coronary artery calcium dec plaque progression?

 the CAUGHT-CAD trial was done to see if adding coronary artery calcium (CAC) scoring to our calculated cardiovascular risk would lead to a decrease in the progression of atherosclerotic plaques (see coronary calcium and statin dec plaque progression JAMA2025 in dropbox, or doi.org/10.1001/jama.2025.0584). Overall, this was not a decisive trial, but it provided a segue to me to discuss the relative merits and weaknesses of CAC scores and benefits of coronary CT angiography (CCTA)

 

Details:

-- in this prospective, randomized, open-blinded endpoint clinical trial in seven hospitals across Australia, 365 participants 40 to 70 years old who were asymptomatic and had a first-degree relative with coronary artery disease (CAD) younger than 60 years old or a second degree relative with CAD onset at younger than 50 years old, from 2013-2020.

    -- these participants all had intermediate cardiovascular risk and were not to be on statins, per the Australian guidelines, and underwent CAC scoring; those with a CAC score greater than zero but less than 400 had coronary CT angiography (CCTA), and they were randomized to CAC score-informed prevention or usual care:

        -- CAC score-informed group (n=179): counselled about self-management of cardiovasc risk and lifestyle, care coordination and risk modification. they were followed every 6 months and all started on lipid-lowering therapy with atorvastatin 40 mg

        -- usual care group (n=186): received education on CAD prevention and guideline-based management of weight, hypertension, and dysglycemia (not defined in the article); they were blinded to their CAC scores

-- baseline characteristics:

    -- mean age 58, 57.5% male, BP 129/79 mmHg

    -- total cholesterol 211 mg/dL, HDL 59, LDL 130, triglycerides 97

    -- comorbidities: hypertension 22%, dyslipidemia 11% (no definition of what this means, in the article or supplement),

    -- 10-year ASCVD risk assessment (includes age, sex, total cholesterol, HDL, systolic BP, diabetes, and smoking status): 7%

    -- 5-yr Australian CVD score (age, sex, smoking status, BP, total and HDL cholesterol, EKG evidence of LVH): high risk defined as >10%, low risk as <2%

    -- coronary artery calcium score (CAC): mean 68, median 34, at least 100 in 47%

    -- total plaque 116 mm³, noncalcified plaque 87 mm³, fibrofatty and necrotic core 18 mm³, calcified plaque 28 mm³, fibrous plaque 68 mm³, fibrofatty plaque 131 mm³, necrotic core plaque 6 mm³

    -- cumulative lesion length 24 mm, vessel volume 326 mL, lumen volume 211 mL

 

-- CCTA was subsequently obtained in all participants at three years with plaque volume measured to assess changes by the intervention

 

primary outcome: total plaque volume, with further analysis for calcified and noncalcified plaque volume

 

Results:

-- overall changes from baseline:
    --LDL levels:

        -- CAC score-informed group: LDL decreased from 130 mg/dL to 79 mg/dL (ie mean difference of 51 mg/dL), and 84 of them achieved an LDL <70mg/dL

        --usual care group: LDL decreased minimally from 129 mg/dL to 127 mg/dL (ie mean difference of 2 mg/dL), with 6 achieving an LDL <70, though 3 of them were prescribed a statin by their physicians

    -- waist circumference and systolic blood pressure were not statistically significantly different between the groups, and there were no other differences in risk factors or comorbidities identified

 

Primary outcome:

-- total plaque volume at three years:

    -- CAC score-informed group: increased from 116.9 to 132.2 mm³, increase of 15.4 mm³

    -- usual care group: increased from 115.7 to 140.6 mm³, increase of 24.9 mm³

        -- difference: 9.5 mm³, p=0.009

 

-- secondary outcomes:

    -- the following differences between the groups:

        -- non-calcified plaque: 10 mm³, p=0.002

        -- fibrofatty and necrotic core: 5.3 mm³, p=0.02

        -- calcified plaque: nonsignificant

        -- fibrous plaque: 4.9 mm³, p=0.05

        -- fibrofatty plaque: 3 mm³, p=0.009

        -- necrotic core plaque: 2.3 mm³, p=0.04

    -- no significant difference in the cumulative lesion length, vessel volume, or lumen volume between the groups

 

-- There was no significant difference in outcomes in the per-protocol analysis

-- Of note here, a significantly greater proportion of the patients who had a favorable reduction in LDL Level had less plaque progression in the CAC score-informed group, and this was true across all plaque subtypes

 

-- 9 patients in the usual care group had a statin prescribed by their physician before the end of the three-year study; they received either atorvastatin or rosuvastatin, though all but one patient was given a lower statin equivalent dose than those in the CAC score-informed group

 

-- adverse events: 27 individuals in the CAC score-informed group stopped their statins, mostly for myalgias, GI intolerance, or just nonadherence. No difference in CK levels or new incidence of diabetes

 

Commentary:

--Though there is some indication in the guidelines on the appropriate preventative therapy in patients who are at cardiovascular low risk and those who are at high risk, there is not much information about what to do with the 50% who lie in the intermediate atherosclerotic risk range

    --And, this intermediate range is quite broad. for example, prior to this Australian study, there has been essentially no information for people who are in this intermediate range but also have a significant family history of premature clinical CAD (and family history is not even included in several of the risk calculators)

--this Australian study relied on radiologic CAC risk analysis and CT angiography (CCTA) as a means to assess the progression of atherosclerotic plaques, raising a few issues:

    -- these assessments are complementary, in the sense that CAC assessment identifies only calcified plaques, which are themselves not as clinically important for identifying culprit lesions that are associated with acute coronary syndrome(ACS)/MI  (though these calcified lesions can may lead to highly occlusive plaques if they have at least 70 or 75% obstruction, that can be associated with angina).

        -- A few studies have found that these culprit lesions for ACS are much more likely to be from noncalcified younger fresh plaques that have large lipid cores and inflammation, in combination with a much more fragile fibrous cap, and this combination is associated with higher risk of rupture, thrombosis,  and bad clinical outcomes, given that their internal inflammation elaborates enzymes (metalloproteinases) that digest and weaken the fibrous cap; and the externally passing blood in the arteries causes mechanical shear stress on that cap. Some older studies have found that 78-97% of lesions in patients with ACS were <75% stenotic (the level of occlusion associated with angina) and half <50%. A more recent study using CCTA found that in patients with ACS, 65% had nonobstructive lesions: see acute coronary syndrome mostly nonobstructive JACC2018 in dropbox, or/doi.org/10.1016/j.jacc.2018.02.079

        -- another study of 1241 patients with acute coronary syndromes found that only 12.7% actually had calcified plaques as their culprit lesion: see JACCcardiointerv2019 in dropbox or https://doi.org/10.1016/j.jcin.2018.12.013

        -- this finding was actually confirmed in this current Australian study: the calcified plaques did not change significantly during the 3-year study by the intervention/statins, just the non-calcified ones (these are more susceptible to statins, which decreases the internal inflammation within the plaque within months and leads to a thicker fibrous cap, as opposed to the old calcified ones which have much more fibrosis internally)

        -- CAC scores of 0 do consistently lower the risk of a future cardiovascular event; the large the MESA study found that rates of cardiovascular events were 1.3% in women and 5.6% in men with no calcification identified a small but not insignificant group: see https://pubmed.ncbi.nlm.nih.gov/29688297/

        -- another study from 2022 found negative CAC scores occur patients with solely noncalcified plaques, which happens especially in younger patients. This  study of 23,759 symptomatic patients found that 14% of those with obstructive CAD had a CAC score of 0, varying from 58% of those <40yo to 34% of those 40-49yo to 18% of those 50-59yo to 9% of those 60-69yo to 5% of those at least 70yo (https://pubmed.ncbi.nlm.nih.gov/34705022/ )

 

-- a big limitation in this Australian study is that it is not really a study of the performance of CAC scores, but one of CAC scores in the setting of doing a more a more sophisticated coronary artery CT angiography that really reveals the true extent of the coronary artery disease

    -- which suggests that we perhaps should do screening CCTA instead of CAC screening, especially in those who are more likely to have a negative or low CAC assessment (eg younger people)

        -- though there is the finding that a positive CAC score by itself helps motivate people to improve the lifestyle risk factors.

    -- this CTTA issue does bring up the question of cost, especially if CCTA were to become a standard screening test and perhaps performed more than once (though likely most helpful in younger people), with the caveats that actual cost may vary dramatically from institution to institution and there may be major differences in insurance coverage (though this might be mitigated a lot if the USPSTF adopts it). there was a recent assessment of the cost-effectiveness for those patients with "both with low risk acute chest pain presenting to the emergency department and low-to-intermediate risk with stable chest pain as outpatients", and that computed tomography-fractional flow reserve was cost-effective for those at higher risk of stenosis: https://pmc.ncbi.nlm.nih.gov/articles/PMC9863924/

    -- the segue here is that atherosclerotic disease overall is still the number one killer and morbidity. 

        -- the CDC reports that one person dies every 33 seconds from cardiovascular disease: https://www.cdc.gov/heart-disease/data-research/facts-stats/index.html ; 702,880 people died in 2022 new heart attacks https://www.cdc.gov/heart-disease/data-research/facts-stats/index.html

        -- and we do know that a first heart attack has a significant mortality: an older study found that 2/3 of patients with cardiac arrest outside of the hospital die (https://pmc.ncbi.nlm.nih.gov/articles/PMC1112895/); a more recent study noted that about 18% of patients died withing 28 days of their heart attack and 62% of them died instantly

        -- and that the atherosclerotic process starts early (in the teens in men, a bit later in women)

 

-- and the other elephant in the room is that the CAC score-informed group was put on statins. We do know from many studies that statins decrease cardiovascular events by about 30% (though the absolute risk reduction is more in those who have known cardiovascular disease). 

  -- this Australian study also found that there was a very strong relationship between changes in LDL and changes in plaque volume

    -- there have been many, many studies on the positive effects of lowering LDL levels on actual cardiovascular events

    -- there have also been studies (in very high risk patients) that the lower the LDL, the lower the future cardiovascular events, down to LDL levels of 21 mg/dL https://gmodestmedblogs.blogspot.com/2018/08/very-low-ldl-levels-benefit-without-harm.html; a recent analysis of the Fourier found that an LDL<20 continued to provide cardiovascular benefit (see cad high risk LDL less than 20 fourier studyCirc2023 in dropbox, or doi/suppl/10.1161/CIRCULATIONAHA.122.063399

 

Limitations:

-- they included intermediate ASCVD risk with CAC scoring of 1-399 in the same bucket. there is a pretty big difference between the clinical cardiovascular risk within this wide range (most clinical events actually happen in those with CAC scores >100; and this study found that those with a CAC score less than 100 had significant change in only noncalcified plaque volume, versus those with higher CAC scores who had the array of plaque changes noted above). a larger study might be needed to disentangle the more precise level of CAC score and cardiovascular outcomes, but it would be clinically important to have much smaller ranges of CAC scoring if we want these results to be clinically useful

-- and there was a more aggressive nurse involvement in the CAC score-informed group, leading to more clinical contact and likely stronger participant relationships with the ongoing study, which could affect the results

-- as per above, these intermediate risk patients could not be on statins, per Australian guidelines. so, is this a study really showing that it is the CAC score or the effects of statins in the intervention group???

-- this study was based on a surrogate marker, positive CAC screening, which seems to be a pretty good predictor of cardiac risk, though to the extent it reflects the old, calcified plaques with lots of fibrosis and a less active lipid core (vs newer lesions), there could be some risk overassessment in those with positive CAC scores who do not have newer lesions (eg, perhaps they modified their lifestyle lots, or started statins, and did not have new lesions) and are at lower risk of an ACS (though might still have angina because of the degree of coronary occlusion). but probably more often, those with high CAC scores overall also have old plus new lesions, and treatment does decrease the incidence of ACS by targeting these newer lesions

-- there was no measure in this study of other important risk factors for atherosclerosis, including diet, exercise, overweight, and the many other risk factors noted in http://gmodestmedblogs.blogspot.com/2023/10/update-ascvd-risk-factor-critique.html , including chronic inflammatory diseases (lupus, rheumatoid arthritis, psoriasis, even controlled HIV infections), air pollution, microplastics, visceral obesity, stress, depression, alcohol, peripheral arterial disease, chronic kidney disease...

    -- and there is only baseline information in the study. did some people change their diet, smoking, exercise, weight.... over the course of the study, thereby muddying the results???

 

So, the results of this study are not surprising. It confirms what would be expected, that if high CAC scoring is associated with increased atherosclerotic plaque progression, then increasing the aggressiveness of primary prevention (eg statins) would lead to positive effects on atherosclerosis development.

-- We do know over decades of studies that lowering LDL cholesterol, or perhaps the more sensitive strategies of cholesterol-to-HDL ratio or non-HDL cholesterol levels, does have a significant clinical benefit, and this is a relatively linear relationship

   -- however, this study does not provide a clear answer to the utility of CAC screening by itself, since only the intervention group was put on statins, which decrease not only plaque inflammation and increases plaque stability, but also decreases plaque progression as found in earlier studies (eg with intracoronary ultrasound)

 

-- though currently most people do survive their first heart attack https://cardiosound.com/heart-attack-survivors :

    -- the 1-year mortality after a heart attack is also quite high, around 23% of women and 18% of men https://cardiosound.com/heart-attack-survivors

    -- and the morbidity of having a heart attack is quite high, both the clinical sequelae (heart failure, arrhythmias, etc), the psychological sequelae (depression, decreased self-esteem/self-worth), and the social ones (changes in the family to take care of the individual as well as their own psychological changes in terms of their own fragility and perhaps more social isolation, loss of income from patient and family members who need to take care of the patient)

    -- and the CDC reports that one person dies every 33 seconds from cardiovascular disease: https://www.cdc.gov/heart-disease/data-research/facts-stats/index.html ; 702,880 people died in 2022 new heart attacks https://www.cdc.gov/heart-disease/data-research/facts-stats/index.html

 

    -- so all of this would argue that we should study and perhaps institute routine screening of people before they have a heart attack in order to prevent one.

        -- which might mean routine CAC screening

        -- but also might mean the more accurate routine screening for coronary artery disease with coronary CT angiography!!!

        -- though one aspect that needs to be assessed is the likely effects of increased radiation of CCTA (about 2.88 mSv,  per https://pmc.ncbi.nlm.nih.gov/articles/PMC8789964/ vs about 1 mSv for CAC.) As a reference here, screening mammography has 0.36 mSv, but this is higher in people with larger breasts and those who need more extensive mammography because of inadequate screening mammograms

 

        -- but, bottom line from a public health perspective:

            -- atherosclerosis begins early (in many people in their teens) and is a progressive process

            -- when it reaches a clinically-evident level (eg an acute coronary syndrome), there is a very significant mortality and morbidity (which affects huge numbers of people, given the high incidence of atherosclerotic disease)

            -- in this context, it is very likely that the cost-benefit analysis would reveal benefit from routine screening CCTA (study should be done, but it is important to remember that we do not have much data on long-term benefits of finding/treating early-detected atherosclerosis, the ASCVD 10-year risk calculator is useless in younger people likely to live many decades, and doing a study would likely take decades to get results: ie we would likely need preliminary data of markers of benefit along with mathematical modeling)

            -- early treatment focusing on lifestyle changes (eg, interventions to improve diet, exercise, decrease overweight, avoid exposures to cigarettes/alcohol) and statins as needed would pretty clearly decrease later cardiovascular events (and if initiated earlier, the likely benefit would be huge if done well before clinical cardiovascular disease occurs, given the notable finding that statins do really benefit those who had a clinical event but this group still remains at a much higher cardiovascular risk and, as noted this group will be exposed to markedly increased mortality and morbidity from that initial clinical event)

            -- and the goal of public health (and the medicine we in clinical care perform routinely) really should be primary prevention of disease, as we do for many of our most frequent interventions in common conditions (controlling blood pressure, diabetes, etc, early and aggressively to prevent the expected bad outcomes of these diseases)

 

Geoff

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