August 30th, 2012

Low-Dose Methotrexate to Prevent Recurrent MI and Stroke?

Last week, the National Heart, Lung, and Blood Institute (NHLBI) announced the launch of the Cardiovascular Inflammation Reduction Trial (CIRT), a large clinical trial testing whether treatment with low-dose methotrexate, an anti-inflammatory drug, can 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. 

We asked Paul Ridker, who is the principal investigator of CIRT, 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, to answer this question about the study:

Why the interest in using low-dose methotrexate (LDM) for prevention of MI and stroke?

I have been thinking about inflammation and cardiovascular disease since the mid 1990s, when we made our first observations about inflammation and cardiac risk, and realized that targeting inflammation might be the key to halting atherosclerosis. At that time, we learned that biomarkers of inflammation predict future heart attack and stroke even when other risk factors are normal, and that aspirin — an anti-inflammatory drug — was more effective at preventing heart disease when levels of inflammation were high.

Over the next decade, we went on to demonstrate that statins are not only powerful lipid-lowering agents, but that they also reduce inflammation. Finally, in our 2008 JUPITER trial we showed that patients with low levels of LDL-C, but increased levels of CRP, clearly benefit from statin therapy in primary prevention. However,  there is no way to disentangle the anti-inflammatory effects from the lipid-lowering effects in a statin trial. We believe the time has come to formally test the inflammatory hypothesis of atherosclerosis and see directly whether targeted anti-inflammatory therapies that do not have concomitant effects on lipids and other pathways can reduce vascular-event rates, particularly among those already on statin therapy.

Our group is exceptionally grateful to the NHLBI for funding CIRT, which will compare LDM with placebo in the secondary prevention of heart attack, stroke, and cardiovascular death among high-risk individuals who have had a prior heart attack and who have either diabetes or metabolic syndrome — conditions associated with an enhanced pro-inflammatory response. In addition to all standard therapies, eligible trial participants will be allocated to placebo or to LDM at a target dose of 15 to 20 mg per week. This dose of methotrexate is far lower than that used in combination chemotherapy and is well within the common range used by millions of elderly Americans who take oral methotrexate as first-line treatment for rheumatoid arthritis (RA). Methotrexate in this dose range is well-tolerated and safety guidelines for its use are already in place so that no unknown off-target issues should occur in the trial.

In addition to the core biologic rationale for reducing inflammation as a potential new target, we know from observational studies that RA patients taking LDM appear to have lower vascular-event rates, that LDM reduces CRP and IL-6 levels, and that methotrexate inhibits atherosclerotic progression in animal models. Thus, CIRT will test the fundamental hypothesis of whether or not reducing inflammation with LDM among 7,000 stable post-MI patients will reduce rates of recurrent cardiovascular events and all-cause mortality.

CIRT will begin enrollment in early 2013 at sites across the U.S. and Canada. Physicians interested in serving as a trial site can obtain more details at the trial’s website ( or by calling (855) 437-9330.

6 Responses to “Low-Dose Methotrexate to Prevent Recurrent MI and Stroke?”

  1. David Powell , MD, FACC says:

    As I mentikned in a prior post, there is evidenve that methotrexate promotes reverse cholesterol transport, via upregulation of the Tangier’s receptor (apparantly mediated by adenosine receptors). This may be particularly relevant in patients with the metabolic syndrome.
    Although I am not a believer in statin hepatotoxicity, safety of high dose statins with LDM must be established.

  2. Robin Motz, M.D., Ph.D. says:

    The guidelines for treatment with low dose MTX include periodic liver biopsies, because MTX-induced cirrhosis can occur with normal liver tests; contrariwise, elevated liver tests are not necessarily a harbinger of future cirrhosis. Have the patients been informed of this recommendation, and are they receiving periodic biopsies? Under the doctrine of primum non nocere, it seems to me they should.

  3. Robin Motz, M.D., Ph.D. says:

    Not to be overly pedantic, but I assume that before these patients were placed on an immunosuppressant that a PPD was planted and their stool was checked for strongyloides infection.

  4. Nicola Piepenbrock, MD says:

    Daer Professor Ridker

    My high repsect concerning the scientific protocol that is published at In my opinion, this is an excellent example for a very well planned clinical trial that will contribute to reduce the burden of disease and give very important new scentific insight.In my opinion, you address the issue that the preventive effet of statins is in part due to an antiinflammatory effect – which is not sufficient- in an excellent scientific way.

    With respectful saltations
    Nicola Piepenbrock

  5. Dan Hackam, MD PhD says:

    Kudos to NHLBI for having the wisdom to fund this line of research, which will attempt to answer the question of causality in the association of inflammation with atherosclerotic cardiovascular disease. A large and positive reduction in cardiovascular events with LDM would add very strong support to a causal mechanism and likely revolutionize cardiology and preventive medicine.

    I also firmly believe that NIH needs to have the courage to take a step back along the causal pathway and test the effects of modifying primordial upstream determinants of atherosclerotic cardiovascular disease. Specifically, I am referring to diet. A large, robust, well-designed and adequately powered randomized trial needs to be conducted to compare the effects of a plant-based diet, a carbohydrate-restricted diet, a Mediterranean diet, and a standard western diet on cardiovascular events, cancer and all cause mortality. Only a public funder will support such a trial. We need to compare diets promulgated by Esselstyn, Weil and Ornish with diets promulgated by Atkins, Taubes and de Lorgeril. Otherwise, we run the risk of shuffling the deck chairs on the titanic with our current therapeutics (the provocative potential of LDM notwithstanding). Current cardiology practice is in its essence a palliative attempt to slow the progression of vascular disease by using multiple, modestly effective pharmacological therapies in combination, at high cost, and with significant adverse effects and potential toxicity – to be taken for life. A dietary strategy could be highly cost-effective, free of adverse effects, markedly more efficient, and might prevent cancer and other degenerative diseases as well (a concept which obviously requires testing but for which epidemiological data already exist).

  6. Kasim Salim, MBBS MD MRCP FRCP MRCpath FRCpath says:

    Dear Prof. Ridker,
    CIRT seems very interesting as this seems to be the beginning of a new era of anti- inflammatory therapy to ameliorate Atherosclerosis which is the background for MI & Stroke as we all know. I am already on such a course of anti- inflammatory therapy with Curcumin(from the Cuury Spice Turmeric) as I already had a CABG 14 years back for Proximal LAD and Diagonal lesions and a repeat Evrolimus eluting stent in my RCA 3 years back for an unstable plaque. Of course Curcumin is on top of Statin,Clopidogrel, Aspirin and Ramipril. I have some reservations on LDM as my wife developed lung injury after an 8 month’s course of MTX 15 mg weekly as a Steroid sparing agent for her recently diagnosed RA in Autum 2010, and She had no other choice but to continue low dose steroids, Salazopyrine,and Hydroxychloroquine. The problem of Liver fibrosis on long term MTX is another red herring as already brought in by Dr.Motz though to some extent the recent introduction of FIBROSCAN from France may serve as a non-invasive way of monitoring the Liver instead of the unwelcome Liver Biopsies while on MTX.
    Let us hope that CIRT will lead us to a new era in Cardiovascular Preventive Medidicine.