Table 2

Sensitivity analyses

Main analysis*Sensitivity analyses
90-day gap period†True OAC naive‡Standardised to 12-month follow-up§Intention to treat analysis¶
Standard dose NOACs vs warfarin
Stroke/SESubhazard ratio (95% CI)
 WarfarinRefRefRefRefRef
 Dabigatran0.80 (0.57 to 1.13)0.82 (0.58 to 1.15)0.80 (0.56 to 1.14)0.95 (0.62 to 1.43)0.81 (0.62 to 1.08)
 Rivaroxaban1.07 (0.89 to 1.30)1.08 (0.89 to 1.30)1.02 (0.84 to 1.25)1.02 (0.80 to 1.30)0.97 (0.83 to 1.14)
 Apixaban0.95 (0.78 to 1.15)0.95 (0.78 to 1.16)0.92 (0.75 to 1.22)1.00 (0.79 to 1.28)0.88 (0.74 to 1.04)
Major bleedingSubhazard ratio (95% CI)
 WarfarinRefRefRefRefRef
 Dabigatran0.75 (0.52 to 1.08)0.73 (0.51 to 1.05)0.77 (0.73 to 1.12)0.86 (0.53 to 1.39)0.67 (0.50 to 0.87)
 Rivaroxaban0.96 (0.78 to 1.16)0.95 (0.78 to 1.15)0.90 (0.58 to 0.90)0.88 (0.67 to 1.16)0.84 (0.72 to 0.99)
 Apixaban0.74 (0.60 to 0.91)0.70 (0.57 to 0.87)0.72 (0.58 to 0.90)0.66 (0.50 to 0.86)0.63 (0.53 to 0.75)
All-cause deathHR (95% CI)
 WarfarinRefRefRefRefRef
 Dabigatran0.77 (0.57 to 1.05)0.79 (0.54 to 0.91)0.75 (0.55 to 1.02)0.76 (0.49 to 1.20)0.66 (0.55 to 0.79)
 Rivaroxaban1.12 (0.97 to 1.28)0.90 (0.80 to 1.02)1.06 (0.91 to 1.23)0.96 (0.78 to 1.18)0.84 (0.77 to 0.92)
 Apixaban0.99 (0.85 to 1.15)0.79 (0.70 to 0.91)0.93 (0.79 to 1.08)0.84 (0.69 to 1.03)0.72 (0.65 to 0.80)
Reduced dose NOACs vs warfarin
Stroke/SESubhazard ratio (95% CI)
 WarfarinRefRefRefRefRef
 Dabigatran0.87 (0.70 to 1.07)0.86 (0.70 to 1.06)0.83 (0.66 to 1.03)0.91 (0.70 to 1.18)0.87 (0.74 to 1.03)
 Rivaroxaban1.05 (0.85 to 1.30)1.08 (0.87 to 1.33)1.06 (0.85 to 1.32)1.19 (0.92 to 1.54)1.06 (0.89 to 1.26)
 Apixaban1.12 (0.92 to 1.38)1.15 (0.94 to 1.41)1.10 (0.89 to 1.35)1.15 (0.90 to 1.47)1.00 (0.84 to 1.18)
Major bleedingSubhazard ratio (95% CI)
 WarfarinRefRefRefRefRef
 Dabigatran0.85 (0.69 to 1.05)0.83 (0.68 to 1.03)0.86 (0.68 to 1.07)0.86 (0.65 to 1.14)0.87 (0.74 to 1.01)
 Rivaroxaban1.15 (0.95 to 1.40)1.14 (0.94 to 1.38)1.16 (0.94 to 1.42)1.15 (0.89 to 1.48)0.95 (0.81 to 1.12)
 Apixaban0.78 (0.64 to 0.96)0.79 (0.65 to 0.96)0.81 (0.66 to 1.00)0.77 (0.60 to 0.99)0.67 (0.57 to 0.80)
All-cause deathHR (95% CI)
 WarfarinRefRefRefRefRef
 Dabigatran1.11 (0.97 to 1.27)0.89 (0.79 to 1.00)1.05 (0.91 to 1.21)1.08 (0.89 to 1.30)0.89 (0.82 to 0.96)
 Rivaroxaban1.42 (1.25 to 1.61)1.14 (1.02 to 1.27)1.35 (1.18 to 1.54)1.14 (0.95 to 1.36)0.98 (0.91 to 1.07)
 Apixaban1.38 (1.22 to 1.56)1.09 (0.99 to 1.22)1.34 (1.18 to 1.51)1.24 (1.06 to 1.44)0.96 (0.89 to 1.04)
  • *Multivariate competing risk regression, adjusted for NOAC dose, gender, age, year of inclusion into the study, chronic kidney disease, hypertension, diabetes, ischaemic heart disease, peripheral artery disease, heart failure, dementia, thyroid disorders, active cancer (cancer diagnosis last 12 months), chronic lower respiratory tract disease, history of stroke/SE, history of bleeding-related hospitalisation, history of anaemia, use of cholesterol lowering drugs, use of antiplatelet drugs and use of NSAIDs during the last 12 months, treating death as a competing risk.2

  • †Analyses of the risk of stroke/SE and major bleeding among users of different OACs, allowing a longer gap period of 90 days between the calculated end of OAC supply and a new prescription dispensing before censoring.

  • ‡Analyses of the risk of stroke/SE and major bleeding among users of different OACs, excluding patients with a dispensing of any anticoagulant from pharmacies during the last 5 years (12 months was used in the main analyses).

  • §Analyses of the risk of stroke/SE and major bleeding restricting follow-up time for all OACs to 12 months.

  • ¶An ‘intention-to-treat’-like analysis: investigating risk of stroke/SE and major bleeding without censoring by treatment switch or discontinuation of NOACs.

  • NOACs, non-vitamin K antagonist oral anticoagulants; NSAIDs, non-steroidal anti-inflammatory drugs; OACs, oral anticoagulants; SE, systemic embolism.