Randomized Trial of Anti-inflammatory Medications and Coronary Endothelial Dysfunction in Patients With Stable Coronary Disease

Abstract

Aims: Inflammation plays a critical role in the pathogenesis of coronary artery disease (CAD), however the impact of anti-inflammatory therapies to reduce those processes which promote atherosclerosis in CAD patients is unknown. We aimed to test the hypothesis that anti-inflammatory approaches improve impaired coronary endothelial function (CEF), a driver of coronary atherosclerosis, in stable CAD patients. Methods and Results: We performed a single-center, randomized, placebo-controlled, double-blinded trial to assess whether low dose methotrexate (MTX), low dose colchicine (LDC), and/or their combination (MTX+LDC), improves CEF using non-invasive MRI measures in patients with stable CAD (N = 94). The primary endpoint was the MRI-detected change in coronary cross-sectional area from rest to isometric handgrip exercise (IHE), a predominantly nitric oxide-dependent endothelial dependent stressor. Coronary and systemic endothelial endpoints, and serum inflammatory markers, were collected at baseline, 8 and 24 weeks. Anti-inflammatory study drugs were well-tolerated. There were no significant differences in any of the CEF parameters among the four groups (MTX, LDC, MTX+LDC, placebo) at 8 or 24 weeks. Serum markers of inflammation and systemic endothelial function measures were also not significantly different among the groups. Conclusion: This is the first study to examine the effects of the anti-inflammatory approaches using MTX, LDC, and/or the combination in stable CAD patients on CEF, a marker of vascular health and the primary endpoint of the study. Although these anti-inflammatory approaches were relatively well-tolerated, they did not improve coronary endothelial function in patients with stable CAD. Clinical Trial Registration: www.clinicaltrials.gov, identifier: NCT02366091.

Keywords: coronary artery disease; coronary endothelial function; flow mediated dilatation; inflammation; magnetic resonance imaging.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Hays, Schär, Bonanno, Lai, Meyer, Afework, Steinberg, Stradley, Gerstenblith and Weiss.

Figures

Figure 1

Trial flow chart.

Figure 2

Representative coronary artery MRI images for CEF. (A) A scout MRI obtained parallel to the right coronary artery (RCA) is shown with the location for subsequent cross-sectional imaging (yellow outline). (B) Image acquired along the yellow-outlined region in (A) with RCA in cross-section (white arrow). The dotted rectangle in (B) is magnified in subsequent panels and shows the region analyzed for cross-sectional area at rest (C) and during exercise (D). Flow velocity images of the same segment at rest (E) and during IHE (F) using a phase contrast technique wherein signal darkness increases only slightly during IHE, indicating an impaired velocity response. (G,H) Relative changes (%) in coronary artery cross sectional area (CSA), and coronary blood-flow (CBF) detected by MRI during isometric handgrip exercise at 8 weeks (G) and 24 weeks (H) for those on methotrexate (MTX, black), colchicine (gray), MTX and colchicine (red), and placebo (blue). Error bars indicate standard error of the mean. There were no significant differences in coronary endothelial function parameters between the placebo and anti-inflammatory treatments at the 8 week (primary) end point. % CSA change was lower in colchicine than placebo (*p = 0.02) at 24 weeks. Ao, aorta; LV, left ventricle; RV, right ventricle.

Figure 3

Bar graphs showing the effects of low-dose methotrexate (MTX, dotted bar), colchicine (LDC, striped bar), the combination of MTX and LDC (gray bar), and placebo (white bar) on (A). interleukin-6, (B) low-density lipoprotein [LDL] cholesterol, (C) hsCRP, (D) interleukin-1β, hepatic enzyme levels (E) alanine aminotransferase [ALT] and (F) aspartate aminotransferase [AST], and hematologic measures (G) hematocrit level, (H) white-cell count. Data shown are the changes from study enrollment to 8 weeks after randomization. The horizontal line in each box represents the median, the top and bottom of the boxes represent the interquartile range, and the whiskers represent 1.5 times the interquartile range. *Statistically significant difference (P ≤ 0.05) compared to placebo.