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1.  COST EFFECTIVENESS OF CARDIAC RESYNCHRONIZATION FOR THE PREVENTION OF HEART FAILURE 
Background
The Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT) trial demonstrated that cardiac resynchronization therapy (CRT) when added to the implantable cardiac defibrillator (ICD) reduces risk of heart failure (HF) or death in minimally symptomatic patients with reduced cardiac ejection fraction and wide QRS complex.
Objectives
To evaluate 4-year cost-effectiveness of CRT-ICD compared to ICD alone using MADIT-CRT data.
Research Design
Patients enrolled in the trial were randomized to implantation of either ICD or CRT-ICD in a 2:3 ratio, with up to 4-year follow-up period. Cost-effectiveness analyses were conducted, and sensitivity analyses by age, gender and left bundle branch block (LBBB) conduction pattern were performed.
Subjects
1271 patients with ICD or CRT-ICD (U.S. centers only) who reported healthcare utilization and health-related quality of life data (HRQOL).
Measures
We used the EQ-5D (U.S. weights) to assess patient HRQOL and translated utilization data to costs using national Medicare reimbursement rates.
Results
Average 4-year healthcare expenditures in CRT-ICD patients were higher than costs of ICD patients ($62,600 vs. 57,050, p=0.015), mainly due to the device and implant-related costs. The incremental cost-effectiveness ratio of CRT-ICD compared to ICD was $58,330/quality-adjusted life years (QALY) saved. The cost effectiveness improved with longer time horizon and for the LBBB subgroup ($7,320/QALY), with no cost-effectiveness benefit being evident in the non-LBBB group.
Conclusions
In minimally symptomatic patients with low ejection fraction and LBBB, CRT-ICD is cost effective within 4-year horizon when compared to ICD-only
doi:10.1111/j.1540-8167.2012.02413.x
PMCID: PMC3711178  PMID: 22913474
implantable cardioverter-defibrillator (ICD); cardiac resynchronization therapy (CRT); cost-effectiveness; health-related quality-of-life (HRQOL); survival; MADIT-CRT
2.  Left Ventricular Mechanical Dyssynchrony by Cardiac Magnetic Resonance is Greater in Patients with Strict vs. Non-strict ECG Criteria for Left Bundle Branch Block 
American heart journal  2013;165(6):956-963.
Background
Left bundle branch block (LBBB) is a marker of increased delay between septal and left ventricular (LV) lateral wall electrical activation, and is a predictor of which patients will benefit from cardiac resynchronization therapy (CRT). Recent analysis has suggested that one third of patients meeting conventional ECG criteria for LBBB are misdiagnosed and new strict LBBB criteria have been proposed. We tested the hypothesis that strict LBBB patients have greater LV mechanical dyssynchrony than patients meeting non-strict LBBB criteria while there is no difference between patients with non-strict LBBB and LV conduction delay with QRS duration 110–119 ms.
Methods
Sixty-four patients referred for primary prevention implantable cardioverter-defibrillators (ICD) underwent 12-lead ECG and cardiac magnetic resonance (CMR) myocardial tagging. The patients were classified as strict LBBB, non-strict LBBB or non-LBBB (nonspecific LV conduction delay with QRS duration 110–119 ms). The time delay between septal and lateral LV wall peak circumferential strain (septal-to-lateral wall delay) was measured by CMR.
Results
Patients with strict LBBB (n=31) had a greater septal-to-lateral wall delay, compared to patients with non-strict LBBB (n=19) (210±137 ms vs. 122±102 ms, p=0.045). There was no significant difference between non-strict LBBB and non-LBBB (n=14) septal-to-lateral wall delay (122±102 ms vs. 100±86 ms, p=0.51).
Conclusions
Strict-LBBB criteria identify patients with greater mechanical dyssynchrony compared to patients only meeting non-strict LBBB criteria, while there was no significant difference between non-strict LBBB and non-LBBB patients. The greater observed LV dyssynchrony may explain why strict-LBBB patients have better response to CRT.
doi:10.1016/j.ahj.2013.03.013
PMCID: PMC3664936  PMID: 23708167
Cardiac Resynchronization Therapy; Left Bundle Branch Block; Tagged Cardiac Magnetic Resonance Imaging; Left Ventricular Dyssynchrony
3.  Biventricular Pacing (Cardiac Resynchronization Therapy) 
Executive Summary
Issue
In 2002, (before the establishment of the Ontario Health Technology Advisory Committee), the Medical Advisory Secretariat conducted a health technology policy assessment on biventricular (BiV) pacing, also called cardiac resynchronization therapy (CRT). The goal of treatment with BiV pacing is to improve cardiac output for people in heart failure (HF) with conduction defect on ECG (wide QRS interval) by synchronizing ventricular contraction. The Medical Advisory Secretariat concluded that there was evidence of short (6 months) and longer-term (12 months) effectiveness in terms of cardiac function and quality of life (QoL). More recently, a hospital submitted an application to the Ontario Health Technology Advisory Committee to review CRT, and the Medical Advisory Secretariat subsequently updated its health technology assessment.
Background
Chronic HF results from any structural or functional cardiac disorder that impairs the ability of the heart to act as a pump. It is estimated that 1% to 5% of the general population (all ages) in Europe have chronic HF. (1;2) About one-half of the patients with HF are women, and about 40% of men and 60% of women with this condition are aged older than 75 years.
The incidence (i.e., the number of new cases in a specified period) of chronic HF is age dependent: from 1 to 5 per 1,000 people each year in the total population, to as high as 30 to 40 per 1,000 people each year in those aged 75 years and older. Hence, in an aging society, the prevalence (i.e., the number of people with a given disease or condition at any time) of HF is increasing, despite a reduction in cardiovascular mortality.
A recent study revealed 28,702 patients were hospitalized for first-time HF in Ontario between April 1994 and March 1997. (3) Women comprised 51% of the cohort. Eighty-five percent were aged 65 years or older, and 58% were aged 75 years or older.
Patients with chronic HF experience shortness of breath, a limited capacity for exercise, high rates of hospitalization and rehospitalization, and die prematurely. (2;4) The New York Heart Association (NYHA) has provided a commonly used functional classification for the severity of HF (2;5):
Class I: No limitation of physical activity. No symptoms with ordinary exertion.
Class II: Slight limitations of physical activity. Ordinary activity causes symptoms.
Class III: Marked limitation of physical activity. Less than ordinary activity causes symptoms. Asymptomatic at rest.
Class IV: Inability to carry out any physical activity without discomfort. Symptoms at rest.
The National Heart, Lung, and Blood Institute estimates that 35% of patients with HF are in functional NYHA class I; 35% are in class II; 25%, class III; and 5%, class IV. (5) Surveys (2) suggest that from 5% to 15% of patients with HF have persistent severe symptoms, and that the remainder of patients with HF is evenly divided between those with mild and moderately severe symptoms.
Overall, patients with chronic, stable HF have an annual mortality rate of about 10%. (2) One-third of patients with new-onset HF will die within 6 months of diagnosis. These patients do not survive to enter the pool of those with “chronic” HF. About 60% of patients with incident HF will die within 3 years, and there is limited evidence that the overall prognosis has improved in the last 15 years.
To date, the diagnosis and management of chronic HF has concentrated on patients with the clinical syndrome of HF accompanied by severe left ventricular systolic dysfunction. Major changes in treatment have resulted from a better understanding of the pathophysiology of HF and the results of large clinical trials. Treatment for chronic HF includes lifestyle management, drugs, cardiac surgery, or implantable pacemakers and defibrillators. Despite pharmacologic advances, which include diuretics, angiotensin-converting enzyme inhibitors, beta-blockers, spironolactone, and digoxin, many patients remain symptomatic on maximally tolerated doses.
The Technology
Owing to the limitations of drug therapy, cardiac transplantation and device therapies have been used to try to improve QoL and survival of patients with chronic HF. Ventricular pacing is an emerging treatment option for patients with severe HF that does not respond well to medical therapy. Traditionally, indications for pacing include bradyarrhythmia, sick sinus syndrome, atrioventricular block, and other indications, including combined sick sinus syndrome with atrioventricular block and neurocardiogenic syncope. Recently, BiV pacing as a new, adjuvant therapy for patients with chronic HF and mechanical dyssynchrony has been investigated. Ventricular dysfunction is a sign of HF; and, if associated with severe intraventricular conduction delay, it can cause dyssynchronous ventricular contractions resulting in decreased ventricular filling. The therapeutic intent is to activate both ventricles simultaneously, thereby improving the mechanical efficiency of the ventricles.
About 30% of patients with chronic HF have intraventricular conduction defects. (6) These conduction abnormalities progress over time and lead to discoordinated contraction of an already hemodynamically compromised ventricle. Intraventricular conduction delay has been associated with clinical instability and an increased risk of death in patients with HF. (7) Hence, BiV pacing, which involves pacing left and right ventricles simultaneously, may provide a more coordinated pattern of ventricular contraction and thereby potentially reduce QRS duration, and intraventricular and interventricular asynchrony. People with advanced chronic HF, a wide QRS complex (i.e., the portion of the electrocardiogram comprising the Q, R, and S waves, together representing ventricular depolarization), low left ventricular ejection fraction and contraction dyssynchrony in a viable myocardium and normal sinus rhythm, are the target patients group for BiV pacing. One-half of all deaths in HF patients are sudden, and the mode of death is arrhythmic in most cases. Internal cardioverter defibrillators (ICDs) combined with BiV pacemakers are therefore being increasingly considered for patients with HF who are at high risk of sudden death.
Current Implantation Technique for Cardiac Resynchronization
Conventional dual-chamber pacemakers have only 2 leads: 1 placed in the right atrium and the other in the right ventricle. The technique used for BiV pacemaker implantation also uses right atrial and ventricular pacing leads, in addition to a left ventricle lead advanced through the coronary sinus into a vein that runs along the ventricular free wall. This permits simultaneous pacing of both ventricles to allow resynchronization of the left ventricle septum and free wall.
Mode of Operation
Permanent pacing systems consist of an implantable pulse generator that contains a battery and electronic circuitry, together with 1 (single-chamber pacemaker) or 2 (dual-chamber pacemaker) leads. Leads conduct intrinsic atrial or ventricular signals to the sensing circuitry and deliver the pulse generator charge to the myocardium (muscle of the heart).
Complications of Biventricular Pacemaker Implantation
The complications that may arise when a BiV pacemaker is implanted are similar to those that occur with standard pacemaker implantation, including pneumothorax, perforation of the great vessels or the myocardium, air embolus, infection, bleeding, and arrhythmias. Moreover, left ventricular pacing through the coronary sinus can be associated with rupture of the sinus as another complication.
Conclusion of 2003 Review of Biventricular Pacemakers by the Medical Advisory Secretariat
The randomized controlled trials (RCTs) the Medical Advisory Secretariat retrieved analyzed chronic HF patients that were assessed for up to 6 months. Other studies have been prospective, but nonrandomized, not double-blinded, uncontrolled and/or have had a limited or uncalculated sample size. Short-term studies have focused on acute hemodynamic analyses. The authors of the RCTs reported improved cardiac function and QoL up to 6 months after BiV pacemaker implantation; therefore, there is level 1 evidence that patients in ventricular dyssynchrony who remain symptomatic after medication might benefit from this technology. Based on evidence made available to the Medical Advisory Secretariat by a manufacturer, (8) it appears that these 6-month improvements are maintained at 12-month follow-up.
To date, however, there is insufficient evidence to support the routine use of combined ICD/BiV devices in patients with chronic HF with prolonged QRS intervals.
Summary of Updated Findings Since the 2003 Review
Since the Medical Advisory Secretariat’s review in 2003 of biventricular pacemakers, 2 large RCTs have been published: COMPANION (9) and CARE-HF. (10) The characteristics of each trial are shown in Table 1. The COMPANION trial had a number of major methodological limitations compared with the CARE-HF trial.
Characteristics of the COMPANION and CARE-HF Trials*
COMPANION; (9) CARE-HF. (10)
BiV indicates biventricular; ICD, implantable cardioverter defibrillator; EF, ejection fraction; QRS, the interval representing the Q, R and S waves on an electrocardiogram; FDA, United States Food and Drug Administration.
Overall, CARE-HF showed that BiV pacing significantly improves mortality, QoL, and NYHA class in patients with severe HF and a wide QRS interval (Tables 2 and 3).
CARE-HF Results: Primary and Secondary Endpoints*
BiV indicates biventricular; NNT, number needed to treat.
Cleland JGF, Daubert J, Erdmann E, Freemantle N, Gras D, Kappenberger L et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure (CARE-HF). New England Journal of Medicine 2005; 352:1539-1549; Copyright 2003 Massachusettes Medical Society. All rights reserved. (10)
CARE H-F Results: NYHA Class and Quality of Life Scores*
Minnesota Living with Heart Failure scores range from 0 to 105; higher scores reflect poorer QoL.
European Quality of Life–5 Dimensions scores range from -0.594 to 1.000; 1.000 indicates fully healthy; 0, dead
Cleland JGF, Daubert J, Erdmann E, Freemantle N, Gras D, Kappenberger L et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure (CARE-HF). New England Journal of Medicine 2005; 352:1539-1549; Copyright 2005 Massachusettes Medical Society. All rights reserved.(10)
GRADE Quality of Evidence
The quality of these 3 trials was examined according to the GRADE Working Group criteria, (12) (Table 4).
Quality refers to criteria such as the adequacy of allocation concealment, blinding, and follow-up.
Consistency refers to the similarity of estimates of effect across studies. If there is an important unexplained inconsistency in the results, confidence in the estimate of effect for that outcome decreases. Differences in the direction of effect, the size of the differences in effect, and the significance of the differences guide the decision about whether important inconsistency exists.
Directness refers to the extent to which the people interventions and outcome measures are similar to those of interest. For example, there may be uncertainty about the directness of the evidence if the people of interest are older, sicker, or have more comorbid conditions than do the people in the studies.
As stated by the GRADE Working Group, (12) the following definitions were used in grading the quality of the evidence:
High: Further research is very unlikely to change our confidence on the estimate of effect.
Moderate: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low: Any estimate of effect is very uncertain.
Quality of Evidence: CARE-HF and COMPANION
Conclusions
Overall, there is evidence that BiV pacemakers are effective for improving mortality, QoL, and functional status in patients with NYHA class III/IV HF, an EF less than 0.35, a QRS interval greater than 120 ms, who are refractory to drug therapy.
As per the GRADE Working Group, recommendations considered the following 4 main factors:
The tradeoffs, taking into account the estimated size of the effect for the main outcome, the confidence limits around those estimates, and the relative value placed on the outcome
The quality of the evidence (Table 4)
Translation of the evidence into practice in a specific setting, taking into consideration important factors that could be expected to modify the size of the expected effects such as proximity to a hospital or availability of necessary expertise
Uncertainty about the baseline risk for the population of interest
The GRADE Working Group also recommends that incremental costs of health care alternatives should be considered explicitly alongside the expected health benefits and harms. Recommendations rely on judgments about the value of the incremental health benefits in relation to the incremental costs. The last column in Table 5 shows the overall trade-off between benefits and harms and incorporates any risk/uncertainty.
For BiV pacing, the overall GRADE and strength of the recommendation is moderate: the quality of the evidence is moderate/high (because of some uncertainty due to methodological limitations in the study design, e.g., no blinding), but there is also some risk/uncertainty in terms of the estimated prevalence and wide cost-effectiveness estimates (Table 5).
For the combination BiV pacing/ICD, the overall GRADE and strength of the recommendation is weak—the quality of the evidence is low (because of uncertainty due to methodological limitations in the study design), but there is also some risk/uncertainty in terms of the estimated prevalence, high cost, and high budget impact (Table 5). There are indirect, low-quality comparisons of the effectiveness of BiV pacemakers compared with the combination BiV/ICD devices.
A stronger recommendation can be made for BiV pacing only compared with the combination BiV/ICD device for patients with an EF less than or equal to 0.35, and a QRS interval over or equal to 120 ms, and NYHA III/IV symptoms, and refractory to optimal medical therapy (Table 5).
There is moderate/high-quality evidence that BiV pacemakers significantly improve mortality, QoL, and functional status.
There is low-quality evidence that combined BiV/ICD devices significantly improve mortality, QoL, and functional status.
To date, there are no direct comparisons of the effectiveness of BiV pacemakers compared with the combined BiV/ICD devices in terms of mortality, QoL, and functional status.
Overall GRADE and Strength of Recommendation
BiV refers to biventricular; ICD, implantable cardioverter defibrillator; NNT, number needed to treat.
PMCID: PMC3382419  PMID: 23074464
4.  Internet-Based Device-Assisted Remote Monitoring of Cardiovascular Implantable Electronic Devices 
Executive Summary
Objective
The objective of this Medical Advisory Secretariat (MAS) report was to conduct a systematic review of the available published evidence on the safety, effectiveness, and cost-effectiveness of Internet-based device-assisted remote monitoring systems (RMSs) for therapeutic cardiac implantable electronic devices (CIEDs) such as pacemakers (PMs), implantable cardioverter-defibrillators (ICDs), and cardiac resynchronization therapy (CRT) devices. The MAS evidence-based review was performed to support public financing decisions.
Clinical Need: Condition and Target Population
Sudden cardiac death (SCD) is a major cause of fatalities in developed countries. In the United States almost half a million people die of SCD annually, resulting in more deaths than stroke, lung cancer, breast cancer, and AIDS combined. In Canada each year more than 40,000 people die from a cardiovascular related cause; approximately half of these deaths are attributable to SCD.
Most cases of SCD occur in the general population typically in those without a known history of heart disease. Most SCDs are caused by cardiac arrhythmia, an abnormal heart rhythm caused by malfunctions of the heart’s electrical system. Up to half of patients with significant heart failure (HF) also have advanced conduction abnormalities.
Cardiac arrhythmias are managed by a variety of drugs, ablative procedures, and therapeutic CIEDs. The range of CIEDs includes pacemakers (PMs), implantable cardioverter-defibrillators (ICDs), and cardiac resynchronization therapy (CRT) devices. Bradycardia is the main indication for PMs and individuals at high risk for SCD are often treated by ICDs.
Heart failure (HF) is also a significant health problem and is the most frequent cause of hospitalization in those over 65 years of age. Patients with moderate to severe HF may also have cardiac arrhythmias, although the cause may be related more to heart pump or haemodynamic failure. The presence of HF, however, increases the risk of SCD five-fold, regardless of aetiology. Patients with HF who remain highly symptomatic despite optimal drug therapy are sometimes also treated with CRT devices.
With an increasing prevalence of age-related conditions such as chronic HF and the expanding indications for ICD therapy, the rate of ICD placement has been dramatically increasing. The appropriate indications for ICD placement, as well as the rate of ICD placement, are increasingly an issue. In the United States, after the introduction of expanded coverage of ICDs, a national ICD registry was created in 2005 to track these devices. A recent survey based on this national ICD registry reported that 22.5% (25,145) of patients had received a non-evidence based ICD and that these patients experienced significantly higher in-hospital mortality and post-procedural complications.
In addition to the increased ICD device placement and the upfront device costs, there is the need for lifelong follow-up or surveillance, placing a significant burden on patients and device clinics. In 2007, over 1.6 million CIEDs were implanted in Europe and the United States, which translates to over 5.5 million patient encounters per year if the recommended follow-up practices are considered. A safe and effective RMS could potentially improve the efficiency of long-term follow-up of patients and their CIEDs.
Technology
In addition to being therapeutic devices, CIEDs have extensive diagnostic abilities. All CIEDs can be interrogated and reprogrammed during an in-clinic visit using an inductive programming wand. Remote monitoring would allow patients to transmit information recorded in their devices from the comfort of their own homes. Currently most ICD devices also have the potential to be remotely monitored. Remote monitoring (RM) can be used to check system integrity, to alert on arrhythmic episodes, and to potentially replace in-clinic follow-ups and manage disease remotely. They do not currently have the capability of being reprogrammed remotely, although this feature is being tested in pilot settings.
Every RMS is specifically designed by a manufacturer for their cardiac implant devices. For Internet-based device-assisted RMSs, this customization includes details such as web application, multiplatform sensors, custom algorithms, programming information, and types and methods of alerting patients and/or physicians. The addition of peripherals for monitoring weight and pressure or communicating with patients through the onsite communicators also varies by manufacturer. Internet-based device-assisted RMSs for CIEDs are intended to function as a surveillance system rather than an emergency system.
Health care providers therefore need to learn each application, and as more than one application may be used at one site, multiple applications may need to be reviewed for alarms. All RMSs deliver system integrity alerting; however, some systems seem to be better geared to fast arrhythmic alerting, whereas other systems appear to be more intended for remote follow-up or supplemental remote disease management. The different RMSs may therefore have different impacts on workflow organization because of their varying frequency of interrogation and methods of alerts. The integration of these proprietary RM web-based registry systems with hospital-based electronic health record systems has so far not been commonly implemented.
Currently there are 2 general types of RMSs: those that transmit device diagnostic information automatically and without patient assistance to secure Internet-based registry systems, and those that require patient assistance to transmit information. Both systems employ the use of preprogrammed alerts that are either transmitted automatically or at regular scheduled intervals to patients and/or physicians.
The current web applications, programming, and registry systems differ greatly between the manufacturers of transmitting cardiac devices. In Canada there are currently 4 manufacturers—Medtronic Inc., Biotronik, Boston Scientific Corp., and St Jude Medical Inc.—which have regulatory approval for remote transmitting CIEDs. Remote monitoring systems are proprietary to the manufacturer of the implant device. An RMS for one device will not work with another device, and the RMS may not work with all versions of the manufacturer’s devices.
All Internet-based device-assisted RMSs have common components. The implanted device is equipped with a micro-antenna that communicates with a small external device (at bedside or wearable) commonly known as the transmitter. Transmitters are able to interrogate programmed parameters and diagnostic data stored in the patients’ implant device. The information transfer to the communicator can occur at preset time intervals with the participation of the patient (waving a wand over the device) or it can be sent automatically (wirelessly) without their participation. The encrypted data are then uploaded to an Internet-based database on a secure central server. The data processing facilities at the central database, depending on the clinical urgency, can trigger an alert for the physician(s) that can be sent via email, fax, text message, or phone. The details are also posted on the secure website for viewing by the physician (or their delegate) at their convenience.
Research Questions
The research directions and specific research questions for this evidence review were as follows:
To identify the Internet-based device-assisted RMSs available for follow-up of patients with therapeutic CIEDs such as PMs, ICDs, and CRT devices.
To identify the potential risks, operational issues, or organizational issues related to Internet-based device-assisted RM for CIEDs.
To evaluate the safety, acceptability, and effectiveness of Internet-based device-assisted RMSs for CIEDs such as PMs, ICDs, and CRT devices.
To evaluate the safety, effectiveness, and cost-effectiveness of Internet-based device-assisted RMSs for CIEDs compared to usual outpatient in-office monitoring strategies.
To evaluate the resource implications or budget impact of RMSs for CIEDs in Ontario, Canada.
Research Methods
Literature Search
The review included a systematic review of published scientific literature and consultations with experts and manufacturers of all 4 approved RMSs for CIEDs in Canada. Information on CIED cardiac implant clinics was also obtained from Provincial Programs, a division within the Ministry of Health and Long-Term Care with a mandate for cardiac implant specialty care. Various administrative databases and registries were used to outline the current clinical follow-up burden of CIEDs in Ontario. The provincial population-based ICD database developed and maintained by the Institute for Clinical Evaluative Sciences (ICES) was used to review the current follow-up practices with Ontario patients implanted with ICD devices.
Search Strategy
A literature search was performed on September 21, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from 1950 to September 2010. Search alerts were generated and reviewed for additional relevant literature until December 31, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search.
Inclusion Criteria
published between 1950 and September 2010;
English language full-reports and human studies;
original reports including clinical evaluations of Internet-based device-assisted RMSs for CIEDs in clinical settings;
reports including standardized measurements on outcome events such as technical success, safety, effectiveness, cost, measures of health care utilization, morbidity, mortality, quality of life or patient satisfaction;
randomized controlled trials (RCTs), systematic reviews and meta-analyses, cohort and controlled clinical studies.
Exclusion Criteria
non-systematic reviews, letters, comments and editorials;
reports not involving standardized outcome events;
clinical reports not involving Internet-based device assisted RM systems for CIEDs in clinical settings;
reports involving studies testing or validating algorithms without RM;
studies with small samples (<10 subjects).
Outcomes of Interest
The outcomes of interest included: technical outcomes, emergency department visits, complications, major adverse events, symptoms, hospital admissions, clinic visits (scheduled and/or unscheduled), survival, morbidity (disease progression, stroke, etc.), patient satisfaction, and quality of life.
Summary of Findings
The MAS evidence review was performed to review available evidence on Internet-based device-assisted RMSs for CIEDs published until September 2010. The search identified 6 systematic reviews, 7 randomized controlled trials, and 19 reports for 16 cohort studies—3 of these being registry-based and 4 being multi-centered. The evidence is summarized in the 3 sections that follow.
1. Effectiveness of Remote Monitoring Systems of CIEDs for Cardiac Arrhythmia and Device Functioning
In total, 15 reports on 13 cohort studies involving investigations with 4 different RMSs for CIEDs in cardiology implant clinic groups were identified in the review. The 4 RMSs were: Care Link Network® (Medtronic Inc,, Minneapolis, MN, USA); Home Monitoring® (Biotronic, Berlin, Germany); House Call 11® (St Jude Medical Inc., St Pauls, MN, USA); and a manufacturer-independent RMS. Eight of these reports were with the Home Monitoring® RMS (12,949 patients), 3 were with the Care Link® RMS (167 patients), 1 was with the House Call 11® RMS (124 patients), and 1 was with a manufacturer-independent RMS (44 patients). All of the studies, except for 2 in the United States, (1 with Home Monitoring® and 1 with House Call 11®), were performed in European countries.
The RMSs in the studies were evaluated with different cardiac implant device populations: ICDs only (6 studies), ICD and CRT devices (3 studies), PM and ICD and CRT devices (4 studies), and PMs only (2 studies). The patient populations were predominately male (range, 52%–87%) in all studies, with mean ages ranging from 58 to 76 years. One study population was unique in that RMSs were evaluated for ICDs implanted solely for primary prevention in young patients (mean age, 44 years) with Brugada syndrome, which carries an inherited increased genetic risk for sudden heart attack in young adults.
Most of the cohort studies reported on the feasibility of RMSs in clinical settings with limited follow-up. In the short follow-up periods of the studies, the majority of the events were related to detection of medical events rather than system configuration or device abnormalities. The results of the studies are summarized below:
The interrogation of devices on the web platform, both for continuous and scheduled transmissions, was significantly quicker with remote follow-up, both for nurses and physicians.
In a case-control study focusing on a Brugada population–based registry with patients followed-up remotely, there were significantly fewer outpatient visits and greater detection of inappropriate shocks. One death occurred in the control group not followed remotely and post-mortem analysis indicated early signs of lead failure prior to the event.
Two studies examined the role of RMSs in following ICD leads under regulatory advisory in a European clinical setting and noted:
– Fewer inappropriate shocks were administered in the RM group.
– Urgent in-office interrogations and surgical revisions were performed within 12 days of remote alerts.
– No signs of lead fracture were detected at in-office follow-up; all were detected at remote follow-up.
Only 1 study reported evaluating quality of life in patients followed up remotely at 3 and 6 months; no values were reported.
Patient satisfaction was evaluated in 5 cohort studies, all in short term follow-up: 1 for the Home Monitoring® RMS, 3 for the Care Link® RMS, and 1 for the House Call 11® RMS.
– Patients reported receiving a sense of security from the transmitter, a good relationship with nurses and physicians, positive implications for their health, and satisfaction with RM and organization of services.
– Although patients reported that the system was easy to implement and required less than 10 minutes to transmit information, a variable proportion of patients (range, 9% 39%) reported that they needed the assistance of a caregiver for their transmission.
– The majority of patients would recommend RM to other ICD patients.
– Patients with hearing or other physical or mental conditions hindering the use of the system were excluded from studies, but the frequency of this was not reported.
Physician satisfaction was evaluated in 3 studies, all with the Care Link® RMS:
– Physicians reported an ease of use and high satisfaction with a generally short-term use of the RMS.
– Physicians reported being able to address the problems in unscheduled patient transmissions or physician initiated transmissions remotely, and were able to handle the majority of the troubleshooting calls remotely.
– Both nurses and physicians reported a high level of satisfaction with the web registry system.
2. Effectiveness of Remote Monitoring Systems in Heart Failure Patients for Cardiac Arrhythmia and Heart Failure Episodes
Remote follow-up of HF patients implanted with ICD or CRT devices, generally managed in specialized HF clinics, was evaluated in 3 cohort studies: 1 involved the Home Monitoring® RMS and 2 involved the Care Link® RMS. In these RMSs, in addition to the standard diagnostic features, the cardiac devices continuously assess other variables such as patient activity, mean heart rate, and heart rate variability. Intra-thoracic impedance, a proxy measure for lung fluid overload, was also measured in the Care Link® studies. The overall diagnostic performance of these measures cannot be evaluated, as the information was not reported for patients who did not experience intra-thoracic impedance threshold crossings or did not undergo interventions. The trial results involved descriptive information on transmissions and alerts in patients experiencing high morbidity and hospitalization in the short study periods.
3. Comparative Effectiveness of Remote Monitoring Systems for CIEDs
Seven RCTs were identified evaluating RMSs for CIEDs: 2 were for PMs (1276 patients) and 5 were for ICD/CRT devices (3733 patients). Studies performed in the clinical setting in the United States involved both the Care Link® RMS and the Home Monitoring® RMS, whereas all studies performed in European countries involved only the Home Monitoring® RMS.
3A. Randomized Controlled Trials of Remote Monitoring Systems for Pacemakers
Two trials, both multicenter RCTs, were conducted in different countries with different RMSs and study objectives. The PREFER trial was a large trial (897 patients) performed in the United States examining the ability of Care Link®, an Internet-based remote PM interrogation system, to detect clinically actionable events (CAEs) sooner than the current in-office follow-up supplemented with transtelephonic monitoring transmissions, a limited form of remote device interrogation. The trial results are summarized below:
In the 375-day mean follow-up, 382 patients were identified with at least 1 CAE—111 patients in the control arm and 271 in the remote arm.
The event rate detected per patient for every type of CAE, except for loss of atrial capture, was higher in the remote arm than the control arm.
The median time to first detection of CAEs (4.9 vs. 6.3 months) was significantly shorter in the RMS group compared to the control group (P < 0.0001).
Additionally, only 2% (3/190) of the CAEs in the control arm were detected during a transtelephonic monitoring transmission (the rest were detected at in-office follow-ups), whereas 66% (446/676) of the CAEs were detected during remote interrogation.
The second study, the OEDIPE trial, was a smaller trial (379 patients) performed in France evaluating the ability of the Home Monitoring® RMS to shorten PM post-operative hospitalization while preserving the safety of conventional management of longer hospital stays.
Implementation and operationalization of the RMS was reported to be successful in 91% (346/379) of the patients and represented 8144 transmissions.
In the RM group 6.5% of patients failed to send messages (10 due to improper use of the transmitter, 2 with unmanageable stress). Of the 172 patients transmitting, 108 patients sent a total of 167 warnings during the trial, with a greater proportion of warnings being attributed to medical rather than technical causes.
Forty percent had no warning message transmission and among these, 6 patients experienced a major adverse event and 1 patient experienced a non-major adverse event. Of the 6 patients having a major adverse event, 5 contacted their physician.
The mean medical reaction time was faster in the RM group (6.5 ± 7.6 days vs. 11.4 ± 11.6 days).
The mean duration of hospitalization was significantly shorter (P < 0.001) for the RM group than the control group (3.2 ± 3.2 days vs. 4.8 ± 3.7 days).
Quality of life estimates by the SF-36 questionnaire were similar for the 2 groups at 1-month follow-up.
3B. Randomized Controlled Trials Evaluating Remote Monitoring Systems for ICD or CRT Devices
The 5 studies evaluating the impact of RMSs with ICD/CRT devices were conducted in the United States and in European countries and involved 2 RMSs—Care Link® and Home Monitoring ®. The objectives of the trials varied and 3 of the trials were smaller pilot investigations.
The first of the smaller studies (151 patients) evaluated patient satisfaction, achievement of patient outcomes, and the cost-effectiveness of the Care Link® RMS compared to quarterly in-office device interrogations with 1-year follow-up.
Individual outcomes such as hospitalizations, emergency department visits, and unscheduled clinic visits were not significantly different between the study groups.
Except for a significantly higher detection of atrial fibrillation in the RM group, data on ICD detection and therapy were similar in the study groups.
Health-related quality of life evaluated by the EuroQoL at 6-month or 12-month follow-up was not different between study groups.
Patients were more satisfied with their ICD care in the clinic follow-up group than in the remote follow-up group at 6-month follow-up, but were equally satisfied at 12- month follow-up.
The second small pilot trial (20 patients) examined the impact of RM follow-up with the House Call 11® system on work schedules and cost savings in patients randomized to 2 study arms varying in the degree of remote follow-up.
The total time including device interrogation, transmission time, data analysis, and physician time required was significantly shorter for the RM follow-up group.
The in-clinic waiting time was eliminated for patients in the RM follow-up group.
The physician talk time was significantly reduced in the RM follow-up group (P < 0.05).
The time for the actual device interrogation did not differ in the study groups.
The third small trial (115 patients) examined the impact of RM with the Home Monitoring® system compared to scheduled trimonthly in-clinic visits on the number of unplanned visits, total costs, health-related quality of life (SF-36), and overall mortality.
There was a 63.2% reduction in in-office visits in the RM group.
Hospitalizations or overall mortality (values not stated) were not significantly different between the study groups.
Patient-induced visits were higher in the RM group than the in-clinic follow-up group.
The TRUST Trial
The TRUST trial was a large multicenter RCT conducted at 102 centers in the United States involving the Home Monitoring® RMS for ICD devices for 1450 patients. The primary objectives of the trial were to determine if remote follow-up could be safely substituted for in-office clinic follow-up (3 in-office visits replaced) and still enable earlier physician detection of clinically actionable events.
Adherence to the protocol follow-up schedule was significantly higher in the RM group than the in-office follow-up group (93.5% vs. 88.7%, P < 0.001).
Actionability of trimonthly scheduled checks was low (6.6%) in both study groups. Overall, actionable causes were reprogramming (76.2%), medication changes (24.8%), and lead/system revisions (4%), and these were not different between the 2 study groups.
The overall mean number of in-clinic and hospital visits was significantly lower in the RM group than the in-office follow-up group (2.1 per patient-year vs. 3.8 per patient-year, P < 0.001), representing a 45% visit reduction at 12 months.
The median time from onset of first arrhythmia to physician evaluation was significantly shorter (P < 0.001) in the RM group than in the in-office follow-up group for all arrhythmias (1 day vs. 35.5 days).
The median time to detect clinically asymptomatic arrhythmia events—atrial fibrillation (AF), ventricular fibrillation (VF), ventricular tachycardia (VT), and supra-ventricular tachycardia (SVT)—was also significantly shorter (P < 0.001) in the RM group compared to the in-office follow-up group (1 day vs. 41.5 days) and was significantly quicker for each of the clinical arrhythmia events—AF (5.5 days vs. 40 days), VT (1 day vs. 28 days), VF (1 day vs. 36 days), and SVT (2 days vs. 39 days).
System-related problems occurred infrequently in both groups—in 1.5% of patients (14/908) in the RM group and in 0.7% of patients (3/432) in the in-office follow-up group.
The overall adverse event rate over 12 months was not significantly different between the 2 groups and individual adverse events were also not significantly different between the RM group and the in-office follow-up group: death (3.4% vs. 4.9%), stroke (0.3% vs. 1.2%), and surgical intervention (6.6% vs. 4.9%), respectively.
The 12-month cumulative survival was 96.4% (95% confidence interval [CI], 95.5%–97.6%) in the RM group and 94.2% (95% confidence interval [CI], 91.8%–96.6%) in the in-office follow-up group, and was not significantly different between the 2 groups (P = 0.174).
The CONNECT Trial
The CONNECT trial, another major multicenter RCT, involved the Care Link® RMS for ICD/CRT devices in a15-month follow-up study of 1,997 patients at 133 sites in the United States. The primary objective of the trial was to determine whether automatically transmitted physician alerts decreased the time from the occurrence of clinically relevant events to medical decisions. The trial results are summarized below:
Of the 575 clinical alerts sent in the study, 246 did not trigger an automatic physician alert. Transmission failures were related to technical issues such as the alert not being programmed or not being reset, and/or a variety of patient factors such as not being at home and the monitor not being plugged in or set up.
The overall mean time from the clinically relevant event to the clinical decision was significantly shorter (P < 0.001) by 17.4 days in the remote follow-up group (4.6 days for 172 patients) than the in-office follow-up group (22 days for 145 patients).
– The median time to a clinical decision was shorter in the remote follow-up group than in the in-office follow-up group for an AT/AF burden greater than or equal to 12 hours (3 days vs. 24 days) and a fast VF rate greater than or equal to 120 beats per minute (4 days vs. 23 days).
Although infrequent, similar low numbers of events involving low battery and VF detection/therapy turned off were noted in both groups. More alerts, however, were noted for out-of-range lead impedance in the RM group (18 vs. 6 patients), and the time to detect these critical events was significantly shorter in the RM group (same day vs. 17 days).
Total in-office clinic visits were reduced by 38% from 6.27 visits per patient-year in the in-office follow-up group to 3.29 visits per patient-year in the remote follow-up group.
Health care utilization visits (N = 6,227) that included cardiovascular-related hospitalization, emergency department visits, and unscheduled clinic visits were not significantly higher in the remote follow-up group.
The overall mean length of hospitalization was significantly shorter (P = 0.002) for those in the remote follow-up group (3.3 days vs. 4.0 days) and was shorter both for patients with ICD (3.0 days vs. 3.6 days) and CRT (3.8 days vs. 4.7 days) implants.
The mortality rate between the study arms was not significantly different between the follow-up groups for the ICDs (P = 0.31) or the CRT devices with defribillator (P = 0.46).
Conclusions
There is limited clinical trial information on the effectiveness of RMSs for PMs. However, for RMSs for ICD devices, multiple cohort studies and 2 large multicenter RCTs demonstrated feasibility and significant reductions in in-office clinic follow-ups with RMSs in the first year post implantation. The detection rates of clinically significant events (and asymptomatic events) were higher, and the time to a clinical decision for these events was significantly shorter, in the remote follow-up groups than in the in-office follow-up groups. The earlier detection of clinical events in the remote follow-up groups, however, was not associated with lower morbidity or mortality rates in the 1-year follow-up. The substitution of almost all the first year in-office clinic follow-ups with RM was also not associated with an increased health care utilization such as emergency department visits or hospitalizations.
The follow-up in the trials was generally short-term, up to 1 year, and was a more limited assessment of potential longer term device/lead integrity complications or issues. None of the studies compared the different RMSs, particularly the different RMSs involving patient-scheduled transmissions or automatic transmissions. Patients’ acceptance of and satisfaction with RM were reported to be high, but the impact of RM on patients’ health-related quality of life, particularly the psychological aspects, was not evaluated thoroughly. Patients who are not technologically competent, having hearing or other physical/mental impairments, were identified as potentially disadvantaged with remote surveillance. Cohort studies consistently identified subgroups of patients who preferred in-office follow-up. The evaluation of costs and workflow impact to the health care system were evaluated in European or American clinical settings, and only in a limited way.
Internet-based device-assisted RMSs involve a new approach to monitoring patients, their disease progression, and their CIEDs. Remote monitoring also has the potential to improve the current postmarket surveillance systems of evolving CIEDs and their ongoing hardware and software modifications. At this point, however, there is insufficient information to evaluate the overall impact to the health care system, although the time saving and convenience to patients and physicians associated with a substitution of in-office follow-up by RM is more certain. The broader issues surrounding infrastructure, impacts on existing clinical care systems, and regulatory concerns need to be considered for the implementation of Internet-based RMSs in jurisdictions involving different clinical practices.
PMCID: PMC3377571  PMID: 23074419
5.  Cardiac Resynchronization Therapy Corrects Dyssynchrony-induced Regional Gene Expression Changes on a Genomic Level 
Background
Cardiac electromechanical dyssynchrony causes regional disparities in workload, oxygen consumption, and myocardial perfusion within the left ventricle. We hypothesized that such dyssynchrony also induces region-specific alterations in the myocardial transcriptome that are corrected by cardiac resynchronization (CRT).
Methods and Results
Adult dogs underwent left bundle branch ablation (LBBB) and right atrial pacing at 200 bpm for either 6 weeks (dyssynchronous heart failure, DHF, n=12) or 3 weeks followed by 3 weeks of resynchronization by bi-ventricular pacing at the same pacing rate (CRT, n=10). Control animals without LBBB were not paced (NF, n=13). At 6 weeks, RNA was isolated from the anterior and lateral LV walls and hybridized onto canine-specific 44K microarrays. Echocardiographically, CRT led to a significant decrease in the dyssynchrony index, while DHF and CRT animals had a comparable degree of LV dysfunction. In DHF, changes in gene expression were primarily observed in the anterior LV, resulting in increased regional heterogeneity of gene expression within the left ventricle. Dyssynchrony-induced expression changes in 1050 transcripts were reversed by CRT to levels of NF hearts (false discovery rate <5%). CRT remodeled transcripts with metabolic and cell signaling function and greatly reduced regional heterogeneity of gene expression compared with DHF.
Conclusions
Our results demonstrate a profound effect of electromechanical dyssynchrony on the regional cardiac transcriptome, causing gene expression changes primarily in the anterior LV wall. CRT corrected the alterations in gene expression in the anterior wall, supporting a global effect of biventricular pacing on the ventricular transcriptome that extends beyond the pacing site in the lateral wall.
doi:10.1161/CIRCGENETICS.108.832345
PMCID: PMC2801868  PMID: 20031609
Cardiac Resynchronization Therapy; Heart Failure; Gene Expression; Microarray
6.  Bundle-Branch Block Morphology and Other Predictors of Outcome After Cardiac Resynchronization Therapy in Medicare Patients 
Circulation  2010;122(20):2022-2030.
Background
Clinical trials of cardiac resynchronization therapy (CRT) have enrolled a select group of patients, with few patients in subgroups such as right bundle-branch block (RBBB). Analysis of population-based outcomes provides a method to identify real-world predictors of CRT outcomes.
Methods and Results
Medicare Implantable Cardioverter-Defibrillator Registry (2005 to 2006) data were merged with patient outcomes data. Cox proportional-hazards models assessed death and death/heart failure hospitalization outcomes in patients with CRT and an implantable cardioverter-defibrillator (CRT-D). The 14 946 registry patients with CRT-D (median follow-up, 40 months) had 1-year, 3-year, and overall mortality rates of 12%, 32%, and 37%, respectively. New York Heart Association class IV heart failure status (1-year hazard ratio [HR], 2.23; 3-year HR, 1.98; P<0.001) and age ≥80 years (1-year HR, 1.74; 3-year HR, 1.75; P<0.001) were associated with increased mortality both early and late after CRT-D. RBBB (1-year HR, 1.44; 3-year HR, 1.37; P<0.001) and ischemic cardiomyopathy (1-year HR, 1.39; 3-year HR, 1.44; P<0.001) were the next strongest adjusted predictors of both early and late mortality. RBBB and ischemic cardiomyopathy together had twice the adjusted hazard for death (HR, 1.99; P<0.001) as left BBB and nonischemic cardiomyopathy. QRS duration of at least 150 ms predicted more favorable outcomes in left BBB but had no impact in RBBB. A secondary analysis showed lower hazards for CRT-D compared with standard implantable cardioverter-defibrillators in left BBB compared with RBBB.
Conclusions
In Medicare patients, RBBB, ischemic cardiomyopathy, New York Heart Association class IV status, and advanced age were powerful adjusted predictors of poor outcome after CRT-D. Real-world mortality rates 3 to 4 years after CRT-D appear higher than previously recognized.
doi:10.1161/CIRCULATIONAHA.110.956011
PMCID: PMC3659803  PMID: 21041691
bundle-branch block; heart failure; outcomes; registries
7.  Dual-site right ventricular and left ventricular pacing in a patient with left ventricular systolic dysfunction and atrial fibrillation using a standard CRT-D device 
In patients undergoing cardiac resynchronization therapy with defibrillator (CRT-D) implantation for left ventricular systolic dysfunction (LVSD) accompanied by permanent atrial fibrillation (AF), generally, the unused atrial port is plugged at device implantation. We describe an alternative use for the atrial-port in this case report.
A 43 year old gentleman with LVSD due to left ventricular non-compaction (LVNC) and AF of unknown duration underwent a CRT-D implantation after optimization of cardiac failure treatment. The atrial-port which would otherwise have been plugged was connected to a high right ventricular septal (RVS) pacing-lead and the shock-lead was positioned at the right ventricular apex (RVA). This approach permitted modified cardiac resynchronization in a high RVS to left ventricular (LV) and RVA pacing sequence using the high RVS and LV pacing combined with a shock vector including the RV apex. A standard CRT-D device with a minimum programmable A–V delay of 30 ms (technically RVS to LV delay in the ‘DDD’ pacing mode) was used. The device was programmed to a ‘DDD’ pacing mode (sequential multi-site ventricular pacing with some programmability). The mode switch operation was programmed ‘OFF’ since atrial sensing is unavailable. Device-delivered shocks did not cardiovert the patient back to sinus rhythm suggesting that the AF was permanent (no prior cardioversion attempts were made on the presumption that the chances of maintaining sinus rhythm, given the underlying cardiac condition, were low). Subsequently, the patient required radio-frequency ablation of the atrio-ventricular node for conducted AF. Symptomatic, echocardiographic and radiological improvement preceded atrio-ventricular node ablation.
Conclusion
Amongst AF patients with permanent AF undergoing CRT-D implantation, those patients who are likely to have the CRT-D device atrial-ports plugged could benefit from having both the options of (i) a RVA shock vector as well as (ii) a high RVS-pacing feasible, by utilizing the atrial-port of a conventional CRTD device for a RVS pacing lead, should a RVA shock-lead position be preferred. New device programming algorithms will be necessary to make patient-customized programming in this lead configuration flexible, more useful clinically and easy.
doi:10.1016/j.jsha.2013.01.003
PMCID: PMC3809458  PMID: 24174862
Cardiac resynchronization therapy with defibrillator (CRT-D); Left ventricular systolic dysfunction (LVSD); Atrial fibrillation (AF); Left ventricular non-compaction (LVNC); High right ventricular septum (high RVS); Right ventricular apex (RVA); Left ventricle (LV); Atrio-ventricular node (A-VN); Radio-frequency ablation (RFA)
8.  Implantable Cardioverter Defibrillators. Prophylactic Use 
Executive Summary
Objective
The use of implantable cardiac defibrillators (ICDs) to prevent sudden cardiac death (SCD) in patients resuscitated from cardiac arrest or documented dangerous ventricular arrhythmias (secondary prevention of SCD) is an insured service. In 2003 (before the establishment of the Ontario Health Technology Advisory Committee), the Medical Advisory Secretariat conducted a health technology policy assessment on the prophylactic use (primary prevention of SCD) of ICDs for patients at high risk of SCD. The Medical Advisory Secretariat concluded that ICDs are effective for the primary prevention of SCD. Moreover, it found that a more clearly defined target population at risk for SCD that would be likely to benefit from ICDs is needed, given that the number needed to treat (NNT) from recent studies is 13 to 18, and given that the per-unit cost of ICDs is $32,000, which means that the projected cost to Ontario is $770 million (Cdn).
Accordingly, as part of an annual review and publication of more recent articles, the Medical Advisory Secretariat updated its health technology policy assessment of ICDs.
Clinical Need
Sudden cardiac death is caused by the sudden onset of fatal arrhythmias, or abnormal heart rhythms: ventricular tachycardia (VT), a rhythm abnormality in which the ventricles cause the heart to beat too fast, and ventricular fibrillation (VF), an abnormal, rapid and erratic heart rhythm. About 80% of fatal arrhythmias are associated with ischemic heart disease, which is caused by insufficient blood flow to the heart.
Management of VT and VF with antiarrhythmic drugs is not very effective; for this reason, nonpharmacological treatments have been explored. One such treatment is the ICD.
The Technology
An ICD is a battery-powered device that, once implanted, monitors heart rhythm and can deliver an electric shock to restore normal rhythm when potentially fatal arrhythmias are detected. The use of ICDs to prevent SCD in patients resuscitated from cardiac arrest or documented dangerous ventricular arrhythmias (secondary prevention) is an insured service in Ontario.
Primary prevention of SCD involves identification of and preventive therapy for patients who are at high risk for SCD. Most of the studies in the literature that have examined the prevention of fatal ventricular arrhythmias have focused on patients with ischemic heart disease, in particular, those with heart failure (HF), which has been shown to increase the risk of SCD. The risk of HF is determined by left ventricular ejection fraction (LVEF); most studies have focused on patients with an LVEF under 0.35 or 0.30. While most studies have found ICDs to reduce significantly the risk for SCD in patients with an LVEF less than 0.35, a more recent study (Sudden Cardiac Death in Heart Failure Trial [SCD-HeFT]) reported that patients with HF with nonischemic heart disease could also benefit from this technology. Based on the generalization of the SCD-HeFT study, the Centers for Medicare and Medicaid in the United States recently announced that it would allocate $10 billion (US) annually toward the primary prevention of SCD for patients with ischemic and nonischemic heart disease and an LVEF under 0.35.
Review Strategy
The aim of this literature review was to assess the effectiveness, safety, and cost effectiveness of ICDs for the primary prevention of SCD.
The standard search strategy used by the Medical Advisory Secretariat was used. This included a search of all international health technology assessments as well as a search of the medical literature from January 2003–May 2005.
A modification of the GRADE approach (1) was used to make judgments about the quality of evidence and strength of recommendations systematically and explicitly. GRADE provides a framework for structured reflection and can help to ensure that appropriate judgments are made. GRADE takes into account a study’s design, quality, consistency, and directness in judging the quality of evidence for each outcome. The balance between benefits and harms, quality of evidence, applicability, and the certainty of the baseline risks are considered in judgments about the strength of recommendations.
Summary of Findings
Overall, ICDs are effective for the primary prevention of SCD. Three studies – the Multicentre Automatic Defibrillator Implantation Trial I (MADIT I), the Multicentre Automatic Defibrillator Implantation Trial II (MADIT II), and SCD-HeFT – showed there was a statistically significant decrease in total mortality for patients who prophylactically received an ICD compared with those who received conventional therapy (Table 1).
Results of Key Studies on the Use of Implantable Cardioverter Defibrillators for the Primary Prevention of Sudden Cardiac Death – All-Cause Mortality
MADIT I: Multicentre Automatic Defibrillator Implantation Trial I; MADIT II: Multicentre Automatic Defibrillator Implantation Trial II; SCD-HeFT: Sudden Cardiac Death in Heart Failure Trial.
EP indicates electrophysiology; ICD, implantable cardioverter defibrillator; NNT, number needed to treat; NSVT, nonsustained ventricular tachycardia. The NNT will appear higher if follow-up is short. For ICDs, the absolute benefit increases over time for at least a 5-year period; the NNT declines, often substantially, in studies with a longer follow-up. When the NNT are equalized for a similar period as the SCD-HeFT duration (5 years), the NNT for MADIT-I is 2.2; for MADIT-II, it is 6.3.
GRADE Quality of the Evidence
Using the GRADE Working Group criteria, the quality of these 3 trials was examined (Table 2).
Quality refers to the criteria such as the adequacy of allocation concealment, blinding and follow-up.
Consistency refers to the similarity of estimates of effect across studies. If there is important unexplained inconsistency in the results, our confidence in the estimate of effect for that outcome decreases. Differences in the direction of effect, the size of the differences in effect, and the significance of the differences guide the decision about whether important inconsistency exists.
Directness refers to the extent to which the people interventions and outcome measures are similar to those of interest. For example, there may be uncertainty about the directness of the evidence if the people of interest are older, sicker or have more comorbidity than those in the studies.
As stated by the GRADE Working Group, the following definitions were used to grade the quality of the evidence:
High: Further research is very unlikely to change our confidence n the estimate of effect.
Moderate: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low: Any estimate of effect is very uncertain.
Quality of Evidence – MADIT I, MADIT II, and SCD-HeFT*
MADIT I: Multicentre Automatic Defibrillator Implantation Trial I; MADIT II: Multicentre Automatic Defibrillator Implantation Trial II; SCD-HeFT: Sudden Cardiac Death in Heart Failure Trial.
The 3 trials had 3 different sets of eligibility criteria for implantation of an ICD for primary prevention of SCD. Conclusions
Conclusions
Overall, there is evidence that ICDs are effective for the primary prevention of SCD. Three trials have found a statistically significant decrease in total mortality for patients who prophylactically received an ICD compared with those who received conventional therapy in their respective study populations.
As per the GRADE Working Group, recommendations consider 4 main factors:
The tradeoffs, taking into account the estimated size of the effect for the main outcome, the confidence limits around those estimates, and the relative value placed on the outcome;
The quality of the evidence (Table 2);
Translation of the evidence into practice in a specific setting, taking into consideration important factors that could be expected to modify the size of the expected effects, such as proximity to a hospital or availability of necessary expertise; and
Uncertainty about the baseline risk for the population of interest
The GRADE Working Group also recommends that incremental costs of health care alternatives should be considered explicitly with the expected health benefits and harms. Recommendations rely on judgments about the value of the incremental health benefits in relation to the incremental costs. The last column in Table 3 is the overall trade-off between benefits and harms and incorporates any risk or uncertainty.
For MADIT I, the overall GRADE and strength of the recommendation is “moderate” – the quality of the evidence is “moderate” (uncertainty due to methodological limitations in the study design), and risk/uncertainty in cost and budget impact was mitigated by the use of filters to help target the prevalent population at risk (Table 3).
For MADIT II, the overall GRADE and strength of the recommendation is “very weak” – the quality of the evidence is “weak” (uncertainty due to methodological limitations in the study design), but there is risk or uncertainty regarding the high prevalence, cost, and budget impact. It is not clear why screening for high-risk patients was dropped, given that in MADIT II the absolute reduction in mortality was small (5.6%) compared to MADIT I, which used electrophysiological screening (23%) (Table 3).
For SCD-HeFT, the overall GRADE and strength of the recommendation is “weak” – the study quality is “moderate,” but there is also risk/uncertainty due to a high NNT at 5 years (13 compared to the MADIT II NNT of 6 and MADIT I NNT of 2 at 5 years), high prevalent population (N = 23,700), and a high budget impact ($770 million). A filter (as demonstrated in MADIT 1) is required to help target the prevalent population at risk and mitigate the risk or uncertainty relating to the high NNT, prevalence, and budget impact (Table 3).
The results of the most recent ICD trial (SCD-HeFT) are not generalizable to the prevalent population in Ontario (Table 3). Given that the current funding rate of an ICD is $32,500 (Cdn), the estimated budget impact for Ontario would be as high as $770 million (Cdn). The uncertainty around the cost estimate of treating the prevalent population with LVEF < 0.30 in Ontario, the lack of human resources to implement such a strategy and the high number of patients required to prevent one SCD (NNT = 13) calls for an alternative strategy that allows the appropriate uptake and diffusion of ICDs for primary prevention for patients at maximum risk for SCD within the SCD-HeFT population.
The uptake and diffusion of ICDs for primary prevention of SCD should therefore be based on risk stratification through the use of appropriate screen(s) that would identify patients at highest risk who could derive the most benefit from this technology.
Overall GRADE and Strength of Recommendation for the Use of Implantable Cardioverter Defibrillators for the Primary Prevention of Sudden Cardiac Death
MADIT I: Multicentre Automatic Defibrillator Implantation Trial I; MADIT II: Multicentre Automatic Defibrillator Implantation Trial II; SCD-HeFT: Sudden Cardiac Death in Heart Failure Trial.
NNT indicates number needed to treat. The NNT will appear higher if follow-up is short. For ICDs, the absolute benefit increases over time for at least a 5-year period; the NNT declines, often substantially, in studies with a longer follow-up. When the NNT are equalized for a similar period as the SCD-HeFT duration (5 years), the NNT for MADIT-I is 2.2; for MADIT-II, it is 6.3.
NSVT indicates nonsustained ventricular tachycardia; VT, ventricular tachycardia.
PMCID: PMC3382404  PMID: 23074465
9.  Circumferential myocardial strain in cardiomyopathy with and without left bundle branch block 
Background
Cardiac resynchronization therapy (CRT) has been shown to decrease mortality in 60-70% of advanced heart failure patients with left bundle branch block (LBBB) and QRS duration > 120 ms. There have been intense efforts to find reproducible non-invasive parameters to predict CRT response. We hypothesized that different left ventricular contraction patterns may exist in LBBB patients with depressed systolic function and applied tagged cardiovascular magnetic resonance (CMR) to assess circumferential strain in this population.
Methods
We determined myocardial circumferential strain at the basal, mid, and apical ventricular level in 35 subjects (10 with ischemic cardiomyopathy, 15 with non-ischemic cardiomyopathy, and 10 healthy controls). Patterns of circumferential strain were analyzed. Time to peak systolic circumferential strain in each of the 6 segments in all three ventricular slices and the standard deviation of time to peak strain in the basal and mid ventricular slices were determined.
Results
Dyskinesis of the anterior septum and the inferior septum in at least two ventricular levels was seen in 50% (5 out of 10) of LBBB patients while 30% had isolated dyskinesis of the anteroseptum, and 20% had no dyskinesis in any segments, similar to all of the non-LBBB patients and healthy controls. Peak circumferential strain shortening was significantly reduced in all cardiomyopathy patients at the mid-ventricular level (LBBB 9 ± 6%, non-LBBB 10 ± 4% vs. healthy 19 ± 4%; both p < 0.0001 compared to healthy), but was similar among the LBBB and non-LBBB groups (p = 0.20). The LBBB group had significantly greater dyssynchrony compared to the non-LBBB group and healthy controls assessed by opposing wall delays and 12-segment standard deviation (LBBB 164 ± 30 ms vs. non-LBBB 70 ± 17 ms (p < 0.0001), non-LBBB vs. healthy 65 ± 17 ms (p = 0.47)).
Conclusions
Septal dyskinesis exists in some patients with LBBB. Myocardial circumferential strain analysis enables detailed characterization of contraction patterns, strengths, and timing in cardiomyopathy patients with and without LBBB.
doi:10.1186/1532-429X-12-2
PMCID: PMC2806866  PMID: 20047696
10.  Double left ventricular pacing following accidental malpositioning of the right ventricular electrode during implantation of a cardiac resynchronization therapy device 
Accidental malpositioning of a right ventricular (RV) electrode has not been previously reported in the context of cardiac resynchronization therapy (CRT).
The case of a 75-year old male patient with dilative cardiomyopathy, left ventricular (LV) ejection fraction 23%, New York Heart Association functional heart failure status stage III, left bundle branch block (LBBB) with QRS width of 136 ms, and misplacement of the RV lead to the LV apex during implantation of a CRT defibrillator is described.
Following unremarkable implantation, routine interrogation of the CRT device on the first day after the implantation revealed uneventful technical findings. The 12-lead surface electrocardiogram (ECG) showed biventricular stimulation featuring a narrow QRS complex with incomplete right bundle branch block (RBBB) and R>S in V1. The biplane postoperative chest X-ray was graded normal. On routine follow-up one month later, a transthoracic echocardiogram revealed an increased ejection fraction of 51% but the RV lead was placed in the LV apex. An additional transesophageal echocardiogram exhibited an Eustachian valve guiding the lead via the patent foramen ovale through the mitral valve into the LV apex. Operative revision was scheduled and the active fixation lead was uneventful removed from the LV. A new electrode was inserted and placed in the RV apex.
Accidental malplacement of the RV electrode to the LV may be difficult to diagnose in the context of CRT patients as a stimulated biventricular ECG with incomplete RBBB appearance is expected in this situation. Careful analysis of lateral radiographic views during the operation is important to ensure correct lead positioning. As timely revision is the preferred procedure, early routine transthoracic echocardiography may be considered for detection of malplacement.
doi:10.1186/1749-8090-8-162
PMCID: PMC3729408  PMID: 23806123
Misplaced Leads; Malpositioned Leads; Implantable Cardioverter-defibrillator; Pacemaker; Cardiac Resynchronzation Therapy; Complications
11.  QRS pattern and improvement in right and left ventricular function after cardiac resynchronization therapy: a radionuclide study 
Background
Predicting response to cardiac resynchronization therapy (CRT) remains a challenge. We evaluated the role of baseline QRS pattern to predict response in terms of improvement in biventricular ejection fraction (EF).
Methods
Consecutive patients (pts) undergoing CRT implantation underwent radionuclide angiography at baseline and at mid-term follow-up. The relationship between baseline QRS pattern and mechanical dyssynchrony using phase analysis was evaluated. Changes in left and right ventricular EF (LVEF and RVEF) were analyzed with regard to baseline QRS pattern.
Results
We enrolled 56 pts, 32 with left bundle branch block (LBBB), 4 with right bundle branch block (RBBB) and 20 with non-specific intraventricular conduction disturbance (IVCD). A total of 48 pts completed follow-up. LBBB pts had significantly greater improvement in LVEF compared to RBBB or non-specific IVCD pts (+9.6 ± 10.9% vs. +2.6 ± 7.6%, p = 0.003). Response (defined as ≥ 5% increase in LVEF) was observed in 68% of LBBB vs. 24% of non-specific IVCD pts (p = 0.006). None of the RBBB pts were responders. RVEF was significantly improved in LBBB (+5.0 ± 9.0%, p = 0.007), but not in non-specific IVCD and RBBB pts (+0.4 ± 5.8%, p = 0.76). At multivariate analysis, LBBB was the only predictor of LVEF response (OR, 7.45; 95% CI 1.80-30.94; p = 0.006), but not QRS duration or extent of mechanical dyssynchrony.
Conclusions
Presence of a LBBB is a marker of a positive response to CRT in terms of biventricular improvement. Pts with non-LBBB pattern show significantly less benefit from CRT than those with LBBB.
doi:10.1186/1471-2261-12-27
PMCID: PMC3352038  PMID: 22494365
Cardiac resynchronization therapy; Left ventricular ejection fraction; Right ventricular ejection fraction; Dyssynchrony; Nuclear angiography; QRS morphology
12.  Electrophysiological Consequences of Dyssynchronous Heart Failure and Its Restoration by Resynchronization Therapy 
Circulation  2009;119(9):1220-1230.
Background
Cardiac resynchronization therapy (CRT) is widely applied in patients with heart failure and dyssynchronous contraction (DHF), but the electrophysiological consequences of CRT in heart failure remain largely unexplored.
Methods and Results
Adult dogs underwent left bundle-branch ablation and either right atrial pacing (190 to 200 bpm) for 6 weeks (DHF) or 3 weeks of right atrial pacing followed by 3 weeks of resynchronization by biventricular pacing at the same pacing rate (CRT). Isolated left ventricular anterior and lateral myocytes from nonfailing (control), DHF, and CRT dogs were studied with the whole-cell patch clamp. Quantitative polymerase chain reaction and Western blots were performed to measure steady state mRNA and protein levels. DHF significantly reduced the inward rectifier K+ current (IK1), delayed rectifier K+ current (IK), and transient outward K+ current (Ito) in both anterior and lateral cells. CRT partially restored the DHF-induced reduction of IK1 and IK but not Ito, consistent with trends in the changes in steady state K+ channel mRNA and protein levels. DHF reduced the peak inward Ca2+ current (ICa) density and slowed ICa decay in lateral compared with anterior cells, whereas CRT restored peak ICa amplitude but did not hasten decay in lateral cells. Calcium transient amplitudes were depressed and the decay was slowed in DHF, especially in lateral myocytes. CRT hastened the decay in both regions and increased the calcium transient amplitude in lateral but not anterior cells. No difference was found in CaV1.2 (α1C) mRNA or protein expression, but reduced CaVβ2 mRNA was found in DHF cells. DHF reduced phospholamban, ryanodine receptor, and sarcoplasmic reticulum Ca2+ ATPase and increased Na+-Ca2+ exchanger mRNA and protein. CRT did not restore the DHF-induced molecular remodeling, except for sarcoplasmic reticulum Ca2+ ATPase. Action potential durations were significantly prolonged in DHF, especially in lateral cells, and CRT abbreviated action potential duration in lateral but not anterior cells. Early afterdepolarizations were more frequent in DHF than in control cells and were reduced with CRT.
Conclusions
CRT partially restores DHF-induced ion channel remodeling and abnormal Ca2+ homeostasis and attenuates the regional heterogeneity of action potential duration. The electrophysiological changes induced by CRT may suppress ventricular arrhythmias, contribute to the survival benefit of this therapy, and improve the mechanical performance of the heart.
doi:10.1161/CIRCULATIONAHA.108.794834
PMCID: PMC2703676  PMID: 19237662
ion channels; remodeling; heart failure; resynchronization; electrophysiology
13.  Effect of QRS morphology on clinical event reduction with cardiac resynchronization therapy: Meta-analysis of randomized controlled trials 
American heart journal  2012;163(2):260-7.e3.
Background
Cardiac resynchronization therapy (CRT) is effective in reducing clinical events in systolic heart failure patients with a wide QRS. Previous retrospective studies suggest only patients with QRS prolongation due to a left bundle-branch block (LBBB) benefit from CRT. Our objective was to examine this by performing a meta-analysis of all randomized controlled trials of CRT.
Methods
Systematic searches of MEDLINE and the Food and Drug Administration official website were conducted for randomized controlled CRT trials. Trials reporting adverse clinical events (eg, all-cause mortality, heart failure hospitalizations) according to QRS morphology were included in the meta-analysis.
Results
Four randomized trials totaling 5,356 patients met the inclusion criteria. In patients with LBBB at baseline, there was a highly significant reduction in composite adverse clinical events with CRT (RR = 0.64 [95% CI (0.52–0.77)], P = .00001). However no such benefit was observed for patients with non-LBBB conduction abnormalities (RR = 0.97 [95% CI (0.82–1.15)], P = .75). When examined separately, there was no benefit in patients with right-bundle branch block (RR = 0.91 [95% CI (0.69–1.20)], P = .49) or non-specific intraventricular conduction delay (RR = 1.19 [95% CI (0.87–1.63)], P = .28). There was no heterogeneity among the clinical trials with regards to the lack of benefit in non-LBBB patients (I2 = 0%). When directly compared, the difference in effect of CRT between LBBB versus non-LBBB patients was highly statistically significant (P = .0001 by heterogeneity analysis).
Conclusions
While CRT was very effective in reducing clinical events in patients with LBBB, it did not reduce such events in patients with wide QRS due to other conduction abnormalities.
doi:10.1016/j.ahj.2011.11.014
PMCID: PMC4113034  PMID: 22305845
14.  Clinical Effectiveness of Cardiac Resynchronization Therapy Versus Medical Therapy Alone Among Patients With Heart Failure 
Circulation. Heart Failure  2014;7(6):926-934.
Supplemental Digital Content is available in the text.
Background—
Cardiac resynchronization therapy with defibrillator (CRT-D) reduces morbidity and mortality among selected patients with heart failure in clinical trials. The effectiveness of this therapy in clinical practice has not been well studied.
Methods and Results—
We compared a cohort of 4471 patients from the National Cardiovascular Data Registry’s Implantable Cardioverter-Defibrillator (ICD) Registry hospitalized primarily for heart failure and who received CRT-D between April 1, 2006, and December 31, 2009, to a historical control cohort of 4888 patients with heart failure without CRT-D from the Acute Decompensated Heart Failure National Registry (ADHERE) hospitalized between January 1, 2002, and March 31, 2006. Both registries were linked with Medicare claims to evaluate longitudinal outcomes. We included patients from the ICD Registry with left ventricular ejection fraction ≤35% and QRS duration ≥120 ms who were admitted for heart failure. We used Cox proportional hazards models to compare outcomes with and without CRT-D after adjustment for important covariates. After multivariable adjustment, CRT-D was associated with lower 3-year risks of death (hazard ratio, 0.52; 95% confidence interval, 0.48–0.56; P<0.001), all-cause readmission (hazard ratio, 0.69; 95% confidence interval, 0.65–0.73; P<0.001), and cardiovascular readmission (hazard ratio, 0.60; 95% confidence interval, 0.56–0.64; P<0.001). The association of CRT-D with mortality did not vary significantly among subgroups defined by age, sex, race, QRS duration, and optimal medical therapy.
Conclusions—
CRT-D was associated with lower risks of mortality, all-cause readmission, and cardiovascular readmission than medical therapy alone among patients with heart failure in community practice.
doi:10.1161/CIRCHEARTFAILURE.113.000838
PMCID: PMC4244212  PMID: 25227768
cardiac resynchronization therapy; comparative effectiveness research; defibrillators, implantable; heart failure
15.  Relationship between mechanical and electrical remodelling in patients with cardiac resynchronization implanted defibrillators 
Europace  2011;13(8):1180-1187.
Aims
Cardiac resynchronization therapy (CRT) is associated with reverse left ventricular (LV) remodelling. However, the effects of CRT-induced mechanical remodelling on electrical remodelling, and the occurrence of ventricular arrhythmias have not been clearly established. We studied the relationship between mechanical remodelling, electrical remodelling, and the occurrence of appropriate implantable cardioverter-defibrillator (ICD) therapy 1 year after CRT.
Methods and results
We analysed data from 45 patients who underwent ICD-CRT implantation at our centre. Significant LV reverse remodelling was defined by a minimum 10% decrease in the LV end-diastolic diameter (LVEDd) at 1 year of follow-up. Electrocardiographic indices of dispersion of repolarization [QTc, Tpeak-Tend (Tp-e) and their dispersion] were measured immediately and 1 year post-CRT implantation. The occurrence of appropriate ICD therapy was noted for each patient. Patients with (n= 21) and without (n= 24) significant LV reverse remodelling had similar baseline characteristics. At 1 year of follow-up, patients with mechanical reverse LV remodelling exhibited a significant decrease in QTc (505 ± 42 vs. 485 ± 52 ms, P < 0.05) and Tp–e (107 ± 26 vs. 92 ± 22 ms, P < 0.0001). However, patients without mechanical LV reverse remodelling exhibited a significant increase in QT dispersion (29 ± 43 vs. 98 ± 47 ms, P = 0.002) and Tp–e dispersion (22 ± 21 vs. 54 ± 36 ms, P = 0.0001). Finally patients with mechanical LV reverse remodelling experienced a lower rate of ICD therapy (P = 0.0025) after a mean follow-up of 19 months.
Conclusion
Reverse LV mechanical remodelling is associated with reversal of electrical remodelling and a lower rate of appropriate ICD therapy following CRT.
doi:10.1093/europace/eur106
PMCID: PMC3148818  PMID: 21486911
Dispersion of repolarization; Cardiac resynchronization therapy; Remodelling
16.  123I-MIBG Scintigraphy as a Powerful Tool to Plan an Implantable Cardioverter Defibrillator and to Assess Cardiac Resynchronization Therapy in Heart Failure Patients 
Iodine-123-metaiodobenzylguanidine (123I-MIBG) scintigraphy is a nuclear medicine technique which describes the functional status of the cardiac sympathetic nervous system. It is well known that an autonomic dysfunction is present in heart failure setting as a neuronal uptake of norepinephrine is impaired in the failing myocardium. Reduction in sympathetic nervous function in the heart, measured by reduced myocardial uptake of 123I-MIBG, is an indicator of poor prognosis for heart failure patients. The aim of this paper was to investigate the role of 123I-MIBG scintigraphy in evaluating the need of implantable cardioverter defibrillator (ICD) and the response to cardiac resynchronization therapy (CRT) in heart failure patients. For this purpose scientific literature data on these topics were reviewed. Based on literature data, 123I-MIBG scintigraphy seems to be a useful tool to assess which patients may benefit most from an ICD implantation to reduce the risk of ventricular arrhythmia or sudden cardiac death. Furthermore, 123I-MIBG scintigraphy seems to predict which patients will response to CRT with an improvement in left ventricular function.
doi:10.1155/2012/690468
PMCID: PMC3463902  PMID: 23056938
17.  An individual patient meta-analysis of five randomized trials assessing the effects of cardiac resynchronization therapy on morbidity and mortality in patients with symptomatic heart failure 
European Heart Journal  2013;34(46):3547-3556.
Aims
Cardiac resynchronization therapy (CRT) with or without a defibrillator reduces morbidity and mortality in selected patients with heart failure (HF) but response can be variable. We sought to identify pre-implantation variables that predict the response to CRT in a meta-analysis using individual patient-data.
Methods and results
An individual patient meta-analysis of five randomized trials, funded by Medtronic, comparing CRT either with no active device or with a defibrillator was conducted, including the following baseline variables: age, sex, New York Heart Association class, aetiology, QRS morphology, QRS duration, left ventricular ejection fraction (LVEF), and systolic blood pressure. Outcomes were all-cause mortality and first hospitalization for HF or death. Of 3782 patients in sinus rhythm, median (inter-quartile range) age was 66 (58–73) years, QRS duration was 160 (146–176) ms, LVEF was 24 (20–28)%, and 78% had left bundle branch block. A multivariable model suggested that only QRS duration predicted the magnitude of the effect of CRT on outcomes. Further analysis produced estimated hazard ratios for the effect of CRT on all-cause mortality and on the composite of first hospitalization for HF or death that suggested increasing benefit with increasing QRS duration, the 95% confidence bounds excluding 1.0 at ∼140 ms for each endpoint, suggesting a high probability of substantial benefit from CRT when QRS duration exceeds this value.
Conclusion
QRS duration is a powerful predictor of the effects of CRT on morbidity and mortality in patients with symptomatic HF and left ventricular systolic dysfunction who are in sinus rhythm. QRS morphology did not provide additional information about clinical response.
ClinicalTrials.gov numbers
NCT00170300, NCT00271154, NCT00251251.
doi:10.1093/eurheartj/eht290
PMCID: PMC3855551  PMID: 23900696
Cardiac resynchronization therapy; Morbidity; Mortality; Heart failure
18.  Characteristics of Responders to Cardiac Resynchronization Therapy: The Impact of Echocardiographic Left Ventricular Volume 
Clinical cardiology  2012;35(12):777-780.
Summary
Background
One third of patients who receive cardiac resynchronization therapy (CRT) are classified as nonresponders. Characteristics of responders to CRT have been studied in multiple clinical trials.
Hypothesis
We aimed to examine characteristics of CRT responders in a routine clinical practice.
Method
One hundred and twenty five patients were examined retrospectively from a multidisciplinary CRT clinic program. Echocardiographic CRT response was defined as a decrease in left ventricular (LV) end systolic volume (ESV) of ≥ 15% and/or absolute increase of 5% in LV ejection fraction (EF) at 6 month visit.
Results
There were 81 responders and 44 nonresponders. By univariate analyses, female gender, nonischemic cardiomyopathy etiology, baseline QRS duration, the presence of left bundle branch block (LBBB) and left ventricular end-diastolic volume (LVEDV) index predicted CRT response. However, multivariate analysis demonstrated only QRS duration, LBBB and LVEDV index were independent predictors (QRS width: Odd ratio [OR] 1.027, 95% CI 1.004 – 1.050, p = 0.023; LBBB: OR 3.568, 95% CI 1.284 – 9.910, p=0.015; LV EDV index: OR 0.970, 95% CI 0.953 – 0.987, p= 0.001). While female gender and nonischemic etiology were associated with an improved CRT response on univariate analyses, after adjusting for LV volumes, they were not independent predictors.
Conclusion
QRS width, LBBB and LVEDV index are independent predictors for echocardiographic CRT response. Previously reported differences in CRT response for gender and cardiomyopathy etiology are associated with differences in baseline LV volumes in our clinical practice.
doi:10.1002/clc.22043
PMCID: PMC3498521  PMID: 22886700
Cardiac resynchronization therapy; Predictor to CRT response; Left Ventricular Volume
19.  The relationship of QRS morphology and mechanical dyssynchrony to long-term outcome following cardiac resynchronization therapy 
European Heart Journal  2012;33(21):2680-2691.
Aims
Because benefits of cardiac resynchronization therapy (CRT) appear to be less favourable in non-left bundle branch block (LBBB) patients, this prospective longitudinal study tested the hypothesis that QRS morphology and echocardiographic mechanical dyssynchrony were associated with long-term outcome after CRT.
Methods and results
Two-hundred and seventy-eight consecutive New York Heart Association class III and IV CRT patients with QRS ≥120 ms and ejection fraction ≤35% were studied. The pre-specified primary endpoint was death, heart transplant, or left ventricular assist device over 4 years. Dyssynchrony assessed before CRT included interventricular mechanical delay (IVMD) and speckle-tracking radial strain using pre-specified cut-offs for each. Of 254 with baseline quantitative echocardiographic data available, 128 had LBBB, 81 had intraventricular conduction delay (IVCD), and 45 had right bundle branch block (RBBB). Radial dyssynchrony was observed in 85% of the patients with LBBB, 59% with IVCD*, and 40% with RBBB* (*P < 0.01 vs. LBBB). Of 248 (98%) with follow-up, LBBB patients had a significantly more favourable long-term survival than non-LBBB patients. However, non-LBBB patients with dyssynchrony had a more favourable event-free survival than those without dyssynchrony: radial dyssynchrony hazard ratio 2.6, 95% confidence interval (CI) 1.47–4.53 (P = 0.0008) and IVMD hazard ratio 4.9, 95% CI 2.60–9.16 (P = 0.0007). Right bundle branch block patients who lacked dyssynchrony had the least favourable outcome.
Conclusion
Non-LBBB patients with dyssynchrony had a more favourable long-term survival than non-LBBB patients who lacked dyssynchrony. Mechanical dyssynchrony and QRS morphology are associated with outcome following CRT.
doi:10.1093/eurheartj/ehs013
PMCID: PMC3485574  PMID: 22351700
Cardiac resynchronization therapy; Heart failure; Conduction disturbance
20.  Hyperglycemia-Induced T-Wave Oversensing as a Cause of Cardiac Resynchronization Therapy (CRT) Failure 
T-wave oversensing occurs when the counter starts giving dual beeps for every cardiac cycle instead of one. This usually happens when the monitoring lead displays a tall T wave, which is also sharp. R wave sensing algorithms of the devices do not sense T wave because the slow rate of the T wave is much less than that of the R wave. But the slow rate of T waves may change with time and also because of parameters like potassium levels and hyperglycemia. We present a 67-year-old female who underwent the implantation of cardiac resynchronization therapy (cardiac resynchronization and implantable cardioverter defibrilator [CRT-D]) because of severe left ventricular systolic dysfunction and ventricular dyssynchrony experienced recurrent inappropriate implantable cardioverter-defibrillator (ICD) shocks and CRT failure. Device analysis showed that the CRT failure was in consequence of T-wave oversensing due to hyperglycemia. Elimination of the T-wave oversensing after hyperglycemia control conferred good biventricular pacing and good response to CRT during a 6-month follow-up period.
PMCID: PMC3466884  PMID: 23074632
Cardiac resynchronization therapy; Cardiac pacing, artficial; Hyperglycemia
21.  Effectiveness of cardiac resynchronization therapy in mild congestive heart failure: systematic review and meta-analysis of randomized trials 
European Journal of Heart Failure  2010;12(4):360-366.
Aims
Cardiac resynchronization therapy (CRT) improves echocardiographic parameters, symptoms, hospitalizations, and mortality in patients with New York Heart Association (NYHA) Class III or IV symptoms with left ventricular systolic dysfunction, sinus rhythm, and a prolonged QRS duration. The effectiveness of CRT in patients with mild heart failure symptoms has not been systematically reviewed.
Methods and results
Randomized controlled trials of CRT in patients with NYHA Class I or II heart failure were identified from MEDLINE and EMBASE. The effects of CRT on left ventricular remodelling at 1 year were systematically reviewed, and the effects of CRT on clinical outcomes at 1 year were meta-analysed. Two studies met the pre-specified search criteria, with a total of 2430 patients (REVERSE n = 610 and MADIT-CRT n = 1820). CRT was associated with a reduction in heart failure events in both trials [combined OR 0.57, 95% confidence interval (CI) 0.46–0.70], but not mortality (combined OR 0.96, 95% CI 0.67–1.36). The effect of CRT on the combined endpoint of heart failure events or death favoured CRT (OR 0.63, 95% CI 0.51–0.77). CRT was also associated with improvement in left ventricular remodelling parameters in both studies, including a greater increase in left ventricular ejection fraction in the CRT group than in the control group, at 1 year after randomization. Serious adverse events were rare with CRT.
Conclusion
CRT reduces heart failure events in patients with mild heart failure symptoms, left ventricular dysfunction, sinus rhythm, and prolonged QRS duration.
doi:10.1093/eurjhf/hfq029
PMCID: PMC2844759  PMID: 20335354
Artificial cardiac pacemaker; Artificial pacemaker; Heart failure; Mortality; Cardiac resynchronization therapy
22.  Local electrogram delay recorded from left ventricular lead at implant predicts response to cardiac resynchronization therapy: Retrospective study with 1 year follow up 
Background
Considerable proportion of patients does not respond to the cardiac resynchronization therapy (CRT). This study investigated clinical relevance of left ventricular electrode local electrogram delay from the beginning of QRS (QLV). We hypothesized that longer QLV indicating more optimal lead placement in the late activated regions is associated with the higher probability of positive CRT response.
Methods
We conducted a retrospective, single–centre analysis of 161 consecutive patients with heart failure and LBBB or nonspecific intraventricular conduction delay (IVCD) treated with CRT. We routinely intend to implant the LV lead in a region with long QLV. Clinical response to CRT, left ventricular (LV) reverse remodelling (i.e. decrease in LV end-systolic diameter - LVESD ≥10%) and reduction in plasma level of NT-proBNP >30% at 12-month post-implant were the study endpoints. We analyzed association between pre-implant variables and the study endpoints.
Results
Clinical CRT response rate reached 58%, 84% and 92% in the lowest (≤105 ms), middle (106-130 ms) and the highest (>130 ms) QLV tertile (p < 0.0001), respectively. Longer QRS duration (p = 0.002), smaller LVESD and a non-ischemic cardiomyopathy (both p = 0.02) were also univariately associated with positive clinical CRT response. In a multivariate analysis, QLV remained the strongest predictor of clinical CRT response (p < 0.00001), followed by LVESD (p = 0.01) and etiology of LV dysfunction (p = 0.04). Comparable predictive power of QLV for LV reverse remodelling and NT-proBNP response rates was observed.
Conclusion
LV lead position assessed by duration of the QLV interval was found the strongest independent predictor of beneficial clinical response to CRT.
doi:10.1186/1471-2261-12-34
PMCID: PMC3447687  PMID: 22607487
Cardiac resynchronization therapy; Reverse remodelling; LV lead location; Electrical dyssynchrony
23.  The relationship between ventricular electrical delay and left ventricular remodelling with cardiac resynchronization therapy 
European Heart Journal  2011;32(20):2516-2524.
Aims
The aim of the present study was to evaluate the relationship between left ventricular (LV) electrical delay, as measured by the QLV interval, and outcomes in a prospectively designed substudy of the SMART-AV Trial.
Methods and results
This was a multicentre study of patients with advanced heart failure undergoing cardiac resynchronization therapy (CRT) defibrillator implantation. In 426 subjects, QLV was measured as the interval from the onset of the QRS from the surface ECG to the first large peak of the LV electrogram. Left ventricular volumes were measured by echocardiography at baseline and after 6 months of CRT by a blinded core laboratory. Quality of life (QOL) was assessed by a standardized questionnaire. When separated by quartiles based on QLV duration, reverse remodelling response rates (>15% reduction in LV end systolic volume) increased progressively from 38.7 to 68.4% and QOL response rate (>10 points reduction) increased from 50 to 72%. Patients in the highest quartile of QLV had a 3.21-fold increase (1.58–6.50, P = 0.001) in their odds of a reverse remodelling response after correcting for QRS duration, bundle branch block type, and clinical characteristics by multivariate logistic regression analysis.
Conclusion
Electrical dyssynchrony, as measured by QLV, was strongly and independently associated with reverse remodelling and QOL with CRT. Acute measurements of QLV may be useful to guide LV lead placement.
doi:10.1093/eurheartj/ehr329
PMCID: PMC3195261  PMID: 21875862
Cardiac resynchronization therapy; Heart failure; Electrical dyssynchrony; Left ventricular reverse remodelling; Outcomes
24.  Cardiac resynchronization therapy and AV optimization increase myocardial oxygen consumption, but increase cardiac function more than proportionally☆ 
International Journal of Cardiology  2014;171(2):144-152.
Background
The mechanoenergetic effects of atrioventricular delay optimization during biventricular pacing (“cardiac resynchronization therapy”, CRT) are unknown.
Methods
Eleven patients with heart failure and left bundle branch block (LBBB) underwent invasive measurements of left ventricular (LV) developed pressure, aortic flow velocity-time-integral (VTI) and myocardial oxygen consumption (MVO2) at 4 pacing states: biventricular pacing (with VV 0 ms) at AVD 40 ms (AV-40), AVD 120 ms (AV-120, a common nominal AV delay), at their pre-identified individualised haemodynamic optimum (AV-Opt); and intrinsic conduction (LBBB).
Results
AV-120, relative to LBBB, increased LV developed pressure by a mean of 11(SEM 2)%, p = 0.001, and aortic VTI by 11(SEM 3)%, p = 0.002, but also increased MVO2 by 11(SEM 5)%, p = 0.04.
AV-Opt further increased LV developed pressure by a mean of 2(SEM 1)%, p = 0.035 and aortic VTI by 4(SEM 1)%, p = 0.017. MVO2 trended further up by 7(SEM 5)%, p = 0.22.
Mechanoenergetics at AV-40 were no different from LBBB.
The 4 states lay on a straight line for Δexternal work (ΔLV developed pressure × Δaortic VTI) against ΔMVO2, with slope 1.80, significantly > 1 (p = 0.02).
Conclusions
Biventricular pacing and atrioventricular delay optimization increased external cardiac work done but also myocardial oxygen consumption. Nevertheless, the increase in cardiac work was ~ 80% greater than the increase in oxygen consumption, signifying an improvement in cardiac mechanoenergetics. Finally, the incremental effect of optimization on external work was approximately one-third beyond that of nominal AV pacing, along the same favourable efficiency trajectory, suggesting that AV delay dominates the biventricular pacing effect — which may therefore not be mainly “resynchronization”.
doi:10.1016/j.ijcard.2013.10.026
PMCID: PMC3919205  PMID: 24332598
Biventricular pacing; Optimization; Myocardial oxygen consumption
25.  OptiVol fluid index predicts acute decompensation of heart failure with a high rate of unexplained events 
Background
Intrathoracic impedance monitoring has emerged as a promising new technique for the detection of impending heart failure (HF). Although false positive episodes have been reported in case reports and clinical trials, the efficacy and false positive rate in real-world practice remain unclear.
Objective
The aim of this study is to investigate the utility and reliability of the OptiVol alert feature in clinical practice.
Methods
We continuously recruited patients who underwent implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy with defibrillator (CRT-D) implantation with feature of intrathoracic impedance monitoring system in our center from Sep. 2010 to Oct. 2012. Regular in-office follow-up were required of all patients and the following information was collected at each visit: medical history, device interrogation, N-terminal pro-brain natriuretic peptide (NT-proBNP) measurement and an echocardiogram. Worsening HF was defined as hospitalization or the presentation of signs or symptoms of HF.
Results
Forty three patients (male: 76.7%, mean age: 57 ± 15 years, left ventricular ejection fraction (LVEF): 33% ± 14%) were included in this observational study. Fifty four alert events and 14 adjudicated worsening HF were detected within 288 ±163 days follow-up. Eleven (20.4%) alert episodes were associated with acute cardiac decompensation in 9 patients with a positive predictive value of 78.6%. Forty three audible alerts showed no connection to worsening HF. The unexplained alerts rate was 79.6% and 1.27 per person-year. Thirty seven alarm alerts were detected in patients with EF < 45%, among which 9 accompanied with HF, 17 alerts detected in patients with LVEF ≥ 45% and 2 associated with HF. There was no significant difference between the two groups (9/37 vs. 2/17; P = 0.47).
Conclusions
Patients with normal or nearly normal left ventricular systolic function also exhibited considerable alert events. The OptiVol fluid index predicted worsening cardiac events with a high unexplained detection rate, and any alert must therefore be analyzed with great caution. Efforts to improve the specificity of this monitoring system represent a significant aspect of future studies.
doi:10.3969/j.issn.1671-5411.2013.03.012
PMCID: PMC3796699  PMID: 24133513
Heart failure; Intrathoracic impedance measurement; OptiVol fluid index; Left ventricular ejection fraction

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