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Background
Patients with diabetes mellitus (DM) or aspirin resistance are exposed to recurrent atherothrombotic events after acute coronary syndrome (ACS). Aspirin once-daily can allow the recovery of platelet cyclooxygenase activity before the next intake in these patients. Twice-daily administration provides more stable inhibition of platelet aggregation and may improve prognosis in these patients.
AimTo demonstrate the superiority of twice-daily aspirin compared to once daily in reducing major adverse cardiovascular events (MACE) in patients with DM or aspirin resistance after ACS.
MethodsThe ANDAMAN trial is a randomized, multicenter study including patients (aged ≥18 years) with DM or with aspirin resistance defined as: (1) index event occurring under aspirin; (2) body mass index ≥27 kg/m
The trial will evaluate the prognostic impact of twice-daily aspirin for ACS patients with DM or aspirin resistance and may change the way aspirin is administered to these patients.
Trial registrationClinicalTrials.gov Identifier: NCT02520921.
American and European guidelines recommend once-daily low-dose aspirin in secondary prevention after acute coronary syndrome (ACS). 1 , 2 The benefit of aspirin in treating ACS has been first established by the ISIS-2 (Second International Study of Infarct Survival) study. 3 This randomized clinical trial demonstrated that patients with suspected ACS taking 160 mg of aspirin daily for one month had a 23% reduction in total vascular mortality compared to placebo. These results were confirmed in other trials and a large meta-analysis of 287 studies involving 135,000 patients demonstrating that aspirin treatment was associated with a significant reduction in major cardiovascular events (MACE). 4
In ACS, dual antiplatelet therapy (DAPT) is required as several studies have demonstrated that increasing antiplatelet therapy by adding P2Y12 inhibitors on top of aspirin, especially the most potent (ticagrelor or prasugrel), decreases the rate of subsequent ischemic events after ACS. 2 , 5 , 6 Although DAPT reduces the incidence of atherothrombotic recurrences, patients with DM or aspirin resistance are still at high risk within the first year after ACS 7–11 and every effort must be made to optimize antiplatelet treatment in these patients.
An option could be the way aspirin is administered to these patients. Indeed, an increasing literature has addressed the issue of “aspirin resistance.” 12-14 Definition of aspirin resistance varies widely, some are based on clinical events (failure to aspirin to prevent clinical atherothrombotic events), others on laboratory parameters assessing the effect of aspirin on the reduction of thromboxane A2 production by platelets. The prevalence of aspirin resistance is highly variable from 5% to 60% according to the different studies and definitions. 15 , 16 The aspirin resistance (inability of aspirin to reduce platelet activation and aggregation) is due to the pharmacokinetics and pharmacodynamics of aspirin. Once-daily aspirin is usually enough in healthy controls or stable patients to achieve complete inhibition of thromboxane A2 synthesis ( Figure 1 A). 17 , 18 However, our working group and others have demonstrated that the effect of once-daily aspirin may not be sufficiently stable over 24 hours in specific subgroups. 19 In some patients, thromboxane inhibition is insufficient, and the ability to synthesize thromboxane may be restored less than 24 hours before the next dose ( Figure 1B). 20 , 21 These findings were particularly significant in patients with DM or aspirin resistance. 12 , 19 , 22–25
To resolve the interindividual variability under once-daily aspirin, a simple option is the administration of aspirin twice a day ( Figure 1C). Our working group have previously demonstrated that twice-daily aspirin offers a better cyclooxygenase 1 (COX-1) inhibition during 24 hours in several patients with aspirin resistance, including those with DM. 25-28 Then, we can assume that twice-daily aspirin could be an efficient treatment after ACS for these patients with aspirin resistance.
Therefore, the ANDAMAN (Aspirin with a Novel twice-a-day administration in patients with Diabetes mellitus or aspirin resistance after Acute coronary syndrome to Minimize recurrence of Acute ischemic events or New urgent revascularization) trial will aim to demonstrate the superiority of twice-daily low-dose aspirin compared to once-daily aspirin to reduce MACE in patients with DM or aspirin resistance after ACS.
Material and methods Study designThe ANDAMAN trial is a PROBE (Prospective, Randomized, Open-label, Blinded Endpoint) study and the design is shown in Figure 2 . Patients will be enrolled in 39 preselected centers in France. The list of participating centers is provided in Supplementary File 2. All centers are staffed with trained and experienced professionals, fully equipped to care for ACS patients and perform primary percutaneous interventions (PCI) 24 hours a day. The study is approved by the Ethics Committee (Committee for the Protection of Human Subjects, Ile de France-X, France). Written informed consent will be obtained from all participants. Anonymized data supporting the findings of this study will be collected using CleanWeb software and will be available from the corresponding author upon reasonable request. The trial is registered on the Clinicaltrials.gov website: https://clinicaltrials.gov under the number NCT02520921 and on the EU Clinical Trials Register (EudraCT2015-000947-18). All authors and investigators of this trial have read and approved the manuscript as written.
Study populationPatients aged 18 years or older with DM (type 1 or type 2) or with aspirin resistance admitted to intensive cardiac care unit for ACS will be eligible for inclusion. Main inclusion criteria are presented in Table 1 . Briefly, patients with ACS with ST-segment elevation (STEMI) or without ST-segment elevation (NSTEMI), and with a coronary angiography showing at least one coronary stenosis ≥50% will be eligible. Diabetes mellitus (type 1 or type 2) at enrolment will be defined using the American Diabetes Association (ADA) definition 29 as one of the following: (1) hemoglobin A1c (HbA1c) ≥6.5%; or (2) two fasting plasma glucose ≥7 mmol/L; or (3) plasma glucose ≥ 11 mmol/L any time during hospitalization; or (4) treated diabetes mellitus. Aspirin resistance in patients without DM will be defined as (1) index event occurring under chronic low-dose of aspirin (<300 mg); (2) obesity defined as body mass index ≥27 kg/m 2; (3) waist circumference ≥88 cm for women or ≥102 cm for men. Exclusion criteria are listed in Table 2 . Main exclusion criteria will be essentially unstable patients and patients with a contraindication to aspirin or at high risk of bleeding (ie, allergy to aspirin, chronic anticoagulation, previous bleeding).
Randomization and intervention with study drugPatients who meet the inclusion criteria without exclusion criteria and agree to participate in the trial will be randomized using an Interactive Web Response System available via the electronic Case Report Form. Randomization will be stratified by center, clinical presentation (STEMI or NSTEMI) and ADP inhibitor (prasugrel, ticagrelor or clopidogrel), and will be performed in blocks to ensure balanced distribution of treatment groups. Patients will receive twice-daily or once-daily aspirin in a 1:1 ratio before hospital discharge. Acetyl salicylic acid is enteric-coated aspirin (Aspirin protect, Bayer) for all patients in both randomization arms. Patients will be assigned to receive twice-daily low-dose aspirin (experimental arm, 100 mg in the morning and 100 mg in the evening) vs once-daily aspirin (control group, 100 mg in the morning). The management of each patient will be at the discretion of the treating physicians following the current European Society of Cardiology guidelines and the recommended default strategy of dual antiplatelet therapy will be 12 months after ACS. 2 As Proton pump inhibitors reduce the risk of upper gastroduodenal bleeding in patients treated with antiplatelet agents, widespread use of proton pump inhibitors was recommended.
Study endpoints and follow-upThe primary composite endpoint will be the rate of MACE defined as the first event of all-cause death, nonfatal MI including stent thrombosis, stroke, urgent coronary revascularization, or acute arterial thrombotic event (i.e. acute limb ischemia) over 18 months of follow-up. The main secondary (safety) endpoint will be the rate of Bleeding Academic Research Consortium (BARC) type 3 to 5 bleeding. 30 Definitions of the different endpoints are provided in the Supplementary File 3. Other secondary endpoints, assessed using time-to-first-event analyses, will include a composite of death, nonfatal MI and nonfatal stroke and a net clinical benefit (combining the primary ischemic endpoint and the main secondary endpoint). All secondary endpoints are listed in the Supplementary File 4. All patients will be followed at 1, 6, 12 months and the final visit occurred at 18 months. On each visit, ischemic endpoints and bleeding will be collected. Patient adherence to the study drug will be assessed, and temporary cessation or discontinuation of aspirin will be collected. If aspirin is interrupted, it will be recommended to restart treatment according to the randomization arm whenever possible. Drug adherence will be evaluated by indirect methods, which include patient self-reporting and pill counts. Additional visits will be at the discretion of attending physicians. When a patient will not show up for a scheduled visit, an investigator or research coordinator will contact the patient via telephone to quickly reschedule the visit to minimize the risk of underreporting clinical events.
Sample size calculationAccording to the literature, in the PLATO trial 6, the rate of MACE at one year in patients with DM is 16.2% in the group of patients treated with clopidogrel, and 14.1% in the group of patients treated with ticagrelor corresponding to a relative risk reduction of 13%. In TRITON trial 5, the rate of MACE at 450 days in patients with DM is 17.2% in the arm treated with clopidogrel and 12.2% in the arm treated with prasugrel corresponding to a relative risk reduction of 30%.
In the ANDAMAN trial, we will assume an event rate of 22% at 18 months for the MACE in the group of patients with DM or aspirin resistance treated with once-daily aspirin which includes 18% of death, MI or stroke and adding 4% of urgent coronary revascularization or acute arterial thrombotic event. We will expect a relative risk reduction of the MACE of 20% in the experimental arm. Therefore, we calculate that we will need a total of 2,574 patients (1,287 patients per group) to be included in the trial, allowing 80% power to detect this difference using a log-rank test at a 2-sided 5% significance level. No interim analysis will be performed.
Statistical analysisThe main efficacy analysis will be based on all events that occurred in the intention to treat population defined as all randomized patients who have signed an informed consent form. In case of consent withdrawal, only data collected before withdrawal will be used. The primary analysis on the primary endpoint will be carried out using a Cox model for survival analysis with stratification factors of the randomization as covariables. The 95% confidence interval of the adjusted hazard ratio will be presented. Survival status during 18 months of follow-up will be described by showing Kaplan–Meier curves. The reference date is defined as the randomization date. The date of the event corresponding to a composite endpoint is the date corresponding to the first event occurred. In case of missing information on the date of an event, the date considered will correspond to the middle of the time interval between the 2 visits adjacent to the event. Patients lost to follow-up before 18 months will be censored at the time of the last available information. A sensitivity analysis will be performed using a censoring not at random approach using the control-based Cox model. This approach is a jump-to-reference model that will assume that censored subjects on the twice-daily low-dose aspirin arm follow the same distribution as similar subjects in the once-daily group after the censored time.
All tests will be 2-sided at 5% level. In order to avoid inflation of alpha risk, a hierarchical procedure of test will be used for efficacy criteria. Secondary criteria will be tested only if a significant difference is found for the primary criteria
Statistical test on the n + 1th criterion of the list below will be performed only if the test of the n th criterion is significant: (1) A composite end point based of the first occurrence of one of the following events: death; nonfatal MI; nonfatal stroke, (2) Cardiac endpoint: cardiovascular death; nonfatal MI, (3) Net clinical benefit defined as a composite end point based of the first occurrence of one of the following events: death (any); nonfatal MI; stroke; urgent coronary revascularization and/or stent thrombosis; acute arterial thrombotic event; major bleeding (type 3-5 BARC classification), (4) Urgent coronary revascularization, or acute arterial thrombotic event, (5) Nonfatal MI including stent thrombosis, (6) Stroke, (7) All cause death. In any case values of adjusted hazard ratio with associated 95% CI will be calculated.
In addition, an explanatory analysis (per protocol) of all patients randomized and treated without major protocol violations/deviations will be carried out. Predefined major protocol violations/deviations are: (1) missing data for the primary efficacy endpoint; (2) inclusion in another clinical study; and iii) major violations defined at the blinded data review meeting.
Predefined subgroup of patients and ancillary studiesAn exploratory analysis on the primary endpoint including the first event and the recurrent events of the primary endpoint (recurrent event analysis) will be carried out using a negative binomial regression model for recurrent events analysis. Several predefined subgroups have been planned and will be analyzed for the primary and secondary endpoints to assess the homogeneity of results: patients with STEMI, patients with NSTEMI, elderly (≥75 years old) patients, males vs females, patients with DM vs those with aspirin resistance, patients with DM with insulin vs no insulin, type of ADP inhibitor, no revascularization vs PCI or CABG. All prespecified subgroups are listed in Supplementary File 4. Moreover, a landmark analysis will be performed with discontinuation of the P2Y12 antagonist as the time endpoint and only those subjects who have survived until the landmark time will be analyzed until the end of the follow-up.
StatusThe first patient was randomized on July 6, 2016, and enrollment was concluded on December 31, 2022. The recruitment was slowed down in particular due to the COVID outbreak and the first lock-down in France. The follow-up of all patients is completed. Data monitoring in all centers is currently underway, and the database is due to be closed in April 2025. Results are expected during the second semester of 2025.
Funding and responsibilitiesThis trial is an investigator-initiated study supported by the ACTION group and funded by the French ministry of Health (PHRC) and unrestricted grants from Bayer France and Biosensors. Enteric-coated aspirin will be furnished by Bayer France using commercial pills. The trial will be led by the Study Chairman (Prof. Patrick Henry) and the Study Scientific Director (Prof. Jean-Guillaume Dillinger) assisted by the steering committee responsible for the medical, scientific, and operational conduct of the study (Supplementary File 5). The clinical endpoint committee, composed of independent members not involved in the trial, will review and adjudicate the outcomes during follow-up according to the prespecified definitions, and using source document, imaging data, biomarker measurements, and any other relevant medical document. The authors will be solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper and its final contents. The trial will be performed in accordance with the ethical principles that have been laid down in the Declaration of Helsinki and that are consistent with the International Conference on Harmonization/Good Clinical Practice and applicable regulatory requirements. Assistance Publique – Hôpitaux de Paris (AP-HP) will be the sponsor of this research and by delegation, the Clinical Research and Development Department (DRCD) carries out the research's missions in accordance with Article L.1121-1 of the French Public Health Code.
Discussion The ANDAMAN objectivesThe ANDAMAN trial will be conducted to demonstrate the superiority of twice-daily aspirin compared to once-daily aspirin to reduce MACE in patients with DM or aspirin resistance during a follow-up of 18 months after ACS. This trial will be the first to evaluate the clinical impact of twice vs once-daily low-dose aspirin to overcome biological resistance in patients particularly exposed to it.
Rationale for twice-daily aspirinIn 1971, Sir John Vane discovered that inhibition of prostaglandin synthesis explains the main pharmacological effects of aspirin. 31 Fifty years later, aspirin remains the leading antiplatelet drug in cardiovascular secondary prevention. 32 However, in the 2000s, the concept of aspirin resistance defined as the occurrence of an ischemic event despite chronic low-dose of aspirin 12 , 33 , 34 allowed us to better understand pharmacokinetics and pharmacodynamics of aspirin. During 4 hours after aspirin intake, a complete and definitive inhibition of platelets COX-1 activity and a subsequent inhibition of thromboxane A2 synthesis induce a decrease in platelet aggregation. 12 , 13 Recovery of platelet aggregation depends on the generation of new platelets capable of COX-1 activity allowing a recovery of platelet aggregation usually within 48 to 72 h after aspirin intake. 13 Once daily low-dose of aspirin is usually enough in most patients to achieve complete inhibition of thromboxane A2 synthesis. However, our group and others have demonstrated that the effect of once-daily aspirin may be insufficiently effective over 24 hours, and some patients have the ability to synthesize thromboxane A2 in less than 24 hours before the next aspirin intake. 20 , 21 , 32 The interindividual variability in responsiveness to low-dose aspirin is more frequent in patients with DM or those with obesity. 22 , 23 , 35 , 36
Thus, twice-daily aspirin is an attractive and simple option to obtain a better COX-1 inhibition over 24 hours. 26–28 While this solution is effective in inhibiting platelets when measuring thromboxane A2 concentration or platelet aggregation, it has not yet been evaluated on clinical ischemic events. In the current trial, we will use the lowest doses of aspirin recommended in the guidelines (75 mg-100 mg) once or twice-daily. In the experimental arm, patients will receive twice-daily aspirin, with a total cumulative dose of 200 mg, which can also impact aspirin efficacy in patients with increased body weight, as previously described. 35 , 37 These 2 reasons explain the design of the study and the strategy of the experimental arm. However, the addition of a P2Y12 antagonist can reduce the impact of aspirin twice daily to reduce aspirin resistance. For this reason, the study design includes an 18-month follow-up to measure a possible rebound effect due to aspirin resistance when P2Y12 is stopped.
Of note, a higher dose of aspirin may expose patients to an increased risk of bleeding, particularly peptic ulcer bleeding 38 , 39 but recent studies show that there was no significant differences in the safety of 2 aspirin doses (81mg vs 325mg). 40 , 41 However, the trial is designed with a key safety endpoint, which will include the BARC type 3-5 bleeding to carefully assess this issue.
Population of the studyPatients with DM or with aspirin resistance still have a significant higher rate of ischemic events after ACS compared to nondiabetic patients despite the use of new antiplatelet agents (ticagrelor or prasugrel). In the PLATO trial 10, in the ticagrelor arm, patients with DM remained with an excess risk of ischemic events of 68% compared to nondiabetic patients (14.1% vs 8.4%; P < .001). In the TRITON trial 9, in the prasugrel arm, patients with DM remained with an excess risk of ischemic events of 33% compared to nondiabetic (12.2% vs 9.2%). These results are confirmed in most recent trials as the BIOVASC study 42 which found an excess of ischemic events in patients with DM (10.8% vs 7.5%; P = .04). Moreover, metabolic syndrome is also a strong independent predictor of mortality and morbidity in patients with nonclinically diagnosed DM with ACS. 43 Several pathophysiological mechanisms are involved in patients with DM or aspirin resistance as extensive atherosclerosis 44 associated with accelerated platelet turn-over 23 or high platelet reactivity. 45 Obesity and metabolic syndrome are associated with low grade inflammatory syndrome and accelerated platelet turn-over 46 and several studies have shown that this population have impaired response to aspirin. 37 , 46 , 47 In the current study, aspirin resistance will correspond to therapeutic failure of aspirin to prevent atherothrombotic events and will be defined using known factors of aspirin resistance 15 , 36 , 37 but without using platelet function tests. 48
Endpoints of the studyThe primary endpoint of this trial will be the rate of MACE including coronary related endpoints, stroke but also acute arterial thrombotic event (i.e. acute limb ischemia) which is frequent in patients with DM or aspirin resistance. 44 , 49 , 50 Regarding the safety endpoint, bleeding is always a concern in patients treated by aspirin. 4 , 51 In the experimental arm, we cannot exclude that higher dose of aspirin, even if split twice-daily, will increase the risk of bleeding. For this reason, we will plan a main secondary endpoint defined as bleeding using BARC classification (type 3 to 5). Bleeding will also be classified according to ISTH and TIMI classifications. Finally, the net benefit of the experimental strategy, including both efficacy and safety events, will be presented.
LimitationsFirst, our trial will be open label; patients and physicians will be informed of the randomization arm. However, we believe that the PROBE design using a blinded adjudication of well-defined endpoints will be an acceptable approach for this type of study hypothesis. Moreover, the open label design will test the feasibility of twice-daily aspirin for patients as chronic twice-daily aspirin could induce poorer adherence compared to once-daily aspirin. A blind study could not assess the impact of twice-daily aspirin administration on compliance in the experimental group. Of note, in the current trial, compliance during 18-month follow-up will be evaluated in each group (question on every visit). Secondly, the study will include patients with ACS with at least one significant coronary stenosis. The study cannot be extrapolated to all ACS, such as myocardial infarction with nonobstructive coronary disease. This choice is made to include patients with coronary atheroma and not to include patients with myocarditis or coronary dissection, for example. Thirdly, in the current study, aspirin resistance will not be determined by laboratory tests of platelet thromboxane A2 production or platelet function. Indeed, we know that “biological” aspirin resistance can evolve over time and according to clinical circumstances. We have chosen to use a clinical definition that corresponds to therapeutic failure of aspirin (ie, failure to aspirin to prevent clinical atherothrombotic events) and adding known factors of aspirin resistance (DM, increased BMI or waist circumference). Fourthly, the use of more potent P2Y12 antagonists (ie, ticagrelor or prasugrel) may have a potential impact on the results of the study decreasing the potential effect of aspirin twice daily. Randomization will be stratified by P2Y12 antagonists (prasugrel, ticagrelor or clopidogrel) and a prespecified analysis will be performed based on the different P2Y12 antagonists. Similarly, concomitant anticoagulation therapy could potentially affect the power of the study. This is an exclusion criterion, but it is important to anticipate that some patients will receive an anticoagulant during their follow-up in the study. Finally, aspirin used in the trial will be enteric-coated aspirin 100 mg and the results of the trial cannot be extrapolated to patients treated by uncoated aspirin even if no clinical difference has yet been demonstrated between the 2 aspirin formulations. 52
ConclusionThe ANDAMAN trial will evaluate with a PROBE study design, the superiority of twice-daily aspirin compared to once-daily aspirin in reducing major ischemic cardiac events in patients with DM or aspirin resistance after ACS. The results of this trial may have an impact on future recommendations for antiplatelet treatment in these patients after ACS.
FundingThis trial is funded by the French ministry of Health (PHRC) and unrestricted grants from Bayer France and Biosensors. Enteric-coated aspirin will be furnished by Bayer France using commercial pills.
CRediT authorship contribution statementJean-Guillaume Dillinger: Writing – original draft, Supervision, Investigation, Funding acquisition, Conceptualization. Théo Pezel: Writing – original draft, Supervision, Investigation, Conceptualization. Laure Batias: Writing – review & editing, Investigation. Denis Angoulvant: Writing – review & editing, Investigation. Marc Goralski: Writing – review & editing, Investigation. Emile Ferrari: Writing – review & editing, Investigation. Guillaume Cayla: Writing – review & editing, Investigation. Johanne Silvain: Writing – review & editing, Investigation. Martine Gilard: Writing – review & editing, Investigation. Gilles Lemesle: Writing – review & editing, Investigation. Géraud Souteyrand: Writing – review & editing, Investigation. Pascal Lim: Writing – review & editing, Investigation. François Roubille: Writing – review & editing, Investigation. Jean-Louis Georges: Writing – review & editing, Investigation. Claire Bal dit Sollier: Writing – original draft, Conceptualization. Thibaut Petroni: Writing – review & editing, Investigation. Olivier Morel: Writing – review & editing, Investigation. Nicolas Delarche: Writing – review & editing, Investigation. Meier Elbaz: Writing – review & editing, Investigation. Etienne Puymirat: Writing – review & editing, Investigation. Solenn Toupin: Writing – review & editing, Supervision, Project administration, Methodology. Gilles Montalescot: Writing – review & editing, Resources, Methodology, Investigation. Ludovic Drouet: Writing – review & editing, Supervision, Conceptualization. Eric Vicaut: Writing – review & editing, Resources, Methodology, Funding acquisition, Conceptualization. Patrick Henry: Writing – original draft, Supervision, Investigation, Funding acquisition, Conceptualization.
Conflicts of interestJean-Guillaume Dillinger reports receiving consulting and lecture fees from AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb/Pfizer, Sanofi, and grants from Bayer, Bristol-Myers Squibb/Pfizer and Biosensors. Théo Pezel reports receiving consulting and lecture fees from AstraZeneca, Bayer, Bristol-Myers Squibb/Pfizer, General Electric and grants from Bayer and Servier. Laure Batias reports receiving consulting and lecture fees from Novartis and Pfizer.
Denis Angoulvant reports having received payment or honoraria for lectures, presentations, speakers bureaus or educational events in the last 3 years from Amgen, Alnylam, Amarin, Astra Zeneca, Boehringer, BMS, Bouchara Recordati, Pfizer, Novartis, Novo Nordisk, Organon, Sanofi, Servier, Vifor. Marc Goralski reports no disclosure. Emile FERRARI reports research grants from Amgen, Astra Zeneca, Bayer, Sanofi-Aventis. Guillaume CAYLA reports research grants/consultant fees/lectures fees from Amgen, AstraZeneca, Abbott, Bayer, Biotronik, Bristol-Myers Squibb, Edwards, Microport, Medtronic, Pfizer, Sanofi-Aventis. Johanne SILVAIN reports consulting fees/lectures Abbott Medical France SAS, Biotronik France SAS, CSL Behring SA, Sanofi-Aventis France; travel support hospitality from Abbott Medical France SAS, Biotronik France SAS, Medtronic international trading SARL, Novo-Nordisk; Stockholder of 4P-Pharma.
Martine Gilard reports no disclosure. Gilles Lemesle reports honoraria/fees from Alnylam, Amarin, Amgen, Astra Zeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Boston, MSD, Novartis, Novo-Nordisk, Organon, Pfizer, Sanofi Aventis. Géraud Souteyrand reports honoraria/fees from Abbott, Boston, B Braun, Medtronic, Terumo. Pascal Lim reports no disclosure. François Roubille reports honoraria/fees from Astra Zeneca, Servier, Boehringer, Astra Zeneca, Vifor, Bayer, Pfizer, Novartis, Servier, Novonordisk, Air liquid, Abbott, QuidelOrtho, Newcard, MSD, BMS, Sanofi, Alnylam, Zoll, Implicity, GSK, BMS. Jean-Louis Georges reports honoraria/fees from Novartis, Sanofi-Aventis France, MSD, Lilly
Claire Bal dit Sollier reports no disclosure. Thibaut Petroni reports no disclosure
Olivier Morel reports no disclosure. Nicolas Delarche reports grants/consultant fees from Medtronic, Novo-Nordisk. Meier Elbaz reports no disclosure. Etienne Puymirat reports fees for lectures and/or consulting: Amgen, Astra-Zeneca, Bayer, Biotronik, BMS, Boehringer Ingelheim, Daiichi-Sankyo, Lilly, MSD, The Medicine Company, Sanofi, Saint Jude Medical, Servier, Siemens. Solenn Toupin reports no disclosure. Gilles MONTALESCOT research grants/consultant fees/lectures fees from Abbott, Amgen, AstraZeneca, Axis, Bayer, BMS, Boehringer-Ingelheim, Boston-Scientific, Cell Prothera, CSL Behring, Idorsia, Leo-Pharma, Lilly, Medtronic, Novartis, Pfizer, Quantum Genomics, Sanofi, Terumo. Ludovic Drouet reports no disclosure. Eric VICAUT reports consulting or speaker fees from Abbott, Bristol Myers Squibb, Celgene, Edwards, Pfizer, Sanofi and Novartis. Patrick Henry reports receiving consulting and lecture fees from AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb/Pfizer, Sanofi, and Daiichi-Sankyo and grants from Bayer, Bristol-Myers Squibb/Pfizer and Biosensors.
AcknowledgmentsThe authors would like to thank all the investigators of the centers for agreeing to participate in this trial and the team of the “Unité de Recherche Clinique Fernand-Widal”, in particular Julie BUSSONE, Claudia DANCIU, Candy ESTEVEZ for their help in the design and implementation of this trial. Special thanks to Nadhira BENNACER for her support at the Lariboisière center, Alain Gay and Ingrid Billaut from Bayer for their logistical help.
Supplementary materialsSupplementary material associated with this article can be found, in the online version, at doi:10.1016/j.ahj.2025.04.016.
Appendix Supplementary materialsImage, application 1 Image, application 2 Image, application 3
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©2025. The Author(s)