Age-Stratified Risk Categories for Cardiovascular Disease Prevention Therapies

Optimization of blood pressure (BP) and cholesterol are core tenets of cardiovascular disease (CVD) prevention. Beyond the promotion of healthy lifestyle, identifying individuals who would benefit most from initiation of BP and lipid-lowering therapies remains a process in evolution. Persons predicted to be at higher absolute risk for future CVD events are more likely to derive net benefit from CVD prevention treatments than lower risk individuals.¹ Therefore, both the American College of Cardiology/American Heart Association (ACC/AHA) and the European Society of Cardiology (ESC) primary prevention guidelines recommend that adults should have their 10-year risk of CVD events estimated and provide absolute risk thresholds above which treatment should generally be initiated.¹ The risk thresholds chosen determine the proportion of adults eligible for treatment and, at a population level, the number of events that will be prevented. Accordingly, risk threshold selection has substantial implications for CVD prevention.

Emergence of Age-specific CVD Risk Thresholds

Most international guidelines currently endorse risk thresholds that are not stratified by age. For instance, ACC/AHA guidelines divide 10-year absolute CVD risk estimates into four categories: low risk (<5%), borderline risk (5% – <7.5%), intermediate risk (7.5% – <20%), and high risk (≥20%).¹ Relatedly, ACC/AHA guidelines recommend lipid-lowering therapy for adults with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL plus 10-year CVD risk ≥7.5% and BP-lowering therapy for adults with stage 1 hypertension plus 10-year CVD risk ≥10%.¹

In contrast, the 2021 ESC CVD prevention guidelines introduced new age-specific risk thresholds for primary prevention.^1,2 These ESC guidelines define the 10-year threshold for very-high CVD risk as ≥15% for individuals aged ≥70 years, ≥10% for adults 50 – 69 years, and ≥7.5% for adults less than 50 years.^1,2 This decision was motivated by concern that uniform age-independent cut-offs could result in overtreatment of older adults and undertreatment of younger adults. Age-specific thresholds impact millions of individuals by altering the proportion of adults in each age category that are eligible for treatment.³ The potential pros and cons of this major change in approach to primary prevention for European adults have not been reviewed.

More recently, the 2024 ESC guidelines for the management of elevated BP and hypertension were published.⁴ These guidelines included, for the first time in a European guideline, a recommendation for CVD risk-based treatment of elevated BP values that do not meet the traditional threshold for hypertension. This inclusion necessitated a decision; either to ratify the age-specific risk thresholds recommended in the 2021 ESC prevention guidelines or to endorse a single uniform CVD risk threshold like in the ACC/AHA hypertension guideline. In this Viewpoint, we summarize the debate that informed this important decision.

Potential pros and cons of age-stratified risk categories for older adults

Age is the strongest predictor of CVD risk. Therefore, most older adults are categorized as high or very-high CVD risk when a uniform absolute risk threshold is implemented, even with conventionally “normal” LDL-C and BP values.⁵ Furthermore, some risk prediction models may overestimate CVD risk in older populations, conceivably when the competing risk of non-cardiovascular mortality is not accounted for.⁶ Accordingly, proponents of age-specific risk thresholds believe their implementation may mitigate the risk of overtreating older adults.

However, several counterarguments exist. First, during clinical trial follow-up, the relative reduction in CVD events for a given lowering of BP or LDL-C is consistent across age. In other words, the relative risk reduction in CVD outcomes for a 10 mm Hg lowering of BP or a 40 mg/dL lowering of LDL-C is the same in an 80-year-old as it is in a 55-year-old. Yet, at the same level of BP or LDL-C or CVD risk, it is possible when using age-stratified risk categories that an older person is not eligible for treatment whereas a younger person is. Is it ethical to withhold a medication with a fixed relative CVD risk reduction in one older person but give it to a younger person with a similar elevation in BP or cholesterol? Should the ethics of this approach be further questioned given the older person’s higher absolute CVD risk translates into a lower number needed to treat?

Second, guidelines do not use predicted risk alone to identify individuals for treatment. For both BP and LDL-C, a specific threshold value for each risk factor must be met before risk-based treatment allocation is applied.¹ Third, it is technically possible for an adult aged 69 to be categorized as high CVD risk by the 2021 ESC guideline but on their 70^th birthday to then be categorized as low-to-moderate risk without a change in their risk factors. This is biologically and logically implausible. Fourth, the use of more contemporary, better calibrated, and competing risk adjusted models, such as Systematic COronary Risk Evaluation 2-Older Persons (SCORE2-OP) and Predicting Risk of CVD EVENTs (PREVENT), may mitigate concerns for overestimation of risk in older adults.^5,7 Lastly, chronological age is not biological age. We think the decision to withhold therapies due to concerns of adverse events is better made by assessing comorbidity burden, frailty, and patient preferences.

Potential pros and cons of age-stratified risk categories for younger adults

Despite abnormal elevations in BP or lipids, 10-year CVD risk estimates may be lower in younger adults than guideline treatment thresholds using age-independent risk categories. Consequently, the 2021 ESC CVD prevention guidelines lowered the 10-year CVD risk threshold for treatment initiation for younger adults.¹ Extrapolating from Mendelian randomization studies, it has been hypothesized that earlier treatment initiation may provide greater risk reduction than delayed initiation.⁸

However, this approach has shortcomings. First, it requires a larger number of young adults to be treated, as compared to older adults, to prevent an equivalent number of CVD events over a 10-year time-period. Accordingly, treatment becomes less cost-effective.⁹ Lowering the 10-year CVD risk threshold for younger adults also increases exposure to medication side effects which could arguably outweigh the short to medium term benefit. Lastly, due to pleiotropic effects and other factors, Mendelian randomization is not the same as testing the lifelong effect of a drug in a clinical trial.

Alternative Approaches for assessing and communicating CVD risk

While not currently a Class 1 recommendation in guidelines, other potential approaches to guide treatment allocation including lifetime or 30-year risk models may be helpful for younger adults.⁷ Similarly, providing adults with their age- and sex-specific CVD risk percentiles may help to contextualize risk.¹⁰ In addition, an absolute risk reduction approach, which incorporates both 10-year predicted CVD risk and a varying relative risk reduction dependent on the baseline LDL-C or BP level, has been suggested though is not yet guideline-endorsed.⁹

Conclusions

While the use of age-specific risk thresholds is motivated by a desire to reduce overtreatment of older adults and undertreatment of young adults, we believe the drawbacks of this approach are substantial and raise potential ethical concerns by withholding CVD preventive treatment for older adults based solely on age. Accordingly, we recommend that single 10-year absolute risk thresholds be used for primary prevention therapy allocation. This approach was endorsed by the 2024 ESC guidelines for elevated BP and hypertension.⁴ When determining a single absolute risk threshold, guideline committees should consider the average CVD risk of populations included in pivotal clinical trials and studies examining anticipated net-benefit of treatment at various risk thresholds.