The present study shows that patients, suffering from severe NS under anticoagulant therapy with apixaban had reduced risk of venous and arterial thromboembolism compared to patients previously described in the literature, without increased risk of bleeding.
The direct-acting oral anticoagulants (DOACs) have many advantages over warfarin. In particular, apixaban has rapid onset (1–3 h) and offset (half-life 8–15 h) of action, with predictable dosing, which precludes the need for routine coagulation monitoring in the general population. However, in patients with NS, concerns exist about optimal dosage of DOACs and their clinical risk/benefit ratio. DOACs are highly protein bound, and hypoalbuminemia could alter blood levels of DOAC with higher free drug levels, precluding possible safety issues. Furthermore, in NS, factor X levels may vary influencing the clinical impact of DOAC15
Moreover, thromboprophylaxis interest in NS has not been proven in large randomized controlled trials. Evidence is only based on case reports, case series and retrospective studies using heparin and warfarin as anticoagulants. A recent study by Kelddal and colleagues5 included 79 patients, of which 44 were treated with low molecular weight heparine (LMWH) and/or warfarin compared to 35 patients without anticoagulation. Four among the 35 patients without thromboprophylaxis presented a VTE but no patient in the prophylaxis group had thrombosis.5 Selection bias cannot be excluded since patients without treatment had a higher serum albumin level and no propensity score was used to account for the covariates that could predict receiving the treatment. This study reinforces the clinical interest of thromboprophylaxis in patients with NS. The use of DOACs is tempting and may even obviate the need for concern about heparin resistance due to antithrombin urinary losses.1
In the current study, we measured for each individual patient Cmin and Cmax anti-Xa apixaban levels. Apixaban was the molecule of choice because of its predictable pharmacokinetic and pharmacodynamic properties that are consistent across the range of different patient populations studied (elderly and those with renal impairment), the fast onset of action, and the low potential for food and drug interactions.15 We could not compare the levels to previous published studies on Apixaban (ARISTOTLE, AMPLIFY and AMPLIFY-Ext)16–18, since these are the first data gathered in this particular population. However, we notice that the levels are within the therapeutic ranges of the large clinical trials published and observe a normal intra-individual variability of Apixaban levels with only one patient experiencing a new thromboembolic event during follow-up. We must underline the fact that all patients in the study were at high risk of TE events, because of the degree of hypoalbumenia and predominance of MN.
Lionaki et al19 confirmed that the severity of hypoalbuminemia is significantly associated with VTE occurrence. These authors have shown that each decrease of 10 g/L in albumin serum level is associated with a two- fold increase of VTE risk. A serum albumin level of 28 g/l was the threshold required for anticoagulation implementation. All of the patients included in our study had a serum albumin level < 25 g/L, with only 3 patients having a serum albumin level above 20 g/L, conferring to this retrospective cohort a significantly high thromboembolic risk.
VTE risk is the highest within the first 6 months after NS onset. The median follow-up time of our study cohort was 11 months [IQR 6–14] and the median duration of anticoagulation was 129 days [IQR 45–224]. Anticoagulation was stopped when serum albumin rose above 20 g/l, with the exception for patients suffering from MN where the threshold was 25 g/l. The follow-up interval was therefore sufficiently large to collect any thrombotic episode
Importantly no minor nor major bleeding adverse events were recorded during follow-up. These findings confirm and extent that anticoagulation with DOACs are safe and well tolerated in patients with severe NS.
Weaknesses of the study were its uncontrolled monocentric historical cohort design, the limited number of patients and the lack of standard of care comprising heparin and/or warfarin arm. 21
To the best of our knowledge this is the first study that measured apixaban levels in patients with NS and where VTE episodes were carefully recorded in the follow-up. We were able to show the encouraging benefit/risk ratio of apixaban in this particular clinical setting in very high risk patients. Apixaban seems very safe in patients with NS with no bleeding and very effective regarding thrombosis occurrence during a long follow-up. The sole thrombotic episode with PE was reported in a patient with a doubtful compliance.
All these data suggest that thromboprophylaxis in patients suffering from severe NS could be simpler and safer and efficacious with apixaban. Further large multicenter randomized, controlled trials should be conducted to confirm these encouraging results.