Study setting {9}
This single-center study will be carried out at the 1st Department of Cardiology at the Medical University of Warsaw, an academic, public hospital in the capital of Poland. Cardiologists and fellows of cardiology will conduct all study-related procedures. The Department ensures all treatment options for patients with AMI and during their cardiac rehabilitation process. It is regarded as the leading Department of Cardiology in Poland.
Eligibility criteria {10}
Inclusion Criteria:
- signing the informed consent to participate in the study
- hospitalization due to myocardial infarction, based on the Guidelines on Fourth Universal Definition of Myocardial Infarction (10)
- owning a mobile device with Internet access and the Android/iOS operating system
- age ⩾18 years old
- positive results of a test verifying the basic skills of using mobile applications
Exclusion Criteria:
- Life expectancy shorter than 6 months due to non-cardiac illness
Who will take informed consent? {26a}
After screening a list of patients admitted to the department of cardiology, a staff member will check the reason for admission. A study team member will approach every patient presenting with AMI, and the inclusion criteria will be assessed. The study design will be thoroughly described to the patient, including all potential benefits, harms, and ethical implications. Each eligible patient will be proposed to enter the study. If the patient agrees to participate in the research, the informed consent will be signed in 2 copies: one for the participant and one for the research archives. Every participant will receive a note with a summary of the study design.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Not applicable; this trial does not have biological specimens.
Interventions
Explanation for the choice of comparators {6b}
Participants will be randomly assigned to one of the two groups (1) a control group with standard cardiological care or (2) a mobile application-supported interventional group. The trial is set in a relatively big, academic centre. Every year approximately 400 patients is hospitalised due to acute myocardial infarction. However, a significant part of those patients is unable to use mobile application and therefore they don’t meet one of the main inclusion criterion. Going further, only some of the patients who meet inclusion criteria are willing to take part in a trial. The recruitment began in December 2020. Approximately 7 patients per month is included into the trial. Last patient recruitment is expected in Q1 2022.
Intervention description {11a}
The rehabilitation process of patients in the intervention group will be supported by the mobile application (afterAMI) with a synchronized, dedicated web page.
Patients in the intervention group will also be given access to educational data regarding their diseases. Every educational chapter was prepared by a cardiologist experienced in managing patients after MI.
Additionally, every patient will regularly receive messages with notifications about lifestyle interventions and adherence to therapy. An optimal scheme for messeges quantity and structure has not bec described yet in cardiac patients. In recent metaanalysis Bashi et al. concluded that the results of mobile application assisted patient education generally shows positive result. However due to poor reporting quality and heterogenity of the interventions further studies are needed to develop optimal educational scheme (11). On the other hand a cardiac telerehabilitation programme augmented by short message service (SMS) deliverd to patients once a week showed improvement in physical fitness and quality of life (12). Based on those reports authors of this trial decided to send 2 messages weekly.
Another essential feature of the application is the possibility to report patients’ vital signs (blood pressure, heart rate, weight, and other), which will be daily analyzed and if necessary, a short message will be sent to the patient, advising to present to the primary healthcare clinic or emergency department. A possible clinical scenario is an alarming rapid bodyweight increase, which might foreshadow incoming heart failure exacerbation.. Another potential use of the application lies when the patients report rapid pulse. In this case, new-onset atrial fibrillation might be suspected. In every case requiring confirmation, the patient will be referred to the nearest emergency room. However, all patients will be informed that they should immediately present to the nearest emergency unit or contact the emergency services in case of recurring angina or any other acute complaints.
Additionally, the application will send notifications with reminders to take drugs. This solution has been previously evaluated in many studies and proved to be a successful tool in increasing adherence to the therapy (13).
Moreover, the application includes a module with air pollution parameters measured amidst the localization setup. If they exceed the alarming levels, the patients will be notified, and outdoor physical activities will be minimized.
Moreover, every patient will have a medical history card created based on the discharge documents from the hospital. This solution aims for the patient always to have brief information about underwent coronary interventions. This knowledge might be crucial for the physicians performing the subsequent percutaneous coronary intervention (PCI) and might decrease time-to-balloon.
Finally, the application offers a possibility to text message and call the cardiologists and the hospital. We believe that this will translate into better work organization, better time management (as fewer consultations are likely to be missed by patients), and patient safety. All patients randomised to IG will be thoroughly trained in application features and capabilities before discharge from the hospital.
In contrary, patients randomised to the CG will be provided with the best available care worked out based on the available literature (14). Rehabilitation programmes are voluntary. They consist of regular cardiac consultations with experienced physician, psychological sessions, exercise trainings, stress management programmes and diatary recommendations. Patient is offered a support for a year after MI. Patients who refuse to take part in the rehbilitation programme are taken care of by general practitioner. Thanks to randomisation patients distribution is expected to be close to even.
All data impleneted into the application was prepared by experienced cardiologists with big experience in both clinical practice and eHealth use on a daily basis.
There are several mobile applications offering simple feature for general population (i.e. blood pressure diaries). However, according to autorhs’ knowledge this is one of the very first, which combines several options previously tested in clinical settings, which proved to be effective, Moreover mobile applications dedicated for patients after MI are lacking, and one should keep in mind how unstable first weeks and months after discharge from hospital can be. Described tool should be regarded as a possibility of impoving patients’ prognosis when added on top of the current practice.
Criteria for discontinuing or modifying allocated interventions {11b}
The only criterion for discontinuing is the participants’ request.
Strategies to improve adherence to interventions {11c}
Not applicable; this trial does not have strategies to improve adherence.
Relevant concomitant care permitted or prohibited during the trial {11d}
Not applicable; this trial does not have concomitant care permitted or prohibited.
Provisions for post-trial care {30}
Not applicable; participants will continue with traditional care after the trial is finished. Trial participation is beneficial for the patients due to more intense medical care. Every patient included in the study will have two additional cardiological consultations.
Outcomes {12}
All 100 patients will be observed for 6 months after discharge from the hospital. We will assess the Endpoints twice, during two control visits, in 1- and 6-months, after inclusion in the study. Primary outcomes encompass rehospitalization and urgent outpatient visit combined and second combined Endpoint; cardiovascular risk factors control (blood pressure, body mass, nicotinism, dyslipidemia). Detailed target values regarding risk factors control have been presented in Table 1 based on ESC Chronic Coronary Syndrome guidelines (15). Secondary outcomes will include quality of life and depression severity assessment (MacNew, EQ-5D-5L, and DASS-21 questionnaires), cardiovascular risk factors’ knowledge, and return to work in case of professionally active patients.
Moreover, data collection will include sex, age, laboratory tests, and prescribed pharmacotherapy.
Rehospitalization or urgent outpatient visit
The number of admissions to hospital or urgent outpatient visits will be assessed between baseline and control visits.
Cardiovascular risk factors
Blood pressure
All patients at discharge from the hospital are asked to measure and note blood pressure values daily. The mobile application-obtained mean blood pressure values covering 5 days prior to their visits will be averaged for the IG patients. The mean blood pressure values of CG-comprised patients will also be averaged but based only on the presented notes. Additionally, meeting guidelines-based recommended values will be checked in both groups. Hypertension is one of the main cardiovascular risk factors, with a significant prevalence of 1.13 billion worldwide (16). Hypertension control in patients after MI is crucial and correlates with patients’ prognosis (17).
Body mass
All patients will be weighed at admission to the hospital and during control visits 1- and 6-months after discharge. Weight change will be measured. Maintaining healthy body weight is one of the fundamental aspects of preventing cardiovascular diseases and an essential treatment element after an MI.
Nicotinism
All patients will be asked about smoking at admission and during control visits 1- and 6-months after discharge. Smoking cessation is one of the main goals of patients after MI. Quitting smoking is necessary to reduce the risk of another ischemic incident. It has been documented that patients who stopped smoking have reduced the risk of another MI by 50% (18).
Dyslipidemia
All patients after MI will have their cholesterol levels measured during hospitalization. Subsequent cholesterol level measurements will be performed during control visits. According to ESC guidelines, different groups of patients have different LDL cholesterol target values, which should be met during the rehabilitation process (19). Lowering LDL cholesterol levels correlates with a better prognosis after MI (20).
Secondary Outcome Measures:
Quality of life – MacNew (21)
Quality of life will be assessed with the MacNew questionnaire containing 27 questions. The scoring of the MacNew is as follows, the maximum score in every domain is 7 [high quality], and the minimum is 1 [poor quality]. The quality of life is assessed in the context of physical, emotional, and social aspects.
Quality of life - descriptive profile of the respondent's health state (22)
Quality of life will be assessed with the help of the EQ-5D-5L questionnaire, gauging 5 aspects: mobility, self-care, usual activity, pain/discomfort, and anxiety/depression. Every segment is assessed based on a 5 level scale:
LEVEL 1: indicating no problem; LEVEL 2: indicating slight problems; LEVEL 3: indicating moderate problems; LEVEL 4: indicating severe problems; LEVEL 5: indicating an inability to/extreme problems
DASS 21 - Depression, anxiety and stress assessment (23)
Depression, anxiety, and stress assessment will be assessed with DASS 21 scale. The DASS is a quantitative measure of distress along the 3 axes of depression, anxiety, and stress.
There are 21 questions; each has 4 possible answers:
0 Did not apply to me at all - NEVER
1. Applied to me to some degree, or some of the time - SOMETIMES
2. Applied to me to a considerable degree, or a good part of the time - OFTEN
3. Applied to me very much, or most of the time - ALMOST ALWAYS
Seven questions are assigned to every aspect: depression, anxiety, and stress.
Higher result in each section contributes to higher severity in depression, anxiety, and stress.
Cardiovascular risk factors knowledge
Cardiovascular risk factors knowledge will be assessed with a previously prepared questionnaire (10 questions).
Return to work
In the cases of previously working patients, the likelihood of returning to work will be assessed, and the timing of returning to work will be counseled.
Participant timeline {13}
Figure 1 shows the recommended SPIRIT figure with the participant timeline.
Sample size {14}
Currently, the data regarding the reduction of rehospitalizations or urgent visits impacted by mobile applications is limited. Previous studies were conducted on smaller populations. This calculation was based on Widmer and colleagues' (5) study, considering rehospitalization and urgent ambulatory visits — comparing the effects of an online and smartphone-based program with standard rehabilitation on the mentioned endpoint. There was a 40% decrease in the primary endpoint. 50% of patients in the control group and 20% in the interventional arm were rehospitalized or visited the emergency department.
An online calculator (https://clincalc.com/) was used to determine the sample size, assuming the power of 80% and significance of 5%. A total of 76 patients (38 per group) were required. However, considering a possible lost-to-follow-up group and possible dropouts, a decision to recruit 100 patients was made.
Recruitment {15}
Participant recruitment will occur daily from Monday to Friday. Patients eligible for the study and willing to participate will be provided with complete and detailed information on the study protocol. Lastly, patients will sign two copies of the informed consent.
Assignment of interventions: allocation
Sequence generation {16a}
Concealment mechanism {16b}
Implementation {16c}
Randomization will be performed with an online tool available at https://www.randomizer.org. A hundred sets will be generated, each with a number (1 for CG and 2 for IG). All allocations to CG and IG will be executed before the study begins. The list of subsequent allocations will not be visible for the recruiting physician until the initial eligibility assessment of the patient and obtaining the patient’s consent for study participation. After collecting the initial documentation, the physician will be unblinded and receive the group allocation information from the principal investigator. It should be underlined that the person who checks for inclusion criteria and introduces the patient into the trial protocol is blinded until patient agreement. Figure 2 shows the study design flow chart, describing all the steps of the study (Fig. 2).
Assignment of interventions: Blinding
Who will be blinded {17a}
This is an open-label study. The only blinded study participants will be physicians who will check the patients’ will to participate in the study. After obtaining agreement, the randomized group will be unblinded. Person performing statistical analysis will be blinded, as well as nurses collecting blood samples on the follow-up visits. Taking into consideration use of mobile application in everyday practice it is impossible to blind phisicians performing follow-up visits. It could be regarded as ethically doubtful, because based on the data provided via mobile application clinical decisions an be made (i.e. blood pressure treatment augmentation).
Procedure for unblinding if needed {17b}
This is an open-label study. The recruiting physicians will be unblinded after obtaining agreement from the patient.
Data collection and management
Plans for assessment and collection of outcomes {18a}
The assessments will be carried out at the 1st Department of Cardiology, Medical University of Warsaw, and the rehabilitation will follow a scheduled program. The intervention involves installing the afterAMI mobile application on patients’ smartphones. Control visits will take place in the cardiac ambulatory clinic. Blood samples will be sent to the local laboratory. Patients will be asked to fulfill the MacNew, EQ-5D-5L, and DASS21 questionnaires. An experienced cardiologist familiar with the study protocol will conduct all the control visits. Highest data quality is one author’s primary goal while conducting a trial. Every information will be entered into database and subsequently checked by another investigator. Every investigator will have valid good clinical practice certificate.
Plans to promote participant retention and complete follow-up {18b}
Patients will be called to schedule the control visit’s date after discharge. Additionally, patients in the IG will receive a notification in their mobile app reminding them about the upcoming ambulatory visits.
Data management {19}
All data collected during the study and medical documents will be protected and stored in a room dedicated to clinical trials’ records. All electronic materials will be duly stored in the principal researcher’s computer protected with a password known only to the principal researcher. Additionally, a backup in the cloud will be performed after new data collection.
Confidentiality {27}
The highest level of confidentiality will be applied. The participants’ data will be kept separately from any identifying information. According to good clinical practice, all investigators will make every effort to keep the sensitive data confidential.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
Not applicable; all blood samples will be tested in the laboratory according to the locally implemented standards and subsequently utilized. There are no plans for future blood use. No other biological specimen will be tested during this trial.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
The distribution of continuous variables will be estimated using the Shapiro-Wilk test. In the case of variables with a normal and non-normal distribution, the groups will be compared using the Student's t-test and the non-parametric Mann-Whitney U test. The comparison of qualitative variables between the groups will be performed using the Fisher exact test. In order to compare changes in the values of continuous variables over time, the analysis of variance will be performed. To compare the outcome of the patients, the Kaplan-Meier estimators will be utilized. Primary endpoint will be assessed together and separately. For quantitative variables the change from baseline will be assessed. Additionally, in order to diminish differences in sex and age related to group size, propensity score matching analysis will be performed as well.
Interim analyses {21b}
Not applicable; interim analyses will not be performed in the present study.
Methods for additional analyses (e.g. subgroup analyses) {20b}
Not applicable; additional analyses are not planned in the present study.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
A per-protocol analysis will be performed after completing all of the follow-up visits. In the analysis, we will include all patients who meet inclusion criteria and sign informed consent regardless of the follow-up completion. Statistical calculations will be performed twice; after obtaining data from the first follow-up visit from all patients and after the final follow-up, 6 months after discharge. In case of missing data, patients will be excluded from the particular analysis.
Plans to give access to the full protocol, participant level-data and statistical code {31c}
Not applicable; access to the data sets and statistical code are not planned for this study. However, this material might be available upon an adequately justified request to the corresponding author while maintaining participants’ anonymity.
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
The research center is coordinated and managed by GO and the researcher MG. The principal investigator-BK will direct the trial. There is no additional steering committee considered for this study. All researchers will meet monthly to discuss the recruitment progress and solve possible issues.
Composition of the data monitoring committee, its role and reporting structure {21a}
No additional external monitoring committee is considered for this study. The principal investigator will meet monthly with all the researchers involved in this study via an online platform (Zoom) to discuss the research progress and solve possible issues. Researchers are instructed to immediately report any issues to the principal investigator, who will subsequently organize an additional committee meeting and inform the board review committee from the Medical University of Warsaw and the Ethics Committee of the Medical University of Warsaw, Warsaw, Poland, when appropriate.
Adverse event reporting and harms {22}
Serious adverse events of mobile application usage have not been described so far. However, any adverse events will be reported and thoroughly documented and presented in the study summary.
Frequency and plans for auditing trial conduct {23}
The principal investigator will continuously monitor the trial conduct. Monthly reports regarding any potential adverse events and protocol violations will be prepared. Additional auditing will be conducted on request from the Ethics Committee of the Medical University of Warsaw.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
Any protocol amendments will be reported to and approved by the Ethics Committee of the Medical University of Warsaw. All modifications will be updated at clinicaltrials.gov by the principal investigator (BK). Any important protocol modifications will be communicated to the investigators and patients verbally.
Dissemination plans {31a}
The participants will receive a full report with the results of their assessments after the data is analyzed. At the end of the study, the principal investigator will contact the participants to provide them with final educational materials and information regarding secondary cardiovascular prevention. Study outcomes will be reported at both local and international cardiological conferences. The final study results will be submitted to a peer-reviewed indexed scientific journal within the 3 years after the last patient's enrollment.