The ReInforcement of adherence via self-monitoring app orchestrating biosignals and medication of RivaroXaban in patients with atrial fibrillation and co-morbidities: a study protocol for a randomized controlled trial (RIVOX-AF)

Background Because of the short half-life of non-vitamin K antagonist oral anticoagulants (NOACs), consistent drug adherence is crucial to maintain the effect of anticoagulants for stroke prevention in atrial fibrillation (AF). Considering the low adherence to NOACs in practice, we developed a mobile health platform that provides an alert for drug intake, visual confirmation of drug administration, and a list of medication intake history. This study aims to evaluate whether this smartphone app-based intervention will increase drug adherence compared with usual care in patients with AF requiring NOACs in a large population. Methods This prospective, randomized, open-label, multicenter trial (RIVOX-AF study) will include a total of 1,042 patients (521 patients in the intervention group and 521 patients in the control group) from 13 tertiary hospitals in South Korea. Patients with AF aged ≥19 years with one or more comorbidities, including heart failure, myocardial infarction, stable angina, hypertension, or diabetes mellitus, will be included in this study. Participants will be randomly assigned to either the intervention group (MEDI-app) or the conventional treatment group in a 1:1 ratio using a web-based randomization service. The intervention group will use a smartphone app that includes an alarm for drug intake, visual confirmation of drug administration through a camera check, and presentation of a list of medication intake history. The primary endpoint is adherence to rivaroxaban by pill count measurements at 12 and 24 weeks. The key secondary endpoints are clinical composite endpoints, including systemic embolic events, stroke, major bleeding requiring transfusion or hospitalization, or death during the 24 weeks of follow-up. Discussion This randomized controlled trial will investigate the feasibility and efficacy of smartphone apps and mobile health platforms in improving adherence to NOACs. Trial registration The study design has been registered in ClinicalTrial.gov (NCT05557123).

[1]  Sungyoung Lee,et al.  Rationale design and efficacy of a smartphone application for improving self-awareness of adherence to edoxaban treatment: study protocol for a randomised controlled trial (adhere app) , 2022, BMJ Open.

[2]  K. Reynolds,et al.  Long‐Term Medication Adherence Trajectories to Direct Oral Anticoagulants and Clinical Outcomes in Patients With Atrial Fibrillation , 2021, Journal of the American Heart Association.

[3]  M. Turakhia,et al.  Efficacy of a Centralized, Blended Electronic and Human Intervention to Improve Direct Oral Anticoagulant Adherence: Smartphones to improve rivaroxaban ADHEREnce in Atrial Fibrillation (SmartADHERE) A Randomized Clinical Trial: SmartADHERE rivaroxaban adherence trial. , 2021, American heart journal.

[4]  Jeroen J. Bax,et al.  2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS). , 2020, European heart journal.

[5]  Xi Li,et al.  Smartphone-based application to improve medication adherence in patients after surgical coronary revascularization. , 2020, American heart journal.

[6]  G. Lip,et al.  The optimal drug adherence to maximize the efficacy and safety of non-vitamin K antagonist oral anticoagulant in real-world atrial fibrillation patients. , 2020, Europace.

[7]  S. Sutton,et al.  Do mobile device apps designed to support medication adherence demonstrate efficacy? A systematic review of randomised controlled trials, with meta-analysis , 2020, BMJ Open.

[8]  C. Nam,et al.  NOAC Adherence of Patients with Atrial Fibrillation in the Real World: Dosing Frequency Matters? , 2019, Thrombosis and Haemostasis.

[9]  Peter M. A. Sloot,et al.  A Smartphone App to Improve Medication Adherence in Patients With Type 2 Diabetes in Asia: Feasibility Randomized Controlled Trial , 2019, JMIR mHealth and uHealth.

[10]  Hugh Calkins,et al.  Correction to: 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. , 2019, Circulation.

[11]  G. Humphrey,et al.  Impact of a smartphone app on prescriber adherence to antibiotic guidelines in adult patients with community acquired pneumonia or urinary tract infections , 2019, PloS one.

[12]  Hugh Calkins,et al.  2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. , 2019, Heart rhythm.

[13]  B. Joung,et al.  2018 Korean Guideline of Atrial Fibrillation Management , 2018, Korean circulation journal.

[14]  L. Saxon,et al.  Use of software applications to improve medication adherence and achieve more integrated disease management in heart failure. , 2018, Trends in cardiovascular medicine.

[15]  Leslie Oley,et al.  Association of a Smartphone Application With Medication Adherence and Blood Pressure Control: The MedISAFE-BP Randomized Clinical Trial , 2018, JAMA internal medicine.

[16]  C. Willey,et al.  Real-World Health Care Costs Based on Medication Adherence and Risk of Stroke and Bleeding in Patients Treated with Novel Anticoagulant Therapy. , 2018, Journal of managed care & specialty pharmacy.

[17]  H. Heidbuchel,et al.  Telemonitoring-based feedback improves adherence to non-vitamin K antagonist oral anticoagulants intake in patients with atrial fibrillation , 2018, European heart journal.

[18]  Seil Oh,et al.  Temporal trends of antithrombotic therapy for stroke prevention in Korean patients with non-valvular atrial fibrillation in the era of non-vitamin K antagonist oral anticoagulants: A nationwide population-based study , 2017, PloS one.

[19]  D. Gothelf,et al.  P.7.d.012 Testing the efficacy of a smartphone application in improving medication adherence among children with ADHD , 2017, European Neuropsychopharmacology.

[20]  L. Sharp,et al.  Real‐World Adherence and Persistence with Direct Oral Anticoagulants in Adults with Atrial Fibrillation , 2017, Pharmacotherapy.

[21]  Paul L. Hess,et al.  Adherence and outcomes to direct oral anticoagulants among patients with atrial fibrillation: findings from the veterans health administration , 2017, BMC Cardiovascular Disorders.

[22]  Laura Shafner,et al.  Using Artificial Intelligence to Reduce the Risk of Nonadherence in Patients on Anticoagulation Therapy , 2017, Stroke.

[23]  C. Given,et al.  Beta Testing a Novel Smartphone Application to Improve Medication Adherence. , 2017, Telemedicine journal and e-health : the official journal of the American Telemedicine Association.

[24]  G. Lip,et al.  The Changing Landscape for Stroke Prevention in AF: Findings From the GLORIA-AF Registry Phase 2. , 2017, Journal of the American College of Cardiology.

[25]  G. Lip,et al.  Adherence to oral anticoagulant therapy in patients with atrial fibrillation , 2016, Thrombosis and Haemostasis.

[26]  Joakim Alfredsson,et al.  Effects of interactive patient smartphone support app on drug adherence and lifestyle changes in myocardial infarction patients: A randomized study. , 2016, American heart journal.

[27]  M. Woodward,et al.  Mobile Telephone Text Messaging for Medication Adherence in Chronic Disease: A Meta-analysis. , 2016, JAMA internal medicine.

[28]  G. Caleb Alexander,et al.  Effect of Adherence to Oral Anticoagulants on Risk of Stroke and Major Bleeding Among Patients With Atrial Fibrillation , 2016, Journal of the American Heart Association.

[29]  C. How.  Novel oral anticoagulants for atrial fibrillation. , 2015, Singapore medical journal.

[30]  Alexander Parkhomenko,et al.  Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials , 2014, The Lancet.

[31]  E. Antman,et al.  Edoxaban versus warfarin in patients with atrial fibrillation. , 2013, The New England journal of medicine.

[32]  S. Erdine,et al.  Monitoring Treatment Adherence in Hypertension , 2013, Current Hypertension Reports.

[33]  S. Kelders,et al.  Persuasive System Design Does Matter: A Systematic Review of Adherence to Web-Based Interventions , 2012, Journal of medical Internet research.

[34]  D. Atar,et al.  Apixaban versus warfarin in patients with atrial fibrillation. , 2011, The New England journal of medicine.

[35]  G. Breithardt,et al.  Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. , 2011, The New England journal of medicine.

[36]  Gregory Y H Lip,et al.  Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. , 2010, Chest.

[37]  S. Yusuf,et al.  Dabigatran versus warfarin in patients with atrial fibrillation. , 2009, The New England journal of medicine.

[38]  F. Schmidt.  Meta-Analysis , 2008 .

[39]  Dietrich Andresen,et al.  Atrial fibrillation management: a prospective survey in ESC member countries: the Euro Heart Survey on Atrial Fibrillation. , 2005, European heart journal.

[40]  T. Wilt,et al.  A meta-analysis of randomised trials suggests a survival benefit for combined radiotherapy and radical cystectomy compared with radical radiotherapy for invasive bladder cancer: are these data relevant to modern practice? , 2004, Clinical oncology (Royal College of Radiologists (Great Britain)).

[41]  K. Farmer,et al.  Methods for measuring and monitoring medication regimen adherence in clinical trials and clinical practice. , 1999, Clinical therapeutics.

[42]  Yelena P. Wu,et al.  Use of a Smartphone Application for Prompting Oral Medication Adherence Among Adolescents and Young Adults With Cancer , 2018, Oncology nursing forum.

[43]  D. Laurent,et al.  A randomized study , 2010 .