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Long-term statin therapy is associated with severe coronary artery calcification

 

Background

Atherosclerosis and consequent risk of cardiovascular events or mortality can be accurately assessed by quantifying coronary artery calcium score (CACS) derived from computed tomography. HMG-CoA-reductase inhibitors (statins) are the primary pharmacotherapy used to reduce cardiovascular events, yet there is growing data that support statin use may increase coronary calcification. We set out to determine the likelihood of severe CACS in the context of chronic statin therapy.


Methods

We established a retrospective, case-control study of 1,181 U.S. veterans without coronary artery disease (CAD) from a single site, the Providence VA Medical Center. Duration of statin therapy for primary prevention was divided into 5-year categorical increments. The primary outcome was CACS derived from low-dose lung cancer screening computed tomography (LCSCT), stratified by CACs severity (none = 0; mild = 1–99; moderate = 100–399; and severe ≥400 AU). Statin duration of zero served as the referent control. Ordinal logistic regression analysis determined the association between duration of statin use and CACS categories. Proportional odds assumption was tested using likelihood ratio test. Atherosclerotic cardiovascular disease (ASCVD) risk score, body mass index, and CKD (glomerular filtration rate of <60 ml/min/1.73 m2) were included in the adjustment models.


Results

The mean age of the study population was 64.7±7.2 years, and 706 (60%) patients were prescribed a statin at baseline. Duration of statin therapy was associated with greater odds of having increased CACS (>0–5 years, OR: 1.71 [CI: 1.34–2.18], p<0.001; >5–10 years, OR: 2.80 [CI: 2.01–3.90], p<0.001; >10 years, OR: 5.30 [CI: 3.23–8.70], p<0.001), and the relationship between statin duration and CACS remained significant after multivariate adjustment (>0–5 years, OR: 1.49 [CI: 1.16–1.92], p = 0.002; >5–10 years, OR: 2.38 [CI: 1.7–3.35], p<0.001; >10 years, OR: 4.48 [CI: 2.7–7.43], p<0.001).


Conclusions

Long-term use of statins is associated with an increased likelihood of severe CACS in patients with significant smoking history. Using CACS to interpret cardiovascular event risk may require adjustment in the context of chronic statin therapy.


Risk of increased vessel calcification with long-term statin use. Note - up to a 500% increase in calcification reported over 10 years.

 

Research paper details.


While statins impact atherosclerotic plaque lipid burden, the exact effect of statin therapy on coronary artery calcification has been less clear [12,25–28]. Some initial reports suggested that statin use either reduced calcification or slowed the progression of atherosclerotic calcification [25,27,29], while others indicated statin use resulted in little to no change in the progression of calcification [26,30].


More recently, a growing number of studies have demonstrated the impact of statin use to be associated with increasing measures of coronary artery calcification [28,31–33]. For example, while coronary lipid atheroma indices have been shown to decline in individuals taking high-intensity statin, this effect was accompanied by a paradoxical increase in coronary calcium indices [28,31]. Additionally, while patients with diabetes mellitus demonstrated increased atherosclerotic calcification, statin use by patients with diabetes mellitus was associated with even more progressive coronary atheroma calcification [34–36].


Review of the population stratified by duration of time on statin therapy revealed that patients on a statin for longer periods of time demonstrated a higher prevalence of cardiovascular risk factors (Table 1). Increased duration of statin therapy was associated with slightly older age, increased BMI, and a higher prevalence of DM, hypertension, and hyperlipidemia. Patients with increased duration of statin therapy also had a higher prevalence of CKD and higher ASCVD risk scores.


Increased duration of time on statin therapy, divided into 5-year increments, was also associated with increased CACS categories in the unadjusted analyses (Table 2). Further, 2-year increments in the duration of statin therapy demonstrated incremental increases in the median CACS of approximately 100–120 Agatston units for every additional 2 years of statin therapy relative to no statin therapy (S1 Fig). Though the majority of participants were Caucasian males, when the sample was stratified by sex and race, there appeared to be no differences in statin use between men and women or white and non-white participants at baseline.


 

As mentioned, the effect of statin therapy on CAC has remained controversial to date with some studies showing a decrease or no change in calcification [25–27,29,30]. However, there were several concerns with these studies, including open label design, lack of simultaneous comparison between treatment and control groups, small sample size, and short follow-up duration (<1–2 years) [25–27,29,30].


Our findings appear consistent with a number of preclinical and clinical studies supporting the pro-calcific effects of statins [28,31,32]. Recently, a substudy of the prospective PARADIGM registry revealed baseline statin therapy to be associated with higher total CACS at baseline compared to those that were not prescribed statins and that calcified plaques were more likely to increase in the statin treated group [28]. In the cohort of patients already taking statins, CACS was also correlated with calcified plaque volume and density.


However, the statin use was treated as a binary in the analysis and duration of time on statin therapy was not taken into account which could have been an important confounder in the analyses. A recent analysis of two clinical trials indicated that 4–6 years of high-intensity statin therapy was associated with progressive CACS [33].


Our data further strengthens the conclusion of a relationship between statin and CACS in about 1200 patients with extensive smoking history and higher cardiovascular risk, incorporating a longer total duration of time (5–10 and >10 years) on statin therapy prior to the CT. Moreover, we studied a higher cardiovascular risk population, taking advantage of low-dose lung cancer screening CT and the application of non-gated image analysis for calcium scoring.


 

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