Inflammation and Coronary Endothelial Function

Inflammation and Coronary Endothelial Function in Patients With Coronary Artery Disease

The investigators are studying whether anti-inflammatory agents can improve abnormal coronary artery function in patients with coronary artery disease (CAD) and abnormal coronary artery endothelial function.

Study Overview

• Status: Completed
• Conditions: Coronary Artery Disease
• Intervention / Treatment: Drug: Methotrexate; Drug: Placebo; Drug: Colchicine

Detailed Description

Sometimes, in patients with coronary artery disease (CAD), even though blood pressure is controlled, the patients are on cholesterol medication, not smoking, eating properly and have normal levels of physical activity; the investigators still see development of new blockages, progression of existing blockages, and sometimes even clinical events like heart attacks and strokes. Therefore, the investigators are always trying to find additional ways to decrease the progression of existing blockages and to prevent new ones.

What the investigators are studying in this program is the function of the coronary arteries and in particular the inner lining of the arteries called the endothelium. It has several important functions; one of them is that under conditions of stress it releases a substance called nitric oxide which increases the size of the artery and increases blood flow. When it is not functioning normally the artery does not increase as much and blood flow does not increase during stress.

The investigators study coronary artery function with magnetic resonance imaging, or MRI. MRI is a method of obtaining images of what is happening inside the body. MRI does not involve radiation, x-ray, and injection of contrast. The investigators can measure flow in the artery and the dimension of the artery at rest and with a handgrip stress and learn the extent to which the artery dilates and flow increases with the stress. The investigators believe that inflammation can interfere with normal function and that by decreasing inflammation abnormal endothelial function may be improved.

Methotrexate and colchicine are anti-inflammatory agents approved by the Food and Drug Administration (FDA) to treat arthritis and some other conditions. These drugs are not approved for use to suppress inflammation in patients with coronary artery disease and improve coronary artery endothelial function. The FDA is allowing the use of methotrexate, colchicine and/or their combination in this research study.

This study will involve 24 weeks of anti-inflammatory drugs and 3 Magnetic Resonance Imaging (MRI) scans of the heart and other study procedures.

• Study Type: Interventional
• Enrollment (Actual): 111
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Participants of either gender who are 21 years of age (no upper age limit),
• History of prior Myocardial Infarction (MI), coronary revascularization, or coronary angiography or Multidetector Computer Tomography (MDCT) demonstrating at least one coronary artery with >50% luminal stenosis and no plans for revascularization,
• Clinically stable for 3 months,
• Vascular inflammation based on elevated hsCRP (>2mg L-1), or a clinical diagnosis of diabetes mellitus or metabolic syndrome (metabolic syndrome is defined by three or more of the following): Abdominal obesity (waist circumference: Men>102 cm (>40 in), Women >88 cm (>35 in)), Serum triglycerides ≥150 mg/dL (or taking medication to treat high triglycerides), HDL cholesterol: Men<40 mg/dL, Women<50 mg/dL (or taking medication to treat low HDL cholesterol), High blood pressure: ≥130/≥85 mm Hg (or taking medication to treat high blood pressure), or Fasting glucose: ≥100 mg/dL (or taking medication to treat high fasting glucose).
• Abnormal Coronary Endothelial Function (CEF) (change in CSA during IHE of <0% of the resting value: by this we mean any decrease in CSA or no change (0%) from baseline during IHE),
• Permission of patient's clinical attending physician,
• Patients being treated with a statin.

Exclusion Criteria:

• Patients unable to understand the risks, benefits, and alternatives of participation and give meaningful consent,
• Patients with contraindications to MRI such as implanted metallic objects (pre-existing cardiac pacemakers, cerebral clips) or indwelling metallic projectiles,
• Acute coronary syndrome within the prior three months,
• Pregnant women,
• Contraindications to methotrexate or colchicine as outlined by the American College of Rheumatology; including active bacterial infection, tuberculosis, or herpes zoster infection, leukopenia (<4000/mm3), thrombocytopenia (<135,000/mm3), elevation in hepatic transaminases (>2x upper limit of normal), hepatitis B or C, moderate renal disease (estimated creatine clearance <45ml/min), or planned surgery,
• Chronic inflammatory condition such as lupus or rheumatoid arthritis, ulcerative colitis or Crohn's disease,
• Interstitial lung disease or pulmonary fibrosis,
• HIV positive,
• Requirement for, or intolerance to, methotrexate or colchicine ,
• Intolerance to methotrexate, colchicine or folate,
• History of non-basal cell malignancy or treatment for lymphoproliferative disease in the past 5 years,
• Requirement for use of drugs that alter folate metabolism,
• History of alcohol abuse or unwillingness to limit consumption to < 4 drinks per week,
• Women of childbearing potential or intention to breastfeed.
• Men who plan to father children during the study period; men who have sexual intercourse with women of childbearing potential must agree to use a condom,
• Chronic use of oral or IV steroid therapy or other immunosuppressive or biologic response modifiers,
• History of chronic pericardial effusion, pleural effusion or ascites,
• New York Heart Association Class IV heart failure.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Methotrexate; Methotrexate 15 mg weekly by mouth and placebo for colchicine 1 tablet by mouth daily and folate 1 mg by mouth daily	Drug: Methotrexate; Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease; Other Names: Trexall; Drug: Placebo; Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.; Other Names: A substance containing no medication
Experimental: Colchicine; Colchicine 0.6 mg daily by mouth and placebo for methotrexate 1 tablet weekly by mouth and folate 1 mg by mouth daily	Drug: Placebo; Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.; Other Names: A substance containing no medication; Drug: Colchicine; Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease.; Other Names: Colcrys
Experimental: Methotrexate & Colchicine; Methotrexate 15 mg by mouth weekly and colchicine 0.6 mg by mouth daily and folate 1 mg by mouth daily	Drug: Methotrexate; Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease; Other Names: Trexall; Drug: Colchicine; Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease.; Other Names: Colcrys
Experimental: Placebo; Placebo for methotrexate 1 tablet by mouth weekly and placebo for colchicine 1 tablet by mouth daily and folate 1 mg by mouth daily	Drug: Placebo; Prepared by Johns Hopkins Investigational Drug Service to mimic methotrexate and colchicine.; Other Names: A substance containing no medication

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change in Coronary Cross Sectional Area (CSA) From Rest to That During Isometric Handgrip Exercise (IHE)	Coronary segment endothelial function, measured by MRI as the percent change in coronary cross sectional area (CSA) from rest to that during isometric handgrip exercise (IHE) (as % rest) at 8 weeks.	At 8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change in Coronary Cross Sectional Area (CSA) From Rest to That During Isometric Handgrip Exercise (IHE)	Change in coronary segment endothelial function, measured by MRI as the percent change in coronary cross sectional area (CSA) from rest to that during isometric handgrip exercise (IHE) (as % rest) at 24 weeks.	At 24 weeks
Percent Change in Coronary Blood Flow (CBF), Measured by MRI as the Change From Rest to IHE Stress	Change in coronary blood flow (CBF), measured by MRI as the percent change from rest to IHE stress (as % rest) at 8 weeks.	At 8 weeks
Serum High-sensitivity C Reactive Protein (Hs-CRP)	Serum high-sensitivity C reactive protein (hs-CRP), measured by laboratory assessment in mg/l at 8 weeks.	At 8 weeks
Serum Interleukin-6 (IL-6)	Serum interleukin-6 (IL-6), measured by laboratory assessment in pg/ml at 8 weeks.	At 8 weeks
Brachial Flow Mediated Dilation (FMD)	Brachial flow mediated dilation (FMD), measured as percent brachial artery dilation by ultrasound at 8 weeks.	At 8 weeks

Collaborators and Investigators

• Sponsor: Johns Hopkins University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)

Publications and helpful links

General Publications

• Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol. 2013 Jan 29;61(4):404-410. doi: 10.1016/j.jacc.2012.10.027. Epub 2012 Dec 19.
• Everett BM, Pradhan AD, Solomon DH, Paynter N, Macfadyen J, Zaharris E, Gupta M, Clearfield M, Libby P, Hasan AA, Glynn RJ, Ridker PM. Rationale and design of the Cardiovascular Inflammation Reduction Trial: a test of the inflammatory hypothesis of atherothrombosis. Am Heart J. 2013 Aug;166(2):199-207.e15. doi: 10.1016/j.ahj.2013.03.018. Epub 2013 May 3.
• Hays AG, Hirsch GA, Kelle S, Gerstenblith G, Weiss RG, Stuber M. Noninvasive visualization of coronary artery endothelial function in healthy subjects and in patients with coronary artery disease. J Am Coll Cardiol. 2010 Nov 9;56(20):1657-65. doi: 10.1016/j.jacc.2010.06.036.
• Hays AG, Stuber M, Hirsch GA, Yu J, Schar M, Weiss RG, Gerstenblith G, Kelle S. Non-invasive detection of coronary endothelial response to sequential handgrip exercise in coronary artery disease patients and healthy adults. PLoS One. 2013;8(3):e58047. doi: 10.1371/journal.pone.0058047. Epub 2013 Mar 11.
• Hays AG, Kelle S, Hirsch GA, Soleimanifard S, Yu J, Agarwal HK, Gerstenblith G, Schar M, Stuber M, Weiss RG. Regional coronary endothelial function is closely related to local early coronary atherosclerosis in patients with mild coronary artery disease: pilot study. Circ Cardiovasc Imaging. 2012 May 1;5(3):341-8. doi: 10.1161/CIRCIMAGING.111.969691. Epub 2012 Apr 5.
• Weiss RG, Bottomley PA, Hardy CJ, Gerstenblith G. Regional myocardial metabolism of high-energy phosphates during isometric exercise in patients with coronary artery disease. N Engl J Med. 1990 Dec 6;323(23):1593-600. doi: 10.1056/NEJM199012063232304.
• Hays AG, Schär M, Bonanno G, Lai S, Meyer J, Afework Y, Steinberg A, Stradley S, Gerstenblith G, Weiss RG. Randomized Trial of Anti-inflammatory Medications and Coronary Endothelial Dysfunction in Patients With Stable Coronary Disease. Front Cardiovasc Med. 2021 Oct 15;8:728654. doi: 10.3389/fcvm.2021.728654. eCollection 2021.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2015
• Primary Completion (Actual): August 1, 2020
• Study Completion (Actual): September 1, 2020

Study Registration Dates

• First Submitted: February 5, 2015
• First Submitted That Met QC Criteria: February 11, 2015
• First Posted (Estimate): February 19, 2015

Study Record Updates

• Last Update Posted (Actual): October 21, 2021
• Last Update Submitted That Met QC Criteria: September 24, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Inflammation; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Gout Suppressants; Methotrexate; Colchicine
• Other Study ID Numbers: IRB00047206; R01HL120905 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No