Both lipoprotein(a) and coronary artery calcium (CAC) are independently associated with an increased risk of atherosclerotic cardiovascular disease, with the highest risk seen among people with elevated Lp(a) and CAC ≥ 100, a new analysis of the MESA study shows.

While CAC has become a more-routine clinical test, the medical community has not yet embraced Lp(a) in the same way, because the question of what to do about an elevated measure remains unanswered. Some preventive cardiologists, however, have started using it to justify more aggressive lipid-lowering therapy.

These data can give them confidence that CAC can still be used as a tiebreaker for these decisions, according to senior author Parag H. Joshi, MD (UT Southwestern Medical Center, Dallas, TX). “A calcium score of zero in this population does reassure us that their risk is low, and that’s helpful at least at the 10-year level,” he told TCTMD. “And then similarly, if their score is quite high, then there’s reason for concern—as there would be if you just had the calcium score, but even more so when they have a high Lp(a) and a high calcium score.”

Commenting on the study for TCTMD, Michelle O’Donoghue, MD (Brigham and Women’s Hospital, Boston, MA), pointed out that several studies have now demonstrated the power of CAC to predict risk and identify patients who would benefit from statins. “The current study now builds upon earlier findings by showing that elevations in Lp(a) further potentiate that risk,” she wrote in an email.

Further, “most guidelines now endorse measurement of Lp(a) at least once in a person’s life, but we know that this is still infrequently done,” she added. “The current findings underscore the value of obtaining an Lp(a) value and to factor that into risk assessment.”

Zero CAC Trumps Elevated Lp(a)

For the study, published in the March 1, 2022, issue of the Journal of the American College of Cardiology, Anurag Mehta, MD (Emory University School of Medicine, Atlanta, GA), Joshi, and colleagues looked at Lp(a) and CAC measurements from 4,512 asymptomatic participants of the MESA study (mean age 61.9 years; 52.5% women; 36.8% white; 29.3% Black; 22.2% Hispanic, and 11.7% Chinese). There were 476 incident atherosclerotic cardiovascular disease (ASCVD) events over 13.2 years follow-up.

Elevated Lp(a), defined as the highest race-specific quintile, as well as CAC score 1-99 and ≥ 100 each were associated with increased risk of ASCVD over 10 years. There was no interaction identified between Lp(a) and CAC score.

Independent Associations With 10-Year ASCVD Risk

Those with elevated Lp(a) and CAC ≥ 100 were at the highest risk of ASCVD in the study compared with individuals who had nonelevated Lp(a) and zero CAC (HR 4.71; 95% CI 3.01-7.40). Those with elevated Lp(a) and zero CAC had a similar risk (HR 1.31; 95% CI 0.73-2.35).

The findings confirm that at least over a decade, a “calcium score of zero sort of trumps the Lp(a) being high,” Joshi said.

However, he was not expecting to see the CAC score “tell the whole story” up to a score of 100 at least. “So if you have a calcium score that’s between 1 and 99, the Lp(a) being high or low doesn’t matter as much,” he said. “The risk is about the same, but where it really does change is above a hundred.”

This is where the implications of the study lie, Joshi continued. “They’re reflecting slightly different risk pieces to what leads to heart attacks and strokes. . . . Lp(a) can be high and not lead to risk, and those are people with the calcium score of zero. But when it is causing a lot of plaque buildup, it’s generally the riskier kind of patient phenotype, if you will.”

‘Primary-and-a-Half Prevention’

In an accompanying editorial, Sotirios Tsimikas, MD (UC San Diego, La Jolla, CA), also pointed out the varying determinants of both CAC and Lp(a), citing no “convincing association” between the two.

“The striking findings in the present study are that Lp(a) and CAC provide independent risk prediction, but when combined with CAC ≥ 100 demonstrate a nearly fivefold higher hazard ratio for Lp(a) levels in the top fifth of the population at large, representing >1 billion people globally,” he writes, adding that the 10-year risk of an ASCVD event of 23% in this analysis is “a rate typically seen in the lower range of secondary prevention studies.”

This means, Tsimikas says, that when a patient without known CVD is found to have either CAC ≥ 100 or Lp(a) > 50 mg/dL, “the next step in the risk evaluation should be to measure either Lp(a) or CAC, respectively, if not already performed to identify the patients at highest risk.” These patients can be denoted to be at secondary prevention risk, he continues, “and, pending approval of specific Lp(a)-lowering agents, treatment and targets of therapy for all risk factors should be according to this higher risk.”

Joshi said he is looking forward to more studies of Lp(a), especially in the secondary prevention space, but noted the main challenges for these will be affordability and recruiting participants at high enough risk to capture an adequate number of events over follow-up to show a difference between the drug and placebo.

“I would urge the companies [manufacturing drugs for this population] to look at that group [as] ‘primary-and-a-half prevention,’ where they haven’t had a heart attack or stroke but their risk is at that level,” he said. This would be “a nice compromise in terms of [having] enough events that you can power a study for and not break the bank in terms of cost to run that trial.”

Tsimikas added that while “it may be expensive to logistically perform CAC as part of study inclusion and leading to many screening failures, this cost may be offset by enriching the study in the patients without prior events most likely to benefit from Lp(a)-lowering.”

Another issue in this space is that values for Lp(a) vary greatly by ethnicity, so using the same threshold for elevated measurements across the board may not be ideal, Joshi said. “Black people have much higher Lp(a) on average as a population than whites, and so does that mean they are more likely to get into these trials?” he asked, noting that this would actually “be great because there’s a lot of underrepresentation.” The ongoing HCHS/SOL study looking at Hispanic and Latino populations should also add needed information to the literature, he said.

O’Donoghue, too, noted the “marked variability in Lp(a) levels” by race. “The authors took the approach of using race-based categorization,” she noted. “However, there may still be value for applying a race ‘agnostic’ approach as an Lp(a) value of > 50 mg/dL in a Black patient may carry the same prognostic significance as individuals of other races.”

Mendelian randomization studies have indicated a causal role for Lp(a) in the progression of atherogenesis, O’Donoghue said, “and the current findings serve as additional supportive evidence in that regard.” Ongoing trials are looking at novel therapeutics that lower Lp(a) by more than 75%, she added.