The risk of stroke/systemic embolism and major bleeding in Asian patients with non-valvular atrial fibrillation treated with non-vitamin K oral anticoagulants compared to warfarin: Results from a real-world data analysis

Abstract

Background: Although randomized trials provide a high level of evidence regarding the efficacy of non-vitamin K oral anticoagulants (NOACs), the results of such trials may differ from those observed in day-to-day clinical practice.

Aims: To compare the risk of stroke/systemic embolism (S/SE) and major bleeding (MB) between NOAC and warfarin in clinical practice.

Methods: Patients with non-valvular atrial fibrillation (NVAF) who started warfarin/NOACs between January 2015 and November 2016 were retrospectively identified from Korea's nationwide health insurance claims database. Using inpatient diagnosis and imaging records, the Cox models with inverse probability of treatment weighting using propensity scores were used to estimate hazard ratios (HRs) for NOACs relative to warfarin.

Results: Of the 48,389 patients, 10,548, 11,414, 17,779 and 8,648 were administered apixaban, dabigatran, rivaroxaban and warfarin, respectively. Many patients had suffered prior strokes (36.7%, 37.7%, 31.4%, and 32.2% in apixaban, dabigatran, rivaroxaban, and warfarin group, respectively), exhibited high CHA2DS2-VASc (4.8, 4.6, 4.6, and 4.1 in apixaban, dabigatran, rivaroxaban, and warfarin group, respectively) and HAS-BLED (3.7, 3.6, 3.6, and 3.3 in apixaban, dabigatran, rivaroxaban, and warfarin group, respectively) scores, had received antiplatelet therapy (75.4%, 75.7%, 76.8%, and 70.1% in apixaban, dabigatran, rivaroxaban, and warfarin group, respectively), or were administered reduced doses of NOACs (49.8%, 52.9%, and 42.8% in apixaban, dabigatran, and rivaroxaban group, respectively). Apixaban, dabigatran and rivaroxaban showed a significantly lower S/SE risk [HR, 95% confidence intervals (CI): 0.62, 0.54-0.71; 0.60, 0.53-0.69; and 0.71, 0.56-0.88, respectively] than warfarin. Apixaban and dabigatran (HR, 95% CI: 0.58, 0.51-0.66 and 0.75, 0.60-0.95, respectively), but not rivaroxaban (HR, 95% CI: 0.84, 0.69-1.04), showed a significantly lower MB risk than warfarin.

Conclusions: Among Asian patients who were associated with higher bleeding risk, low adherence, and receiving reduced NOAC dose than that provided in randomised controlled trials, all NOACs were associated with a significantly lower S/SE risk and apixaban and dabigatran with a significantly lower MB risk than warfarin.

Fig 1. Cohort creation flowchart.

AF, atrial fibrillation; HCMP, hypertrophic cardiomyopathy; ICD-10, International Classification of Diseases 10^th Revision; NOAC, non-vitamin K antagonist oral anticoagulant; OAC, oral anticoagulant; VTE, venous thromboembolism. * Patients were required to have made at least one inpatient claim/two outpatient claims with a diagnosis of ICD-10 code I48 (atrial fibrillation and flutter) within 8.5 years prior to or on the index date. ** No OACs (apixaban/dabigatran/rivaroxaban/warfarin) should have been prescribed 1 year prior to the index date.

Fig 2. Crude cumulative incidence curves.

(A) stroke/systemic embolism, (B) major bleeding, (C) intracranial hemorrhage and (D) gastrointestinal bleeding.

Fig 3. Hazard ratios for stroke/systemic embolism, major bleeding, intracranial haemorrhage and gastrointestinal bleeding for non-vitamin K antagonist oral anticoagulants relative to warfarin.

NOACs, non-vitamin K antagonist oral anticoagulants. 1) Obtained using inverse probability of treatment weighting. The patient group treated with warfarin served as the reference. * Reported hazard ratio at 1 year since the proportional hazard assumption was violated.

Fig 4. Subgroup analyses for the comparisons of stroke/systemic embolism and major bleeding between the three non-vitamin K antagonist oral anticoagulants and warfarin.

(A) apixaban vs warfarin, (B) dabigatran vs warfarin, (C) rivaroxaban vs warfarin. CHA₂DS₂-VASc, score based on congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke, vascular disease, age 65–74 years and sex; CI, confidence interval; CKD, chronic kidney disease; HAS-BLED, score based on hypertension/abnormal renal and liver function/stroke/bleeding/labile international normalized ratio/elderly/drugs/alcohol; NOACs, non-vitamin K antagonist oral anticoagulants. The P value is for the interaction.