A consistent criticism of the ESC congress in recent years has been that, outside of the chronic heart failure arena at least, the late breaker sessions have lacked headline-grabbing, big-hitting landmark trials.
Not this year. “This is our 1994!” proclaimed chief investigator, Paul Ridker (Brigham and Women’s Hospital, Boston, USA), on presentation of the results of CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study), drawing parallels with the practice-changing impact of the 4S (Scandinavian Simvastatin Survival Study) trial, which demonstrated the efficacy of statins for the first time and opened the door to lipid lowering as a highly prosperous therapeutic pathway in cardiovascular disease in the process.
Atherosclerosis has long been characterised as a chronic inflammatory condition. Elevation of the non-specific inflammatory marker high sensitivity c-reactive protein (hs-CRP) is an accepted predictor of adverse cardiovascular events and its reduction in JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) and other statin trials has been linked with improved outcomes, even with low-density lipoprotein (LDL) cholesterol levels within the normal range.1 Although a specific aetiological link has proven harder to delineate, the cytokine interleukin 1β (IL-1β), pro-inflammatory messenger of the innate immune system and driver of the interleukin-6 signalling pathway, is implicated in atherogenesis and its inhibition in animal models results in atherosclerotic plaque regression.
A sound basis therefore for CANTOS, a phase III clinical trial in which canakinumab (Ilaris®, Novartis), a monoclonal human IL-1β antibody currently employed for the treatment of rare rheumatological conditions, was investigated in patients with prior myocardial infarction (MI) and hs-CRP > 2 mg/L. Testing three doses (50 mg, 150 mg and 300 mg) alongside a placebo arm, the relatively long half-life permitted three-monthly subcutaneous administration. Some 10,061 patients (mean age 61 years, 25% women) were enrolled with high rates of conventional secondary preventative therapy (statin and antithrombotic use > 90%).
Presented to the packed main auditorium to palpable excitement (delegates lining floor in the isles while many more queued outside), the main results did not disappoint.
In a high-risk cohort (25% event rate in the placebo arm) both the 150 mg and 300 mg doses of canakinumab were associated with 15% relative risk reduction in the primary composite outcome of nonfatal MI, nonfatal stroke and cardiovascular death over median follow-up of 3.7 years (hazard ratio [HR] 0.85 vs. 0.86; 95%; confidence interval [CI] 0.74-0.98 vs. 0.75-0.99; p=0.021 vs. 0.031) for the 150 mg and 300 mg doses, respectively; the lower dose being the most statistically robustly following adjustment for multiple comparisons. In addition, incredibly, treatment at 300 mg was also associated with relative risk reductions of 51% in all-cause- and 77% in non-small cell lung cancer-specific mortality. The cardiovascular paper was simultaneously published in the New England Journal of Medicine, with a separate cancer outcomes paper in The Lancet.2,3 The latter effect was not a surprise to the investigators, since IL-1β and inflammation are heavily implicated in cancer development and progression.
A drug that reduces cardiovascular events and cancer mortality certainly ranks in the headline-grabbing category! Yet, as ever, the devil is in the detail.
Firstly, an important adverse effect was the small but significant increase in the incidence of leukopenia and fatal infection across all active treatment arms. Moreover, the primary outcome benefit was driven by nonfatal MI, with no significant reduction in stroke or cardiovascular mortality, and can be best described as modest; translating to an absolute risk reduction of 0.64% or a number needed to treat of around 156. Further information on the type of MIs is awaited (size, transmurality, spontaneous vs. periprocedural etc.)
Caution is also required in interpreting the cancer-related findings, as this seemingly dramatic finding is small in absolute terms (0.33%) in a subgroup (1.9%) of participants in a trial not powered for this event. Further work will clearly follow.
Thus, with an annual cost of circa US$200,000 to treat a single patient, canakinumab is clearly not yet ready for ‘primetime’ clinical practice. Nevertheless, the important take home message is the ‘proof of concept’ that targeting the inflammatory cascade can affect outcomes in atherosclerotic disease, opening up an exciting novel therapeutic pathway. In this vein, the results of the US National Heart Lung and Blood Institute sponsored trial CIRT (Cardiovascular Inflammation Reduction Trial), evaluating the ability of low methotrexate to reduce cardiovascular events in those with diabetes mellitus or metabolic syndrome, will be eagerly awaited. In the interim, expect Wikipedia searches for ‘inflammasome’ to increase exponentially, and a number of new inflammatory mediator targets to emerge.
You can find all of our reports from the ESC 2017 here.
1. Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195–2207. https://doi.org/10.1056/NEJMoa0807646
2. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119-1131 https://doi.org/10.1056/NEJMoa1707914
3. Ridker PM, MacFadyen JG, Thuren T, Everett BM, Libby P, Glynn RJ, CANTOS Trial Group. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet. 2017 published online 27 August 2017 https://doi.org/10.1016/S0140-6736(17)32247-X