Anticoagulation in renal failure poses two challenges. First, the kidneys are involved in the metabolism of many anticoagulants. And second, bleeding risk is high in patients with renal failure, even if they are receiving appropriate anticoagulation.
Bleeding with Anticoagulation in Renal Failure
Significant bleeding occurs in patients with renal failure who receive anticoagulation. For example, clinically relevant bleeding occurred in 26%-32% patients with atrial fibrillation who were taking either warfarin or apixaban over a 1 year period in a randomized trial. Stroke risk over the same time was about 3% (on anticoagulation). A systemic review from 2022 summarized overall similar results in patients with stage 4 and 5 renal failure.
Of course, this is not to say that patients with end stage renal failure and atrial fibrillation should not receive anticoagulation. But it is to say that there is going to be significant risk for bleeding if they do.
Similarly, high bleeding risk occurs with apixaban in patients with venous thromboembolism. In fact, in real-life analyses bleeding risk seems to be higher than that published in landmark studies. A United States claims database analysis echoed high bleeding risk for both apixaban and warfarin in all stages of renal failure. Again, this is not to say we should not use anticoagulation when we have to. But it is to say that we should weigh bleeding against clotting risk carefully.
Which Anticoagulation to Use in Renal Failure?
If a patient with renal failure needs anticoagulation, there are two solutions. The first, is to choose anticoagulation that has little renal excretion. And the second, is to reduce the dose of the anticoagulant.
Anticoagulants with Little Renal Excretion
The two anticoagulants with little renal excretion are apixaban (Eliquis) and Warfarin (Coumadin). The FDA has approved apixaban in patients with end-stage renal disease for the treatment of atrial fibrillation or venous thromboembolism. But, we need to remember that very little data supported this approval. Three Italian medical societies issued a position statement on anticoagulation in renal failure. They pointed to data that show efficacy of anticoagulation, but to limited data to support safety.
In the future we should consider asundexian. But we do not yet have data in patients with renal failure.
Reduced Dose Anticoagulation
Perhaps the safest approach is to use one of the approved medications, and to reduce their dose? A retrospective study examined this theory regarding apixaban for venous thromboembolism. They compared outcomes in patients who received the standard 5 mg BID dose to those of patients who took a reduced dose of 2.5 mg BID. They found that the higher dose was associated with more bleeding but that the lower dose achieved similar effectiveness.
Over the years various societies have issued different guidelines regarding anticoagulation dosing. But I think we need to focus on the approved doses. Here are links to the package inserts for apixaban, dabigatran, edoxaban and rivaroxaban.
There are a few highlights you should notice:
- The dosing might change depending on the indication. I am not sure I always understand this, and I suspect some of it has to do with trial design more than with biology.
- Some of these medications do not have an ESRD approved dose. They should be avoided in patients with advanced renal failure.
- Avoid edoxaban in patients with a CrCl of >95 ml/min
Monitoring Drug Levels
Some medical centers have DOAC-specific anti-Xa assays. These assays are not accurate enough to tell us the exact anticoagulant effect. They are also not predictive of bleeding risk. At least not in a convincing manner. But they might be able to point us toward a safer dose by helping us avoid high levels. Indeed, there are publications on the use of this approach. And the Italian societies I quoted above also suggest to use these levels in challenging cases. But there are no strong data to suggest how to use these tests exactly.