Hope in the 11th Hour: Are New Anticoagulation Options on the Horizon for Patients Undergoing Hemodialysis?

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Anticoagulation in patients undergoing hemodialysis for conditions such as atrial fibrillation has long posed a clinical challenge given competing elevated risks of both thromboembolism and bleeding (1). Even the efficacy and safety of direct oral anticoagulants compared with vitamin K antagonists remain uncertain (2, 3). This has led to ambiguity and thus heterogeneity in prescribing practices for oral anticoagulation in kidney failure. A recent Kidney International study of a phase II dose-ranging randomized controlled trial (4) evaluated the safety of the subcutaneously injected novel factor XI inhibitor, fesomersen, in patients undergoing hemodialysis. Factor XI inhibitors have shown promise for prevention of thromboembolic events with relatively low bleeding incidence in some prior phase II trials (5), a pharmacologic approach that could offer a promising avenue for anticoagulation in the population on dialysis. This trial demonstrated a dose-dependent reduction in factor XI levels without an increase in bleeding events among 307 patients undergoing hemodialysis.

In addition to studying an innovative therapy, the trial had numerous strengths. It is commendable that this study specifically enrolled patients undergoing hemodialysis, given frequent exclusion of this highly complex cohort from most cardiovascular trials (6). Participants from 69 sites in 15 countries were enrolled at an impressive pace from a broad international pool, seeming to overcome enrollment challenges seen in other related trials (2, 3). Patient characteristics were well matched across placebo and dosage categories. Pharmacodynamic studies of factor XI levels demonstrated a clear inverse correlation to a fesomersen dose (albeit with wide standard deviation), and these levels were further shown to correspond to the more clinically relatable activated partial thromboplastin time. Endpoints included thrombotic events of hemodialysis accesses, a morbid complication specific to this population that would benefit from further primary and secondary prevention options.

Although results for an impressive array of safety and efficacy endpoints were given, event rates were low with wide confidence intervals. For example, only one major atherothrombotic event per group, including placebo (pooled hazard ratio, 0.92; 95% confidence interval, 0.10–8.81; p = 0.94), was detected in the trial period. Additionally, patients who would seemingly be at highest risk for safety or efficacy events, such as those with a recent bleeding or thromboembolic incident and those already on anticoagulants, were excluded from this trial, which may help explain why these endpoints were seen at such low rates. These analyses were descriptive without a formal sample size calculation prior to enrollment, so the study was not actually powered to detect differences. Finally, the population studied was a general population undergoing hemodialysis in whom anticoagulation may not be indicated; further research of more applicable patients (e.g., those with atrial fibrillation) would be informative.

So where does this leave us? Fesomersen may represent a novel anticoagulant that could confer some advantages over existing options, and further data and therapeutics in this arena are greatly needed for patients on dialysis. This trial demonstrates that factor XI levels respond in a dose-dependent manner to fesomersen. However, due to lack of power, reported results related to efficacy and safety are not conclusive but certainly warrant further investigation. Importantly, this trial gives us hope that it is feasible to enroll patients undergoing hemodialysis in cardiovascular trials. After the success of recent chronic kidney disease trials, the time is now to focus on patients undergoing hemodialysis. We hope that this study (and others) paves a new path forward for investigation of novel cardiovascular therapies in this high-risk population.