Less Plaque Progression With CAC-Guided Primary Prevention: CAUGHT-CAD

Using coronary artery calcium (CAC) scoring to guide treatment in intermediate-risk patients, as opposed to usual care, results in a slower development of atherosclerotic plaque, including high-risk fibrofatty and necrotic core plaque volumes, according to findings from the CAUGHT-CAD randomized trial.

The CAC-guided strategy also led to significant improvements in LDL cholesterol and a better 10-year predicted risk of atherosclerotic cardiovascular disease (ASCVD), investigators reported this week in JAMA.

Senior investigator Thomas Marwick, MBBS, PhD (Baker Heart and Diabetes Institute, Melbourne, Australia), believes the evidence of coronary calcification helped patients stick with lipid-lowering therapy during the 3-year study period.  

“I think the adherence to medical therapy is what made it a positive study,” Marwick told TCTMD. “Almost everyone stayed on medication after being shown their CT images, compared to the wider community where only 50% stay on statins in primary prevention at 12 months. I think the benefit of CAC is as much of an educational tool as it is as a guide for doctors to start preventive therapy. It moves the patient’s perception from: ‘I’ve got risk factors that could or could not be important in 20 years’ time’ to ‘I have evidence of early coronary disease.’”

The shift in perception is “a real motivation to get on with medical therapy,” he said.

Khurram Nasir, MD (Houston Methodist, TX), who has long advocated for the use of CAC screening to guide treatment decisions in select patients, called CAUGHT-CAD a “game changer.”

“As a preventive cardiologist, one of the biggest dilemmas that we have while managing patients is the question: what is your risk?” said Nasir. “That simple question demands a smarter answer. We have spent decades trying to estimate risk with risk scores, but why are we still guessing? [With] risk scores like the pooled cohort equations, the PREVENT score, and even the Australian risk scores, there is a growing realization that they are inherently imprecise. They don't detect disease. They just estimate probabilities.”

The result is that patients are misclassified, with some overtreated with lipid-lowering therapy while others are undertreated. “Many are falling through the cracks,” Nasir told TCTMD. “This is particularly important in a younger population where conventional risk models always fail to capture early disease.”  

For this reason, Nasir thinks it’s time to shift from risk estimation to disease detection. CAC testing is easily available, noninvasive, and a clear, objective marker of coronary disease, he said.

Currently, the 2019 American College of Cardiology/American Heart Association primary-prevention guidelines state there should be a discussion about the risks and benefits of statins in intermediate-risk patients (10-year ASCVD risk ≥ 7.5% to < 20%). If there are factors that enhance the risk, such as family history of ASCVD, treatment is favored, but if there is uncertainty around the decision, CAC testing can be used to help with treatment decisions, according to the guidelines.

CAUGHT-CAD Study

The randomized, open-blinded CAUGHT-CAD study took place at seven hospitals across Australia between 2013 and 2020, and included asymptomatic people 40 to 70 years who had a first-degree relative with CAD onset before age 60 or a second-degree relative with CAD onset before age 50. All participants underwent CAC testing, and those with a score greater than 0 but less than 400 underwent coronary CT angiography (CCTA).

In total, 179 participants were randomized to the CAC-informed prevention strategy. The nurse-led intervention used CT images to speak with participants about ASCVD and included education around lifestyle and risk modification. In addition to standard blood-pressure control, those in the intervention arm all started lipid-lowering therapy.

I think the adherence to medical therapy is what made it a positive study. Thomas Marwick

For usual care, 186 participants underwent standard education about disease prevention and guideline-based risk management from their general practitioner, with both blinded to the CAC results. Patients were statin-naive at the start of the study, and none were recommended to start treatment initially, but they could be prescribed by their doctor at any time point. Only nine patients started a statin prior to the end of the trial.

On CCTA, plaque progression at 3 years was significantly greater in patients treated with usual care. Total plaque volume, the study’s primary endpoint, increased by a mean of 15 mm³ in the intervention arm compared with 24.9 mm³ with usual care (P = 0.009). There were also significantly greater increases in noncalcified plaque volume, the amount of fibrofatty plaque, and the amount of necrotic plaque in the usual-care group. When stratified by CAC score, those with a score less than 100 had less progression of noncalcified plaque compared with usual care. In those with a score of 100 to less than 400, there was significantly less progression of total, noncalcified, and fibrofatty and necrotic core volumes.

In a regression model, baseline plaque volume was a stronger predictor of plaque progression than were other risk factors, including LDL cholesterol.   

With cholesterol, there was a significant between-group difference in total- and LDL-cholesterol levels (P < 0.001 for both). In the CAC-informed intervention, total and LDL cholesterol declined from 210 and 130 mg/dL at baseline to 154 and 79 mg/dL, respectively. With usual care, total and LDL cholesterol was essentially unchanged, going from 212 and 129 mg/dL at baseline to 208 and 127 mg/dL. 

The 10-year risk of ASCVD increased from 6.6% to 7.0% at 3 years in the intervention arm compared with an increase from 7.2% to 9.4% in the usual-care group (P < 0.001 between-group difference). There was no difference in body mass index, waist circumference, or blood pressure between the two strategies.

Middle Ground

Marwick believes CAC testing should be standard in people at intermediate risk of ASCVD, such as those with a 0.5% to 2.0% annual risk, and especially in people with a family history of CAD.

“Some of them worry a lot about their risk, but in this trial half had a CAC score of zero,” he said. The intervention, he added, is also scalable to larger primary-prevention populations. “We have done some cost-effective analyses in the US and [Australia], and based on our numbers and the literature’s outcome data, it looks pretty good.” 

While CAUGHT-CAD investigators used a surrogate endpoint, prior studies have linked noncalcified plaque, such as fibrofatty and necrotic core plaque volume, to an increased risk of clinical events, such as MI. In the contemporary REPRIEVE trial with pitavastatin, which was conducted in a different patient population, lipid-lowering therapy was associated with plaque regression and led to a significant reduction in risk of MACE, the researchers point out.

Less plaque progression is “a crucial predictor of future cardiovascular events,” said Nasir, noting that the higher-risk cohort—those with a CAC score 100 or greater—had a notable slowdown of plaque development.

We have spent decades trying to estimate risk with risk scores, but why are we still guessing? Khurram Nasir

While it might be argued that all patients in CAUGHT-CAD could have received statin therapy on the basis of family history, not all will have subclinical evidence of ASCVD, said Nasir.

“That is going to lead to possible overtreatment in many patients,” he said. “Family history is also subjective and incomplete—not many patients will have atherosclerotic disease. It lacks precision, because like anything else, family history is going to suggest susceptibility [to ASCVD], but it does not tell us who already has the disease.”

The CAC-informed strategy in intermediate-risk patients is the “middle ground” that avoids missing patients who’d benefit from primary prevention with statins but aren’t picked up by risk estimation and overtreating those without subclinical disease.

In a viewpoint published in JAMA Cardiology, Alexander Zheutlin, MD (Northwestern University Feinberg School of Medicine, Chicago, IL), and colleagues highlight different clinical scenarios when CAC testing is used “too early, too late, and too often.”

For example, CAC testing is not needed when a patient is already on a statin, is 65 years and older with numerous ASCVD risk factors, and is younger and lacks risk factors. It should also not be used in people with a 10-year ASCVD risk less than 5% unless they have a strong lifetime risk, such as those with a family history or who are current smokers.

Future Clinical Trials

Nasir, who wrote an editorial along with Ron Blankstein, MD (Brigham and Women’s Hospital, Boston), said the present study also challenges traditional ways of doing CVD prevention trials.

Currently, these trials require thousands of patients, years of follow-up, and massive financial investment to measure the effect on hard clinical endpoints. It might be time to use measurable changes in plaque burden as a surrogate endpoint, he said.  

“If we keep designing trials that are going to take 10 to 15 years to show an effect on hundreds and thousands of patients, we're always going to be a decade behind in prevention,” said Nasir. “This study shows there is an alternative. You can focus on the plaque burden as a surrogate outcome. It's a measurable short-term indicator of long-term risk.”

Adopting the surrogate endpoint would allow for smaller, quicker, more cost-effective studies, and regulators could explore conditional approvals on the basis that follow-up be done to confirm clinical benefit. Such approaches have been successfully applied in oncology, said Nasir.

Michael Blaha, MD (Johns Hopkins University School of Medicine, Baltimore, MD), who also wrote an editorial in JAMA Cardiology, notes that the National Institutes of Health is planning to fund an early intervention trial in young adults with evidence of early atherosclerosis.