Introduction
With every third adult being affected by primary arterial hypertension, it is one of the most prevalent diseases in industrialised countries, accountable for over 7 million deaths per year worldwide.1 2 Although the course of the disease frequently remains unrecognised for several years, untreated hypertension causes serious complications, like coronary artery disease, myocardial infarction, heart failure and stroke. Additionally, therapeutic measures like lifestyle changes and medication intake are often characterised by low patient compliance.3 Early detection and consistent treatment have a significant impact, not only on the individual health status but also in terms of global health economics.4 5 Therefore, it is important to establish a concept that facilitates long-term adherence to the therapy regime for patients and physicians.
Today, there are numerous devices for digital self-administered blood pressure measurements. In general, digital blood pressure recordings have proven to optimise treatment in medically underserved areas and to facilitate the transition from inpatient to outpatient care.6–10 First systems implementing the use of digital blood pressure recordings, mostly in combination with telemedical consultations, have shown an additional lowering of systolic blood pressure by 4 mm Hg while optimising health economic costs at the same time.11–13 Furthermore, several studies concluded that digital health programmes including, but not limited to self-administered measurings, not only have the ability to positively impact the individual health but might also have the ability to transform the pathways of disease management.14–16 Digital health applications have the potential to implement the latest guideline-based recommendations into the patients’ therapy regimes without actively consulting a physician. In addition, recommendations can be adjusted to the individual needs and might be able to improve compliance.14 15 However, studies on this comparably new topic are rare and often investigate rather small samples.14 Besides the individual health benefits, digital disease management programmes provide the possibility of data processing using artificial intelligence, which introduces new and innovative strategies for risk stratification and potentially early detection based on individualised patient data.10
The eXPLORE study (Trial Registration: ClinicalTrials.gov NCT05580068) aims to evaluate the feasibility of a clinical study on the impact of a supplementary digital therapy programme (iATROS digital therapy programme) for the treatment of primary arterial hypertension. Furthermore, the dispersion of the outcome measure serves as data basis for the power analyses of following larger-scaled trials. Therefore, no a priori research hypotheses were established due to the explorative approach of the study. Subsequent data analyses aim to generate research hypotheses for upcoming trials.
Methods and analysis
Study background
The eXPLORE study is a cooperative project of the Department of Cardiology at Ludwig-Maximilians-University (LMU) in Munich, Germany and the company iATROS (Munich, Germany). Data collection and handling were exclusively performed by registered study physicians at LMU Munich, Germany. The company iATROS only had access to pseudonymised data. The study was approved by the local ethics committee of LMU Munich (project nr.: 22–0115).
The iATROS digital therapy programme
The technical platform consists of an electronic health record connected on the patient’s side to a smartphone app and on the physician’s side to a dashboard for the staff of the telemedicine centre (iATROS, Munich, Germany, with technical functions provided by DocCirrus, Berlin, Germany). The platform is a CE-certified medicinal product and complies with the German and European Union data protection regulations. The app serves as the interface between the patient and the platform and includes the following functions: (1) manually entering blood pressure data as well as other vital parameters (option to connect bluetooth blood pressure measurement device if available), (2) feedback on blood pressure data, (3) displaying educational content such as videos, texts and short messages, (4) generating tasks such as reminders to measure blood pressure, watch a video, take medication, perform exercise or follow nutritional advice and (5) scheduling appointments for videoconsultations with a Telemedicine Centre physician (iATROS, Munich, Germany).
The dashboard for staff and physicians of the telemedicine centre displays blood pressure and all other medical information that the patient has entered, the documentation of previous teleconsultations, and information on which tasks were performed and skipped by the patient (iATROS, Munich, Germany).
A core function of the system is to display the educational content of the digital health programme to treat hypertension which consists of >100 elements over 180 days to the patient over the app. The education programme includes content on health literacy (disease, diagnosis and treatment) and lifestyle education including nutrition and sports (iATROS, Munich, Germany). Remote technical assistance and telemedicine consultation via video or phone are provided initially at the start of the programme and thereafter, when booked by the patient (Deutsche Telemedizin, Duisburg, Germany).
The programme is designed to provide patient support in accordance with the current European Society of Cardiology/European Society of Hypertension (ESC/ESH) guidelines on arterial hypertension.17
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Home-based blood pressure (BP) measurement: the guidelines generally recommend measurement of BP at home rather than in office, as this method provides more reproducible BP data, is more closely related to hypertension-mediated organ dysfunction and left ventricular hypertrophy, appears to better predict morbidity and mortality, and to have positive effects on medication adherence.18–21
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Education on self-measurement: the training content in the digital health programme to treat hypertension teaches the patient to measure blood pressure according to the ESC/ESH guidelines: taken in a quiet room after 5 min of rest, with the patient seated with their back and arm supported. Two measurements should be taken at each measurement session, performed 1–2 min apart.22
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Education of lifestyle optimisation, including nutrition and exercise: healthy lifestyle is recommended to prevent or delay the onset of hypertension and reduce cardiovascular risk, and can augment the efficacy of blood pressure-lowering medication.17 23 Recommendations that the patients receive through the programme via the app include restriction of dietary salt, moderation of alcohol consumption, high consumption of vegetables and fruits, maintaining an ideal body weight and regular physical activity.
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Telemedicine: The possibility to book an appointment with a telemedicine doctor gives the patient the possibility to get high-urgency medical attention.
This study is the first to evaluate the efficacy of the digital health programme to treat hypertension in a randomised controlled trial. Internal systematic analyses of real-world data with the platform have shown that blood pressure can be significantly reduced. Moreover, recent research has shown additional benefits in the combination of different therapeutic measures for lowering of blood pressure in patients with hypertension. In a meta-analysis investigating the relationship between blood pressure lowering and care intensity, reduction of up to 6 mm Hg was observed.24 Consequently, the intervention was designed to combine the different therapy elements of home blood pressure measurements, measurement value feedback, patient education and telemedical care by physicians.
Study design and setting
The eXPLORE study is a prospective randomised controlled feasibility study exploring the changes in blood pressure of an intervention group (iATROS digital therapy programme) vs standard care therapy.
The intervention group receives access to the iATROS digital therapy programme which serves as an outpatient therapy programme to optimise lifestyle factors and improve compliance. Furthermore, patients have the opportunity to book teleconsultations. Participants are required to enter data on blood pressure and heart frequency three times a day (08:00 a.m., 12:00 p.m. and 6:00 p.m.). Push messages serve as a reminder to ensure the data entry at standardised time points. Participants that are randomised into the standard care group do not need to take any additional actions but they are free to do so at their own discretion.
For inclusion in the eXPLORE study, participants had to meet the following criteria:
Inclusion criteria
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Age ≥18 years
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Diagnosed arterial hypertension (ICD 10 diagnosis: I10.- to I13.-)
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Mean systolic blood pressure between 130 mm Hg and 170 mm Hg in a 24-hour long-term blood pressure measurement. respectively between 135 mm Hg and 175 mm Hg in a 7-day at-home measure. Since the recruitment numbers turned out to be temporarily limited by the availability of 24 hours measuring devices, the methodological approach of data collection was extended: in addition to the ambulatory 24 hours blood pressure measure (ABPM), all participants must document their blood pressure for 7 days in a standardised RR-diary (three times a day, two consecutive measures). If no 24 hours blood pressure device is available, the mean value of all 7 days at-home measures (HBPM) serves as screening and subsequently follow-up tool
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Usage of a smartphone capable of running the iATROS application
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Physical and mental abilities to operate the digital tool
Exclusion criteria
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Missing capability to give informed consent
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Age <18 years
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No use of a smartphone
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Lack of physical and mental abilities to operate the digital tool
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Pre-existing usage of the iATROS app
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Participation in any other clinical study that may impact the compliance of the app usage or may bias the study results
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If ESC guideline classification for blood pressure is not applicable
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Substance abuse
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Medical contraindications:
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Pre-existing illness with a limited life expectation under 1 year
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Immune suppression
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Dementia
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Underlying disease that restricts participation
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Pregnancy and nursing
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Secondary hypertension
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Systolic blood pressure at baseline: ABPM >170 mm Hg, HBPM >175 mm Hg
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Stroke within the last 3 months
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Transitory ischaemic attack within the last 3 months
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Recruitment and data collection
Recruitment started in November 2022 and will be continued until the enrolment of 100 individuals who completed the entire follow-up. Patients are recruited via public advertisement for the eXPLORE study, for example, newspaper, online marketing and poster advertising. As a second strain of recruitment, former patients of the Medical Clinic I (Cardiology) of the LMU Hospital of the Ludwigs Maximilians University within 2021 to 2023 who had a confirmed diagnosis of arterial hypertension are selectively informed via letter. Since this is a feasibility study, different strains of recruitment are pursued and evaluated during the recruitment process.
The eXPLORE study is entirely based on a remote concept. The advertisement and information letters include a link for scheduling an initial information session (via Webex software) with a study physician. For participation, informed consent has to be signed digitally (https://app.pandadoc.com/), followed by a short survey on patients’ sociodemographic data as well as medical history and a self-administered 24 hours long-term blood pressure measurement (custo med GmbH, Germany). If eligible, participants are randomised 1:1 via an iATROS proprietary online tool matching for the range of the mean systolic blood pressure at baseline (130–140 mm Hg; 141–150 mm Hg; 151–169 mm Hg). After inclusion into the study, the general practitioner of every practitioner was informed about the participation and study objective of the eXPLORE study. Importantly, the general practitioner was also provided with the full results of the baseline 24 hours long-term blood pressure measurement, which shows hypertensive values, and was instructed that the study protocol imposes no restrictions to treat her/his patient according to best medical practice.
The total study period is 180 days, containing 90 days in-live phase and an additional 90 days follow-up phase (online supplemental material 1). Data of all participants was collected at baseline, after 90 days (3 months follow-up) and 180 days (6 months follow-up), including
Supplemental material
(1) an interview-based questionnaire survey (online supplemental material 2) on (serious) adverse events, medical data and lifestyle changes performed by a study physician via Webex conference call, (2) a self-administered 24 hours long-term blood pressure measurement and a 7 days at-home blood pressure monitoring (if no 24 hours blood pressure tool was available, only HBPM needs to be performed; subsequently, also the follow-up measures need to be HBPM), and (3) an online questionnaire on health literacy (HLQ-questionnaire) and self-sufficient health behaviour (PAM-13 questionnaire) that was sent to the participants after each meeting via email.
Supplemental material
After inclusion into the eXPLORE study participants, general practitioner is informed about the study participation. The iATROS digital therapy programme does not make suggestions on alterations of the existing antihypertensive medication, but alterations in medication can be made whenever medically necessary. Patients in the intervention group using the iATROS digital therapy programme have a reminder function for drug intake and the opportunity to book telemedicine consultations, in which the medication can be adjusted if medically necessary. These patients receive a doctor’s note and revised medication plan to inform their general practitioner. In any case, information on changes in the medication is documented during the prescheduled follow-up visits (3 months/6 months follow-up).
Study endpoints
For the methodological feasibility of the study, the primary endpoint was the evaluation of
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Usage of the iATROS App under controlled study conditions
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Compliance, dropout rates, loss-to-follow-up rates
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Testing of various advertising measures for recruitment
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Recruitment process
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Estimation of sample size
Secondary endpoints were defined as follows:
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Evaluation of systolic blood pressure at baseline, 90 days and 180 days within the intervention group (iATROS digital therapy programme) and the control group (standard care)
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Evaluation of changes in health literacy
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Evaluation of changes in self-sufficient health behaviour
Sample size
For the eXPLORE feasibility study, a sample size of 100 participants (n=50 intervention group vs n=50 control group) to complete the follow-up was predetermined as the primary goal was to evaluate the feasibility of the study concept. Additionally, the collected data provides information about the spread of the blood pressure data which will be considered for the power calculation of larger-scaled follow-up studies. The present investigation was not powered to detect blood pressure differences between the groups.
Data analyses
Feasability outcomes
Since the study aims to test for methodological feasibility, follow-up rates achieved via different recruitment strategies will be analysed. For process optimisation, all members of the study group are requested to regularly report about their experiences, problems and suggestions. Furthermore, participants are asked for their feedback on the study process in a standardised questionnaire (1) at baseline (information on the recruitment process) and (2) at the end of the follow-up, including:
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Baseline questionnaire
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Comprehensability of the main subject of the study, the timeline and the outcome measures
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Quality and contentment of information delivery and explanations
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Remaining questions before inclusion into the study
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Sufficient and satisfactory supply of information
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Follow-up questionnaire (Study Participant Feedback Questionnaire)25
Primary and secondary endpoints
In accordance with the primary endpoints response rates will be analysed stratified for different advertisement strategies, as well as dropout and loss-to-follow-up counts.
The analyses on the dispersion of the outcome ‘changes in mean blood pressure’ will serve for power calculation of larger-scaled follow-up surveys.
All secondary endpoints will be examined in an explorative approach; analyses aim to generate research hypotheses in order to establish a reliable concept for larger-scaled follow-up trials.
For the analyses of the differences between the groups,1 intergroup comparisons will be calculated, including data on sociodemographics, health and lifestyle data as well as blood pressure measures for every timepoint (baseline, 90 days, 180 days). Additionally,2 intragroup comparisons will be analysed aiming to detect changes within the study groups.
For descriptive analyses, measures of central tendency and dispersion will be calculated. Statistics on the group comparisons will be derived according to the scaling of the variables and the dispersion of the data.
All analyses above can only serve to generate hypothesis since the study was not powered for these analyses.
Data monitoring
Data monitoring is carried out at the study site by an independent body at predefined study milestones:
The monitoring is commissioned by the sponsor who receives a monitoring report and is informed about any violations of the study protocol.
Patient and public involvement
Patient and members of the public were involved at several stages of the trial, including the design, management and conduct of the trial. The entirely remote concept of this study is a result of several informal patient discussions as well as evaluations of the study team to facilitate recruitment and enhance patient comfort. In a preliminary phase, the iATROS App was tested and improved on continuous patient feedback. Public involvement was further strengthened by public advertisement campaigns. We intend to disseminate the main results to trial participants and will seek patient and public involvement in the development of an appropriate method of dissemination.
Ethics and dissemination
The study was approved by the local ethics committee of LMU Munich (project nr.: 22–0115). A positive cost-benefit ratio is ensured by the continuous evaluation of the study. Adverse events were predefined and classified according to intensity and duration (serious adverse event vs adverse event). As a part of the survey, all (serious) adverse events are documented and reported to the responsible authority within a statutory deadline where applicable, taking all relevant legal regulations into account.
In general, the eXPLORE study investigates a non-invasive approach for the ambulant management of arterial hypertension via a novel non-invasive digital healthcare tool that aims to improve patient compliance and enhance the management of lifestyle adjustments. Since the measure of participation in a digital health programme is non-invasive, no study-related disadvantages are expected. The control group still receives the standard care treatment; no study-related changes will be made.
Therefore, to the investigators’ best knowledge, no ethical concerns in connection to the study approach are anticipated.
For the dissemination, all health-relevant data from the eXPLORE study will be provided for analyses and publication to the investigators of LMU Hospital. The authorisation to authorship demands a substantial contribution to the conception of the study, data collection and analyses as well as the preparation of a publication manuscript; additionally, the specific requirements for authorship of the respective journal have to be met.
Interim results
Recruitment and data collection are currently ongoing, within the time frame of 1 year, n=162 individuals signed up for an online information appointment; of these, 50% (n=81) wanted to participate in the study. From 81 potential participants, 62% (n=50) were eligible and subsequently included in the study.
In July 2023, the recruitment was stopped for the period of 6 months since at-home blood pressure measurements were included into the study and changes in the study protocol had to be approved by the ethics committee.
Considering the participation rates, the study is expected to reach the sample size goal of 100 participants to complete the follow-up by March 2025. Up to now, no serious adverse events related to the iATROS digital therapy programme were observed.
Detailed study data will not be published until the completion of the eXPLORE study.
Discussion
The eXPLORE study was designed to test for methodological feasibility of a remote approach for recruitment and data collection. This new approach could have an impact beyond the present study since it simplifies especially the process of data collection which could result in an improvement of response rates and a reduction in loss to follow-up and dropout rates. Additionally, the remote design facilitates the inclusion of subjects beyond regional borders even without a multicentre study approach which might improve generalisability of study results and reduce systematic bias.
Due to temporal limitations in the availability of 24 hours blood pressure measuring devices (ABPM), we included an alternative approach of repetitive 7 days at-home measurements (HBPM) in our recruitment process and adapted the study protocol. In fact, a majority of our patients performed both measurements in parallel and ABPM device limitations were only rare. This dual measurement will potentially allow us to establish the optimal methodology for measuring blood pressure in the subsequent larger-scaled trials. Indeed, the current ESC guidelines on hypertension give both methods an equivalent (class I C) recommendation.17
While the present feasibility study is not powered to measure health improvements of study participants, it nevertheless forms a first basis for the evaluation of combined smartphone-delivered therapy acceptance and feasibility. As this mode of patient-centric treatment will likely continue to gain traction in healthcare, it warrants the investigation of its advantages and drawbacks.
In the long run, the eXPLORE study aims to establish a new approach in the treatment of arterial hypertension. A beneficial usage of digital health programmes to improve lifestyle factors could have a great impact on cardiovascular disease management since it would impact primary as well as secondary disease prevention. Therefore, it would not only positively impact the individual’s health but might also reduce health costs that arise from secondary diseases caused by hypertension.
This post was originally published on https://bmjopen.bmj.com