Axel Kloppe

Effect of Long-Detection Interval vs Standard-Detection Interval for Implantable Cardioverter-Defibrillators on Antitachycardia Pacing and Shock Delivery: The ADVANCE III Randomized Clinical Trial

IMPORTANCE Using more intervals to detect ventricular tachyarrhythmias has been associated with reducing unnecessary implantable cardioverter-defibrillator (ICD) therapies. OBJECTIVE To determine whether using 30 of 40 intervals to detect ventricular arrhythmias (VT) (long detection) during spontaneous fast VT episodes reduces antitachycardia pacing (ATP) and shock delivery more than 18 of 24 intervals (standard detection). DESIGN, SETTING, AND PARTICIPANTS Randomized, single-blind, parallel-group trial that enrolled 1902 primary and secondary prevention patients (mean [SD] age, 65 [11] years; 84% men; 75% primary prevention ICD) with ischemic and nonischemic etiology undergoing first ICD implant at 1 of 94 international centers (March 2008-December 2010). INTERVENTIONS Patients were randomized 1:1 to programming with long- (n = 948) or standard-detection (n = 954) intervals. MAIN OUTCOMES AND MEASURES Total number of ATPs and shocks delivered for all episodes (primary outcomes) and inappropriate shocks, mortality, and syncopal rate (secondary outcomes). RESULTS During a median follow-up of 12 months (interquartile range, 11-13), long-detection group had 346 delivered therapies (42 therapies per 100 person-years, 95% CI, 38-47) vs 557 in the standard-detection group (67 therapies per 100 person-years [95% CI, 62-73]; incident rate ratio [IRR], 0.63 [95% CI, 0.51-0.78]; P < .001). The long- vs the standard-detection group experienced 23 ATPs per 100 person-years (95% CI, 20-27) vs 37 ATPs per 100 person-years (95% CI, 33-41; IRR, 0.58 [95% CI, 0.47-0.72]; P < .001); 19 shocks per 100 person-years (95% CI, 16-22) vs 30 shocks per 100 person-years (95% CI, 26-34; IRR, 0.77 [95% CI, 0.59-1.01]; P = .06), with a significant difference in the probability of therapy occurrence (P < .001); and a reduction in first occurrence of inappropriate shock (5.1 per 100 patient-years [95% CI, 3.7-6.9] vs 11.6 [95% CI, 9.4-14.1]; IRR, 0.55 [95% CI, 0.36-0.85]; P = .008). Mortality (5.5 [95% CI, 4.0-7.2] vs 6.3 [95% CI, 4.8-8.2] per 100 patient-years; HR, 0.87; P = .50) and arrhythmic syncope rates (3.1 [95% CI, 2.6-4.6] vs 1.9 [95% CI, 1.1-3.1] per 100 patient-years; IRR, 1.60 [95% CI, 0.76-3.41]; P = .22) did not differ significantly between groups. CONCLUSIONS AND RELEVANCE Among patients receiving an ICD, the use of a long- vs standard-detection interval resulted in a lower rate of ATP and shocks, and inappropriate shocks. This programming strategy may be an appropriate alternative. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00617175.

The Influence of Left Ventricular Ejection Fraction on the Effectiveness of Cardiac Resynchronization Therapy MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy)

OBJECTIVES The aim of this study was to evaluate the relationship between left ventricular (LV) ejection fraction and clinical outcome to cardiac resynchronization therapy (CRT) in mild heart failure patients enrolled in MADIT-CRT [corrected]. BACKGROUND Left ventricular ejection fraction (LVEF) is a surrogate marker of heart failure (HF) status and associated risk. Data on the effectiveness of cardiac resynchronization therapy with defibrillator (CRT-D) in patients with mild HF and better LVEF are limited. METHODS In the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy) study, the echocardiography core laboratory assessed baseline LVEF independent of the enrolling centers and identified a range of LVEFs, including those >30% (i.e., beyond the eligibility criteria). Echocardiographic response with CRT, defined as percent change in left ventricular end-diastolic volume (LVEDV), was analyzed in 3 prespecified LVEF groups: >30%, 26% to 30%, and ≤25%. The primary endpoint was HF or death. Secondary endpoint included all-cause mortality. RESULTS LVEF was evaluated in 1,809 study patients. There were 696 (38%) patients with LVEF >30% (in the range of 30.1% to 45.3%); 914 patients (50.5%) with LVEF 26% to 30%; and 199 patients with LVEF ≤25% (11%). The mean reduction in LVEDV with CRT-D therapy at the 1-year follow-up was directly related to increasing LVEF (LVEF >30%: 22.3%; LVEF 26% to 30%: 20.1%; and LVEF ≤25%: 18.7% reduction, respectively [p = 0.001]). CRT-D treatment similarly reduced the risk of HF/death in patients with LVEF >30% (hazard ratio [HR]: = 0.56 [95% confidence interval (CI): 0.39 to 0.82], p = 0.003), LVEF 26% to 30% (HR: 0.67: [95% CI: 0.50 to 0.90], p = 0.007), and LVEF ≤25% (HR: 0.57 [95% CI: 0.35 to 0.95], p = 0.03; all p values for LVEF-by-treatment interactions >0.1). CONCLUSIONS In MADIT-CRT, the clinical benefit of CRT was evident regardless of baseline LVEF, including those with LVEF >30%, whereas the echocardiographic response was increased with increasing LVEF, indicating that CRT might benefit patients with better LVEF. (Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy [MADIT-CRT]; NCT00180271).

Efficacy of Long Detection Interval Implantable Cardioverter-Defibrillator Settings in Secondary Prevention Population Data From the Avoid Delivering Therapies for Nonsustained Arrhythmias in ICD Patients III (ADVANCE III) Trial

Background —Three trials recently demonstrated that a long detection window reduce ICD therapy in primary prevention (PP) patients. Advance III was the only trial enrolling both PP and secondary prevention (SP) patients. Methods and Results —Out of 1902 patients enrolled in the ADVANCEIII trial, 477 received a defibrillator for SP : 248 pts were randomly assigned to a long detection setting (30/40 intervals) and 229 pts to the nominal setting (18/24 intervals) for ventricular arrhythmias (VA) with cycle length ≤320 ms. Patients were 85% men with mean age of 65±12, previous history of ventricular fibrillation in 37% of the cases and mean ejection fraction of 38%±13%. ICD device mix was 37% single, 47% dual and 16% triple chamber. Over a median period of 12 months, the long detection was associated with a 25% reduction in the number of overall therapies (115.6 rate per 100/pts years vs 86.8; IRR: 0.75 95%CI:0.61-0.93, p=0.008) and 34% reduction in the number of shocks (51.2 rate per 100 pts years vs 38.1; IRR: 0.66; 95%CI:0.48-0.89, p=0.007). Appropriate therapies (89.7 vs 67.7; IRR: 0.77 95%CI:0.60-0.97, p=0.029) and appropriate shocks (37.1 vs 28.1; IRR:0.64 95%CI:0.45-0.93, p=0.018) were also reduced. Conclusions —Advance III is the first randomized trial that assessed an ICD long detection window setting in both PP and SP populations and demonstrates a reduction of overall therapies and shocks in the subgroup of SP patients. These data suggest that even SP population may benefit from a programming that combines a long detection with ATP during charging. Clinical Trial Registration Information —clinicaltrials.gov. Identifier: [NCT00617175][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00617175&atom=%2Fcirculationaha%2Fearly%2F2014%2F05%2F16%2FCIRCULATIONAHA.114.009468.atomBackground— Three trials demonstrated recently that a long detection window reduces implantable cardioverter-defibrillator (ICD) therapy in primary prevention patients. Avoid Delivering Therapies for Nonsustained Arrhythmias in ICD Patients III (ADVANCE III) was the only trial that enrolled both primary and secondary prevention patients. Methods and Results— Of the 1902 patients enrolled in the ADVANCE III trial, 477 received a defibrillator for secondary prevention; 248 patients were randomly assigned to a long detection setting (30 of 40 intervals) and 229 to the nominal setting (18 of 24 intervals) for ventricular arrhythmias with cycle length ⩽320 ms. Eight-five percent of patients were men, with a mean age of 65±12 years, a previous history of ventricular fibrillation in 37% of the cases, and a mean ejection fraction of 38±13%. The ICD device mix was 37% single chamber, 47% dual chamber, and 16% triple chamber. Over a median period of 12 months, the long detection period was associated with a 25% reduction in the number of overall therapies (115.6 versus 86.8 per 100 patient-years; incidence rate ratio, 0.75; 95% confidence interval, 0.61–0.93; P=0.008) and a 34% reduction in the number of shocks (rate per 100 patient-years, 51.2 versus 38.1; incidence rate ratio, 0.66; 95% confidence interval, 0.48–0.89; P=0.007). Appropriate therapies (89.7 versus 67.7; incidence rate ratio, 0.77; 95% confidence interval, 0.60–0.97; P=0.029) and appropriate shocks (37.1 versus 28.1; incidence rate ratio, 0.64; 95% confidence interval, 0.45–0.93; P=0.018) were also reduced. Conclusions— ADVANCE III is the first randomized trial to assess a long detection window setting in ICDs in both primary and secondary prevention populations and demonstrates a reduction of overall therapies and shocks in the subgroup of secondary prevention patients. These data suggest that even the secondary prevention population may benefit from programming that combines a long detection period with antitachycardia pacing during charging. Clinical Trial Registration— URL: http://www/clinicaltrials.gov. Unique identifier: NCT00617175.

Efficacy of Long Detection Interval ICD Settings in Secondary Prevention Population: Data from the Advance III Trial

Background —Three trials recently demonstrated that a long detection window reduce ICD therapy in primary prevention (PP) patients. Advance III was the only trial enrolling both PP and secondary prevention (SP) patients. Methods and Results —Out of 1902 patients enrolled in the ADVANCEIII trial, 477 received a defibrillator for SP : 248 pts were randomly assigned to a long detection setting (30/40 intervals) and 229 pts to the nominal setting (18/24 intervals) for ventricular arrhythmias (VA) with cycle length ≤320 ms. Patients were 85% men with mean age of 65±12, previous history of ventricular fibrillation in 37% of the cases and mean ejection fraction of 38%±13%. ICD device mix was 37% single, 47% dual and 16% triple chamber. Over a median period of 12 months, the long detection was associated with a 25% reduction in the number of overall therapies (115.6 rate per 100/pts years vs 86.8; IRR: 0.75 95%CI:0.61-0.93, p=0.008) and 34% reduction in the number of shocks (51.2 rate per 100 pts years vs 38.1; IRR: 0.66; 95%CI:0.48-0.89, p=0.007). Appropriate therapies (89.7 vs 67.7; IRR: 0.77 95%CI:0.60-0.97, p=0.029) and appropriate shocks (37.1 vs 28.1; IRR:0.64 95%CI:0.45-0.93, p=0.018) were also reduced. Conclusions —Advance III is the first randomized trial that assessed an ICD long detection window setting in both PP and SP populations and demonstrates a reduction of overall therapies and shocks in the subgroup of SP patients. These data suggest that even SP population may benefit from a programming that combines a long detection with ATP during charging. Clinical Trial Registration Information —clinicaltrials.gov. Identifier: [NCT00617175][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00617175&atom=%2Fcirculationaha%2Fearly%2F2014%2F05%2F16%2FCIRCULATIONAHA.114.009468.atomBackground— Three trials demonstrated recently that a long detection window reduces implantable cardioverter-defibrillator (ICD) therapy in primary prevention patients. Avoid Delivering Therapies for Nonsustained Arrhythmias in ICD Patients III (ADVANCE III) was the only trial that enrolled both primary and secondary prevention patients. Methods and Results— Of the 1902 patients enrolled in the ADVANCE III trial, 477 received a defibrillator for secondary prevention; 248 patients were randomly assigned to a long detection setting (30 of 40 intervals) and 229 to the nominal setting (18 of 24 intervals) for ventricular arrhythmias with cycle length ⩽320 ms. Eight-five percent of patients were men, with a mean age of 65±12 years, a previous history of ventricular fibrillation in 37% of the cases, and a mean ejection fraction of 38±13%. The ICD device mix was 37% single chamber, 47% dual chamber, and 16% triple chamber. Over a median period of 12 months, the long detection period was associated with a 25% reduction in the number of overall therapies (115.6 versus 86.8 per 100 patient-years; incidence rate ratio, 0.75; 95% confidence interval, 0.61–0.93; P=0.008) and a 34% reduction in the number of shocks (rate per 100 patient-years, 51.2 versus 38.1; incidence rate ratio, 0.66; 95% confidence interval, 0.48–0.89; P=0.007). Appropriate therapies (89.7 versus 67.7; incidence rate ratio, 0.77; 95% confidence interval, 0.60–0.97; P=0.029) and appropriate shocks (37.1 versus 28.1; incidence rate ratio, 0.64; 95% confidence interval, 0.45–0.93; P=0.018) were also reduced. Conclusions— ADVANCE III is the first randomized trial to assess a long detection window setting in ICDs in both primary and secondary prevention populations and demonstrates a reduction of overall therapies and shocks in the subgroup of secondary prevention patients. These data suggest that even the secondary prevention population may benefit from programming that combines a long detection period with antitachycardia pacing during charging. Clinical Trial Registration— URL: http://www/clinicaltrials.gov. Unique identifier: NCT00617175.

Safety of mid-septal electrode placement in implantable cardioverter defibrillator recipients — Results of the SPICE (Septal Positioning of ventricular ICD Electrodes) study

BACKGROUND Detrimental effects of right ventricular (RV) apical pacing have directed the interest toward alternative pacing sites such as the RV mid-septum. As safety data are scarce for implantable cardioverter defibrillator (ICD) recipients the study aims to evaluate ICD lead performance in the mid-septal position. METHODS AND RESULTS A total of 299 ICD recipients (79% male, aged 65.2 ± 12.1 years, 83% primary prevention of sudden cardiac death) were randomized to receive the RV ICD electrode either in a mid-septal (n=145) or apical (n=154) location. Event-free survival was evaluated at 3 (primary endpoint) and 12 months (secondary endpoint). Events included a composite of lead revision, suboptimal right ventricular electrode performance (including defibrillation thresholds (DFT)>25 J) or lead position not in accordance with randomized location. Event-free survival at 3 (12) months was observed in 80.6% (72.3%) of patients randomized to a mid-septal and in 82.2% (72.1%) of patients randomized to an apical lead position, p=0.726 (p=0.969). Pre-defined margins for non-inferiority were not reached at 3 or 12 months. High DFT was found in 7 patients (5.0%) of the mid-septal and in 3 (2.2%) patients of the apical group (p=0.209). CONCLUSION In ICD recipients electrode positioning to the RV mid-septum or the RV apex results in slightly different rates concerning the survival free of lead revision, suboptimal right ventricular electrode performance or non-randomized lead position. Non-inferiority of the mid-septal lead location cannot be concluded. This should be taken into consideration when a mid-septal lead position is pursued. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov identifier NCT00745745.

A fiberoptic sensor system for cardiac monitoring and electrotherapy.

Abstract Commercially available cardiac pacemakers and implantable cardioverters/defibrillators (ICD) predominantly use the intracardiac derived electrocardiogram (ECG) for detection of arrhythmias. To achieve an automatic control of the heart frequency in accordance with cardiovascular strain and an improved detection of life-threatening arrhythmias, it is desirable to monitor the heart by an input signal correlated with the hemodynamic state. One possible approach to derive such a signal, is to measure the inotropy (mechanical contraction strength of the heart muscle). For this purpose an optoelectronic measurement system has been designed. The fundamental function of the system has been shown in earlier investigations using an isolated beating pig heart. In this paper further results showing the correlation of the fiberoptic sensor signal with the left ventricular stroke volume are presented. To make the system useful for implantable devices, further improvements with regard to power consumption and signal quality were achieved. Zur Zeit auf dem Markt befindliche Herzschrittmacher und implantierbare Defibrillatoren (ICD) verwenden zur Erkennung von Arrhythmien überwiegend das im Herzen abgeleitete EKG. Um eine der Herz/Kreislauf-Belastung angepasste Regelung der Herzfrequenz bzw. eine verbesserte Erkennung von lebensbedrohlichen Arrhythmien zu ermöglichen, ist es wünschenswert, den hämodynamischen Status des Herzens als weitere Eingangsgröße messen zu können. Ein möglicher Ansatz zur Bestimmung einer solchen Größe ist die Messung der Inotropie (mechanische Kontraktionskraft des Herzmuskels). Zu diesem Zweck wurde ein optoelektronisches Messsystem entwickelt. Die grundlegende Funktion des Systems konnte in vorangegangenen Untersuchungen an isoliert schlagenden Schweineherzen nachgewiesen werden. In dem vorliegenden Beitrag werden weitergehende Ergebnisse zur Korrelation des Sensorsignals mit dem linksventrikulären Schlagvolumen dargestellt. Um das Sensorsystem für implantierbare Geräte nutzbar zu machen, wurden weiterhin Verbesserungen im Hinblick auf die Leistungsaufnahme sowie die Signalqualität vorgenommen.

Rate-responsive pacing based on the atrio-ventricular conduction time

Chronotropic incompetent patients are unable to adapt their heart rate adequately to the level of exertion. One treatment for this disease is a rate-responsive pacemaker that stimulates the heart at a rate proportional to an exertion-related variable derived from an implemented sensor (e.g., ventilation). The atrio-ventricular conduction time (AVCT), which can act as such a sensor, corresponds to a well-defined interval in the intracardial electrogram. The AVCT is coupled to the sympathetic/parasympathetic activity of the autonomous nervous system (dromotropic effect), leading to a shortening of AVCT during exercise. We found that AVCT is also sensitive to the pacing frequency (pf). Hence, an AVCT-based pacemaker always constitutes a closed-loop system. General design rules for an AVCT pacemaker have been developed from our experimental results and a system-theoretical treatment with reasonable assumptions. Problems addressed were uncertainties concerning the AVCT dynamics and disturbances in the signal. The following rules for the controller design have been derived: 1) The controller gain strongly depends on the therapeutic range of the pf, which is set by the medical doctor; 2) the closed-loop bandwidth of the system should be smaller than the respiratory frequency; and 3) a robust control strategy, capable of guaranteeing stability for a certain set of plant models, should be applied.

A randomized comparison of 5 versus 12 hours per day of cardiac contractility modulation treatment for heart failure patients: A preliminary report.

BACKGROUND Cardiac contractility modulation (CCM) signals are non-excitatory electrical signals delivered during the absolute refractory period intended to improve contraction and cardiac function. Clinical trials have shown that CCM treatment significantly improves exercise tolerance and quality of life in symptomatic heart failure patients. Studies with CCM therapy typically include CCM delivery for 3, 5 or 7 h per day, although other configurations are also commonly used. Each has been associated with improved outcomes in heart failure, but it is not clear whether different application durations are associated with the various degrees of benefit. The purpose of the current pilot evaluation study was to evaluate the quality of life, exercise tolerance, and cardiac function, over a 6-month period when CCM was delivered for 5 h/day vs. 12 h/day. Increasing the daily CCM therapy duration is safe and as good as the standard CCM periods of application per day. METHODS This single center pilot evaluation study involved 19 medically refractory symptomatic patients with heart failure and reduced left ventricular function who underwent implantation of an Optimizer™ system (Impulse Dynamics, Orangeburg, NY, USA). Patients were randomized into one of two treatment groups; 5 h/day CCM treatment or 12 h/day CCM treatment. Subjects and evaluating physicians were blinded to the study group. Subjects returned to the hospital after 12 and 24 weeks. Efficacy evaluations included changes from baseline to 24 weeks in Minnesota Living With Heart Failure Questionnaire score (MLWHFQ), maximal oxygen consumption in the cardio-pulmonary stress test (peak VO2), New York Heart Association classification (NYHA), 6-min walk distance (6MWD), and ejection fraction (EF). RESULTS At the end of 24 weeks, clinical improvement was observed in the entire cohort in all efficacy measures (mean change from baseline of -17.1 in MLWHFQ, -0.86 in NYHA, and improvement trend of 1.48 mL O2/kg/min in peak VO2, 31.3 m in 6MWD, and 2.25% in EF). There were no significant differences, either clinically or statistically, between the groups receiving CCM for 5 h/day vs. 12 h/day. Three subjects were voluntarily withdrawn before completing the study. One subject died from pneumonia after 125 days, and 6 serious adverse events were reported, none of which was classified as related to either the device or the procedure. CONCLUSIONS Together with previously reported experience with CCM, delivery of CCM therapy is equally safe and appears similarly effective over the range of shorter (5 h) to longer (12 h) daily periods of application. Given the small sample size, further studies are warranted.

Long-term survival with Cardiac Contractility Modulation in patients with NYHA II or III symptoms and normal QRS duration

AIMS Cardiac Contractility Modulation (CCM) is a treatment for heart failure based on electrical signals applied during the absolute refractory period. CCM improves myocardial molecular and biochemical characteristics of heart failure and improves exercise tolerance and quality of life. However, the long term impact on survival has not been described. METHODS AND RESULTS Survival was determined retrospectively from a cohort of 68 consecutive heart failure cases with NYHA II or III symptoms and QRS duration ≤130ms, implanted with a CCM device between May 2002 and July 2013 in either Bochum or Ludenscheid, Germany. Results were compared with predicted survival (Seattle Heart Failure Model; SHFM) pre-implant for each patient. Mean follow-up was 4.5years (range 0.25-10.3years). Baseline characteristics were as follows: mean age 61years, 88% male, 68% with ischemic heart disease, 78% with an ICD, mean NYHA class 2.9±0.3, LVEF 26%±6% (range 15-40%) and mean QRS duration 106±11ms. Mortality rates (Kaplan-Meier analysis) at 1-, 2- and 5-years were lower with CCM than predicted by SHFM for the cohort (0% with CCM vs. 6.1% per SHFM, 3.5% vs. 11.8%, and 14.2% vs. 27.7%, respectively, p=0.007). CONCLUSIONS Long-term mortality rates in heart failure patients with NYHA (II-III) and QRS≤130ms are lower when treated by CCM than predicted for the cohort. These findings warrant substantiation in a prospective study.

Cardiac contractility modulation in heart failure patients: Randomized comparison of signal delivery through one vs. two ventricular leads

BACKGROUND Cardiac contractility modulation (CCM) is an electrical stimulation treatment for symptomatic heart failure (HF) patients. The procedure involves implantation of two ventricular leads for delivery of CCM impulses. The purpose of this study is to compare the efficacy and safety of CCM when the signal is delivered through one vs. two ventricular leads. METHODS This prospective blinded randomized trial enrolled 48 patients. Eligible subjects had symptoms despite optimal HF medications, left ventricular ejection fraction <40% and peakVO2≥9ml O2/kg/min. All patients received a CCM system with two ventricular leads, and were randomized to CCM active through both or just one ventricular lead; 25 patients were randomized to receive signal delivery through two leads (Group A) and 23 patients to signal delivery through one lead (Group B). The study compared the mean changes from baseline to 6 months follow-up in peakVO2, New York Heart Association (NYHA) classification, and quality of life (by MLWHFQ). RESULTS Following 6 months, similar and significant (p<0.05) improvements from baseline in NYHA (-0.7±0.5 vs. -0.9±0.7) and MLWHFQ (-14±20 vs. -16±22) were observed in Group A and in Group B. PeakVO2 showed improvement trends in both groups (0.34±1.52 vs. 0.10±2.21ml/kg/min; p=ns). No patient died. Serious adverse event rates (20 events in 10 subjects) were not different between groups. No statistically significant difference was found in any of the study endpoints. CONCLUSIONS The efficacy and safety of CCM in this study were similar when the signal was delivered through either one or two ventricular leads. These results support the potential use of a single ventricular lead for delivery of CCM.