Follow-up of Remotely Monitored ICD Recipients
Follow-up of Remotely Monitored ICD Recipients
The Remote Follow-Up for ICD-Therapy in Patients Meeting MADIT II Criteria (REFORM) study was a randomized, non-blinded, parallel-design trial, in which three German and two Czech medical centres participated. The study was conducted in accordance with the Declaration of Helsinki. The protocol was approved by the Ethics Committees of the participating institutions. All patients gave their written informed consent to participate in the trial.
To be enrolled, patients had to meet the MADIT II trial enrolment criteria; that is, to be survivors of a myocardial infarction and to have a left-ventricular ejection fraction of <30%. The exclusion criteria were myocardial infarction within 30 days before enrolment, New York Heart Association functional class IV, a secondary prevention indication for ICD therapy, or living in an area lacking the GSM mobile phone coverage needed for remote monitoring transmission. Patients indicated for cardiac pacing were excluded for safety concerns because the ICDs used in this trial did not have the capability to automatically measure the pacing threshold. Furthermore, patients indicated for cardiac resynchronization therapy (CRT) according to clinically accepted criteria at the time of enrolment were not included because the required remote monitoring system was not available for devices providing CRT.
The ICDs used were equipped with the Home Monitoring (HM) capability (Biotronik, Berlin, Germany) described previously. Briefly, the implant transmits data once per day, comprising counts of arrhythmia episodes and therapies, rhythm information, and technical parameters. Transmission of intracardiac electrograms was available in only a few devices used in this study. The message sent by the implant is relayed by the patient device to the HM Service Center (HMSC) via the mobile phone network. The HMSC makes the data available to the treating physician on a secure internet site, and also sends alerts by e-mail or SMS if the data meet user-defined criteria. For long-term performance, HM was designed to require the patient only to switch on the patient device and keep it by the bedside. Transmission performance is calculated as the number of days with data transmission divided by the total number of days since the first message.
Patients were evenly randomized to quarterly clinic visits (Q-group) or yearly clinic visits (Y-group). After implantation of a single- or dual-chamber ICD (Belos®, Lexos®, or Lumos®; Biotronik, Berlin, Germany), patients in both study arms received the HM patient device. They were under continuous, automatic remote monitoring during the entire study. The response to HM alerts was left to the investigators' discretion. No calendar-based remote data checks or remote follow-up sessions were scheduled. All treatments up to the 3-month follow-up were done according to institutional standards and were equal in both study arms (Figure 1).
(Enlarge Image)
Figure 1.
Clinical follow-up schedule. Full circles indicate the phase affected by patient randomization to quarterly (Q-group) or yearly (Y-group) routine in-office ICD follow-ups. For the whole duration of the study, all patients were under automatic, daily Home Monitoring surveillance, without calendar-based remote follow-up sessions. ICD, implantable cardioverter-defibrillator.
At the 3-month follow-up, all patients' ventricular function was re-evaluated. An improved left-ventricular ejection fraction (≥30%) or the development of a permanent pacing indication was ground for exclusion from the trial. The devices were programmed as follows: ventricular demand pacing with 40 beats per min (bpm); ventricular tachycardia zone from 180 bpm with anti-tachycardia pacing therapy; ventricular fibrillation zone from 200 bpm with shock therapy; stability and sudden onset criteria for arrhythmia discrimination 'ON'. This programming was subject to adjustments after the occurrence of a first event.
Patients were followed for 2 years after the 3-month follow-up. They were instructed to refer to the investigational site for ICD-related issues and heart rhythm disorders. Care for the patients' concomitant diseases, most prominently heart failure, was provided by specialists as clinically indicated; however, they had no role in the study. Study data were collected by staff dedicated to the trial under the direct supervision of the principal investigators. Data management was provided by the sponsor. Data processing was supervised by the clinical team of the first author.
Patients assigned to the Q-group were scheduled to return for outpatient visits every 3 months, and those assigned to the Y-group had visits at 3, 15, and 27 months after discharge (Figure 1). A follow-up examination was classified as regular if occurring within a window of 4 weeks before or after an appropriate date relative to the discharge date. At each outpatient visit, the ICD was interrogated and tested and its memory was analysed in order to adapt patient management accordingly. The generic health-related QoL was assessed by the 36-item General Health Survey (SF-36) questionnaire at baseline, 15-month follow-up, and 27-month follow-up, in both study arms.
Patients were seen outside of the scheduled visits for the following pre-specified HM alerts: (i) elective battery replacement indicator; (ii) any lead impedance out of range; (iii) delivery of a first shock after discharge of the patient from the hospital; (iv) delivery of ≥5 episodes of anti-tachycardia pacing; (v) delivery of ≥2 shocks per month for the first time, or occurrence of ≥2 supraventricular tachycardia or VT episodes per week. Patients could also be seen at unscheduled visits due to HM trend data or for any other reason, upon the patient's request or initiated by the investigator. Scheduled and unscheduled follow-up examinations were conducted similarly.
To get an estimate of additional patient contacts to medical professionals, the patients were instructed to notify such visits in a diary and were interviewed at each ICD follow-up.
The primary study hypothesis was that the rate of unscheduled ICD follow-up visits in the Y-group would exceed the rate in the Q-group by <1.0 per patient-year, after the 3-month follow-up point. A confirmation of this non-inferiority hypothesis would mean that the total rate of scheduled and unscheduled ICD follow-up visits would be substantially lower in the Y-group than in the Q-group.
Secondary endpoints were the intra-individual difference in QoL scores between 27 months and baseline, total and cardiovascular mortality, and the rate and duration of all hospitalizations and cardiovascular hospitalizations. Furthermore, we made a post-hoc analysis of all available arrhythmia and therapy data (12 different items) extracted from the HMSC database. The data comprised, per study group, the numbers of patients fulfilling various criteria such as having episodes in different arrhythmia zones, started or delivered therapies, or unsuccessful maximum-energy shocks. The underlying arrhythmias in this analysis were not adjudicated by the investigator. Shock therapy was considered ineffective if the device delivered more than one shock during one arrhythmia episode, and this could include cases of repeated shocks in episodes of supraventricular tachycardia.
The sample size was based on the primary study hypothesis and calculated on a Blackwelder-type test of non-inferiority. Unscheduled ICD follow-up visits were assumed to occur independently from one other, to have a daily probability (equivalent to 0.21 or 0.96 visits per patient-year in the Q-group and the Y-group, respectively), and, hence, to obey binomial distribution. Assuming a 2-year attrition rate of 28% in both groups, a sample of 150 patients needed to remain in the study after the 3-month follow-up (for 1-ß = 80%).
All patients with baseline QoL data were included in the intention-to-treat based QoL analysis. Missing 27-month QoL data were accounted for using the last-observation-carried-forward (LOCF) method. Due to slight post-implantation increase in patients' QoL and greater loss to follow-up in the Y-group, this approach can be considered conservative.
For normally distributed continuous data (verified using the Shapiro–Wilk test), mean values and standard deviations were calculated. For non-normally distributed data, median values, interquartile ranges (IQR), and mean values, if appropriate for comparison with reference data, are shown. For categorical data, the absolute and relative frequencies were calculated. Continuous data were compared using the t-test (if normally distributed) or the Wilcoxon–Mann–Whitney rank test (if non-normally distributed). Categorical data were compared with a χ test according to Pearson's or Fisher's exact test as appropriate. One-sided statistical significance for the primary study hypothesis, or two-sided statistical significance for all other tests, was established as P < 0.05.
Methods
The Remote Follow-Up for ICD-Therapy in Patients Meeting MADIT II Criteria (REFORM) study was a randomized, non-blinded, parallel-design trial, in which three German and two Czech medical centres participated. The study was conducted in accordance with the Declaration of Helsinki. The protocol was approved by the Ethics Committees of the participating institutions. All patients gave their written informed consent to participate in the trial.
Patient Selection
To be enrolled, patients had to meet the MADIT II trial enrolment criteria; that is, to be survivors of a myocardial infarction and to have a left-ventricular ejection fraction of <30%. The exclusion criteria were myocardial infarction within 30 days before enrolment, New York Heart Association functional class IV, a secondary prevention indication for ICD therapy, or living in an area lacking the GSM mobile phone coverage needed for remote monitoring transmission. Patients indicated for cardiac pacing were excluded for safety concerns because the ICDs used in this trial did not have the capability to automatically measure the pacing threshold. Furthermore, patients indicated for cardiac resynchronization therapy (CRT) according to clinically accepted criteria at the time of enrolment were not included because the required remote monitoring system was not available for devices providing CRT.
Remote Monitoring
The ICDs used were equipped with the Home Monitoring (HM) capability (Biotronik, Berlin, Germany) described previously. Briefly, the implant transmits data once per day, comprising counts of arrhythmia episodes and therapies, rhythm information, and technical parameters. Transmission of intracardiac electrograms was available in only a few devices used in this study. The message sent by the implant is relayed by the patient device to the HM Service Center (HMSC) via the mobile phone network. The HMSC makes the data available to the treating physician on a secure internet site, and also sends alerts by e-mail or SMS if the data meet user-defined criteria. For long-term performance, HM was designed to require the patient only to switch on the patient device and keep it by the bedside. Transmission performance is calculated as the number of days with data transmission divided by the total number of days since the first message.
Study Protocol
Patients were evenly randomized to quarterly clinic visits (Q-group) or yearly clinic visits (Y-group). After implantation of a single- or dual-chamber ICD (Belos®, Lexos®, or Lumos®; Biotronik, Berlin, Germany), patients in both study arms received the HM patient device. They were under continuous, automatic remote monitoring during the entire study. The response to HM alerts was left to the investigators' discretion. No calendar-based remote data checks or remote follow-up sessions were scheduled. All treatments up to the 3-month follow-up were done according to institutional standards and were equal in both study arms (Figure 1).
(Enlarge Image)
Figure 1.
Clinical follow-up schedule. Full circles indicate the phase affected by patient randomization to quarterly (Q-group) or yearly (Y-group) routine in-office ICD follow-ups. For the whole duration of the study, all patients were under automatic, daily Home Monitoring surveillance, without calendar-based remote follow-up sessions. ICD, implantable cardioverter-defibrillator.
At the 3-month follow-up, all patients' ventricular function was re-evaluated. An improved left-ventricular ejection fraction (≥30%) or the development of a permanent pacing indication was ground for exclusion from the trial. The devices were programmed as follows: ventricular demand pacing with 40 beats per min (bpm); ventricular tachycardia zone from 180 bpm with anti-tachycardia pacing therapy; ventricular fibrillation zone from 200 bpm with shock therapy; stability and sudden onset criteria for arrhythmia discrimination 'ON'. This programming was subject to adjustments after the occurrence of a first event.
Patients were followed for 2 years after the 3-month follow-up. They were instructed to refer to the investigational site for ICD-related issues and heart rhythm disorders. Care for the patients' concomitant diseases, most prominently heart failure, was provided by specialists as clinically indicated; however, they had no role in the study. Study data were collected by staff dedicated to the trial under the direct supervision of the principal investigators. Data management was provided by the sponsor. Data processing was supervised by the clinical team of the first author.
Scheduled Follow-up Visits
Patients assigned to the Q-group were scheduled to return for outpatient visits every 3 months, and those assigned to the Y-group had visits at 3, 15, and 27 months after discharge (Figure 1). A follow-up examination was classified as regular if occurring within a window of 4 weeks before or after an appropriate date relative to the discharge date. At each outpatient visit, the ICD was interrogated and tested and its memory was analysed in order to adapt patient management accordingly. The generic health-related QoL was assessed by the 36-item General Health Survey (SF-36) questionnaire at baseline, 15-month follow-up, and 27-month follow-up, in both study arms.
Unscheduled Follow-up Visits
Patients were seen outside of the scheduled visits for the following pre-specified HM alerts: (i) elective battery replacement indicator; (ii) any lead impedance out of range; (iii) delivery of a first shock after discharge of the patient from the hospital; (iv) delivery of ≥5 episodes of anti-tachycardia pacing; (v) delivery of ≥2 shocks per month for the first time, or occurrence of ≥2 supraventricular tachycardia or VT episodes per week. Patients could also be seen at unscheduled visits due to HM trend data or for any other reason, upon the patient's request or initiated by the investigator. Scheduled and unscheduled follow-up examinations were conducted similarly.
To get an estimate of additional patient contacts to medical professionals, the patients were instructed to notify such visits in a diary and were interviewed at each ICD follow-up.
Study Hypothesis and Endpoints
The primary study hypothesis was that the rate of unscheduled ICD follow-up visits in the Y-group would exceed the rate in the Q-group by <1.0 per patient-year, after the 3-month follow-up point. A confirmation of this non-inferiority hypothesis would mean that the total rate of scheduled and unscheduled ICD follow-up visits would be substantially lower in the Y-group than in the Q-group.
Secondary endpoints were the intra-individual difference in QoL scores between 27 months and baseline, total and cardiovascular mortality, and the rate and duration of all hospitalizations and cardiovascular hospitalizations. Furthermore, we made a post-hoc analysis of all available arrhythmia and therapy data (12 different items) extracted from the HMSC database. The data comprised, per study group, the numbers of patients fulfilling various criteria such as having episodes in different arrhythmia zones, started or delivered therapies, or unsuccessful maximum-energy shocks. The underlying arrhythmias in this analysis were not adjudicated by the investigator. Shock therapy was considered ineffective if the device delivered more than one shock during one arrhythmia episode, and this could include cases of repeated shocks in episodes of supraventricular tachycardia.
Statistical Analysis
The sample size was based on the primary study hypothesis and calculated on a Blackwelder-type test of non-inferiority. Unscheduled ICD follow-up visits were assumed to occur independently from one other, to have a daily probability (equivalent to 0.21 or 0.96 visits per patient-year in the Q-group and the Y-group, respectively), and, hence, to obey binomial distribution. Assuming a 2-year attrition rate of 28% in both groups, a sample of 150 patients needed to remain in the study after the 3-month follow-up (for 1-ß = 80%).
All patients with baseline QoL data were included in the intention-to-treat based QoL analysis. Missing 27-month QoL data were accounted for using the last-observation-carried-forward (LOCF) method. Due to slight post-implantation increase in patients' QoL and greater loss to follow-up in the Y-group, this approach can be considered conservative.
For normally distributed continuous data (verified using the Shapiro–Wilk test), mean values and standard deviations were calculated. For non-normally distributed data, median values, interquartile ranges (IQR), and mean values, if appropriate for comparison with reference data, are shown. For categorical data, the absolute and relative frequencies were calculated. Continuous data were compared using the t-test (if normally distributed) or the Wilcoxon–Mann–Whitney rank test (if non-normally distributed). Categorical data were compared with a χ test according to Pearson's or Fisher's exact test as appropriate. One-sided statistical significance for the primary study hypothesis, or two-sided statistical significance for all other tests, was established as P < 0.05.