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CANTOS: Magnitude of CRP reduction linked with canakinumab clinical benefit
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ANAHEIM, Calif. — The magnitude of reduction in high-sensitivity C-reactive protein after anti-inflammatory therapy with canakinumab may identify which patients with a history of MI are likely to yield the greatest benefits from continued treatment with canakinumab, Paul M. Ridker, MD, said while presenting a secondary analysis of the CANTOS trial at the American Heart Association Scientific Sessions.
Ridker, director of the Center for Cardiovascular Disease Prevention and the Eugene Braunwald Professor of Medicine at Brigham and Women’s Hospital, and colleagues analyzed data from patients enrolled in the CANTOS trial with on-treatment high-sensitivity C-reactive protein levels of 2 mg/L (n = 3,484) and those with levels < 2 mg/L after one dose of subcutaneous canakinumab (Novartis; n = 2,868). Patients assigned placebo (n = 3,182) were also included in the analysis.
As Cardiology Today has previously reported, results from the overall CANTOS trial were presented at the European Society of Cardiology Congress in August showing a lower rate of recurrent CV events with canakinumab compared with placebo.
“While [the previously presented findings] demonstrated and provided proof of the inflammatory hypothesis of atherosclerosis, it left us with a number of critical, unanswered questions, particularly in this era of monoclonal antibodies and personalized medicine, ultimately asking the question can we predict who benefits the most from effective but expensive treatments,” Ridker said during a press conference.
New analysis
Among those with CRP levels that were reduced to < 2 mg/L, continued long-term treatment was associated with a 31% reduction in CV mortality (P = .0004), a 31% reduction in all-cause mortality (P < .0001) and a 25% reduction in major adverse CV events (P < .0001), Ridker said during the press conference. Among patients with on-treatment high-sensitivity CRP 2 mg/L, thus deemed as having a less profound inflammatory response, the treatment effects were “smaller in magnitude and nonsignificant” for these endpoints, he said.
The number needed to treat (NNT) at 5 years for the endpoint of MI, stroke, coronary revascularization or death from any cause was 16 among those with on-treatment CRP < 2 mg/L compared with 57 for those with higher levels, according to data presented.
Ridker also presented data showing greater risk reduction for incident lung cancer in patients who achieved greater CRP reductions. Among those with CRP levels below the median, the cumulative incidence of lung cancer was reduced by 71%, whereas there was no significant benefit for patients with higher CRP levels.
The effects were consistent across all doses of canakinumab studied. Overall, the proportion of patients who achieved CRP < 2 mg/L was 44% in the 50-mg group, 55% in the 150-mg group and 65% in the 300-mg group, according to Ridker.
An additional finding regarding a significant increase in fatal infection was observed with canakinumab, but this was not related to on-treatment CRP levels, Ridker said. The incidence rate of fatal infection was 0.27 per 100 person-years among patients with on-treatment CRP < 2 mg/L and 0.35 per 100 person-years among patients with on-treatment CRP 2 mg/L compared with 0.18 per 100 person-years in the placebo group.
“Baseline clinical characteristics did not define patient groups with greater or lesser cardiovascular benefits when treated with canakinumab,” the researchers wrote in the simultaneous publication in Lancet.
The data from this secondary analysis of CANTOS were analyzed in 3,484 patients with on-treatment CRP 2 mg/L, 2,868 with CRP < 2 mg/L at 3 months after canakinumab treatment and 3,182 patients assigned placebo.
Findings in context
During a media briefing prior to the AHA Scientific Sessions, Vas Narasimhan, MD, global head of drug development and chief medical officer at Novartis, said the company plans to share these analyses with regulators and work through “how to best reflect this subgroup [analysis] in the labeling of canakinumab during the regulatory review process.”
As Cardiology Today has previously reported, results from the overall CANTOS trial were presented at the European Society of Cardiology Congress in August showing a lower rate of recurrent CV events with canakinumab compared with placebo.
“While [the previously presented findings] demonstrated and provided proof of the inflammatory hypothesis of atherosclerosis, it left us with a number of critical, unanswered questions, particularly in this era of monoclonal antibodies and personalized medicine, ultimately asking the question can we predict who benefits the most from effective but expensive treatments,” Ridker said during the press conference.
During a discussion of the trial, Cardiology Today Editorial Board Member Karol E. Watson, MD, PhD, said, “mechanisms that can modulate inflammation that are tolerable and cost-effective are going to be essential to helping this to stem the tide of atherosclerosis in cardiovascular mortality.” Watson is professor of medicine/cardiology at the Geffen School of Medicine at UCLA, director of the UCLA Women’s Cardiovascular Health Center, co-director of the UCLA program in preventive cardiology and director of the UCLA fellowship program in cardiovascular diseases.
“If canakinumab is eventually approved to reduce cardiovascular disease risk, hsCRP measurement at 3 months might well help guide discussions about cost-effectiveness with longer-term treatment,” Erin D. Michos, MD, MHS, associate director of preventive cardiology at the Ciccarone Center for the Prevention of Heart Disease, associate professor of medicine at Johns Hopkins School of Medicine, and a Cardiology Today Next Gen Innovator, and Roger S. Blumenthal, MD, director of the Johns Hopkins Ciccarone Center for the Prevention of Heart Disease and professor of medicine at Johns Hopkins School of Medicine, and editor of the Cardiology Today Prevention section, wrote in a related editorial. “Those reaching goals are more likely to succeed. In the meantime, clinicians and patients need to lower inflammation by achieving more success in smoking cessation, weight loss and increased exercise.” – by Darlene Dobkowski
References:
Ridker PM, et al. LBS.02 – Late-Breaking Science in Prevention. Presented at: American Heart Association Scientific Sessions; Nov. 11-15, 2017; Anaheim, California.
Michos ED, et al. Lancet. 2017;doi:10.1016/S0140-6736(17)32865-9.
Ridker PM, et al. Lancet. 2017;doi:10.1016/S0140-6736(17)32814-3.
Disclosures: The study was funded by Novartis. Ridker reports he received research grants from Kowa and Novartis, is listed as a coinventor on patents related to use of inflammatory biomarkers in CVD licensed to AstraZeneca and Siemens, and serves as a consultant/advisory board member for Janssen and Novartis. Watson reports she serves on the speaker’s bureau for Boehringer Ingelheim and consults for Amgen and Boehringer Ingelheim. Narasimhan is an employee of Novartis. Michos reports she received an honorarium from Siemens Healthcare Diagnostics. Blumenthal reports no relevant financial disclosures.
Perspective
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C. Michael Valentine, MD, FACC
The goal of trying to identify patients with a favorable cost-benefit ratio from an expensive medication is a good one. This is important, because if a subgroup can be found with effective improvement in results, then it may make canakinumab a much more realistic long-term therapy, considering that it’s an expensive injectable drug that will not be easy in regards to compliance and cost. If a subgroup can be found for which this is extremely effective and cost-effective, then it makes it much more plausible to move forward with this drug as a therapy to reduce CV risk.
Perspective
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Daniel W. Jones, MD
We’ve known for a long time that there is an association between inflammation and CAD. We have tested many anti-inflammatory drugs in the past: aspirin and Plavix (clopidogrel), and so forth. They have some short-term benefits in some patients, but we’ve never had a study that looked like this, using an agent in a broad group of patients that showed a reduction in mortality. It’s really important. Like every first study, it has to be repeated; other studies have to show that this works. But it could become another really good tool in managing people with atherosclerosis and people with CAD.
Perspective
Back to TopIra Tabas, MD, PhD
I believe there is potential for inflammation-targeting therapy to build upon CANTOS in the post-CANTOS era. We know now that advanced human atheroma have impaired resolution of inflammation and are deficient in inflammation resolution mediators, and that resolution mediator therapy blocks plaque progression in animal models of advanced atherosclerosis. Before CANTOS, many of us interested in translating our ideas about inflammation were met, quite frankly, with closed doors. I believe one of the greatest benefits of CANTOS is that the doors are now wide open.
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