By Michael Crawford, MD
Professor of Medicine, Chief of Clinical Cardiology, University of California, San Francisco
Dr. Crawford reports no financial relationships relevant to this field of study.
SYNOPSIS: Adding additional risk factors not in the pooled risk equation to low-risk subjects identified a sub-group with an observed event rate > 7.5% who may warrant statin therapy.
SOURCES: Yeboah J, et al. Utility of nontraditional risk markers in individuals ineligible for statin therapy according to the 2013 American College of Cardiology/American Heart Association Cholesterol Guidelines. Circulation 2015;132:916-922.
Superko HR. Nontraditional markers of cardiovascular disease risk can improve the 2013 American College of Cardiology/American Heart Association Prevention Guidelines: Insights from the multi-ethnic study of atherosclerosis investigation. Circulation 2015;132:904-906.
The new cholesterol treatment guidelines recommend that in selected individuals in whom the decision to start statin therapy is unclear, other factors not in the pooled risk equation (PRE) may be considered. However, the guidelines do not delineate the yield of considering other markers in otherwise low-risk individuals by the PRE. Thus, these investigators interrogated the multiethnic study of atherosclerosis (MESA) database to assess the yield of adding information about coronary artery calcium on CT scan (CAC), high sensitivity (hs) CRP, ankle brachial index (ABI), LDL-cholesterol, and family history to the PRE-derived risk estimates in asymptomatic adults 45-84 years of age. The primary endpoint was the development of atherosclerotic disease as defined by myocardial infarction, cardiac death, or stroke. In 4185 subjects with a mean age of 61 years not on statins with a PRE risk < 7.5% over 10 years, 6% had an atherosclerotic event during 10 years of follow-up. Subjects with a CAC > 300 Agatston units had an event rate of 13%, family history 15%, hs-CRP > 2 mg/dL 10%, ABI < 0.9, 9%, and LDL > 160 mg/dL, 5%. In total, 11% of the subjects without diabetes were reclassified to > 7.5% 10-year risk of an event by adding at least one additional risk factor. The authors concluded that adding additional risk factors not in the PRE to low-risk subjects identified a sub-group with an observed event rate > 7.5% who may warrant statin therapy.
Considerable controversy has surrounded the introduction of using the PRE estimation of a 10-year risk of a cardiovascular event > 7.5% as the cutoff to start statin therapy in apparently healthy adults. As this and other studies have pointed out, the majority of cardiovascular events occurred in subjects estimated to be at low risk. This realization has led to our current approach of recommending lifestyle modifications for everyone and targeting statin therapy to the highest risk patients. What this analysis of the MESA database explores is whether adding non-traditional risk factors to the PRE will identify among the low-risk patients those who are actually at high risk and deserve consideration of statin therapy. Among the five additional risk factors considered, two were particularly valuable. A family history of atherosclerotic events at any age among those with a PRE risk < 7.5% over 10 years showed an actual event rate of 15%. The number needed to treat (NNT) about family history to reclassify risk upward was 22. A CAC > 300 raised the risk to 13% with an NNT of 15. For hs-CRP, the NNT was 40 and the observed event rate was 10%. ABI and LDL had very high NNTs (177 and 193) and event rates < 10%.
Adding family history to your clinical decision making is a no brainer since it costs almost nothing, but CAC is a bigger issue due to the cost and risk of the procedure, although both have come down recently. Considering ABI and LDL did not seem cost effective, CRP was of some value, which does little to quell the controversy about when to perform this test. Other studies of CRP’s value have had mixed results.
This study is limited in that MESA enrollees were 45-84 years of age, so the results may not apply to younger individuals. Also, we don’t know the efficacy of statin therapy in patients deemed high risk only by adding a non-traditional risk factor to the PRE. Additionally, although none of the patients in this analysis were on statins initially, 28% received statins during the 10-year follow-up. Does this study support a change in practice? Even before this study, I have always considered family history without any age cutoffs in my decision making about statin therapy, so I appreciated the finding that it was important. This study probably wasn’t necessary to establish the value of CAC and I use it selectively in borderline patients. CRP may be of some value, but I tend to order it only when the patient requests it. Most patients expect a lipid panel, and if the LDL is > 130 but < 190 in low-risk PRE patients, I really push lifestyle change. Although ABI is useful to detect vascular disease, its value in statin decision making is uncertain and this study didn’t support its general use.