The “ A trial F ibrillation integrated approach in F ra I l, multimo R bid and poly M edicated O lder people ” ( AFFIRMO ) trial is a European multicenter open-label cluster-randomized study designed to test the efficacy of a mobile-health supported intervention on the clinical management of older adults with AF and multimorbidity against usual care, on the reduction of the occurrence of unplanned all-cause hospitalization over a 12-month follow-up observation period. This trial, conducted in 6 different European countries, is sponsored, and promoted by the Italian Heart Care Foundation (HFC), and funded by the European Union’s Horizon 2020 research and innovation program under the grant agreement No. 899871 as part of the AFFIRMO project consortium activities.

The HFC established the study network, acting as the Central Coordinating Centre (CCC). Patients were recruited from 6 AFFIRMO Consortium partner countries: Bulgaria, Denmark, Italy, Romania, Serbia, and Spain. Centers have been identified in each participating country under the oversight of the National Coordinating Centers (NCCs) and National Coordinators, based on a demonstrated interest in managing high volumes of patients with AF. All sites must possess adequate facilities, resources, and patient volume to conduct the study to be eligible. General hospital centers, with more than 250 new patients with AF referred per year, were preferably selected. Each center received a feasibility form that was completed and evaluated by the CCC to be considered for participation in the study. Each National Coordinator initially selected up to 14 sites, from which the final sites included in the study were finally selected. An even number of sites was chosen in each country to ensure an adequate distribution of clusters. After all the centers were selected and the ethical approval was obtained, each center was randomized to be an intervention or control cluster. The randomization process was also stratified according to the presence of an interventional electrophysiology facility in the hospital.

Study participants were all AF outpatients aged 65 years or older with multimorbidity, defined as having at least one other chronic clinical condition among 14 cardiovascular and noncardiovascular conditions ( Table 1 ). The main exclusion criteria were the presence of a mechanical prosthetic heart valve or moderate to severe mitral stenosis; a patient unwilling to be enrolled and sign the written informed consent; or being unable to understand the study and attend the follow-up. Additionally, all patients enrolled in the intervention clusters were excluded if they didn’t have a suitable electronic device. Inclusion and exclusion criteria are summarized in Table 1 . The enrolment of patients was initially planned to proceed for 12 months.

The study intervention consists of the iABC system, which includes the AFFIRMO mobile app ( Figure 1 ) and the AFFIRMO clinician dashboard ( Figure 2 ). The mobile app and clinician dashboard will streamline the ABC pathway implementation for each enrolled patient according to its standard definition. The mobile app is downloaded and installed during the baseline visit through an activation process that begins after the signing of the consent form and the completion of the enrolment form by the study physician. Simultaneously, the patient profile is activated on the clinician dashboard.

AFFIRMO mobile app.

AFFIRMO clinician dashboard.

Accordingly, the app will assist the patient regarding all 3 ABC pathway pillars, collecting data on vital signs, adherence to OAC therapy, AF symptomatic status and the symptomatic status of the other chronic clinical conditions and providing the patient with health tips and guidance for optimizing life habits and stabilizing comorbidities, according to the chronic clinical conditions identified at the baseline visit ( Table 2 ). Indeed, for each chronic clinical condition recorded at baseline, among those listed in the inclusion criteria, a specific symptomatic questionnaire and related health tips are activated in the mobile app for each patient. Throughout the clinical follow-up, patients will be asked about the occurrence of a new diagnosis related to the chronic clinical conditions considered at enrolment. If a new condition is diagnosed and reported by the patient, the corresponding symptomatic questionnaire is activated within the mobile app, provided it is confirmed by the study physician.

Moreover, at the moment of mobile app activation, each patient receives a questionnaire regarding overall patient empowerment and disease awareness, the Patient Health Engagement scale (PHE-s). Accordingly, each patient will receive specific, informative materials regarding AF and its clinical consequences, tailored to their level of disease awareness (i.e., access to the Empowerment Toolbox, as described in the related paragraph below).

Furthermore, each patient enrolled by the iABC system clusters received a complete CGA at the baseline visit to identify the relevant functional dimensions to be addressed with specific interventions. Accordingly, the following geriatric functional dimensions have been tested: (1) autonomy in daily activities (Katz and Lawton scales); (2) cognitive function (short portable mental status questionnaire ); (3) motor function (short physical performance battery ); (4) nutritional status (mini-nutritional assessment short form ); (5) mood status (geriatric depression scale 4 items ). Through the mobile app, each patient received specific health tips for optimizing functional dimensions ( Table 2 ). Moreover, each study physician has received specific training regarding the execution of these questionnaires and general clinical recommendations regarding managing each functional dimension.

Meanwhile, the AFFIRMO clinician dashboard provided the study physicians with an overall report of the AFFIRM mobile app usage and a comprehensive view of all data entered by the patient in the mobile app, divided into the 3 ABC pathway pillars, for consultation during follow-up visits and to adjust clinical management to optimize the symptomatic status of chronic clinical conditions and their functional dimensions ( Table 2 ). As detailed in Table 2 , specific references to international guidelines regarding AF and other chronic clinical conditions are provided for the study physicians’ reference.

No restrictions are imposed on AF management and follow-up. Patients followed in the centers randomized to the control arm are managed by their usual primary health-care providers, following international and local clinical guidelines.

At the baseline visit, the following data were collected: demographic characteristics, clinical status, clinical history including the definition of comorbidities and AF characteristics, neurosensory disabilities, ECG, relevant laboratory values, prior and ongoing treatments. Furthermore, the level of frailty was assessed at baseline using the FRAIL scale for all the patients. A complete CGA had to be performed in patients from clusters randomized to the intervention group. Also, quality of life was assessed according to the EuroQOL EQ-5D-5L questionnaire. Levels of patients’ empowerment measured with the Patient Health Engagement Scale (PHEs) ^, were also collected at enrolment.

Follow-up visits will occur at 3, 6, and 12 months, during which the following data will be collected: current clinical status, ECG, clinical events that have happened or new chronic clinical conditions that have been diagnosed since the last visit, safety profile, and prior and ongoing treatments. Additionally, all patients assigned to treatment-randomized clusters will receive recommendations to reinforce app use at each follow-up visit. At the end of the study, relevant laboratory values, neurosensory disabilities, EQ-5D-5L, PHEs and the FRAIL scale will be collected again for all patients. The complete CGA will be performed again at the end of the study, only for patients enrolled in the intervention clusters. All data are collected through a centralized electronic case report form (eCRF). A PDF version of the study CRFs is available in the Supplementary Materials.

The technical development of the iABC system followed the subsequent approach. The technical team held sessions with the RCT team to gather requirements and created a scope document that guided the software project work. From the scope, the main requirements were prioritized as “Must have, Could have, Should have, or Won’t have” (MoSCoW), and then shared it with the broader team for feedback. This approach helped the technical teamwork and kept everyone informed about the needs and priorities. A co-design method was employed, involving workshops with potential participants to showcase designs, gather their feedback, and implement necessary changes. This allowed the technical team to understand the real needs of future participants and refine the designs until they were complete.

Once the initial designs were agreed upon, clickable prototypes were created to illustrate how the app would function without using real data. For software development, the Agile methodology was followed, enabling an iterative development process with continuous feedback and improvement. The codebase and other essentials were set up, then the design work was carried out according to the MoSCoW prioritization. Internally, the technical team tested features using automated end-to-end tests, and additional manual testing was also conducted.

To use the AFFIRMO mobile app in the 6 European countries involved, specific localization was needed. The mobile app was first developed in English and then tested before being sent to National Leaders for feedback on the app and translation into the local language. After adding the translations, an iterative process of feedback was employed until the final versions were approved.

A participatory action research approach was employed across the 6 European countries involved to develop and validate an Empowerment Toolbox aimed at improving the knowledge and skills of patients and their carers dealing with AF. The process involved: (1) a literature review to identify existing educational materials, (2) multidisciplinary workshops to co-design the toolbox, and (3) cross-cultural adaptation interviews with clinicians and patients to ensure readability, cultural relevance, and usability. Materials were categorized into informational, educational, and motivational resources tailored to patients’ engagement levels as defined by the PHE model.

The final toolbox, hosted on a digital platform, consists of informative, educational, and motivational documents tailored according to the PHEs level of the patient (Blackout, Arousal, Adhesion, Eudaimonic project). Informational materials tailored for individuals with low health literacy were allocated to the “Blackout” group. Educational materials suitable for individuals with low health literacy were assigned to the “Arousal” group. In contrast, those appropriate for individuals with higher health literacy were classified for the “Adhesion” and “Eudaimonic project” groups. Motivational materials were exclusively assigned to the “Eudaimonic project” group, reflecting the high level of engagement among these patients.

Specific training sessions were developed and provided for clinicians and researchers involved in the RCT (only the intervention harm) to raise awareness about the importance of measuring and promoting patients’ empowerment. It also aimed to educate them on how to use feedback generated by the Empowerment monitoring process and the Empowerment Toolbox, as well as how to access these resources through the AFFIRMO platform.

Thanks to the didactic virtual environment of the Blackboard platform, 6 dedicated training rooms (1 for each country involved in the trial) were built. Part of the training activities were covered by video short lessons or tutorials delivered by AFFIRMO partners.

The videos cover the following themes of interest for medical professionals and patients: (1) Video on the medical principles of the ABC approach for atrial fibrillation; (2) Introductory video on the psychological principles of empowerment in AF; (3) Video on the structure and use of the digital platform; (4) Video on the Empowerment Toolbox. The trainee’s activity on the platform was tracked, monitored, and assessed. Completing the training was mandatory for being enrolled as a researcher/clinician in the trial process; at least 1 researcher for each iABC cluster had to complete the training to start their participation in the trial. If the trainee failed more than 15% of the questionnaire, they need to see the dedicated video again and retake the test.

The primary outcome of the study is the occurrence of all-cause unplanned hospitalization over the 12-month follow-up period. As secondary outcomes, the following will be considered:

• 1.

  a composite of nonfatal ischemic stroke or transient ischemic attack and cardiovascular death

• 2.

  all-cause death

• 3.

  a composite of all-cause death and all-cause hospitalizations (both planned and unplanned)

• 4.

  new diagnosis of HF or worsening HF requiring hospitalization

• 5.

  major bleeding as defined according to the ISTH definitions

• 6.

  intracranial bleeding

• 7.

  occurrence of renal dysfunction or worsening renal function

• 8.

  level of quality of life at the end of follow-up

• 9.

  adherence to OAC therapy

• 10.

  level of physical activity

• 11.

  level of adherence to the iABC system

• 12.

  level of engagement/empowerment

Safety assessments will consist of monitoring and recording predefined safety aspects, including bleeding episodes, all serious adverse events, and regular measurements of vital signs.

All serious clinical events are recorded in the eCRF, and supporting documentation is required from study investigators for hospitalizations and deaths. An event validation committee (EVC), with 1 member in each country coordinated by the CCC, adjudicates all primary outcome events and the causes of death. To prevent selective assessment bias, the EVC is blinded to the intervention received by participants.

The CCC, the NCCs, the Study Steering Committee, and the Data Monitoring Committee manage all aspects related to overall trial management.

This clinical study was designed, implemented and shall be reported following the International Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for good clinical practice, with applicable local regulations (Directive 2001/20/EC—Clinical Trials Directive, Regulation EU No 536/2014—Clinical Trials Regulation) and with the ethical principles laid down in the Declaration of Helsinki.

All patients’ information is managed according to the purposes of art. Thirteen of the EU Regulation no. 679 of 2016, as well as under the “Guidelines for Data Processing within the Framework of Clinical Drug Trials” issued by the Italian Data Protection Authority on the 24th of July, 2008.

The protocol, along with the study documents, has been reviewed and approved in each country by the Competent Authority, if requested, and by the Central and/or Local Institutional Review Boards/Ethical Committees, as per local national regulations.

The sample size was determined under the assumption that 30% of patients receiving usual care would experience the primary endpoint within an average follow-up duration of around 1 year. The intervention group, treated with the iABC system, is anticipated to achieve a 25% relative reduction in the event rate, resulting in an absolute decrease from 30% to 22.5%. To identify this difference with 80% power and a 2-sided alpha error level of 0.05, 1,250 patients were estimated as the necessary sample size considering the cluster randomized design of the study.

Since the outcomes of this study are likely driven by individual-level characteristics rather than cluster-level characteristics, we expect slight variations between centers. Therefore, assuming low variation between clusters (coefficient of variance between clusters K ≤ 0.1), a total of 50 clusters with approximately 25 patients each was estimated.

The primary analysis of efficacy and safety will be conducted using an intention-to-treat approach. The primary approach will be to estimate the incidence of the primary outcome in the 2 study arms using a multilevel approach, which takes into consideration the nesting of participants within clusters.

A multilevel logistic regression model, incorporating random intercepts and, where supported by the data, random slopes and adjusted for a set of clinically relevant baseline covariates prespecified a priori based on their known or plausible association with the outcome, as well as for the stratification covariates included in the randomization procedure, will be used to assess the effect of the iABC system. Patients in the usual care strategy will be regarded as the reference arm. The criteria for success will be to evaluate whether the upper 2-sided 95% confidence interval (95% CI) for the adjusted incidence of the primary endpoint (as described above) is less than 1.0. Time-to-event analyses will be performed according to Kaplan–Meier curves (and log-rank tests) and subsequently Cox Proportional Hazards models, adjusted for relevant baseline factors and the effect of clustering. A similar approach will be used for the main secondary outcomes. Data regarding quality of life, empowerment, and engagement will be assessed descriptively between groups using specific questionnaires. Physical activity will be evaluated based on the data collected in the eCRF.

Several subgroup analyses will be performed as prespecified in the study protocol:

• 1.

  Age (below median value vs above median value)

• 2.

  Sex

• 3.

  Number and severity of comorbidities (considering number and severity)

• 4.

  Number of medications (≤5 vs >5)

• 5.

  Time from first AF diagnosis (<6 vs 6-12 vs >12 months)

• 6.

  Participating country

Baseline characteristics will be described using the mean (SD) and medians (IQR) for continuous variables, with comparisons between groups made using the Wilcoxon test. Ordinal variables will be described in terms of counts and percentages, and their comparison between groups will be performed using the χ ²– test. All analyses will be conducted with SAS version 9.4.