TL;DR
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The ZEUS trial found that monthly ziltivekimab did not reduce major cardiovascular events compared with placebo in people with established ASCVD, chronic kidney disease and elevated inflammation. The drug substantially lowered IL-6 and C-reactive protein, but serious infections and venous thromboembolism were more frequent in the treatment group.
Ziltivekimab did not reduce major cardiovascular events compared with placebo in the ZEUS trial of people with atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD) and elevated inflammation, researchers reported November 7. The antibody lowered inflammatory markers, but the primary outcome occurred in nearly identical proportions in the two groups.
Over a median 33 months of follow-up, the primary composite outcome—death from cardiovascular causes, nonfatal heart attack or nonfatal stroke—occurred in 561 of 3,184 participants assigned ziltivekimab, or 17.6%, and 565 of 3,192 assigned placebo, or 17.7%. The hazard ratio was 0.99 (95% confidence interval 0.88 to 1.11; P=0.84), indicating no statistically significant reduction in the trial’s primary endpoint.
The global, double-blind trial enrolled 6,376 people with established ASCVD and CKD whose high-sensitivity C-reactive protein (hs-CRP) level was above 2 milligrams per liter. Participants received a 15-milligram injection of ziltivekimab or placebo once a month. The results were presented at the American Heart Association’s annual meeting in Chicago and published at the same time in the New England Journal of Medicine.
Treatment produced a 76% placebo-adjusted reduction in free interleukin-6 and a 64% placebo-adjusted reduction in hs-CRP from baseline, as reported by lead investigator Paul M. Ridker of Harvard Medical School and Mass General Brigham. The report said there was also no treatment benefit on the secondary outcomes described, including a broader cardiovascular composite, kidney outcomes, heart-failure outcomes and all-cause mortality. Serious adverse events occurred in 54.6% of the ziltivekimab group and 54.8% of the placebo group. Serious infections were more frequent with treatment (20.4% versus 17.9%), as was venous thromboembolism (1.6% versus 0.6%); both differences were reported as statistically significant.
Lower Inflammation, No Event Reduction
The findings separate a measurable biological effect from a demonstrated clinical benefit. Ziltivekimab substantially reduced two inflammatory markers, but that change did not translate into fewer events in this group during the trial. The results caution against assuming that lowering a biomarker will, on its own, prevent heart attacks, strokes or cardiovascular deaths.
They do not establish that inflammation is irrelevant to cardiovascular disease. Ridker and colleagues reported that higher levels of both CRP and IL-6 were associated with higher risk of the primary outcome and all-cause death. Those associations do not show that treating inflammation with this particular drug will reduce risk. For clinicians and patients, the result means ziltivekimab’s marker reductions cannot be treated as proof of cardiovascular protection in the population studied.
The reported differences in serious infections and venous thromboembolism also matter when weighing a drug’s potential benefits and risks. The trial did not show a cardiovascular benefit to offset those imbalances, although the available report does not establish why they occurred or what they mean for other populations.
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How ZEUS Fits Inflammation Research
Ziltivekimab is a monoclonal antibody that directly targets the interleukin-6 (IL-6) ligand. Its monthly 15-milligram dose was selected after an earlier phase II study showed substantial CRP lowering, Ridker said. ZEUS tested the treatment in people with established cardiovascular disease, significant CKD and elevated hs-CRP—not in a general population at cardiovascular risk.
The neutral result contrasts with prior evidence cited by Ridker from CANTOS, which tested canakinumab, and the colchicine trials LoDoCo2 and COLCOT, which found reductions in cardiovascular events in their study populations. Ridker said ZEUS participants had more CKD, diabetes and heart failure than those in CANTOS, and that all-cause mortality during the trial was twice as high. He raised the possibility that more advanced disease may be less responsive to anti-inflammatory treatment, but that is an interpretation, not a conclusion established by this trial.
Ridker also cautioned that genetic evidence linking IL-6 to cardiovascular risk does not guarantee that a drug targeting the pathway later in life will reverse that risk. He summarized the distinction as: “genetic causality is not therapeutic reversibility.”
“The relevant question moving forward is what drug, in which patient group?”
— Paul M. Ridker, ZEUS investigator, at the American Heart Association meeting
Why Biomarker Gains Did Not Translate
ZEUS established that ziltivekimab lowered IL-6 and hs-CRP in the studied population without reducing the primary cardiovascular endpoint. It did not determine why those effects diverged. Possible explanations raised by investigators and the discussant include treatment starting too late in the course of disease, the choice of IL-6 target, or whether intervening elsewhere in the inflammatory pathway might work differently. These remain hypotheses, not findings demonstrated by ZEUS.
The reported results also do not establish whether another dose, treatment duration or patient group would produce a different outcome. Although serious infections and venous thromboembolism were more frequent in the ziltivekimab arm, the supplied report does not provide further detail on the causes of those differences. Results from other trials will be needed before drawing conclusions about ziltivekimab outside the ZEUS population.
ARTEMIS Trial Remains Ongoing
Other studies are testing ziltivekimab in different settings. Ridker said the HERMES trial, involving people with heart failure with mildly reduced or preserved ejection fraction, had also been stopped for futility. He said ARTEMIS, in acute coronary ischemia, was allowed to continue. Its results may clarify whether the treatment has a role in a different patient group, but no outcome from ARTEMIS is reported here.
Researchers and clinicians will also assess the published ZEUS findings, including the primary and safety outcomes. Until further evidence is available, the trial supports a narrow conclusion: ziltivekimab lowered inflammatory markers but did not reduce the measured cardiovascular events in people with ASCVD, CKD and elevated hs-CRP over the study period.
Key Questions
What did the ZEUS trial find?
Among 6,376 participants with ASCVD, CKD and elevated hs-CRP, ziltivekimab did not reduce the primary composite of cardiovascular death, nonfatal heart attack or nonfatal stroke compared with placebo over a median 33 months.
Did ziltivekimab lower inflammation?
Yes. The trial reported a 76% placebo-adjusted reduction in free IL-6 and a 64% placebo-adjusted reduction in hs-CRP from baseline. Those changes did not correspond to a reduction in the primary cardiovascular outcome.
Were there safety differences between the groups?
Overall serious adverse events were similar: 54.6% with ziltivekimab and 54.8% with placebo. Serious infections and venous thromboembolism were reported more often in the ziltivekimab group, and the differences were statistically significant.
Does the result show inflammation is not a cardiovascular risk factor?
No. The trial tested one drug in a specific, high-risk population. Investigators reported that higher IL-6 and CRP levels were associated with greater risk, but ZEUS did not show that lowering these markers with ziltivekimab reduced events.
What ziltivekimab research is continuing?
Ridker said HERMES, a trial in certain heart-failure patients, had been halted for futility, while ARTEMIS in acute coronary ischemia was continuing. The supplied report does not give an expected date for ARTEMIS results.
Source: medpagetoday.com
