statins increase coronary artery calcium

 A recent study found that statin therapy was associated with increased coronary artery calcium (CAC) scores after even just one year of statin therapy (see statin use inc CAC score JClinMed2024 in dropbox, or doi.org/10.3390/jcm12020476). Though I often focus on cardiovascular disease issues in my blogs, I was unaware of the several studies finding this association, even though many of the studies are 10 years old…..

 

Details:

-- these researchers performed a pooled analysis of two randomized controlled trials (BELLES and EBEAT), that compared the effects of high-intensity statin therapy (HIST) using atorvastatin 80 mg versus low intensity statin therapy (LIST) using either pravastatin 40 mg or atorvastatin 10 mg

-- 852 patients were involved in this combination assessment, all with available baseline and follow-up CT evaluations

    -- the BELLES study included hypercholesterolemic postmenopausal mostly white women; the EBEAT study included mostly men (75%)

-- overall in the combined studies, 67% female, 63yo, BMI  28, systolic BP >130mmHg in 55%, smoking status none 30%/current 33%/former 35%

-- patients on HIST: 46%

-- main outcome: pooled analysis of the BELLES and EBEAT studies, comparing the effects of HIST vs LIST on several CAC measurements (see below) after 1 year

 

Results:

--HIST vs LIST

    -- LDL reduction: -72.9 ±46.0 mg/dL vs -45.8 ±38.5 mg/ dL, p<0.001

    -- Triglyceride: -48.4 ± 94.0 mg/dL vs -22.3 ±74.6 mg/dL

 

-- Agatston score, comparing HIST to LIST:

    -- baseline: 154.5 vs 187.7

    -- followup: 184.8 vs  238.2

        -- difference: 58.2 vs 53.4, p=0.68

-- CAC volume, comparing HIST to LIST:

    -- baseline: 184.2 vs 146.4

    -- followup: 229.5 vs  180.9

        -- difference: 43.9 vs 41.4, p=0.78

-- Density of lesions, comparing HIST to LIST:

    -- baseline: 227.8 vs 229.7

    -- followup: 231.9 vs 233.3

        -- difference: 4.0 vs 3.6, p=0.73

-- Number of lesions, comparing HIST to LIST:

    -- baseline: 6 vs 6

    -- followup: 7 vs 7

        -- difference: 0.8  vs 0.9, p=0.75

 

-- Comparison between degree of LDL reduction (greater than vs less than the median) and CT findings:

-- Agatston score:

    -- baseline: 149.2  vs 184.2

    -- followup: 180.8 vs 238.6

        -- difference: 47.0 vs 65.6, p=0.063

-- CAC volume:

    -- baseline: 117.8 vs 154.1

    -- followup: 142.6 vs  184.9

        -- difference: 36.4 vs 51.0, p=0.062

-- Density of lesions,:

    -- baseline: 225.9 vs 230.8

    -- followup: 229.5 vs  232.8

        -- difference: 3.6 vs 2.0, p=0.35

-- Number of lesions:

    -- baseline: 6 vs7

    -- followup: 7 vs 8

        -- difference: 0.5  vs 01.0, p=0.071

 

Commentary:

--it is abundantly clear that statins prevent cardiovascular disease in both primary and secondary prevention, both with a relative risk reduction on the order of a 30% decrease, though the absolute risk and absolute benefit are much less in those without a history of heart disease (primary prevention)

--cardiovascular disease should be seen as a cumulative progression starting at a young age:

    -- several older studies have found that essentially everyone aged 15-30 has lipid streaks in their coronaries, and in this age group 2% of men and 0% of women have more advanced lesions. By the ripe old age of 30-34, 20% of men and 8% of women have advance atherosclerosis

    -- catheterization studies in patients with acute coronary syndromes (acute MIs, unstable angina) have found that 78-97% of the culprit atherosclerotic lesions (the ones that caused the MIs) are in arteries with <75% stenosis (the 75% threshold is the degree of stenosis when patients have enough decrease in coronary blood flow to cause anginal symptoms on exertion; ie, these culprit lesions are mostly not causing stable angina), and half of the patients have lesions that are <50% stenoses.  What causes an ACS is basically that small young fresh atherosclerotic lesions have more lipid and more inflammation in their core, along with a less-developed fibrous cap. The inflammation elaborates metaloproteinases and other enzymes that weaken the fibrous cap, and the passive physical shear stress of blood rushing over the plaque leads to plaque disruption, exposure of the contents to the blood stream, attraction of platelets etc, and the development of a clot leading to vessel occlusion and an acute cardiovascular event. The older and more occlusive atherosclerotic plaques have a smaller lipid core, less inflammation, and more fibrosis and calcification

        -- statins stabilize the lipid core and decrease inflammation within a few months, these being  major factors in their resulting decrease in adverse cardiovascular events

 

-- the Agatston score is a relatively simple but reliable measure of coronary artery calcium and is used to quantify the extent of CAC (https://www.sciencedirect.com/science/article/pii/S0002934323005375):

    --a CAC score of 1-10 (ie, minimal CAC) vs a score of zero is still associated with a 3-fold increased incidence of adverse cardiovascular events. And the higher the score, the higher the likelihood of these cardiovascular events

        --a score of 0 reflects a very low risk of a cardiovasc event, even in patients with diabetes or other risk factors, over the next 4-5 years (negative predictive value of 99%), and some clinicians withhold statin therapy until the CAC is >0, based on one study

        – a score of >1000 is  associated with a cardiovasc event within 3 years in 1/3 of individuals

        – overall, a score of 1-99 is considered low to moderate risk of a cardiovasc event, 100-499 is significant risk, 500-999 very significant risk, >1000 great risk. The imperative is to treat each of these cutpoints increasingly aggressively with meds (non-pharmactologic treatment should also be reinforced in all cases)

-- assessing coronary artery calcium does have a few concerns:

    -- it involves ionizing radiation, and there are concerns about ionizing radiation exposure and the subsequent development of cancer

    -- there clearly are false negative results: the young lesions that can cause ACS often do not have much calcification and may have low or zero CAC scores (of course, there may be several other lesions in different arteries that are more advanced and calcified in the same person, leading to a positive CAC test). Studies suggest that these false negatives are not frequent, on the order of 6.5% of patients

    -- and there are potential false positives, notably in those on statins.... (see below)

 

-- this current study found:

    -- all of the CAC parameters measured (Agatston score, density of lesions, CAC volume score, or number of lesions) were much higher after 1 year of statin therapy

    -- there was no difference in any of these CAC parameters between the high- vs low-intensity statin groups, even if stratified by either the degree of LDL reduction (greater vs less than the median) or by the baseline Agatston score ( <100 vs >100)

 

-- the incentive for this current study was that prior studies have found a relationship between statin therapy and progression of coronary artery calcification. There was, however, a prior small study that failed to find a difference in the Agatston score or CAC volume with statins. Hence the current larger study was done

    -- progression of CAC is associated with more cardiovasc events (as noted above), and many clinicians feel that progression of CAC is a marker for initiating statin therapy in primary prevention. So, the current finding of increased CAC scores with statins, despite lower cardiovascular risk by their use, is problematic in this regard. Unfortunately, there is very limited use of CAC in the general population (often this is not covered by insurance). 

-- this current study was based on 2 large RCTs that lasted only a year, likely perhaps explaining why there was not a significant difference between patients on HIST vs LIST. Other studies have had longer follow-up but were not RCTs:

    -- rapid progression of CAC in a >5-year study: the Heinz Nixdorf recall study of 3483 participants (mean age 59) found a median CAC score at baseline of 58.8 in the 230 people on statins and 5.9 for those not on statins, this median score increased by 141.3 if on statin and 21.2 if not. Of course, there may have been fundamental differences between those who were put on a statin vs not, but they did an analysis controlling for the standard cardiovascular risk factors finding that their results were only “slightly attenuated”. They did find that those with LDL >115mg/dL had lower CAC progression than in those with higher LDL levels. They found that there was a nonsignificant 26% decrease in cardiovascular events in those with increased CAC scores on statins. They posited that an increase in CAC might be from the statins stabilizing atherosclerotic plaques which might lead to more calcification as statins increased plaque "repair":(see Statin Medication Enhances Progression of Coronary Artery Calcification: The Heinz Nixdorf Recall Study - ScienceDirect )

    -- combining the St Francis Heart Study (SFHC) that had 419 patients on placebo and 432 on atorvastatin 20mg with the above EBEAT study with 164 on 10mg of atorvastatin 10mg and 179 on atorvastatin 80mg daily (High dose and long-term statin therapy accelerate coronary artery calcification - International Journal of Cardiology ):

        – the  St Francis Heart Study was a double-blind, placebo-controlled RCT of atorvastatin 20mg daily, vitamin C 1gram daily, and vitamin E 1,000 IU daily vs placebo in 1,005  asymptomatic men and women aged 50-70 with CAC scores above the 80^th percentile, found a 40% decrease in LDL, about a 30% decrease in cardiovascular events, no significant change in Agatston score after 4.3 years, though there were decreased cardiovascular events in those with baseline Agatston score of >400

        -- short-term followup of the combined study: after 12-24 months, there was no significant difference in CAC increase between low-dose atorvastatin and placebo, but atorvastatin 80mg increased CAC 12-14% over placebo (p<0.001)

        -- long-term followup: atorvastatin was associated with an additional 1.1% increase in CAC over placebo (p=0.04)

        -- overall results showed that cardiovasc events did not increase with high or low dose statins, and the baseline CAC results and family history of premature cardiovascular disease (but not progression of CAC) were the independent predictors of cardiovasc events

    -- a more recent article found that the natural progression of coronary artery progression is from small microcalcifications to more extensive calcification with sheet-like deposits identifiable by CT or intravascular imaging. These imaging techniques lead to the conclusion that the early microcalcifications are found in unstable plaques but those with more extensive calcification are associated with plaque stabilization (Coronary Artery Calcification and its Progression: What Does it Really Mean? - ScienceDirect )

        -- this finding and supposition are congruent with the model of atherosclerosis noted above: it is the new, smaller lesions that lead to acute coronary syndromes from plaque rupture, and the older calcified ones that lead to later angina symptoms from higher degrees of coronary obstruction and angina when insufficient oxygen reaches the heart.  as per the model of atherosclerosis above, the correlation of CAC with acute cardiovascular events is largely because there is diffuse atherosclerotic disease in many people, and the older calcified lesions are a marker for high cardiovascular risk overall but the actual culprit lesions leading to the acute event are the newer smaller lesions with larger lipid cores and inflammation leading to plaque rupture.

 

--CAC density  has been shown to have an inverse correlations with cardiovasc events, at any level of CAC volume (Calcium Density of Coronary Artery Plaque and Risk of Incident Cardiovascular Events | Cardiology | JAMA | JAMA Network)

-- for a review of CAC, see coronary calcifications in atherosclerosis NatRevCardiol2009 in dropbox, or doi:10.1038/nrcardio.2009.165

-- and serial ultrasound assessments have confirmed that statin therapy leads to plaque stabilization of the plaques with early microcalcifications, which also  found that HIST (defined in this study as atorvastatin 80 or rosuvastatin 40) was associated with plaque regression, not so with placebo or LIST which seem to just stabilize the plaque (Impact of Statins on Serial Coronary Calcification During Atheroma Progression and Regression - ScienceDirect )

 

Limitations:

-- this study was based on 2 well-conducted RCTs, but the duration was only 1 year, which might limit the ability to find the full effect of statins on the  various parameters of coronary artery calcification (since atherosclerosis is a progressive phenomenon over decades, and statin use is also a long-term intervention)

-- the data from the above studies are basically either observational studies or comparisons of HISD vs LISD and not vs placebo, which limit conclusions about the true statin effect

    -- and the usual issues with these studies: observational ones might well have unrecognized cofounders that might alter the results; RCTs may have specific demographics, sites of the studies, inclusion or exclusion criteria that limit their generalizability to other populations

-- these patients had high baseline Agatston scores of 155 and 188 for the 2 statin groups. do similar statin-induced coronary calcifications apply to patients with lower or zero scores. i would guess that the calcification effect of statins may not be linear and may be much less at lower baseline Agatston levels. we need studies with diverse groups of patients carried out for several years on statins vs not

  

So,

-- cardiovascular disease is still a huge issue in the US, and increasingly so globally as more people adopt a more “western” lifestyle

-- the main vehicle for decreasing cardiovascular morbidity and mortality is through lifestyle improvements: consuming a diet with more vegetables and fruits and less junk foods, carbohydrates, red meat, etc; increasing exercise; maintaining a healthy weight; decreasing stressors; ... And that, in and of itself, is as good as statins for many people

-- but many other people (ie most) need medications to decrease their cardiovascular risk sufficiently, largely targeting LDL cholesterol levels. And statins are the go-to meds for both primary and secondary prevention (though it is really important that the lifestyle issues continue to be stressed, given their multitude of benefits for the whole body and not just the heart)

-- this study does raise some questions, however:

    -- CAC is being increasingly used to risk stratify patients for cardiovascular outcomes, and is being used to help determine optimal lipid management

    -- but, there is significant concern that the CAC score may be increased in those on statins, more so with long-term use and more so with higher statin dosing to achieve the appropriate LDL goal

    -- and this increase in CAC associated with statins seems to undercut the utility of CAC screening (even small increases in CAC scores are considered to confer significant cardiovascular risk increases), since there seem to be very important false negatives and perhaps increasing amounts of false positives (especially with the increasingly widespread use of statins) with CAC scores. this appears to throw the whole CAC screening algorithm off

        -- for example, will there be the vicious cycle of: a person being on low dose statins that lead them from a CAC score of 0 to a score of <10 from the statin, leading to the misleading assumption therefore that they are at a 3-fold increased risk of a cardiovascular event from this increase, leading to a hospital admission if they have potential cardiac chest pain or just leading to intensifying the statin therapy because of this assumed higher cardiovascular risk, leading to higher CAC scores from this intensified statin dosing, leading to…..

    – which means: we really need more higher quality studies (more varied populations, more varied baseline CAC scores, longer studies) that help lead us out of this potential quagmire.....

        – but, my guess, these studies will never happen (no way that we can have high risk patients stratified to placebo vs statin for several years). so we are probably left with future longer-term observational studies, hopefully with varied baseline CAC scores, and more diverse populations

 

geoff

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