Anti-Inflammatory Drug Does Not Halt Plaque Progression in Overweight Patients With CAD
When given on top of guideline-recommended therapies, including statins, salsalate does not reduce progression of noncalcified coronary plaques in overweight and obese patients with established coronary heart disease, results from the randomized TINSAL-CVD trial show.
Noncalcified plaque volume did not change in either the active treatment or placebo group, Thomas Hauser, MD (Beth Israel Deaconess Medical Center, Boston, MA), and colleagues report online May 25, 2016, ahead of print in JAMA Cardiology.
“Current statin use, blood pressure control, and high compliance with guideline-directed care are associated with stable noncalcified plaque in those with advanced disease,” they write, leaving the door open for further study of anti-inflammatory treatment in this setting.
“It remains unknown if salsalate treatment earlier in disease might reduce initiation or progression of initial lesions,” they say. “Further evidence is needed to support whether targeting inflammation may be a valuable therapeutic intervention for cardiometabolic complications of obesity.”
Plaques Stable in Both Arms
Obesity-related subacute chronic inflammation has long been believed to be involved in the pathogenesis of atherosclerosis, diabetes, and other metabolic diseases.
Salsalate is a prodrug dimer of salicylates, which have been used to treat pain and inflammation for more than 3,500 years, Hauser et al note. To find out whether anti-inflammatory treatment with salsalate reduces coronary plaque progression, the researchers randomized 257 patients to 30 months of salsalate 3.5 grams/day or placebo on a background of standard, guideline-recommended therapies. All patients were overweight or obese, had established stable coronary heart disease, and were taking statins.
The primary outcome was progression of noncalcified coronary plaque assessed using multidetector CT angiography, and no change was seen for this endpoint in either the salsalate or placebo group.
Calcified plaque volume and coronary calcium score increased in both arms, but there were no between-group differences. Remodeling index and maximal diameter stenosis remained unchanged with both salsalate and placebo.
Salsalate did result in some changes, however. Treatment reduced triglycerides and total white blood cell, lymphocyte, monocyte, and neutrophil counts. It also increased adiponectin levels without affecting other markers and mediators of inflammation, including C-reactive protein.
Fasting glucose, uric acid, and bilirubin levels were lower in the salsalate group, whereas hemoglobin and urinary albumin levels were higher.
In terms of adverse effects, tinnitus—an established adverse effect of salicylates—and atrial arrhythmias were more common with salsalate.
Lessons From a Neutral Trial
In an accompanying editorial, Paul Ridker, MD (Brigham and Women’s Hospital, Boston, MA), called TINSAL-CVD “an informative neutral trial that deserves our attention.”
The trial takes a major step toward understanding the effects salsalate, an inexpensive agent, has on the vasculature, which remains an important topic, he argues.
Also significant, he says, is the fact that there was no progression of noncalcified plaque in the placebo group. “While it is possible that this effect reflects a limitation of [multidetector CT angiography], it is also possible that this neutral finding represents an important reality of current cardiovascular care,” Ridker says. “All participants in TINSAL-CVD were appropriately treated with statin therapy, and these agents have been shown not only to slow atherosclerotic progression overall but also to reverse progression in some patients.”
He also notes that the anti-inflammatory effect of salsalate was “virtually opposite” that seen with statins, in that neutrophil and lymphocyte counts were lowered but C-reactive protein level was unaffected. “As nicely shown, the cell count effects are unlikely to be due to bone marrow suppression because hemoglobin levels and hematocrits increased,” he writes.
Finally, Ridker says, it is possible that starting salsalate earlier in the disease process could have yielded different results.
“All of these issues have considerable relevance for ongoing and planned investigations of the inflammatory hypothesis of atherothrombosis,” he concludes.
- Hauser TH, Salastekar N, Schaefer EJ, et al. Effect of targeting inflammation with salsalate: the TINSAL-CVD randomized clinical trial on progression of coronary plaque on overweight and obese patients using statins. JAMA Cardiol. 2016;Epub ahead of print.
- Ridker PM. Informative neutral studies matter—why the Targeting Inflammation With Salsalate in Cardiovascular Disease (TINSAL-CVD) trial deserves our attention. JAMA Cardiol. 2016;Epub ahead of print.
- This project was supported by the National Heart, Lung, and Blood Institute (NHLBI), the National Institute of Diabetes and Digestive and Kidney Diseases, and the Joslin Clinical Research Center and its philanthropic donors. Caraco Pharmaceuticals and Amneal Pharmaceutical provided salsalate and identical placebo. Boston Heart Diagnostics provided assay determinations and performed assays free of charge.
- Hauser reports receiving grants from the National Institutes of Health during the conduct of the study and personal fees from the Harvard Cardiovascular Research Institute outside of the present work.
- Ridker reports being listed as a coinventor on patents held by Brigham and Women’s Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease and diabetes that have been licensed to AstraZeneca and Siemens and currently serving as principal investigator and trial chairman of the NHLBI-funded Cardiovascular Inflammation Reduction Trial and the Novartis-funded Canakinumab Anti-inflammatory Thrombosis Outcomes Trial.