LABORATORIO DE URGENCIAS

Coronary Calcium Score and Treatment on Plaque Progression in Familial Coronary Artery Disease

A Randomized Clinical Trial

Nitesh Nerlekar, MBBS, MPH, PhD^1,2,3; Sheran A. Vasanthakumar, MBBS²; Kristyn Whitmore, BSN^1,4; et alCheng Hwee Soh, PhD¹; Jasmine Chan, MBBS²; Vinay Goel, MBBS²; Jacqueline Ryan, MN, NP⁵; Catherine Jones, MBBS⁶; Tony Stanton, MBChB, PhD⁷; Geoffrey Mitchell, MBBS, PhD⁸; Andrew Tonkin, MD⁹; Gerald F. Watts, DSc, PhD, MD⁵; Stephen J. Nicholls, MBBS, PhD^2,3,9; Thomas H. Marwick, MBBS, PhD, MPH^1,4,10

  ¹Baker Heart and Diabetes Research Institute, Melbourne, Victoria, Australia
  ²Victorian Heart Hospital, Melbourne, Victoria, Australia
  ³Victorian Heart Institute, Monash University, Melbourne, Victoria, Australia
  ⁴Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
  ⁵Royal Perth Hospital and School of Medicine, University of Western Australia, Perth, Western Australia,   
  ⁶Regional Imaging, Hobart, Tasmania, Australia
  ⁷Sunshine Coast University Hospital, Birtinya, Queensland, Australia
  ⁸University of Queensland, Brisbane, Queensland, Australia
  ⁹School of Population Health and Preventive Medicine, Monash University, Victoria, Australia
  ¹⁰Royal Hobart Hospital, Hobart, Tasmania, Australia

                                                                                                   JAMA. Published online March 5, 2025. doi:10.1001/jama.2025.0584

ABSTRACT

Importance  Coronary artery calcium (CAC) scoring provides prognostic information, especially in patients at intermediate risk for coronary artery disease (CAD). However, the benefit of combining CAC score with a primary prevention strategy has not been tested in a randomized trial.
Objective  To assess whether combining the CAC score with a prevention strategy can be used to limit plaque progression in intermediate-risk patients with a family history of premature CAD.
Design, Setting, and Participants  Prospective, randomized, open-blinded end point clinical trial in 7 hospitals across Australia (between 2013 and 2020; the last date of follow-up was June 5, 2021). Asymptomatic people aged 40 to 70 years with a first-degree relative with CAD onset at younger than 60 years old or second-degree relative with onset at younger than 50 years old were recruited from the community.
Interventions  Intermediate-risk participants underwent CAC scoring. Those with a CAC score greater than 0 but less than 400 underwent coronary computed tomography angiography (CCTA) and were randomized to CAC score–informed prevention or usual care.
Main Outcomes and Measures  Follow-up CCTA was obtained at 3 years, with plaque volume measured by an independent core laboratory. The primary outcome was total plaque volume, with further analysis for calcified and noncalcified plaque volume.
Results  This study included 365 participants (mean [SD] age, 58 [6] years; 57.5% male); 179 in the CAC score–informed and 186 in the usual care groups. Compared with usual care, the CAC score–informed group showed a sustained reduction in total (mean [SD], −3 [31] mg/dL vs −56 [38] mg/dL; P < .001) and LDL (mean [SD], −2 [31] vs −51 [36] mg/dL; P < .001) cholesterol levels at 3 years, which was associated with a reduction in pooled cohort equation risk calculation (mean [SD], 2.1% [2.9%] vs 0.5% [2.9%]; P < .001). Plaque progression was greater in usual care than CAC score–informed participants for total plaque volume (mean [SD], 24.9 [37.7] mm³ vs 15.4 [30.9] mm³; P = .009), noncalcified plaque volume (mean [SD], 15.7 [32.2] mm³ vs 5.6 [28.5] mm³; P = .002), and fibrofatty and necrotic core plaque volume (mean [SD], 4.5 [25.8] mm³ vs −0.8 [12.6] mm³; P = .02). These plaque volume changes were independent of other risk factors including baseline plaque volume, blood pressure, and lipid profile.
Conclusions and Relevance  The combination of CAC score with a primary prevention strategy in intermediate-risk patients with a family history of CAD was associated with reduction of atherogenic lipids and slower plaque progression compared with usual care. These data support the use of CAC score to assist intensive preventive strategies in intermediate-risk patients.

Introduction

The integration of traditional coronary artery disease (CAD) risk factors and lifestyle factors¹ identifies up to 50% of people as being at intermediate risk, in whom the optimal management is uncertain. This is especially problematic in the presence of a family history of premature CAD. Although not included in most CAD risk scores,² family history is associated with the development of CAD, imaging evidence of CAD, and lifetime risk.^3-5 Although a family history of premature CAD can provoke treatment at lower thresholds, standard pharmacological or lifestyle interventions show only modest returns in the intermediate-risk group.⁶
The coronary artery calcium (CAC) score is a marker of subclinical atherosclerosis and a powerful risk predictor⁷ that could guide the management of these patients. To date, observational evidence indicates that the CAC score can be used to reclassify risk,^8,9 with most incident events occurring in participants with CAC scores of 100 or greater.⁹ Visual presentation of CAC scores has been shown to positively influence patient behavior and improve lifestyle-related risk factors.¹⁰ To date, no randomized trials have studied whether treatment decisions based on CAC score provide an outcome benefit. This randomized clinical trial of intermediate-risk participants with a family history of premature CAD was designed to demonstrate whether the progression of CAD could be altered by the use of the CAC score.

METHODS

*Study Design
The CAUGHT-CAD (Coronary Artery Calcium Score: Use to Guide Management of Hereditary Coronary Artery Disease; ACTRN12614001294640) randomized clinical trial was a prospective, randomized, blinded end point trial that sought to determine whether a CAC score–informed strategy could slow the progression of coronary plaque volume over 3 years in people who did not satisfy current Australian guidelines for primary prevention
The study received ethical and governance approval at each site, with written informed consent provided by all patients. This study is reported according to Consolidated Standards of Reporting Trials guidelines.
*Patient Selection
Asymptomatic statin-naive participants, aged 40 to 70 years, with a family history of premature CAD (defined as a CAD event in a first-degree relative at <60 years old or second-degree relative at <50 years old) were recruited to 7 study sites in 5 Australian cities, mainly by direct advertising in the community via social media and large workplaces. At the screening visit, it was ascertained that the participants did not satisfy the contemporary criteria for statin use (total cholesterol level ≤250 mg/dL and low-density lipoprotein cholesterol [LDL-C] <193 mg/dL) (to convert total cholesterol and LDL-C to mmol/L, multiply by 0.0259). Participants at intermediate risk for CAD (annualized risk, 0.4%-3%) on the basis of the Australian risk calculator (https://www.cvdcheck.org.au/) progressed to CAC scoring. A more detailed description of the selection process, exclusion criteria, and clinical variables has been published.¹¹
*Coronary Computed Tomography
Coronary computed tomography angiography (CCTA) was performed at baseline and repeated after 3 years to calculate longitudinal change in plaque volume. All sites were moderate- to high-volume cardiac CT centers with trained, on-site cardiac radiographers and radiologists. Appropriate governance for calibration of CT imaging was performed on a regular basis. β-Blockade was used to control heart rate to less than 60 beats per minute. Further details about CT methodology and measurement plaque and plaque components¹² are provided in eFigures 1 and 2 and eTable 1 in Supplement 3).
*Postrandomization Management and Follow-Up

CAC Score–Informed Group
The intervention was based on a standardized, nurse-based intervention in which the participant’s CT images were used to communicate about disease. The intervention included education about self-management of risk and lifestyle, care coordination, and risk modification. Patients were followed up at 6-month intervals until 36 months. In addition to standard blood pressure control, participants in the CAC score–informed group all commenced lipid-lowering therapy. In participants with drug intolerance, dose reductions and/or statin substitution were used to maintain statin therapy, with dose reduction in the first instance.
Usual Care Group
These participants underwent standard education about CAD prevention and guideline-based risk management (weight control; treatment of hypertension, dysglycemia, and hypertension) from their general practitioner, blinded to the CAC score. All were statin naive at the time of randomization and none were recommended to start statin therapy. If statin therapy was commenced later by their treating physician, this was reported to the clinical trial coordinators. Because formal plaque quantification was performed after all baseline and follow-up imaging was completed, the results of the CCTA or plaque volumes were not available during the management phase. During 3 years of follow-up, participants’ lipid profiles and other risk factors were reassessed at annual review, and adherence was reinforced.
*Safety
Patients with CAC scores greater than 400 or significant coronary stenoses at CCTA were referred for functional testing and referred for invasive angiography and intervention at the discretion of their physicians. Patients were followed up for coronary interventions and major adverse cardiac events (death, myocardial infarction, stroke). Progress in the study was presented to an independent data and safety monitoring board.
*Statistical Analyses
The original study design¹¹ anticipated that 638 patients would need to undergo serial imaging to have 80% power to detect a difference between the groups of 20 mm³ with an SD of 90 mm³.¹³ Because recruitment needed to be concluded before this goal (to complete 3-year follow-up by the end of the funding period), we anticipated that serial imaging in 388 patients would provide 80% power to detect a between-group difference of 20 mm³ (2-sided P = .05), if the SD was 70 mm³, projected in a scenario in our methods article and reported in a similar 3-year follow-up CT study comparing patients taking statins vs control patients (mean [SD] total plaque volume change, 36.3 [67.7] mm³).¹⁴ Assuming a 15% dropout rate, this would require a total recruitment of 450 patients.
Cholesterol data were converted from millimoles per liter to milligrams per deciliter using standard conversion factors. Data analyses were performed with descriptive statistics. Despite a mild degree of right skewing for plaque volumes, we chose to not use log-transformation to allow better interpretation of the clinical data, consistent with other serial plaque quantification studies. Delta plaque volumes were normally distributed and suitable for parametric testing. Analysis was performed following intention-to-treat and per-protocol principles. Missing and excluded data were imputed using multiple imputation by chained equations with predictive mean matching with 365 participants with all available data (number of imputations = 5, number of iterations = 0). Five donors were used in the imputation and the stability was confirmed by checking the estimates and standard errors across different imputations.
The 3-year change in plaque volume within group was compared using paired t tests and between groups with unpaired t tests. Linear regression modeling was used to assess the features associated with plaque progression with inclusion into a multiple variable model if univariable P < .20. Beta coefficients with respective 95% confidence intervals are reported. A binary categorical by categorical interaction term of treatment group and CAC score of 1 to 100 or CAC score of 101 to 400 was additionally added to multivariable modeling. Data are presented as mean (SD) or median (IQR) as appropriate. A 2-sided P < .05 was considered statistically significant. The majority of analyses was performed within Stata MP18 (StataCorp). Regression analyses were performed in both Stata and R version 4.4 (R Foundation for Statistical Computing), and no differences in results were identified. Multiple imputation was performed in R. Graphics were created using GraphPad Prism version 10.

RESULTS

*Baseline Characteristics
Of the 1091 original intermediate-risk participants recruited between 2015 and 2018, 449 with a CAC score greater than 0 and less than 400 were randomized. Patient withdrawal during the trial caused 27 exclusions, and at the end of 3-year follow-up (2021), 57 patients were excluded from plaque analysis due to either missing CT images, suboptimal quality or artifact-affected images, or unmatched CT technical parameters (Figure 1). The characteristics of the final 365 patients suitable for plaque measurements (Table 1) were not significantly different from the original 449 randomized patients (eTable 2 in Supplement 3). The mean (SD) effective radiation dose for the baseline CAC scan among participants was 0.78 (0.32) milliSieverts.
*Progress Over Follow-Up
The CAC score–informed group (compared with usual care) showed a reduction in total cholesterol and LDL-C levels at 3 years. The mean achieved LDL-C level was 79 mg/dL (Table 1), and 84 individuals achieved LDL-C levels less than 70 mg/dL (compared with 6 in the usual care group, of whom 3 had a statin commenced by their physician). This drove a change in clinical risk of the pooled cohort equation (Table 2). Both groups showed a change in waist circumference and systolic blood pressure without a significant difference between them. No other differences in risk factors or comorbidities were identified.
*Change in Plaque Volume
Plaque volume increased in both groups after 3 years. The primary end point (change in total plaque volume) was lower in the CAC score–informed group compared with usual care (Table 2, Figure 2).
For the secondary end points, the CAC score–informed group demonstrated a significant difference in the change of noncalcified plaque and summed fibrofatty and necrotic core plaque volumes, with a reduction in the latter in the CAC score–informed group. No difference was seen with calcified plaque volume change. Examples of changes in plaque are shown in Figure 3. The relationship between change in LDL-C values and change in plaque (eFigure 3 in Supplement 3) demonstrated a significantly greater proportion of patients with favorable reduction in LDL-C level and less plaque progression in the CAC score–informed group; this relationship was seen across all plaque subtypes. There was no difference in total plaque progression (mean [SD], 19.5 [39.8] mm³ vs 20.5 [33.1] mm³; P = .82) between the 90 individuals who achieved LDL-C levels less than 70 mg/dL at follow-up compared with the 275 individuals with LDL-C levels greater than 70 mg/dL. There was no significant association of Δ LDL-C with plaque change (β coefficient, −2.18 [95% CI, −5.1 to 0.7]; P = .14).
A CAC score–informed strategy was independently associated with change in total plaque volume after adjustment for multiple risk factors, clinical variables, and plaque burden represented as either total baseline plaque volume or CAC score greater than 100 (Table 3). Patients with a CAC score less than 100 showed significant change in only noncalcified plaque volume, but those with a CAC score greater than 100 showed significant differences for total, noncalcified, and summed fibrofatty and necrotic core plaque volume (eTable 3 in Supplement 3). A statistically significant interaction was identified between the treatment group and the group with CAC scores greater than 100, indicating significant mitigation of plaque progression in the CAC score–informed individuals. Because of the exclusion of patients due to dropout and technical limitations, we also derived results using multiple imputation (eTable 4 in Supplement 3). This also showed differences in total plaque volume, noncalcified volume, and summed fibrofatty and necrotic core plaque volume.
*Statin Adherence, Dosing, and Safety
Nine patients in the usual care group had a statin commenced at physician discretion prior to the end of 3-year follow-up. These participants were prescribed either atorvastatin or rosuvastatin—all but 1 at a lower dose-equivalent than in the trial. Five people commenced therapy within 3 months of the scan, 2 within 6 months, and 2 within 12 months.
Twenty-seven individuals in the CAC score–informed group withdrew their statin therapy. There were no reported major statin adverse effects such as rhabdomyolysis or acute hepatitis, with the most common causes of withdrawal being myalgia, gastrointestinal discomfort, or inadequate adherence. No differences were seen in average serum creatinine kinase levels at baseline and after 3 years. There were new incidences of diabetes in both groups, but no difference between groups (usual care, 5.9% vs CAC score–informed, 6.7%; P = .74). Most CAC score–informed patients continued the initial 40-mg starting dose of atorvastatin (n = 129), with 5 patients changing to rosuvastatin and 18 patients requiring a dose reduction (14 patients changed to 20 mg, 2 to 5 mg, and 1 to 10 mg). The difference in follow-up plaque volume change remained significant in the per-protocol analysis and similar changes were seen in the noncalcified plaque volume and summed fibrofatty and necrotic core plaque volumes, with no difference in calcified plaque (eTable 5 in Supplement 3). Statin dose intensity did not have any effect on plaque volume change (P = .09), although LDL-C level was reduced by a greater amount with higher-dose (≥40 mg) atorvastatin (mean [SD], −65.6 [38.6] mg/dL vs −42.4 [34.7] mg/dL; P = .007). The mean (SD) plaque volume difference in those taking higher-dose statin was 16 (35) mm³ vs 13.9 (24.6) mm³ with a lower statin dose (P = .73). Excluding patients in the CAC score–informed group who were no longer taking a statin at study end, and patients from the usual care group who commenced statin therapy, there remained a significant difference in plaque volume change at follow-up (CAC score–informed group, 14 [31] mm³ [n = 152] vs usual care group, 23.9 [37] mm³ [n = 177]; P = .01).
*CT Safety and Cardiovascular Outcomes
During CCTA, there were 4 reported adverse events—all transient symptoms of rash and hypotension and none required hospital admission or ongoing therapy. Two patients withdrew from the study prior to repeat CT due to the need for coronary revascularization (1 from each study group). In patients completing the study, there were 9 cardiac events: 1 transient ischemic attack (usual care), 2 atrial fibrillation episodes (both in the CAC score group), 1 pacemaker insertion (usual care), and 5 revascularization (1 myocardial infarction in the usual care group, 2 percutaneous interventions for angina in the usual care group and 2 in the CAC score group). There was 1 death (cancer-related).

DISCUSSION

In this randomized clinical trial, patients with a family history of premature CAD, and concomitant estimated intermediate short-term clinical cardiovascular disease risk, showed progression of coronary atheroma over 3 years’ follow-up. The combination of CAC score with a primary prevention strategy in intermediate-risk patients with a family history of CAD was associated with slower plaque progression compared with the standard of care. Additionally, significant reductions in LDL-C level, noncalcified plaque volume, and summed fibrofatty and necrotic core plaque volume phenotypes were observed.
CAC score is an important tool for identification of subclinical atherosclerosis. Observational studies have supported the benefits from therapeutic intervention for patients with CAC scores greater than 400 and derisking in patients without CAC scores. The most recent iteration of US primary prevention clinical practice guidelines (which followed design of this study) suggested considering statin initiation in intermediate-risk patients with CAC scores between 0 and 400.¹⁵ However, the global practice of CAC utilization still suggests equipoise.¹⁶ The use of the CAC score has been described as beneficial in patients with a positive family history of premature CAD, but the evidence base remains scant.¹⁷
The management of intermediate risk—not least the issue of adherence—is difficult in the absence of personalized risk prediction. Family history of CAD is a common presenting concern for patients and is considered as a risk enhancer rather than being incorporated into most risk calculators.¹⁵ The CAC score has been used as a potential risk arbiter and has demonstrated excellent prognostic validation.¹⁸ However, it has not seen widespread uptake for various reasons, including inconsistent incremental potential over traditional risk-factor prediction.¹⁹ However, the power of the CAC score also lies in the ability to visually convey the presence of atherosclerosis, unique to that individual, and this has been shown to have significant effects in improving patient adherence to risk reduction therapies.¹⁰ In contrast, in the absence of CAC score information, few intermediate-risk patients are initiated with therapy, and they demonstrate plaque progression, which is known to be associated with adverse cardiovascular events.²⁰
The use of CT coronary plaque quantification as a surrogate for clinical events in this trial was based on the intravascular ultrasound literature that has associated plaque volume and components with outcome.²⁰ Noncalcified plaques (fibrofatty and necrotic core plaque volume) are most likely to result in future myocardial infarction,²¹ while calcified plaques are considered a more stable phenotype. While contemporary studies are shifting to use of a noncalcified phenotype as a primary end point, at the time of study design, total atheroma volume was chosen as a primary end point because this is an accurate reflection of overall plaque burden with an abundance of supportive clinical data indicating its risk potential. Although performed in a distinct risk-enhanced population with HIV, the results of the recent Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE)²² support the notion that the plaque reduction shown in the CAUGHT-CAD trial is likely to translate to improvement in outcome. In REPRIEVE, the regression of noncalcified plaque in low-risk participants with HIV treated with pitavastatin²³ matched a 55% risk reduction. The similarities between the REPRIEVE and CAUGHT-CAD trials include randomized assignment to statin therapy, treatment of lower-risk patients than would normally be provided primary prevention, and a follow-up duration of approximately 2 years before repeat imaging. However, the results of CAUGHT-CAD build on REPRIEVE in 3 fundamental ways. First, the CAUGHT-CAD trial involved a whole prevention strategy (including presentation of CAC score images and intensive practitioner-led lifestyle intervention), rather than medication alone. Second, the risk enhancer in CAUGHT-CAD was family history, rather than inflammation and other risk factors associated with risk in HIV. Third, rather than treat the entire risk-enhanced population, a strategy based on CAC score was highlighted.
The CAUGHT-CAD trial showed a reduction in plaque progression, rather than a reduction in plaque in the treatment-initiated group. This may be due to the low-risk cohort, lack of titration to defined LDL-C targets, and lack of high-dose therapy (atorvastatin, 40 mg, was the maximal dose). It is notable that the calcified plaque volumes increased in both groups, including in the on-treatment analysis. Statins have been shown to result in increased calcification of plaques and some studies have concluded that a higher calcific burden in statin-taking compared with statin-naive patients should be expected.²⁴ However, more contemporary data in CCTA studies have suggested that while statins regress higher-risk plaque volumes, they are more likely to result in a transformation in the density of calcific plaques without significantly altering the calcified plaque volume.²⁵
The results of this study support the use of the CAC score as a rapid and reproducible adjunct to assessment in those with intermediate clinical risk. A CAC score greater than 400 is well established as a risk threshold warranting more intensive prevention treatment, but lower CAC scores have fewer data demonstrating prognostic benefits of therapy. This study demonstrates risk of plaque progression with CAC scores greater than 100, with lesser plaque progression in statin-treated participants—these results support observational evidence of reduced risk when treatment is initiated with CAC scores greater than 100.²⁶ While about 75% of patients in this study had CAC scores less than 100, there was also less noncalcified plaque progression in this group of CAC score–informed participants, which may suggest a benefit of therapy in these patients as well. While CAC score may eventually be superseded by CT-derived plaque quantification, CCTA is currently used in symptomatic individuals, rather than in primary prevention. Moreover, CT-derived plaque quantification remains investigational, largely reflecting technical challenges, including different output and processing algorithms from varying software.

LIMITATIONS

There are several limitations of this study. First, although distribution of change of plaque measures was narrower than anticipated (eg, the SD for Δ total plaque was <40 mm³), this relatively small study was underpowered for the secondary analyses, which could explain some negative results. Second, quantitative plaque calculation was inherently dependent on excellent image quality. As algorithms stratify plaque based on Hounsfield unit thresholds, image quality may influence the parameterization of plaque. Therefore, 13% of patients were excluded from final analysis due to image quality concerns, albeit a similar exclusion rate to other studies involving longitudinal CCTA plaque quantification. Reassuringly, there were no differences in risk score and LDL-C level reduction between the excluded and finally included groups, and replacement of the missing data in a multiple imputation model provided the same findings. Third, there were very few adverse outcomes as expected from a small primary prevention cohort, although there is plausible and growing evidence that beneficial changes in plaque correlate to benefits in outcomes.²⁷ Fourth, this was an open-label design, which lacks the rigor of double-blind studies. For example, the small reduction in weight and blood pressure on follow-up in the usual care group could represent a Hawthorne effect. However, the CCTA results (the primary trial end point) were blinded to all investigators and patients.

CONCLUSIONS

In individuals at intermediate risk of CAD with a family history of premature CAD, a practitioner-led, CAC score–informed lifestyle intervention with moderate-intensity statin therapy resulted in less progression of plaque parameters that are associated with future adverse cardiovascular risk. This reduced plaque progression paralleled a sustained reduction in risk estimation scores and LDL-C levels that reflected high levels of adherence by use of CAC score as part of a risk reduction strategy. These results may support the use of the CAC score to inform the use of more intensive preventive strategies in intermediate-risk patients.

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