Chris Pepper

Cost-effectiveness of radiofrequency catheter ablation for the treatment of atrial fibrillation in the United Kingdom

Objective: To assess the cost-effectiveness of radiofrequency catheter ablation (RFCA) compared with anti-arrhythmic drug (AAD) therapy for the treatment of atrial fibrillation (AF) from the perspective of the UK NHS. Design: Bayesian evidence synthesis and decision analytical model. Methods: A systematic review and meta-analysis was conducted and Bayesian statistical methods used to synthesise the effectiveness evidence from randomised control trials. A decision analytical model was developed to assess the costs and consequences associated with the primary outcome of the trials over a lifetime time horizon. Main outcome measure: Costs from a health service perspective and outcomes measured as quality-adjusted life years (QALYs). Results: The incremental cost-effectiveness ratio of RFCA varied between £7763 and £7910 for each additional QALY according to baseline risk of stroke, with a probability of being cost-effective from 0.98 to 0.99 for a cost-effectiveness threshold of £20 000. Results were sensitive to the duration of quality of life benefits from treatment. Conclusions: RFCA is potentially cost-effective for the treatment of paroxysmal AF in patients’ predominantly refractory to AAD therapy provided the quality-of-life benefits from treatment are maintained for more than 5 years. These findings remain subject to limitations in the existing evidence regarding the nature of life benefits and the prognostic importance of restoring normal sinus rhythm conferred using RFCA.

Implantable cardioverter-defibrillator therapy in adult patients with tetralogy of Fallot

AIMS Adults with repaired tetralogy of Fallot (TOF) are at risk of sudden cardiac death (SCD). ESC and AHA guidelines suggest the use of implantable cardioverter defibrillators (ICDs) to protect from this. Few data are available on the benefits of these devices in this population, and there are no randomized studies. METHODS AND RESULTS We analysed outcomes with respect to death, ICD therapy delivery, and complications for 20 patients with repaired TOF and 39 dilated cardiomyopathy (DCM) patients followed up at a UK teaching hospital. All TOF patients had clinical ventricular tachycardia (VT), electrophysiological study-inducible VT, or previous arrest due to tachyarrhythmia and received dual-chamber devices with individualized atrial detection algorithms. Tetralogy of Fallot patients were younger than DCM patients, but follow-up duration was not different between the groups. Tetralogy of Fallot patients were more likely to have experienced oversensing (45 vs. 13%; P < 0.02), inappropriate anti-tachycardia pacing delivery (20 vs. 2%; P < 0.05), and inappropriate cardioversion (25 vs. 4%; P = 0.06) than DCM patients and less likely to receive appropriate therapies than DCM patients. The death rate in TOF patients was significantly lower than that in DCM patients (5 vs. 21%; P < 0.05). CONCLUSION Tetralogy of Fallot patients have a higher risk of inappropriate therapies and other complications yet a lower incidence of appropriate therapies from their ICD than DCM patients. Further research into identification of factors predicting SCD in TOF and the benefits of ICD implantation is essential given the potential complications of ICD implantation in young congenital heart disease patients.

X-ray dose reduction in fluoroscopically guided electrophysiology procedures

This study assessed the efficacy of a new dose reduction regime in fluoroscopically guided electrophysiology (EP) procedures, which included diagnostic electrophysiological investigations, radiofrequency ablation, and biventricular pacing. A modified dose regime for fluoroscopy was implemented in one of our cardiac electrophysiology laboratories. The x‐ray system was programmed with a hierarchy of three fluoroscopy doses, and therefore image quality and settings. The default (lowest) dose mode was not expected to be suitable for all patient sizes or for the entirety of all procedures. Staff raised the dose level in a stepped manner as and when required to optimize the imaging requirements of the procedure. Phantom studies indicated that the low dose mode provided adequate image quality for visualizing EP catheters, while significantly lowering patient skin dose. In 52 clinical cases, questionnaires were used to assess the subjective clinical image quality. The mean image quality score for the low dose setting was rated between “adequate” and “good.” The fluoroscopy dose level was raised from the lowest level for 6% of the total fluoroscopy time. Procedural Dose Area Product (DAP) meter readings were analyzed for patients prior to (n = 85) and after (n = 150) the implementation of the low dose regime and showed an overall reduction in DAP rate of 74%. The hierarchical dose regime proved to be acceptable in routine clinical practice for EP procedures, leading to significant reductions in patient doses.

Dronedarone for the Treatment of Atrial Fibrillation

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of dronedarone (Multaq®, Sanofi-Aventis Limited, UK) to submit evidence on the clinical and cost effectiveness of the anti-arrhythmic drug (AAD) for the treatment of atrial fibrillation (AF) and atrial flutter, as part of the Institute’s single technology appraisal (STA) process. The Centre for Reviews and Dissemination and the Centre for Health Economics, both at the University of York, were commissioned to act as the independent Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and NICE’s subsequent decisions regarding the use of dronedarone within the UK NHS.The ERG review comprised a critique of the submitted evidence on the clinical effectiveness and cost effectiveness of dronedarone. The ERG examined the search strategy used to obtain relevant evidence, the selection of studies included in the assessment, outcome measures chosen and statistical methods employed. The ERG also validated the manufacturer’s decision analytic model and used it to explore the robustness of the cost-effectiveness results to key assumptions.The main clinical effectiveness evidence supporting the use of dronedarone as a treatment for AF came from four randomized controlled trials. These trials were compared with a broader set of trials examining the effectiveness of other AADs for AF: amiodarone, sotalol and class 1c agents (flecainide and propafenone). The evidence suggested that all AADs decreased the recurrence of AF but dronedarone had the smallest effect. A mixed treatment comparison analysis of the trials showed that dronedarone was associated with a lower risk of all-cause mortality than other AADs, but this was highly uncertain. There was limited evidence to assess the effect of dronedarone on stroke, and no statistically significant differences between dronedarone and other AADs were found for treatment discontinuation.From the evidence presented by the manufacturer, dronedarone appeared highly cost effective in each of the population groups examined compared with using standard baseline therapy alone as first-line treatment, or compared with sotalol or amiodarone as first-line AAD, with incremental cost-effectiveness ratios (ICERs) well below £20 000 per QALY gained. The ICER for dronedarone relative to class 1c agents was around £19000 per QALY. Although the evidence presented by the manufacturer indicated that dronedarone was cost effective, the estimates of treatment effect relative to other AADs and safety in the longer term were highly uncertain. The NICE Appraisal Committee in its preliminary guidance did not recommend the use of dronedarone for AF. However, following the response from a large number of consultees and commentators, NICE revised its preliminary guidance to allow the use of the drug in a specific subgroup of AF patients with additional cardiovascular risk factors.

Genetics of congenital and drug-induced long QT syndromes: current evidence and future research perspectives

The long QT syndrome (LQTS) is a condition characterized by abnormal prolongation of the QT interval with an associated risk of ventricular arrhythmias and sudden cardiac death. Congenital forms of LQTS arise due to rare and highly penetrant mutations that segregate in a Mendelian fashion. Over the years, multiple mutations in genes encoding ion channels and ion channel binding proteins have been reported to underlie congenital LQTS. Drugs are by far the most common cause of acquired forms of LQTS. Emerging evidence suggests that drug-induced LQTS also has a significant heritable component. However, the genetic substrate underlying drug-induced LQTS is presently largely unknown. In recent years, advances in next-generation sequencing technology and molecular biology techniques have significantly enhanced our ability to identify genetic variants underlying both monogenic diseases and more complex traits. In this review, we discuss the genetic basis of congenital and drug-induced LQTS and focus on future avenues of research in the field. Ultimately, a detailed characterization of the genetic substrate underlying congenital and drug-induced LQTS will enhance risk stratification and potentially result in the development of tailored genotype-based therapies.

CRT improves the exercise capacity and functional reserve of the failing heart through enhancing the cardiac flow- and pressure-generating capacity

While information on how cardiac resynchronisation therapy (CRT) affects cardiac performance at rest is readily available, the mechanisms whereby CRT alters cardiac function during maximal exercise are unclear.

A Mechanistic Investigation Into How Long-Term Resynchronization Therapy Confers Ongoing Cardiac Functional Benefits and Improved Exercise Capacity

The exact mechanisms underpinning the longer term benefits of cardiac resynchronization therapy (CRT) were not fully understood. It was still unclear whether there was any ongoing functional benefit conferred by the partial resynchronization of ventricular contraction. To resolve this, a randomized controlled double-blind crossover trial was conducted to investigate the impact of temporary cessation of CRT on cardiac function both at rest and during peak exercise. Fifteen patients with severe heart failure and a CRT device implanted at least 3 months previously were randomly assigned to have the CRT mode switched to either off or on during exercise tests with central hemodynamic measurements (including noninvasive cardiac output measured using rebreathing methods), then crossed over on separate days to the opposite CRT mode. There were no significant changes in hemodynamic variables at rest with either mode of CRT. When CRT was acutely turned off, there was 19% lower peak exercise cardiac power (2.10 +/- 0.46 vs 2.59 +/- 0.75 W; p <0.005), 6% lower mean arterial pressure (92 +/- 12 vs 98 +/- 13 mm Hg; p <0.05), and 11.5% lower peak cardiac output (10.4 +/- 1.9 vs 11.8 +/- 2.5 L/min; p <0.05). Exercise capacity was also diminished with lower peak oxygen uptake (15.7 +/- 4.3 vs 17.2 +/- 4.9 ml/kg/min; p <0.01) and shorter exercise duration (542 +/- 204 vs 587 +/- 212 seconds; p <0.05). These changes were seen without differences in peak respiratory exchange ratio and peak systemic vascular resistance. In conclusion, these observations provided evidence that after CRT, left ventricular resynchronization continued to confer cardiac functional benefits manifest during peak exercise, but imperceptible at rest.

Short-Axis 2D Strain from Speckle Tracking Predicts Echocardiographic Response to Cardiac Resynchronization Therapy

Aims: Two‐dimensional (2D) strain imaging from speckle tracking is a Doppler independent technique allowing assessment of left ventricular (LV) strain (ɛ); systolic strain rate (SRs’) and early diastolic strain rate (SRe’) in the radial and circumferential planes. We set out to investigate whether (i) these parameters facilitated assessment of dyssynchronous contraction and (ii) these measures could predict response to cardiac resynchronization therapy (CRT). Methods and Results: Forty‐one patients with severe, symptomatic heart failure on optimal medical therapy were recruited. Thirty‐two healthy subjects were used as controls. Time to peak ɛ, SRs’, and SRe’ of 6 LV segments were measured in the parasternal short axis prior to and 6 weeks post CRT implantation. Time delays between segments were then calculated and ANOVA assessed for prediction of response, classified as reduction in LV end systolic volume of >15%. 2D strain demonstrated significantly more dyssynchronous contraction in the heart failure population at baseline compared to healthy controls. Significant reduction in dyssynchrony was seen in ɛ and SRs’ following CRT, largely confined to those with evidence of remodeling. The time delay between peak circumferential SRs’ of opposing walls was the best predictor of reverse remodeling. Conclusion: 2D strain imaging appears to be a useful measure to predict response to CRT. The time to peak circumferential SR is a new predictor of response. (Echocardiography 2011;28:76‐84)

Left atrial voltage, circulating biomarkers of fibrosis, and atrial fibrillation ablation. A prospective cohort study

Aims To test the ability of four circulating biomarkers of fibrosis, and of low left atrial voltage, to predict recurrence of atrial fibrillation after catheter ablation. Background Circulating biomarkers potentially may be used to improve patient selection for atrial fibrillation ablation. Low voltage areas in the left atrium predict arrhythmia recurrence when mapped in sinus rhythm. This study tested type III procollagen N terminal peptide (PIIINP), galectin-3 (gal-3), fibroblast growth factor 23 (FGF-23), and type I collagen C terminal telopeptide (ICTP), and whether low voltage areas in the left atrium predicted atrial fibrillation recurrence, irrespective of the rhythm during mapping. Methods 92 atrial fibrillation ablation patients were studied. Biomarker levels in peripheral and intra-cardiac blood were measured with enzyme-linked immunosorbent assay. Low voltage (<0.5mV) was expressed as a proportion of the mapped left atrial surface area. Follow-up was one year. The primary endpoint was recurrence of arrhythmia. The secondary endpoint was a composite of recurrence despite two procedures, or after one procedure if no second procedure was undertaken. Results The biomarkers were not predictive of either endpoint. After multivariate Cox regression analysis, high proportion of low voltage area in the left atrium was found to predict the primary endpoint in sinus rhythm mapping (hazard ratio 4.323, 95% confidence interval 1.337–13.982, p = 0.014) and atrial fibrillation mapping (hazard ratio 5.195, 95% confidence interval 1.032–26.141, p = 0.046). This effect was also apparent for the secondary endpoint. Conclusion The studied biomarkers do not predict arrhythmia recurrence after catheter ablation. Left atrial voltage is an independent predictor of recurrence, whether the left atrium is mapped in atrial fibrillation or sinus rhythm.

Intra-cardiac and peripheral levels of biochemical markers of fibrosis in patients undergoing catheter ablation for atrial fibrillation

Aims Measurement of circulating biomarkers of fibrosis may have a role in selecting patients and treatment strategy for catheter ablation. Pro-collagen type III N-terminal pro-peptide (PIIINP), C-telopeptide of type I collagen (ICTP), fibroblast growth factor 23 (FGF-23), and galectin 3 (gal-3) have all been suggested as possible biomarkers for this indication, but studies assessing whether peripheral levels reflect intra-cardiac levels are scarce. Methods and results We studied 93 patients undergoing ablation for paroxysmal atrial fibrillation (AF) (n = 63) or non-paroxysmal AF (n = 30). Femoral venous, left and right atrial, and coronary sinus blood were analysed using ELISA to determine biomarker levels. Levels were compared with control patients (n = 36) and baseline characteristics, including left atrial voltage mapping data. C-telopeptide of type I collagen levels were higher in AF than in non-AF patients (P = 0.007). Peripheral ICTP levels were higher than all intra-cardiac levels (P < 0.001). Peripheral gal-3 levels were higher than left atrial levels (P = 0.001). Peripheral levels of FGF-23 and PIIINP were not significantly different from intra-cardiac levels. CS levels of ICTP were higher than right and left atrial levels (P < 0.001). gal-3 was higher in women vs. men (P ≤ 0.001) and with higher body mass index (P ≤ 0.001). ICTP levels increased with reducing ejection fraction (P ≤ 0.012). Conclusions Atrial fibrillation patients have higher levels of circulating ICTP than matched non-AF controls. In AF ablation patients, intra-cardiac sampling of FGF-23 or PIIINP gives no further information over peripheral sampling. For gal-3 and ICTP, intra-cardiac sampling may be necessary to assess their association with intra-cardiac processes. None of the biomarkers is related to fibrosis assessed by left atrial voltage.