Apixaban in Primary Membranous Nephropathy - Report from the iTANGIBLE Registry

Dear Editor,

Patients with glomerular disease, particularly with membranous nephropathy (MN), have an elevated risk for venous thromboembolism (VTE), especially when their serum albumin levels are <2.8 g/dL.^1,2 Using Vitamin K antagonists (VKAs) in nephrotic syndrome is challenging, primarily due to urinary drug losses that necessitate frequent dose adjustments to achieve target international normalized ratio (INR) levels.³ This often leads to multiple clinic visits, which may be impractical in resource-limited settings where patients must travel long distances for treatment. Consequently, patients may use VKAs without adequate monitoring, increasing the risk of bleeding due to prolonged INR values. Newer non-vitamin K oral anticoagulants (NOACs) require limited monitoring.⁴ However, the effectiveness and safety of NOACs for primary prophylaxis remain uncertain. Given that glomerular diseases are rare and thrombosis has relatively low incidence, evidence from a well-powered randomized trial is not feasible. In this manuscript, we share the iTANGIBLE cohort experience with NOACs as primary prophylaxis in MN patients with hypoalbuminemia.

We extracted data on consecutive patients aged ≥18 years with biopsy-confirmed MN from certain participating centres in the iTANGIBLE glomerulonephritis registry who were receiving apixaban or dabigatran for anticoagulant prophylaxis. We included patients with nephrotic syndrome and serum albumin levels <2.7 g/dL. Patients with lupus nephritis, other connective tissue disorders, or those testing positive for hepatitis B, hepatitis C, or HIV-I/II were excluded, as were individuals with documented clinical or radiological evidence of vascular thrombosis. Apixaban/ dabigatran was discontinued once the serum albumin was > 2.7 g/dL. The study was approved by the Institute Ethics Committee (INT/IEC/2024/SPL-1486) of the Postgraduate Institute of Medical Education and Research, Chandigarh. All the patients who fulfilled both the inclusion and exclusion criteria and received apixaban (2.5 mg BD) or dabigatran (110 mg twice daily) immediately after MN diagnosis were evaluated for VTE episodes or bleeding complications. The values were expressed as percentages, mean with standard deviation, or median with interquartile range, depending on the normality of the distribution. Statistical analysis was performed using GraphPad Prism 10 (San Diego, California, USA).

Of 64 cases, 40 (62.5%) were PLA2R-related, with the median antibody titer being 576 (185,1270) RU/mL. Rituximab and cyclical cyclophosphamide with corticosteroids were administered to 27 (42.18%) and 32 (50%) Thirty-two (50%) and 27 (42.18%) patients, respectively. The median values for proteinuria, serum creatinine, and mean serum albumin at the initiation of NOAC therapy were 7.24 (4.42–11.04) g/day, 0.83 (0.61–1.07) mg/dL, and 1.98 ± 0.40 g/dL, respectively [Table 1].

The anticoagulant (apixaban or dabigatran) was chosen based on the unit’s protocol. Three patients received dabigatran and 61 patients received apixaban. Over a mean follow-up period of 3.4 months, no cases of VTE were observed. The anticoagulant could be stopped in 54 patients as their serum albumin rose above the threshold, and 10 remained on apixaban therapy as their serum albumin levels were below 2.7 g/dL. At the last follow-up, 28 (43.75%) patients were in clinical remission (seven in complete remission and 21 in partial remission). Two patients experienced bleeding from hemorrhoids, necessitating temporary cessation of dabigatran and apixaban, which was subsequently resumed without complications. One additional patient developed menorrhagia, requiring cessation of apixaban therapy. Another patient developed an infection requiring inpatient care, during which apixaban was withheld and replaced with unfractionated heparin.

The present manuscript highlights the short-term efficacy and safety of NOACs in patients with PMN. None of the patients treated with NOACs in this report developed clinical VTE, and NOACs showed an acceptable safety profile.

PMN is the leading cause of nephrotic syndrome in adults and poses the highest risk of thrombosis among all glomerular diseases. The thrombosis incidence in untreated PMN ranges from 7-36%.^5,6 Among various clinical parameters, hypoalbuminemia is the strongest predictor of thrombosis in PMN patients, with serum albumin levels below 2.8 g/dL associated with the highest thrombotic risk.² The initial 3-6 months after diagnosis pose the most risk before spontaneous or treatment-induced remission is achieved, when the patients are most likely to have significant hypoalbuminemia. The 2021 Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend anticoagulation in nephrotic syndrome patients after carefully evaluating additional risk factors, such as severe hypoalbuminemia, prolonged immobilization, or a history of thromboembolic events, while balancing the benefits against the risk of bleeding.⁷

VKAs are recommended as the preferred anticoagulation therapy in nephrotic syndrome. However, despite this recommendation, NOACs remain the more commonly used option in clinical practice.³ This preference is primarily driven by growing familiarity with the use of NOACs, particularly in patients with atrial fibrillation and advanced kidney injury.⁸ NOACs offer several advantages, including the absence of routine monitoring, fewer drug interactions, and no dietary restrictions. The latter is particularly relevant in predominantly vegetarian populations, such as in India, where dietary restrictions can significantly impact quality of life. Cost is another consideration. While VKA (warfarin 4 mg) and apixaban therapies monthly cost ₹182 and ₹990, respectively, the overall expenses increase when the cost of monitoring is also added (twice a month for three months, ₹1,500), in addition to the cost and inconvenience of clinic visits. Travel contributes to carbon footprints, caregiver burden, and loss of daily wages for dose adjustments. Taken together, these factors often make NOACs a more practical and cost-effective alternative to VKAs, even in low-resource settings.

Despite PMN being the most common cause of nephrotic syndrome in adults and the heightened need for anticoagulation in this population, there remains a paucity of data on the efficacy and safety of NOACs in NS. Apixaban is highly protein-bound, and its pharmacokinetics in patients with NS remain poorly understood. Urinary protein loss could result in altered drug behavior, potentially leading to elevated levels of unbound NOACs in circulation, thereby increasing the risk of bleeding, or decreased circulating apixaban levels due to urinary excretion of the protein-bound fraction. A Phase 1 study observed reduced total apixaban levels (the protein-bound apixaban fraction plus the protein-unbound “free” apixaban fraction) and increased free apixaban (protein-unbound fraction only) levels in patients with nephrotic syndrome compared to healthy controls.⁹ However, the clinical significance of these divergent total and free apixaban concentrations remains uncertain.

Reynolds et al. reported the risk of recurrent thrombosis in a PMN patient receiving apixaban therapy for secondary prophylaxis.¹⁰ In contrast, the current study focuses exclusively on primary prophylaxis. Kelddal et al. reported the successful use of apixaban in 21 patients with nephrotic syndrome (seven PMN cases), with five experiencing minor bleeding events.¹¹ The low incidence of bleeding in the present study may be attributed to the low apixaban dose (5 mg versus 10 mg as used in Kelddal et al.’s study).¹¹

While this study is among the first to assess the efficacy and safety of NOACs in PMN, its limitations include a small sample size, a short follow-up duration, and a non-randomized design. In conclusion, the study’s findings signal that NOACs are safe and effective for short-term VTE prevention in patients with PMN.