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A U.S. subanalysis of the POSEIDON registry found elevated hsCRP in about half of participants with each major heart failure ejection-fraction type, higher than the corresponding rates in the full international registry. The findings indicate substantial measured inflammatory burden, but do not show that lowering inflammation improves heart failure outcomes; recent trials of the IL-6 inhibitor ziltivekimab were stopped early for futility.
A U.S. subanalysis of the POSEIDON registry found that about half of participants with heart failure had elevated high-sensitivity C-reactive protein, or hsCRP of at least 2 mg/L, a marker associated with inflammation. Presented by Duke University cardiologist Marat Fudim at the Heart Failure Society of America annual conference, the findings point to a common risk marker but do not establish that an anti-inflammatory treatment can improve heart failure outcomes.
Elevated hsCRP was recorded in 50.8% of U.S. participants with preserved ejection fraction (HFpEF), 44.7% with mildly reduced ejection fraction (HFmrEF), and 50.3% with reduced ejection fraction (HFrEF). In POSEIDON’s full cohort across 18 countries, the corresponding proportions were 38.8%, 38.1% and 38.2%. The figures describe the share above the study’s threshold, not a comparison of individual patients’ risk or proof that inflammation caused their heart failure.
POSEIDON prospectively enrolled 18,904 adults with atherosclerotic cardiovascular disease and/or heart failure receiving routine care in 18 countries from 2023 through 2025. The U.S. heart failure groups in this analysis included 315 people with HFpEF, 94 with HFmrEF and 392 with HFrEF. Fudim reported that elevated hsCRP was linked to higher levels of interleukin-6 and NT-proBNP across the three heart failure types. Insulin and diuretic use also appeared higher among people with elevated hsCRP, though the presentation did not establish why.
Fudim said residual inflammatory risk remained apparent despite use of guideline-directed medical therapy. He described hsCRP as a practical marker for identifying that risk and informing discussions with patients. The analysis was cross-sectional, however, and it does not show whether measuring hsCRP or acting on its result changes outcomes.
Inflammation Is Common, Treatment Is Unsettled
The results highlight a gap between the prevalence of a measurable risk marker and the availability of treatments proven to address it in heart failure. For patients and clinicians, an elevated hsCRP result may help flag residual inflammatory risk, but it is not by itself a diagnosis of a specific inflammatory disease or evidence that a particular drug will help.
The comparison with the international registry also shows that the U.S. participants had higher proportions above the study threshold in each heart failure category. The analysis does not explain that difference, and it cannot establish whether it reflects differences in health conditions, treatment, participant selection or other factors. Fudim pointed to obesity, diabetes and chronic kidney disease as key contributors to inflammation among people with heart failure.
The treatment question remains consequential because inflammation has been associated with adverse outcomes, while trials targeting individual inflammatory pathways have had disappointing results. The registry findings describe prevalence; they do not demonstrate that reducing hsCRP will lower hospitalization or mortality.
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From Registry Findings to Drug Trials
The POSEIDON analysis was presented at the Heart Failure Society of America annual conference. It examined hsCRP in people with three categories of heart failure defined by ejection fraction. The report characterizes it as a subanalysis of a large international registry, rather than a randomized treatment study. Participants were recruited during routine care, and the U.S. heart failure subset was smaller than the full registry.
Drug development has not yet supplied a clear targeted option. Novo Nordisk announced in September that two placebo-controlled trials of ziltivekimab, an IL-6 inhibitor, HERMES and ATHENA, were stopped early for futility. The trials were designed to assess hard and softer endpoints in heart failure patients with elevated hsCRP. Before that, ziltivekimab had not reduced major adverse cardiovascular events in the ZEUS trial, which studied people with atherosclerotic cardiovascular disease, chronic kidney disease and inflammation.
At the conference, Fudim suggested that approaches affecting multiple inflammatory pathways could warrant consideration, citing GLP-1 medicines as an example. That was his view on a possible direction for research, not evidence from this POSEIDON analysis that GLP-1 drugs treat heart failure inflammation. He also cautioned that suppressing immune activity too broadly could carry risks.
“We are very inflamed as a nation of HF patients.”
— Marat Fudim, MD, MHS, Duke University Medical Center
What the Registry Cannot Answer
The analysis does not establish whether inflammation causes worsening heart failure, whether lowering hsCRP improves outcomes, or why the U.S. rates were higher than those in the full international registry. Because it was cross-sectional, it captures measurements at a point in time rather than showing how inflammation or patients’ health changed over time. It also does not test a treatment.
The source report does not provide confidence intervals or a statistical test for the differences between the U.S. and international proportions, so their statistical significance is unclear. The U.S. HFmrEF group, at 94 participants, was also smaller than the HFpEF and HFrEF groups. No dedicated therapy has been established from these findings, and the early stoppage of HERMES and ATHENA leaves their planned evaluations incomplete.
What Researchers and Clinicians May Track
The next evidence will need to come from studies that test whether an intervention aimed at inflammation improves outcomes that matter to patients, not only a biomarker reading. The available report does not identify a new trial milestone or provide a timeline for further ziltivekimab research. HERMES and ATHENA were stopped early, and their results cannot be treated as proof that all approaches to inflammation will fail.
For now, Fudim said he uses hsCRP to inform risk discussions and motivate attention to lifestyle, exercise, weight management and conditions such as chronic kidney disease. These comments are not evidence that any one measure lowers heart failure events in this registry. Patients should discuss individual test results and treatment choices with their clinicians rather than changing prescribed heart failure medicines on the basis of hsCRP alone.
Key Questions
What did the POSEIDON subanalysis find?
It found hsCRP of at least 2 mg/L in 50.8% of U.S. participants with HFpEF, 44.7% with HFmrEF and 50.3% with HFrEF. These are proportions above a marker threshold, not evidence that inflammation caused the condition.
Does an elevated hsCRP mean a patient needs an anti-inflammatory drug?
No. The registry analysis did not test treatments or establish a specific therapy for people with an elevated result. Patients should interpret hsCRP with a clinician and should not stop or change prescribed treatment based on this finding alone.
Why were the U.S. proportions compared with the international registry?
The U.S. figures were higher than the corresponding proportions in the full POSEIDON cohort across 18 countries. The report does not establish why, or provide enough information to determine the statistical significance of those differences.
What happened to the ziltivekimab heart failure trials?
Novo Nordisk said in September that the HERMES and ATHENA trials of the IL-6 inhibitor were stopped early for futility. The report does not give a new timeline for further trials or establish whether other anti-inflammatory approaches will work.
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