METhotrexate Therapy Effects in the Physical Capacity of Patients With ISchemic Heart Failure (METIS Trial)

Study Overview
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Brief Summary
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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
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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.

Official Title
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METhotrexate Therapy Effects in the Physical Capacity of Patients With ISchemic Heart Failure: Randomized Double-blind, Placebo-controlled Trial (METIS Trial)

Conditions
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Heart Failure, Myocardial Ischemia

Intervention / Treatment
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* Drug: Methotrexate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Methotrexate<br>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. | Drug: Methotrexate<br>* 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.<br>* Other names: Trexall;|
| Placebo Comparator: Placebo<br>Patients receiving conventional treatment to heart failure who will receive placebo oral plus folic acid 5mg oral once a week for 12 weeks. | Drug: Placebo<br>* 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.<br>* Other names: Control;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Baseline and 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart Failure, Myocardial Ischemia, Methotrexate, Inflammation, Anti-Inflammatory Agents, Inflammation Mediators