ACCEL | The "Endgame" for the Inflammatory Hypothesis of Atherothrombosis? Studies underway may confirm or douse inflammation as a CVD target

Each year, more than 2 million people in the United States have MIs or strokes, and many of them die. We know that inflammation, along with high blood pressure and high cholesterol, plays a major role in these events, but it's unclear whether inflammation provides independent prognostic information or whether inhibition of inflammation per se will lower vascular event rates.

Evidence to date has been mixed. Numerous epidemiologic studies support a key role for measures of subclinical vascular inflammation in the identification of patients at increased risk for MI and stroke. On the other hand, SIESTA (Systemic Inflammation Evaluation in Patients with non-ST Segment Elevation Acute Coronary Syndromes) was a prospective multicenter study assessing the comparative prognostic value of eight markers of inflammation and two other biomarkers of cardiovascular risk measured at hospital admission.1 In 549 low-to-moderate risk Mediterranean acute coronary syndrome (ACS) patients, high-sensitivity C-reactive protein (hsCRP), IL-6, IL-10, IL-18, cystatin C, sCD40L, and E- and P-selectin all failed to provide significant independent incremental prognostic information at 1 year of follow-up. Only NT-proBNP and fibrinogen were independent predictors of cardiovascular events at 12 months, perhaps because they interrogate biological pathways implicated in coronary artery disease (CAD) progression and the development of cardiovascular events rather than just those linked to inflammation.

The early logical choice among anti-inflammatory therapies was corticosteroids but this approach was abandoned amidst concern for impaired wall healing resulting in cardiac rupture. In subsequent years, attention focused on selective and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). All of these agents, with the exception of aspirin, increase the risk for acute MI, especially in those patients known to have coronary heart disease. A recent Danish study of 99,187 patients experiencing a first-time acute MI reported that subsequent NSAID use was persistently associated with increased mortality (HR = 1.63; 95% CI 1.52- 1.74) over a 5-year period.2

Still, provocative hints remain. The well-documented anti-inflammatory effects of statins may play a role in reducing cardiac events and some anti-inflammatory drugs used in noncardiac conditions, such as methotrexate in arthritis and psoriasis, seem to reduce cardiac events. In a 2013 paper in JACC, investigators reported positive results of the LoDoCo trial, evaluating low-dose colchicine for secondary prevention of cardiovascular disease.3 Also in 2013, Tawakol et al. reported that intensification of statin therapy results in a rapid reduction in atherosclerotic inflammation.4

Extraordinary Work
Paul M. Ridker, MD, MPH, is the director of the Center for Cardiovascular Disease Prevention at Brigham and Women's Hospital and the Eugene Braunwald Professor of Medicine at Harvard Medical School, Boston. He has done extraordinary work developing the inflammatory hypothesis of heart disease, the clinical application of hsCRP testing as a method to better evaluate cardiovascular risk, and the demonstration in 2008 in the large-scale JUPITER trial that statin therapy is highly effective at reducing MI and stroke when given to men or women with elevated hsCRP levels.

In addition to Dr. Ridker's work, Brigham and Women's Hospital has two other researchers— Peter Libby, MD, chief of cardiology, and Michael Gimbrone, MD, director of the Center for Excellence in Vascular Biology—who have performed groundbreaking work investigating basic mechanisms of inflammation in heart disease. Additionally, low-dose methotrexate as a treatment for rheumatoid arthritis was pioneered at the same facility by Michael E. Weinblatt, MD, and others in the 1980s. Currently, Dr. Ridker serves as trial chair and principal investigator of two multinational, randomized, placebo-controlled clinical trials designed to address whether reducing inflammation can reduce cardiovascular event rates. These trials are the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) and the NHLBI-funded Cardiovascular Inflammation Reduction Trial (CIRT).

CANTO S: Promising Pilot Data
The CANTOS study is trying to determine whether reducing inflammation among men and women who have had a prior MI can reduce the risk of another cardiovascular event.5 The study is being conducted in more than 40 countries around the world and will specifically test whether blocking the pro-inflammatory cytokine interleukin -1β (IL- 1β) with canakinumab, compared to placebo, can reduce rates of recurrent MI, stroke, and cardiovascular death among patients with a previous MI who remain at high risk due to a persistent elevation of hsCRP (≥2mg/L) despite optimal medical care.

Canakinumab is a human monoclonal antibody that neutralizes IL-1β, an inflammatory protein that plays multiple roles in heart disease and that increases in cells where cholesterol crystals deposit, increasing the risk of MI and stroke. The drug is approved in the United States and Europe as a treatment for several rare inflammatory diseases and has proven to be well-tolerated in people with diabetes or arthritis.

Coordinated by researchers at the Brigham and Women's Hospital and Harvard Medical School in Boston, CANTOS will enroll more than 10,000 MI survivors worldwide.

Ridker et al. have reported the pilot data (a phase IIb trial) of 551 men and women with well-controlled diabetes mellitus and high CV risk who were randomly allocated to monthly subcutaneous placebo or subcutaneous canakinumab at doses of 5, 15, 50, or 150 mg monthly and then followed for 4 months.6 Active therapy was associated with substantial reductions in CRP, interleukin-6, and fibrinogen versus little effect seen with placebo. These effects were observed in women and men.

However, canakinumab had modest and nonsignificant effects on change in hemoglobin A1c, glucose, and insulin levels. No effects were seen for low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or non–HDL cholesterol, although triglyceride levels increased 10% in the 50 mg (p = 0.02) and 150 mg (p = 0.03) groups. Clinical adverse events were similar in the canakinumab and placebo groups.

Endgame is Playing Out
CIRT is being called the "endgame" for years of research examining the link between inflammation and heart disease. Its primary aim is to directly test the inflammatory hypothesis of atherothrombosis by evaluating whether or not low-dose methotrexate will reduce rates of recurrent myocardial infarction, stroke, and cardiovascular death among stable coronary artery disease patients with type 2 diabetes or metabolic syndrome, conditions associated with an enhanced pro-inflammatory response.

Investigators are enrolling 7,000 adults from the United States and Canada who have had an MI within the past 5 years and who also have type 2 diabetes or metabolic syndrome.7 The trial is randomly assigning participants to receive methotrexate given at a target dose of 20 mg/week for 3 to 4 years or placebo. "This new study is the endgame for more than 15 years of research by investigators worldwide demonstrating that inflammation is a central part of the process that leads to heart attack and stroke," said Dr. Ridker. "Whether or not reducing that inflammation can benefit our patients is unknown, but a positive finding in this trial has the potential to dramatically reshape how we think about and treat heart disease."

In addition to measuring the number of strokes, MIs, 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 heart failure, non-surgical procedures or CABG surgery, and newly diagnosed type 2 diabetes. (Remember, many of those enrolled in the trial will have metabolic syndrome but not frank 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.

1. Kaski JC, Fernandez-Berges DJ, Consuegra-Sanchez L, et al. Atherosclerosis. 2010;212:636-43.
2. Olsen AM, Fosbol EL, Lindhardsen J, et al. Circulation. 2012;126:1955-63.
3. Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. J Am Coll Cardiol. 2013;61:404-10.
4. Tawakol A, Fayad ZA, Mogg R, et al. J Am Coll Cardiol. 2013;62:909-17.
5. Ridker PM, Thuren T, Zalewski A, Libby P. Am Heart J. 2011;162:597-605.
6. Ridker PM, Howard CP, Walter V, et al. Circulation. 2012;126:2739-48.
7. Everett BM, Pradhan AD, Solomon DH, et al. Am Heart J. 2013;166:199-207.

To listen to an interview with Paul M. Ridker, MD, MPH, about inflammation and atherosclerosis, visit The interview was conducted by C. Richard Conti, MD.

Keywords: Interleukin-10, Insulin, DNA, National Heart, Lung, and Blood Institute (U.S.), Interleukin-6, Risk Factors, Methotrexate, Cholesterol, Interleukin-1beta, Interleukin-18, C-Reactive Protein, Thrombosis, Schools, Medical, Cardiovascular Diseases, Fibrinogen, Cystatin C

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