{"id":31248,"date":"2012-08-30T10:32:05","date_gmt":"2012-08-30T14:32:05","guid":{"rendered":"http:\/\/blogs.nejm.org\/cardioexchange\/?post_type=expert-is-in&p=31248"},"modified":"2012-08-30T10:32:05","modified_gmt":"2012-08-30T14:32:05","slug":"low-dose-methotrexate-to-prevent-recurrent-mi-and-stroke","status":"publish","type":"post","link":"https:\/\/blogs.nejm.org\/cardioexchange\/2012\/08\/30\/low-dose-methotrexate-to-prevent-recurrent-mi-and-stroke\/","title":{"rendered":"Low-Dose Methotrexate to Prevent Recurrent MI and Stroke?"},"content":{"rendered":"

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. <\/em><\/p>\n

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:<\/em><\/p>\n

Why the interest in using low-dose methotrexate (LDM) for prevention of MI and stroke?<\/strong><\/p>\n

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 \u2014 an anti-inflammatory drug \u2014 was more effective at preventing heart disease when levels of inflammation were high.<\/p>\n

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,\u00a0 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.<\/p>\n

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 \u2014 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.<\/p>\n

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.<\/p>\n

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\u2019s website (theCIRT.org)<\/a> or by calling (855) 437-9330.<\/p>\n","protected":false},"excerpt":{"rendered":"

Paul Ridker discusses the Cardiovascular Inflammation Reduction Trial, which will formally test the inflammatory hypothesis.<\/p>\n","protected":false},"author":433,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[],"tags":[],"class_list":["post-31248","post","type-post","status-publish","format-standard","hentry"],"_links":{"self":[{"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/posts\/31248","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/users\/433"}],"replies":[{"embeddable":true,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/comments?post=31248"}],"version-history":[{"count":0,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/posts\/31248\/revisions"}],"wp:attachment":[{"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/media?parent=31248"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/categories?post=31248"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/tags?post=31248"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}