ABSTRACT
The perioperative management in adult cardiac surgery patients remains highly variable across centres and regions. The APECx study (Anaesthesia, Perfusion and surgical practicEs in Cardiac surgery) aims to describe the incidence of key clinical patient outcomes, map global variation in anaesthesia, perfusion and surgical practices in cardiac surgery, identify potential modifiable factors associated with relevant clinical outcomes, and explore global, socioeconomic and sex‐based differences within these practices. APECx is a prospective multicentre observational study scheduled to start in 2026 that will be conducted in cardiac surgery centres worldwide. Through a modular design, the research focus will evolve over time by going through multiple study phases during a 10‐year period. Participating centres can join or leave each study phase and will be actively recruited over the course of the entire study period. Data collection will occur biannually, including all consecutive eligible cases during two prospectively pre‐specified locally defined consecutive weeks within a 3‐month window. Data will be collected using a web‐based electronic case report form. Collected data will be limited to a clearly delineated minimised dataset. All data are routinely obtained as part of standard clinical care. Overall clinical outcomes include, but are not limited to, intensive care unit (ICU) and hospital length of stay, and in‐hospital mortality with a maximum follow‐up of 30 days. A pilot study will evaluate the feasibility and quantify the workload for participating sites. This study protocol was approved by the Medical Ethics Review Committee of Amsterdam UMC and will be conducted in accordance with local regulations at each participating centre. APECx is a modular, multiphase, large‐scale, international, multicentre cohort study with the potential to contribute to standardised, evidence‐based care worldwide. By minimising site burden, APECx will allow centres with varying amounts of resources from various economies to join. The modular design uniquely positions it to provide a broad overview of global perioperative practices in cardiac surgery, while enabling detailed investigation of specific evidence gaps.
1. Introduction
1.1. Background and Rationale
Adult cardiac surgery encompasses a broad spectrum of procedures, ranging from isolated coronary artery bypass grafting to complex aortic or combined valvular procedures. In‐hospital mortality rates of the cardiac procedures range from < 1% in elective low‐risk procedures to over 17% in high‐risk or emergency settings [1, 2]. Morbidity rates vary between 8% and 42%, depending on patient characteristics and surgical complexity [3, 4]. Although surgical management has evolved over the years, the perioperative management, particularly anaesthetic management, cardiopulmonary bypass (CPB) strategies and surgical techniques, remain highly variable across centres and regions [5].
Although previous studies have described variations in perfusion or surgical practices, a comprehensive, integrated overview of anaesthesia, perfusion and surgical strategies in adult cardiac surgery is lacking [6, 7, 8]. Knowledge gaps in anaesthesia, perfusion and surgical practices limit the development of evidence‐based international guidelines. Over two‐thirds of the recommendations continue to rely on expert opinion, with little change over the past decade [5, 9, 10, 11, 12].
Given the complexity and physiological burden of cardiac surgery, understanding global variation in anaesthetic, perfusion and surgical strategies is critical. To address these knowledge gaps, promote consistent, evidence‐based care and identify potential modifiable factors to improve clinical outcomes, we propose the APECx initiative (Anaesthesia, Perfusion and surgical practicEs in Cardiac surgery).
1.2. Objectives
The objectives of this study are:
To describe the incidence of key clinical outcomes in adult cardiac surgery patients;
To provide a comprehensive overview of anaesthesia, perfusion and surgical practices across the globe;
To identify potentially modifiable perioperative factors that are independently associated with clinical outcomes;
To explore global, socioeconomic and sex‐based differences in these practices.
2. Methods
2.1. Design
APECx is an investigator‐initiated, prospective, international, multicentre, observational study that will collect data on anaesthesia, perfusion and surgical practices in cardiac surgery patients across the globe. It is a long‐term study that will cover multiple phases through a modular design that will be running over a 10‐year period.
2.2. Modular Multiphase Study
APECx has a unique infrastructure, involving a modular design that allows the research focus to evolve over time. The study will proceed through multiple distinct study phases, starting in 2026. Each study phase will focus on a specific perioperative practice in cardiac surgery. A single phase will span approximately 1 year, concluding once the phase‐specific, predefined sample size is reached, at which point the study will transition to the next phase. This framework enables the collection of comprehensive data on specific practices and outcomes within a single, continuously evolving study. To ensure transparency and reproducibility, a detailed phase‐specific study protocol, including phase‐specific objectives, hypotheses, in‐ and exclusion criteria, endpoints, sample size calculations and planned statistical analyses including multiplicity handling, will be registered on ClinicalTrials.gov prior to the start of each study phase. Phase I will focus on anaesthesia management, particularly mechanical ventilation during cardiac surgery. Centres will have the flexibility to join or leave the study at the beginning of each new phase, a design feature intended to lower the threshold for participation.
2.3. Setting
This study will be conducted at cardiac surgery centres worldwide. We aim to enrol a broad spectrum of centres with different levels of research involvement, complexity of surgical interventions, number of surgical interventions per year and geographic location. This inclusive approach aims to capture a globally representative and inclusive dataset.
2.4. Participants
Patients of age 18 years and older undergoing cardiac surgery at a participating centre will be included. Various types of cardiac surgical procedures will be included, ranging from isolated coronary artery bypass grafting to complex heart lung transplantations and adult congenital heart surgery. Transcatheter cardiac or endovascular interventions (e.g., transcatheter aortic valve implantation or thoracic endovascular aortic repair) will be excluded. Each study phase may have additional phase‐specific in‐ and exclusion criteria.
2.5. Patient and Operative Characteristics
A core set of baseline and operative characteristics will be collected throughout the whole study to facilitate risk adjustment. However, individual study phases may include additional datapoints depending on phase‐specific hypotheses and outcomes. The core dataset comprises, but is not limited to: age, sex, height, weight and comorbidities (including cardiac, pulmonary, neurologic, renal, inflammatory, connective tissue, oncologic and hematologic disorders). Furthermore, EuroSCORE II, preoperative creatinine and haemoglobin level, and preoperative left ventricular ejection fraction (LVEF) will be collected. Operative characteristics include the date, type and setting of surgery, redo surgery, the use of minimally invasive techniques and the duration of surgery, cardiopulmonary bypass, aortic cross‐clamp and circulatory arrest.
2.6. Outcomes
Overall study endpoints include a range of clinical outcomes. Each study phase may include additional phase‐specific endpoints tailored to the phase‐specific topic. Core clinical outcomes include, but are not limited to: ICU and hospital length of stay, in‐hospital mortality with a maximum follow‐up of 30 days, duration of mechanical ventilation, perioperative bleeding (defined according to the universal definition of perioperative bleeding [13]), perioperative transfusions (erythrocytes, fresh frozen plasma, thrombocytes in units), postoperative myocardial infarction (defined according to the 4th universal definition of myocardial infarction [14]), postoperative stroke (defined as permanent neurological dysfunction, diagnosed by a neurologist, resulting from focal ischemia of the brain, spinal cord, or retina, caused by an acute infarction of neurological tissue due to thrombosis, embolism, systemic hypoperfusion, or haemorrhage [15]), postoperative atrial fibrillation (defined according to the European Society of Cardiology (ESC) guidelines as new onset atrial fibrillation in the immediate postoperative period [16]), acute kidney injury (defined according to the KDIGO creatinine criteria [17]), need for renal replacement therapy, postoperative pulmonary complications (PPCs; defined as a composite outcome within 5 days postoperative [18]) and need for temporary cardiac mechanical circulatory (e.g., intra‐aortic balloon pump [IABP], Impella) and/or cardiac, respiratory or cardiorespiratory extracorporeal life support (ECLS) modalities.
2.7. Data Collection and Follow‐Up
All data will be prospectively collected by local investigators and entered into Castor (Castor Electronic Data Capture, Amsterdam, the Netherlands), a web‐based electronic Case Report Form (eCRF). It takes approximately 20 min per individual case to complete the eCRF. Data collection will occur biannually, including all consecutive eligible cases during two prospectively pre‐specified locally defined consecutive weeks, within a 3‐month window (Figure 1). Centres with over 200 anticipated inclusions per week may reduce data collection to seven consecutive days to minimise overrepresentation and balance workload across sites. Standardised procedures and monitoring will ensure data quality. Prior to each phase, the scope of data collection is carefully delineated to ensure high‐quality data while minimising workload for participating centres. To assess whether data collection adheres to APECx's fundamental principle of limiting strain on participating sites while maximising data quality, a pilot and feasibility study will be conducted prior to Phase I. The results will be published together with the outlines of the first study phase.
FIGURE 1.
The APECx study design. A graphical overview of the APECx study design. Phase I is planned to start in 2026, followed by subsequent phases. APECx is expected to continue until 2036. Centres can join or leave each study phase. Data collection is designed to minimise workload on‐site while maximising data quality.
Follow‐up will continue for 30 days after the initial cardiac surgery or until hospital discharge, whichever occurs first. Given the inpatient setting, no loss to follow‐up is expected. All data collected will be derived from routine clinical care. No additional measurements or interventions beyond standard care will be performed.
2.8. Sample Size
Prior to each study phase, the required sample size will be calculated based on the phase‐specific objectives, primary outcomes and statistical considerations such as expected event rates and desired power. Adaptive sample size calculations will be implemented, meaning initial sample size calculations may be adjusted based on the observed event rates after each primary data collection period. Detailed sample size justifications and assumptions will be documented and made publicly available through ClinicalTrials.gov.
2.9. Statistical Methods
Before a phase ends, a detailed statistical plan tailored to phase specific outcomes will be published. A broad, overarching statistical plan applicable to all study phases is outlined below.
Descriptive statistics will summarise patient characteristics. Categorical variables will be reported as frequencies and proportions and continuous variables using distribution‐appropriate summary statistics. Appropriate statistical tests will assess baseline imbalances between groups. Simple to more complex prognostic modelling approaches will be used to explore associations between explanatory variables and clinical outcomes. Mixed‐effects models and competing risk analyses will be applied where appropriate. Confounding will be addressed through multivariable adjustment and propensity score methods. Missing data will be handled using the most appropriate methods, based on the type, extent and pattern of missing data. Sensitivity analyses will evaluate the robustness of results to modelling assumptions, missing data handling and subgroup differences. Interaction terms will be included to assess effect modification.
Data analyses will be performed using either R (R Core Team, 2022; R Foundation for Statistical Computing, Vienna, Austria; available at: https://www.R‐project.org) or Python (Python Software Foundation; available at: https://www.python.org).
2.10. Ethics and Dissemination
This study protocol was approved by the Institutional Review Board of the University of Amsterdam, the Netherlands (METc 2025.0597). The APECx initiative is registered at ClinicalTrials.gov (Study Identifier NCT07255924). This study will be conducted in accordance with the locally applicable ethical regulation and informed consent legislation in all participating countries. In The Netherlands a waiver for consent has been obtained, where an opt‐out procedure will be applied.
Handling of personal data will comply with the General Data Protection Regulation. Directly identifying personal data will be separated from the research data and replaced by an assigned code. Directly identifying data will only be used to contact the patients. Access to the assigned codes linked with personal data will be controlled with password protection. The passwords will only be given to directly involved local investigators.
2.11. Phase Design and Governance
Phase‐specific topics are selected through a standardised, inclusive process. Twice yearly, discussion‐based meetings are held to allow all collaborators to provide input on and discuss urgent clinical topics. The Executive and Steering Committees receive advice or obtain input from all collaborators via online meetings that are held twice yearly, research panels, or directly. Final decisions of the topics fall within the responsibility of the Executive and Steering Committees. Once a phase's topic is selected, a phase‐specific Writing Committee is assembled, consisting of a multidisciplinary panel of domain experts. The writing committee is responsible for drafting the phase‐specific protocol, including in‐ and exclusion criteria, hypotheses, objectives, endpoints and the eCRF.
3. Discussion
This manuscript describes the overarching study protocol of the APECx initiative. APECx aims to describe the incidence of clinical outcomes in cardiac surgery patients, to map global anaesthesia, perfusion and surgical practices, to identify potentially modifiable factors independently associated with clinical outcomes, and to explore global, socioeconomic and sex‐based differences within these practices.
The APECx study has several strengths. First, minimal site burden facilitates the inclusion of a broad spectrum of participating centres across diverse healthcare systems worldwide, which strengthens the external validity of future findings. Second, the modular multiphase design allows the investigation of multiple focused research questions without compromising statistical power, methodological transparency, or reproducibility. Third, the study will facilitate a strong multidisciplinary worldwide collaboration in cardiac surgery by integrating surgical, anaesthetic and perfusion practices within a continuously evolving study. Ultimately, this study may shed light on the most pressing questions of both cardiac surgeons, anaesthetists and perfusionists.
There is a clear need for such a platform: more than two‐thirds of recommendations in current guidelines are based on expert opinion, underlining the great amount of evidence gaps currently existing [5, 9, 10, 11, 12]. Due to the majority of recommendations in guidelines being based on expert opinion, substantial practice variations exist. Moreover, a recent study showed these variations are directly associated with increased patient morbidity [19]. Previous large international cohort studies have demonstrated the value of multicentre collaboration in cardiac surgery [20, 21]. While these large‐scale databases are foundational, APECx is designed to build upon their capabilities. These registries serve a different, more static purpose, great for identifying preoperative risk factors and benchmarking, but thereby lacking the flexible granularity to investigate the perioperative process.
APECx addresses these limitations by functioning as a modular data collection framework. It maintains a set of core datapoints for long‐term tracking while incorporating additional, phase‐specific datapoints. This unique, modular multiphase design allows the research focus to evolve over time and investigate critical evidence gaps in detail. Finally, participation in traditional benchmark‐focused databases is resource‐intensive and often unfeasible for centres with limited resources. In contrast, APECx is designed for minimal site burden, utilising locally adapted inclusion periods rather than continuous year‐round tracking, which enables worldwide participation.
The design also has several limitations. First, given the observational nature of the design, causal inferences, with conventional statistical methods, cannot be established. Nonetheless, the findings may provide a foundation for future international studies or large‐scale randomised clinical trials. Second, the use of periodic inclusion periods rather than year‐round data collection introduces potential temporal sampling bias. We mitigate this by incorporating biannual 3‐month data collection windows to ensure the aggregate dataset covers all seasons. Third, fixed two‐week inclusion periods may lead to the overrepresentation of larger centres; therefore, locally adapted inclusion periods will be applied to minimise overrepresentation and balance workload. Fourth, data collection will intentionally be limited to a minimal dataset. This carries a risk of unmeasured confounding; however, all variables will be carefully selected by a panel of field experts to ensure the most significant predictors will be included. Fifth, institutional selection bias may be introduced as centres with a specific interest in cardiac surgery research might be more willing to participate, which should be taken into account when generalising the findings to a broader clinical context.
To conclude, by combining a unique, large‐scale international observational data collection platform with focused, phase‐specific research questions, APECx is well positioned to describe key clinical outcomes, map global practices in cardiac surgery and identify variations that warrant further investigation or standardisation. This dual approach, with minimal burden on participating sites, offers a unique and scalable framework for evidence generation on perioperative practices in cardiac surgery.
Author Contributions
Anne M. Beukers, Nimrat Grewal and David MP van Meenen conceptualised the study. Anne M. Beukers, Nimrat Grewal, David MP van Meenen and Jord C. Seegers designed the study. Jord C. Seegers drafted the manuscript. Anne M. Beukers, Nimrat Grewal and David MP van Meenen supervised the writing process. All authors contributed to the study protocol, critically reviewed and approved the study protocol and final manuscript for publication.
Funding
European Association of Cardiothoracic Anaesthesiology and Intensive Care (EACTAIC) Research Grant 2025 to AM Beukers, on behalf of the APECx Steering Committee.
Conflicts of Interest
The authors declare no conflicts of interest.
Data Availability Statement
Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data sharing not applicable to this article as no datasets were generated or analysed during the current study.