Risk Factors Still Matter for Patients With Zero CAC Score: MESA

Even among adults with zero coronary artery calcium (CAC), cigarette smoking, diabetes, and hypertension are still independently associated with incident atherosclerotic cardiovascular disease (ASCVD) events, according to 16-year follow-up data from the MESA study.

The absence of detectable atherosclerosis on CAC testing has been said to provide a ”warranty period” against the future risk of ASCVD, but these new findings reinforce the message that traditional risk factors are still important predictors of risk in the setting of zero calcification, say researchers. 

Mahmoud Al Rifai, MD, MPH (Baylor College of Medicine, Houston, TX), who led the study, said the findings should help physicians inform patients at low-to-intermediate ASCVD risk who might be on the fence about starting lifelong preventive therapies, such as statins. Based on the 2018 US cholesterol guidelines, patients at intermediate risk of ASCVD may forgo or delay statin treatment if the CAC score is zero unless there are other risk factors, such as smoking, diabetes, or a strong family history of ASCVD (class IIa). 

“If the calcium score is more than zero, I would just go ahead and treat,” Al Rifai told TCTMD. “If it's zero, I may consider withholding unless the patient is a current smoker, has diabetes, hypertension, or a family history of premature ASCVD. Then I may consider starting statin therapy.” For patients who turn down statins, their calcium score can be rechecked in about 3 to 5 years, he added.

What’s noteworthy here, though, is an emphasis on the fact that patients with zero CAC do not carry zero risk, said Sadiya S. Khan, MD (Northwestern University Feinberg School of Medicine, Chicago, IL), who commented on the study for TCTMD. “Diabetes, hypertension, and smoking are strong predictors of ASCVD,” she said. “I think the important thing to highlight is that those risk factors are true whether you have a coronary artery calcium score of zero or not.”

Similarly, David Playford, MBBS (The University of Notre Dame, Fremantle, Australia), also emphasized that risk factors for ASCVD matter no matter how good the coronary arteries might look on a CAC scan. “The more risk factors, the more likely it is a future ASCVD event will occur,” he told TCTMD in an email. “Along similar lines, the more risk factors, the more likely it is that instituting preventative measures will decrease ASCVD event rates.”

Zero CAC Doesn’t Equal Zero Events

For the study, published online last week ahead of print in Circulation, Al Rifai along with senior author Salim Virani, MD, PhD (Baylor College of Medicine, Houston, TX), and colleagues looked at 3,416 patients (mean age 58 years; 63% female) with zero baseline CAC from MESA. Over a median follow-up period of 16 years, there were 189 ASCVD events, of which 91 were coronary heart disease (CHD), 88 were stroke, and 10 were both CHD and stroke events. This resulted in an unadjusted ASCVD event rate of ≤ 5 per 1,000 person-years among individuals with a CAC score of 0 for most risk factors, except for current smokers (7.3 per 1,000 person-years), and those with diabetes (8.9), hypertension (5.4), and chronic kidney disease (6.8).

On multivariate analysis, current cigarette smoking (HR 2.12; 95% CI 1.32-3.42), diabetes (HR 1.68; 95% CI 1.01-2.80, and hypertension (HR 1.57; 95% CI 1.06-2.33) were independently associated with ASCVD.

Looking at incident CHD events alone, only cigarette smoking was significantly associated (HR 2.19; 95% CI 1.14-4.17), while hypertension was the only risk factor associated with stroke on its own (HR 1.91; 95% CI 1.09-3.35).

In sex-stratified analyses, family history of premature ASCVD was linked with incident ASCVD events among women but not men. Notably, there was no interaction between sex and any cardiovascular risk factors on multivariate analysis, but Al Rifai said this should be taken with a grain of salt as the study was “a little underpowered to look at sex differences.”

The study has clinical implications for younger patients in particular, he said.

“Calcium scores are typically zero in younger people because most of their plaque is noncalcified, but that doesn't mean they can't still have a high plaque burden of noncalcified plaques which are still likely to rupture,” said Al Rifai. “So, I would still be cautious of a calcium score of zero in someone with a significant family history of premature ASCVD and I would still recommend statins in those people, despite calcium score of zero, and that affirms what the guidelines recommend.”

Starting lifelong statin treatment “is a big commitment,” he continued. “We do want [patients] to be informed and educated about their disease course. Their knowledge of their calcium score really helps them make that decision and so it's just all about shared decision-making and empowering our patients [about] their disease risk. And I think that's really where the power of calcium lies.”

The findings also “confirm that the warranty period of CAC = 0 may extend up to 15 years among most individuals,” the authors write.

However, Khan said she would like to see the discussion of zero CAC “as a warranty” integrated with consideration of other risk factors. “I think that's what this paper shows very nicely is that it's not an island—coronary artery calcium is not the only thing that matters.” Clinicians need to take care of “the whole person,” she continued, which means assessing risk factors, managing lifestyle, smoking cessation, and—“if it's useful”—assessing coronary artery calcium.

Khan homed in specifically on smoking, which has likely increased over the course of the COVID-19 pandemic, as an important risk factor. “I think we have had a lot of obviously different things that we're focusing on as a country for public health, but [don’t let] go of the emphasis of these really, really powerful risk factors for ASCVD like smoking,” she said.

As far as repeating CAC scoring in patients with risk factors, Playford said it seems “reasonable” to do so every 5 years, although “in patients with diabetes, an even shorter period between CAC investigations may be appropriate.”

Future Research Avenues

Going forward, Khan said she would like to see future research look at how tools like CT angiography can be used to help identify higher-risk individuals, especially those who have zero CAC but might have had soft of noncalcified plaque.

Additionally, Playford said he would like to see randomized trials look at how treating patients with zero CAC, or basing any lipid-lowering therapy on CAC, may affect ASCVD outcomes. “The cholesterol/LDL story has not been addressed at all in this study because of the very high use of cholesterol-modification therapies,” he said. “This data is essential, since cholesterol treatment based around CAC has become standard clinical practice.”

Al-Rifai made a similar point, calling for a clinical trial that allocates statin therapy based on CAC score. “I think there is still a knowledge gap in that there is no trial to date that has tested that paradigm,” he said.