By Michael H. Crawford, MD, Editor
SOURCE: Cohen R, et al. Significance of a positive family history for coronary heart disease in patients with a zero coronary artery calcium score (from the Multi-Ethnic Study of Atherosclerosis). Am J Cardiol 2014;114:1210-1214.
Although a routine part of the patient’s medical history, little is known about the value of family history in predicting coronary artery disease (CAD) events in otherwise low-risk patients. Thus, these investigators from the Multi-Ethnic Study of Atherosclerosis (MESA) assessed the risk of a cardiovascular (CV) event in subjects with a coronary artery calcium score by computed tomography (CT) of zero, separating the subjects by whether they had a family history of CAD. A positive family history was one of a myocardial infarction in a parent, sibling, or child. Age of the family member was not considered. Of the 6814 men and women (50-50 distribution) without known CVD, 3185 had a baseline calcium score of zero and complete data. Their mean age was 58 years and 37% were men. The subjects were followed for a median of 10 years with yearly telephone follow-up. All CV events included: myocardial infarction, cardiac death, cardiac arrest, angina pectoris, stroke, stroke, death, and other CV deaths. CAD events (myocardial infarction, CAD death, cardiac arrest, and angina) were analyzed separately. A history of a first-degree relative with CAD was self-reported in 1185 subjects (37%). Baseline hypertension, statin use, and aspirin use were more common in those with a family history of CAD.
Overall, 3.2% of subjects with zero calcium score had a CV event and 1.8% had a CAD event. Among those with a positive family history, more events were noted (4.3% vs 2.5% for CV events and 2.4% vs 1.4% for CAD events, P = 0.007 and P = 0.056, respectively). After adjustments for age, sex, ethnicity, Framingham risk score, and baseline aspirin and statin use, a family history of CAD was only significantly associated with CV events (hazard ratio, 1.72; 95% confidence interval, 1.01-2.91), but not CAD events. Adjustments for anti-hypertensive medications, and the new CV risk score did not effect the risk of events. The authors concluded that subjects without known CV disease and a zero calcium score, who had a family history of CAD in a first-degree relative, were at increased risk for CV events, but the absolute event rates were <5% over 10 years.
COMMENTARY
Clearly, the subjects selected for this study were low risk with no clinical evidence of CVD and a CT calcium score of zero. Previous studies have suggested that such patients have a 10-year CAD event rate of around 1%. In this study, the CAD event rate was 1.8% for the whole group and 3.2% if all CV events were included. A family history of CAD in a first-degree relative raised the CAD events to 2.4% and all CV events to 4.3%. Only the increase in all CV events was statistically significant. The results remained the same if adjustments were made for the Framingham risk score and the new CV risk score, neither of which includes family history as a variable. Thus, as clinicians have suspected, family history is a predictor of the risk of CV events in a low-risk population and it would be reasonable to include these data in decisions about the aggressiveness of risk reduction strategies.
Perhaps the results would have been more robust if only premature CAD events were labelled a positive family history. The authors performed a sensitivity analysis of those in whom this information was available and it did raise the risk further, but not significantly (P = 0.09). However, this analysis was underpowered. On the other hand, why would someone middle aged with a CT calcium score of zero ever have an event? Other studies using CT angiography have shown non-calcified soft plaque in 5-25% of subjects with a zero or < 10 calcium score and no overt disease. Perhaps family history helps identify these individuals. Also, a family history may be associated with more risk factors. For example, more of the subjects in this study with a family history were hypertensive (38 v 33%, p=0.003) and were on statin (12% v 9%, p=0.005). So a family history may shorten the warranty on a zero calcium score.
The authors estimated the potential impact of family history in this low risk group. It would raise the CV event rate from 0.33% a year to 0.44% and the CAD event rate from 0.18% to 0.24% per year. The number needed to treat (NNT) to prevent one CV event over 5 years for statins would be 197 with a family history and 327 without. For aspirin the NNT would be 312 with a family history and 605 without. It should be pointed out that family history in this study was defined as a history of a "heart attack", which is fraught with misinterpretation. Perhaps a more robust analysis of family history would have strengthened its predictive value. I believe a more nuanced family history is valuable information and despite its limitations, this study lends strength to that belief.
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