Significant lowering in risk of recurrent heart attacks, strokes, and cardiovascular death was found among people who received canakinumab, a targeted anti-inflammatory drug that lowers inflammation but has no effects on cholesterol, a new study found.

The report, by a team from Brigham and Women’s Hospital, was based on results of a clinical trial that encompassed 25 years of cardiovascular research.

“These findings represent the end game of more than two decades of research, stemming from a critical observation: Half of heart attacks occur in people who do not have high cholesterol. For the first time, we’ve been able to definitively show that lowering inflammation independent of cholesterol reduces cardiovascular risk. This has far-reaching implications. It tells us that by leveraging an entirely new way to treat patients—targeting inflammation—we may be able to significantly improve outcomes for certain very high-risk populations,"

Paul M. Ridker, director of the Center for Cardiovascular Disease Prevention at BWH, said.

Canakinumab Anti-inflammatory Thrombosis Outcomes Study

The clinical trial, called the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), investigated if reducing inflammation among people who have had a prior heart attack can reduce risk of another cardiovascular event in the future.

Designed by Ridker and his colleagues, the trials is sponsored by Novartis Pharmaceuticals, the manufacturer of the drug canakinumab, which targets inflammation. The research team enrolled more than 10,000 patients who previously had a heart attack and had persistent, elevated levels of high sensitivity C-reactive protein (hsCRP), a marker of inflammation.

All patients in the trial received aggressive standard care, which included high doses of cholesterol-lowering statins. In addition, participants were randomized to receive 50, 150, or 300 mg of canakinumab (or a placebo for the control group), administered subcutaneously once every three months.

Patients were followed for up to four years.

“In my lifetime, I’ve gotten to see three broad eras of preventative cardiology. In the first, we recognized the importance of diet, exercise, and smoking cessation. In the second, we saw the tremendous value of lipid-lowering drugs such as statins. Now, we’re cracking the door open on the third era,” said Ridker. “This is very exciting."

15% Cardiovascular Event Risk Reduction

The team reported a 15 percent reduction in risk of a cardiovascular event — including fatal or nonfatal heart attacks and strokes — for patients who received either the 150- or 300-mg dose of canakinumab. They also saw a 17 percent reduction in a composite endpoint that included hospitalization for unstable angina requiring urgent cardiovascular procedures.

The need for expensive interventions, such as bypass surgery and angioplasty, was cut by more than 30 percent in the trial. Importantly, these reductions are above and beyond the reduction in risk seen after taking statins alone. No effect was observed for the lower 50-mg dose.

In the general population, about 25 percent of heart attack survivors will have another cardiovascular event within five years, despite taking statins or other medications.

Canakinumab is a human monoclonal antibody that neutralizes interleukin-1β. Interleukin-1 is a pro-inflammatory cytokine that, if overexpressed, results in increased inflammation throughout the body as well as increased levels of hsCRP.

Overall, the drug was found to be safe in the CANTOS population, but the researchers did note an increase in fatal infection among approximately one in every 1,000 patients treated. On the other hand, cancer deaths were cut in half by canakinumab such that there was a nonsignificant reduction in death from any cause.

Interleukin-1 In Cardiovascular Disease

Ridker said that CANTOS participants who achieved greater-than-average reductions in hsCRP with canakinumab experienced the largest clinical benefit, a nearly 30 percent reduction in the risk of a recurrent heart attack, stroke, or cardiovascular death. These data suggest that it will be possible to target canakinumab to those in greatest need and, simultaneously, reduce toxicity for others.

“CANTOS represents a milestone in a long journey implicating interleukin-1 in cardiovascular disease. The results not only establish the role of innate immunity in human atherosclerosis and make actionable decades of research, but they also usher in a new era of therapeutics,"

said Peter Libby, also of Brigham and Women’s Hospital.

In the future, the research team hopes to study patients with sudden plaque ruptures and to look at additional biological agents that take aim at inflammatory pathways.

Paul M Ridker, M.D., et al Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease NEJM; August 27, 2017DOI: 10.1056/NEJMoa1707914

Image: Paul M. Ridker. Credit: Brigham and Women’s Hospital

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