ABSTRACT
Background
Current guidelines recommend a combination therapy with aspirin and a parenteral anticoagulant in patients with non-ST-elevation myocardial infarction (NSTEMI) prior to invasive assessment. However, these recommendations are based on clinical trials conducted at a time when NSTEMI patients were not routinely assessed invasively. Today, nearly all NSTEMI patients in Denmark undergo coronary angiography within 72 hours, and the necessity of routine anticoagulation remains uncertain. The FOXY trial aims to assess whether aspirin alone is noninferior to a combination therapy with aspirin and fondaparinux in preventing death, recurrent myocardial infarction, and refractory ischemia while lowering the risk of bleeding.
Trial Design
The FOXY trial is a multicenter, open-label, noninferiority, randomized controlled trial enrolling 5,076 patients with NSTEMI. Participants will be randomized 1:1 to receive either aspirin alone or aspirin plus fondaparinux before invasive evaluation. The primary endpoint is a composite of 30-day mortality, recurrent MI, and refractory ischemia. Secondary outcomes include long-term ischemic events, cerebrovascular accidents, left ventricular function, hospital length of stay, and major bleeding. The study will be conducted across multiple cardiology centers, with the first patients enrolled in spring 2025.
Conclusion and Perspective
The FOXY trial is the first study to investigate parenteral anticoagulant use in NSTEMI patients undergoing routine invasive management. By comparing aspirin alone to combination therapy, the study seeks to challenge current guideline recommendations and potentially simplify NSTEMI treatment. If noninferiority is demonstrated, the trial may support a shift toward a safer and more cost-effective management of NSTEMI patients. This could lead to a revision of clinical guidelines, minimizing bleeding risk, improving patient safety, and reducing healthcare costs.
Trial registration
EU Trial Number: 2024-517229-18-00; ClinicalTrials.gov identifier: NCT06710184.
Graphical Abstract
Background
Management and treatment of patients with Non-ST-elevation Myocardial Infarction (NSTEMI) are based on guidelines from the American College of Cardiology/ American Heart Association (ACC/AHA) and the European Society of Cardiology (ESC). , These guidelines advocate for a routine invasive strategy with coronary angiography (CAG) for all NSTEMI patients. , Additionally, aspirin and a parenteral anticoagulant are recommended as part of the initial medical treatment prior to invasive assessment. , In Denmark, fondaparinux is the preferred parenteral anticoagulant. However, the current recommendation for parenteral anticoagulant use is primarily based on clinical trials conducted in the 1980s and 1990s. ,,,,,, A meta-analysis by Eikelboom et al., based on pooled data from these trials, demonstrated that aspirin combined with a parenteral anticoagulant was superior to aspirin alone in reducing the risk of death and recurrent myocardial infarction (MI) within the first 7 days. Notably, this benefit was driven entirely by a reduction in recurrent MI, with no significant difference in mortality. However, the studies included in this meta-analysis were conducted before CAG became a routine part of NSTEMI management. This is particularly evident in the FRISC study (1996), the largest and most recent trial included in the meta-analysis by Eikelboom et al.. In this study, only 0.8% of patients underwent revascularization within 6 days. This differs significantly from current practice, where 96% of NSTEMI patients in Denmark undergo CAG within 72 hours. The shift towards invasive management in NSTEMI patients occurred after 1999, primarily driven by the FRISC II study. This study demonstrated that an invasive strategy reduced recurrent MI and mortality compared to medical management alone, leading to a paradigm shift in NSTEMI treatment. The parenteral anticoagulants used in the studies included in the meta-analysis were unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). The introduction of fondaparinux as a recommended parenteral anticoagulant option was primarily based on the OASIS-5 trial (2006), which compared enoxaparin (LMWH) and fondaparinux in over 20,000 NSTEMI patients. The study demonstrated that fondaparinux was noninferior to enoxaparin in terms of efficacy, while enoxaparin was associated with a higher risk of bleeding, increased long-term mortality, and morbidity.
Objectives and hypotheses
The primary objective is to compare efficacy in patients treated with aspirin alone compared to a combination therapy with fondaparinux and aspirin prior to an early invasive strategy in patients with NSTEMI. The secondary objective is to evaluate and compare the relative bleeding risk associated with aspirin alone compared to aspirin and fondaparinux.
We hypothesize that treatment with aspirin alone is noninferior to a combination therapy with aspirin and fondaparinux in preventing death, recurrent MI, and clinical deterioration resulting in acute CAG within 30 days in NSTEMI patients undergoing an early invasive strategy.
Furthermore, we hypothesize that aspirin alone is superior to a combination therapy regarding bleeding risk, as defined by Bleeding Academic Research Consortium (BARC) ≥3 criteria.
Methods
Study design and organization
The FOXY trial is an investigator-initiated, multicenter, open-label, noninferiority, randomized controlled trial. The trial will be conducted nationwide and will run in 4 out of 5 regions in Denmark (Central Denmark Region, Capital Region of Denmark, Region of Southern Denmark, and North Denmark Region). The Department of Cardiology, Aarhus University Hospital, is the Sponsor of the FOXY trial. Currently, ten departments have agreed to participate in the trial, including the 4 central invasive centers (Aarhus University Hospital, Rigshospitalet, Odense University Hospital, and Aalborg University Hospital) (Supplementary Table I). We plan to include 20 trial sites. The first patients were enrolled at Aarhus University Hospital in May 2025, and enrollment is expected to finalize in fall 2028. Publication of the primary endpoint is expected in the spring of 2029.
Randomization and inclusion
All patients with verified NSTEMI will be screened for inclusion in this trial. Eligible patients, who meet all the inclusion criteria and no exclusion criteria ( Table 1 ), will be invited to participate in the study. The eligible patients will be identified by the treating medical doctor (sub-investigator) to avoid delay in time for randomization and treatment. Patients will be randomized 1:1 to either standard treatment with aspirin in combination with fondaparinux or the experimental therapy with aspirin alone ( Figure 1 ).
Table 1
Inclusion and exclusion criteria
| Inclusion criteria | Exclusion criteria |
|---|---|
| Diagnosis of NSTEMI | Current treatment with anticoagulants |
| Age ≥18 years | CAG and PCI within 72 hours considered not feasible at randomization. |
| Expected remaining lifespan ≥1 year | Unsuitable for CAG and possible PCI due to poor condition |
| Independent capacity to act and provide informed written and oral consent | • Estimated glomerular filtration rate (eGFR) <20 ml/min/1.73m 2 |
| • Known liver disease | |
| • Active bleeding or high risk of bleeding where Fondaparinux is contraindicated | |
| • Anemia (B-Hemoglobin <6.0 mmol/L) | |
| • Pregnancy or breastfeeding | |
| • Endocarditis | |
• Indication for acute CAG before enrolment and randomization, including:
|
NSTEMI, non-ST-elevation myocardial infarction; CAG, coronary angiography; PCI, percutaneous coronary intervention; eGFR, estimated glomerular filtration rate; STEMI, ST-elevation myocardial infarction; ESC, European Society of Cardiology
*Very High Risk NSTEMI defined as: Hemodynamic instability or cardiogenic shock, Recurrent or ongoing chest pain refractory to medical treatment, Acute heart failure presumed secondary to ongoing myocardial ischemia, Life-threatening arrhythmias or cardiac arrest after presentation, Mechanical complications, Recurrent dynamic ECG changes suggestive of ischemia.
Flowchart for patients with NSTEMI included in the study.
Relevant concomitant care and interventions
Permitted:
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1.
Standard care for patients with NSTEMI such as:
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•
Glyceryl nitrate either sublingually or as an infusion
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•
Initiation of treatment for hypertension or hypercholesterolemia
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•
Medication for pain relief, including opioid agonist or paracetamol.
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•
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2.
Computed tomography coronary angiogram (CTCA) as an initial assessment of the coronaries instead of a diagnostic CAG before a possible PCI.
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3.
All patients will follow the routine procedures and tests for NSTEMI patients, which will include ECG, echocardiography, standard blood sample, including repeated measurements of cTN.
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4.
CT scan to exclude differential diagnosis or possible complications
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•
Preferably, the CT-scan for differential diagnostic purposes should be performed before randomization and enrollment.
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•
Patients already receiving treatment with an adenosine diphosphate (ADP) receptor inhibitor will continue this therapy instead of receiving aspirin.
Prohibited:
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1.
Anticoagulant medication not specified in the study protocol.
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2.
Experimental treatments outside of the study protocol.
Procedures during the intervention period
Percutaneous coronary intervention:
The indication for PCI is determined by the treating cardiologist performing the invasive evaluation. CAG and PCI are performed according to current guidelines and best practice, regardless of the intervention group.
Cardiology departments only performing diagnostic CAG/CTCA and not PCI will follow the assigned treatment protocol, and if indication for PCI in these patients, then the assigned treatment will continue until the PCI has been performed.
Early invasive strategy:
In this study, early invasive strategy is defined as CAG or CTCA, with the potential for PCI within 72 hours. This differs slightly from the traditional definition, where early invasive strategy typically refers to CAG with potential PCI within 24 hours. ,
Postinterventional treatment
In the Fondaparinux arm, treatment with Fondaparinux will be discontinued after PCI or if PCI is not indicated. Medical treatment after the invasive evaluation and potential PCI or CABG will follow the national and regional guidelines and will be independent of the assigned intervention group.
The subsequent antithrombotic treatment will be decided by the treating interventional cardiologist.
Follow-up:
No clinical visits are scheduled after discharge. Since fondaparinux will only be administered during hospitalization and until CAG and possible PCI are performed, any side effects are expected to occur within this period. The defined primary endpoints will be collected directly from the patient’s electronic medical records 30 days after enrollment. A registry-based follow-up will be used to assess long-term endpoints.
Endpoints:
Primary endpoint:
The primary endpoint will consist of a composite endpoint of:
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1.
30-day mortality
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2.
30-day recurrent MI
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3.
Clinical deterioration resulting in acute CAG
Clinical deterioration resulting in acute CAG is defined as patients who convert into the “Very High Risk” NSTEMI group, followed by an immediate CAG (within 2 hours) before the scheduled. The definition of “Very High Risk” is from the ESC guideline (2023) and consists of the following clinical presentations:
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1.
Hemodynamic instability or cardiogenic shock
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2.
Recurrent or ongoing chest pain refractory to medical treatment
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3.
Acute heart failure presumed secondary to ongoing myocardial ischemia
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4.
Life-threatening arrhythmias or cardiac arrest after presentation
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5.
Mechanical complications
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6.
Recurrent dynamic ECG changes suggestive of ischemia.
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Particularly intermittent ST-segment elevation changes.
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Primary safety endpoints:
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1.
Incidence of severe bleeding defined as BARC criteria ≥ 3 within 30 days.
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2.
Incidence of ischemic cerebrovascular accident (CVA) within 30 days, including:
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Ischemic Stroke
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Transient ischemic attack (TIA)
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Secondary endpoints:
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1.
Composite of occurrence of death and recurrent MI within 180 days, 1 year, 3 years, 5 years, and 10 years.
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Individual components will also be presented separately.
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•
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2.
Length of hospital stay
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3.
Left ventricular ejection fraction (LVEF) at discharge.
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