Nationwide Comparison of Oral Anticoagulants in Nonvalvular Atrial Fibrillation Patients of Low Body Weight

The first nationwide comparison of the effectiveness and safety of warfarin and direct oral anticoagulants (DOACs) in a large atrial fibrillation (AF) cohort with data on low body weight (LBW) was conducted.  The findings, published in JACC, showed that DOACs are associated with a reduced risk of ischemic stroke, intracranial hemorrhage, hospitalization for gastrointestinal or major bleeds, all-cause death or the composite outcome in patients with LBW (<60kg).  A consistent trend was observed in patients with extremely LBW (<50kg), with the exception of hospitalization for gastrointestinal bleeding.

 OACs are the most fundamental therapy for patients with AF because it prevents ischemic stroke and reduces mortality.  Warfarin has been used for decades as the only available OAC, but not used as much due to a narrow therapeutic range, frequent monitoring, and concerns about bleeding complications.  In comparison, the introduction of direct OACs has been proven to be convenient, safe and effective alternatives to warfarin.  The effects of OACs are closely related to plasma concentrations which are affected by body distribution volume; therefore, extremely low body weight may influence the efficacy and safety of OACs.  LBW is relatively common in Asian populations, and individuals frequently present with comorbidities such as old age, frailty and renal impairment which may increase the risk of thromboembolic and bleeding events.   However, no data is available for patients weighing <60kg or <50kg based on a large AF cohort that analyzed four DOACs.  Additionally, it’s unclear whether overall effectiveness and safety of DOACs are consistent in patients with LBW and nonvalvular AF.

This retrospective cohort study was conducted in South Korea, using data from the Korean National Health Insurance Services (NHIS) database from January 2014 to December 2016.  The trial enrolled 21,589 adult nonvalvular AF participants with body weight <60kg treated with either warfarin (n=7,576) or DOACs (n=14,013).  The study population was supplemented by stratified analysis according to the doses, regular and reduced, label adherence of DOAC dosing, and types of DOACs; Rivaroxaban, Dabigatran, Apixaban, Edoxaban.  The study outcome included six clinical outcomes to determine effectiveness and safety of warfarin and DOACs: ischemic stroke, intracranial hemorrhage, hospitalization for GI bleeding, hospitalization for major bleeding, all-cause death, and the composite outcome.  Trial results showcased that in comparison with warfarin use, DOACs were associated with lower risks of ischemic stroke (hazard ratio [HR]: 0.591; 95% confidence interval [CI]: 0.510 to 0.686), major bleeding (HR: 0.705; 95% CI 0.601 to 0.825), a greater reduction in intracranial hemorrhage (HR: 0.554; 95% CI: 0.429 to 0.713), and a lower risk of all-cause death (HR: 0.705; 95% CI: 0.630 to 0.789). DOAC use showed improved net clinical benefit compared with warfarin (HR for the composite outcome: 0.660; 95% CI: 0.606 to 0.717), and this was consistent in patients who weighed <50 kg (HR for the composite outcome: 0.665; 95% CI: 0.581 to 0.762).

 In this study where an LBW Asian population was the prime focus, the investigators established that DOACs showed better effectiveness and safety as compared to warfarin.  The results remained consistent in patients with extremely LBW.  Additionally, regular doses of DOACs showed comparable results to reduced doses of DOACs.  As per discussion, study limitations do exist.  First, the quality of warfarin treatment represented as time in the therapeutic range (TTR) was not evaluated.  The Korean NHIS claims the database and health checkup database did not include individual data on the International Normalized Ratio (INR) of prothrombin time.  Poor TTR control in Asian patients treated with warfarin has been consistently observed in previous studies.  Secondly, the study was based on the database of the entire Korean population; therefore ethnic uniformity of cohort studies should be considered when these results are interpreted.  Thirdly, patients with a history of intracranial hemorrhage, ischemic stroke or GI bleed were excluded from the study.  And lastly, although both study groups achieved well-balanced cohorts, the possibility of confounding variables from unmeasured factors still exists. Commenting on the study results and its generalizability, Dr. Freek W.A. Verheugt,  from the department of cardiology, Heartcenter, Amsterdam, the Netherlands stated, “In conclusion, as previously stated, dosing with oral anticoagulation is crucial, not only with warfarin, in which INR is used for analysis, but also with DOACs. Most dose reduction schemes are simple (dabigatran and rivaroxaban), but some are more complex (edoxaban) or very complex (apixaban). Although the criterion of body weight looks simple, additional characteristics of patients with AF (age, renal function, and concomitant medications) have to be taken into account for candidates to be eligible for dose reduction of DOACs. Although the current study is reassuring that DOACs can be used in AF patients with low to very low body weight, we must take into
account that the study results originate from a region where low body weight is common. Because of this characteristic, the results do not necessarily apply for such patients in the Western world.”