Lower bleeding risk with NOACs vs VKA in low-risk AF patients
Effectiveness and Safety of Standard-Dose Non vitamin K Antagonist Oral Anticoagulants and Warfarin Among Patients With Atrial Fibrillation With a Single Stroke Risk Factor - A Nationwide Cohort Study
Background
Randomized clinical trials of NOACs for stroke prevention included mainly AF patients with 2 or more stroke risk factors, with the exception of dabigatran or apixaban studies, in which a few AF patients had only 1 stroke risk factor [1,2].
In this observational cohort study, the comparative effectiveness and safety of standard-dose NOACs (dabigatran at 150mg twice daily, rivaroxaban at 20mg once daily, and apixaban at 5 mg twice daily) compared with warfarin, was evaluated in 14 020 low-risk AF patients included in Danish nationwide databases.
Only patients who had not received OAC treatment within 1 year before entering the study, and with 1 non-gender-related stroke risk factor in the CHA2DS2-VASc score, were recruited. Patients younger than 75 years or with a history of a prior stroke, TIA, systemic embolism, venous thromboembolism, valvular AF, or with contraindications for standard NOAC dose regimens because of renal impairment were excluded from the study. The mean follow-up was 2.6 ± 1.6 years.
The main safety endpoint, defined as ‘any bleeding’ included traumatic and non-traumatic intracranial bleedings, as well as gastrointestinal and clinically relevant non-major bleedings.
Main results
- For the main effectiveness endpoint of ischemic stroke/systemic embolism, 103 events (80.5% as primary diagnoses) were observed within the first year, representing a rate between 0.65 and 1.20 per 100 person-years.
- The estimated effect sizes in terms of HRs of the NOACs ranged between 0.81 (95%CI: 0.49-1.34) and 1.46 (0.79-2.70), with all treatment groups displaying statistically non-significant differences compared with warfarin.
- There was a significantly lower risk of all-cause mortality across all treatment groups compared with warfarin, although effect sizes became non-significant when they were restricted to patients who were hospitalized with AF.
- When restricting the study population to patients without conditions associated with increased mortality (HF, chronic pulmonary disease, or cancer), all effect estimates were lower for NOAC agents compared with warfarin, while only treatment with rivaroxaban reached a statistically significant lower death rate (HR: 0.39; 95%CI: 0.17-0.91).
- A total of 157 any bleeding events (90% primary diagnoses) were observed during the first year. The weighted event rates ranged between 0.57 (apixaban) and 1.53 (warfarin).
- When compared with warfarin, apixaban and dabigatran were associated with lower rates of bleeding events (HR: 0.35; 95%CI: 0.17-0.72; and HR: 0.48; 95%CI: 0.30-0.77, respectively), whereas the comparison of rivaroxaban and warfarin was statistically non-significant (HR: 0.84; 95%CI: 0.49-1.44).
- Compared with warfarin, each NOAC exhibited a lower RR of intracranial bleeding with HRs ranging from 0.11 (95%CI: 0.01-0.78) to 0.53 (95%CI: 0.15-1.87).
- Falsification outcomes analyses on the associated treatment-exposure relationship indicated a possible persistent bias.
Conclusion
In a Danish observational cohort study, the risk of an ischemic stroke or systemic embolism was similar between NOACs compared with warfarin in AF patients with a single non-sex stroke CHA2DS2-VASc risk factor. Lower mortality rates were seen for all NOACs compared with warfarin, but this appeared to be the consequence of selective prescription patterns. The risk of any bleeding was lower for apixaban and dabigatran compared with warfarin.
These data should be interpreted with caution because of possible residual unmeasured confounding due to selective prescribing and unobserved comorbidities, or other factors known to influence treatment selection that were not present in the data set.
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