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Coagulation Factor XI Level and Cardiac Events and Function
Quick Takes
- Animal models have associated lower levels of factor XI with increased HFpEF risk and AF.
- Using two large longitudinal cohort studies, the authors associated lower levels of factor XI with increased HF risk.
- Future evaluation of ongoing factor XI/XIa inhibitor therapies should examine for any signs of increased HF or AF risk.
Study Questions:
Are plasma factor XI levels associated with cardiovascular events and cardiac function in humans?
Methods:
The authors used two large longitudinal cohort studies to examine the association of factor XI levels with cardiac event risk and function. The first is the ARIC (Atherosclerosis Risk in Communities) cohort of predominately Black and White individuals. This analysis included 4,471 participants between 2011 and 2013 who had factor XI levels and echocardiographic cardiac function assessment. Prevalent heart failure (HF) and atrial fibrillation (AF) cases were identified at or before the time of study entry while incident events were ascertained through 2021. Prospective validation was performed in the CHS (Cardiovascular Health Study) cohort.
Results:
The ARIC cohort included older patients (median age 75 years) or predominantly female (57%) and White (83%) participants. At study enrollment, there were 665 cases of prevalent HF and 419 cases of prevalent AF. During the follow-up period, there were 580 new HF cases and 788 new AF cases. Lower factor XI levels were associated with a higher incidence of new HF (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.01-1.83 for each 1-unit decrement of log-transformed factor XI level) but not for new AF. From a cross-sectional analysis, lower factor XI levels were associated with an increased odds of prevalent AF (odds ratio, 1.96; 95% CI, 1.23-3.07) but not prevalent HF. The inverse relationship between factor XI level and incident HF was validated in the CHS population (HR, 1.18; 95% CI, 1.02-1.36). At ARIC study enrollment, lower factor XI level was associated with a higher prevalence of diastolic dysfunction, worse E/A ratio, larger left atrial (LA) size, worse LA function, and increased left ventricular (LV) mass index. There was no association between factor XI level and LV ejection fraction (EF) or global longitudinal strain.
Conclusions:
The authors conclude that decreased factor XI level is associated with a greater incidence of HF, prevalent AF, worse LA function, and greater LA size.
Perspective:
Several agents are currently in phase 2 and 3 trials to inhibit factor XI and/or XIa to prevent thrombosis with a theoretically lower risk of bleeding than currently available anticoagulants. However, recent animal studies have identified an association between factor XI levels and cardiac outcomes, including HF with preserved EF (HFpEF) and AF. This study leveraged two large and diverse cohort studies to see if similar associations were found in human populations. By grouping participants into quartiles of baseline factor XI levels, the authors were able to associate lower factor XI levels with increased risk of incident HF and prevalent AF. These findings were consistent across both cohorts. However, this finding does not necessarily mean that use of a factor XI/XIa inhibitor would have the same association with cardiovascular risk. If the ongoing and planned phase 3 studies of factor XI/XIa medications are deemed to be efficacious at preventing thrombosis, post hoc and secondary analyses should then be conducted to monitor for any signal of increased HF risk.
Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Anticoagulation Management and Atrial Fibrillation, Atrial Fibrillation/Supraventricular Arrhythmias, Heart Failure and Cardiomyopathies
Keywords: Atrial Fibrillation, Atrial Function, Blood Coagulation Factor Inhibitors, Factor Xa Inhibitors, Heart Failure, Preserved Ejection Fraction
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