Biomarker-based prediction of sinus rhythm in atrial fibrillation patients: the EAST-AFNET 4 biomolecule study.

BACKGROUND AND AIMS: In patients with atrial fibrillation (AF), recurrent AF and sinus rhythm during follow-up are determined by interactions between cardiovascular disease processes and rhythm-control therapy. Predictors of attaining sinus rhythm at follow-up are not well known. METHODS: To quantify the interaction between cardiovascular disease processes and rhythm outcomes, 14 biomarkers reflecting AF-related cardiovascular disease processes in 1586 patients in the EAST-AFNET 4 biomolecule study (71 years old, 46% women) were quantified at baseline. Mixed logistic regression models including clinical features were constructed for each biomarker. Biomarkers were interrogated for interaction with early rhythm control. Outcome was sinus rhythm at 12 months. Results were validated at 24 months and in external datasets. RESULTS: Higher baseline concentrations of three biomarkers were independently associated with a lower chance of sinus rhythm at 12 months: angiopoietin 2 (ANGPT2) (odds ratio [OR] 0.76 [95% confidence interval 0.65-0.89], p=0.001), bone morphogenetic protein 10 (BMP10) (OR 0.83 [0.71-0.97], p=0.017) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (OR 0.73 [0.60-0.88], p=0.001). Analysis of rhythm at 24 months confirmed the results. Early rhythm control interacted with the predictive potential of NT-proBNP (pinteraction=0.033). The predictive effect of NT-proBNP was reduced in patients randomized to early rhythm control (usual care: OR 0.64 [0.51-0.80], p<0.001; early rhythm control: OR 0.90 [0.69-1.18], p=0.453). External validation confirmed that low concentrations of ANGPT2, BMP10 and NT-proBNP predict sinus rhythm during follow-up. CONCLUSIONS: Low concentrations of ANGPT2, BMP10 and NT-proBNP identify patients with AF who are likely to attain sinus rhythm during follow-up. The predictive ability of NT-proBNP is attenuated in patients receiving rhythm control.

One-year outcomes of rate versus rhythm control of atrial fibrillation in the Kerala-AF Registry.

Background: There is ongoing debate around rate versus rhythm control strategies for managing atrial fibrillation (AF), however, much of the data comes from Western cohorts. Kerala-AF represents the largest prospective AF cohort study from the Indian subcontinent. Objectives: To compare 12-month outcomes between rate and rhythm control strategies. Methods: Patients aged ≥18 years with non-transient AF were recruited from 53 hospitals across Kerala. Patients were stratified by rate or rhythm control. The primary outcome was a composite of all-cause mortality, arterial thromboembolism, acute coronary syndrome or hospitalization due to heart failure or arrhythmia at 12 months. Secondary outcomes included bleeding events and individual components of the primary. Predictors of the composite outcome were analysed by logistic regression. Results: A total of 2901 patients (mean age 64.6 years, 51% female) were included (2464 rate control, 437 rhythm control). Rates of the primary composite outcome did not differ between groups (29.7% vs 30.0%; p = .955), nor did any component of the primary. Bleeding outcomes were also similar (1.6% vs 1.9%; p = .848). Independent predictors of the primary composite outcome were older age (aOR 1.01; p = .013), BMI <18 (aOR 1.51; p = .025), permanent AF (aOR 0.78; p = .010), HFpEF (aOR 1.40; p = .023), HFrEF (aOR 1.39; p = .004), chronic kidney disease (aOR 1.36; p < .001), and prior thromboembolism (aOR 1.31; p = .014). Conclusion: In the Kerala-AF registry, 12-month outcomes did not differ between rate and rhythm control cohorts.

Catheter ablation for atrial fibrillation and impact on clinical outcomes.

Aims: Catheter ablation is the most effective rhythm-control option in patients with atrial fibrillation (AF) and is currently considered an option mainly for improving symptoms. We aimed to assess the impact of catheter ablation on hard clinical outcomes. Methods and results: We performed a systematic review of randomized controlled trials (RCTs) comparing catheter ablation vs. optimized medical treatment. We searched MEDLINE, EMBASE, and CENTRAL on 8 January 2024, for trials published ≤10 years. We pooled data through risk ratio (RR) and mean differences (MDs), with 95% confidence interval (CI), and calculated the number needed to treat (NNT). Sub-group and sensitivity analyses were performed for the presence/absence of heart failure (HF), paroxysmal/persistent AF, early ablation, higher/lower quality, and published ≤5 vs. >5 years. Twenty-two RCTs were identified, including 6400 patients followed for 6-52 months. All primary endpoints were significantly reduced by catheter ablation vs. medical management: all-cause hospitalization (RR = 0.57, 95% CI 0.39-0.85, P = 0.006), AF relapse (RR = 0.48, 95% CI 0.39-0.58, P < 0.00001), and all-cause mortality (RR = 0.69, 95% CI 0.56-0.86, P = 0.0007, NNT = 44.7, driven by trials with HF patients). A benefit was also demonstrated for all secondary endpoints: cardiovascular mortality (RR = 0.55, 95% CI 0.34-0.87), cardiovascular (RR = 0.83, 95% CI 0.71-0.96), and HF hospitalizations (RR = 0.71, 95% CI 0.56-0.89), AF burden (MD = 20.6%, 95% CI 5.6-35.5), left ventricular ejection fraction (LVEF) recovery (MD = 5.7%, 95% CI 3.5-7.9), and quality of life (MLHFQ, AFEQT, and SF-36 scales). Conclusion: Catheter ablation significantly reduced hospitalizations, AF burden, and relapse, and improved quality of life. An impact on hard clinical outcomes, with an important mortality reduction and improvement in LVEF, was seen for patients with AF and HF.

A Systematic Review of Ongoing Registered Research Studies on Post-Operative Atrial Fibrillation after Cardiac Surgery.

Background/Objectives: New-onset atrial fibrillation (AF) after cardiac surgery is associated with patient-important outcomes. Uncertainty persists regarding its prevention, detection, and management. This review seeks to identify, compile, and describe ongoing registered research studies involving patients with or at risk for post-operative AF (POAF) after cardiac surgery. Methods: We searched clinical trial registries in January 2023 for studies focusing on POAF prediction, prevention, detection, or management. We extracted data from each record and performed descriptive analyses. Results: In total, 121 studies met the eligibility criteria, including 82 randomized trials. Prevention studies are the most common (n = 77, 63.6%), followed by prediction (n = 21, 17.4%), management (n = 16, 13.2%), and detection studies (n = 7, 5.8%). POAF after cardiac surgery is an area of active research. Conclusions: There are many ongoing randomized prevention studies. However, two major clinical gaps persist; future randomized trials should compare rate and rhythm control in patients who develop POAF, and long-term follow-up studies should investigate strategies to monitor for AF recurrence in patients with POAF.

Atrial fibrillation rhythm management: a matter of timing.

Rhythm control in patients with atrial fibrillation (AF) has evolved dramatically in the last decades. Several studies have informed us of the benefits of an early rhythm control strategy and primary rhythm control by catheter ablation (CA). Similarly, several studies have investigated the effects of CA in patients with longer AF duration and more comorbidities, especially heart failure. In the current review, we summarize the current evidence on rhythm control at different time points during the disease course of AF [Table 1 and Central illustration].

Implementation of an atrial fibrillation better care (ABC) pathway management strategy: Findings from the Iranian registry of atrial fibrillation.

Introduction: The Atrial Fibrillation Better Care (ABC) pathway is such an integrated care approach, recommended in guidelines. The aim of this service evaluation study was to evaluate the impact of implementing the ABC pathway in Iranian population. Methods: In this prospective longitudinal cohort study, consecutive patients with a diagnosis of AF were initially evaluated. Patients at baseline were evaluated in hence of adherence to ABC pathway strategy. After study enrolment, first and second follow-up service evaluations were conducted at 6 and 12 months, respectively. Results: The use of vitamin K antagonists (VKA) decreased from 25.1 % at enrolment to 13.8 % at follow-up; instead, non-VKA oral anticoagulants (NOAC) utilization increased from 40.0 % to 86.1 %, while antiplatelet treatment decreased from 34.9 % to 0 %. Use of antihypertensive drugs, ARBs, diuretics, and statins increased after implementation of the ABC pathway. Implementation of the ABC pathway approach led to a decrease in the occurrence of stroke/TIA (from 6.3 % to 2.2 %, p = 0.002), systemic thromboembolism (from 1.4 % to 0.0 %, p = 0.04), nose bleeds (from 0.8 % to 0.6 %, p = 0.04), skin bruising (from 1.2 % to 0.0 %, p = 0.002), and heart failure (from 7.7 % to 4.7 %, p = 0.04). The proportion of patients in EHRA Class I-II increased from 93.3 % at enrolment to 98.1 % at follow-up. Conclusion: In this first study from a Middle East population, compliance with ABC pathway strategy in the management of AF was associated with optimization of management and general improvements in patient outcomes during follow-up.

Rate control or rhythm control in patients with atrial fibrillation and acute coronary syndrome or percutaneous coronary intervention.

Background: Restoring and maintaining sinus rhythm in patients with atrial fibrillation (AF) and acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI) has been studied in clinical trials to reduce symptoms and improve quality of life. Limited data exist on the effectiveness of rate or rhythm control therapy in these patients. Methods: Consecutive patients with AF and ACS or referred for PCI were prospectively recruited in Fuwai Hospital during 2017-2020. The primary endpoints were all-cause death and major adverse cardiovascular and cerebrovascular events (MACCEs), including cardiovascular mortality, myocardial infarction, ischemic stroke, non-central nervous system embolism and ischemia-driven revascularization. Kaplan-Meier curves and Cox regressions were performed to evaluate the association between rhythm/rate control and subsequent outcomes. For the primary endpoints, we used the Benjamini-Hochberg correction for multiple comparisons. Results: A total of 1499 patients with AF and ACS or undergoing PCI were included, with a median follow-up of 34.7 months. Compared to non-rate control, rate control strategy reduced the risk of subsequent MACCEs (adjusted HR, 0.320; 95 % CI 0.220-0.466; p <0.001; *p <0.002) and all-cause death (adjusted HR, 0.148; 95 % CI 0.093-0.236; p <0.001; *p <0.002). Similar trends were observed across all predefined subgroups (p <0.001). In the final multivariate model, rhythm control was not associated with a lower subsequent MACCEs but significantly improved all-cause mortality compared to non-rhythm control (adjusted HR, 0.546; 95 % CI 0.313-0.951; p =0.033; *p =0.044). Conclusions: In this real-world study, rate control strategy was associated with lower risk of MACCEs and all-cause death in AF and ACS or undergoing PCI. Besides, management with rhythm control strategy may improve all-cause mortality.

Prevalence and outcomes of heart failure phenotypes in patients with atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is common in patients with heart failure (HF). Real-world data about long-term outcomes and rhythm control interventions use in AF patients with and without HF remain scarce. METHODS: AF patients from two prospective, multicentre studies were classified based on the HF status at baseline into: HF with preserved ejection fraction (HFpEF), HF with reduced or mildly reduced ejection fraction (HFrEF/HFmrEF), and no HF. The prespecified primary outcome was risk of HF hospitalisation. Other outcomes of interest included mortality, cardiovascular events, AF progression, and quality of life. RESULTS: A total of 1265 patients with AF were analysed (mean age 69.6 years, women 27.4%) with a median follow-up of 5.98 years. Patients with HFpEF (n = 126) had a 2.69-fold and patients with HFrEF/HFmrEF (n = 308) had a 2.12-fold increased risk of HF hospitalisation compared to patients without HF (n = 831, p < 0.001). Similar results applied for all-cause and cardiovascular mortality. The risk for AF progression was higher for patients with HFpEF and HFrEF/HFmrEF (6.30 and 6.79 per 100 patient-years, respectively) compared to patients without HF (4.20). The use of rhythm control strategies during follow-up was least in the HFpEF population (4.56 per 100 patient-years) compared to 7.74 in HFrEF/HFmrEF and 8.03 in patients with no HF. With regards to quality of life over time, this was worst among HFpEF patients. CONCLUSIONS: The presence of HFpEF among patients with AF carried a high risk of HF hospitalisations and AF progression, and worse quality of life. Rhythm control interventions were rarely offered to HFpEF patients. These results uncover an unmet need for enhanced therapeutic interventions in patients with AF and HFpEF.

Atrial fibrillation burden: a new outcome predictor and therapeutic target.

Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is not a dichotomous disease trait. Technological innovations enable long-term rhythm monitoring in many patients and can estimate AF burden. These technologies are already used to detect and monitor AF. This review describes the relation between AF burden and outcomes and potential effects of AF burden reduction. A lower AF burden is associated with a lower risk of stroke and heart failure in patients with AF: stroke risk without anticoagulation is lower in patients with device-detected AF and a low AF burden (stroke rate 1%/year) than in patients with persistent and permanent AF (stroke rate 3%/year). Paroxysmal AF shows intermediate stroke rates (2%/year). Atrial fibrillation burden-reducing interventions can reduce cardiovascular outcomes in patients with AF: early rhythm control reduces cardiovascular events including stroke and heart failure in patients with recently diagnosed AF and cardiovascular conditions. In patients with heart failure and AF, early rhythm control and AF ablation, interventions that reduce AF burden, reduce mortality and heart failure events. Recent technological innovations allow to estimate AF burden in clinical care, creating opportunities and challenges. While evidence remains limited, the existing data already suggest that AF burden reduction could be a therapeutic goal. In addition to anticoagulation and treatment of cardiovascular conditions, AF burden reduction emerges as a therapeutic goal. Future research will define the AF burden that constitutes a relevant risk of stroke and heart failure. Technologies quantifying AF burden need careful validation to advance the field.

Risk Factors for Treatment Transition in Patients with Low-Risk Atrial Fibrillation Patients Undergoing Anticoagulation Monotherapy: A Large Claims Database Study in Japan.

The global prevalence of atrial fibrillation (AF) is rising, paralleling increased life expectancy. Early rhythm control benefits AF management. However, in low-risk, often asymptomatic, AF patients, anticoagulant monotherapy is the selected treatment, aligning with current guidelines. However, early AF progression in these low-risk individuals is not well-understood. Thus, this study aims to: 1) determine the proportion of low-risk AF patients who worsen within a year of initial AF diagnosis and 2) identify risk factors such treatment transitions. We analyzed data from 18623 AF patients, spanning January 2005 to June 2017. Low-risk patients were those on anticoagulant monotherapy ± rate control, following the JCS/JHRS 2020 Guideline on Pharmacotherapy of Cardiac Arrhythmias. We defined 2 patterns of treatment transition for 1) initiating ablation or antiarrhythmic drug therapy and 2) solely using antiarrhythmic drugs. This retrospective cohort study was employed a 12-month study, following a 6-month screening period. We included 1874 patients for all rhythm control (analysis 1) and 1503 for only medication-based control (analysis 2). The primary endpoint, treatment transition of AF under monotherapy, occurred in 28.4% of patients in analysis 1 and 10.8% in analysis 2. Risk factors common to both scenarios were male gender, baseline rate control drug use, and rivaroxaban selection, as identified by multiple logistic regression. These findings suggest a higher AF treatment transition trend in patients starting rivaroxaban, calling for further research. The study highlights the importance of informed early rhythm control initiation decisions in clinical settings.

Real-world evidence of early rhythm control in patients with atrial fibrillation: A systematic review and meta-analysis.

BACKGROUND: The favorable benefits of early rhythm control (ERC) therapy in newly diagnosed patients with atrial fibrillation (AF) have been demonstrated in the EAST-AFNET 4 trial. However, the generalizability and applicability of ERC in real-world clinical settings remain inconclusive. METHODS: We conducted a systematic search of the PubMed and Embase databases to identify observational studies published between January 2020 and February 2024 that focused on real-world evidence pertaining to ERC. The effectiveness and safety outcomes in our study were analogous to those evaluated in the EAST-AFNET 4 trial. RESULTS: A total of 4 observational studies that fulfilled the inclusion criteria of EAST-AFNET 4 were included, involving 130,970 patients with AF, 30.7% of whom received ERC therapy. In our pooled analysis using the fixed-effects model, compared with rate control, ERC significantly decreased the occurrence risk of the primary composite outcome (hazard ratio [HR] 0.86, 95% confidence interval[CI] 0.82-0.91), cardiovascular death (HR 0.87, 95% CI 0.78-0.98), stroke (HR 0.80, 95% CI 0.73-0.87), and hospitalization with worsening heart failure (HR 0.91, 95% CI 0.84-0.99) or acute coronary syndrome (HR 0.72, 95% CI 0.59-0.87). In terms of safety outcomes, there were no differences in the composite safety outcome (HR 1.00, 95% CI 0.95-1.05) and all-cause death (HR 0.93, 95% CI 0.82-1.06) between the two studied groups. CONCLUSIONS: ERC therapy showed favorable effectiveness outcomes compared with rate control, whereas the safety outcomes between the two therapeutic strategies did not differ significantly, supporting the benefits of ERC therapy over rate control in selected real-world patients with AF. REGISTRATION: The study protocol was registered to PROSPERO (CRD42023443569).

Outcome of tailored therapy in rheumatic heart disease with persistent atrial fibrillation (RHD-AF).

INTRODUCTION: Rheumatic heart disease with persistent atrial fibrillation (RHD-AF) is associated with increased morbidity. However, there is no standardized approach for the maintenance of sinus rhythm (SR) in them. We aimed to determine the utility of a stepwise approach to achieve SR in RHD-AF. METHODS: Consecutive patients with RHD-AF from July 2021 to August 2023 formed the study cohort. The stepwise approach included pharmacological rhythm control and/or electrical cardioversion (Central illustration). In patients with recurrence, additional options included AF ablation or pace and ablate strategy with conduction system pacing or biventricular pacing. Clinical improvement, NT-proBNP, 6-Minute Walk Test (6MWT), heart failure (HF) hospitalizations, and thromboembolic complications were documented during follow-up. RESULTS: Eighty-three patients with RHD-AF (mean age 56.13 ± 9.51 years, women 72.28%) were included. Utilizing this approach, 43 (51.81%) achieved and maintained SR during the study period of 11.04 ± 7.14 months. These patients had improved functional class, lower NT-proBNP, better distance covered for 6MWT, and reduced HF hospitalizations. The duration of AF was shorter in patients who achieved SR, compared to those who remained in AF (3.15 ± 1.29 vs 6.93 ± 5.23, p = 0.041). Thirty-five percent (29) maintained SR after a single cardioversion over the study period. Only one underwent AF ablation. Of the 24 who underwent pace and ablate strategy, atrial lead was implanted in 22 (hybrid approach), and 50% of these achieved and maintained SR. Among these 24, none had HF hospitalizations, but patients who maintained SR had further improvement in clinical and functional parameters. CONCLUSIONS: RHD-AF patients who could achieve SR with a stepwise approach, had better clinical outcomes and lower HF hospitalizations.

Ablation of Paroxysmal Atrial Fibrillation: between Present and Future.

Pulmonary vein isolation (PVI) is the established cornerstone for atrial fibrillation (AF) ablation, indeed current guidelines recognize PVI as the gold standard for first-time AF ablation, regardless of if it is paroxysmal or persistent. Since 1998 when Haïssaguerre pioneered AF ablation demonstrating a burden reduction after segmental pulmonary vein (PV) ablation, our approach to PVI was superior in terms of methodology and technology. This review aims to describe how paroxysmal atrial fibrillation ablation has evolved over the last twenty years. We will focus on available techniques, a mechanistic understanding of paroxysmal AF genesis and the possibility of a tailored approach for the treatment of AF, before concluding with a future perspective.

[Atrial fibrillation and heart failure]. / Vorhofflimmern und Herzinsuffizienz.

Atrial fibrillation and heart failure are among the most common cardiovascular diseases and have a significant impact on the mortality and morbidity of affected patients. From a pathophysiological perspective, the two diseases are closely related and often perpetuate each other. Therefore, effective management of atrial fibrillation is now a central component of modern heart failure treatment. Based on current data, sinus rhythm should primarily be permanently maintained in patients with systolic heart failure. Catheter ablation has recently proven to be advantageous over purely pharmacological therapy and is therefore the treatment of choice for many patients with heart failure and atrial fibrillation. In patients with diastolic heart failure (heart failure with preserved ejection fraction [HFpEF]), the effect of catheter ablation is less clear. Data from randomized studies are urgently needed in order to further assess efficacy in this population.

Efficacy of cryoablation in atrial fibrillation: comparison with antiarrhythmic therapy.

Atrial fibrillation (AF) represents the most common arrhythmia in clinical practice, characterized by irregular atrial electrical activity originating mainly in and around the pulmonary veins. This condition can manifest itself symptomatically or silently but still dangerously. Complications associated with AF include stroke, heart failure, worst clinical outcome in patients with underlying conditions, increased emergency room visits, hospitalizations, and cardiovascular mortality. Currently, according to the main international guidelines, antiarrhythmic therapy is considered the first choice for rhythm control in patients with AF despite modest efficacy and non-negligible side effects. In recent decades, radiofrequency catheter ablation has emerged as an alternative to antiarrhythmic drugs for rhythm control. Cryoablation was developed with the aim of reducing procedural times and reducing complications related to the ablative procedure with radiofrequency without losing efficacy. Recent studies conducted with rigour and scientific solidity have demonstrated on the one hand that the results of this technique are not inferior compare with radiofrequency. This study aims to compare data on the safety and efficacy of cryoablation with those obtained from antiarrhythmic drugs through a review of the most recent scientific evidence.

Revitalizing brain perfusion: Unveiling advancements through rhythm control strategies in atrial fibrillation-A systematic review.

Background: Recent evidence suggests an elevated risk of cognitive impairment and dementia in individuals with atrial fibrillation (AF), irrespective of stroke occurrence. AF, known to reduce brain perfusion, particularly through silent cerebral ischemia, underscores the intricate relationship between cardiac and cerebral health. The heart plays a crucial role in supporting normal brain function, and rhythm control, a standard AF treatment, has demonstrated enhancements in brain perfusion. This systematic review aimed to examine published data concerning the influence of rhythm control on brain perfusion in patients with atrial fibrillation. Methods: A systematic search for relevant studies was carried out in Scopus, PubMed, Cochrane Reviews, ProQuest, and EBSCOhost, spanning from their inception until April 30, 2023. Studies that specifically examined brain perfusion following any form of rhythm control in atrial fibrillation were included in the review. Results: The review encompassed 10 studies involving 436 participants. Among these, six utilized electrical cardioversion for rhythm control. The majority (8 out of 10) demonstrated that restoring sinus rhythm markedly enhances brain perfusion. In one of the two remaining studies, notable improvement was observed specifically in a region closely linked to cognition. Additionally, both studies reporting data on the Mini-Mental State Examination (MMSE) showed a consistent and significant increase in scores following rhythm control. Conclusion: Successful rhythm control in AF emerges as a significant contributor to enhanced brain perfusion, suggesting a potential therapeutic avenue for reducing cognitive impairment incidence. However, further validation through larger prospective studies and randomized trials is warranted.

Design and deployment of the STEEER-AF trial to evaluate and improve guideline adherence: a cluster-randomized trial by the European Society of Cardiology and European Heart Rhythm Association.

AIMS: The aim is to describe the rationale, design, delivery, and baseline characteristics of the Stroke prevention and rhythm control Treatment: Evaluation of an Educational programme of the European society of cardiology in a cluster-Randomized trial in patients with Atrial Fibrillation (STEEER-AF) trial. METHODS AND RESULTS: STEEER-AF is a pragmatic trial designed to objectively and robustly determine whether guidelines are adhered to in routine practice and evaluate a targeted educational programme for healthcare professionals. Seventy centres were randomized in six countries (France, Germany, Italy, Poland, Spain, and UK; 2022-23). The STEEER-AF centres recruited 1732 patients with a diagnosis of atrial fibrillation (AF), with a mean age of 68.9 years (SD 11.7), CHA2DS2-VASc score of 3.2 (SD 1.8), and 647 (37%) women. Eight hundred and forty-three patients (49%) were in AF at enrolment and 760 (44%) in sinus rhythm. Oral anticoagulant therapy was prescribed in 1543 patients (89%), with the majority receiving direct oral anticoagulants (1378; 89%). Previous cardioversion, antiarrhythmic drug therapy, or ablation was recorded in 836 patients (48.3%). Five hundred fifty-one patients (31.8%) were currently receiving an antiarrhythmic drug, and 446 (25.8%) were scheduled to receive a future cardioversion or ablation. The educational programme engaged 195 healthcare professionals across centres randomized to the intervention group, consisting of bespoke interactive online learning and reinforcement activities, supported by national expert trainers. CONCLUSION: The STEEER-AF trial was successfully deployed across six European countries to investigate guideline adherence in real-world practice and evaluate if a structured educational programme for healthcare professionals can improve patient-level care. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT04396418.