Banishing Inflammation

Single treatment with anti-inflammatory drug predicts which heart patients benefit the most

Single treatment with anti-inflammatory agent predicts which heart patients would benefit the most

Which heart attack patients are likely to gain the greatest cardiovascular benefit when treated with the anti-inflammatory agent canakinumab?

A new analysis presented Nov. 13 at the 2017 American Heart Association Scientific Sessions and published simultaneously in The Lancet answers that very question.

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The research identifies a simple clinical method to define populations of patients with previous heart attacks most likely to benefit from long-term canakinumab treatment.

The results could have a profound impact not only on patient selection and cost-effectiveness but also on the future development of anti-inflammatory agents for cardiovascular disease, the researchers said.

“We believe the clinical approach of targeting treatment to those who truly benefit on the basis of biologic response represents an elegant step toward personalized medicine and rational resource utilization,” said Paul Ridker, the Eugene Braunwald Professor of Medicine at Harvard Medical School and director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital.

 “Figuring out which patients with residual inflammatory risk benefit the most will allow us to get the right drug to the right patient, greatly reducing costs as well as hazards.” 

Major findings from the trial were presented earlier this year. The trial was designed to test whether canakinumab, which lowers inflammation independent of lipid levels, could reduce risk of a future cardiovascular event by reducing inflammation among people who have had a prior heart attack and who have persistently elevated levels of the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) despite aggressive care.

Overall, the trial found a 15 percent reduction in risk of recurrent heart attacks, strokes and cardiovascular death among participants who received canakinumab at doses of either 150 or 300 milligrams given once every three months.

The next critical question was whether reductions in the magnitude of inflammation achieved after a single treatment with canakinumab predicted greater or lesser clinical benefit for individual patients.

In the new analysis, the team found that baseline patient characteristics did not modify the effect of treatment. However, the magnitude of decrease in hsCRP with canakinumab predicted the magnitude of clinical benefit associated with continued long-term therapy.

Patients who achieved hsCRP levels below 2 milligrams per liter of blood after one dose were 31 percent less likely to die of cardiovascular disease and any other causes.

By contrast, researchers found no statistically significant reduction in these endpoints among people treated with canakinumab who achieved hsCRP levels equal to or above 2 milligrams per liter.

Similar large differences in all major cardiovascular outcomes were observed among those who did and did not have robust responses to initial therapy.

“The magnitude of hsCRP reduction following a single dose of canakinumab may provide a simple clinical method to identify individuals most likely to accrue the largest benefit from continued treatment. These data further suggest that ‘lower is better’ for inflammation reduction with canakinumab,” said investigator Brendan Everett, HMS assistant professor of medicine and director of the General Cardiology Inpatient Service at Brigham and Women’s.

While prior analyses have examined hsCRP as a predictive biomarker in the context of statin therapy, which lowers both cholesterol and inflammation, the newly published study is the first to analyze outcome data for a drug that reduces inflammation only without concomitant effects on cholesterol.

“Our work suggests that patients with ‘residual inflammatory risk’ represent a separate and distinct group from patients with ‘residual cholesterol risk’ who likely require different personalized approaches to treatment,” Ridker said.

The authors note that their findings could have implications for patient selection, cost-effectiveness, and drug design and development going forward, with the potential to increase canakinumab’s benefit to risk ratio. For example, the five-year number needed to treat (NNT) is 16 among those treated with canakinumab who achieved hsCRP concentrations less than 2 milligrams per liter. By contrast, the five-year NNT was 57 for those who did not achieve this on-treatment hsCRP threshold. The occurrence of fatal infection observed in the trial among nearly one in every 1,000 patients treated was not related to the magnitude of inflammation reduction. 

“The new analyses will be quite relevant to physicians, regulators and payers who are all trying to understand how to achieve the greatest efficacy with the minimal hazard,” said Peter Libby, the HMS Mallinckrodt Professor of Medicine and a cardiovascular medicine specialist at Brigham and Women’s.

More details about the cardiovascular findings from the trial can be found here. In the original trial, cancer deaths were cut in half by canakinumab. Details about findings related to cancer death reductions can be found here. Ridker is also the principal investigator of the Cardiovascular Inflammation Reduction Trial, funded by the National Heart, Lung and Blood Institute, that seeks to find out if low-dose methotrexate, an inexpensive generic anti-inflammatory agent, might have similar effects. That trial will complete in two to three years.

The trial was proposed and designed by investigators in the Center for Cardiovascular Disease Prevention at Brigham and Women’s in collaboration with Novartis Pharmaceuticals. In addition to Ridker, Everett, and Libby, other Brigham and Women’s researchers who contributed critically to this work include Jean MacFadyen and Robert Glynn. Ridker and Glynn received financial support for clinical research from Novartis Pharmaceuticals. Ridker has served as a consultant to Novartis Pharmaceuticals and is listed as a co-inventor on patents held by Brigham and Women’s that relate to the use of inflammatory biomarkers in cardiovascular disease and diabetes that have been licensed to AstraZeneca and Siemens.