Is Frailty Index the Most Accurate Predictor of CVD?

The Rockwood Frailty Index (FI) has been shown to significantly enhance prediction of cardiovascular disease (CVD) risk beyond traditional methods like the Framingham Risk Score (FRS) and the Systematic Coronary Risk Evaluation (SCORE2)/SCORE2-Older Persons (OP) in middle-aged and older adults without prior CVD.¹

Published in Age and Ageing, these findings suggest that incorporating biological aging markers can improve clinical decision-making in preventive cardiology. Even though 2 patients may be the same chronological age, one who is “biologically older” is more susceptible to earlier onset of age-related diseases and disabilities compared with their same-aged peers, and knowing this about the patient can get them the care they need when they need it.

TL had mixed results and did not significantly enhance CVD risk prediction. | Image credit: InsideCreativeHouse – stock.adobe.com

Researchers analyzed data from 3 population-based cohorts: TwinGene, Health 2000 (H2000), and the Helsinki Birth Cohort Study (HBCS), including more than 14,000 middle-aged and older adults. Participants were divided into 2 groups based on whether they were younger or older than 70 years at baseline, and their health outcomes were tracked over 10 years. The study focused on the Rockwood FI and leukocyte telomere length (TL) as potential biological aging indicators, with primary outcomes of CVD incidence and mortality.

The study showed that a higher FI value at baseline was significantly associated with an increased risk of incident CVD in both age groups, occurring in up to 18% of adults younger than 70 and in up to 53% of adults older than 70. These corresponded to CVD mortality rates of up to 2% and 9%, respectively. The predictive accuracy of CVD also improved when FI was added to the existing FRS or SCORE2/SCORE2-OP risk models—an improvement observed consistently across all 3 cohorts. The most effective model combined SCORE2/SCORE2-OP with the FI, which consistently demonstrated higher predictive accuracy than using traditional scores alone.

While the FI showed consistent improvements in predicting CVD incidence, its performance was less robust for predicting CVD mortality. The authors noted that the frailty measure’s predictive value for mortality varied between cohorts, suggesting that more research is needed to clarify this relationship.

“Generally, the variation in the C-indices by population may be explained by sample sizes and event rates as well as demographics, healthcare systems, lifestyles, environment and genetics,” the authors explained. “In our study, the observed differences in C-indices by country and cohort likely relate to differences in sample sizes, event rates, baseline risk scores and age ranges.”

On the other hand, TL had mixed results and did not significantly enhance CVD risk prediction, as age- and sex-adjusted TL was only linked to CVD incidence among younger ages in the H2000 cohort. However, this inconsistency aligns with a prior meta-analysis of 25 studies that still linked shorter TL to a higher risk of all-cause mortality.²

“In previous reports, the FI, a multi-systems BA indicator, has appeared as a more accurate predictor of poor outcomes than TL or other cellular BA indicators such as the epigenetic clocks,” the authors said.¹ “This is in line with our findings: the FI is more accurate than the TL in identifying CVD risk.”

Important to cardiovascular research, all 3 cohorts included more women than men. However, there are several factors limiting the generalizability of these findings, especially considering the lack of race-stratified data. The cohorts were from 2 Nordic countries, Sweden and Finland, and the TwinGene cohort consisted of twins, but twin clustering was adjusted for all analyses. With no universal gold standard for BA indicators, the accuracy of FI in predicting CVD incidence in this study warrants further, larger research but is clinically relevant according to the researchers.

“For example, the FI can be constructed automatically based on routinely collected electronic health records or administrative claims data,” they said. “Further, accelerated BA is a risk factor for all age-related diseases, and in addition to CVDs, the FI predicts, for example, cancer and dementia incidence. Therefore, we hypothesize that the FI reflecting BA should be considered as a general risk indicator in a similar way as chronological age and sex.”

References

1. Tirkkonen A, Mak JKL, Eriksson JG, et al. Predicting cardiovascular morbidity and mortality with SCORE2 (OP) and Framingham risk estimates in combination with indicators of biological ageing. Age Ageing. 2025;54(4):afaf075. doi:10.1093/ageing/afaf075
2. Wang Q, Zhan Y, Pedersen NL, Fang F, Hägg S. Telomere length and all-cause mortality: a meta-analysis. Ageing Res Rev. 2018;48:11-20. doi:10.1016/j.arr.2018.09.002