A randomised controlled trial evaluating arrhythmia burden, risk of sudden cardiac death and stroke in patients with Fabry disease: the role of implantable loop recorders (RaILRoAD) compared with current standard practice.

BACKGROUND: Fabry disease (FD) is a genetic disorder caused by a deficiency in the enzyme alpha-galactosidase A, leading to an accumulation of glycosphingolipids in tissues across the body. Cardiac disease is the leading cause of morbidity and mortality. Advanced disease, characterised by extensive left ventricular hypertrophy, ventricular dysfunction and fibrosis, is known to be associated with an increase in arrhythmia. Data identifying risk factors for arrhythmia are limited, and no Fabry-specific risk stratification tool is available to select those who may benefit from initiation of medical or device therapy (implantable cardiac defibrillators). Current monitoring strategies have a limited diagnostic yield, and implantable loop recorders (ILRs) have the potential to change treatment and clinical outcomes. AIM: The aim of this study is to determine whether ILRs can (1) improve arrhythmia detection in FD and (2) identify risk predictors of arrhythmia. METHODS: A prospective, 5-year, open-label, international, multi-centre randomised controlled trial of a minimum of 164 participants with genetically or enzymatically confirmed FD (or both) who have evidence of cardiac disease will be recruited from five centres: Queen Elizabeth Hospital, Birmingham, UK; Salford Royal Hospital, Salford, UK; Royal Free Hospital, London, UK; Addenbrookes Hospital, Cambridge, UK; and Westmead Hospital, Sydney, Australia. Participants will be block-randomised (1:1) to two study arms for cardiac monitoring (i) control arm: standard of care with annual 24 h or 5-day Holter monitor or (ii) treatment arm: continuous cardiac monitoring with ILR implantation plus standard of care. Participants will undergo multiple investigations-blood/urine biomarkers, 12-lead and advanced electrocardiogram (ECG) recording, echocardiography and cardiovascular magnetic resonance (CMR) imaging-at baseline and 6-12 monthly follow-up visits. The primary endpoint is identification of arrhythmia requiring initiation or alteration in therapy. Secondary outcome measures include characterising the risk factors associated with arrhythmia and outcome data in the form of imaging, ECG and blood biomarkers. DISCUSSION: This is the first study evaluating arrhythmia burden and the use of ILR across the spectrum of risk profiles in Fabry cardiomyopathy. This will enable detailed characterisation of arrhythmic risk predictors in FD and ultimately support formulation of Fabry-specific guidance in this high-risk population. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT03305250 ). Registered on 9 October 2017.

Clinical outcomes and costs of cardiac revascularisation in England and New York state.

Objectives: Healthcare expenditure per-capita in the USA is higher than in England. We hypothesised that clinical outcomes after cardiac revascularisation are better in the USA. We compared costs and outcomes of patients undergoing coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) in England and New York State (NYS). Methods: Costs and total mortality were assessed using the Hospital Episode Statistics for England and the Statewide Planning and Research Cooperative System for NYS. Outcomes after a first CABG or PCI were assessed in patients undergoing a first CABG (n=142 969) or PCI (n=431 416). Results: After CABG, crude total mortality in England was 0.72% lower at 30 days and 3.68% lower at 1 year (both P<0.001). After PCI, crude total mortality was 0.35% lower at 30 days and 3.55% lower at 1 year (both P<0.001). No differences emerged in total mortality at 30 days after either CABG (England: HR 1.02,95% CI 0.94 to 1.10) or PCI (HR 1.04, 95% CI 0.99 to 1.09) after covariate adjustment. At 1 year, adjusted total mortality was lower in England after both CABG (HR 0.74, 95% CI 0.71 to 0.78) and PCI (HR 0.66, 95% CI 0.65 to 0.68). After adjustment for cost-to-charge ratios and purchasing power parities, costs in NYS amounted to uplifts of 3.8-fold for CABG and 3.6-fold for PCI. Conclusions: Total mortality after CABG and PCI was similar at 30 days and lower in England at 1 year. Costs were approximately fourfold higher in NYS.

Effect of telemonitoring of cardiac implantable electronic devices on healthcare utilization: a meta-analysis of randomized controlled trials in patients with heart failure.

AIMS: Implantable device telemonitoring (DTM) is a diagnostic adjunct to traditional face-to-face hospital visits. Remote device follow-up and earlier diagnoses facilitated by DTM should reduce healthcare utilization. We explored whether DTM reduces healthcare utilization over standard of care (SoC), without compromising patient outcomes. METHODS AND RESULTS: This systematic review and meta-analysis of 11 randomized controlled trials on DTM in patients with heart failure consisted of 5702 patients, with a median of 117 [interquartile range (IQR) 76-331] patients per study [age 65 years (IQR 63-67)] and follow-up range of 12-36 months. DTM was associated with a reduction in total number of visits [planned, unplanned, and emergency room (ER)] [relative risk (RR) 0.56; 95% confidence interval (CI) 0.43-0.73, P < 0.001]. Rates of cardiac hospitalizations (RR 0.96; 95% CI 0.82-1.12, P = 0.60) and the composite endpoints of ER, unplanned hospital visits, or hospitalizations (RR 0.99; 95% CI 0.68-1.43, P = 0.96) was similar between the DTM and the SoC groups. An increase in the total number of ER or unscheduled visits (RR 1.37; 95% CI 1.11-1.70, P = 0.004) was observed. This effect was consistent and statistically significant for all studies. Total and cardiac mortality were similar between the groups (DTM RR 0.90; 95% CI 0.69-1.16, P = 0.41; and DTM RR 0.93; 95% CI 0.51-1.69, P = 0.80). Monetary costs favoured DTM (10-55% reduction in five studies). CONCLUSIONS: Compared with SoC, DTM is associated with a marked reduction in planned hospital visits. In addition, DTM was associated with lower monetary costs, despite a modest increase in unplanned hospital and ER visits. DTM did not compromise survival.

Implementation and reimbursement of remote monitoring for cardiac implantable electronic devices in Europe: a survey from the health economics committee of the European Heart Rhythm Association.

Remote monitoring (RM) of cardiac implantable electronic devices (CIEDs) permits early detection of arrhythmias, device, and lead failure and may also be useful in risk-predicting patient-related outcomes. Financial benefits for patients and healthcare organizations have also been shown. We sought to assess the implementation and funding of RM of CIEDs, including conventional pacemakers (PMs), implantable cardioverter defibrillators (ICDs), and cardiac resynchronization therapy (CRT) devices in Europe. Electronic survey from 43 centres in 15 European countries. In the study sample, RM was available in 22% of PM patients, 74% of ICD patients, and 69% of CRT patients. The most significant perceived benefits were the early detection of atrial arrhythmias in pacemaker patients, lead failure in ICD patients, and worsening heart failure in CRT patients. Remote monitoring was reported to lead a reduction of in-office follow-ups for all devices. The most important reported barrier to the implementation of RM for all CIEDs was lack of reimbursement (80% of centres). Physicians regard RM of CIEDs as a clinically useful technology that affords significant benefits for patients and healthcare organizations. Remote monitoring, however, is perceived as increasing workload. Reimbursement for RM is generally perceived as a major barrier to implementation.

Feature-tracking cardiovascular magnetic resonance as a novel technique for the assessment of mechanical dyssynchrony.

BACKGROUND: Myocardial tagging using cardiovascular magnetic resonance (CMR) is the gold-standard for the assessment of myocardial mechanics. Feature-tracking cardiovascular magnetic resonance (FT-CMR) has been validated against myocardial tagging. We explore the potential of FT-CMR in the assessment of mechanical dyssynchrony, with reference to patients with cardiomyopathy and healthy controls. METHODS: Healthy controls (n=55, age: 42.9 ± 13 yrs, LVEF: 70 ± 5%, QRS: 88 ± 9 ms) and patients with cardiomyopathy (n=108, age: 64.7 ± 12 yrs, LVEF: 29 ± 6%, QRS: 147 ± 29 ms) underwent FT-CMR for the assessment of the circumferential (CURE) and radial (RURE) uniformity ratio estimate based on myocardial strain (both CURE and RURE: 0 to 1; 1=perfect synchrony) RESULTS: CURE (0.79 ± 0.14 vs. 0.97 ± 0.02) and RURE (0.71 ± 0.14 vs. 0.91 ± 0.04) were lower in patients with cardiomyopathy than in healthy controls (both p<0.0001). CURE (area under the receiver-operator characteristic curve [AUC]: 0.96), RURE (AUC: 0.96) and an average of these (CURE:RUREAVG, AUC: 0.98) had an excellent ability to discriminate between patients with cardiomyopathy and controls (sensitivity 90%; specificity 98% at a cut-off of 0.89). The time taken for semi-automatically tracking myocardial borders was 5.9 ± 1.4 min. CONCLUSION: Dyssynchrony measures derived from FT-CMR, such as CURE and RURE, provide almost absolute discrimination between patients with cardiomyopathy and healthy controls. The rapid acquisition of these measures, which does not require specialized CMR sequences, has potential for the assessment of mechanical dyssynchrony in clinical practice.

New devices in heart failure: an European Heart Rhythm Association report: developed by the European Heart Rhythm Association; endorsed by the Heart Failure Association.

Several new devices for the treatment of heart failure (HF) patients have been introduced and are increasingly used in clinical practice or are under clinical evaluation in either observational and/or randomized clinical trials. These devices include cardiac contractility modulation, spinal cord stimulation, carotid sinus nerve stimulation, cervical vagal stimulation, intracardiac atrioventricular nodal vagal stimulation, and implantable hemodynamic monitoring devices. This task force believes that an overview on these technologies is important. Special focus is given to patients with HF New York Heart Association Classes III and IV and narrow QRS complex, who represent the largest group in HF compared with patients with wide QRS complex. An overview on potential device options in addition to optimal medical therapy will be helpful for all physicians treating HF patients.

Impact of extending device longevity on the long-term costs of implantable cardioverter-defibrillator therapy: a modelling study with a 15-year time horizon.

AIMS: To determine the long-term costs of extending device longevity in four patient populations requiring a single-chamber implantable cardioverter-defibrillator (ICD) or requiring cardiac resynchronization therapy with defibrillation (CRT-D) device over a 15-year time window. METHODS AND RESULTS: We considered patient populations with an accepted indication for a single-chamber ICD for prevention of sudden cardiac death in the context of preserved (Population A) or impaired (Population B) left ventricular function; or with indication for a CRT-D device in the context of heart failure in New York Heart Association class II (Population C) or III (Population D). Expected patient survival and a cost analysis, including the cost of complications, was undertaken from a hospital perspective. Extended device longevity of 5 vs. 9 years for ICDs (Populations A and B); 4 vs. 7 years for CRT-Ds (Populations C and D) were considered. Over a 15-year time horizon, total, yearly, and per diem savings, per patient, from extending ICD longevity to 9 years were €10 926.91, €728.46, and €1.99 for Population A, and €7661.32, €510.75, and €1.40 for Population B. Total, yearly, and per diem savings from extending CRT-D longevity to 7 years were €13 630.38, €908.69, and €2.49 for Population C, and €10 968.29, €731.22, and €2.00 for Population D. Avoidance of a generator replacement amounted up to 46.6-62.5% of the saving. CONCLUSION: Extending device longevity has an important effect on the long-term cost of device therapy, both for ICD and CRT-D. This has important implications for device choice.

Prophylactic cardioverter defibrillator utilization in the "real world": a conundrum.

Randomized controlled trials have shown that implantable cardioverter defibrillator (ICD) therapy improves survival in appropriately selected patients with left ventricular dysfunction due to myocardial infarction (MI). Specific recommendations for ICD therapy have been included in consensus guidelines. There is, however, uncertainty as to whether guidelines on prophylactic ICD therapy are being applied in "real world" clinical practice. A report from a tertiary care center in Israel shows that in the period between 2005 and 2009, a prophylactic ICD was implanted in only 14% of post-MI patients in whom it was indicated, according to current guidelines. Importantly, failure to systematically reassess left ventricular function after a MI was linked to underuse of ICDs. Various factors such as differential coverage by health care insurances, patients' decision, physician's evaluation of co-morbidities and age, as well as under-referral to specialized centers may be involved in limiting the use of prophylactic ICDs. The shortfall in ICD implant rate in relation to that expected from current guidelines calls for further integration of healthcare systems.

Cardioverter-defibrillators: a cost or an investment?

Implantable cardioverter-defibrillator (ICD) therapy has emerged as the most effective treatment for life-threatening ventricular arrhythmias. Most studies indicate that ICD therapy in appropriately selected patients at high risk of sudden cardiac death (SCD) is associated with cost-effectiveness ratios similar to, or better than, other accepted treatments, including renal dialysis. The up-front costs of ICD therapy are admittedly high and as such, ICD implantation is more akin to an operation than a drug. As would be the case for a life-saving operation, the adoption of short time horizons is apt to lead to underestimations of cost effectiveness. As well as the time horizon, the underlying aetiology of the arrhythmic substrate, implantation technique, ICD battery life, and the presence of co-morbidities are important issues in maximizing cost effectiveness. Above all, we should consider that ICD therapy is the only available option for prolonging survival in patients who are at risk of SCD.

Device therapy and hospital reimbursement practices across European countries: a heterogeneous scenario.

As in other settings, in the field of clinical use of cardiac implantable electrical devices (CIEDs), the implementation, in various ways, of diagnosis-related groups (DRGs) has created new scenarios in most European healthcare systems. A DRG system is primarily a financial tool with the aim of promoting efficiency and improving utilization of resources. However, there are a variety of ways in which this system is used for funding the activity of centres implanting CIEDs. It is possible that the specific type and method of reimbursement may influence the implementation of CIEDs in the 'real world' through a variable spectrum of practices. These may range from the situation where reimbursement may, together with other factors, constitute a true barrier to the implementation of guidelines, to scenarios where reimbursement is adequate, and/or to situations where reimbursement may be adequate for standard devices but not for prompt implementation of effective technological innovations. The variety in reimbursement also affects how in-office checks of CIEDs are covered and, above all, the possibility to pay for remote follow-up of CIEDs. In the field of medical devices, refinement of DRG systems and adoption of new strategies and policies are needed to sustain and enhance those effective technological innovations that may be beneficial for specific patient populations. It is also important that physicians are deeply involved in the development and deployment of DRGs, and that each country DRGs agency has a transparent approach to engagement with stakeholders, along with robust and transparent mechanisms for updating these systems.

Assessment of a novel device-based diagnostic algorithm to monitor patient status in moderate-to-severe heart failure: rationale and design of the CLEPSYDRA study.

AIMS: Monitoring systems integrated into electronic implantable devices for heart failure (HF) have significantly expanded the possibility of obtaining diagnostic information and can be used to enhance patient follow-up. The ability to obtain advance warning of worsening HF is currently being explored using a variety of diagnostic parameters. A novel device-based algorithm, physiological diagnostic (PhD), combines data from minute ventilation and accelerometer sensors to provide an indicator of the overall status of HF patients and detect clinically relevant acute HF events. The objective of this study was to evaluate the effectiveness of the PhD algorithm for detecting HF events in patients with HF. METHODS: CLEPSYDRA is a multicentre, prospective, non-randomized, single-arm double-blinded study in 62 centres in Europe, the USA, and Canada. Patients with moderate-to-severe HF, on stable optimal pharmacological therapy, QRS≥120 ms, and ejection fraction≤0.35% will be included. Patients will be followed at 3-month intervals until study end, or for a minimum of 13 months. The primary endpoint is the sensitivity of the PhD (proportion of HF-related clinical events occurring within a 4-week period after a PhD HF indication). Secondary endpoints include the sensitivity of PhD with regard to HF events related to oral treatment modification, and adverse events. The first patient was included in October 2009. At the time of manuscript submission (Week 26, 2010), 214 patients had been enrolled. Study results are expected in 2012. PERSPECTIVE: CLEPSYDRA will provide essential data on the utility of the PhD algorithm in a HF population with blinded investigators and patients. A successful outcome will demonstrate the potential for the algorithm to be implemented in clinical practice. This would improve clinical management and further the ability to generate dynamic and reliable risk profiles for patients with HF.

Modelling the economic and health consequences of cardiac resynchronization therapy in the UK.

OBJECTIVE: Clinical evidence supports the use of cardiac resynchronization therapy (CRT) in advanced heart failure, but its cost-effectiveness is still unclear. This analysis assessed the economic and health consequences in the UK of implanting a CRT in patients with NYHA class III-IV heart failure. METHODS: A discrete event simulation of heart failure was used to compare the course over 5 years of 1000 identical pairs of patients -- one receiving both CRT and optimum pharmacologic treatment (OPT), the other OPT alone. All inputs were obtained from the data collected in the CArdiac REsynchronization in Heart Failure (CARE-HF) trial and a hospital in the UK. Direct medical costs (in 2004 pound) from the perspective of the National Health Service were considered. Both costs and benefits were discounted at 3.5%. Sensitivity analyses addressed all model inputs and multivariate analyses were performed by varying key parameters simultaneously. RESULTS: The model predicted 471 deaths and 2263 hospitalizations over 5 years with OPT alone and 348 deaths and 1764 hospitalizations with CRT, equivalent to a 26% reduction in mortality and 22% in hospitalizations, at a discounted cost of pound 11,423 per patient with CRT vs. pound 4,900 with OPT alone. CRT was predicted to increase quality-adjusted survival by 0.43 QALYs per patient, resulting in an incremental cost-effectiveness ratio of pound 15,247 per QALY gained (range: pound 12,531- pound 23,184). Sensitivity analyses revealed that this outcome was most sensitive to time horizon and cost of implantation. CONCLUSION: Based on these 5-year analyses, CRT is expected to yield substantial health benefits at a reasonable cost.