Absence of CAC May be Protective Even in Patients With Very High Cholesterol

Symptomatic patients with severe hypercholesterolemia who do not have any evidence of coronary artery calcium (CAC) appear to be at lower risk of atherosclerotic cardiovascular disease (ASCVD) and mortality than what might be expected given their LDL cholesterol levels, according to the results of a new study.  

The findings suggest that even among patients with severely elevated LDL cholesterol, noninvasive imaging might be used to stratify patients who don’t require aggressive medical therapy, say investigators.

“In patients with very high LDL cholesterol, it’s fair to start them on statin therapy,” lead investigator Martin Bødtker Mortensen, MD, PhD (Aarhus University Hospital, Denmark), told TCTMD. “These are middle-aged adults who are expected to live many years, so atherosclerosis can develop over time if we didn’t do anything for them. But in my opinion, before you start to intensify treatment further—if you think the LDL cholesterol is still uncontrolled by just the statin—I would think it would be a good idea to see the underlying plaque burden, to see if it makes sense to start additional therapies.”

Both the US and European guidelines strongly recommend the use of statins for the prevention of ASCVD in patients with LDL cholesterol levels of 190 mg/dL or greater. In the European Atherosclerosis Society/European Society of Cardiology (EAS/ESC) 2019 guidelines, these patients are considered to be at high risk for ASCVD. As such, it’s recommended that physicians reduce LDL cholesterol by more than 50% from baseline and aim for an LDL target of less than 70 mg/dL.

However, achieving that target often requires additional medications, such as ezetimibe or a PCSK9 inhibitor, on top of maximally tolerated statin therapy, say investigators.

Ann Marie Navar, MD, PhD (UT Southwestern Medical Center, Dallas, TX), who wasn’t involved in the study, stressed that physicians should be very cautious when interpreting these latest results. People with extremely high LDL levels are more likely to have premature/early coronary artery disease, yet they would have been excluded in this analysis. Also, the median age of people in the study was just 58 years, meaning they were a young group.

“Clinically, when we think about cardiovascular disease prevention, we are thinking about prevention over a lifetime, not 4 years,” Navar told TCTMD. “We know from countless studies that people with very high LDL cholesterol are at extremely high risk of developing atherosclerotic cardiovascular disease, and that risk accumulates over time. We also know that statins are very safe and effective in lowering this risk.”

Given the low short-term event rate, “it may be reasonable to not use extremely expensive therapies, like PCSK9 inhibitors, but that’s more of a cost consideration,” she added. “Again, when we are treating someone with LDL that high, it’s to prevent long-term events, not just short-term ones.”

Zero CAC Protective Even at High LDL

Previous studies have shown that the burden of atherosclerosis can be quite heterogeneous across different patient populations, including those with and without cardiovascular disease, as well as those with multiple ASCVD risk factors, according to Mortensen. Recent studies, for example, have shown that a “sizeable proportion” of patients with severe hypercholesterolemia don’t have evidence of calcified plaque. CAC burden has been demonstrated in multiple studies to stratify patients into higher- or lower-risk categories.

“We wanted to know if in those with high LDL levels, is the [ASCVD] risk also heterogeneous?” he said. “Or are all the patients who have high LDL cholesterol at high risk?”

The new analysis, which was published February 11, 2022, in JAMA Network Open, included 23,143 symptomatic patients (55.6% women) from the Western Denmark Heart Registry who were referred for cardiac intervention and underwent coronary computed tomographic angiography (CCTA).

Overall, 46.3% of patients had no detectable calcified or noncalcified plaque. In terms of CAC scores, 53.3% had a score of zero. For the patients with zero CAC, 86.8% had no detectable plaque and 13.2% had noncalcified plaque. Of the 438 people with noncalcified plaque on CCTA, 43 (9.8%) had obstructive noncalcified plaques.

Stratified by cholesterol levels, 46.2% of 948 patients with LDL cholesterol levels ≥ 190 mg/dL had a CAC score of zero. Interestingly, the proportion of patients with zero coronary calcification was similar to those with lower cholesterol. For example, 49.5% of those with LDL levels < 77 mg/dL had a zero CAC score. Looking specifically at patients with a CAC score of zero, most patients had no calcified plaque regardless of LDL levels, but the presence of noncalcified plaque increased in a stepwise fashion with increasing LDL cholesterol. In those with zero CAC, noncalcified plaque was present in 11.4% of patients with LDL cholesterol < 77 mg/dL and in 22.8% of patients with LDL levels ≥ 190 mg/dL.

After a median follow-up of 4.2 years, the absence of calcified and noncalcified plaque was associated with low rates of death and ASCVD (stroke and MI), across the range of LDL cholesterol levels. In the population of patients with a CAC score of zero, the event rate in all patients regardless of LDL cholesterol level was 6.3 per 1,000 person-years. The event rate was equally low in patients with zero CAC and LDL cholesterol levels ≥ 190 mg/dL: 6.9 events per 1,000 person-years.

To TCTMD, Mortensen said the study shows that in patients with zero CAC, “it would be of extremely limited benefit to give more than a statin to such individuals, even though it would be guideline-recommended.” While LDL cholesterol drives atherosclerosis, Mortensen said there is some variability in the amount of atherosclerosis that will develop with high LDL cholesterol levels. “And you won’t have an event if you don’t have atherosclerotic disease,” he said. “If you find those without atherosclerosis, then you’ve found a group that are relatively protected from the high LDL.”

Michael Blaha, MD (Johns Hopkins University School of Medicine, Baltimore, MD), one of the study authors, said that in patients with an LDL cholesterol level > 190 mg/dL but without detectable plaque, he would still recommend a moderate- or high-intensity statin. That might be optional in an older patient, but he’d still advocate for the lipid-lowering therapy. “If LDL was markedly high, I may recommend a statin and ezetimibe,” he told TCTMD. “If there was no plaque, I would not recommend expensive add-on therapy like a PCSK9 inhibitor and I would not recommend a baby aspirin.”

Those recommendations, he added, are consistent with the new treatment guidelines from the National Lipid Association, which use CAC to guide prevention strategies for ASCVD risk reduction.

One concern is that patients with severe dyslipidemias might have a higher burden of noncalcified plaque. In the analysis, though, ASCVD/mortality rates in patients with zero CAC were only slightly higher in patients with evidence of noncalcified plaque. Mortensen said the results suggest that noncalcified plaque doesn’t appear to be a “big problem” in these middle-age adults. 

For those with a CAC score of zero, the presence of noncalcified obstructive plaque on CCTA was associated with higher ASCVD/death. This was particularly pronounced in those with LDL levels ≥ 190 mg/dL (17.7 events per 1,000 person-years). What this shows is that using a CAC score of zero to solely guide practice will miss a small proportion of patients at high risk of events, say the investigators.  

Young Patients, Short Follow-up

For Navar, the study does not alter her recommendation—supported by all the major guidelines—to start statin therapy in patients with LDL cholesterol levels > 190 mg/dL regardless of what imaging shows. One concern about the present study, she noted, is that some patients seem to be looking for reasons not to use statins, yet it’s critical to remember that LDL cholesterol particles are a fundamental cause of atherosclerosis.

“When LDL is elevated, so is long-term cardiovascular risk,” she said. “We’d never tell someone who smoked they shouldn’t quit because they don’t have coronary artery calcification or plaque, nor would we fail to treat someone with a systolic BP over 160 [mm Hg] because their risk of cardiovascular events is not high in the next 4 years. Given the safety of statins, and known risks of LDL cholesterol, we should approach LDL cholesterol in the same way.”

Navar added that one of the striking findings from the Western Denmark Heart Registry is that just 55% of patients with LDL levels > 190 mg/dL at baseline were on statin therapy at 1 year, which is a missed opportunity for prevention. 

In an editorial, Raul D. Santos, MD, PhD (University of São Paulo Medical School Hospital, Brazil), highlighted the known implications of LDL cholesterol—that it is a causal factor of ASCVD and people with severe hypercholesterolemia are at high risk for adverse events independent of other risk factors or biomarkers. CAC, on the other hand, is a surrogate for plaque presence and burden, and studies have shown that its absence is associated with low risk for ASCVD, even in people with severe hypercholesterolemia.

This latest study, writes Santos, “extends the apparent ‘safety bubble’ when CAC or plaque is absent to people with severe hypercholesterolemia and possible symptoms of coronary artery disease.” Like Navar, he emphasizes that the study does not mean that people with zero CAC and severe hypercholesterolemia should not be treated with statins, especially younger patients, given their lifetime risks. Imaging might be helpful, he added, to guide use of expensive therapies, such as PCSK9 inhibitors, for those who still have elevated LDL cholesterol levels.