Cardiovascular Disease
Conditions
Keywords
Myocardial Infarction, Stroke, Cardiovascular death, Type 2 Diabetes, Metabolic Syndrome, Cardiovascular Inflammation, Atherothrombosis
Brief summary
The Cardiovascular Inflammation Reduction Trial (CIRT) is a randomized clinical trial investigating whether taking low-dose methotrexate reduces heart attacks, strokes, or death in people with type 2 diabetes or metabolic syndrome that have had a heart attack or multiple coronary blockages. This trial is funded by the National Heart, Lung, and Blood Institute (NHLBI)/National Institutes of Health (NIH).
Detailed description
While inflammation contributes crucially to atherothrombosis, it is unknown whether inhibition of inflammation per se will lower vascular event rates. The primary aim of the Cardiovascular Inflammation Reduction Trial (CIRT) is to directly test the inflammatory hypothesis of atherothrombosis by evaluating whether or not low-dose methotrexate (LDM) will reduce rates of myocardial infarction, stroke, and cardiovascular death among stable coronary artery disease patients with type 2 diabetes or metabolic syndrome, conditions associated with an enhanced pro-inflammatory response. CIRT is a randomized, double-blind, placebo-controlled, multi-center, event-driven trial that will randomize 7,000 men and women from the United States and Canada. Following a five- to six-week open-label run-in (maximum 8 weeks), eligible participants who have either suffered documented myocardial infarction in the past or have angiographically demonstrated multivessel coronary artery disease in the past will be randomly allocated over a three to four year period to usual care plus placebo or usual care plus LDM. The target methotrexate dose among those allocated to active therapy is 15 to 20 mg po per week, a dose within the range of that commonly used for the treatment of rheumatoid arthritis. All study participants will additionally receive 1.0 mg oral folate to be taken daily six days per week. LDM complications will be minimized through education programs for all investigators and coordinators, through enhanced communication with study participants, by limiting enrollment to those with no evidence of malignancy, hepatitis, renal dysfunction, chronic infection, pulmonary disease, or other risk factors for toxicity; by conducting an initial 5- to 6-week active-therapy run-in (maximum 8 weeks) designed to eliminate individuals who are either intolerant of or unable to adhere to treatment before randomization; and through regular monitoring of liver function and hematologic indices using a centralized methodology designed to ensure participant safety, allow for dose adjustments while maintaining the study blind, and provide an efficient method to address issues of compliance and follow-up on a cost-effective centralized basis. The primary trial endpoint is the rate of myocardial infarction, stroke, or cardiovascular death. Secondary and tertiary endpoints include all-cause mortality, coronary revascularization, incident congestive heart failure, incident peripheral artery disease, incident venous thrombosis, clinically significant aortic stenosis, incident atrial fibrillation, incident diabetes among those with metabolic syndrome but not diabetes at study entry, and hemoglobin A1c (HbA1c) control among those with diabetes at study entry. The trial is event driven such that in the absence of extreme effects, the trial will conclude after accrual of at least 530 primary endpoints, an effect estimated to provide 90 percent power to detect a 25 percent relative risk reduction. The potential clinical impact of CIRT is broad as it has sufficient power to directly address core issues in the inflammatory hypothesis of atherothrombosis, and thus, if successful, will open major new directions for cardiovascular treatment.
Interventions
DRUGMethotrexate
Tablet, Oral, Target dose 15-20 mg weekly plus 1.0 mg folic acid 6 days/week
DRUGPlacebo
Tablet, Oral, weekly plus 1.0 mg folic acid 6 days/week
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥ 18 years at screening * Documented past history of myocardial infarction OR past evidence of multivessel coronary artery disease by angiography. * To qualify on the basis of past history of myocardial infarction, the event must be documented either by hospital records or by evidence on current ECG of Q waves in two contiguous leads and/or an imaging test demonstrating wall motion abnormality or scar. The patient must also have completed any planned coronary revascularization procedures associated with the qualifying event, and be clinically stable for at least 60 days prior to screening. * To qualify on the basis of multivessel coronary disease, there must be past angiographic evidence of atherosclerosis in at least 2 major epicardial vessels defined either as the presence of a stent, a coronary bypass graft, or an angiographic lesion of 60% or greater. Left main coronary artery disease 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. The patient must also have completed any planned coronary revascularization procedures associated with the qualifying event, and be clinically stable for at least 60 days prior to screening. * History of type 2 diabetes or metabolic syndrome at time of study enrollment * Willingness to participate as evidenced by signing the study informed consent
Exclusion criteria
* 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 Cockcroft-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; * Chronic use of oral steroid therapy or other immunosuppressive or biologic response modifiers. Eligible study participants will be encouraged to have up to date pneumococcal and influenza vaccinations as recommended based on their age and underlying medical conditions. * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Major Adverse Cardiovascular Events | From randomization to trial end (April 2, 2018) up to a maximum of 5 years | The first occurrence of Major Adverse Cardiovascular Event which is defined as the occurrence of one or more of the following: Cardiovascular Death, Non-Fatal Myocardial Infarction or Non-Fatal Stroke. |
| Number of Subjects With Major Adverse Cardiovascular Event or Hospitalization for Unstable Angina That Led to Urgent Coronary Revascularization | From randomization to trial end (April 2, 2018) - up to a maximum of 5 years | The first occurrence of Major Adverse Cardiovascular Event or Hospitalization for Unstable Angina that led to Urgent Coronary Revascularization. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With All-cause Mortality | From randomization to the trial end (April 2, 2018) up to a maximum of 5 years | Subjects who died from any cause. |
| Number of Subjects With Major Adverse Cardiovascular Event or Any Coronary Revascularization | From randomization to the trial end (April 2, 2018) - up to a maximum of 5 years | The first occurrence of Major Adverse Cardiovascular Event or Any Coronary Revascularization. |
| Number of Subjects With Hospitalization for Congestive Heart Failure | From randomization to trial end (April 2, 2018) up to a maximum of 5 years | The first occurrence of Hospitalization for Congestive Heart Failure |
| Number of Subjects With Major Adverse Cardiovascular Event, Coronary Revascularization, Hospitalization for Congestive Heart Failure or All Cause Mortality | From randomization to trial end (April 2, 2018) up to a maximum of 5 years | The first occurrence of Major Adverse Cardiovascular Event, Coronary Revascularization, Hospitalization for Congestive Heart Failure or All Cause Mortality. |
| Number of Subjects With New Onset Type 2 Diabetes | From randomization to the trial end (April 2, 2018) - up to 5 years | New onset type 2 diabetes among those without diabetes at baseline. Baseline diabetes is defined as any of the following prior to randomization: clinician report of diabetes, use of antidiabetic medication, hbA1c \>=6.5 or fasting plasma glucose \>=126. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Peripheral Artery Disease | From randomization to the trial end (April 2, 2018) - up to 5 years | The first occurrence of new or worsening of peripheral artery disease |
| Number of Subjects With Coronary Revascularization | From randomization to trial end (April 2, 2018) up to 5 years | The first occurrence of coronary revascularization |
| Number of Subjects With Deep Vein Thrombosis or Pulmonary Embolism | From randomization to the trial end (April 2, 2018) - up to 5 years | The first occurrence of symptomatic deep vein thrombosis or pulmonary embolism |
| Number of Subjects With Aortic Stenosis | From randomization to the trial end (April 2, 2018) - up to 5 years | The first occurrence of clinically significant aortic stenosis |
| Number of Subjects With Atrial Fibrillation | From randomization to the trial end (April 2, 2018) - up to 5 years | The first occurrence of new or worsening of atrial fibrillation |
| Number of Subjects With Hospitalization for Unstable Angina That Led to Unplanned Coronary Revascularization | From randomization to the trial end (April 2, 2018) up to 5 years | The first occurrence of hospitalization for unstable angina that led to unplanned coronary revascularization |
Countries
Canada, Puerto Rico, United States
Participant flow
Recruitment details
9321 subjects were screened and 4786 subjects were randomized starting from April, 2013 through March 2018 in 417 clinical sites in Canada and the United States
Pre-assignment details
9321 subjects were screened, 2987 were found to be ineligible and 176 were discontinued due to premature trial closure prior to entering the open label run-in. 6158 started the run-in. Of those, 1171 were ineligible, 201 were discontinued due to premature trial closure and 4786 subjects were randomly assigned to either Methotrexate or Placebo
Participants by arm
| Arm | Count |
|---|---|
| Methotrexate Methotrexate: Tablet, Oral, Target dose 15-20 mg weekly plus 1.0 mg folic acid 6 days/week | 2,391 |
| Placebo Placebo: Tablet, Oral, weekly plus 1.0 mg folic acid 6 days/week | 2,395 |
| Total | 4,786 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 96 | 83 |
| Overall Study | Lost to Follow-up | 5 | 5 |
| Overall Study | Withdrawal by Subject | 60 | 63 |
Baseline characteristics
| Characteristic | Methotrexate | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 65.6 years | 66.0 years | 65.8 years |
| Alcohol use <=1 drink/week | 514 Participants | 520 Participants | 1034 Participants |
| Alcohol use >1 drink/week | 390 Participants | 402 Participants | 792 Participants |
| Alcohol use Rarely/Never | 1487 Participants | 1473 Participants | 2960 Participants |
| Body Mass Index | 31.6 kilograms per meter squared | 31.3 kilograms per meter squared | 31.5 kilograms per meter squared |
| Family history of premature myocardial infarction No | 1568 Participants | 1580 Participants | 3148 Participants |
| Family history of premature myocardial infarction Yes | 550 Participants | 536 Participants | 1086 Participants |
| Family history of premature stroke No | 2002 Participants | 2024 Participants | 4026 Participants |
| Family history of premature stroke Yes | 142 Participants | 136 Participants | 278 Participants |
| Glycated hemoglobin level | 6.6 % | 6.5 % | 6.5 % |
| High density lipoprotein cholesterol | 41.0 mg/dL | 41.0 mg/dL | 41.0 mg/dL |
| High-sensitivity C-reactive protein level | 1.53 mg/liter | 1.50 mg/liter | 1.51 mg/liter |
| History of congestive heart failure No | 2103 Participants | 2062 Participants | 4165 Participants |
| History of congestive heart failure Yes | 288 Participants | 332 Participants | 620 Participants |
| History of coronary-artery bypass grafting No | 1381 Participants | 1362 Participants | 2743 Participants |
| History of coronary-artery bypass grafting Yes | 1010 Participants | 1032 Participants | 2042 Participants |
| History of diagnosed hypertension No | 238 Participants | 225 Participants | 463 Participants |
| History of diagnosed hypertension Yes | 2153 Participants | 2169 Participants | 4322 Participants |
| History of percutaneous coronary intervention No | 995 Participants | 974 Participants | 1969 Participants |
| History of percutaneous coronary intervention Yes | 1396 Participants | 1420 Participants | 2816 Participants |
| Low density lipoprotein cholesterol | 68.0 mg/dL | 68.0 mg/dL | 68.0 mg/dL |
| Qualifying coexisting condition Diabests and metabolic syndrome | 832 Participants | 792 Participants | 1624 Participants |
| Qualifying coexisting condition Diabetes only | 788 Participants | 823 Participants | 1611 Participants |
| Qualifying coexisting condition Metabolic syndrome only | 771 Participants | 780 Participants | 1551 Participants |
| Qualifying event Multivessel coronary disease | 940 Participants | 937 Participants | 1877 Participants |
| Qualifying event Myocardial infarction | 1451 Participants | 1458 Participants | 2909 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 6 Participants | 6 Participants | 12 Participants |
| Race/Ethnicity, Customized Asian | 89 Participants | 92 Participants | 181 Participants |
| Race/Ethnicity, Customized Black or African American | 186 Participants | 152 Participants | 338 Participants |
| Race/Ethnicity, Customized Hispanic/Latino | 206 Participants | 177 Participants | 383 Participants |
| Race/Ethnicity, Customized Multiracial | 13 Participants | 7 Participants | 20 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 3 Participants | 6 Participants | 9 Participants |
| Race/Ethnicity, Customized Other | 42 Participants | 45 Participants | 87 Participants |
| Race/Ethnicity, Customized White/Non-hispanic or Latino | 1801 Participants | 1837 Participants | 3638 Participants |
| Race/Ethnicity, Customized White, Unknown Ethnicity | 45 Participants | 73 Participants | 118 Participants |
| Region of Enrollment Canada | 407 participants | 404 participants | 811 participants |
| Region of Enrollment Puerto Rico | 19 participants | 17 participants | 36 participants |
| Region of Enrollment United States | 1965 participants | 1974 participants | 3939 participants |
| Sex: Female, Male Female | 461 Participants | 437 Participants | 898 Participants |
| Sex: Female, Male Male | 1930 Participants | 1958 Participants | 3888 Participants |
| Smoking status Current smoker | 267 Participants | 270 Participants | 537 Participants |
| Smoking status Never smoked cigarettes | 951 Participants | 910 Participants | 1861 Participants |
| Smoking status Past smoker | 1173 Participants | 1215 Participants | 2388 Participants |
| Total cholesterol | 141.0 mg/dL | 140.9 mg/dL | 141.0 mg/dL |
| Triglycerides | 135.4 mg/dL | 136.0 mg/dL | 135.4 mg/dL |
| Use of a beta-blocker No | 521 Participants | 490 Participants | 1011 Participants |
| Use of a beta-blocker Yes | 1870 Participants | 1905 Participants | 3775 Participants |
| Use of ACE inhibitor or ARB No | 655 Participants | 671 Participants | 1326 Participants |
| Use of ACE inhibitor or ARB Yes | 1736 Participants | 1724 Participants | 3460 Participants |
| Use of antiplatelet or antithrombotic agent No | 309 Participants | 341 Participants | 650 Participants |
| Use of antiplatelet or antithrombotic agent Yes | 2082 Participants | 2054 Participants | 4136 Participants |
| Use of a statin No | 333 Participants | 343 Participants | 676 Participants |
| Use of a statin Yes | 2058 Participants | 2052 Participants | 4110 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 96 / 2,391 | 83 / 2,395 |
| other Total, other adverse events | 1,488 / 2,391 | 1,399 / 2,395 |
| serious Total, serious adverse events | 569 / 2,391 | 549 / 2,395 |
Outcome results
Primary
Number of Subjects With Major Adverse Cardiovascular Event or Hospitalization for Unstable Angina That Led to Urgent Coronary Revascularization
The first occurrence of Major Adverse Cardiovascular Event or Hospitalization for Unstable Angina that led to Urgent Coronary Revascularization.
Time frame: From randomization to trial end (April 2, 2018) - up to a maximum of 5 years
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Methotrexate | Number of Subjects With Major Adverse Cardiovascular Event or Hospitalization for Unstable Angina That Led to Urgent Coronary Revascularization | 201 participants |
| Placebo | Number of Subjects With Major Adverse Cardiovascular Event or Hospitalization for Unstable Angina That Led to Urgent Coronary Revascularization | 207 participants |
p-value: 0.6795% CI: [0.79, 1.16]Log Rank
Primary
Number of Subjects With Major Adverse Cardiovascular Events
The first occurrence of Major Adverse Cardiovascular Event which is defined as the occurrence of one or more of the following: Cardiovascular Death, Non-Fatal Myocardial Infarction or Non-Fatal Stroke.
Time frame: From randomization to trial end (April 2, 2018) up to a maximum of 5 years
Population: All randomized subjects
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Methotrexate | Number of Subjects With Major Adverse Cardiovascular Events | 170 participants |
| Placebo | Number of Subjects With Major Adverse Cardiovascular Events | 167 participants |
p-value: 0.9195% CI: [0.82, 1.25]Log Rank
Secondary
Number of Subjects With All-cause Mortality
Subjects who died from any cause.
Time frame: From randomization to the trial end (April 2, 2018) up to a maximum of 5 years
Population: All Randomized Participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Methotrexate | Number of Subjects With All-cause Mortality | 96 participants |
| Placebo | Number of Subjects With All-cause Mortality | 83 participants |
p-value: 0.3295% CI: [0.87, 1.56]Log Rank
Secondary
Number of Subjects With Hospitalization for Congestive Heart Failure
The first occurrence of Hospitalization for Congestive Heart Failure
Time frame: From randomization to trial end (April 2, 2018) up to a maximum of 5 years
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Methotrexate | Number of Subjects With Hospitalization for Congestive Heart Failure | 48 participants |
| Placebo | Number of Subjects With Hospitalization for Congestive Heart Failure | 53 participants |
p-value: 0.5495% CI: [0.6, 1.31]Log Rank
Secondary
Number of Subjects With Major Adverse Cardiovascular Event, Coronary Revascularization, Hospitalization for Congestive Heart Failure or All Cause Mortality
The first occurrence of Major Adverse Cardiovascular Event, Coronary Revascularization, Hospitalization for Congestive Heart Failure or All Cause Mortality.
Time frame: From randomization to trial end (April 2, 2018) up to a maximum of 5 years
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Methotrexate | Number of Subjects With Major Adverse Cardiovascular Event, Coronary Revascularization, Hospitalization for Congestive Heart Failure or All Cause Mortality | 344 participants |
| Placebo | Number of Subjects With Major Adverse Cardiovascular Event, Coronary Revascularization, Hospitalization for Congestive Heart Failure or All Cause Mortality | 345 participants |
p-value: 0.895% CI: [0.84, 1.14]Log Rank
Secondary
Number of Subjects With Major Adverse Cardiovascular Event or Any Coronary Revascularization
The first occurrence of Major Adverse Cardiovascular Event or Any Coronary Revascularization.
Time frame: From randomization to the trial end (April 2, 2018) - up to a maximum of 5 years
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Methotrexate | Number of Subjects With Major Adverse Cardiovascular Event or Any Coronary Revascularization | 278 participants |
| Placebo | Number of Subjects With Major Adverse Cardiovascular Event or Any Coronary Revascularization | 288 participants |
p-value: 0.5795% CI: [0.81, 1.12]Log Rank
Secondary
Number of Subjects With New Onset Type 2 Diabetes
New onset type 2 diabetes among those without diabetes at baseline. Baseline diabetes is defined as any of the following prior to randomization: clinician report of diabetes, use of antidiabetic medication, hbA1c \>=6.5 or fasting plasma glucose \>=126.
Time frame: From randomization to the trial end (April 2, 2018) - up to 5 years
Population: Randomized participants without pre-randomization diabetes
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Methotrexate | Number of Subjects With New Onset Type 2 Diabetes | 4 Participants |
| Placebo | Number of Subjects With New Onset Type 2 Diabetes | 6 Participants |
Other Pre-specified
Number of Subjects With Aortic Stenosis
The first occurrence of clinically significant aortic stenosis
Time frame: From randomization to the trial end (April 2, 2018) - up to 5 years
Population: The trial ended prematurely. There were not sufficient outcome measures for analysis.
Other Pre-specified
Number of Subjects With Atrial Fibrillation
The first occurrence of new or worsening of atrial fibrillation
Time frame: From randomization to the trial end (April 2, 2018) - up to 5 years
Other Pre-specified
Number of Subjects With Coronary Revascularization
The first occurrence of coronary revascularization
Time frame: From randomization to trial end (April 2, 2018) up to 5 years
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Methotrexate | Number of Subjects With Coronary Revascularization | 190 participants |
| Placebo | Number of Subjects With Coronary Revascularization | 205 participants |
p-value: 0.3895% CI: [0.75, 1.12]Log Rank
Other Pre-specified
Number of Subjects With Deep Vein Thrombosis or Pulmonary Embolism
The first occurrence of symptomatic deep vein thrombosis or pulmonary embolism
Time frame: From randomization to the trial end (April 2, 2018) - up to 5 years
Population: The trial was ended prematurely. There were not sufficient outcome measures for analysis
Other Pre-specified
Number of Subjects With Hospitalization for Unstable Angina That Led to Unplanned Coronary Revascularization
The first occurrence of hospitalization for unstable angina that led to unplanned coronary revascularization
Time frame: From randomization to the trial end (April 2, 2018) up to 5 years
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Methotrexate | Number of Subjects With Hospitalization for Unstable Angina That Led to Unplanned Coronary Revascularization | 41 participants |
| Placebo | Number of Subjects With Hospitalization for Unstable Angina That Led to Unplanned Coronary Revascularization | 50 participants |
p-value: 0.3195% CI: [0.53, 1.22]Log Rank
Other Pre-specified
Number of Subjects With Peripheral Artery Disease
The first occurrence of new or worsening of peripheral artery disease
Time frame: From randomization to the trial end (April 2, 2018) - up to 5 years