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New analyses strengthen CANTOS findings

CANTOS is a landmark trial for showing the importance of inflammation in causing cardiovascular disease events. The new analyses from CANTOS strengthen the biological premise of the study and better address some concerns about the magnitude of benefit raised following the first report of the CANTOS findings. We now see an increased effect on major cardiovascular disease events and, for the first time, an impact from treatment on cardiovascular death and all-cause death in the subgroup of patients with a robust anti-inflammatory response to the drug. This shows the possibility of an enhanced benefit-to-risk balance by focusing canakinumab treatment on responsive patients.

Dr. Ira Tabas, professor of medicine, cell biology, and physiology at Columbia University in New York Mitchel L. Zoler/Frontline Medical News

Dr. Ira Tabas

The observed significant increase in fatal infections following canakinumab treatment is obviously a major concern, but the new findings offer an opportunity to optimize efficacy and minimize adverse effects by using a more targeted approach to treatment, along with more careful monitoring for the onset of infection.

New anti-inflammatory agents now in development offer the prospect for oral drugs that could have similar benefits, and by targeting such treatments to selected patients we can envision using an anti-inflammatory strategy for primary prevention of cardiovascular disease events as well as for secondary prevention. We can also anticipate studies that will show how to better integrate anti-inflammatory interventions with lipid-lowering drugs, as well as selected drugs used to treat diabetes.

The data from CANTOS has opened a new world of possibilities related to anti-inflammatory treatments for preventing and treating cardiovascular diseases.

Ira Tabas, MD , is professor of medicine, cell biology, and physiology at Columbia University in New York. He had no disclosures. He made these comments as designated discussant for Dr. Ridker’s report.



ANAHEIM, CALIF.– Targeting the anti-inflammatory drug canakinumab to cardiovascular disease patients with a robust response to a single dose may be an effective way to enhance the cost benefit of this novel treatment that is effective but also expensive.

A post hoc analysis of data collected in the ground-breaking CANTOS trial showed that among patients with a robust anti-inflammatory response to their first dose of canakinumab, the 4-year rate of major adverse cardiovascular events fell by 25% compared with patients who received placebo, a much higher relative risk reduction compared with all canakinumab recipients in the study. In this responsive subgroup, which constituted 55% of all patients assessed after their first dose, canakinumab also cut both cardiovascular death and all-cause death by 31% each relative to placebo, statistically significant reductions that had not been seen in the trial’s primary analysis that included all drug recipients, Paul M. Ridker, MD, said at the American Heart Association scientific sessions.

“The current analysis suggests that the magnitude of hsCRP [high sensitivity C-reactive protein] reduction following a single dose of canakinumab may provide a simple clinical method to identify individuals most likely to accrue the largest cardiovascular and cancer benefits from continued treatment.” The findings have importance “for patient selection, cost-effectiveness, and personalized medicine” as researchers and clinicians begin using anti-inflammatory drugs such as canakinumab to treat cardiovascular disease patients, said Dr. Ridker, professor of medicine at Harvard Medical School and director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital, both in Boston.

“The magnitude of the hsCRP reduction” after the first dose “is telling us who benefits most,” Dr. Ridker said in a video interview.

The Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) enrolled patients with a history of a MI and a “residual” inflammatory risk based on having an hsCRP level above 2 mg/L at baseline despite receiving optimized standard treatments and having a median LDL cholesterol level of 82 mg/dL. Dr. Ridker and his associates reported the study’s primary outcome results in August at the European Society of Cardiology meeting and in a simultaneously-published article (N Engl J Med. 2017 Sept 21; 377[12]:1119-31).

For the current analyses they defined a robust anti-inflammatory response as CANTOS patients who maintained an hsCRP level below 2 mg/L when measured 3 months after their first canakinumab dose. When the researchers divided all canakinumab recipients into tertiles based on their achieved hsCRP level after one dose, those with the lowest level, less than 1.2 mg/L, also had the best outcome, with a 4-year rate of major adverse cardiovascular events that was 29% lower than the placebo patients. Patients in the middle tertile of achieved hsCRP, from 1.2 up to but not including 2.6 mg/L, showed a smaller but still statistically significant relative 17% reduction in events, while patients with the tertile with the highest hsCRP levels following one canakinumab dose had essentially no difference in their outcomes compared with placebo-treated control patients.

These findings suggest that for hsCRP, “lower is better,” Dr. Ridker noted. “It’s similar to where we were in 1994” when trial results showed how LDL levels related to cardiovascular disease events and the potential that statin treatment held had for reducing event rates.

The new analyses included three additional notable findings:

• The main serious adverse effect from canakinumab treatment, fatal infections, which occurred at a small but significantly higher rate than in control patients, had a similar incidence of about one episode/300 patient years regardless of whether the achieved hsCRP level fell below 2 mg/L or remained above that level. The placebo rate of fatal infections was about one for every 500 patient years.

• The substantially reduced incidence of lung cancer seen in the primary CANTOS results also tracked with achieved hsCRP. Patients with an achieved hsCRP that was below the median for all treated patients had a 71% cut in new-onset lung cancer compared with controls, while patients with hsCRP levels that fell above the median showed no significant difference compared with control patients.

• All three doses of canakinumab tested in CANTOS – 50 mg, 150 mg, and 300 mg administered by subcutaneous injection once every 3 months – produced a drop in hsCRP to below 2 mg/L in some patients, but the rate at which patients reached this level differed depending on dose: 44% among patients who received the lowest dose, 55% of those who received a 150-mg dose, and 65% among those on the highest dose.

But this “responder analysis” of patients who received canakinumab received a strong cautionary caveat from Robert M. Califf, MD, professor of medicine and vice chancellor for health data sciences at Duke University in Durham, N.C.

“Beware of responder analyses,” Dr. Califf said during a talk at the meeting in which he commented on the new CANTOS findings. “There is a long history in cardiology of being misled” by responder analyses, he said.

Dr. Ridker added that the mechanism that determines whether patients have a robust or modest response to canakinumab remains unclear, although it likely depends on genetic factors. He also noted that research being done by himself and others is investigating the efficacy of other anti-inflammatory drugs that could potentially cut cardiovascular disease rates, including methotrexate and colchicine.

Canakinumab (Ilaris) had Food and Drug Administration marketing approval to treat systemic juvenile idiopathic arthritis and pediatric fever syndromes. Concurrently with the meeting report, the results appeared in an article online (Lancet 2017 Nov 13. doi: 10.1016/S0140-6736[17]32814-3).

CANTOS was sponsored by Novartis, the company that markets canakinumab. Dr. Ridker has been a consultant to Novartis and was lead investigator of CANTOS. He also holds patents on using hsCRP to assess cardiovascular disease risk. Dr. Califf is an adviser to Verily Health Sciences.

On Twitter @mitchelzoler

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