Beyond Validation: Getting Wearable Activity Trackers into Cardiovascular Care - A Discussion Paper.

This paper addresses the challenge of integrating wearable activity trackers into cardiovascular disease care. Despite evidence supporting the use of trackers for monitoring and promoting physical activity, implementation challenges persist in clinical settings. The paper emphasises the lack of systematic, evidence-based implementation approaches for integrating trackers. It underscores the urgent need for stakeholder collaboration between clinicians, patients, implementation scientists, researchers, health and technology partners, and the use of proven implementation science methodologies. This is crucial for bridging the gap and ensuring effective translation of wearable activity trackers into cardiovascular disease care, meeting the increasing demand from patients and clinicians.

Digital consults to optimize guideline-directed therapy: design of a pragmatic multicenter randomized controlled trial.

AIMS: Many heart failure (HF) patients do not receive optimal guideline-directed medical therapy (GDMT) despite clear benefit on morbidity and mortality outcomes. Digital consults (DCs) have the potential to improve efficiency on GDMT optimization to serve the growing HF population. The investigator-initiated ADMINISTER trial was designed as a pragmatic multicenter randomized controlled open-label trial to evaluate efficacy and safety of DC in patients on HF treatment. METHODS AND RESULTS: Patients (n = 150) diagnosed with HF with a reduced ejection fraction will be randomized to DC or standard care (1:1). The intervention group receives multifaceted DCs including (i) digital data sharing (e.g. exchange of pharmacotherapy use and home-measured vital signs), (ii) patient education via an e-learning, and (iii) digital guideline recommendations to treating clinicians. The consults are performed remotely unless there is an indication to perform the consult physically. The primary outcome is the GDMT prescription rate score, and secondary outcomes include time till full GDMT optimization, patient and clinician satisfaction, time spent on healthcare, and Kansas City Cardiomyopathy Questionnaire. Results will be reported in accordance to the CONSORT statement. CONCLUSIONS: The ADMINISTER trial will offer the first randomized controlled data on GDMT prescription rates, time till full GDMT optimization, time spent on healthcare, quality of life, and patient and clinician satisfaction of the multifaceted patient- and clinician-targeted DC for GDMT optimization.

Ultra-low-dose CT versus chest X-ray for patients suspected of pulmonary disease at the emergency department: a multicentre randomised clinical trial.

BACKGROUND: Chest CT displays chest pathology better than chest X-ray (CXR). We evaluated the effects on health outcomes of replacing CXR by ultra-low-dose chest-CT (ULDCT) in the diagnostic work-up of patients suspected of non-traumatic pulmonary disease at the emergency department. METHODS: Pragmatic, multicentre, non-inferiority randomised clinical trial in patients suspected of non-traumatic pulmonary disease at the emergency department. Between 31 January 2017 and 31 May 2018, every month, participating centres were randomly allocated to using ULDCT or CXR. Primary outcome was functional health at 28 days, measured by the Short Form (SF)-12 physical component summary scale score (PCS score), non-inferiority margin was set at 1 point. Secondary outcomes included hospital admission, hospital length of stay (LOS) and patients in follow-up because of incidental findings. RESULTS: 2418 consecutive patients (ULDCT: 1208 and CXR: 1210) were included. Mean SF-12 PCS score at 28 days was 37.0 for ULDCT and 35.9 for CXR (difference 1.1; 95% lower CI: 0.003). After ULDCT, 638/1208 (52.7%) patients were admitted (median LOS of 4.8 days; IQR 2.1-8.8) compared with 659/1210 (54.5%) patients after CXR (median LOS 4.6 days; IQR 2.1-8.8). More ULDCT patients were in follow-up because of incidental findings: 26 (2.2%) versus 4 (0.3%). CONCLUSIONS: Short-term functional health was comparable between ULDCT and CXR, as were hospital admissions and LOS, but more incidental findings were found in the ULDCT group. Our trial does not support routine use of ULDCT in the work-up of patients suspected of non-traumatic pulmonary disease at the emergency department. TRIAL REGISTRATION NUMBER: NTR6163.

A comparison of ECG-based home monitoring devices in adults with CHD.

BACKGROUND: Various electrocardiogram (ECG)-based devices are available for home monitoring, but the reliability in adults with CHD is unknown. Therefore, we determined the accuracy of different ECG-based devices compared to the standard 12-lead ECG in adult CHD. METHODS AND RESULTS: This is a single-centre, prospective, cross-sectional study in 176 consecutive adults with CHD (54% male, age 40 ± 16.6 years, 24% severe CHD, 84% previous surgery, 3% atrial fibrillation (AF), 24% right bundle branch block). Diagnostic accuracy of the Withings Scanwatch (lead I), Eko DUO (precordial lead), and Kardia 6L (six leads) was determined in comparison to the standard 12-lead ECG on several tasks: 1) AF classification (percentage correct), 2) QRS-morphology classification (percentage correct), and 3) ECG intervals calculation (QTc time ≤ 40 ms difference). Both tested AF algorithms had high accuracy (Withings: 100%, Kardia 6L: 97%) in ECGs that were classified. However, the Withings algorithm classified fewer ECGs as inconclusive (5%) compared to 31% of Kardia (p < 0.001). Physician evaluation of Kardia correctly classified QRS morphology more frequently (90% accuracy) compared to Eko DUO (84% accuracy) (p = 0.03). QTc was underestimated on all ECG-based devices (p < 0.01). QTc duration accuracy was acceptable in only 51% of Withings versus 70% Eko and 74% Kardia (p < 0.001 for both comparisons). CONCLUSIONS: Although all devices demonstrated high accuracy in AF detection, the Withings automatic algorithm had fewest uninterpretable results. Kardia 6L was most accurate in overall evaluation such as QRS morphology and QTc duration. These findings can inform both patients and caregivers for optimal choice of home monitoring.

Clinical applicability of artificial intelligence for patients with an inherited heart disease: A scoping review.

The number of inherited heart disease (IHD) studies using artificial intelligence (AI) has increased rapidly over the last years. In this scoping review, we aimed to present an overview of the current literature available on the applicability of AI within the field of IHD. The literature search resulted in eighteen articles in which an AI model was trained and tested, mostly for diagnostic and predictive purposes. The areas under the receiver operating characteristic curves ranged from 0.78-0.96, but varied between IHD types, used methods and outcome measures. Only three out of eighteen did perform validation on an external dataset and most studies did not use explainable deep learning models. To be able to integrate AI as a tool to aid physicians in their diagnoses and clinical decisions within the IHD field, generalizability has to be better evaluated and explainability of DL models has to be increased.

Six-lead device superior to single-lead smartwatch ECG in atrial fibrillation detection.

This was a head-to-head comparative study on different electrocardiogram (ECG)-based smartwatches and devices for atrial fibrillation detection. We prospectively included 220 patients scheduled for electrical cardioversion and recorded ECGs with 3 different devices (Withings Move ECG, Apple Watch 5, Kardia Mobile 6-leads) as well as the standard 12-lead ECG (gold standard), both before and after cardioversion. All atrial fibrillation detection algorithms had high accuracy (sensitivity and specificity: 91-99%) but were hampered by uninterpretable recordings (20-24%). In cardiologists' interpretation, the 6-lead device was superior (sensitivity 99%, specificity 97%) to both single-lead smartwatches (P < .05) for atrial fibrillation detection.

Risk of aerosol transmission of SARS-CoV-2 in a clinical cardiology setting.

Cardiac exercise stress testing (CEST) is an important diagnostic tool in daily cardiology practice. However, during intense physical activity microdroplet aerosols, potentially containing SARS-CoV-2 particles, can persist in a room for a long time. This poses a potential infection risk for the medical staff involved in CEST, as well as for the patients entering the same room afterwards. We measured aerosol generation and persistence, to perform a risk assessment for SARS-CoV-2 transmission through aerosols during CEST. We find that during CEST, the aerosol levels remain low enough that SARS-CoV-2 transmission through aerosols is unlikely, with the room ventilation system producing 14 air changes per hour. A simple measurement of CO2 concentration gives a good indication of the ventilation quality.

Accuracy and clinical relevance of the single-lead Apple Watch electrocardiogram to identify atrial fibrillation.

Background: The Apple Watch (AW) is the first commercially available wearable device with built-in electrocardiogram (ECG) electrodes to perform a single-lead ECG to detect atrial fibrillation (AF). Methods: Patients with AF who were scheduled for electrical cardioversion (ECV) were included in this study. The AW ECGs were obtained pre-ECV and post-ECV. In case of an unclassified recording, the AW ECG was obtained up to 3 times. The 12-lead ECG was used as the reference standard. Sensitivity, specificity, and kappa coefficient were calculated. Results: In total, 74 patients were included. Mean age was 67.1 ± 12.3 years and 20.3% were female. In total 65 AF and 64 sinus rhythm measurements were obtained. The first measurement with the AW showed a sensitivity of 93.5% and specificity of 100% (κ = 0.94). A second measurement resulted in a sensitivity of 94.6% and specificity of 100% (κ = 0.95). A third measurement resulted in a sensitivity of 93% and a specificity of 96.5% (κ = 0.90). Adjudication of unclassified recordings by a physician reduced the total unclassified recordings from 27.9% to 1.6%, but also reduced the accuracy. The kappa coefficient for unclassified single-lead ECGs was 0.58. Conclusion: The single-lead ECG of the AW shows a high accuracy for identifying AF in a clinical setting. Repeating the recording once decreases the total of unclassified recordings; however, a third recording resulted in a lower accuracy and the occurrence of false-positive measurements. Unclassified results of the AW can be reduced by physicians' interpretation of the single-lead ECG; however, the interrater agreement is only moderate.

Success factors in high-effect, low-cost eHealth programs for patients with hypertension: a systematic review and meta-analysis.

BACKGROUND: eHealth programs can lower blood pressure but also drive healthcare costs. This study aims to review the evidence on the effectiveness and costs of eHealth for hypertension and assess commonalities in programs with high effect and low additional cost. RESULTS: Overall, the incremental decrease in systolic blood pressure using eHealth, compared to usual care, was 3.87 (95% confidence interval (CI) 2.98-4.77) mmHg at 6 months and 5.68 (95% CI 4.77-6.59) mmHg at 12 months' follow-up. High intensity interventions were more effective, resulting in a 2.6 (95% CI 0.5-4.7) (at 6 months) and 3.3 (95% CI 1.4-5.1) (at 12 months) lower systolic blood pressure, but were also more costly, resulting in €170 (95% CI 56-284) higher costs at 6 months and €342 (95% CI 128-556) at 12 months. Programs that included a high volume of participants showed €203 (95% CI 99-307) less costs than those with a low volume at 6 months, and €525 (95% CI 299-751) at 12 months without showing a difference in systolic blood pressure. Studies that implemented eHealth as a partial replacement, rather than addition to usual care, were also less costly (€119 (95% CI -38-201 at 6 months) and €346 (95% CI 261-430 at 12 months)) without being less effective. Evidence on eHealth programs for hypertension is ambiguous, heterogeneity on effectiveness and costs is high (I2 = 56-98%). CONCLUSION: Effective eHealth with limited additional costs should focus on high intensity interventions, involve a large number of participants and use eHealth as a partial replacement for usual care.

Review of Digitalized Patient Education in Cardiology: A Future Ahead?

INTRODUCTION: An increased focus on shared decision-making and patient empowerment in cardiology and on patient outcomes such as quality of life (QoL), depression, and anxiety underline the importance of high-quality patient education. Studies focusing on digital means of patient education performed in other disciplines of medicine demonstrated its positive effect in these areas. Therefore, a review of the current literature was performed to (i) evaluate the status of innovative, digitalized means of patient education in cardiology and (ii) assess the impact of digital patient education on outcome parameters (i.e., patient knowledge (or health literacy), QoL, depression, anxiety, and patient satisfaction). METHOD: A review of the current literature was performed to evaluate the effect of digitalized patient education for any purpose in the field of cardiology. Medline and EMBASE were searched for articles reporting any digital educational platform used for patient education up to May 2020. The articles were compared on their effect on patient knowledge or health literacy, QoL, depression or anxiety, and patient satisfaction. RESULTS: The initial search yielded 279 articles, 34 of which were retained after applying in, and exclusion criteria. After full-text analysis, the total number of articles remaining was 16. Of these, 6 articles discussed the use of smartphone or tablet applications as a means of patient education, whereas 3 reviewed web-based content, and 7 evaluated the use of video (2 three-dimensional videos, from which one on a virtual reality headset). CONCLUSION: This review demonstrates that digital patient education increases patient knowledge. Overall, digital education increases QoL and lowers feelings of depression and anxiety. The majority of patients express satisfaction with digital platforms. It remains important that developers of digital patient education platforms remain focused on clear, structured, and comprehensible information presentation.

Patient-reported outcomes in symptom-driven remote arrhythmia monitoring: evaluation of the Dutch HartWacht-telemonitoring programme.

Aims: There is limited quantitative evidence on the effect of symptom-driven telemonitoring for cardiac arrhythmias on patient-reported outcomes. We evaluated the effect of a symptom-driven remote arrhythmia monitoring programme on the patient-reported health-related quality of life (HRQoL), sense of safety, physical limitations, and self-management. Methods and results: This was an observational retrospective longitudinal study of the symptom-driven HartWacht-telemonitoring programme using a remote single-lead electrocardiogram monitoring system. Real-world patient data from participants who were enrolled in the telemonitoring programme for (suspected) symptomatic atrial fibrillation (AF) between July 2017 and September 2019 were evaluated. Primary outcomes were the patient-reported generic HRQoL, disease-specific HRQoL, sense of safety, physical limitations, and self-management at date of enrolment, 3 months and 6 months of follow-up. Outcomes were compared to a historical control group consisting of AF patients receiving standard care. A total of 109 participants in the HartWacht programme [59 men (54%); mean age 61 ± 11 years; 72% diagnosed AF] were included in complete case analysis. There was no significant change in HRQoL and sense of safety during follow-up. A significant improvement in the perceived physical limitations was observed. The level of self-management declined significantly during follow-up. Comparisons to the historic control group (n = 83) showed no difference between the patient-reported disease-specific HRQoL, sense of safety and physical limitations at 6 months of follow-up. Conclusion: Symptom-driven remote arrhythmia monitoring for AF does not seem to affect HRQoL and sense of safety, whereas the perceived physical limitations tend to improve. Patient-reported self-management declined during the first 6 months of participation.

Computer versus cardiologist: Is a machine learning algorithm able to outperform an expert in diagnosing a phospholamban p.Arg14del mutation on the electrocardiogram?

BACKGROUND: Phospholamban (PLN) p.Arg14del mutation carriers are known to develop dilated and/or arrhythmogenic cardiomyopathy, and typical electrocardiographic (ECG) features have been identified for diagnosis. Machine learning is a powerful tool used in ECG analysis and has shown to outperform cardiologists. OBJECTIVES: We aimed to develop machine learning and deep learning models to diagnose PLN p.Arg14del cardiomyopathy using ECGs and evaluate their accuracy compared to an expert cardiologist. METHODS: We included 155 adult PLN mutation carriers and 155 age- and sex-matched control subjects. Twenty-one PLN mutation carriers (13.4%) were classified as symptomatic (symptoms of heart failure or malignant ventricular arrhythmias). The data set was split into training and testing sets using 4-fold cross-validation. Multiple models were developed to discriminate between PLN mutation carriers and control subjects. For comparison, expert cardiologists classified the same data set. The best performing models were validated using an external PLN p.Arg14del mutation carrier data set from Murcia, Spain (n = 50). We applied occlusion maps to visualize the most contributing ECG regions. RESULTS: In terms of specificity, expert cardiologists (0.99) outperformed all models (range 0.53-0.81). In terms of accuracy and sensitivity, experts (0.28 and 0.64) were outperformed by all models (sensitivity range 0.65-0.81). T-wave morphology was most important for classification of PLN p.Arg14del carriers. External validation showed comparable results, with the best model outperforming experts. CONCLUSION: This study shows that machine learning can outperform experienced cardiologists in the diagnosis of PLN p.Arg14del cardiomyopathy and suggests that the shape of the T wave is of added importance to this diagnosis.

Advantages of mobile health in the management of adult patients with congenital heart disease.

BACKGROUND: Adults with congenital heart disease (ACHD) often suffer from deterioration related to cardiac arrhythmias, hypertension (HT) or heart failure (HF), frequently occurring between planned visits. Mobile health (mHealth) could improve management through remote monitoring by enabling swift therapeutic response and detecting new diagnoses. METHODS: We performed a prospective study employing mHealth in ACHD patients, weekly monitoring heart rhythm, weight and blood pressure. In case of consecutive threshold exceeding measurements or in case of new diagnosis, patients were contacted and if needed the treating physician was consulted. Inclusion criteria were: palpitations within the last three years (with or without arrhythmia diagnosis) or HF NYHA class ≥ II. We evaluated the detection of recurrences and new diagnosis of arrhythmias, HT and HF, adherence and patient experience (Net Promotor Score (NPS)). RESULTS: In total, 109 of the 268 invited ACHD patients were enrolled, 80 with palpitations, 13 with HF, 16 experienced both, mean age 45 (±13) years, 33% male. Median follow-up was 12 (Q1-Q3;9-14) months, 91 patients initiated all measurements (heart rhythm, weight and blood pressure). In 25% of the patients with diagnosed arrhythmias (14/56) recurrences of arrhythmias were detected; 13% of the patients with undiagnosed palpitations (4/32) were diagnosed with novel arrhythmias. In 38% of the patients with HT at baseline (6/16), treatment adjustment was necessary, 4% of the patients without HT (4/76) received novel HT diagnosis. Diuretics were adjusted in 7% of the patients with HF (2/29). Adherence was > 70% in 77% of the patients that started weekly measurements (70/91). Patients that were female, older of age and experienced palpitations at inclusion were more likely to acquire an adherence of > 70%. NPS was completed by 68 patients, 57 patients (84%) were promotors or neutral, and 11 patients (16%) were critics. CONCLUSIONS: mHealth offers advantages in the management of selected ACHD patients; it enabled early detection of recurrences and new diagnosis of arrhythmias, hypertension and heart failure, which lead to swift therapeutic response or remote reassurance. Furthermore, mHealth was well accepted with high adherence and positive patient experience.

Long-term clinical outcomes of valsartan in patients with a systemic right ventricle: Follow-up of a multicenter randomized controlled trial.

OBJECTIVES: In the VAL-SERVE (Valsartan in Systemic Right Ventricle) trial, three-year valsartan treatment improved systemic ventricular function only in symptomatic patients with congenitally or with an atrial switch corrected transposition of the great arteries. The aim of the current study was to investigate the longer-term clinical outcomes after valsartan treatment. METHODS: From 2006 to 2009, 88 adults were randomly allocated 1:1 to either valsartan or placebo for three consecutive years. Endpoints were defined as overall survival and freedom from clinical events (arrhythmia, heart failure, tricuspid valve surgery, death). RESULTS: Cardiac drug use and median follow-up after trial close-out (8.3 years) was similar between the randomization groups. Six patients (valsartan n = 3, placebo n = 3) died in 364 and 365 person-years (P = 0.999). No difference in the composite or separate clinical endpoints was found between the randomization groups, with corresponding long-term event-free survival rates of 50% and 34%. Nevertheless, in symptomatic patients valsartan significantly reduced the risk for events compared to placebo (HR 0.37, 95% CI 0.17-0.92). Analysis for repeated events and on-treatment analysis with any renin-angiotensin-aldosterone-system-inhibitor did not alter these results. CONCLUSIONS: Valsartan treatment in systemic RV patients did not result in improved survival at longer-term follow-up, but was associated with decreased risk of events in symptomatic patients.

Safety and effectiveness of home-based, self-selected exercise training in symptomatic adults with congenital heart disease: A prospective, randomised, controlled trial.

BACKGROUND: The purpose of this prospective randomised controlled trial was to assess whether home-based, self-selected exercise training is safe, results in high compliance and improves exercise capacity in symptomatic adults with congenital heart disease (CHD). METHODS: Forty adults with moderate or severe CHD (40 ±â€¯12 years, 56% male, New York Heart Association [NYHA] II/III 37/3) were randomly assigned, stratified by CHD complexity, either to home-based exercise training or usual care. The exercise training protocol consisted of three exercise sessions per week for six consecutive months. Patients were free to choose any sports of their preference. RESULTS: Thirty-four patients (each randomisation group n = 17) completed the protocol and were analysed. The majority was involved in high-dynamic sports (76%); none had to discontinue the training programme due to exercise-related adverse events. More than 70% adhered to the exercise programme at or above the target training level. Peak VO2 increased significantly in the exercise group by +1.7 ±â€¯2.7 ml∙kg∙min-1 (p = 0.025), whereas it remained unchanged in the control group by +0.8 ±â€¯2.2 ml∙kg∙min-1 (p = 0.184). No significant changes were found in serum N-Terminal pro-brain natriuretic peptide levels or quality of life in either randomisation group or between groups. CONCLUSIONS: In symptomatic adults with moderate or severe CHD, home-based exercise training of their preference appeared safe, with good compliance and favourable effects on exercise capacity. Our results demonstrate that it is appropriate to stimulate our patients to regularly perform moderate to vigorous physical activities, in absence of medical restrictions.

A successful crowdfunding project for eHealth research on grown-up congenital heart disease patients.

BACKGROUND: Scarce data on crowdfunding report a maximal funding of €10.000,-, and state that research is needed to attract attention of larger granting organizations. The aims of this project were 1) to fund an eHealth study in grown-up congenital heart disease (GUCH) patients 2) to contemplate on critical success factors. METHODS: After peer review of the Dutch Heart Foundation a project was published at a donation platform, which was open for donations during a predetermined period of two months. Copywriters were hired to create an easy-to-understand message to donors. A video teaser was created with a motivated patient, and rewards were available. The crowdfunding targeted €25.000 and the Dutch Heart Foundation doubled the donations to €50.000, and return of donations were guaranteed in case this was not met. RESULTS: Initially, donations came from the investigators' private inner circle. In total, 44 potential donors were contacted, but refused to donate originally. Multiple (social) media campaigns were published to promote the project, and an offline mailing was sent to contributors to the Dutch Heart Foundation. During the project support emerged, resulting in extra donations and public awareness. In the lasts three weeks, after sufficient private donations, five major donors decided to support the project. The project became a big success: the predetermined target was exceeded and a total of €74.450,- was raised. CONCLUSION: Innovative crowdfunding gave the opportunity to start eHealth research in GUCH patients. Critical success factors include support of a professional organization, support of stakeholders, and easy-to-understand messages.

eHealth in patients with congenital heart disease: a review.

INTRODUCTION: Mobile health (mHealth), an advanced form of eHealth is expected to drastically change the field of traditional healthcare in the near future as wearables and mobile applications are rapidly increasing in number. The majority of patients with congenital heart disease (CHD) now reach adulthood and this relative young patient population seems particularly suited for mHealth, as they require lifelong follow-up, experience high morbidity burden, and were raised in this digital era. In patients with acquired heart disease the potential of eHealth has been demonstrated, yet data are still inconclusive. Areas covered: In this review of the current literature we evaluated the effect of various eHealth interventions in patients with CHD. Our search resulted in a mere 10 studies, which comprised mostly of children or adolescents with severe CHD. Home-monitoring of saturation and weight through mHealth was found to be beneficial in patients after palliation procedures, and video conferencing was found to have a positive effect on anxiety and healthcare utilization. Expert commentary: Due to high morbidity and mortality in patients with CHD and the promising results of eHealth interventions, further research is desperately needed.

The effect of exercise training in symptomatic patients with grown-up congenital heart disease: a review.

INTRODUCTION: The number of grown-up congenital heart disease (GUCH) patients is steadily increasing. Unfortunately, the majority of these patients suffer from late sequelae, with heart failure being the most common cause of death. Exercise training is beneficial and safe in patients with acquired heart failure, as well as in asymptomatic GUCH patients. However, its effect remains unknown in symptomatic GUCH patients. This could cause reticence on positive sports advice, with possible counterproductive effects. Areas covered: A review of current literature was performed to evaluate the effect of exercise training in symptomatic (NYHA≥2) GUCH patients. The search yielded a mere three studies including symptomatic patients, and another six studies including also patients in NYHA 1 without making clear distinction between the NYHA subgroups. Expert commentary: Suboptimal trial designs, low patient numbers, and homogeneity of investigated cardiac anomalies make this review insufficient to draw definite conclusions. However, all studies describe overall positive effects of exercise training in symptomatic GUCH patients in terms of exercise capacity and quality of life. There were no safety concerns. Larger-scaled, randomized controlled trials are needed to obtain certainty.

Effect of Losartan on Right Ventricular Dysfunction: Results From the Double-Blind, Randomized REDEFINE Trial (Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-Angiotensin-Aldosterone System) in Adults With Repaired Tetralogy of Fallot.

BACKGROUND: The effect of angiotensin II receptor blockers on right ventricular (RV) function is still unknown. Angiotensin II receptor blockers are beneficial in patients with acquired left ventricular dysfunction, and recent findings have suggested a favorable effect in symptomatic patients with systemic RV dysfunction. The current study aimed to determine the effect of losartan, an angiotensin II receptor blocker, on subpulmonary RV dysfunction in adults after repaired tetralogy of Fallot. METHODS: The REDEFINE trial (Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-Angiotensin-Aldosterone System) is an investigator-initiated, multicenter, prospective, 1:1 randomized, double-blind, placebo-controlled study. Adults with repaired tetralogy of Fallot and RV dysfunction (RV ejection fraction [EF] <50%) but without severe valvular dysfunction were eligible. Patients were randomly assigned between losartan (150 mg daily) and placebo with target treatment duration between 18 and 24 months. The primary outcome was RV EF change, determined by cardiovascular MRI in intention-to-treat analysis. RESULTS: Of 95 included patients, 47 patients received 150 mg losartan daily (age, 38.0±12.4 years; 74% male), and 48 patients received placebo (age, 40.6±11.4 years; 63% male). Overall, RV EF did not change in patients allocated to losartan (n=42) (44.4±5.1% to 45.2±5.0%) and placebo (n=46) (43.2±6.3% to 43.6±6.9%). Losartan did not significantly improve RV EF in comparison with placebo (+0.51%; 95% confidence interval, -1.0 to +2.0; P=0.50). No significant treatment effects were found on secondary outcomes: left ventricular EF, peak aerobic exercise capacity, and N-terminal pro-brain natriuretic peptide (P>0.30 for all). In predefined subgroup analyses, losartan did not have a statistically significant impact on RV EF in subgroups with symptoms, restrictive RV, RV EF<40%, pulmonary valve replacement, or QRS fragmentation. However, in a post hoc analysis, losartan was associated with improved RV EF in a subgroup (n=30) with nonrestrictive RV and incomplete remodeling (QRS fragmentation and previous pulmonary valve replacement) (+2.7%; 95% confidence interval, +0.1 to +5.4; P=0.045). CONCLUSIONS: Losartan had no significant effect on RV dysfunction or secondary outcome parameters in repaired tetralogy of Fallot. Future larger studies may determine whether there might be a role for losartan in specific vulnerable subgroups. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02010905.