Condition Congestive heart failure I11.0; I13.0; I13.2; I42.0; I50 CO3C Left ventricular dysfunction I50.1; I50.9 E11 1; E11 9

Transcription

1 Comparative effectiveness and safety of non-vitamin K antagonists oral anticoagulants (OACs) and warfarin in daily clinical practice: A propensity weighted nationwide cohort study. Supplementary material Torben Bjerregaard Larsen, MD, PhD 1,2, Flemming Skjøth, MSc, PhD 2,3, Peter Brønnum ielsen, MSc, PhD 1,2, Jette Kjældgaard ordstrøm, MSc 2, Gregory Y.H. Lip, MD 2,4 Supplementary Table 1 Definitions on comorbidity and concomitant medication according to ICD-10 codes and ATC-codes. Conditions marked with was used in the calculation of the CHA 2 DS 2 -VASc score. Conditions marked with # was used in the calculation of the HAS-BLED score. International Classification of Diseases 10th revision (ICD-10) code Anatomical Therapeutic Chemical (ATC) code Condition Congestive heart failure I11.0; I13.0; I13.2; I42.0; I50 CO3C Left ventricular dysfunction I50.1; I50.9 #Hypertension See specified definition* Diabetes mellitus E10.0; E10.1; E10 9; E11 0; A10 E11 1; E11 9 #Ischemic stroke I63; I64 Systemic embolism I74 #Transient ischemic disease G45 Aortic plaque I70 0 Peripheral arterial disease I70 2-I70 9; I71; I73 9 Myocardial infarction I21-I23 #Moderate/severe renal disease I12 I Q61 #Moderate/Severe liver disease B150 B160 B162 B190 K704 K72 K766 I85 Cancer C Chronic pulmonary disorder J44 Mitral stenosis I05 Mechanical heart valve Z952 Z953 Z954 #Haemorrhagic stroke intercranial I60 I61 I62 bleeding #Extracranial or unclassified major bleeding D62 J942 H113 H356 H R04 R31 R58 #Gastrointestinal bleeding K250 K260 K270 K280 K290 #Traumatic intercranial bleeding S063C S064 S065 S066 #Alcohol E224 E529A F10 G312 G621 G721 I426 K292 K70 K860 L278A O354 T51 Z714 Z721 Pulmonary embolism I26 Deep venous thromboembolism I801 I802 I803 I808 I809 I819

2 I636 I676 I822 I823 I829 Atrial fibrillation I48 Medication B01AF02 B01AE07 B01AF01 B01AA03 Phenprocoumon B01AA04 #Aspirin B01AC06 #Clopidogrel B01AC04 Beta-blockers C07 Statins C10 #on Steroidal Anti Inflammatory Drugs M01A * We identified subjects with hypertension from combination treatment with at least two of the following classes of antihypertensive drugs: I Alpha adrenergic blockers (C02A, C02B, C02C) II on-loop diuretics (C02DA, C02L, C03A, C03B, C03D, C03E, C03X, C07C, C07D, C08G, C09BA, C09DA, C09XA52) III Vasodilators (C02DB, C02DD, C02DG, C04, C05) IV Beta blockers (C07) V Calcium channel blockers (C07F, C08, C09BB, C09DB) VI Renin-angiotensin system inhibitors (C09)

3 Supplementary table 2. Risk score definitions Risk score CHA 2 DS 2 VASc a Points if present Congestive heart failure or Left Ventricular Dysfunction 1 Hypertension 1 Age 65 years 1 Age 75 years 1 Diabetes mellitus 1 Stroke (ischemic stroke, transient ischemic disease or systemic embolism) 2 Vascular disease (myocardial infarction, peripheral arterial disease, or aortic 1 plaque) Sex category (female) 1 HAS-BLED b Hypertension 1 Abnormal renal function 1 Abnormal hepatic function 1 Stroke (ischemic stroke or transient ischemic attack) 1 Bleeding 1 Labile international normalized ratio c 1 Elderly age ( 65 years) 1 Drugs (aspirin, clopidogrel, or non-steroidal anti-inflammatory drugs) 1 Alcohol intake 1 a Reflects stroke risk in atrial fibrillation patients not in anticoagulant therapy (Lip GYH, ieuwlaat R, Pisters R, Lane DA, Crijns HJGM. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest 2010;137(2):263-72) b Reflects bleeding risk in atrial fibrillation patients undergoing anticoagulant therapy (Pisters R, Lane DA, ieuwlaat R, de Vos CB, Crijns HJGM, Lip GYH. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010;138(5): ) c ot included due to unavailable information

4 Supplementary Table 3 Odds ratio (OR) for choosing treatment vs any of three alternatives. Highly significant predictors, with OR>1.1 or OR<0.9 are boldfaced and discussed in text. Below one indicate favour for any alternative; above one indicate favour for treatment. Age, 5 years increase* 1.04 ( ) 0.85 ( ) 1.07 ( ) 1.08 ( ) Female sex 1.00 ( ) 0.73 ( ) 1.17 ( ) 1.15 ( ) Prior AF diagnose 1.68 ( ) 1.91 ( ) 1.11 ( ) 0.52 ( ) Cancer 1.05 ( ) 0.68 ( ) 1.06 ( ) 1.22 ( ) Ischemic stroke/se/tia 1.55 ( ) 0.80 ( ) 1.13 ( ) 0.91 ( ) Heart failure or LVD 0.92 ( ) 0.75 ( ) 0.73 ( ) 1.41 ( ) Vascular disease 0.88 ( ) 0.58 ( ) 0.74 ( ) 1.66 ( ) Renal dysfunction 0.50 ( ) 0.20 ( ) 0.36 ( ) 4.25 ( ) COPD 1.02 ( ) 0.64 ( ) 1.01 ( ) 1.30 ( ) Prior Bleeding 1.25 ( ) 0.79 ( ) 1.12 ( ) 1.01 ( ) Hypertension 0.97 ( ) 0.88 ( ) 0.96 ( ) 1.12 ( ) Diabetes 1.06 ( ) 0.88 ( ) 0.91 ( ) 1.10 ( ) Aspirin 0.89 ( ) 0.89 ( ) 0.90 ( ) 1.18 ( ) Beta Blocker 0.92 ( ) 0.99 ( ) 0.94 ( ) 1.07 ( ) SAIDs 0.91 ( ) 1.04 ( ) 0.89 ( ) 1.06 ( ) Statins 1.05 ( ) 0.92 ( ) 0.95 ( ) 1.06 ( ) *Linear effect. SE: Systemic embolism; TIA: Transient ischemic attack; COPD: Compulsive obstructive pulmonary disease; LVD: Left ventricular dysfunction; SAID's: non-steroidal anti-inflammatory drugs.

5 Supplementary Figure 1. Flowchart of patients excluded from study material. Patients with first time prescription of apixaban, dabigatran, rivaroxaban or warfarin in the period August 1, 2011 to ovember 30, ,945 38,259 19,914 50,950 Total 122,068 Reduced dose 2.5 mg 5, mg 22, mg 7, Total 35,035 Valvular AF Prior DVT Prior PE OAC within 1 year , ,150 1,282 1,299 1,421 8,510 5, Total 1,909 11,534 7,159 4,753 Final study population 6,349 12,701 7,192 35,436 Total 61,678

6 umber of new starters pr month Supplementary Figure 2. Time trends of number of treatment naive patients initiated on anticoagulation, since introduction of dabigatran. 01jul jul jul jul jul2015 month

7 Supplementary Figure 3a. Crude cumulative incidence curves of stroke endpoints according to current treatment. Crude failure curves Ischemic stroke/se Ischemic stroke/se Weighted failure curves Ischemic stroke Ischemic stroke Supplementary Figure 3b. Crude cumulative incidence curves of bleeding endpoints according to current treatment. Crude failure curves Any bleeding Any bleeding Weighted failure curves Major bleeding Major bleeding Intracranial bleeding Intracranial bleeding

8 Supplementary Figure 3c. Crude cumulative incidence curves of all-cause death and combined endpoint ischemic stroke/se or all-cause death according to current treatment. Crude failure curves All-cause death All-cause death Weighted failure curves Ischemic stroke/se/all-cause Ischemic death stroke/se/all-cause death

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10 Supplementary Figure 4a. Propensity weighted (IPTW) Cox hazard ratios for 2.5 years follow-up (intension to treat) for OACs compared to warfarin for stroke and death endpoints. Strata / Treatment Ischemic stroke/se Ischemic stroke Death Ischemic stroke/se/death Entire AF cohort (Main analysis) 1.01 ( ) 1.03 ( ) 0.67 ( ) 0.78 ( ) 1.01 ( ) 1.06 ( ) 0.65 ( ) 0.76 ( ) 0.80 ( ) 0.84 ( ) 0.96 ( ) 0.90 ( ) AF hospitalised cohort (Sensitivity analysis) 0.96 ( ) 0.99 ( ) 0.69 ( ) 0.78 ( ) 0.89 ( ) 0.90 ( ) 0.68 ( ) 0.74 ( ) 0.85 ( ) 0.87 ( ) 0.92 ( ) 0.89 ( ) Age<65yr (Supplementary analysis) 1.04 ( ) 1.00 ( ) 0.53 ( ) 0.77 ( ) 0.94 ( ) 1.02 ( ) 0.64 ( ) 0.77 ( ) 0.84 ( ) 0.93 ( ) 1.01 ( ) 0.93 ( ) Age>=65yr (Supplementary analysis) 1.00 ( ) 1.04 ( ) 0.67 ( ) 0.77 ( ) 1.02 ( ) 1.07 ( ) 0.64 ( ) 0.74 ( ) 0.78 ( ) 0.81 ( ) 0.93 ( ) 0.87 ( ) Primary stroke protection (Supplementary analysis) 0.93 ( ) 1.00 ( ) 0.64 ( ) 0.70 ( ) 1.00 ( ) 1.05 ( ) 0.65 ( ) 0.71 ( ) 0.79 ( ) 0.83 ( ) 0.90 ( ) 0.88 ( ) Secondary stroke protection (Supplementary analysis) 1.02 ( ) 1.04 ( ) 0.73 ( ) 0.90 ( ) 0.95 ( ) 0.99 ( ) 0.55 ( ) 0.78 ( ) 0.79 ( ) 0.82 ( ) 1.12 ( ) 0.90 ( ) 10

11 Supplementary Figure 4b. Propensity weighted (IPTW) Cox hazard ratios for 2.5 years follow-up (intension to treat) for OACs compared to warfarin for bleeding endpoints. Strata / Treatment Any bleeding Major bleeding Intracranial bleeding Entire AF cohort (Main analysis) 0.64 ( ) 0.63 ( ) 0.83 ( ) 0.68 ( ) 0.68 ( ) 0.39 ( ) 0.98 ( ) 1.03 ( ) 0.66 ( ) AF hospitalised cohort (Sensitivity analysis) 0.68 ( ) 0.66 ( ) 0.87 ( ) 0.69 ( ) 0.70 ( ) 0.38 ( ) 0.96 ( ) 0.99 ( ) 0.71 ( ) Age<65yr (Supplementary analysis) 0.39 ( ) 0.36 ( ) 0.71 ( ) 0.64 ( ) 0.57 ( ) 0.89 ( ) 0.77 ( ) 0.73 ( ) 0.43 ( ) Age>=65yr (Supplementary analysis) 0.69 ( ) 0.69 ( ) 0.85 ( ) 0.68 ( ) 0.69 ( ) 0.31 ( ) 1.01 ( ) 1.09 ( ) 0.69 ( ) Primary stroke protection (Supplementary analysis) 0.61 ( ) 0.59 ( ) 0.78 ( ) 0.69 ( ) 0.67 ( ) 0.43 ( ) 0.98 ( ) 1.03 ( ) 0.58 ( ) Secondary stroke protection (Supplementary analysis) 0.74 ( ) 0.77 ( ) 0.62 ( ) 0.69 ( ) 0.63 ( ) 0.28 ( ) 0.97 ( ) 1.06 ( ) 0.77 ( )

12 Supplementary Figure 5a. Sensitivity analyses. Cox hazard ratios for 1 year follow-up (intension to treat) for OACs compared to warfarin for main stroke, bleeding and death endpoints. Four analysis methods and 2 cohort definitions are contrasted. Approach / Treatment Ischemic stroke/se Any bleeding Death Crude, entire AF cohort 1.33 ( ) 0.65 ( ) 0.59 ( ) 0.87 ( ) 0.54 ( ) 0.32 ( ) 0.87 ( ) 0.97 ( ) 0.88 ( ) Adjusted, entire AF cohort 1.10 ( ) 0.66 ( ) 0.67 ( ) 1.01 ( ) 0.67 ( ) 0.55 ( ) 0.79 ( ) 1.02 ( ) 0.94 ( ) IPTW, entire AF cohort (Main analysis) 1.08 ( ) 0.63 ( ) 0.65 ( ) 1.17 ( ) 0.61 ( ) 0.63 ( ) 0.83 ( ) 0.99 ( ) 0.92 ( ) SMR, entire AF cohort 1.11 ( ) 0.69 ( ) 0.68 ( ) 1.07 ( ) 0.70 ( ) 0.59 ( ) 0.88 ( ) 1.00 ( ) 0.94 ( ) Crude, AF hospitalised cohort 1.17 ( ) 0.65 ( ) 0.58 ( ) 0.78 ( ) 0.51 ( ) 0.27 ( ) 0.84 ( ) 0.97 ( ) 0.82 ( ) Adjusted, AF hospitalised cohort 1.02 ( ) 0.72 ( ) 0.74 ( ) 0.97 ( ) 0.69 ( ) 0.58 ( ) 0.76 ( ) 1.06 ( ) 0.94 ( ) IPTW, AF hospitalised cohort 1.03 ( ) 0.68 ( ) 0.67 ( ) 1.00 ( ) 0.61 ( ) 0.69 ( ) 0.86 ( ) 1.01 ( ) 0.88 ( ) SMR, AF hospitalised cohort 1.01 ( ) 0.81 ( ) 0.70 ( ) 0.99 ( ) 0.73 ( ) 0.61 ( ) 0.92 ( ) 1.07 ( ) 0.93 ( ) 12

13 Supplementary Figure 5b. Sensitivity analyses. Cox hazard ratios for 2.5 years follow-up (intension to treat) for OACs compared to warfarin for main stroke, bleeding and death endpoints. Four analysis methods and 2 cohort definitions are contrasted. Approach / Treatment Ischemic stroke/se Any bleeding Death Crude, entire AF cohort 1.27 ( ) 0.66 ( ) 0.59 ( ) 0.79 ( ) 0.59 ( ) 0.34 ( ) 0.85 ( ) 0.97 ( ) 0.88 ( ) Adjusted, entire AF cohort 1.07 ( ) 0.66 ( ) 0.67 ( ) 0.94 ( ) 0.71 ( ) 0.60 ( ) 0.78 ( ) 0.99 ( ) 0.94 ( ) IPTW, entire AF cohort (Main analysis) 1.01 ( ) 0.64 ( ) 0.67 ( ) 1.01 ( ) 0.68 ( ) 0.65 ( ) 0.80 ( ) 0.98 ( ) 0.96 ( ) SMR, entire AF cohort 1.05 ( ) 0.66 ( ) 0.68 ( ) 0.97 ( ) 0.72 ( ) 0.62 ( ) 0.86 ( ) 1.01 ( ) 0.95 ( ) Crude, AF hospitalised cohort 1.11 ( ) 0.66 ( ) 0.58 ( ) 0.72 ( ) 0.55 ( ) 0.30 ( ) 0.85 ( ) 0.94 ( ) 0.83 ( ) Adjusted, AF hospitalised cohort 0.99 ( ) 0.70 ( ) 0.73 ( ) 0.93 ( ) 0.72 ( ) 0.63 ( ) 0.77 ( ) 0.99 ( ) 0.94 ( ) IPTW, AF hospitalised cohort 0.96 ( ) 0.68 ( ) 0.69 ( ) 0.89 ( ) 0.69 ( ) 0.68 ( ) 0.85 ( ) 0.96 ( ) 0.92 ( ) SMR, AF hospitalised cohort 0.97 ( ) 0.76 ( ) 0.71 ( ) 0.93 ( ) 0.76 ( ) 0.65 ( ) 0.90 ( ) 1.03 ( ) 0.91 ( ) 13

14 Supplementary Figure 6a. Propensity weighted (IPTW) Cox hazard ratios for 1 years follow-up (continuous treatment) for OACs compared to warfarin for stroke and death endpoints. Strata / Treatment Ischemic stroke/se Ischemic stroke Death Ischemic stroke/se/death Entire AF cohort (Main analysis) 1.08 ( ) 1.11 ( ) 0.67 ( ) 0.81 ( ) 1.14 ( ) 1.22 ( ) 0.59 ( ) 0.75 ( ) 0.78 ( ) 0.82 ( ) 0.96 ( ) 0.88 ( ) AF hospitalised cohort (Sensitivity analysis) 1.03 ( ) 1.06 ( ) 0.71 ( ) 0.82 ( ) 1.00 ( ) 1.02 ( ) 0.65 ( ) 0.73 ( ) 0.83 ( ) 0.84 ( ) 0.91 ( ) 0.87 ( ) Age<65yr (Supplementary analysis) 1.05 ( ) 1.01 ( ) 0.46 ( ) 0.74 ( ) 1.02 ( ) 1.17 ( ) 0.59 ( ) 0.80 ( ) 0.77 ( ) 0.87 ( ) 0.82 ( ) 0.75 ( ) Age>=65yr (Supplementary analysis) 1.09 ( ) 1.14 ( ) 0.69 ( ) 0.81 ( ) 1.17 ( ) 1.23 ( ) 0.58 ( ) 0.73 ( ) 0.77 ( ) 0.80 ( ) 0.96 ( ) 0.89 ( ) Primary stroke protection (Supplementary analysis) 1.03 ( ) 1.12 ( ) 0.64 ( ) 0.71 ( ) 1.25 ( ) 1.35 ( ) 0.56 ( ) 0.65 ( ) 0.81 ( ) 0.85 ( ) 0.86 ( ) 0.85 ( ) Secondary stroke protection (Supplementary analysis) 1.07 ( ) 1.10 ( ) 0.75 ( ) 0.96 ( ) 1.00 ( ) 1.06 ( ) 0.61 ( ) 0.86 ( ) 0.76 ( ) 0.79 ( ) 1.26 ( ) 0.91 ( ) 14

15 Supplementary Figure 6b. Propensity weighted (IPTW) Cox hazard ratios for 1 years follow-up (continuous treatment) for OACs compared to warfarin for bleeding endpoints. Strata / Treatment Any bleeding Major bleeding Intracranial bleeding Entire AF cohort (Main analysis) 0.62 ( ) 0.60 ( ) 0.71 ( ) 0.56 ( ) 0.52 ( ) 0.30 ( ) 1.02 ( ) 1.09 ( ) 0.56 ( ) AF hospitalised cohort (Sensitivity analysis) 0.64 ( ) 0.62 ( ) 0.75 ( ) 0.56 ( ) 0.55 ( ) 0.30 ( ) 1.07 ( ) 1.14 ( ) 0.61 ( ) Age<65yr (Supplementary analysis) 0.42 ( ) 0.37 ( ) 0.73 ( ) 0.51 ( ) 0.41 ( ) 0.60 ( ) 0.72 ( ) 0.67 ( ) 0.16 ( ) Age>=65yr (Supplementary analysis) 0.66 ( ) 0.65 ( ) 0.70 ( ) 0.56 ( ) 0.52 ( ) 0.24 ( ) 1.07 ( ) 1.19 ( ) 0.59 ( ) Primary stroke protection (Supplementary analysis) 0.59 ( ) 0.56 ( ) 0.69 ( ) 0.58 ( ) 0.52 ( ) 0.30 ( ) 1.06 ( ) 1.13 ( ) 0.55 ( ) Secondary stroke protection (Supplementary analysis) 0.72 ( ) 0.74 ( ) 0.50 ( ) 0.66 ( ) 0.50 ( ) 0.27 ( ) 0.95 ( ) 1.04 ( ) 0.52 ( )

16 Supplementary Figure 7a. Propensity weighted (IPTW) Cox hazard ratios for 2.5 years follow-up (continuous treatment) for OACs compared to warfarin for stroke and death endpoints. Strata / Treatment Ischemic stroke/se Ischemic stroke Death Ischemic stroke/se/death Entire AF cohort (Main analysis) 1.03 ( ) 1.06 ( ) 0.69 ( ) 0.80 ( ) 1.04 ( ) 1.10 ( ) 0.58 ( ) 0.71 ( ) 0.77 ( ) 0.81 ( ) 0.98 ( ) 0.90 ( ) AF hospitalised cohort (Sensitivity analysis) 0.99 ( ) 1.02 ( ) 0.72 ( ) 0.81 ( ) 0.93 ( ) 0.95 ( ) 0.61 ( ) 0.69 ( ) 0.83 ( ) 0.85 ( ) 0.95 ( ) 0.89 ( ) Age<65yr (Supplementary analysis) 1.06 ( ) 1.01 ( ) 0.56 ( ) 0.79 ( ) 0.99 ( ) 1.09 ( ) 0.62 ( ) 0.79 ( ) 0.84 ( ) 0.93 ( ) 0.97 ( ) 0.89 ( ) Age>=65yr (Supplementary analysis) 1.03 ( ) 1.08 ( ) 0.69 ( ) 0.79 ( ) 1.04 ( ) 1.09 ( ) 0.55 ( ) 0.68 ( ) 0.74 ( ) 0.76 ( ) 0.95 ( ) 0.87 ( ) Primary stroke protection (Supplementary analysis) 0.94 ( ) 1.01 ( ) 0.65 ( ) 0.71 ( ) 1.05 ( ) 1.11 ( ) 0.59 ( ) 0.66 ( ) 0.76 ( ) 0.80 ( ) 0.90 ( ) 0.88 ( ) Secondary stroke protection (Supplementary analysis) 1.05 ( ) 1.07 ( ) 0.73 ( ) 0.92 ( ) 0.98 ( ) 1.03 ( ) 0.51 ( ) 0.78 ( ) 0.75 ( ) 0.79 ( ) 1.17 ( ) 0.89 ( ) 16

17 Supplementary Figure 7b. Propensity weighted (IPTW) Cox hazard ratios for 2.5 years follow-up (continuous treatment) for OACs compared to warfarin for bleeding endpoints. Strata / Treatment Any bleeding Major bleeding Intracranial bleeding Entire AF cohort (Main analysis) 0.61 ( ) 0.60 ( ) 0.81 ( ) 0.58 ( ) 0.58 ( ) 0.28 ( ) 1.00 ( ) 1.06 ( ) 0.67 ( ) AF hospitalised cohort (Sensitivity analysis) 0.62 ( ) 0.62 ( ) 0.79 ( ) 0.56 ( ) 0.58 ( ) 0.29 ( ) 1.00 ( ) 1.05 ( ) 0.70 ( ) Age<65yr (Supplementary analysis) 0.40 ( ) 0.36 ( ) 0.74 ( ) 0.52 ( ) 0.46 ( ) 0.58 ( ) 0.81 ( ) 0.77 ( ) 0.45 ( ) Age>=65yr (Supplementary analysis) 0.65 ( ) 0.65 ( ) 0.81 ( ) 0.57 ( ) 0.58 ( ) 0.24 ( ) 1.03 ( ) 1.12 ( ) 0.68 ( ) Primary stroke protection (Supplementary analysis) 0.58 ( ) 0.58 ( ) 0.74 ( ) 0.59 ( ) 0.58 ( ) 0.27 ( ) 1.01 ( ) 1.07 ( ) 0.57 ( ) Secondary stroke protection (Supplementary analysis) 0.70 ( ) 0.73 ( ) 0.67 ( ) 0.63 ( ) 0.54 ( ) 0.29 ( ) 1.00 ( ) 1.08 ( ) 0.85 ( )

18 18