Click to Enlarge: CACS among 1,181 veterans at baseline. Source: PLoS One
PROVIDENCE, RI — A retrospective study involving more than 1,000 U.S. veterans has called into question the use of a coronary artery calcium score (CACS) to assess risk of atherosclerosis.
CACS, derived from computed tomography, help clinicians predict the risk of cardiovascular events or mortality. But researchers from the Providence, RI, VAMC and Brown University in Providence pointed out that HMG-CoA-reductase inhibitors, better known as statins, might increase coronary calcification.
That is especially a problem because of the widespread use of statins to reduce cardiovascular events, according to a recent report in PLoS One. The authors sought to determine the likelihood of severe CACS with the use of regular statin therapy.1
To do that, they conducted a retrospective, case-control study of 1,181 U.S. veterans without coronary artery disease (CAD) from a single site, the Providence VAMC. With the duration of statin therapy for primary prevention divided into 5-year groups, the primary outcome was defined as CACS derived from low-dose lung cancer screening computed tomography (LCSCT). Results were stratified by CACs severity (none = 0; mild = 1-99; moderate = 100-399; and severe ≥400 AU). Included in the adjustment models were atherosclerotic cardiovascular disease (ASCVD) risk score, body mass index and CKD (glomerular filtration rate of <60 ml/min/1.73 m2).
Of the veterans, who had a mean age of 64.7±7.2 years, the majority, 60%, of the patients were prescribed a statin at baseline. Results indicated that 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;
- Less than 5-10 years, OR: 2.80 [CI: 2.01-3.90], p<0.001;
- Greater than 10 years, OR: 5.30 [CI: 3.23-8.70], p<0.001.
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), the researchers pointed out.
“Long-term use of statins is associated with increased likelihood of severe CACS in patients with significant smoking history,” the study concluded. “The use of CACS to interpret cardiovascular event risk may require adjustment in the context of chronic statin therapy.”
Worsening Prognosis
“Coronary artery disease (CAD) due to calcific atherosclerosis is a major cause of morbidity and mortality worldwide,” the authors wrote. “Measures of increased atherosclerotic plaque calcification have been predictive of coronary artery disease burden, cardiovascular events, and all-cause mortality. Moreover, an increasing rate of progression of the calcification in the coronary vasculature has been associated with worsening prognosis and increased adverse events.”
Recent research has demonstrated evidence “supporting the association between increased density of calcification in atherosclerotic plaques and more stable disease,” they added.
The study described how statins have shown success at reducing the risk of cardiovascular events and, as a result, have become the current standard of care in patients at moderate to elevated cardiovascular risk. The drugs originally were developed as cholesterol-lowering agents, but multiple studies found that statin therapy reduced the risk of myocardial infarction out of proportion to the lipid-lowering effect.
“While statins impact atherosclerotic plaque lipid burden, the exact effect of statin therapy on coronary artery calcification has been less clear,” according to the researchers. “Some initial reports suggested that statin use either reduced calcification or slowed the progression of atherosclerotic calcification, while others indicated statin use resulted in little to no change in the progression of calcification. More recently, a growing number of studies have demonstrated the impact of statin use to be associated with increasing measures of coronary artery calcification.”
The authors said they recently identified a potential mechanism of statin-induced atherosclerotic plaque calcification through inhibition of the small GTPase, Rac1 protein isoprenylation and the consequent dysregulation of that protein in experimental models.
As a next step, the study team assessed the association between statin use and progressive calcification in humans, using a veterans’ study. The research piggybacked on low dose lung cancer screening CT (LCSCT) to acquire coronary calcification data without need for additional radiation exposure.
“Understanding the impact of statin therapy on atherosclerotic calcification may have important implications in our interpretation of cardiovascular event risk associated with elevated CACS derived from CT,” the authors noted.
They concluded that “long-term duration of time on statin therapy is associated with likelihood of having severe CACS in patients who have sufficient smoking history to qualify for lung cancer screening. These findings highlight an important complexity to the relationship between statin therapy and CACS, indicating that risk from CACS should be interpreted not just in the context of traditional cardiovascular risk factors and serial CACS progression, but also in the context of plaque-altering treatment.”
- Ngamdu KS, Ghosalkar DS, Chung HE, Christensen JL, Lee C, Butler CA, Ho T, Chu A, Heath JR, Baig M, Wu WC, Choudhary G, Morrison AR. Long-term statin therapy is associated with severe coronary artery calcification. PLoS One. 2023 Jul 27;18(7):e0289111. doi: 10.1371/journal.pone.0289111. PMID: 37498869; PMCID: PMC1037406