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Patients with nephrotic syndrome possess an increased risk of venous and arterial thromboembolism due to complex changes in the levels of circulating clotting factors and natural anticoagulants, in addition to increased platelet activation. This increased risk of vascular events has been shown to correlate with the severity of hypoalbuminemia. Warfarin, low-molecular-weight heparin, and aspirin have been studied and used to prevent and treat vascular events in these patients, but little is known about the efficacy and safety of the newer direct oral anticoagulants (DOACs) in this setting. The purpose of this study was to use a large online medical database to compare outcomes of DOACS vs. warfarin in nephrotic syndrome patients.
The TriNetX research database was used for this study. Six cohorts of patients were created, consisting of two serum albumin ranges (≤2 g/dL and >2 g/dL) each for patients taking no anticoagulation, warfarin, or a DOAC. All patients had ≥3.5 g/dL protein on 24-hour urine, and medication use was identified by the medication codes for warfarin, apixaban, rivaroxaban, and dabigatran in the TriNetX system. Comparisons were made for (1) no anticoagulation with ≤2 g/dL albumin vs. >2 g/dL, (2) warfarin ≤2 g/dL vs. DOAC ≤2 g/dL, (3) warfarin >2 g/dL vs. DOAC >2 g/dL, (4) warfarin ≤2 g/dL vs. warfarin >2 g/dL, and (5) DOAC ≤2 g/dL vs. DOAC >2 g/dL. For each run, the cohorts were balanced for age, race, gender, ethnicity, diagnosed coagulation disorders, and renal function. They were then evaluated for the 12-month outcomes of venous thromboembolism (ICD-10 codes I26 and I82.40 for pulmonary embolism and deep venous thrombosis, respectively), arterial thromboembolism, (I63, I21, and I74 for cerebral infarction, myocardial infarction, and arterial embolism and thrombosis), and death.
Patients not receiving anticoagulation had an increased risk of venous and arterial events for albumin levels ≤ 2 g/dL compared to > 2 g/dL (Relative risk 2.4 for venous (P value 0.0006), 1.5 for arterial (P value 0.0005)), as expected. DOACS were found statistically non-inferior to warfarin at both albumin ranges but were associated with approximately 20% fewer arterial events in patients with serum albumin >2g/dL (2,875 patients per cohort). The warfarin group in this comparison was also associated with 25% greater mortality (RR 1.25, 95%CI (1.09,1.43), P value 0.0015). Interestingly, anticoagulated patients with severely low albumin (≤2g/dL) had fewer venous and arterial events than anticoagulated patients with higher albumin levels >2g/dL, although this did not achieve statistical significance.
This study found DOACs to be statistically non-inferior to warfarin for the prevention of thromboembolic events in nephrotic syndrome patients and associated with almost 20% fewer arterial events and improved survival in patients with albumin >2g/dL. Anticoagulated patients with severely low albumin had fewer events than those with higher albumin, although this was not statistically significant. Because DOACS and warfarin are highly albumin-bound, it is possible that more unbound and active medication is the reason for this. Such patients may be at increased risk of bleeding and further studies are needed to evaluate this.