Response by Ji et al to Letter Regarding Article, “Association of Coagulation Factor XI Level with Cardiovascular Events and Cardiac Function in Community-Dwelling Adults: From ARIC and CHS”

We thank Feng et al and Zhong et al for the interest in our recent paper. The authors have contributed some thoughtful comments to our study and we would like to respond in kind.

We appreciate the valuable insight from Feng et al regarding the difference between Factor XI (FXI) antigen level and FXI activity. Although our study did not directly examine FXI activity, prior studies have found that hereditary FXI deficiency is secondary to decreased FXI level¹ and there is a correlation between FXI level and FXI activity.^2,3 Therefore, our examination of FXI level associations does provide useful information regarding FXI activity associations. Nevertheless, emerging FXI therapeutics have differences in mechanisms of action (some target inactive FXI, others target activated FXI) and pharmacokinetics (once-twice daily oral administration, monthly subcutaneous injection).⁴ How these additional factors modify HF risk warrants further investigation.

Both Feng and Zhong et al have pointed out the importance of investigating dynamic changes in the FXI levels over time. Indeed, as Feng et al noted in Supplemental Figure 4 of our manuscript, approximately 50% of ARIC participants in each tertile of plasma FXI level exhibited constant FXI levels across midlife to late life, which is consistent with previous findings of constant FXI levels throughout life.⁵ A single point measurement of FXI therefore can inform associations between FXI level and disease outcomes. We did not incorporate more complex modelling approaches such as linear mixed models or time-dependent Cox model to explore longitudinal relationships between FXI level and outcomes to keep our statistical methods straightforward yet informative. Therefore, we agree that future studies with sufficient sample size should examine the time-varying characteristics of FXI levels in association with cardiovascular events and cardiac function. Conversely, in the other 50% of ARIC participants who experienced a change in FXI level across 20 years, compared to FXI-increasing participants, FXI-decreasing participants were more likely to experience heart failure (HR 1.37, 95% CI: 1.04–1.79). Although this finding further confirmed the results of our primary analysis, we agree with Feng et al that the 20-year timescale lacks temporal granularity and more granular analysis of FXI level trajectories and cardiac events can be performed in the future.

Zhong et al have highlighted the importance of incorporating additional socioeconomic status (SES) covariates into our analysis. Our covariate selection rationale was primarily to maintain consistency in model adjustment with established risk prediction models of heart failure (HF) and atrial fibrillation (AF), specifically PREVENT⁶ and CHARGE-AF.⁷ Although SES is an independent risk factor for cardiovascular disease, its association with FXI level is not well established and thus may not function as a confounder in our analysis

As Zhong et al noted, decomposition of HF and AF co-occurrence is important for comprehensive understanding of disease risk. One potential approach could be to examine the association between FXI level and HF in AF cases or vise-versa. Unfortunately, such subgroup analyses were not feasible in our study because of the limited sample size and case numbers. Future studies incorporating sufficiently powered subgroup analyses may offer deeper insights into the potential interaction of HF and AF.

Finally, we appreciate the insightful comments from both authors regarding the age-specific association between FXI level and HF. We believe that this association is more clinically relevant in older populations (age >75 years) because the risk of ischemic stroke, HF, and also major bleeding is higher. For this population, anticoagulants that can lower thrombosis risk without increasing bleeding risk are being developed and FXI targeted therapies are promising because of their lower risk of bleeding compared to current anticoagulants. However, we agree with Feng et al that understanding the relationship between FXI level and HF risk across a broad age spectrum is important because of potentially different underlying pathophysiologic mechanisms and futures studies should also examine younger populations.