Calcium Burden Drives CV Risk Whether Coronary Disease Is Obstructive or Not

December 07, 2020

Coronary artery calcium (CAC) score as a measure of plaque burden more reliably predicts future cardiovascular (CV) risk in patients with suspected coronary disease (CAD) than whether or not the disease is obstructive, a large retrospective study suggests.

Indeed, CV risk went up in tandem with growing plaque burden regardless of whether there was obstructive disease in any coronary artery, defined as a 50% or greater stenosis by computed tomographic angiography (CTA).

The findings argue for plaque burden as measured by CAC score, rather than percent-stenosis severity, for guiding further treatment decisions in such patients, researchers say.

The research was based on more than 20,000 symptomatic patients referred to diagnostic CTA in the Western Denmark Heart Registry who were then followed for about 4 years for major CV events, including death, myocardial infarction, or stroke.

"What we show is that CAC is important for prognosis, and that patients with no stenosis have similar high risk as patients with stenosis when CAC burden is similar," Martin Bødtker Mortensen, MD, PhD, Aarhus University Hospital, Aarhus, Denmark, told | Medscape Cardiology.

The guidelines "distinguish between primary and secondary prevention patients" based on the presence or absence of obstructive CAD, he said, but "our results challenge this long-held approach. We show that patients with nonobstructive CAD carry similar risk as patients with obstructive CAD."

In practice, risk tends to be greater in patients with obstructive compared with nonobstructive CAD. But the reason "is simply that they normally have higher atherosclerosis burden," Mortensen said. "When you stratify based on atherosclerosis burden, then patients with obstructive and nonobstructive CAD have similar risk."

The analysis was published online today in the Journal of the American College of Cardiology with Mortensen as lead author.

Until recently, it had long been believed that CV-event risk was driven by ischemia — but "ischemia is just a surrogate for the extent of atherosclerotic disease," agreed Armin Arbab-Zadeh, MD, PhD, MPH, who is not connected with the current study, in an interview.

The finding that CV risk climbs with growing coronary plaque burden "essentially confirms" other recent studies, but with "added value in showing how well the calcium scores, compared to obstructive disease, track with risk. So it's definitely a nice extension of the evidence," said Zadeh, director of cardiac CT at Johns Hopkins University School of Medicine, Baltimore.

"This study clearly shows that there is no ischemia 'threshold,' that the risk starts from mild and goes up with the burden of atherosclerotic disease. We were essentially taught wrong for decades."

Mortensen agrees that the new results "are in line with previous studies showing that atherosclerosis burden is very important for risk." They also help explain why revascularization of patients with stable angina failed to cut the risk of MI or death in trials like COURAGE, FAME-2, and ISCHEMIA. It's because "stenosis per se explains little of the risk compared to atherosclerosis burden."

In the current analysis, for example, about 65% of events were in patients who did not show obstructive CAD at CTA. Its 23,759 patients with symptoms suggestive of CAD were referred for CTA from 2008 through 2017; 5043 (21.2%) were found to have obstructive disease and 18,716 (78.8%) either had no CAD or nonobstructive disease.

About 4.4% of patients experienced a first major CV event over a median follow-up of 4.3 years. Only events occurring later than 90 days after CTA were counted in an effort to exclude any directly related to revascularization, Mortensen noted.

The risk of events went up proportionally with both CAC score and the number of coronaries with obstructive disease.

The number of major CV events per 1000 person-years was 6.2 for patients with a CAC score of 0, of whom 87% had no CAD by CTA, 7% had nonobstructive CAD, and 6% had obstructive CAD.

The corresponding rate was 17.5 among patients with a CAC score >100-399 for a hazard ratio (HR) of 1.7 (95% CI 1.4 - 2.1) vs a CAC score of 0.

And it was 42.3 per 1000 patient-years among patients with CAC score >1000, HR 3.4 (95% CI, 2.5 - 4.6) vs a CAC score of 0. Among those with the highest-tier CAC score, none were without CAD by CTA, 17% had nonobstructive disease, and 83% had obstructive CAD.

The major CV event rate rose similarly by number of coronaries with obstructive disease. It was 6.1 per 1000 person-years in patients with no CAD. But it was 12.3 in those with nonobstructive disease, HR 1.3 (95% CI 1.1 - 1.6), up to 34.7 in those with triple-vessel obstructive disease, HR 2.9 (95% CI 2.2 - 3.9), vs no CAD.

However, in an analysis with stratification by CAC score tier (0, 1-99, 100-399, 400-1000, and >1000), obstructive CAD was not associated with increased major CV-event risk in any stratum. The findings were similar in each subgroup with 1-vessel, 2-vessel, or 3-vessel CAD when stratified by CAC score.

Nor did major CV event risk track with obstructive CAD in analyses by age or after excluding all patients who underwent coronary revascularization within 90 days of CTA, the group reported.

"I believe these results support the use of CTA as a first-line test in patients with symptoms suggestive of CAD, as it provides valuable information for both diagnosis and prognosis in symptomatic patients," Mortensen said. Those found to have a higher burden of atherosclerosis, he added, should receive aggressive preventive therapy regardless of whether or not they have obstructive disease.

The evidence from this study and others "supports a CTA-based approach" in such patients, Zadeh said. "And I would go further to say that a stress test is really inadequate," in that it "detects the disease at such a late stage, you're missing the opportunity to identify these patients who have atherosclerotic disease while you can do something about it."

Its continued use as a first-line test, Zadeh said, "is essentially, in my mind, dismissing the evidence."

An accompanying editorial agrees that "it is time that the traditional definitions of primary and secondary prevention evolve to incorporate CAC and CTA measures of patient risk based on coronary artery plaque burden."

But the same article, from Todd C. Villines, MD, and Patricia Rodriguez Lozano, MD, of the University of Virginia Health System, Charlottesville, pointed out some limitations of the current study.

For example, they write, "The authors compared CAC with ≥50% stenosis, not CAC to comprehensive, contemporary coronary CTA," and so "did not assess numerous other well-validated measures of coronary plaque burden that are routinely obtained from coronary CTA that typically improve the prognostic accuracy of coronary CTA beyond stenosis alone." Also not performed was "plaque quantification on coronary CTA, an emerging field of study."

Also, the editorialists note, noncontrast CT as used in the study for CAC scoring "is generally not recommended as a standalone test in symptomatic patients. Most studies have shown that coronary CTA, a test that accurately detects stenosis and identifies all types of coronary atherosclerosis (calcified and noncalcified), has significantly higher diagnostic and prognostic accuracy than CAC when performed in symptomatic patients without known coronary artery disease."

Mortensen has disclosed no relevant financial relationships. Disclosures for the other authors are in the report. Villines and Rodriguez Lozano have disclosed no relevant financial relationships. Zadeh discloses receiving grant support from Canon Medical Systems.

J Am Coll Cardiol. Published online December 7, 2020. Full text, Editorial

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