NHLBI Announces 7000 Patient Trial Testing Inflammation Hypothesis

The National Heart, Lung, and Blood Institute (NHLBI) has announced the launch of a large  clinical trial testing the inflammation hypothesis. Paul Ridker is the principal investigator of the trial, which will be known as  the Cardiovascular Inflammation Reduction Trial (CIRT).

CIRT will enroll 7,000 patients who are stable following a heart attack but are at high risk for a recurrent event because they have either type 2 diabetes or metabolic syndrome. Trial subjects will be randomized to low dose methotrexate or placebo. The primary outcome measure is the rate of recurrent major cardiovascular events (MI, stroke, and cardiovascular death). Low dose methotrexate is now used to treat rheumatoid arthritis.

“If this generic drug, which is already on the market at low cost, proves effective for reducing risk of heart attacks, stroke, or death, it has the potential for broad public health impact in saving lives and reducing disease,” said Ridker, in an NHLBI press release.

The NHLBI said that site selection will begin in November 2012 and patient recruitment will start in March 2013. Patients will be followed for an average of 2.5 years.

Resources:


Here is the NHLBI press release:

NIH launches trial to evaluate anti-inflammatory treatment for preventing heart attacks, strokes, and cardiovascular deaths

An international multi-site trial has launched to determine whether a common anti-inflammatory drug can reduce heart attacks, strokes, and deaths due to cardiovascular disease in people at high risk for them.  This study is being supported by the National Heart, Lung, and Blood Institute (NHLBI), a part of the National Institutes of Health.

Inflammation, along with high blood pressure and high cholesterol, plays a major role in heart attack and stroke.  The Cardiovascular Inflammation Reduction Trial (CIRT) will determine whether treatment with a drug specifically targeting inflammation reduces rates of cardiovascular events among adults who have had a heart attack within the past five years and who also have type 2 diabetes or metabolic syndrome.  The trial will randomly assign participants to receive methotrexate given at 10 to 20 milligrams weekly for three to four years or a placebo.  Methotrexate is an inexpensive generic drug commonly used at low doses to treat rheumatoid arthritis.  It is also used at higher doses to treat certain forms of cancers such as leukemias and lymphomas.

“This trial could have global impact by potentially changing treatment recommendations for millions of individuals with heart disease,” said Gary H. Gibbons, M.D., director of the NHLBI.

Each year, over 2 million people in the United States have heart attacks or strokes, and many of them die.  “If this generic drug, which is already on the market at low cost, proves effective for reducing risk of heart attacks, stroke, or death, it has the potential for broad public health impact in saving lives and reducing disease,” said Paul Ridker, M.D., M.P.H., an expert in inflammation biology as it relates to heart attack and stroke.  Dr. Ridker, who will serve as principal investigator for CIRT, is the Eugene Braunwald Professor of Medicine at Harvard Medical School, and director of the Center for Cardiovascular Disease Prevention at the Brigham and Women’s Hospital, Boston.

Adults who have type 2 diabetes are much more likely to die of heart disease or stroke than people without type 2 diabetes.  Metabolic syndrome–a cluster of traits that includes a large waistline, high blood pressure, high levels of blood triglyceride (a type of fat), high blood sugar, and low blood HDL (the good cholesterol)–also raises the risk of heart attack and stroke.  Many people with type 2 diabetes and obesity also have metabolic syndrome.  People with diabetes or metabolic syndrome typically have elevated blood levels of various markers of inflammation.

CIRT will enroll 7,000 patients at 350-400 sites across the United States and Canada over the next 2.5 years and will follow them for two to four years (average 2.5 years).  Site selection will begin in November 2012, and patient recruitment will start in March 2013.

Eligible participants who tolerate the drug without side effects over a five-week test period will be randomly assigned to receive standard care plus placebo or standard care plus low-dose methotrexate.  Participants will also take folic acid, which is routinely given with methotrexate to prevent vitamin deficiencies.

In addition to measuring the number of strokes, heart attacks, and heart-related deaths among participants, CIRT will determine if low-dose methotrexate reduces death from all causes and certain heart- and blood vessel-related conditions and events, including incident deep vein thrombosis, pulmonary embolism, atrial fibrillation, hospitalization for chest pain or congestive heart failure, non-surgical procedures or coronary artery bypass surgery, and newly diagnosed type 2 diabetes.  CIRT will also establish a blood and DNA bank to study the effect of low-dose methotrexate on a number of inflammatory biomarkers.

CIRT is funded by the NHLBI grants 1 U01 HL101422-01A1 (Clinical Coordinating Center) and 1 U01 HL101389-01A1 (Data Coordinating Center).

Find out more about CIRT at http://clinicaltrials.gov/ct2/show/NCT01594333 and at http://www.thecirt.org/

For additional information or to arrange an interview with an NHLBI spokesperson, please contact the NHLBI Communications Office at 301-496-4236 or nhlbi_news@nhlbi.nih.gov.  To schedule an interview with Dr. Ridker, contact Lori Schroth at 617-534-1604 or ljschroth@partners.org.

Resources

  • Heart Attack

http://www.nhlbi.nih.gov/health/health-topics/topics/heartattack/

  • Stroke

http://www.nhlbi.nih.gov/health/health-topics/topics/stroke/

  • Coronary Heart Disease

http://www.nhlbi.nih.gov/health/health-topics/topics/cad/

  • Metabolic Syndrome

http://www.nhlbi.nih.gov/health/health-topics/topics/ms/

  • Diabetic Heart Disease

http://www.nhlbi.nih.gov/health/health-topics/topics/dhd/

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Comments

  1. Brief review of the BOXED WARNINGS on Methotrexate revealed the following:
    [Methotrexate should be used only by physicians whose knowledge and experience include the use of antimetabolite therapy because of the possibility of serious toxic reactions (which can be fatal):

    Methotrexate should be used only in life threatening neoplastic diseases, or in patients with psoriasis or rheumatoid arthritis with severe, recalcitrant, disabling disease, which is not adequately responsive to other forms of therapy.

    Deaths have been reported with the use of methotrexate in the treatment of malignancy, psoriasis, and rheumatoid arthritis.

    Patients should be closely monitored for bone marrow, liver, lung and kidney toxicities.

    Patients should be informed by their physician of the risks involved and be under a physician’s care throughout therapy.]

    The hypothesis of inflammation in atherosclerosis is tantalizing, if not convincing. However giving a drug like methotrexate with the above mentioned warnings to patients at high risk for cardiovascular disease for years and years, makes any clinician nervous, not withstanding the risks of bone marrow, liver, lung and kidney toxicities for the patients.

    Is this a case of “irrational exuberance” by NIH influenced by the credibility of the hypothesis by the investigator or based on animal studies and or pilot human studies? Just having a generic drug for clinical trial or clinical use doesn’t make it economical or safe after reviewing the warnings for the drug. Hope CIRT will not turn out to have the same fate as AIM-HIGH.

  2. Dr. Chemplavil

    I share your concerns about the safety of methotrexate…

    I see that Ridker et al. did a systematic review and meta-analysis of methotrexate and cardiovascular risk and found a 21% reduction in total cardiovascular disease and 18% reduction in MI.

    http://www.ncbi.nlm.nih.gov/pubmed/21855836

    Marilyn Mann

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