efficacy) and CO2 (safety) for the comparison of event rates in PSM-matched patients who received specific NOAC agents versus VKA patients. The table shows the PSM-IRRs for Cohort 1 (NOAC) vs. Cohort 2 (VKA) separately for Dabigatran, Rivaroxaban and Apixaban. Events Dabigatran vs. VKA Rivaroxaban vs. VKA Apixaban vs. VKA CO 1 1.21 (1.12-1.31)**** 1.38 (1.32-1.45)**** 1.30 (1.10 1.54)**** CO 2 1.18 (0.97-1.44) 1.92 (1.71-2.17)**** 1.23 (0.76-1.97) Observed patients per group (Cohort 1/2) 9,832 25,269 2,338 Observed patient-years Cohort 1 (NOAC) 11,174 23,372 1,201 Observed patient-years Cohort 2 (VKA) * p < 0.050; ** p < 0.010; *** p < 0.005; ****p < 0.001 9,983 25,338 2,167 CI: confidence interval 95%; %; CO1: effectiveness composite outcome 1; CO2: safety composite outcome 2; IRR: Incidence rate ratio; NOAC: non-vitamin K antagonist oral anticoagulants; PSM: Propensity score matching; VKA: vitamin-k-antagonist 5
Table S4: PSM-adjusted IRRs in the two sensitivity analyses considering (a) therapy-naïve patients (Cohort 1a / 2a) and (b) end of follow up if a 30 days gap was observed (Cohort 1 / 2) Events Therapy-naïve patients Considering periods without treatment gaps > 30 days Incidence rate per 100 patient-years in Cohort 1a (NOAC) Incidence rate per 100 patient-years in Cohort 2a (VKA) NOAC vs. VKA CO 1 15.94 13.7 1.16 **** (1.09-1.24) CO 2 2.87 2.27 1.27**** (1.08-1.49) CO 3 18.82 15.99 1.18 **** (1.11-1.25) Incidence rate per 100 patient-years in Cohort 1 (NOAC) Incidence rate per 100 patient-years in Cohort 2 (VKA) NOAC vs. VKA 5.53 4.66 1.19**** (1.09-1.29) 3.45 2.60 1.33**** (1.19-1.49) 8.98 7.26 1.24**** (1.16-1.32) Observed patients per group (Cohort 1/2) Observed patient-years Cohort 1 (NOAC) Observed patient-years - Cohort 2 (VKA) 6,166 37,439 5,799 25,734 5,227 19,023 * p < 0.050; ** p < 0.010; *** p < 0.005; ****p < 0.001 CI: confidence interval 95%; %; CO1: effectiveness composite outcome 1; CO2: safety composite outcome 2; CO3: general composite outcome 3; IRR: Incidence rate ratio; NOAC: non-vitamin K antagonist oral anticoagulants; PSM: Propensity score matching; VKA: vitamin-k-antagonist 6
Supplemental Figures: Figure S1a: Results of the multivariable Cox Regression analysis addressing composite outcome 3, based on Cohorts 1 and 2 Figure Legend: Please note that all independent variables included in the regression estimates were based on the 12 months before index date, except the variable documented cancer diagnosis in observational period 7
Figure S1b: Results of the multivariable Cox Regression analysis addressing composite outcome 1 (effectiveness), based on Cohorts 1 and 2 Figure Legend: Please note that all independent variables included in the regression estimates were based on the 12 months before index date, except the variable documented cancer diagnosis in observational period 8
Figure S1c: Results of the multivariable Cox Regression analysis addressing composite outcome 2 (safety), based on Cohorts 1 and 2 Figure Legend: Please note that all independent variables included in the regression estimates were based on the 12 months before index date, except the variable documented cancer diagnosis in observational period. 9