Attacking Heart Failure Inflammation With Prednisone
Overview
Burst steroid therapy, commonly used in acute respiratory diseases, may provide benefits for patients with acute heart failure (AHF), where inflammation plays a key role in adverse outcomes. The CORTAHF trial aimed to evaluate whether a short course of steroid therapy could reduce inflammation and improve clinical outcomes in AHF patients. In this trial, 101 patients with AHF, elevated N-terminal pro-B-type natriuretic peptide (>1500 pg/mL), and high-sensitivity C-reactive protein (hsCRP >20 mg/L) were randomized to receive either 40 mg of oral prednisone daily for 7 days or standard care. The study was not blinded, and patients were followed for 90 days.
At day 7, hsCRP levels decreased in both treatment arms, with adjusted geometric mean ratios (GMRs) of 0.30 in the prednisone group and 0.40 in the standard care group. The ratio of GMRs between the two groups was 0.75 (95% CI, 0.56–1.00; p = 0.0498). The 90-day risk of worsening heart failure, heart failure readmission, or death was significantly lower in the prednisone group (10.4%) compared to the usual care group (30.8%), with a hazard ratio of 0.31 (95% CI, 0.11–0.86; p = 0.016).
Quality of life, as measured by the EQ-5D visual analogue scale, improved more in the prednisone group by day 7 (least squares mean difference 2.57 points, 95% CI, 0.12–5.01; p = 0.040). These beneficial effects were more pronounced in a pre-specified subgroup of patients with interleukin-6 levels greater than 13 pg/mL. However, adverse events such as hyperglycemia occurred more frequently in the prednisone group, though there was no significant difference in infection rates between the two groups.
Introduction
Inflammation has long been recognized as a significant factor in heart failure (HF), dating back over 70 years when researchers such as Elster, Braunwald, and Wood found that elevated C-reactive protein (CRP) levels were linked to worsening congestion, increased mortality, and recurrent heart failure episodes in patients hospitalized with acute heart failure (AHF). This early observation was subsequently validated by numerous studies that confirmed the association between systemic inflammation and poor outcomes in both chronic heart failure and AHF.
Inflammation in heart failure may contribute to a cascade of detrimental effects, including impaired cardiac and vascular function, fluid redistribution, capillary leakage, and neurohormonal activation. These processes may promote end-organ damage, exacerbate cardio-renal syndrome, and lead to unfavorable clinical outcomes such as recurrent heart failure exacerbations, prolonged hospitalizations, and increased mortality rates. Despite the well-established role of inflammation in heart failure, few therapeutic interventions have directly targeted this pathway, particularly in AHF, where treatment is often focused on symptom relief and fluid management.
About two decades ago, studies investigating tumor necrosis factor-alpha (TNF-α) inhibitors in heart failure failed to show significant benefits, casting doubt on the potential of anti-inflammatory treatments in this context. However, more recent smaller-scale investigations have reignited interest in the role of inflammation. For instance, trials examining anakinra, an interleukin-1 (IL-1) receptor antagonist, showed encouraging trends, such as improved diuresis and potentially better outcomes for patients with AHF. These findings suggested that targeted anti-inflammatory strategies might hold promise, though larger, more definitive studies were lacking.
Additionally, a retrospective study conducted by Miró et al. provided further evidence that corticosteroids might be beneficial in AHF patients with elevated hsCRP levels. This analysis showed trends toward improved outcomes for patients administered corticosteroids in the emergency department, offering a potential therapeutic avenue for addressing inflammation in AHF.
Building on these insights, the CORTAHF (Effect of Short-Term Prednisone Therapy on CRP Change in Emergency Department Patients With Acute Heart Failure and Elevated Inflammatory Markers) trial was developed to evaluate whether a brief course of steroid therapy could reduce inflammation, improve patients’ quality of life, and enhance 90-day clinical outcomes in individuals with AHF. The primary focus was on prednisone, a corticosteroid readily available and affordable, given the financial constraints that precluded the use of more expensive anti-inflammatory agents such as anakinra or IL-6 blockers. While the duration of the steroid burst therapy was not based on previous heart failure studies, it was designed in accordance with common practice in other inflammatory conditions where short-term corticosteroid use is standard.
The trial sought to address a critical gap in AHF treatment by testing whether modulating inflammation through prednisone could alter the disease trajectory. Specifically, it aimed to assess changes in CRP levels as a marker of inflammation, measure improvements in patients’ quality of life, and evaluate clinical outcomes over a 90-day period following treatment. The CORTAHF trial represented an important step in exploring new therapeutic options for AHF by targeting the underlying inflammatory processes that contribute to worsening heart failure.
Also read Heart Failure Polygenic Risk Predictions
Methods
Inclusion Criteria
– Age: Patients aged between 18 and 85 years.
– Diagnosis: Confirmed diagnosis of acute heart failure (AHF) upon unplanned hospital presentation.
– Congestion: Objective evidence of congestion demonstrated by chest X-ray or lung ultrasound.
– Vital Signs: Systolic blood pressure of ≥100 mmHg and heart rate of ≥60 bpm.
– Biomarkers: Elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels >1500 pg/ml and high-sensitivity C-reactive protein (hsCRP) levels >20 mg/L at screening.
– Consent: Written, informed consent provided by patients to participate in the study.
Exclusion Criteria
– Correctable Causes of AHF: Acute heart failure triggered by correctable etiologies, such as:
– Significant arrhythmia
– Severe anemia
– Acute coronary syndrome
– Chronic obstructive pulmonary disease (COPD) exacerbation
– Active infection
– Other Medical Conditions: Patients with underlying conditions that might confound the study results, including those with infections or other treatable causes of AHF.
– Inability to Provide Consent: Patients unable to provide informed consent or comply with the study procedures.
The CORTAHF study is a multicenter, randomized, open-label, controlled pilot trial conducted in parallel groups, with its design previously described. This trial enrolled patients aged 18 to 85 who presented with acute heart failure (AHF) at three hospitals. Ethical approval was obtained from the Ministry of Health of the Republic of Armenia, Yerevan State Medical University’s Ethics Committee, and the Local Ethics Committee of ‘Erebouni’ Medical Center.
Study Procedures
Participants were randomized in a 1:1 ratio to receive either 40 mg of oral prednisone daily for 7 days in addition to standard care or to continue with standard care alone. Specific details of the study procedures are available in the online supplementary material.
Study Endpoints
The primary endpoint of the study was the change in hsCRP levels from baseline to day 7. Secondary endpoints included the time to the first event of worsening heart failure, hospital readmission for heart failure, or death within 91 days. Additionally, the study evaluated changes in quality of life using the EuroQol 5-Dimension 5-Level (EQ-5D-5L) scale from day 1 to day 7. Worsening of HF symptoms or signs was considered an adverse event and reported by investigators. The cause of death and reasons for rehospitalization were classified according to a pre-established list and confirmed by a centralized monitoring team.
Safety Monitoring
Safety was monitored throughout the study, with assessments conducted at each visit up to day 31. Physical examinations, local laboratory tests, and non-directive questioning of patients were used to evaluate safety. Any adverse events reported by the patient or observed by the investigator were recorded, with oversight provided by a medical monitor.
Protocol Amendments
After enrolling 18 patients, the study protocol was amended. The main efficacy analysis was revised to focus on the per-protocol population, and the first secondary endpoint was extended to include events occurring through day 91 rather than day 31. The criteria for adverse events of worsening heart failure were also broadened to include all events rather than those occurring within a more restrictive time frame (24 hours to 7 days after randomization).
This study represents a focused effort to explore the efficacy and safety of short-term prednisone therapy in reducing inflammation and improving outcomes in patients with AHF.
Analysis
The original study aimed to assess steroid therapy in patients with IL-6 levels above 13 pg/ml, but due to feasibility issues, it was adjusted to enroll 120 patients with hsCRP levels >20 mg/L. IL-6 levels were measured centrally post-study, estimating that 100 patients would have IL-6 >13 pg/ml for secondary analysis.
For the primary outcome, 60 patients per group were estimated to provide 80% power to detect a 40% reduction in day 7 hsCRP with prednisone. However, due to funding and enrollment challenges, the trial was terminated after enrolling 100 patients. The power was adjusted to 80% to detect a 43% decrease in hsCRP levels with 50 patients per group.
Outcomes were presented as means, medians, or frequencies. The treatment effect on the primary endpoint (hsCRP change by day 7) was analyzed using a mixed model for repeated measures (MMRM), including treatment, baseline values, and center effects. CRP levels were log-transformed, and results expressed as geometric mean ratios (GMRs).
Subgroup analyses for primary and secondary outcomes by age, sex, and IL-6 were pre-specified. Time-to-event outcomes (e.g., worsening heart failure, hospital readmission, or death) were assessed using a log-rank test and Cox proportional hazards model. Adverse events were coded using the MedDRA system, and the safety population included all patients.
Statistical analyses were performed using SAS version 9.4 and R version 4.2.3, with significance set at p < 0.05.
Results
Between August 11, 2023, and April 15, 2024, 101 eligible patients were randomized in a multicenter study across three hospitals. Two patients were excluded from per-protocol analyses due to protocol violations, one being mistakenly enrolled with acute myocardial infarction. Baseline characteristics are detailed in Table 1.
At day 7, the median hsCRP levels were significantly lower in the prednisone group compared to the usual care group, with adjusted geometric mean ratios (GMR) of 0.30 versus 0.40 (p = 0.0498). By day 31, hsCRP levels had decreased substantially in both groups without significant differences. IL-6 and other markers, such as white blood cells and lymphocyte percentage, showed similar trends.
Patients on prednisone reported a better quality of life improvement (EQ-VAS) by day 7 compared to those receiving usual care, with a least squares mean difference of 2.57 points (p = 0.040). Prednisone also reduced the risk of the composite secondary endpoint (worsening heart failure, readmission, or death) by day 91, with a hazard ratio of 0.31 (p = 0.016). No hospital readmissions were observed in the prednisone group, compared to seven in the usual care group.
A pre-specified analysis of patients with IL-6 >13 pg/ml showed significant benefits in both the primary and secondary outcomes with prednisone therapy.
Lab results and congestion signs tended to improve more in the prednisone group. Rales improved significantly by day 31 (p = 0.0032), with trends toward better improvements in orthopnea and edema. Diuretic doses were lower in the prednisone group by day 31, but the difference was not statistically significant. NT-proBNP levels decreased similarly in both groups.
No significant differences were observed in intensive care unit (ICU) days, hospital stays, or overall mortality between the groups. Medications administered were similar across groups.
Prednisone was associated with more adverse events, primarily due to hyperglycemia, though none were severe. Most hyperglycemia events were mild, with 13 cases in the prednisone group versus none in usual care. One patient in the prednisone group died from heart failure, leading to a serious adverse event report. There was no significant difference in infection rates between groups.
Plasma renin concentration (PRC) was undetectable in over half of the patients at baseline. By day 7, PRC increased significantly in the usual care group but not in prednisone-treated patients. By day 31, PRC levels in the prednisone group had decreased below baseline, though between-group differences were not statistically significant.
Conclusion
Short-term prednisone therapy in patients with acute heart failure (AHF) significantly reduced inflammatory markers, particularly hsCRP, and improved quality of life within the first week of treatment. Prednisone also reduced the risk of adverse outcomes, such as heart failure worsening, readmission, and death by day 91. While there were more mild adverse events, primarily hyperglycemia, prednisone was generally well-tolerated. These findings suggest that targeted anti-inflammatory therapy may offer clinical benefits in AHF patients, although further large-scale studies are needed to confirm these results and refine treatment protocols.
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