Heart Failure, Myocardial Ischemia
Conditions
Keywords
Heart Failure, Myocardial Ischemia, Methotrexate, Inflammation, Anti-Inflammatory Agents, Inflammation Mediators
Brief summary
The aim of the study is to evaluate the efficacy of methotrexate to improve physical capacity in patients with symptomatic ischemic heart failure.
Detailed description
Recent studies have showed the importance of proinflammatory mediators in the heart failure. However, there is a lack of benefit of therapies that tried to neutralize these mediators. Methotrexate has adenosine-mediated anti-inflammatory effects in rheumatoid arthritis and psoriasis. Methotrexate limits infarct size via this adenosine-dependent mechanisms in heart of dogs (J Cardiovasc Pharmacol. 2004 Apr;43(4):574-9). A recent trial showed that this drug reduced proinflammatory mediators in patients with heart failure (Am Heart J. 2006 Jan;151(1):62-8). These data suggest that methotrexate may improve physical capacity in patients ischemic heart failure reducing inflammation, but a randomized clinical trial is necessary to prove it.
Interventions
DRUGMethotrexate
Patients receiving conventional treatment to heart failure who will receive methotrexate 7.5mg oral plus folic acid 5mg oral once a week for 12 weeks. All patients will have evaluated at the baseline and after 12 weeks: physical capacity by the 6-minutes walk test, quality of life by the Brazilian edition SF-36 and inflammatory marker by C-reactive protein. They also will be tested for ALT, AST, blood cell count, creatinine, and prothrombin time at baseline, after 6 weeks and after 12 weeks.
DRUGPlacebo
Patients receiving conventional treatment to heart failure who will receive placebo oral plus folic acid 5mg oral once a week for 12 weeks. All patients will have evaluated at the baseline and after 12 weeks: physical capacity by the 6-minutes walk test, quality of life by the Brazilian edition SF-36 and inflammatory marker by C-reactive protein. They also will be tested for ALT, AST, blood cell count, creatinine, and prothrombin time at baseline, after 6 weeks and after 12 weeks.
Sponsors
Instituto de Cardiologia do Rio Grande do Sul
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Heart failure functional class measured using the New York Heart Association classification class II, III or IV * Left ventricular fraction \<0.45 at the ventriculography * Angiographic coronary lesions higher than 50% or coronary lesion revascularized (coronary artery bypass or percutaneous transluminal coronary angioplasty)
Exclusion criteria
* Myocardial infarction in the past four months * Coronary artery bypass or percutaneous transluminal coronary angioplasty in the past four months * Left ventricular disfunction diagnosed during a acute coronary syndrome * Those who require revascularization in the following 12 weeks * Hepatic disease (ALT and AST higher than the upper limit of the reference value) * Renal failure (plasma creatinine higher than 2.0mg/dl) * Alcoholism (20 doses per week or more) * Illegal drug use * Rheumatoid arthritis or other inflammatory diseases * Infectious disease * Neoplasm * Anemia (hematocrit lower than 30%) * Currently on any anti-inflammatory drugs * Difficulty in walking * Unable to understand/complete the 36-item Short Form health survey (SF-36) * Those who do not give informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Physical Capacity Measured Using the 6-minute Walk Test Distance | Baseline and 12 weeks | The primary outcome of the study was the difference in 6MWT distance before and after the treatment (change in meters evaluated by t test). |
Secondary
| Measure | Time frame |
|---|---|
| Improve in Heart Failure Functional Class Measured Using New York Heart Association | 12 weeks |
| Improve in Quality of Life Measured Using the Brazilian Edition SF-36 | 12 weeks |
| Reduction of Inflammatory Marker Measured Using C-reactive Protein Blood Levels | 12 weeks |
| Incidence of All Cause Mortality, Hospitalization for Worsening Heart Failure, Myocardial Infarct, Stroke or Myocardial Revascularization Need | 12 weeks |
| Incidence of Adverse Effects of the Treatment | 12 weeks |
Countries
Brazil
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Methotrexate Patients receiving conventional treatment to heart failure who will receive methotrexate 7.5mg oral plus folic acid 5mg oral once a week for 12 weeks. | 25 |
| Placebo Patients receiving conventional treatment to heart failure who will receive placebo oral plus folic acid 5mg oral once a week for 12 weeks. | 25 |
| Total | 50 |
Baseline characteristics
| Characteristic | Placebo | Methotrexate | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 7 Participants | 9 Participants | 16 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants | 16 Participants | 34 Participants |
| Age Continuous | 58.2 years STANDARD_DEVIATION 8 | 60.8 years STANDARD_DEVIATION 10.3 | 59.5 years STANDARD_DEVIATION 9.2 |
| Region of Enrollment Brazil | 25 participants | 25 participants | 50 participants |
| Sex: Female, Male Female | 4 Participants | 7 Participants | 11 Participants |
| Sex: Female, Male Male | 21 Participants | 18 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 7 / 23 | 9 / 24 |
| serious Total, serious adverse events | 0 / 23 | 0 / 24 |
Outcome results
Primary
Change in Physical Capacity Measured Using the 6-minute Walk Test Distance
The primary outcome of the study was the difference in 6MWT distance before and after the treatment (change in meters evaluated by t test).
Time frame: Baseline and 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methotrexate | Change in Physical Capacity Measured Using the 6-minute Walk Test Distance | 24.5 meters | Standard Deviation 39.5 |
| Placebo | Change in Physical Capacity Measured Using the 6-minute Walk Test Distance | 21.3 meters | Standard Deviation 43.7 |
Secondary
Improve in Heart Failure Functional Class Measured Using New York Heart Association
Time frame: 12 weeks
Secondary
Improve in Quality of Life Measured Using the Brazilian Edition SF-36
Time frame: 12 weeks
Secondary
Incidence of Adverse Effects of the Treatment
Time frame: 12 weeks
Secondary
Incidence of All Cause Mortality, Hospitalization for Worsening Heart Failure, Myocardial Infarct, Stroke or Myocardial Revascularization Need
Time frame: 12 weeks
Secondary
Reduction of Inflammatory Marker Measured Using C-reactive Protein Blood Levels
Time frame: 12 weeks