Trial schema and rationale

Acute coronary occlusion and reperfusion expose myocardium to both ischemic injury and the biology of sterile inflammation. Among the acute-phase reactants, C-reactive protein (CRP) rises rapidly, binds to damaged membranes, and can activate the classical complement pathway. This interaction has been hypothesized to convert a biomarker of risk into a mediator of harm, amplifying cell clearance and microvascular dysfunction in the peri-infarct zone. The CRP-STEMI randomized trial operationalizes this hypothesis by acutely lowering circulating CRP via selective extracorporeal adsorption while preserving other immunoglobulins and complement proteins to the extent possible with molecularly targeted columns.

The trial is designed as a parallel-group, randomized controlled investigation in patients with ST-elevation myocardial infarction undergoing guideline-directed reperfusion. In this context, extracorporeal apheresis is used not as lipid-lowering therapy but as an anti-inflammatory modulation targeted at a single acute-phase protein. The intervention window is structured around the index infarction and early reperfusion period, when CRP rises and tissue is most vulnerable to immune-mediated injury. The design includes prespecified timing of treatment relative to primary percutaneous coronary intervention (PCI) and serial biomarker and imaging assessments to quantify any signal on myocardial injury and remodeling. The control arm receives standard-of-care STEMI management without CRP-specific removal.

To align biological plausibility with measurable outcomes, the protocol centers on imaging-based quantification of infarct characteristics and ventricular function. The principal rationale is that selective CRP depletion during the early inflammatory surge could reduce complement-driven opsonization and phagocytic clearance of jeopardized, but potentially salvageable, myocytes. Mechanistically, attenuation of CRP may also diminish endothelial activation and microvascular obstruction, processes implicated in the no-reflow phenomenon. The trial is therefore positioned to interrogate a defined mechanistic target rather than broadly suppressing inflammation, which has historically carried trade-offs in host defense and healing.

Eligibility, randomization, and interventions

Eligibility criteria focus on adults with ST-elevation myocardial infarction who are candidates for urgent reperfusion with primary PCI. Inclusion encompasses typical clinical and electrocardiographic definitions of STEMI with symptom onset within a predefined window and angiographic confirmation of a culprit lesion suitable for mechanical revascularization. The protocol excludes conditions that preclude apheresis or raise disproportionate risk, such as severe hemodynamic instability not amenable to extracorporeal circulation, active bleeding, known hypersensitivity to column materials, or profound anemia. Renal or hepatic dysfunction that would complicate extracorporeal therapy, as well as pregnancy, are standard exclusions. Practical considerations include venous access feasibility and the ability to initiate the intervention within the set time boundaries relative to reperfusion.

Randomization is centralized, stratified by key prognostic variables (for example, infarct territory or anticipated time to reperfusion) to balance groups on determinants of infarct size and recovery. Allocation is typically in a 1:1 ratio to either selective CRP apheresis plus standard care or standard care alone, ensuring that contemporary PCI, dual antiplatelet therapy, anticoagulation, and secondary prevention therapies are applied uniformly. The allocation process uses secure, concealed assignment to prevent selection bias, and the clinical team follows a predefined workflow to avoid delaying reperfusion.

The intervention employs an adsorptive column engineered to bind pentameric CRP from plasma while minimizing non-specific protein loss. Treatment sessions are scheduled acutely after reperfusion, when CRP trajectories begin to climb, and may include a repeat session within the early post-infarct window depending on protocol-defined thresholds or time-based criteria. Extracorporeal circulation parameters (blood flow, anticoagulation during apheresis, monitoring of vital signs) adhere to device instructions for use and institutional standards. The protocol requires measurement of pre- and post-procedure CRP concentrations, hematology, and basic chemistry to confirm selectivity and procedural safety.

Standard-of-care therapy mirrors current guideline recommendations for STEMI, including timely reperfusion, antithrombotic regimens, high-intensity statins, beta-blockers, renin-angiotensin-aldosterone system inhibition, and secondary prevention counseling. Adjunctive therapies (e.g., glycoprotein IIb/IIIa inhibitors) are used at the operator’s discretion but recorded to permit adjustment in analyses. Concomitant use of anti-inflammatory agents outside standard indications is discouraged or prohibited to avoid confounding the mechanistic readout of CRP removal.

Operationalizing apheresis in the acute setting requires integration with cath lab and coronary care workflows. The protocol delineates roles for interventional cardiology, perfusion or apheresis nursing, and study coordination to initiate treatment without delaying PCI. Vascular access management is standardized to minimize bleeding risk, and hemodynamic monitoring is intensified during sessions. Device alarms, anticoagulation management during extracorporeal therapy, and troubleshooting algorithms are pre-specified. Post-session, patients are monitored for access-site complications, electrolyte shifts, and procedural adverse events, with clear criteria for escalating care.

Endpoints, safety oversight, and analysis plan

The hierarchy of endpoints prioritizes objective, quantifiable measures that reflect myocardial injury and function. The primary endpoint is designed to capture infarct size by cardiac imaging, typically through contrast-enhanced cardiac magnetic resonance (CMR) or, when CMR is not feasible, a validated surrogate. Imaging is performed within a predefined early window after reperfusion to assess acute necrosis and microvascular obstruction. Secondary endpoints extend to left ventricular ejection fraction, volumes, and myocardial salvage indices, along with serial biomarker kinetics that include CRP, cardiac troponin, and possibly markers of complement activation. Clinical endpoints such as heart failure hospitalization, arrhythmias, reinfarction, and mortality are collected for safety and exploratory analyses but are not positioned as the primary efficacy readouts in this design-and-rationale stage.

Procedural and device-related safety endpoints are central. The protocol tracks adverse events related to extracorporeal circulation, including hypotension, bleeding, access-site complications, citrate effects if present, allergic or hypersensitivity reactions, and unintended depletion of critical plasma proteins. A Data and Safety Monitoring Board (DSMB) reviews unblinded safety data at predefined intervals. Pre-specified stopping rules are based on event rates exceeding acceptable thresholds or on futility boundaries informed by interim assessments of biomarker or imaging surrogates, recognizing that the trial is powered for mechanistic endpoints rather than rare clinical events.

Statistical planning begins with assumptions about the expected difference in infarct size attributable to selective CRP reduction and the variability of imaging measures. These inform sample size calculations, which account for dropout rates due to contraindications to MRI or other practical issues. The primary analysis follows the intention-to-treat principle, preserving randomization benefits. Sensitivity analyses may include per-protocol assessments to account for incomplete apheresis exposure or protocol deviations. Adjustment for covariates such as ischemia time, infarct territory, and success of reperfusion (e.g., TIMI flow or blush grade) are pre-specified to improve precision. Missing data strategies are delineated, favoring methods that align with the presumed data-generating mechanism and avoiding bias in the primary endpoint assessment.

Biomarker kinetics are modeled to capture both the absolute reduction and the area under the curve of CRP exposure following intervention. This provides a quantitative bridge between the mechanistic target and imaging outcomes. The analysis explores correlations between achieved CRP reductions and infarct characteristics, while guarding against overinterpretation by treating such relationships as explanatory rather than confirmatory. Multiplicity adjustments are applied where needed across key secondary endpoints to control type I error. The protocol specifies the statistical software and versioning for reproducibility.

Blinding strategy is adapted to the nature of the intervention. While procedural blinding is not feasible, endpoint adjudication is safeguarded by a blinded core laboratory for imaging and a separate blinded committee for clinical events. Site investigators and treating clinicians manage care per protocol without access to comparative aggregate outcomes. To minimize performance bias, standardized care pathways and checklists aim to equalize co-interventions across arms.

Quality control encompasses site initiation training, procedural competency checks for the apheresis system, and periodic monitoring visits. Source data verification focuses on randomization integrity, timing relative to reperfusion, device parameters, and completeness of endpoint data. Data capture uses an electronic case report form with time-stamped entries for key procedural milestones. Protocol amendments, if any, follow a version-controlled process with ethics approval and communication to sites.

Operational considerations and limitations

Integrating selective CRP apheresis into the hyper-acute care of STEMI introduces logistical challenges. The protocol prioritizes that the intervention must not delay primary PCI; therefore, any apheresis-related steps occur after flow restoration. Coordination between cath lab and apheresis teams is essential to achieve treatment initiation within the intended biological window. Vascular access must balance the need for high flow with bleeding risk in anticoagulated patients. Training and simulation sessions at sites can streamline setup and reduce time-to-therapy variance.

Patient selection seeks to align the intervention with those most likely to benefit mechanistically, such as individuals with anticipated larger infarcts or longer ischemia times, while maintaining generalizability. The protocol may stratify or pre-specify subgroup analyses by infarct territory (e.g., anterior versus non-anterior) or by pre-PCI hemodynamic status. Nevertheless, the trial is not powered for definitive subgroup conclusions; such analyses are exploratory and hypothesis-generating.

Device selectivity is a key consideration. The adsorption column is designed to target pentameric CRP, but off-target binding cannot be entirely excluded. The protocol therefore includes assays to monitor immunoglobulins, complement components, and albumin pre- and post-apheresis to quantify any non-specific depletion. If off-target removal reaches predefined thresholds, mitigation strategies or protocol adjustments can be activated, and such occurrences are logged for safety interpretation.

Imaging feasibility and timing represent another operational constraint. Some patients cannot undergo CMR due to implanted devices, claustrophobia, or instability. The protocol specifies acceptable alternative modalities and adjudication pathways to preserve endpoint integrity without compromising safety. To reduce inter-site variability, imaging protocols are standardized with vendor-neutral parameters, and readers undergo calibration exercises at the core laboratory.

Concomitant therapies introduce potential confounding. For example, high-intensity statins and established antithrombotic regimens have anti-inflammatory properties that may intersect with CRP kinetics. The trial addresses this by protocolizing standard therapies and capturing detailed time-stamped medication data. Timing of blood sampling relative to interventions is harmonized to ensure comparability of biomarker measurements. Additional anti-inflammatory agents outside standard indications are restricted or require pre-approval to preserve the mechanistic signal.

Ethical and regulatory frameworks are explicitly addressed. Informed consent procedures account for the emergent nature of STEMI presentations, accommodating brief consent followed by confirmatory discussions where permitted by local regulations. Institutional review board or ethics committee approvals are in place at each site, and the device has appropriate regulatory clearance for investigational use in the jurisdiction. The DSMB charter defines membership, conflict-of-interest safeguards, and statistical triggers for review.

From a translational perspective, the trial aims to anchor mechanistic plausibility in patient-centered metrics. While infarct size and ventricular function are surrogate outcomes, their quantitative relation to subsequent heart failure and mortality is well established in the literature. Nevertheless, the protocol avoids claims about clinical efficacy and emphasizes that any observed changes in imaging markers would warrant, but not substitute for, larger outcome-focused trials. The design therefore situates selective CRP removal within a stepwise evidence pathway: preclinical rationale, mechanistic trial, then potential expansion to hard outcomes if signals are consistent and safety is acceptable.

Data transparency and reproducibility plans are incorporated. The statistical analysis plan is dated and archived before database lock, and any deviations are documented with justification. The trial considers data sharing in de-identified form after primary analyses, consistent with regulatory and consent constraints, to enable independent methodological scrutiny. Device performance metrics, including column saturation characteristics and treatment duration, are prospectively captured to inform future optimization and to contextualize exposure-response analyses.

Finally, the protocol contemplates practical scalability should the approach prove biologically active and safe. Considerations include required infrastructure, staffing, training, and costs associated with selective apheresis in acute care. The trial captures health resource use during index hospitalization and early follow-up to provide preliminary inputs for future health economic modeling, while acknowledging that robust cost-effectiveness analysis would require outcome data from larger trials.