Lp(a) and CAC Levels Independently Predict Long-term ASCVD Risk

Higher levels of lipoprotein(a) portend a person will have greater risk of developing atherosclerotic cardiovascular disease (ASCVD) over 15 years regardless of their coronary artery calcium (CAC) score, according to newly analyzed data from four large prospective cohort studies.

However, if their CAC score was zero, incident event rates in those with elevated Lp(a) remained low.

With better awareness of the role Lp(a) may play in risk stratification—and the recently updated American dyslipidemia guidelines giving a class 1 recommendation to measuring the biomarker at least once in a lifetime—the population known to have elevated Lp(a) is growing and clinicians need more information as to what to do about it, according to lead author Harpreet S. Bhatia, MD (University of California-San Diego, La Jolla).

“We see that some people have high levels and don’t have events and some people have more modestly elevated levels and have an event at an earlier age,” he told TCTMD. “There’s a need to further understand risk among these people, first, because it’s such a large population, but second, because we see a lot of clinical heterogeneity in who actually has disease.”

These findings, published online this week in JACC and set to be presented at next week’s American College of Cardiology Scientific Session, indicate that CAC scoring is a “good way to risk stratify people with high Lp(a),” said Bhatia. This is especially true when the CAC score is zero.

Commenting on the study for TCTMD, Ron Blankstein, MD (Brigham and Women’s Hospital, Boston, MA), agreed that ASCVD risk is “very heterogeneous” among patients with high Lp(a). “The challenge is that as we test more individuals, we also identify more individuals who have a high lipoprotein(a), and that is still an area of uncertainty for a lot of clinicians,” he said. “As a preventive cardiologist, I may see, on a given day, two individuals who have a very high lipoprotein(a): one has no plaque at all and one might have a substantial amount of plaque. You can’t say: ‘Because your lipoprotein(a) is high you’re bound to have atherosclerosis, [or] you’re bound to have cardiovascular events.’”

Long-term Follow-up

For the study, researchers included data from 11,319 people (mean age 56 years; 54% women) who were enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA), Coronary Artery Risk Development in Young Adults (CARDIA) study, Framingham Offspring Study (FHS-OS), or Jackson Heart Study (JHS). Almost half of the population (46.9%) had a CAC of 0 plus low Lp(a) (< 50 mg/dL), while 11.6% had no CAC but an Lp(a) of more than 50 mg/dL, 32.9% had CAC > 0 and low Lp(a), and finally 8.7% had CAC > 0 and Lp(a) greater than 50 mg/dL.

In total, the population reported 1,569 incident ASCVD events over a mean 14.8 years of follow-up. Without adjusting for CAC, Lp(a) > 50 mg/dL was associated with a greater risk of ASCVD events (HR 1.24; 95% CI 1.09-1.41) as well as coronary heart disease events (HR 1.32; 95% CI 1.12-1.55). CAC > 0, without adjusting for Lp(a), was associated with a higher likelihood of incident ASCVD (HR 2.44; 95% CI 2.14-2.77) and coronary heart disease (HR 3.30; 95% CI 2.78-3.92).

After adjusting for CAC score, Lp(a) > 50 mg/dL was still associated with an increased risk of ASCVD events (HR 1.24; 95% CI: 1.09-1.41).

The greatest risk occurred in patients with both Lp(a) > 50 mg/dL and CAC > 0 (HR 3.03; 95% CI 2.52-3.64). In those with zero CAC but elevated Lp(a), the risk of events was higher than in those with zero CAC and Lp(a) < 50 mg/dL (HR 1.28; 95% CI 1.01-1.61), but the absolute risk was low (4.88 vs 3.83 per 1,000 person-years).

Results were similar when CAC was stratified into categories of 0, 1-99, 100-299, ≥ 300, where risk grew alongside CAC but stayed lower among those with Lp(a) levels below 50 mg/dL compared with above 50 mg/dL.

There were no variations in the main findings when participants were analyzed by age and sex, though overall greater absolute risk was observed in those aged 55 years and older.

“I was a little surprised that it appears coronary artery calcium scoring works almost as well in people with high Lp(a), despite this propensity towards noncalcified plaque,” Bhatia said. “I was surprised at how consistent the results were across the different studies and different demographics that we looked at.”

In an accompanying editorial, Parveen K. Garg, MD, MPH (University of Southern California, Los Angeles), Christie M. Ballantyne, MD (Baylor College of Medicine, Houston, TX), and Michael D. Shapiro, DO (Wake Forest University, Winston-Salem, NC), write that the “more consequential” finding from the study was that among individuals with zero CAC, the ASCVD event rates were low overall even when Lp(a) was high.

“This modest absolute difference highlights the critical distinction between relative and absolute risk and reinforces the strong negative predictive value of a CAC score of 0, even in the presence of a genetically mediated risk factor,” they write.

The implications for primary prevention are notable, the editorialists continue. “Among middle-to-older age individuals with elevated Lp(a) who are not already considered high risk, greater consideration of CAC screening may be appropriate to refine risk assessment and guide the intensity of preventive interventions,” they write. “CAC can identify those persons who benefit from earlier, more aggressive lipid-lowering as well as other cardioprotective therapies while sparing others from overtreatment.”

Blankstein agreed, noting that all these measures must be put in context with a patient’s age and other risk factors.

“If I see a patient with a calcium score of zero [but with] a very high lipoprotein(a), for example, higher than 200 nm/L, or even 300 or 400 nm/L, I am going to be concerned,” he said. “I certainly am not going give the all clear to that patient. They’re certainly not out of the woods despite the calcium score of zero. I will want to treat them with lipid-lowering therapy, which we know decreases LDL, which is still very important in these patients.”

Ongoing Questions

There remain some big questions in this space. For one, Bhatia said that though “you can be fairly comfortable” that a middle-aged patient with zero CAC and a high Lp(a) is at low-risk for events over the next 10 years, “what remains to be seen, and what we’re interested in pursuing studies on as well, is if you get a calcium score of zero and don’t put someone on aggressive preventive therapies, when would be a reasonable time to repeat a calcium score?”

Also, the implications for prognosis among younger patients need more work, he added. “We had individuals as young as the forties in the study and we didn’t see a change generally in the findings based on age. But that being said, there’s probably, younger individuals with high Lp(a) levels, and we need more data to really understand how to use calcium scoring, especially if calcium develops later on in life.”

The ongoing ACCLAIM-Lp(a) and OCEAN(a)-PreEvent trials should hopefully give more insight into how to treat patients who have not yet had ASCVD events, Blankstein said.

“Calcium score, potentially in the future, would actually be a gatekeeper for who might benefit from Lp(a)-lowering therapies,” he commented. “If we march this forward, if we have effective therapies, we certainly would not want to give an expensive treatment to someone who has a high lipoprotein(a) if they don’t have plaque and they’re low risk. And conversely, that patient who has a high calcium score, we would say they may now qualify for some of these therapies.”