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Macrovascular Residual Risk THROUGH LANDMARK STUDY

18 September 2016
TINSAL-CVD does not rule out a role for inflammation as a contributor to residual cardiovascular risk

In the Targeting Inflammation Using Salsalate in Cardiovascular Disease (TINSAL-CVD) trial, targeting inflammation using salsalate, added to best evidence-based treatment including statin, did not reduce progression of noncalcified coronary plaque.

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 in overweight and obese patients using statins. JAMA Cardiol 2016;1:413-23.
Summary
Comments & References
STUDY SUMMARY
Objective: To determine whether targeting inflammation using salsalate compared with placebo reduces progression of noncalcified coronary artery plaque
Study design: Double-masked, randomized, placebo-controlled, parallel clinical trial. Patients were allocated 1:1 to salsalate 3.5 g/day orally or placebo for 30 months.
Study population: 257 overweight and obese patients on statin (mean ±standard age 60.8 ±7.0 years, mean weight 96.1 ± 12.5 kg, 94% male, 95% with dyslipidaemia, 24% with type 2 diabetes). In total, 129 were allocated salsalate and 128 were on placebo.
Primary variable: Change in volume of noncalcified coronary artery plaque assessed by multidetector computed tomographic angiography (MDCTA)
Methods:

Total calcification was assessed using Agatston scoring and was performed independently by two readers. MDCTA images underwent 3-dimensional reconstruction. Multiplanar reconstructed images were used for coronary segment plaque volume analysis.

 Data were analysed by intention-to-treat using linear mixed models with baseline value, time, and treatment group as fixed effects and diabetes status and intercept as random effects (for normally distributed continuous variables, including the primary outcome). A per protocol analysis was performed in patients who were adherent to treatment for more than 80% of the study duration.

Main results:

·       Compared with baseline, there was no increase in noncalcified plaque volume in the placebo-treated patients.

·       There was no difference in the change between the salsalate and placebo groups after 30 months (mean difference, −1 mm3; 95%CI, −11 to 9 mm3; p=0.87).

·       Although there was no significant change in C-reactive protein in the salsalate group (p=0.84), treatment decreased total white blood cell (p<0.001), and lymphocyte (p=0.001), monocyte (p=0.03), and neutrophil counts (p=0.001), and also increased adiponectin levels (p<0.001).

·       Salsalate treatment was also associated with decreases in levels of triglycerides (by 11%, p=0.03), fasting glucose (by 7%, p<0.001), uric acid (by 27%, p<0.001), and bilirubin (by 29%, p<0.001) versus placebo.  

Authors’ conclusion: Salsalate when added to current therapies that include a statin does not reduce progression of noncalcified coronary plaque volume assessed by MDCTA in statin-using patients with established, stable coronary heart disease. The absence of progression of noncalcified plaque volume in the placebo group may limit interpretation of the trial results.

COMMENT

While lipids have attracted most of the attention in interventional studies targeting residual cardiovascular risk, it is recognized that other variables may also contribute. In particular, the role of chronic subclinical systemic inflammation has attracted attention.  This factor may be of particular relevance in individuals who are overweight or obese (1). Indeed, the Multi-Ethnic Study of Atherosclerosis (MESA) showed a graded association between obesity and metabolic syndrome with inflammation and coronary artery calcium (a marker of subclinical atherosclerosis) (2). Given that salsalate, a nonacetylated prodrug of salicylate, is already used in the treatment of inflammatory disorders, such as rheumatoid arthritis, there has been much interest in the potential of this treatment for targeting inflammation in high-risk cardiovascular patients.  This rationale is underpinned by studies showing that salsalate improves glycaemia and metabolic risk profiles in patients with insulin resistant conditions (3-5). Consequently, TINSAL-CVD addressed this key question: Does targeting inflammation using salsalate slow progression of coronary artery plaque over 30 months compared with placebo?

 Interpretation of the results of this study are, however, complicated by the fact that the placebo group showed no change in noncalcified coronary plaque volume over 30 months. As a consequence, no difference was observed between the salsalate and placebo groups for this primary end point. The reason for the lack of progression in the placebo group may relate to the current reality of best evidence-based medicine. In the study, patients were receiving statin therapy, which has been shown to slow and even reverse atherosclerosis progression in clinical trials (6). Moreover, salsalate treatment did not reduce C-reactive protein, an inflammatory marker, but did significantly reduce neutrophil and lymphocyte counts, which might suggest that the underlying mechanism of anti-inflammatory action matters.

 Taken together, the results represent at best a neutral rather than negative finding. Further investigation of inflammation as a potential contributor to residual cardiovascular risk (including risk of subclinical atherosclerotic vascular disease) remains the focus of ongoing trials.

References

1. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest 2006;116:1793-801.

2. Al Rifai M, Silverman MG, Nasir K et al. The association of nonalcoholic fatty liver disease, obesity, and metabolic syndrome, with systemic inflammation and subclinical atherosclerosis: the Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis 2015;239:629-33.

3. Goldfine AB, Fonseca V, Jablonski KA, et al; Targeting Inflammation Using Salsalate in Type 2 Diabetes Study Team. Salicylate (salsalate) in patients with type 2 diabetes: a randomized trial. Ann Intern Med 2013;159:1-12.

4. Goldfine AB, Conlin PR, Halperin F, et al. A randomised trial of salsalate for insulin resistance and cardiovascular risk factors in persons with abnormal glucose tolerance. Diabetologia. 2013;56:714-23.

5. Faghihimani E, Aminorroaya A, Rezvanian H et al. Salsalate improves glycemic control in patients with newly diagnosed type 2 diabetes. Acta Diabetol 2013;50:537-43.

6. Nicholls SJ, Ballantyne CM, Barter PJ et al. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med 2011;365:2078-87.

Key words residual cardiovascular risk; inflammation; obesity; metabolic risk; salsalate