Response after single treatment with canakinumab predicts which patients will benefit most

November 13, 2017, Brigham and Women's Hospital

A new analysis seeks to answer the question of which patients are likely to gain the greatest cardiovascular benefit when treated with the anti-inflammatory agent canakinumab. At the 2017 American Heart Association Scientific Sessions, Paul M. Ridker, MD, director of the Center for Cardiovascular Disease Prevention at Brigham and Women's Hospital, presented a pre-specified analysis on CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) that identifies a simple, clinical method to define patient groups most likely to benefit from long-term canakinumab treatment. The results of this analysis, published simultaneously in The Lancet, could have a major impact not only on patient selection and cost-effectiveness of canakinumab, but also on the future development of anti-inflammatory agents for cardiovascular disease.

"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 Ridker. "Figuring out which 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 CANTOS 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 significant fifteen percent reduction in risk of recurrent heart attacks, strokes and cardiovascular death among participants who received canakinumab at doses of either 150mg or 300mg, given once every three months. The critical question Ridker and colleagues have further investigated is whether reductions in the magnitude of inflammation achieved after a single treatment with canakinumab can predict greater or lesser clinical benefit for individual patients.

In the new analysis, the team found that baseline characteristics did not modify the effect of canakinumab on clinical outcomes. However, the magnitude of decrease in hsCRP with canakinumab related directly to the magnitude of clinical benefit associated with continued long-term therapy. For those treated with canakinumab who achieved hsCRP levels below 2mg/L after one dose, cardiovascular and all-cause mortality were both reduced by 31 percent with prolonged treatment. By contrast, no statistically significant reduction in these endpoints was observed among those treated with canakinumab who achieved hsCRP levels equal to or above 2mg/L. 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 Brendan Everett, MD, an investigator in CANTOS and director of the General Cardiology Inpatient Service at BWH.

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

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 for among those treated with canakinumab who achieved hsCRP concentrations less than 2mg/L. 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 CANTOS among approximately 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, MD, a CANTOS investigator with long-standing interests in inflammation biology.

"Reaching goals is critical for patients and physicians," said Roger Blumenthal, MD, the Kenneth J. Pollin Professor of Cardiology at Johns Hopkins University School of Medicine. "The new CANTOS analysis makes it clear that biologic response matters greatly. Reaching on-treatment hsCRP goals after taking canakinumab is a strong marker for long-term success."

More details about the cardiovascular findings from CANTOS can be found here. In CANTOS, 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 NHLBI-funded Cardiovascular Inflammation Reduction Trial 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.

Explore further: Inflammation reduction could cut risk of heart attack, stroke

More information: Paul M Ridker et al, Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial, The Lancet (2017). DOI: 10.1016/S0140-6736(17)32814-3

Related Stories

Inflammation reduction could cut risk of heart attack, stroke

August 28, 2017
A significant reduction in risk of recurrent heart attacks, strokes, and cardiovascular death was found among people who received a targeted anti-inflammatory drug that lowered inflammation but had no effects on cholesterol, ...

Anti-inflammatory therapy cuts risk of lung cancer

August 28, 2017
In most clinical trials for cancer therapy, investigators test treatments in patients with advanced disease. But a recent cardiovascular secondary prevention study has given researchers a unique opportunity: to explore the ...

A first: Drug lowers heart risks by curbing inflammation

August 28, 2017
For the first time, a drug has helped prevent heart attacks by curbing inflammation, a new and very different approach than lowering cholesterol, the focus for many years.

Canakinumab allows discontinuation of corticosteroids in patients with SJIA

June 13, 2013
Study findings first presented today at EULAR 2013, the Annual Congress of the European League Against Rheumatism, demonstrate the efficacy of canakinumab at tapering corticosteroid (CS) use in patients with SJIA.

Interrupting inflammatory signals decreases repeat artery blockage

May 11, 2017
Peripheral artery disease (PAD) patients who were treated with an anti-inflammatory steroid injected directly into the tissue surrounding their leg artery showed a significant reduction in inflammatory biomarkers. Results ...

Recommended for you

Caffeine from four cups of coffee protects the heart with the help of mitochondria

June 21, 2018
Caffeine consumption has been associated with lower risks for multiple diseases, including type II diabetes, heart disease, and stroke, but the mechanism underlying these protective effects has been unclear. A new study now ...

'Smart stent' detects narrowing of arteries

June 19, 2018
For every three individuals who have had a stent implanted to keep clogged arteries open and prevent a heart attack, at least one will experience restenosis—the renewed narrowing of the artery due to plaque buildup or scarring—which ...

Marriage may protect against heart disease / stroke and associated risk of death

June 18, 2018
Marriage may protect against the development of heart disease/stroke as well as influencing who is more likely to die of it, suggests a pooled analysis of the available data, published online in the journal Heart.

Deaths from cardiac arrest are misclassified, overestimated

June 18, 2018
Forty percent of deaths attributed to cardiac arrest are not sudden or unexpected, and nearly half of the remainder are not arrhythmic—the only situation in which CPR and defibrillators are effective—according to an analysis ...

Tick-borne meat sensitivity linked to heart disease

June 15, 2018
University of Virginia School of Medicine researchers have linked sensitivity to an allergen in red meat—a sensitivity spread by tick bites—with a buildup of fatty plaque in the arteries of the heart. This buildup may ...

The molecules that energize babies' hearts

June 14, 2018
A metabolic process that provides heart muscle with energy fails to mature in newborns with thickened heart walls, according to a Japan–Canada research team.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.