Two new analyses of data from more than 10,000 heart attack survivors worldwide were presented by investigators from Brigham and Women's Hospital at the 2018 American College of Cardiology meeting. Dr Paul Ridker, director of the Centre for Cardiovascular Disease Prevention at BWH, and Dr Brendan Everett, director of the General Cardiology Inpatient Service at BWH, assessed whether the anti-inflammatory therapy canakinumab reduced rates of major adverse cardiovascular events and co-morbidities among high-risk atherosclerotic patients with chronic kidney disease (CKD) or those with pre-diabetes/diagnosed type 2 diabetes, respectively.
They found that canakinumab substantially reduced cardiovascular event rates in both populations, while having neither clinically meaningful benefits nor substantive harms with respect to adverse renal events or glucose control.
"Evidence continues to build that inflammation underlies many diseases and health conditions," said Everett. "We find that among heart attack survivors with diabetes or pre-diabetes, canakinumab is effective at reducing risk of cardiovascular events. Our data also suggest that as cardiovascular disease and diabetes take root, the inflammatory pathways underlying them may diverge."
Everett and colleagues found that canakinumab was equally effective at reducing rates of cardiovascular events among patients with and without diabetes enrolled in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). The drug reduced HbA1C levels – a key indicator of glucose tolerance – in patients with diabetes or pre-diabetes for the first six to nine months of the trial, but this effect was not sustained.
In a new analysis led by Ridker, investigators found that canakinumab reduced major adverse cardiovascular event rates among high-risk atherosclerosis patients with moderate to severe chronic kidney disease, with the largest benefits accrued among those who had the most robust anti-inflammatory response. Canakinumab, an IL-1b inhibitor, represents a new class of therapy for atherosclerotic disease that lowers hsCRP and IL-6 with no effect on lipid levels.
"Moving forward, it will be important to extend these data and test the efficacy of canakinumab in patients with end-stage renal failure undergoing dialysis," said Ridker. "In that setting, hsCRP is a powerful predictor of risk while LDL-C is not, and dialysis is one of the only settings where LDL reduction has not been highly effective."
Abstract
Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved.
Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per litre. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death.
Results: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P=0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P=0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P=0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P=0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P=0.31).
Conclusions: Anti-inflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering.
Authors
Paul M Ridker, Brendan M Everett, Tom Thuren, Jean G MacFadyen, William H Chang, Christie Ballantyne, Francisco Fonseca, Jose Nicolau, Wolfgang Koenig, Stefan D Anker, John JP Kastelein, Jan H Cornel, Prem Pais, Daniel Pella, Jacques Genest, Renata Cifkova, Alberto Lorenzatti, Tamas Forster, Zhanna Kobalava, Luminita Vida-Simiti, Marcus Flather, Hiroaki Shimokawa, Hisao Ogawa, Mikael Dellborg, Paulo RF Rossi, Roland PT Troquay, Peter Libby, Robert J Glynn
[link url="https://www.sciencedaily.com/releases/2018/03/180312085054.htm"]Brigham and Women’s Hospital material[/link]
[link url="http://www.nejm.org/doi/10.1056/NEJMoa1707914"]New England Journal of Medicine abstract[/link]