Comparative Stroke, Bleeding, and Mortality

ARTICLE IN PRESS ( Supplementary Table 8 , available online) were consistent with the HR estimates. Rivaroxaban was associated with 8.6 and 20.9 excess cases of major extracranial bleeding, and 2.3 and 2.8 excess deaths per 1000 person-years of use compared with dabiga- tran or apixaban, respectively ( Supplementary Table 8 ) . The adjusted 30-day case fatality rates across all study drugs combined were 11.1% (thromboembolic stroke), 32.6% (intracranial hemorrhage), and 4.2% (major extra- cranial bleeding). There were no clinically meaningful differences in HRs across subgroups except that the risk of major extracranial bleeding in dabigatran users was reduced in 65- to 74-year- olds but increased in patients 75 years or older, compared with warfarin ( P interaction < .001) ( Supplementary Figure 1 , available online). Sensitivity analyses were generally con- sistent with the primary analysis ( Supplementary Figure 2 , available online). The point estimate for thromboembolic stroke for dabigatran compared with apixaban increased slightly and became statistically significant in the 14-day gap analysis (HR 1.23; 95% CI, 1.05-1.45), but the CIs largely overlapped the main analysis. In the analysis restricted to the period since apixaban’s approval, intracra- nial hemorrhage risk with dabigatran was no longer signifi- cantly reduced compared with apixaban (HR 0.92; 95% CI, 0.63-1.32). Post hoc analyses were generally consistent with the primary analysis ( Supplementary Figure 3 , avail- able online), except that some comparisons for intracranial Table ( Continued ) Characteristic, % Warfarin (n = 183,318) Dabigatran (n = 86,198) Rivaroxaban (n = 106,389) Apixaban (n = 73,039) Maximum Pairwise SM D * NSAIDs 13.0 14.0 14.3 13.9 0.04 Proton pump inhibitors 26.8 25.6 26.6 29.0 0.08 SSRI antidepressants 12.9 12.7 12.5 13.3 0.02 Cardiovascular ACEI/ARB 58.8 58.6 58.1 60.2 0.04 Antiarrhythmics 15.2 16.8 16.7 17.7 0.07 Anticoagulants (injectable) 9.1 6.9 9.0 9.9 0.11 Antiplatelets 14.2 14.3 13.9 15.6 0.05 Beta-blockers 67.6 66.3 67.2 69.9 0.08 Calcium channel blockers 41.8 41.8 41.6 42.1 0.01 Digoxin 13.1 14.8 10.6 8.9 0.18 Diuretics Loop 26.7 24.8 21.8 25.1 0.11 Potassium sparing 8.5 8.3 7.5 8.2 0.04 Thiazide 28.1 28.8 28.4 28.8 0.02 Nitrates 10.0 9.3 8.5 9.7 0.05 Statins 58.3 57.3 57.6 60.8 0.07 Fibrates 4.6 4.6 4.1 4.6 0.03 Diabetes-related Insulin 7.1 6.3 6.0 7.4 0.06 Metformin 15.0 14.8 15.1 15.7 0.02 Sulfonylureas 9.1 9.1 8.0 8.4 0.04 Other 5.9 6.2 5.6 6.2 0.03 Metabolic inhibitors x Amiodarone 9.6 9.0 9.2 9.6 0.02 Dronedarone 2.7 4.5 3.2 3.2 0.09 Prescriber specialty Cardiology 49.5 52.8 54.7 59.1 0.19 Family medicine 9.9 9.9 8.2 6.2 0.14 Internal medicine 22.0 19.7 20.0 17.2 0.12 Other 18.7 17.5 17.0 17.5 0.04 ACEI/ARB = angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker; NSAID = nonsteroidal antiinflammatory drug; SSRI = selective sero- tonin reuptake inhibitor. *SMD = Standardized mean difference. The maximum SMD among all pairwise comparisons is shown for each covariate prior to inverse probability of treatment weighting. y The CHA 2 DS 2 -VASc score assigns points for the presence of Congestive heart failure, Hypertension, Age 65-74 years and age ≥ 75 years, Diabetes melli- tus, Stroke or transient ischemic attack, Vascular disease, and female sex . 13 z The HAS-BLED score assigns points for the presence of Hypertension, Abnormal renal or liver function, Stroke, Bleeding history, Labile international normalized ratio (INR), age ≥ 65 years, and antiplatelet Drug or alcohol use . 14 Labile INR was not included in our estimation of the HAS-BLED score because INR laboratory results were not available in Medicare claims data. x Day’s supply of use overlapped with the date of first prescription for dabigatran or rivaroxaban. Graham et al Comparative Safety and Effectiveness of Anticoagulants in Atrial Fibrillation 5