Highlights
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CRP-STEMI is an investigator-initiated, randomized, open-label, multicenter trial.
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A total of 202 STEMI patients with elevated CRP post PCI enrolled at 5 centers.
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The intervention group receives 3 sessions of selective CRP apheresis post-PCI.
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The primary endpoint is infarct size assessed by CMR at 5 ± 2 days after PCI.
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CRP-STEMI is the first randomized trial to evaluate CRP apheresis in STEMI.
ABSTRACT
Background
Despite the effectiveness of primary percutaneous coronary intervention (PCI) in treating ST-elevation myocardial infarction (STEMI), myocardial salvage is often incomplete, resulting in large infarct size and an increased risk of heart failure and mortality. Inflammation is involved in this process, with C-reactive protein (CRP) potentially contributing to infarct expansion. Whether selective CRP apheresis in addition to standard care can reduce infarct size in STEMI remains to be determined.
Trial Design
Selective C-reactive protein apheresis in ST-elevation myocardial infarction ( CRP-STEMI) is an investigator-initiated, randomized, open-label ( outcome assessor blinded ), multicenter trial investigating whether selective CRP apheresis using the PentraSorb-CRP system, in addition to standard care, can reduce infarct size in STEMI patients undergoing PCI within 12 hours of symptom onset. The trial will enroll 202 patients at 5 tertiary care centers in Austria and Germany, randomized 1:1 to either the intervention group (standard care + CRP apheresis) or the control group (standard care). In the intervention group, CRP apheresis will be performed on days 1, 2, and 3 post-PCI. The primary endpoint is infarct size as assessed by late gadolinium enhanced cardiac magnetic resonance at 5 ± 2 days after PCI.
Outlook
CRP-STEMI is the first randomized trial to investigate whether selective CRP apheresis, as an adjunct to standard care, can effectively reduce infarct size in acute STEMI patients.
Trial Registration
CRP-STEMI, NCT04939805, is registered at https://clinicaltrials.gov/study/ NCT04939805.
Graphical Abstract
Background
Despite optimized reperfusion therapy, patients surviving the acute phase of ST-elevation myocardial infarction (STEMI) remain at high risk of heart failure and mortality, particularly during the first year following the event. ,, The extent of myocardial injury, quantified as infarct size, is a main determinant of postinfarction outcome, as recently confirmed in a patient-level analyses from randomized trials including over 2,600 patients. In this study, imaging-based assessment of infarct size reliably predicted hospitalization for heart failure and all-cause mortality within the first year after myocardial infarction. These findings not only confirm the strong prognostic significance of infarct size but also point to an important unmet clinical need. This need relates to the development and implementation of novel cardioprotective therapies aimed at reducing infarct size. Future trials should therefore prioritize the investigation of therapeutic strategies aimed at reducing infarct size in order to improve clinical outcomes in this patient population. ,
Systemic and local inflammation is a contributor to myocardial injury following STEMI, with C-reactive protein (CRP) identified as a potential causal mediator. CRP levels rise within hours after infarction, peaking at 48 to 72 hours. , Evidence indicates that CRP is not merely a biomarker but plays a direct pathogenic role by promoting complement activation, exacerbating myocardial tissue necrosis, and impairing infarct healing. , Indeed, experimental models have shown that CRP depletion can mitigate myocardial injury, prompting the exploration of CRP apheresis as a potential cardioprotective therapy. ,,, Preclinical studies have demonstrated that CRP apheresis reduces infarct size and preserves cardiac function. Small-scale nonrandomized clinical studies, including the exploratory CRP apheresis after myocardial infarct (CAMI-1) trial, have provided initial feasibility data on CRP apheresis in STEMI patients, showing effective CRP reduction without major safety concerns. , However, the small sample size and nonrandomized design do not allow conclusions to be drawn regarding its efficacy. Taken together, these mechanistic insights, preclinical findings, and early clinical data support the hypothesis that CRP is a viable therapeutic target to limit infarct expansion and improve myocardial salvage. The Selective C-reactive protein apheresis in ST-elevation myocardial infarction (CRP-STEMI) trial is an investigator-initiated, randomized, open-label ( outcome assessor blinded ), multicenter trial designed to evaluate, for the first time, whether CRP apheresis, as an adjunct to standard care, can reduce infarct size in patients with STEMI.
Study design
Study objective
CRP-STEMI aims to investigate the efficacy of selective CRP apheresis, using the PentraSorb-CRP system, as an adjunctive therapy to standard care for patients with acute STEMI treated with primary percutaneous coronary intervention (PCI).
Design
CRP-STEMI is an investigator-initiated, randomized, open-label ( outcome assessor blinded ), multicenter trial. The trial is registered at clinicaltrials.gov under the identifier NCT04939805. A flowchart depicting the trial design is shown in Figure , and data acquisition during hospitalization and follow-up is displayed in Table .
Study Flow Chart.
Legend: This figure illustrates the study design and patient allocation. A total of 202 patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) will be screened and randomized 1:1 to receive either standard care (control group) or standard care + selective C-reactive protein (CRP) apheresis on days 1, 2 and 3 (intervention group). The primary endpoint is infarct size assessed by cardiac magnetic resonance imaging (CMR) at 5 ± 2 days.
Table
Study procedures and assessments
| 0-24h after PCI | 28 ± 8h after PCI | 48 ± 8h after PCI | 72 ± 8h after PCI | 5 ± 2 d after PCI | Discharge | 30 d ± 10 days after PCI | 4 M ± 30 d after PCI | 12 M ± 30 d after PCI | |
|---|---|---|---|---|---|---|---|---|---|
| Informed consent | X | ||||||||
| Randomization | X | ||||||||
| Demographics | X | ||||||||
| Standardized questionnaries | X | X | X | X | X | ||||
| Medical history | X | ||||||||
| Vital signs | X | X | X | X | X | X | |||
| Physical examination | X | ||||||||
| Blood sampling | X | X | X | X | X | X | |||
| CMR * | X | (optional) | (optional) | ||||||
| CRP apheresis † | X | X | X | ||||||
| Medication | X | X | X | X | |||||
| Clinical Endpoints | X | X | X | X | |||||
| AE/SAE | X | X | X | X | X | X | X | X |
Abbreviations: AE = adverse event; CMR = cardiac magnetic resonance; d = days; h = hours; M = months; PCI = percutaneous coronary intervention; SAE = serious adverse event.
*CMR is performed after the third apheresis session, preferably the following day, but no sooner than 8 hours post-treatment.
† Apheresis will only be performed in patients randomized to the test arm.
A total of 202 STEMI patients will be enrolled at 5 tertiary care centers across Austria and Germany. Patients will be randomized in a 1:1 ratio to either the intervention group ( standard care + selective CRP apheresis ) or the control group ( standard care ) (Graphical Abstract). The maximum study duration for each participant is 12 months.
The study received ethics approval from the Ethics Committee at the Medical University of Innsbruck, which served as the leading ethics board. Additionally, each participating institution obtained approval from its respective local ethics committee. All participants provided written informed consent before study enrollment.
Outcome definitions
Primary endpoint
Infarct size as defined by late gadolinium enhanced (LGE) cardiac magnetic resonance (CMR) imaging at 5 ± 2 days post-PCI.
Secondary endpoints
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Safety defined as adverse events according to Common Terminology Criteria for Adverse Events (CTCAE) during hospitalization for the index event.
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Major adverse cardiovascular event (MACE), defined as a composite of all-cause death and hospitalization for new congestive heart failure within 12 months after randomization.
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All-cause death within 12 months after randomization.
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Cardiovascular mortality within 12 months after randomization.
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Hospitalization for new congestive heart failure within 12 months after randomization.
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Nonfatal myocardial re-infarction within 12 months after randomization.
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Left ventricular ejection fraction (LVEF), microvascular obstruction (MVO), intramyocardial haemorrhage (IMH) and exploratory CMR endpoints according to the Journal of American College of Cardiology Scientific Expert Consensus document.
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Left ventricular (LV) remodeling, infarct healing, and persistent microvascular injury assessed by serial transthoracic echocardiography and CMR imaging at 4- and 12-months post-PCI.
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CRP concentrations during index hospitalization.
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Biomarker concentrations of myocardial necrosis (high-sensitivity cardiac troponin T/I), hemodynamic stress (N-terminal pro-B-Type Natriuretic Peptide), inflammation (white blood cell count, procalcitonin, interleukin-6), and kidney function.
Clinical outcome assessment
Clinical endpoints will be assessed at 30 ± 10 days, 4 ± 1 months, and 12±1 months after randomization. Based on the literature, , MACE will be defined as a composite of all-cause death and hospitalization for new congestive heart failure. All-cause death is defined as death from any cause. Heart failure hospitalization is defined as any hospitalization for the following symptoms and signs of heart failure: new or worsening breathlessness, fatigue, ankle swelling, elevated jugular venous pressure, pulmonary crackles, peripheral edema, and elevated brain natriuretic peptides. Outcomes will be adjudicated by a blinded clinical events committee (CEC) unaware of the patient’s assigned treatment. The CEC will evaluate and adjudicate all clinical events. Furthermore, the CEC will assess all unanticipated serious adverse events potentially associated with the study intervention.
Study population
The trial will enroll 202 patients aged 18 to 85 years with a first diagnosis of acute STEMI, treated with primary PCI within 12 hours of symptom onset, according to the European Society of Cardiology (ESC) STEMI guidelines. To ensure inclusion of patients with a high likelihood of CRP elevation in the early post-STEMI phase, only those with a CRP ≥7 mg/L measured 6 to 16 hours after PCI will be included.
High-sensitivity CRP is measured locally at each participating site using validated clinical laboratory assays. All assays are calibrated to international reference standards and are subject to certified external quality assessment schemes, ensuring reliable and comparable CRP measurements across centers.
Primary PCI and subsequent care, including secondary prevention, will follow standard clinical practice and guideline recommendations. The first patient was enrolled on April 18, 2021; with 186 patients currently enrolled. Study completion with final primary endpoint results is expected in the first half of 2026.
The following in- and exclusion criteria were defined:
Inclusion criteria
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Age between 18 and 85 years.
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Diagnosis of first acute STEMI following the ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation.
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Symptoms consistent with STEMI with beginning ≥30 minutes but <12 hours prior to primary PCI.
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CRP elevation of ≥7 mg/L measured between 6 and 16 hours after primary PCI.
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Eligible for primary PCI.
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Written informed consent.
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