Coronary Flow Reserve to Assess Cardiovascular Inflammation (CIRT-CFR)

NCT02786134 | Completed Results

• 1 other identifier: 2013P002186
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

Coronary flow reserve (CFR, calculated as the ratio of hyperemic over rest myocardial blood flow) is emerging as a powerful quantitative prognostic imaging marker of clinical cardiovascular risk. CFR provides a robust and reproducible clinical measure of the integrated hemodynamic effects of epicardial coronary artery disease (CAD), diffuse atherosclerosis, and microvascular dysfunction on myocardial tissue perfusion. Inflammation is a key mediator of this constellation of abnormalities, affecting the entire coronary vasculature, but no clinical trial to date has shown that directly reducing inflammation lowers cardiovascular event rates. As such, the recently launched Cardiovascular Inflammation Reduction Trial (CIRT) provides a unique opportunity for mechanistic investigation of the impact of anti-inflammatory therapy on changes in CFR as a reflection of coronary vascular dysfunction, which may precede clinical outcomes, particularly in patients at high-risk of events. The investigators are ideally positioned to examine the impact of inflammation on CFR, having extensive experience in both the quantitation of CFR using clinically-integrated dynamic positron emission tomography (PET) and the ability to assess its association with cardiovascular outcomes. The central hypothesis of this ancillary proposal, CIRT-CFR, is that reducing systemic inflammation using low-dose methotrexate (LDM) will, compared to placebo, quantitatively improve myocardial blood flow and coronary flow reserve as measured by PET over one year, in stable CAD patients with type 2 diabetes or metabolic syndrome enrolled in CIRT. In so doing, improvement in coronary vasoreactivity, endothelial function, and tissue perfusion may have beneficial effects on myocardial mechanics, left ventricular deformation and function and, ultimately, symptoms and prognosis.

Conditions

Coronary Heart Disease; Metabolic Syndrome; Diabetes Mellitus

Outcome Measures

Primary Outcomes (1)

• Change in Global Myocardial Blood Flow in Response to Vasodilator

  Change (from baseline) in global coronary flow reserve in response to vasodilator as measured by PET imaging at baseline and at one year

  12 months

Study Arms (2)

low-dose methotrexate (LDM)

EXPERIMENTAL

Patients willing to participate in CIRT will be asked to enroll into the sub-study and may sign the CIRT-CFR informed consent at any point between signing the parent CIRT informed consent and completing the parent CIRT randomization visit (Visit 4). After giving informed consent for the ancillary CIRT-CFR, patients will undergo the baseline rest/dipyridamole stress PET scan along with echocardiography. The final PET scan and echocardiogram will occur at approximately 12 months after randomization.

Radiation: PET scan; Radiation: Echocardiogram

placebo

EXPERIMENTAL

Patients willing to participate in CIRT will be asked to enroll into the sub-study and may sign the CIRT-CFR informed consent at any point between signing the parent CIRT informed consent and completing the parent CIRT randomization visit (Visit 4). After giving informed consent for the ancillary CIRT-CFR, patients will undergo the baseline rest/dypridamole stress PET scan along with echocardiography. The final PET scan and echocardiogram will occur at approximately 12 months after randomization.

Radiation: PET scan; Radiation: Echocardiogram

Interventions

PET scan RADIATION

A cardiac PET scan will be performed at baseline (main CIRT trial randomization) and at 12-months.

low-dose methotrexate (LDM); placebo

Echocardiogram RADIATION

An echocardiogram will be performed at baseline (main CIRT trial randomization) and at 12-months.

low-dose methotrexate (LDM); placebo

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥18 years at screening;
• Documented past history of MI OR past evidence of multivessel CAD by angiography, completed any planned coronary revascularization associated with a qualifying event at least 60 days prior to enrollment, and clinically stable for ≥60 days prior to enrollment; qualifying prior MI must be documented either by hospital records, evidence on current ECG of Q waves in 2 contiguous leads, and/or an imaging test demonstrating wall motion abnormality or scar; qualifying evidence of multivessel CAD by angiography must be documented by CAD in at least two major epicardial vessels defined either as the presence of a stent, a coronary artery bypass graft, or an angiographic lesion of 60% or greater (left main CAD that has been revascularized with a stent or bypass graft will qualify as multivessel disease, as will the presence of a 50% or greater isolated left main stenosis);
• History of type 2 DM or metabolic syndrome (meeting 2004 AHA/NHLBI definition\*) at time of study enrollment; \*includes any 3 of the following 5 diagnostic criteria: waist circumference ≥ 102 cm in men or 88 cm in women; triglycerides ≥ 150 mg/dl or on drug treatment for elevated triglycerides; high-density lipoprotein cholesterol (HDL-C)\< 40 mg/dL in men or \< 50 mg/dL in women or on drug treatment for reduced HDL-C; systolic blood pressure ≥ 130 mm Hg or diastolic blood pressure ≥ 85 mm Hg or on drug treatment for hypertension; and elevated fasting glucose ≥ 100 mg/dL or on drug treatment for elevated glucose.
• Willingness to participate as evidenced by signing the CIRT and CIRT-CFR informed consent.

You may not qualify if:

• Prior history of chronic infectious disease, tuberculosis, or severe fungal disease; chronic hepatitis B or C infection; renal insufficiency; interstitial pneumonitis, bronchiectasis, or pulmonary fibrosis; known chronic pericardial effusion, pleural effusion, or ascites; chronic liver disease; myeloproliferative disorders in the past 5 years; non-basal cell malignancy or treated lymphoproliferative disease within the past 5 years; known HIV positive; life expectancy of \<3 years;
• Chronic inflammatory condition such as lupus or rheumatoid arthritis, ulcerative colitis or Crohn's disease
• White blood cell count \<3,500/ul, hematocrit \< 32 percent, or platelet count \< 75,000/ul
• Liver transaminase levels (AST or ALT) \>upper limit of normal (ULN) or albumin \< the lower limit of normal (LLN);
• Creatinine clearance \< 40 ml/min as estimated with the Cockroft-Gault equation;
• History of alcohol abuse or unwillingness to limit alcohol consumption to less than 4 drinks per week
• Women of child bearing potential, even if they are currently using contraception, and women intending to breastfeed.
• Men who plan to father children during the study period or who are unwilling to use effective forms of contraception.
• Requirement for use of drugs that alter folate metabolism (trimethoprim/sulfamethoxazol) or reduce tubular excretion (probenecid) or known allergies to antibiotics making avoidance of trimethoprim impossible;
• Current indication for methotrexate therapy;
• Chest X-ray evidence in the past 12 months of interstitial pneumonitis, bronchiectasis, or pulmonary fibrosis. For participants who do not have a chest X-ray in the prior 12 months, a chest X-ray will be obtained at baseline as part of the study protocol.
• New York Heart Association Class IV congestive heart failure.

Sponsors & Collaborators

• Brigham and Women's Hospital: lead
• Ottawa Heart Institute Research Corporation: collaborator
• University of Alabama at Birmingham: collaborator

Study Sites (1)

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Related Publications (1)

• Taqueti VR, Shah AM, Everett BM, Pradhan AD, Piazza G, Bibbo C, Hainer J, Morgan V, Carolina do A H de Souza A, Skali H, Blankstein R, Dorbala S, Goldhaber SZ, Le May MR, Chow BJW, deKemp RA, Hage FG, Beanlands RS, Libby P, Glynn RJ, Solomon SD, Ridker PM, Di Carli MF. Coronary Flow Reserve, Inflammation, and Myocardial Strain: The CIRT-CFR Trial. JACC Basic Transl Sci. 2022 Dec 21;8(2):141-151. doi: 10.1016/j.jacbts.2022.08.009. eCollection 2023 Feb.

  PMID: 36908662 DERIVED

MeSH Terms

Conditions

Coronary Disease; Metabolic Syndrome; Diabetes Mellitus

Interventions

Magnetic Resonance Spectroscopy

Condition Hierarchy (Ancestors)

Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Insulin Resistance; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Spectrum Analysis; Chemistry Techniques, Analytical; Investigative Techniques

Results Point of Contact

• Title: Dr. Marcelo Di Carli
• Organization: Brigham and Women's Hospital

mdicarli@bwh.harvard.edu

617-732-6290

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chief of Nuclear Medicine

Model Details: The CIRT-CFR study is a sub-study based off the main CIRT trial.

Study Record Dates

• First Submitted: May 20, 2016
• First Posted: May 30, 2016
• Study Start: April 1, 2016
• Primary Completion: October 1, 2019
• Study Completion: October 1, 2019
• Last Updated: January 6, 2021
• Results First Posted: January 6, 2021

Record last verified: 2020-12

Locations

US (1)