Canakinumab Reduces Heart-Failure Hospitalizations Among Responders: CANTOS Subanalysis

Patients with prior MI and elevated high-sensitivity C-reactive protein (hsCRP) see a dose-dependent reduction in heart-failure hospitalization while taking the anti-inflammatory drug canakinumab (Novartis), researchers reported Sunday at the American Heart Association (AHA) 2018 Scientific Sessions in Chicago, IL. The difference between canakinumab and placebo was only significant, however, among patients who achieved on-treatment hsCRP concentrations < 2 mg/L.

Arising from a prespecified subanalysis of the CANTOS trial—which previously found a reduction in CV events but only among responders—the latest results offer up a new endpoint: heart-failure hospitalization.

“The big news here is that this is the first evidence that anti-inflammatory therapy and, specifically, interleukin-1β inhibition affects heart failure. So this idea that inflammation is important in the development and progression of heart failure has been around a long time, and it’s a really important idea. There’s, up until now, been no evidence that treating inflammation in patients with heart failure or at risk for heart failure has actually improved their outcome,” Brendan M. Everett, MD (Brigham and Women’s Hospital, Boston, MA), who presented the findings, told TCTMD.

We say ‘inflammation’ but it’s actually a number of very complex and highly refined, integrated processes. Brendan M. Everett

CANTOS randomized 10,061 patients with prior MI and hsCRP  ≥ 2 mg/L to canakinumab 50 mg, 150 mg, 300 mg, or placebo. Doses were delivered subcutaneously every 3 months.

At baseline, 2,173 patients (22%) reported a history of heart failure at baseline. Over a median follow-up of 3.7 years, 385 patients were hospitalized at least once for heart failure; these patients tended to be older, have higher body mass index (BMI), and were more likely to have diabetes, hypertension, and prior CABG. Median concentration of baseline hsCRP was higher in patients who were versus were not hospitalized (5.7 vs 4.2 mg/L; P < 0.0001).

Overall, though not significantly lower among canakinumab-treated patients than in those receiving placebo, the risk of heart failure-hospitalization did show an inverse association with dose. The unadjusted hazard ratio was 1.04 for 50 mg, 0.86 for 150 mg, and 0.76 for 300 mg (P for trend = 0.025). The same pattern was seen for the composite of hospitalization and mortality related to heart failure.

Dose-dependent reductions in heart failure-related hospitalization “were similar in direction and magnitude for patients with and without a history of heart failure at baseline,” Everett et al report in their paper published simultaneously online in Circulation.

Patients who responded to canakinumab with hsCRP < 2 mg/L were significantly less likely to be hospitalized for heart failure than those who took a placebo (adjusted HR 0.62; 95% CI 0.47-0.81). Nonresponders experienced no such reduction (adjusted HR 1.03, 95% CI 0.81-1.31). For placebo-treated patients, risk was similar whether or not their hsCRP dropped below 2 mg/L.

Everett stressed that the reduction occurring in responders was “substantial.” While the comparison by on-treatment hsCRP level was nonrandomized, the finding “is persuasive and consistent with the data that we’ve published for the atherosclerotic endpoints,” he said. “One hopes at least that if we’re able to continue exploring this particular therapeutic approach in patients with heart failure that there would be the opportunity for significant clinical benefit. It’s certainly too early to say based on what we’ve done so far . . . but I think more exploration is warranted.”

A ‘Path Forward’ for Canakinumab?

Asked why canakinumab seems to be having a unique effect on heart-failure hospitalization, when other anti-inflammatory approaches have not, Everett said: “It’s a very specific therapy directed at an inhibitor of interleukin-1β, for which there’s a wealth of basic and translational research as well as smaller observational studies [suggesting it] is important in key steps in the development of heart failure. Prior studies had focused on different parts of the inflammatory cascade . . . , in particular on TNFα [tumor necrosis factor alpha].

“I think what we’re learning through CANTOS and through other studies is that we say ‘inflammation,’ but it’s actually a number of very complex and highly refined, integrated processes,” he continued. “Inhibiting one of them is not the same as inhibiting another, in terms of patient outcome.”

Everett described the current results as “exploratory and hypothesis-generating,” adding that they simply say that the inflammatory pathway addressed here is worthy of further research in the heart failure setting. Beyond canakinumab, “there are other agents out there that could be potentially used, and certainly more clinical studies and probably blinded randomized controlled trials would be necessary to push the concept forward,” Everett said.

Also presented at AHA 2018, the Cardiovascular Inflammation Reduction Trial (CIRT) showed that low-dose methotrexate, a nonspecific anti-inflammatory agent used for the treatment of rheumatoid arthritis and other autoimmune disorders, failed to prevent cardiovascular events among patients with a prior MI or multivessel coronary artery disease. Notably, the drug also did not reduce levels of interleukin-1β, interleukin-6, or hsCRP.

Last month the US Food and Drug Administration nixed a CV indication for canakinumab, sending a complete response letter to Novartis. Everett said he presumes that the agency was aware of the heart-failure data at the time. “From my standpoint I think it’s frustrating that canakinumab will not be available with a marketing label for use in patients who would fit the eligibility criteria of CANTOS,” he told TCTMD, adding, “But who knows? Maybe when they see [the results] published in this format they’ll be anxious to reconsider, or for that matter maybe Novartis will be anxious to reconsider the path forward.”

In the United States, when given monthly for approved indications, canakinumab is priced at approximately $200,000 per year.