New trials underway to explore impact of anti-inflammatory therapy on CV events

BOSTON — Multiple studies have suggested that measures of inflammatory biomarkers may be predictive of CV events, and the question remains whether treatment with anti-inflammatory therapies can impact the incidence of CV events. At the Cardiometabolic Health Congress, Paul M. Ridker, MD, MPH, outlined two new trials that will explore this possibility.

During his presentation, Ridker highlighted results from the international, double blind, placebo-controlled JUPITER trial, which assessed the benefits of rosuvastatin (Crestor, AstraZeneca; n=8,901) compared with placebo (n=8,901) for the prevention of CV-related events in healthy individuals with elevated levels high-sensitivity C-reactive protein and low LDL cholesterol. Previously reported data demonstrated that patients assigned rosuvastatin experienced a 44% reduction in the incidence of overall CV events, 50% reduction in stroke, 20% reduction in mortality and 43% reduction in venous thromboembolism. Rosuvastatin also reduced LDL levels by 50% and high-sensitivity C-reactive protein levels by 37%. The data were published in The New England Journal of Medicine in 2008.

Paul M. Ridker

The inflammation hypothesis

“The controversy in JUPITER was: [Were these findings] due simply to the powerful LDL-lowering effects of rosuvastatin? That is quite possible … The reality, though, is that these drugs are doing two things,” Ridker said, referring to a reduction in inflammation in addition to having an impact on cholesterol.

The JUPITER trial results suggested more pronounced risk reduction among treated patients who responded with inhibition of both LDL and inflammation. This led to the question of whether targeted anti-inflammatory therapy, in addition to a statin, could further reduce event rates, according to Ridker, who was the trial chairman for JUPITER and is director of the Center for Cardiovascular Disease Prevention and Brigham and Women’s Hospital and the Eugene Braunwald professor of medicine at Harvard Medical School.

New trials underway

Two trials are underway to explore the inflammation hypothesis: CIRT, which will assess methotrexate, and CANTOS, which will assess canakinumab.

The NIH-funded Cardiovascular Inflammation Reduction Trial (CIRT) will include patients with stable CAD following MI. Patients will be randomly assigned to receive weekly low-dose methotrexate 15 g to 20 g or placebo on top of standard of care for a 3-year period. The researchers’ goal is to assess the impact of methotrexate on the incidence of nonfatal MI or stroke, CV-related death and incident diabetes.

Methotrexate does not impact lipids, but has a “powerful” impact on C-reactive protein and interleukin-6, provided an “unconfounded” way to evaluate the effect of inflammation reduction on CV events, Ridker said.

To date, more than 1,000 of a planned 7,000 patients have been enrolled in the CIRT trial and sites are being recruited for participation, he said.

The Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) is designed to evaluate canakinumab (Novartis) in patients with stable CAD following MI. Patients will undergo random assignment to subcutaneous canakinumab 50 mg, 150 mg or 300 mg or placebo every 3 months in addition to standard of care. The aim of the study is to determine whether canakinumab, compared with placebo, can reduce rates of recurrent MI, stroke and CV death in MI patients who remain at high risk due to persistently elevated high-sensitivity C-reactive protein

Canakinumab is a high-affinity human monoclonal anti-human interleukin 1-beta antibody.

The CANTOS study is being conducted in more than 40 countries worldwide. The trial has completed enrollment.

New research aside, “we already have a positive trial in this particular realm,” Ridker said. The LoDoCo trial analyzed patients assigned low-dose colchicine or placebo for secondary prevention of CVD. “It was a probe design, not randomized, double blind or placebo-controlled, and it needs to be replicated. But, [colchicine] is a drug that is a chronic anti-inflammatory … and, in this setting, it lowered vascular event rates,” he said. – by Adam Taliercio

For more information:

Ridker PM. Keynote Session. Testing the Inflammation Hypothesis: The CIRT and CANTOS Trials. Presented at: Cardiometabolic Health Congress; Oct. 22-25, 2014; Boston.

Disclosure: Ridker reports receiving research grants or support from Amgen, AstraZeneca, the NHLBI, Novartis and Pfizer; consulting fees from Boston Heart, ISIS and Vascular Biogenics; and serving as a co-inventor on patents held by Brigham and Women’s Hospital and licensed to AstraZeneca and Siemens.