Has The Warranty Period for a Coronary Calcium Score of Zero Been Revoked?

I’ve seen a flurry of scientific papers and media reports recently suggesting that a zero coronary artery calcium (CAC) score has lost its ability to portend an excellent cardiovascular prognosis. I touched on the zero CAC so-called “warranty period” and whether it applies to younger subjects in a 2019 post entitled “Prevention of Heart Attack and Stroke-Early Detection Of Risk Using Coronary Artery Calcium Scans In The Youngish.”

That post was prompted by the sudden death of the 41-year old son of a patient of mine which highlighted how crucial it is to begin risk assessment for atherosclerotic cardiovascular disease (ASCVD) and potential interventions as early as possible, especially in individuals with a strong family history of premature ASCVD.

We use standard risk factors like cholesterol profile, smoking, age, gender and diabetes to stratify individuals aged 40 to 75 years according to their 10 year risk of ASCVD (using this online risk calculator) but many apparent low risk individuals (often due to inherited familial risk) drop dead or have myocardial infarctions in their forties from ASCVD.

In addition, because increasing age is the major factor driving the risk estimate, women under age 60 and men under age 50 without diabetes or cigarette smoking rarely have a risk estimate that qualifies for drug intervention. Further stratifying this age group’s ASCVD risk with coronary artery calcium (CAC) scans is now widely appreciated.

The 2018 ACC/AHA guidelines finally embraced CAC for

adults 40 to 75 years of age without diabetes mellitus and with LDL-C levels ≥70 mg/dL- 189 mg/dL (≥1.8-4.9 mmol/L), at a 10-year ASCVD risk of ≥7.5% to 19.9%, if a decision about statin therapy is uncertain

They also suggested

If CAC is zero, treatment with statin therapy may be withheld or delayed, except in cigarette smokers, those with diabetes mellitus, and those with a strong family history of premature ASCVD.

The evidence supporting CAC as a risk enhancing factor is immense and includes a 2018 study of 13,644 patients averaging 50 years of age who were followed for a median of 9.4 years. Comparing patients with and without statin exposure, statin therapy was associated with reduced risk of MACE in patients with CAC> zero but not in patients with CAC<zero . The effect of statin use on MACE was significantly related to the severity of CAC with the number needed to treat to prevent 1 initial MACE outcome over 10 years ranging from 100 (CAC 1 to 100) to 12 (CAC >100).

Here’s the figure which encapsulates both the risk prediction power of the CAC (and the benefits of statin treatment restricted to those with >0 (blue lines))

Typically, if we have calculated (using the ASCVD risk estimator) a 10 year risk >7.5% we have a discussion with the patient about beginning drug treatment to reduce risk.
To inform the decision and help us “get off the fence” I usually recommend a CAC. To see how this works in a typical sixty something see my posts here and here.

Some, however, have questioned the value of the CAC in the youngish, claiming that a zero CAC score might lead to deprescribing of potentially valuable statin therapy.

Warranty Period of the Zero CAC

Given the prognostic power of CAC = 0 and the clinical significance of CAC progression, it is important to know when an initial CAC = 0 scan should be repeated, which has been termed the “warranty period.” When a youngish individual converts from zero to nonzero their risk can be better estimated.

Findings published earlier this year from the MESA study (mean age 58 ± 9 years , 63% women, mean 10-year atherosclerotic cardiovascular disease risk 14 ± 13%) in patients with an initial zero CAC showed that the prevalence of CAC >0 increased with time, from 11% at 2 years to 50% at 10 years.

Using a testing yield of 25% (number needed to scan = 4 to detect CAC >0), the estimated time period to CAC conversion of low, intermediate, and high estimated risk men was 7, 4, and 3 years, respectively, and for women was 8, 5, and 3 years, respectively.

We can also see that the “warranty period” of the zero CAC is much less for diabetics (3.4 years) but much higher for those of Chinese ethnicity (7.1%.)

Is CAC of zero of value in Individuals less than 40 years of age?

What about the individual who has a strong family history of premature CAD and is age say 35 or 39 years of age. Do we ignore advanced risk assessment? Very few individuals die in their 30s from ASCVD but I have a number of patients who suffered heart attacks in their forties. In addition, the earlier we can start risk modification the better as the process begins very early in life and accumulates over time.

As I pointed out in 2018

The two sons of another one of my patients both in their late 50s with unremarkable risk factor profiles and both developing anginal type symptoms limiting their activities each underwent multi vessel stent procedures in the last month. If I had seen them  10 to 20 years ago we would have identified the subclinical atherosclerosis building up in their coronaries, started treatment and avoided the need for invasive, expensive procedures.

The Coronary Artery Risk Development in Young Adults (CARDIA) Study demonstrated the early development of nonzero CAC score those less than 30 years of age and the predictive value of the high CAC score for mid life ASCVD events.  

It was  a prospective community-based study that recruited 5115 black and white participants aged 18 to 30 years from March 25, 1985, to June 7, 1986. The cohort has been under surveillance for 30 years, with CAC measured 15 (n = 3043), 20 (n = 3141), and 25 (n = 3189) years after recruitment. The mean follow-up period for incident events was 12.5 years, from the year 15 computed tomographic scan through August 31, 2014.
The conclusions:

Any CAC in early adult life, even in those with very low scores, indicates significant risk of having and possibly dying of a myocardial infarction during the next decade beyond standard risk factors and identifies an individual at particularly elevated risk for coronary heart disease for whom aggressive prevention is likely warranted.

Despite the strong evidence supporting the value of a zero CAC in the young, Medpage Today featured this headline recently:

This paper has been seized on by KOLs to buttress their argument that CAC should not be used at all but, in fact, it does not apply to the individuals I am discussing. The patients in this registry were symptomatic with chest pain that led them to get a coronary CT angiogram. Cardiologists do not use CAC alone to evaluate patients with chest pain

Medpage summarizes it as follows:

Among those with a CAC score of zero, 3% of adults younger than 40 had obstructive CAD compared with 8% of those 70 and older in the large Western Denmark Heart Registry of 23,759 symptomatic patients, reported Martin Bødtker Mortensen, MD, PhD, of Aarhus University Hospital in Denmark, and colleagues.

The risk of myocardial infarction or death in the zero CAC group in the Danish study was very low, <1%, supporting the argument for a zero CAC warranty, but as the authors told Medpage:

“In the meantime, the findings of this study … should be a reminder to physicians that the absence of CAC is not equivalent to the absence of atherosclerosis, particularly in younger adults and women. When CAC scoring is used in these populations, clinicians should remind patients that a CAC score of 0 is not a guarantee against CVD,” the pair concluded.

This is absolutely true. Non calcified plaque can be present in a heart with a zero CAC, especially in men under 50 and women under 60. For those 30 to 50 year olds with a strong family history or very abnormal lipids we look very carefully for other risk markers and we repeat the CAC score every 3 to 5 years.

These patients are almost never on statin therapy because due to their young age, their calculated 10 year ASCVD risk is too low to consider starting statin therapy so we almost never deprescribe a statin in this group.

Risk Enhancers Beyond CAC

Vascular screening in young subjects may detect subclinical atherosclerosis as measured by thickening of the carotid wall (IMT) or early carotid plaque prior to the formation of calcium in the coronary arteries. Advanced IMT precedes the formation of soft plaque in arteries and only later is calcium deposited in the plaque.

Simultaneous with assessing these patients for subclinical atherosclerosis with imaging techniques I check three key biomarkers

1. Lipoprotein (a) (a highly atherogenic, inherited marker that is not measured in standard lipid panels)
2. Apolipoprotein B (apoB, now recognized as our single best measure of atherogenic dyslipidemia)
3. High-sensitivity CRP (the most studied and useful measure of inflammation)

We can blame a lot of heart disease on lifestyle: poor diets and lack of exercise are huge factors leading to obesity, diabetes, hypertension and hyperlipidemia, but in many patients I see who develop heart disease at an early age, lifestyle is not the issue, it is the genetic cards that they have been dealt.

Until we develop reliable genetic methods for identifying all those at high risk it makes sense to utilize methods such as vascular screening or coronary calcium to look for atherosclerosis in individuals with a family history of premature CAD.

The earlier we start looking, the earlier we can intervene and lower the slow and progressive build up of atherosclerotic plaque in the arterials beds.

Given, that we have extremely safe and effective medications that can help  individuals dramatically reduce their lifelong risk of heart attack it makes sense to look early and intervene accordingly.

Antiatherosclerotically Yours,

-ACP