CLEVELAND, OH – The results of a new study suggest that there is a paradoxical relationship between calcification of the coronary artery and atheroma volume among individuals treated with statin therapy. In the analysis, statins, specifically high-intensity statin therapy, actually promoted coronary calcification despite regressing the volume of coronary atheroma[1].
"The question of calcium is very relevant because we have people doing calcium scans as a means to determine the burden of disease," senior investigator Dr Steven Nissen (Cleveland Clinic, OH) told heartwire. "What we were struck by in this analysis was that the most aggressively treated patients—the high-intensity statin patient—if anything, developed more calcification. So if we're going to use coronary calcification as a measure of disease burden, you really have to know if the patient has received a lot of statins or not."
The study, led by Dr Rishi Puri (Cleveland Clinic) and published March 30, 2015 in the Journal of the American College of Cardiology, is a post hoc analysis of eight intravascular ultrasound (IVUS) studies that assessed the effect of medical therapies, including statins, on serial changes in coronary atheroma burden. The studies, among them REVERSAL, SATURN, ILLUSTRATE, and ASTEROID, included 1545 individuals who received high-intensity statin therapy, 1726 who received low-intensity statin therapy, and 224 who didn't receive a statin.
Individuals treated with a high-intensity statin, such as atorvastatin 80 mg or rosuvastatin 40 mg (Crestor, AstraZeneca), had regression of percent atheroma volume measured by IVUS. In these patients, percent atheroma volume declined 0.6% from baseline, whereas percent atheroma volume increased 0.8% and 1.0%, respectively, among those who received a low-intensity statin and those not treated with a statin.
Regarding the change in the IVUS-derived calcium index—a measure of coronary calcification—all three study arms showed an increase in coronary calcification from baseline. In a model that adjusted for the change in percent atheroma volume, the increase in coronary calcium was greater among the low-intensity statin vs no-statin arm (P=0.03) and the high-intensity statin vs no-statin arm (P=0.007). There was no significant difference in the change in coronary calcification among high- and low-intensity statin-treated patients, although there was a numerical difference with more calcification in the high-intensity arm.
The researchers observed no correlation between the change in the calcium index and on-treatment levels of LDL cholesterol or C-reactive protein (CRP).
"It wasn't correlated with the lipid changes," said Nissen. "You can't attribute this just to LDL alterations. It looks like it's related to something that statins do. We know the drugs have complex biological effects, and some of those effects have not been worked out scientifically."
Paradoxical Relationship
To heartwire, Nissen said that the increase in coronary calcification among patients treated with a statin might be a positive finding, as it suggests a stabilization of the coronary plaque.
"We have some physicians—some, not a lot—advocating for serial calcium scans to determine whether or not patients are doing well," he said. "If you give them a high-dose of a statin and their calcium goes up that might actually be a good thing. Instead of saying, 'Oh my goodness, your coronary calcium is increasing,' we might be able to tell patients, 'Your coronary calcium is up, your plaques are stabilizing.' "
The paradoxical relationship between atheroma regression and increases in coronary calcium also suggests that the relationship between statins and coronary calcification is poorly understood.
"With coronary calcium scans being done so commonly, I think we should take another look at this," added Nissen. "Our data, and it's a pretty big group of people studied with a very accurate technique, show patients seem to have more calcium when you treat them more intensively."
Somewhat Controversial, but Data Have Support
In an editorial[2], Dr Leslee Shaw (Emory University, Atlanta, GA), Dr Jagat Narula (Mount Sinai Medical Center, New York, NY), and Dr Yellapragada Chandrashekhar (University of Minnesota, Minneapolis) say the findings, while "somewhat controversial," find support in an analysis of the Multi-Ethnic Study of Atherosclerosis (MESA) that showed "more dense plaque in the setting of more extensive CAC [coronary artery calcification] scores," and these higher scores were observationally associated with a reduced risk of cardiovascular events.
The editorialists speculate that coronary calcification might be better thought of in patterns, such as spotty calcification vs more coalesced calcification, rather than as a "monolithic unit." The density of calcification might also provide more important information than one lone number, such as the Agatston CAC score.
"More important, as a corollary, the CAC score or its progression might not be as predictive once plaque-altering treatment (for example, statins) is initiated," according to the editorialists. "In this latter setting, treatment that changes plaque volume and impacts on event occurrence seems to oppose the directionality of changes in the CAC score or extent. These findings should prompt another look into whether the strong relationship between CAC progression and events stands intact during adequate statin therapy."
Just as Nissen told heartwire, the editorialists say it's possible that once risk is detected with CAC, it might no longer be a good marker for disease progression or a useful goal for therapy. "It probably shouldn't be done more than once," said Nissen.
Nissen has received research support from Amgen, AstraZeneca, Eli Lilly, Orexigen, Vivus, Novo Nordisk, Resverlogix, Novartis, Pfizer, Takeda, Sankyo, and Sanofi. He has also served as a consultant for a number of pharmaceutical companies without financial compensation (all honoraria, consulting fees, or any other payments from any for-profit entity are paid directly to charity so that neither income nor any tax deduction is received). Puri has no relevant financial relationships. Disclosures for the coauthors are listed in the article. Narula has received research grants for his institution in the form of equipment from Philips, GE Healthcare, and Panasonic Healthcare. Shaw, and Chandrashekhar report no relevant financial relationships.
Heartwire from Medscape © 2015 Medscape, LLC
Cite this: Do Statins Promote Coronary Calcification? Study Says Yes, and It Might Be a Good Thing - Medscape - Apr 02, 2015.
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