By Michael H. Crawford, MD, Editor
Synopsis: A randomized trial of computed tomography (CT) coronary artery calcium score augmented management vs. usual care of primary prevention patients at moderate risk of a coronary event and with a family history of premature coronary events has shown that, after three years of follow-up, the calcium score group had lower low-density lipoprotein cholesterol levels and smaller total plaque volumes by CT angiography.
Source: Nerlekar N, Vasanthakumar SA, Whitmore K, et al. Effects of combining coronary calcium score with treatment on plaque progression in familial coronary artery disease: A randomized clinical trial. JAMA. 2025; Mar 5. doi:10.1001/jama.2025.0584. [Online ahead of print].
In patients at intermediate risk of coronary artery disease (CAD), coronary artery calcium (CAC) score might help determine which patients would benefit from intensive lipid lowering, but there are no randomized trials of this concept. Thus, the Coronary Artery Calcium Score: Use to Guide Management of Hereditary Coronary Artery Disease (CAUGHT-CAD) trial is of interest. Although not included in traditional CAD risk scores, a family history of early CAD may identify a group in whom the traditional risk scores underestimate risk and could be ideal patients for a CAC-guided approach to management.
Accordingly, these investigators from Australia conducted a prospective, randomized, blind endpoint trial to test the hypothesis that a CAC-informed strategy could slow the progression of coronary plaques over three years in patients who did not meet Australian guidelines for primary prevention pharmacologic therapy, despite having a family history of early CAD (defined as first-degree relatives with a CAD event before 60 years of age and second-degree relatives with an event before 50 years of age). Excluded were patients with a total cholesterol > 250 mg/dL, and low-density lipoprotein (LDL) cholesterol > 193 mg/dL. This resulted in an Australian CAD annual risk estimation of a CAD event of 0.4% to 3%, which was considered intermediate risk.
CAC score was determined in 1,091 such patients. After exclusion of those with a CAC score of 0 or > 400 Agatston units (Au), 449 patients were randomized and underwent coronary computed tomography angiography (CCTA) to determine coronary plaque presence and characteristics. These patients had a mean age of 58 years, 57% were men, mean LDL cholesterol was 129 mg/dL, mean CAC was 69 Au, less than 2% had diabetes, and less than 4% were smokers.
Those in the CAC score-informed group were started on atorvastatin 40 mg/day and those in the usual care group were not. They were followed for three years and then had a repeat CCTA performed. After excluding those with inadequate images, the final population at three years was 365 patients. In the CAC group, LDL cholesterol had decreased to 79 mg/dL and in 84 patients it was < 70 mg/dL, whereas in the usual care group it decreased by 2 mg/dL (P < 0.001). The primary outcome was the change in total plaque volume by CCTA. Other plaque characteristics were secondary endpoints, and clinical characteristics were tertiary endpoints.
Although total plaque volume increased in both groups after three years, it was lower in the CAC score-informed group compared to the usual care group (25 ± 38 mm3 vs. 15 ± 31 mm3 , P = 0.009), as was noncalcified plaque volume (16 ± 32 mm3 vs. 6 ± 29 mm3 , P = 0.002). In the CAC score-informed group, 27 (7%) patients withdrew statin therapy, mainly because of myalgia, gastrointestinal discomfort, or poor adherence. None experienced major statin adverse effects, such as rhabdomyolysis or acute hepatitis. The authors concluded that in primary prevention patients with a family history of early CAD and at intermediate risk of a CAD event, use of a CAC score of more than zero Au but less than 400 Au to target the patients most likely to benefit from statin therapy resulted in a greater reduction in atherogenic lipids and slower plaque progression compared to usual care.
Commentary
The use of CAC score to determine whether statins should be used for primary prevention in intermediate risk patients has been suggested in the U.S. primary prevention guidelines, but there is little evidence to support this recommendation. The CAUGHT-CAD trial randomized intermediate risk patients who also had a family history of premature CAD to usual care, which included optimal lifestyle training, or usual care plus the use of their CAC score to determine the addition of statin therapy.
Only nine patients in the usual care arm received statins. Statin therapy was recommended in the CAC arm if the CAC score was more than zero Au but less than 400 Au, since > 400 Au is considered an indication for statin use and a CAC score of zero Au is not. After a three-year follow-up period, a CCTA was repeated to assess changes in total plaque volume, which was the primary endpoint and served as a surrogate for adverse clinical events.
The results showed that plaque volume increased in both groups, but much less so in the CAC score-informed group. Also, LDL cholesterol levels were reduced in the CAC score-informed group and other plaque characteristics were improved. These results offer strong support for the use of CAC score in intermediate risk patients with an adverse family history.
There are limitations to the study. It is a small study and was underpowered for changes in plaque characteristics, such as noncalcified, fibrofatty, and necrotic core plaques. CCTA images were of inadequate quality in 13% of patients. It was open label, but the CCTA results were blinded.
In my experience, getting young patients (< 40 years of age) with a family history of premature CAD up to the intermediate risk level is challenging with the current risk estimators available. In CAUGHT-CAD, the mean age was 58 years. Yet I am seeing more and more young patients (< 40 years of age) with adverse family histories in my practice, and my CAC score order is rejected by their insurance carrier because they are low risk. We have a way to go in the United States to get the healthcare industry interested in primary prevention.
Michael H. Crawford, MD, is Professor Emeritus of Medicine and Consulting Cardiologist, UCSF Health, San Francisco.
A randomized trial of computed tomography (CT) coronary artery calcium score augmented management vs. usual care of primary prevention patients at moderate risk of a coronary event and with a family history of premature coronary events has shown that, after three years of follow-up, the calcium score group had lower low-density lipoprotein cholesterol levels and smaller total plaque volumes by CT angiography.
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