Serial coronary artery calcium (CAC) scans showing calcium progression have prognostic significance for all-cause mortality. However, how to use this information and what therapies may be of value remain unknown, according to a study in the December issue of the Journal of the American College of Cardiology: Imaging.

"This is the first large study following patients for one to 16 years and submitted to repeat CT scans demonstrating incremental increase in mortality with progression of CAC over baseline score, time between scans, demographics and cardiovascular risk factors," the authors wrote, adding that it confirms previous smaller studies.

Matthew J. Budoff, MD, director of cardiac CT at UCLA Harborview Medical Center in Los Angeles, and colleagues assessed 4,609 consecutive asymptomatic individuals with electron beam tomography (EBT) who were referred by primary care physicians for CAC measurement. Patients underwent sequential scans at least 10 months apart and the repeat scans were ordered by their primary physicians to assess change in atherosclerosis risk over time.

Researchers also looked at three ways that progression of CAC is assessed:

• The absolute difference between follow-up and baseline CAC score;
• Percent annualized differences between follow-up and baseline CAC score; and
• Difference between square root of baseline and square root of follow-up CAC score greater than 2.5 (the "SQRT method").

They found that progression of CAC in those with a baseline CAC score greater than zero was significantly associated with mortality regardless of the method used to assess progression.

After researchers adjusted for baseline score, age, sex and time between scans, the best CAC progression model to predict mortality was the SQRT method, followed by a greater than 15 percent yearly increase.

"We had a big enough cohort to determine that all three methods of assessing calcium progression work. Any way you look at it, CAC progression is associated with death," Budoff said in an interview.

A baseline CAC score of zero was not predictive of progression or all-cause mortality. "This further validates the concept that a baseline zero score has a significant warranty period for both future cardiovascular events and progression of atherosclerosis," Budoff said.

In a previous study noted by Budoff, Min et al suggested that a CAC score of zero "affords at least a five-year warranty period, and our study strongly supports that evidence with even longer follow-up and interscan periods."

What unique characteristics do those with zero CAC scores have? "We don't know," Budoff said. "We will have to use carefully designed studies such as MESA [Multi-ethnic Study of Atherosclerosis] to determine differences between people who stayed at zero long term and those that converted. One analysis of MESA data suggested a relationship with incident calcium and traditional risk factors, but nothing about characteristics of individuals who don't calcify over time. Are they genetically different or do they have a certain lipid profile or is there something else that identifies them as being unique? We don't know that yet, but such information would be very helpful to the field."

In the current study, nearly three-quarters of the participants were men, and the overall average age was 60.

"You can extrapolate our results to pertain equally to women as men, even though there were only 25 percent women in our study," Budoff said. "It's a large study, so we still had more than 1,000 women. In addition, other studies have shown that calcium in men and women is predictive of negative results."

In future studies, researchers should keep in mind that women generally present with calcium about 11 years later in life than men, Budoff said. "This is a factor that needs attention when designing such studies."

In the current study, more women and younger men tended to have baseline CAC scores of zero, he said.

The prevalence of cardiovascular risk factors in the current study was high: current tobacco use (6.2 percent), diabetes (7.1 percent), high blood pressure (23.6 percent), hypercholesterolemia (41.2 percent) and family history of coronary artery disease (40.4 percent).

Despite having other risk factors, however, the CAC score was a strong independent predictor of mortality and mortality significantly increased with increasing CAC score.

Out of the 4,609 individuals scanned, there were 288 deaths. Broken down, there were 236 deaths out of 2,866 participants with a baseline CAC score greater than zero, and 204 deaths out of 2,183 participants with a baseline CAC score greater than 30. Fifty-two deaths occurred in the cohort of 1,743 patients with a baseline CAC score of zero.

The investigators reported that having CAC at baseline and exhibiting a significant progression of calcium was a significant predictor of future mortality, while having calcium without exhibiting significant progression was only marginally associated with mortality. There was no association with disease progression and death in those with no baseline calcium.

While this study involved the use of an EBT scanner (which is rarely used today), Budoff and colleagues have previously shown that CAC calculations from a 64-slice CT scanner correlate well with EBT data, "being 99 percent similar." He added that he and colleagues now perform all CAC exams on a 64-slice scanner and radiation exposure is generally less than 1 mSv per exam.

When to repeat CAC scans is up for debate, but Budoff has a simple rule. If the initial CAC score is more than 100, perform another scan in two years. If it's below 100, perform a repeat scan in three years; if it's below 10 or at zero, wait at least five years.

New ACCF/AHA (American College of Cardiology Foundation/American Heart Association) guidelines for how to assess cardiovascular risk in asymptomatic adults released in November for the first time acknowledged the value of (CAC) scoring. However, there was not enough evidence to recommend serial CAC exams.

"The MESA study is looking at serial CAC scanning and should have data in about a year," Budoff said. "If those findings in more than 6,000 participants are concordant with ours, it should be good enough for the guidelines to recommend repeat CAC scans."

The next leg of research is to determine how therapeutic interventions in those with CAC progression affect outcomes. Whether aggressive lifestyle modifications and/or statin therapy reduce the overall calcium burden or have an effect on vulnerable plaque or change other mechanisms responsible for adverse events is not entirely known, Budoff said.