By Michael H. Crawford, MD
Professor of Medicine, Lucy Stern Chair in Cardiology, University of California, San Francisco
SYNOPSIS: A large nationwide health systems database study comparing 5 mg apixaban vs. 2.5 mg twice daily in patients with stage 4/5 chronic kidney disease not on dialysis shows that the 5 mg dose increases the risk of bleeding compared to 2.5 mg without any improvement in the risk of stroke, systemic emboli, or death.
SOURCE: Xu Y, Chang AR, Inker LA, et al. Associations of apixaban dose with safety and effectiveness outcomes in patients with atrial fibrillation and severe chronic kidney disease. Circulation 2023; Sep 8. doi: 10.1161/CIRCULATIONAHA.123.065614. [Online ahead of print].
Atrial fibrillation (AF) occurs in up to one-fifth of patients with chronic kidney disease (CKD). These patients have a higher risk of stroke or systemic emboli (SSE) and bleeding. However, most of the trials of direct-acting anticoagulants excluded patients with severe CKD. Thus, this retrospective cohort study from 40 health systems that are part of the Optum Labs Data Warehouse is of interest. Adults with AF and CKD stage 4/5 (estimated glomerular filtration rate [GFR] < 30) who were prescribed apixaban 2.5 mg or 5 mg twice per day from 2013 to 2021 were included. Excluded were patients with other indications for anticoagulation or who were on hemodialysis or had a kidney transplant. A propensity score matching model was used to account for the differences in baseline characteristics between those who got the two doses of apixaban.
The primary outcome for potential benefit was SSE hospitalization and the primary outcome for harm was bleeding-related hospitalization. Secondary outcomes included all-cause mortality, major bleeding, and cardiac death. Pneumonia and bone fractures were used as negative controls. The total population was 4,313 patients, of whom 40% were started on 5 mg and 60% were started on 2.5 mg of apixaban twice per day. The two dose cohorts differed in 17 of 48 covariates but were well matched after propensity weighting.
After the median follow-up of eight months, 4% of those taking 5 mg of apixaban experienced hospitalization for bleeding compared to 3% taking 2.5 mg (hazard ratio [HR] = 1.63; 95% confidence interval [CI], 1.04-2.54). SSE occurred in 2% of the 5-mg group and 3% of the 2.5-mg group (HR = 1.01; 95% CI, 0.59-1.73). Death occurred in 7% of the 5-mg group and in 11% of the 2.5-mg group (HR = 1.03; 95% CI, 0.77-1.38). There were no differences in the two apixaban doses in relation to pneumonia, bone fractures, or cardiac death. The authors concluded that in patients with AF and CKD, a 5 mg dose of apixaban was associated with a higher risk of bleeding compared to a 2.5 mg dose but had no differences in the risk of SSE or death.
COMMENTARY
This large study showed a 1.6 times greater risk of bleeding associated with 5 mg apixaban vs. 2.5 mg twice daily for patients with AF and non-dialysis-dependent CKD stage 4/5, but no differences in SSE or death. For many of those who received the 5 mg dose of apixaban, it was appropriate based on Food and Drug Administration (FDA) guidelines, which recommend a reduced dose if two or more of the following are present: age ≥ 80 years, weight ≤ 60 kg, or serum creatinine (Cr) ≥ 1.5 mg/dL. By contrast, the European Medicines Agency (EMA) recommends a lower dose if Cr is ≥ 2.5 mg/dL and Cr clearance (CrCl) is 15 mL/min to 29 mL/min. If CrCl is < 15 mL/min, anticoagulation is not recommended. Neither guideline has a recommendation regarding patients on dialysis who were excluded from the trials, but it is known that dialysis does remove some apixaban, so it has been suggested that the dose should be 5 mg.
The strengths of this study include the large geographically diverse population, the use of propensity matching to reduce confounding biases, and the null results of two negative control outcomes. Also, in no subgroup were the results different, including those based on age, weight, and HAS-BLED and CHA2DS2-VASc scores. There were limitations to the study. Medication use was by pharmacy records, not actual use. The follow-up period was short, and there were no data on out-of-hospital deaths. Although a randomized controlled trial would be ideal, the Xu study supports the EMA guidelines, which are based on kidney function alone rather than the more complicated FDA recommendations.
