ABSTRACT
Rationale
PCSK9 inhibitors are currently recommended as third-line therapy for post–myocardial infarction (MI) patients, added to high-dose statin, ezetimibe, and potentially bempedoic acid when the LDL-C target of <55 mg/dL is not achieved. These guideline-driven indications result in delayed initiation of PCSK9 inhibitors, potentially missing the opportunity for benefit during the acute phase. Recent studies have demonstrated that early PCSK9 inhibition promotes anti-inflammatory effects and plaque stabilization, suggesting a potential role early in MI management.
Methods
The AMUNDSEN trial is a randomized, international, phase IV study using a PROBE (Prospective Randomized Open, Blinded Endpoint) design to evaluate the effects of early PCSK9 inhibition in high-risk acute MI patients undergoing percutaneous coronary intervention (PCI). A total of 2,166 patients were enrolled, including those with ST-elevation MI undergoing primary PCI and those with non–ST-elevation MI with an indication for PCI, all presenting with at least 1 high-risk clinical characteristic. Patients were randomized to receive either immediate evolocumab prior to PCI alongside standard care or standard care alone. The primary objective is to achieve both a ≥ 50% reduction in LDL-C from baseline and a target LDL-C < 55 mg/dL at 12 months. The main clinical objective is to assess the composite of all-cause death or unplanned hospitalization for a cardiovascular (CV) reason at 12 months.
Current status
Enrollment and randomization are complete. Lipid and clinical follow-up are ongoing. Results from this study will clarify the lipid-lowering efficacy and clinical impact of early evolocumab initiation in the acute MI setting.
Conclusion
The AMUNDSEN trial will provide critical insights into the potential benefits of early PCSK9 inhibition in high-risk MI patients undergoing PCI.
Clinical trial registration
NCT (clinicaltrials.gov): 04951856- EUCT number: 2024-518195-31-00.
AMUNDSEN
Acute myocardial infarction upbound to percutaneous coronary intervention, immediately (STEMI) or in the Next 3 Days (NSTEMI), and randomized to Subcutaneous Evolocumab or Normal strategies to reach guidelines LDL objectives in the real-world
ACS
acute coronary syndrome
APHP
Assistance-Publique des Hôpitaux de Paris
CABG
Coronary artery bypass graft
CEC
Clinical End-point Committee
CI
confidence interval
CV
Cardiovascular
DSMB
Data and Safety Monitoring Board
ESC/EAS
European Society of Cardiology/ European Atherosclerosis Society
ECG
Electrocardiogram
HDL-C
High-density lipoprotein cholesterol
LDL-C
Low-density lipoprotein cholesterol
Lp(a)
Lipoprotein (a)
MI
Myocardial infarction
LVEF
Left ventricular ejection fraction
MACE
Major Adverse Cardiovascular Events
NSTEMI
non-ST segment elevation Myocardial Infarction
PCI
Percutaneous coronary intervention
PCSK9
Proprotein convertase subtilisin/kexin type 9
PET/CT
Positron emission tomography–computed tomography
PP
per-protocol
PROBE
Prospective Randomized Open, Blinded Endpoint
SOC
Standard Of Care
STEMI
ST-segment Elevation Myocardial Infarction
Background
PCSK9 inhibitors are currently recommended as third line therapy in MI patients, following the prior sequential administration of high dose statin at hospital admission, ezetimibe and possibly bempedoic acid to reach the LDL-C target of less than 55 mg/dL. It may take months before a PCSK9 inhibitor is considered in MI patients. On the other hand, advanced imaging technologies used for the evaluation of atherosclerotic plaque volume and vulnerability in MI patients demonstrated that PCSK9 inhibition resulted in significantly greater coronary plaque regression with thicker fibrous cap and a reduced plaque vulnerability in non–infarct-related arteries. , However, these studies were neither designed nor sized to show a long-term control of LDL-C levels or a clinical benefit after the index MI. Interestingly, time to randomization to PCSK9 inhibition or placebo was on average ∼4 days in HUYGENS (The High-Resolution Assessment of Coronary Plaques in a Global Evolocumab Randomized Study) and, <24 hours in PACMAN-AMI (Effects of the PCSK9 Antibody Alirocumab on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction), much earlier than what is currently recommended by guidelines and reimbursed by health care systems worldwide.
Other small size studies have evaluated PCSK9 inhibition during the hospitalization phase of acute MI, showing the rapid decrease of LDL-C but some failed to show a significant impact on systemic markers of thrombosis or inflammation. ,, However, recent randomized, double-blind, placebo-controlled data using PET/CT scan have shown reductions in arterial wall inflammation with PCSK9 inhibitors, while there was no detectable change in plasma inflammatory markers of atherosclerotic patients. PCSK9 inhibition may also favorably impact shear stress/reactive oxygen species, Lp(a) production, platelet aggregation, platelet factor 4 and von Willebrand factor serum levels. AMUNDSEN is the first large scale randomized trial evaluating PCSK9 inhibition in acute MI patients at the time of mechanical reperfusion on top of standard of care (SOC) for lipid management. The goal is to demonstrate a rapid and sustained control of LDL levels and detect the potential clinical benefit of a very early prescription of PCSK9 inhibitor in acute MI undergoing mechanical reperfusion, something not evaluated in the pivotal trials of the currently available PCSK9 inhibitors.
Methods
Study design and population
AMUNDSEN is a randomized, European, phase IV trial using a PROBE (Prospective Randomized Open, Blinded Endpoint) study design presented in Figure 1 . AMUNDSEN aim at recruiting high risk patients with either an ongoing STEMI aged > 55 years (enrichment high risk characteristic) and an indication of primary PCI or, a NSTEMI with a coronary angiogram performed within 72 hours of admission leading to a PCI indication who had at least 1 additional enrichment high-risk characteristic, as indicated in Table 1 . All key inclusion and exclusion criteria are listed in Table 1 . As defined by the ESC/EAS guidelines, the trial population receives statin at maximal tolerated dose, as part of the standard of care. The trial randomized in a 1:1 ratio, 2166 acute MI patients to a strategy of immediate evolocumab treatment with a first injection always given before the start of PCI added on standard of care or, a strategy of standard of care only. In the experimental arm, evolocumab is provided until the end of follow-up i.e. for a minimum of 12 months and a maximum of 36 months. In the 2 groups, the standard of care is applied and all participants are treated according to the 2019 ESC guidelines with all the therapeutic options available in each country. These recommendations are reported in Figure 2 . Importantly, when the LDL-C target is not reached with oral antilipidemic drugs in the control arm, PCSK9 inhibitors can be used according to their indication and reimbursement in each country where it is available.
AMUNDSEN trial design.
CABG, coronary artery bypass graft; cath, catheterisation; FU, follow-up; hrs, hours; LDL-C, low-density lipoprotein-cholesterol; NSTEMI, (non-ST-elevation myocardial infarction; (p)PCI, (primary) percutaneous coronary intervention; Rx, treatment; SOC, standard of care; CV, cardiovascular.
Table 1
AMUNDSEN inclusion and exclusion criteria.
| Inclusion criteria | |
|---|---|
| Type of MI | Type 1 MI, STEMI or NSTEMI, based on the fourth universal definition of MI. |
| STEMI diagnosis | – Symptoms of acute MI for at least 30 minutes AND
Within the previous 24 hours new persistent ST-segment elevation ≥1 mm in ≥2 continuous ECG leads AND – Indication for primary PCI |
| STEMI high-risk characteristic (required) | – Age > 55 years |
| NSTEMI diagnosis | – Age > 18 years
– Chest discomfort or ischemic symptoms for ≥10 minutes at rest within 48 hours prior to entry AND – No persistent ST-segment elevation AND – Elevated troponin ≥ upper limit of normal per local lab AND – Indication for coronary angiogram within 72 hrs with confirmation of PCI indication |
| NSTEMI high-risk characteristics (at least 1 required) | – Diabetes
– Peripheral artery disease – Multivessel (≥2 or LM) disease on coronary angiogram – History of MI or stroke without sequelae – eGFR 15-45 mL/min/1.73 m² calculated by MDRD formula at randomization |
| Statin requirement (for all patients) | – Maximal tolerated statin dose as part of standard care at randomization; first dose given as soon as possible at admission |
| Consent (for all patients) | – Written informed consent obtained |
| Exclusion criteria | |
| Fibrinolysis | – Prior fibrinolysis treatment for the ongoing MI |
| Planned CABG | – CABG scheduled after the angiogram |
| Hemodynamic instability | – Killip Class III or IV
– Sustained/symptomatic hypotension (systolic BP <80 mmHg) – Known LVEF <30% |
| Severe hepatobiliary disease | – Active hepatic dysfunction, biliary obstruction, decompensated cirrhosis, or infectious/inflammatory hepatitis |
| Active malignancy | – Current malignancy |
| Comorbid conditions | – Life expectancy ≤ 12 months |
| PCSK9 inhibitors | – Prior or ongoing treatment with evolocumab or other PCSK9 inhibitors |
| Sensitivity to study products | – Known sensitivity to study products/components |
| Pregnancy/Breastfeeding | – Pregnant, positive pregnancy test, breastfeeding, or planning pregnancy/breastfeeding during treatment and 17 weeks post-treatment |
| Concurrent studies | – Currently enrolled in another investigational device or drug study, or within 30 days of ending treatment in another study |
| Availability | – Likely unable to complete all required study visits or procedures |
Recommendations defining the standard of care for both study groups (2019 ESC guidelines with the therapeutic options available in each country).
Study objectives
The primary objective is to demonstrate the superiority of evolocumab vs standard care in reaching a LDL-C reduction of ≥ 50% from baseline and an LDL-C goal of <1.4 mmol/L (<55 mg/dL) at 12 months follow-up in the overall population.
The main clinical objective is to demonstrate the superiority of evolocumab vs standard care only on the composite endpoint of death or unplanned hospitalization for a cardiovascular reason.
The other prespecified secondary objectives are presented in Supplementary Table 1. A list of exploratory analyses are presented in Supplementary Table 2.
Enrolment and randomization
Patients who fulfilled the inclusion criteria without any exclusion criteria and agreed to participate to the study by signing the inform consent form were randomized using an Interactive Web Response System available via the electronic Case Report Form. Randomization was stratified by center. Patients allocated to the experimental arm received evolocumab (Repatha®) 140 mg every 2 weeks with the first subcutaneous injection at the time of randomization, before PCI. All patients were followed at 6 weeks, 6 months, 9 months, and 12 months and then every 4 months. The duration of follow-up initially 12 months was extended to 36 months by an amendment applicable to all patients who had not terminated the study at the time of this amendment implementation. Thus, the follow-up is 12 months minimum and up to a maximum of 36 months. The study primary endpoint and main clinical endpoint are still evaluated at 12 months. Endpoints at longest follow-up remain exploratory.
Study endpoints
The primary endpoint of the trial is the LDL-C reduction of ≥ 50% from baseline and a final LDL-C of <1.4 mmol/L (<55 mg/dL) at 12 months follow-up. This endpoint considers the LDL-C levels measured at the time of randomization for baseline and at the 12-months follow-up visit. The main clinical endpoint is the composite endpoint of death (any cause) or any unplanned hospitalization for a cardiovascular (CV) reason at 12 months. All clinical events are blindly adjudicated by a clinical event committee (see appendix). Unplanned hospitalization is defined as any hospital admission, including Emergency Room visit without further hospital stay, or day care examination or catheterization without overnight stay which was not scheduled after the index event. The cardiovascular reasons or events leading the patient to seek medical advice are listed in Table 2 .
Table 2
Unplanned hospitalization for cardiovascular reason, list of cardiovascular reasons (blindly adjudicated by the Clinical Event Committee)
| Myocardial infarction (type of MI to be specified [1 to 5, universal definition of MI]) |
| Stroke (type of stroke to be specified) or transient ischemic attack |
| Angina (chronic coronary syndrome) |
| Acute coronary syndrome (if not counted as MI) |
| Coronary angiography |
| PCI |
| CABG |
| Heart failure |
| Supra-ventricular tachycardia, Atrial fibrillation |
| Ventricular tachycardia, ventricular fibrillation |
| Other event deemed as cardiovascular (to be specified) |
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