Atherosclerosis remains the leading cause of morbidity and mortality in the industrialized world. As such, all prevention guidelines emphasize that asymptomatic adults should undergo global risk assessment. However, limitations of the Adult Treatment Panel III version of the Framingham risk score for estimating hard 10-year CHD events have been well described in both underestimating and overestimating risk.
Erin D. Michos
In the 2013 American College of Cardiology/American Heart Association Guideline on the Assessment of Cardiovascular Risk, global risk assessment remains endorsed as the first step for adults aged 40 to 79 years. A new 10-year risk score for estimating hard atherosclerotic CVD (ASCVD) events, including CHD and stroke, but not congestive HF or revascularization, was derived using pooled data from NHLBI-funded cohorts, including ARIC, the Cardiovascular Health Study, CARDIA and Framingham. Importantly, there are now separate risk equations for sex and non-white populations.
Limitations of the new risk score
Although I applaud this progress, the new risk score will still result in overtreatment or undertreatment. I outline some concerns regarding pitfalls of the new risk score.
Performance in diverse populations: One notable absence from the pooled cohorts was the Multi-Ethnic Study of Atherosclerosis (MESA), which had not reached 10-year follow-up. MESA is arguably the most racially/ethnically diverse of the cohorts, and important findings from MESA regarding risk prediction conferred by coronary artery calcium (CAC) was not considered for inclusion in the model. When the new risk score was applied to the MESA and REGARDS studies, it performed suboptimally, with C-statistics of approximately 0.6 to 0.7. For comparison, in MESA, the C-statistic for the prediction of CHD events was 0.76 (95% CI, 0.72-0.79) using a traditional risk factor model, but increased to 0.81 (95% CI, 0.78-0.84) with the addition of CAC. Thus, CAC may perform better than the ASCVD pooled risk score alone.
Exclusion of family history in the model: Family history reportedly did not improve model prediction. However, a family history of premature CHD has been shown to be a strong predictor of subsequent CVD events. In contrast, the Canadian Cardiovascular Society recommends that a person’s calculated risk should be doubled when a family history of premature CVD is positive.
Inclusion of stroke: I agree with the importance of preventing disability from total CVD. However, it is uncertain whether this risk threshold will discriminate who will most and least benefit from statin therapy. Only about 40% of strokes are from large-vessel atherosclerotic disease that would be predicted to be most amenable to risk reduction with statins, with the rest being cardioembolic, lacunar or hemorrhagic.
Lowering the high-risk threshold to >7.5%: Surprisingly, the guidelines recommend treating those with completely normal LDL cholesterol values if above this threshold. Nearly all men older than 65 years would crossover this 7.5% threshold, highlighting the fact that this risk assessment is more for populations rather than individual people. Furthermore, elderly individuals with no CAC actually have a lower mortality than younger individuals with high CAC scores.
Subclinical atherosclerosis: The new guideline gives a weak class IIb indication for optional screening tests when risk-based decisions to start pharmacologic therapy are “uncertain.” There is an option to upgrade to a higher risk class for family history of premature CVD, high-sensitivity C-reactive protein ≥2 mg/L, CAC scores ≥300 or ≥75th percentile, or ankle-brachial index <0.9. Carotid intima-medial thickness was not recommended.
Compared with traditional risk factors, CAC clearly outperforms. Individuals without risk factors but elevated CAC have substantially higher CHD and mortality event rates than those who have multiple risk factors but no CAC. In MESA, individuals with zero risk factors and CAC >300 had a CHD event rate 3.5 times higher than individuals with at least three risk factors and CAC score of 0. Individuals with zero CAC scores have very low event rates; thus, the number needed to treat to prevent one event with statin therapy among those with a CAC score of 0 would be prohibitively high. These findings challenge the exclusive use of traditional risk-assessment algorithms for guiding the intensity of primary prevention therapies.