One of the essential elements of the treatment of heart failure with reduced ejection fraction (HFrEF) is a procedure involving the use of implantable devices, especially cardiac resynchronization therapy (CRT). In a randomized study, the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronisation Therapy (MADIT-CRT), device-based therapy has proven to reduce mortality and incidence of HF [3].

The telemonitoring application allows for the detection of symptoms and abnormal health parameters earlier than during a routine consultation. It may also reduce the need for frequent visits to healthcare facilities, thereby increasing the patient’s quality of life. A detailed study of previous research projects conducted in the field of telemonitoring indicates a reduction in the number of hospitalizations for exacerbation of HF [4]. Therefore, the European Society of Cardiology (ESC) recommends the use of telemonitoring to improve the quality of care of patients with HF [5].

Aim of the study

The primary aim of the study was to identify the clinical relevance of telemedicine devices for the reduction of the composite endpoint defined as death or first-time emergency hospitalization for HF in patients with implanted CRT in long-term observation.

The secondary aim of the study was to determine the relevance of telemetry use in complex HF management for the improvement of the following clinical endpoints and parameters:

• • distance of the six-minute walk test (6MWT);
• • indices of left ventricular (LV) systolic function expressed as left ventricular ejection fraction (LVEF);
• • and left ventricular global longitudinal strain (LV GLS)

in a two-year observation.

METHODS

Consecutive patients with HFrEF eligible for cardiac resynchronization therapy (CRTP/CRTD) fulfilling the criteria of class I or IIa recommendations according to the Cardiac Pacing and Cardiac Resynchronisation Therapy Guidelines of 2013 were prospectively enrolled in the study between 2014 and 2017.

Before CRT implantation, demographic data were obtained. Considering the etiology of HF, laboratory tests including the level of the N-terminal pro-brain natriuretic pep- tide (NT-proBNP), echocardiography, and a 6MWT were performed.

The two-year follow-up assessment included the same set of investigations.

Telemedicine device

At discharge, after a short training, patients from the study group received a telemonitoring set: a blood pressure (BP) monitor, a 3-lead electrocardiogram (ECG) recorder, a weighing machine, and a personal tablet. Each device was connected to the tablet with an application. None of the patients received a remote monitoring system of implantable devices.

Patients were asked to perform the measurements of body weight, BP and to evaluate their subjective well-being once a day. Patients were asked to register ECG every week. To evaluate the biventricular stimulation in 3-lead ECG, each patient had an ECG recording on the day of discharge, which was used as a base to compare with further ECGs.

Data were recorded by the patients themselves and transmitted with the use of a tablet to the monitoring center. Patients were also offered the possibility of medical teleconsultation.

To individualize care in our study, we were guided by the parameter trends in the results from the previous week for each patient separately.

All medical devices used in the project were CE marked and provided by Meditel Company, Poland. Throughout the entire study, patients were under the care of the Cardiological Outpatient Clinic in Katowice-Ochojec. During the planned follow-up appointments, data from the devices were verified. All patients were treated with optimal pharmacotherapy for HF and co-morbidities. All patients were informed about the study and signed a written consent to participate in it. The study protocol was approved by the local bioethical committee.

Laboratory test

NT-proBNP was determined on the first day of hospitalization and during a check-up after 24 months by means of the electrochemiluminescence method using the ELECSYS 1010 (Roche Diagnostics, Basel, Switzerland) analyzer.

Six-minute walk test

6MWT was performed on the day of admission and after 24 months during the outpatient follow-up appointment. The improvement of functional exercise capacity was defined as a relative increase of the distance walked by at least 10%.

Echocardiography

A two-dimensional resting echocardiographic examination was performed upon admission to the hospital and after two years. Left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV) were determined using Simpson’s method; LVEF was calculated as a percentage of change in the volume of the left ventricle between its diastole and systole, as the arithmetic mean from 3 consecutive measurements. LVEF improvement in the long-term observation was defined as a relative increase of at least 5%.

An echocardiographic examination of myocardial strain (systolic time interval [STI]) was performed directly after a traditional echocardiographic examination. The mean peak value of all 16 segments of the left ventricle (GLS, global longitudinal strain) was evaluated. GLS improvement in the long-term observation was defined also as an increase of at least 5%.

Long-term observation

The primary composite endpoint was defined as all-cause death or first-time emergency hospitalization for decompensated HF. The secondary endpoint comprised all components of the primary endpoint, as well as:

• • improvement of 6MWT distance >10%;
• • improvement of LVEF >5%;
• • Improvement of GLS >5%.

Every patient (the study and control groups) underwent a two-year follow-up with regular outpatient appointments at 6, 12, 18, and 24 months. The primary composite endpoint was evaluated on every outpatient visit, while in the case of loss of contact with the patient, data from medical records and National Healthcare Provider were obtained to establish the exact date and cause of the event. The follow-up time was 24 months. The secondary endpoints of improvement of 6MWT and echocardiographic parameters were established at a 24-month follow-up visit.

Statistical analysis

Statistical analysis was performed using Statistica 10 software (BCO Software Inc., Palo Alto, CA, USA). Distribution was verified using the Shapiro-Wilk test. Continuous variables are expressed as the mean (standard deviation [SD]) in the case of a normally distributed variable, whereas non-normally distributed variables were expressed as the median and interquartile range (IQR). Qualitative parameters were expressed as crude values and percentages. Categorical variables were tested using χ2 statistics. The comparison of non-paired continuous variables was performed using the Mann-Whitney U test or Student’s t-test, while paired variables were verified using the Wilcoxon signed-rank test or paired-sample Student’s t-test. Multivariable logistic regression analysis was performed using a stepwise approach to evaluate the predictors of 6MWT, GLS, and LVEF improvement. The Cox proportional hazards model was used to identify independent predictors of composite endpoint occurrence. Kaplan-Meier survival curves were calculated to compare freedom from the composite endpoint in relation to the use of telemedicine devices. The difference between survival curves was compared using the logrank test. The P-value <0.05 was regarded as statistically significant throughout the study analyses.

RESULTS

The patients were treated in accordance with the ESC recommendations, and the applied pharmacotherapy did not differ between the study groups, except for more frequent use of beta-blockers in the control group (100% vs. 85.7%; P = 0.03; Supplementary material, Table S1).

On admission, the median NT-proBNP value for the whole population was 1860 (1020–3410) ng/ml and decreased to 771 (440–2113) ng/ml (P = 0.01). A significant decrease in the median NT-proBNP value, from 1709 (996–2393) ng/ml to 553 (292–1256) ng/ml (P = 0.002), occurred in the study group. The difference in the control group was not significant: 2011 (1054–3912) ng/ml vs. 1560 (583–2671) ng/ml (P = 0.48).

A similar percentage of biventricular stimulation was demonstrated for both groups in the longterm follow-up (96.8% [3] vs. 95.4% [2]; P = 0.85). The occurrence of ICD interventions was also similar: 25% of patients in the study group and 28% in the control group (P = 0.7).

There were 55 consultations in the study group during the follow-up. Most of them (18 phone calls) concerned the exacerbation of dyspnea. Apart from that, 14 consultations were arranged because of abnormal ECGs, 12 consultations due to an increase in body weight, and 11 on account of hyper- or hypotension. Due to these consultations, 29 additional outpatient visits were made to modify therapy. In addition, 13 scheduled hospitalizations were performed, including 3 for coronary angiography, 1 for endocarditis, and 3 for electrical cardioversion. Moreover, 6 hospitalizations were organized for intravenous pharmacotherapy.

Of the 26 remaining phone consultations, pharmacotherapy with diuretics was intensified 15 times, hypertensive therapy was modified 5 times, and beta-blocker therapy was modified 5 times. As pneumonia progressed, the patient was asked to increase hydration because of hypotension.

In the control group, 9 scheduled hospitalizations were organized, five of them to intensify therapy, 3 related to electrical cardioversion, and 3 for coronary angiography.

Clinical endpoints

Six-minute walk test

DISCUSSION

This randomized prospective study was designed to determine the real impact of telemedicine on the occurrence of the endpoints in the long-term observation. The main conclusion of our work is the confirmation of the importance of non-invasive telemonitoring for the improvement of long-term prognosis, as well as the improvement of physical performance in the long-term observation. To the best of our knowledge, it is the first clinical trial that used the transmission of so many relevant parameters exclusively in patients with end-stage HF with implanted CRT, from the patient’s home to a central hub managed by cardiologists, using non-invasive devices. It differs from the results of a recently published meta-analysis, in which the authors emphasize the important role of nurses who act as medical supervisors in 86% of programs [6]. One of the first multicenter clinical trials in the field of non-invasive monitoring was the Tele-HF study. Also, it did not demonstrate the benefits for patients with HF in terms of reducing the number of hospitalizations and mortality. The daily control was performed with the use of an automatic telephone system, interviews with specialized medical personnel were carried out to a small extent, which, as the authors admitted in the discussion, was a significant limitation. Moreover, in the event of irregularities, contact with the attending physician was recommended, unlike in our study, where the treatment was largely based on the medical team that supervised the study. Also, patients in the TIM-HF study were referred by medical staff supervising telemonitoring to their family medicine doctor or a specialist [7]. Such constructions of telemonitoring solutions, in our opinion, may prolong the time to implement the teletheraphy. That is why our study emphasizes the importance of cooperation between patients and cardiologists who provide online teleconsultation.

Telemonitoring in HF can be implemented with the use of non-invasive or invasive devices, the latter are mainly used in patients with implanted devices. Data from clinical trials indicate that this type of monitoring is useful mainly in improving the quality of life and avoiding unnecessary hospitalization in patients at risk of sudden cardiac death. Telemonitoring reduces the number of visits without affecting the risk of stroke, heart attack, or death [8]. The survival rates were 50% higher in the group of telemonitored patients in comparison with patients undergoing routine monitoring [9]. The official European Heart Rhythm Association/Heart Rhythm Society (EHRA/HRS) document confirmed the usefulness of telemonitoring of implantable devices in patients with HF, which consists in the earlier detection of clinical disorders due to damage to the device [10]. Invasive telemonitoring in acute and chronic HF received a class IIb recommendation in the 2016 ESC HF guidelines [1].

Neither BEAT-HF nor TIM-HF resulted in the reduction of the risk of hospitalization for HF [13]. BEAT-HF researchers reported the real necessity of re-hospitalization in a 6-month observation, while the authors of the TIM-HF study did not demonstrate an interaction between treatment effects for the occurrence of the composite endpoint. On the other hand, the results of the meta-analysis by Kitsiou et al. [14] indicate a significant reduction in the risk of mortality and hospitalization for HF in the case of non-invasive telemonitoring. Similar conclusions are provided by the meta-analyses of the studies in the Cochrane Central Register [14, 15]. Despite the quality of the evidence, data were was obtained with the use of the GRADE methodology, the imprecision of effects varied from moderate to low. That is why, as the authors suggest, further research is necessary. Therefore, the results of the TIM-HF2 multicenter, randomized study, with a highly advanced intervention protocol and defined endpoints, similar to those used in our study, suggested that non-invasive monitoring, when used in a well-defined HF population, could reduce unplanned cardiovascular hospitalizations and all-cause mortality [7].

Interesting results are provided by the analysis of the importance of telemetry for improving physical performance, expressed by improving LVEF or increasing 6MWT distance. In both cases, the use of telemetry proved to be an independent factor in predicting improvement in physical performance, in addition to the widely recognized diameter of the left atrium, the presence of the return wave on the tricuspid valve, or the application of angiotensin-converting-enzyme inhibitors (ACEI) or mineralocorticoid receptor antagonists [16]. Therefore, this is the first report documenting the importance of non-invasive telemetry for increasing 6MWT distance.

Improvement of physical performance was also expressed by a decrease in NT-proBNP value in a remote observation, which reached statistical significance only in the study group. The study by Maric et al. [17] did not confirm the clinical benefit of telemedicine use in reducing NT-proBNP values. In contrast, in the multicenter study by Lazarova et al. [18] on a group of 738 patients, a significant decrease in the value of natriuretic peptides in the long-term observation was reported.

In data presented in the literature, during the COVID-19 outbreak, remote monitoring is of clinical importance in outpatient care, and it seems that extrapolation of our experiences may also be helpful during the pandemic [19–21].

Conclusions

The use of non-invasive telemonitoring in a group of patients with CRT therapy improved the prognosis in a 2-year observation period with a significant reduction of hospitalization for severe HF. The use of non-invasive telemetry was an independent predictor of the improvement of left ventricular ejection fraction or the increase of the six-minute walking test distance. It seems that extrapolation of our experiences may be helpful during the outbreak of COVID-19, and non-invasive telemonitoring should improve medical therapy for patients with HF. Clinical application of non-invasive devices with basic parameters such as weight, BP, saturation, or ECG may substantially improve medical care.

Limitations

The main limitation of the study is the small size of the study population and the single-center nature of the study. However, attention should be paid to the heterogeneity of the study group in terms of the incidence of diabetes and in terms of the use of beta-blockers, which were significantly more common in the control group, which is most likely due to the small size of the study group. The exclusion of two patients due to limited access to the network is also a limitation of the study. The study was randomized, but the investigator who performed echocardiography and 6MWT was not blinded. The patients throughout the study were under continuous care by one of the specialists in GCM Electrocardiology Clinic. Therapeutic decisions were based on medical indications and physicians’ experience, but without standardization, and finally, there was no comparison of the data.

Supplementary material

Supplementary material is available at https://journals.viamedica.pl/kardiologia_polska.

Article information

Conflict of interest: None declared.

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REFERENCES