Spotlight Shifts, Again, to Anti-Inflammatories for Cutting CV Risk

Reed Miller

August 26, 2012

August 26, 2012 (Munich, Germany) — It's time to shift some of the attention paid to lipid-lowering drugs onto therapies that fight vascular inflammation, according to a number of experts speaking on the opening day of the European Society of Cardiology (ESC) 2012 Congress.

Statin and aspirin studies tracking markers of inflammation show that "the magnitude of this disease associated with inflammation is at least as large as that of lipids or blood pressure," Dr Paul Ridker (Brigham and Women's Hospital, Boston, MA) told heartwirehere.

Ridker points out that the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER)--for which he was primary investigator--showed that rosuvastatin (Crestor, AstraZeneca) reduced major adverse events 44% compared with placebo in patients with low LDL cholesterol but a high level of C-reactive-protein (CRP), a common marker of systematic inflammation. JUPITER showed a 50% decrease in LDL and a 37% decrease in CRP at 12 months, and the risk reduction was greater in patients with greater CRP reduction.

In his ESC talk, Ridker described two new studies getting under way looking at anti-inflammatory agents for reducing CV risk.

"Statins are weak anti-inflammatory drugs, but we've shown this enormous effect with a weak anti-inflammatory drug, so I said, 'Wow, what might happen with a real anti-inflammatory drug?' " Ridker said. "We've done dozens of lipid-lowering trials and dozens of hypertension trials, but we haven't done a single inflammation-reduction trial. But now we have two, which is very exciting."

The Cardiovascular Inflammation Reduction Trial(CIRT),announced last week [1], will compare methotrexate, given 10 to 20 mg weekly for three to four years, with placebo in about 7000 adults who have had an MI within the past five years, have type 2 diabetes or metabolic syndrome, and are already on a statin. The end point will be a reduction in recurrent MI, stroke, and cardiovascular death among stable post-MI patients with type 2 diabetes or metabolic syndrome. Methotrexate is already widely available as generic drug indicated for rheumatoid arthritis and also sometimes used in higher doses to treat certain types of cancer.

Ridker and colleagues will begin site selection for CIRT in November to begin patient recruitment in March 2013, but he has already begun to talk up the significance of the study. "This is the most exciting new biology in the field," he said. "And [the National Institutes of Health] NIH is trying to back what is the most important science."

Novartis is also betting that directly attacking inflammation will make a big impact on cardiovascular events in patients already on a statin. The company is backing the CANTOS trial of canakinumab (Ilaris), a high-affinity human monoclonal anti–human interleukin-1{:beta:} (IL-1{:beta:}) antibody currently used for the treatment of IL-1{:beta:}–driven inflammatory diseases (cryopyrin-associated periodic syndrome).

The study will compare three doses of canakinumab with placebo in about 17 200 stable post-MI patients with elevated high-sensitivity CRP levels. The primary end point will be first occurrence of a major adverse cardiovascular event, a composite of cardiovascular-related death, nonfatal MI, and stroke over a follow-up of three years. There will also be a substudy measuring the change from baseline in the patients' carotid plaque burden in the bifurcation region of the index carotid artery and another study measuring the change from baseline of the patients' insulin secretion rate.

The study began in April 2011 and is expected to be completed in the summer of 2016.

Ridker reports having received research funding support from multiple not-for-profit entities, including the National Heart, Lung, and Blood Institute, the National Cancer Institute, the American Heart Association, the Doris Duke Charitable Foundation, the Leducq Foundation, the Donald W Reynolds Foundation, and the James and Polly Annenberg La Vea Charitable Trusts. Ridker also reports having received investigator-initiated research support from AstraZeneca and Novartis, as well as nonfinancial research support from Amgen. Ridker is listed as a coinventor on patents held by Brigham and Women's Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease that have been licensed to Siemens and AstraZeneca and has served as a research consultant to Merck, Isis, Vascular Biogenics, Amylin, and Genzyme.