Lead Investigator: Amir Mahabadi, University Hospital Essen, West German Heart and Vascular Center.
Title of Proposal Research: Impact of statin therapy on coronary artery calcification volume and density – A meta-analysis of randomized controlled trials.
Vivli Data Request: 4115
Funding Source: None.
Potential Conflicts of Interest: None.
Summary of the Proposed Research:
Statin therapy leads to not only reduction of cholesterol levels but also stabilization of coronary plaques. In addition, when achieving treatment targets of <70mg/dl, statin therapy has the ability to reduce plaque burden, as documented in randomized controlled trials using intravascular ultrasound (IVUS) of the coronary arteries. Coronary artery calcium (CAC)-scoring is a surrogate marker of coronary atherosclerosis and strongly associated with risk for coronary and cardiovascular events. The Agatston-Score, combining calcium volume and density, is the most commonly used measure of CAC in clinical routine. However, randomized controlled trials failed to detect a meaningful influence of high intensity statin therapy on the progression of the Agatston-Score in primary prevention cohorts. In contrast, recent data from a population based cohort study described an increase in Agatston-Score for subjects under statin medication, suggesting that the stabilizing effect of statins might be reflected in an increase in Agatston-Score, which was confirmed on IVUS-data. In addition to the Agatston-Score, the volume and density as alternatively available measure of CAC, have gained interest. Investigators from the Multi-Ethnic Study of atherosclerosis described that CAC-density was inversely related with cardiovascular disease risk. While in a small randomized controlled trial on 66 patients, statin therapy was associated with progression of CAC volume, larger studies on how statin therapy impacts CAC density and volume currently are lacking.
We aim to perform a meta-analysis of two large randomized controlled trials on the association of statin therapy with CAC-progression to determine, whether high-intensity statin therapy leads to a relevant change in CAC volume and density as compared to the traditional Agatston-Score.
Statistical Analysis Plan:
Descriptive analysis will be performed to describe the baseline characteristics of included studies, stratifying by statin intensity group. Continuous variables will be reported as mean ± standard deviation (SD) for normally distributed data or median and quartiles (Q1; Q3) for non-normally distributed data. Discrete variables will be given in frequency and percent. Differences in change in mean CAC density for the overall coronary artery tree as well as stratified by coronary artery in patients with low vs. intensified lipid lowering therapy will be compared using two-sided t-test, if normally distributed. Linear regression analysis will be performed, using mean change in mean CAC density as dependent variable and intensity of lipid lowering therapy as independent variable. Subgroup analyses will be performed by age group, gender, BMI group, and study. Results will be confirmed by regression analysis using mean CAC density at follow-up as dependent variable, adding mean CAC density at baseline to the model. Further, changes in CAC volume will be evaluated in identical fashion. All data analysis will be performed using the SAS software (Version 9.4, SAS Institute Inc.).
MEASURES TO ADJUST FOR MULTIPLICITY, CONFOUNDERS, HETEROGENEITY, ETC.
Regression analysis will adjust for age, gender, traditional risk factors, and medication. No multiple testing issues arise for the primary and confirmatory analyses.
For sensitivity analyses, analyses will be performed by age group, gender, BMI group, and study. In addition, in case of missing co-variables, sensitivity analysis with best / worst case scenario analyses will be performed.
RATIONALE FOR ANY DEVIATION FROM PRE-SPECIFIED ANALYSIS PLAN PERFORMED BY PFIZER
For both included studies, changes in the absolute CAC score as quantified by the Agatston method were investigated. However, recent research suggests that statin therapy may lead to an increase in calcification, which reflects plaque stabilization. With the present meta-analysis, we aim to evaluate, whether the stabilization of plaque is reflected by an increase in mean CAC density. In conclusion, the present project aims to illuminate a new aspect of the influence of statin therapy on the changes of CAC.
ELECTRON BEAM COMPUTED TOMOGRAPHY ASSESSMENT OF CORONARY CALCIFICATION IN HIGH-RISK PATIENTS WITH MINIMAL OR MODERATE CORONARY ATHEROSCLEROSIS RECEIVING INTENSIFIED LIPID LOWERING ATORVASTATIN THERAPY (EBEAT)
Data Contributor: Pfizer Inc.
Study ID: A2581014
L Vogel, I Dykun, P Raggi, A Schmermund, T Rassaf, A Mahabadi. High- vs. low-intensity statin therapy and changes in coronary artery calcification density after one year. European Heart Journal, Volume 43, Issue Supplement_2, October 2022, ehac544.209. doi: 10.1093/eurheartj/ehac544.209