Anthony Tang

Importance of Implantable Cardioverter‐Defibrillator Back‐Up in Cardiac Resynchronization Therapy Recipients: A Systematic Review and Meta‐Analysis

Background It remains to be determined whether patients receiving cardiac resynchronization therapy (CRT) benefit from the addition of an implantable cardioverter‐defibrillator (ICD). Methods and Results We performed a literature search looking for studies of patients implanted with CRTs. Comparisons were performed between patients receiving CRT‐defibrillator (CRT‐D) versus CRT‐pacemaker (CRT‐P). The primary outcome was all‐cause mortality. Data were pooled using a random‐effects model. The relative risk (RR) and hazard ratio (HR, when available) were used as measurements of treatment effect. Nineteen entries were entitled for inclusion, comprising 12 378 patients (7030 receiving CRT‐D and 5348 receiving CRT‐P) and 29 799 patient‐years of follow‐up. Those receiving CRT‐D were younger, were more often males, had lower NYHA class, lower prevalence of atrial fibrillation, higher prevalence of ischemic heart disease, and were more often on beta‐blockers. Ten studies showed significantly lower mortality rates with the CRT‐D device, while the remaining 9 were neutral. The pooled data of studies revealed that CRT‐D patients had significantly lower mortality rates compared with CRT‐P patients (mortality rates: CRT‐D 16.6% versus CRT‐P 27.1%; RR=0.69, 95% CI 0.62–0.76; P<0.00001). The number needed to treat to prevent one death was 10. The observed I2 values showed moderate heterogeneity among studies (I2=48%). The benefit of CRT‐D was more pronounced in ischemic cardiomyopathy (HR=0.70, 95% CI 0.59–0.83, P<0.001, I2=0%), but a trend for benefit, albeit of lower magnitude, could also be seen in non‐ischemic dilated cardiomyopathy (HR=0.79, 95% CI 0.61–1.02, P=0.07, I2=36%). Conclusions The addition of the ICD associates with a reduction in the risk of all‐cause mortality in CRT patients. This seems to be more pronounced in patients with ischemic cardiomyopathy.

A novel algorithm to assess risk of heart failure exacerbation using ICD diagnostics: validation from RAFT.

BACKGROUND The integrated diagnostics (ID) algorithm is an implantable device-based tool that collates data pertaining to heart rhythm, heart rate, intrathoracic fluid status, and activity, producing a risk score that correlates with 30-day risk of heart failure (HF) hospitalization. OBJECTIVE We sought to validate the ID algorithm using the Resynchronization-Defibrillation for Ambulatory Heart Failure Trial. METHODS Diagnostic measures of the algorithm include OptiVol fluid index, nighttime heart rate, minutes of patient activity, heart rate variability, and combined measure of cardiac rhythm and biventricular pacing. Monthly evaluations of ID parameters were assessed for the development of HF symptoms and hospitalization for HF. RESULTS A total of 1224 patients were included: 741 (61%) with cardiac resynchronization therapy with defibrillator devices and 483 (39%) with implanted cardioverter-defibrillator only. The mean age was 66 ± 9 years, and 1013 (83%) were men. A total of 37,861 months of follow-up data were available, with 258 HF hospitalizations (event rate 0.68% per month). There were 33 HF hospitalizations during low-risk months (0.21% per month), 123 during medium-risk months (0.66% per month), and 102 during high-risk months (2.61% per month). Compared with low-risk months, and 95% confidence intervals) of HF hospitalizations during medium-risk months was 2.9 (2.0-4.4) and during high-risk months was 10.7 (6.9-16.6). Multivariable analysis demonstrated that each ID variable had independent association with HF hospitalization. CONCLUSION The risk of HF as determined by the ID algorithm correlated with HF hospitalization and several HF signs and symptoms among patients in the Resynchronization-Defibrillation for Ambulatory Heart Failure Trial. This may present a useful adjunct to detect early signs of HF and adjust therapy to reduce morbidity and costs involved with hospital admission.

Cardiac resynchronization therapy in chronic heart failure with moderately reduced left ventricular ejection fraction: Lessons from the Multicenter InSync Randomized Clinical Evaluation MIRACLE EF study

BACKGROUND The benefits of CRT for symptomatic heart failure (HF) patients with a wide QRS and reduced left ventricular ejection fraction (LVEF≤35%), are well established .Post-hoc subgroup analyses suggest that CRT benefit may extend to patients with LVEF>35%. METHODS The MIRACLE EF was a prospective, randomized, controlled, double-blinded study to evaluate CRT-P in NYHA II-III HF patients with LBBB and with LVEF of 36%-50% and no previous pacing or ICD. The primary endpoint was a composite of time to first HF event or death. All patients were implanted with a CRT-P and randomized 2:1 to CRT-P ON or CRT-P OFF groups. The minimum follow up time was 24 months. RESULTS The MIRACLE EF study was stopped for enrollment futility after 13 months and enrolling only 44 patients. The main difficulties in recruiting patients were lack of eligible patients, previous ICD implants, and the reluctance of institutions, patients or physicians to enroll in the study which included a potential 5 year CRT OFF period. CONCLUSION Despite a careful design, identification and randomization of eligible patients were challenging and a trial to assess morbidity and mortality trial was not feasible. The MIRACLE EF experience illustrates the difficulties of designing a scientifically robust but feasible study to assess potential new indications for implantable devices. Smaller randomized studies with surrogate endpoints may therefore be more reasonable, although the potential impact of such studies on clinical practice, guidelines, and reimbursement remain to be determined.

Atrial flutter and atrial fibrillation ablation – sequential or combined? A cost-benefit and risk analysis of primary prevention pulmonary vein ablation

BACKGROUND Recent studies have tested the hypothesis that preventive pulmonary vein isolation (PVI) at time of atrial flutter ablation in patients who have not had atrial fibrillation (AF) will reduce future incidence of AF. OBJECTIVE To model relative procedural costs, risks, and benefits of sequential versus combined ablation strategies. METHODS The decision model compares a sequential ablation strategy of atrial flutter ablation, followed by future PVI if necessary, with an initial combined flutter and preventive PVI ablation strategy. Assumptions are AF incidence 20% per year, PVI success rate 70%, PVI complication rate 4%, atrial flutter complication rate 1%, and costs

KCNQ1 p.L353L affects splicing and modifies the phenotype in a founder population with long QT syndrome type 1

13,056 for PVI and

Effect of coronary revascularization on long term clinical outcomes in patients with ischemic cardiomyopathy and recurrent ventricular arrhythmia.

8,466 for atrial flutter ablation. RESULTS The sequential ablation strategy is less expensive, at 1.4 vs 1.6 expected flutter ablation equivalents (FAE) (

Precision Medicine for Cardiac Resynchronization: Predicting Quality of Life Benefits for Individual Patients—An Analysis From 5 Clinical Trials

11,852 vs

The Effect of Aggressive Blood Pressure Control on the Recurrence of Atrial Fibrillation After Catheter Ablation: A Randomized, Open Label, Clinical Trial (Substrate Modification with Aggressive Blood Pressure Control: SMAC- AF)

13,545) per patient, and entails less average risk, at 2% vs 4%. A combined ablation strategy is more expensive if the relative cost of PVI is more than 24.6% higher than atrial flutter ablation. A combined ablation strategy has higher total risk if PVI procedural risk is 24.6% more than atrial flutter ablation. CONCLUSIONS Under base case assumptions of relative cost of PVI to flutter ablation 1.5 and relative risk 4, a sequential ablation approach has less total expected cost and less expected risk. There appears to be no compelling reason to adopt a combined ablation approach into standard practice. Nomograms are presented to allow the reader to assess which strategy is preferred according to local relative costs and risk.

Modifiable Risk Factors in Atrial Fibrillation: The Role of Alcohol, Obesity, and Sleep Apnea

Background Variable expressivity and incomplete penetrance between individuals with identical long QT syndrome (LQTS) causative mutations largely remain unexplained. Founder populations provide a unique opportunity to explore modifying genetic effects. We examined the role of a novel synonymous KCNQ1 p.L353L variant on the splicing of exon 8 and on heart rate corrected QT interval (QTc) in a population known to have a pathogenic LQTS type 1 (LQTS1) causative mutation, p.V205M, in KCNQ1-encoded Kv7.1. Methods 419 adults were genotyped for p.V205M, p.L353L and a previously described QTc modifier (KCNH2-p.K897T). Adjusted linear regression determined the effect of each variant on QTc, alone and in combination. In addition, peripheral blood RNA was extracted from three controls and three p.L353L-positive individuals. The mutant transcript levels were assessed via qPCR and normalised to overall KCNQ1 transcript levels to assess the effect on splicing. Results For women and men, respectively, p.L353L alone conferred a 10.0 (p=0.064) ms and 14.0 (p=0.014) ms increase in QTc and in men only a significant interaction effect in combination with the p.V205M (34.6 ms, p=0.003) resulting in a QTc of ∼500 ms. The mechanism of p.L353Ls effect was attributed to approximately threefold increase in exon 8 exclusion resulting in ∼25% mutant transcripts of the total KCNQ1 transcript levels. Conclusions Our results provide the first evidence that synonymous variants outside the canonical splice sites in KCNQ1 can alter splicing and clinically impact phenotype. Through this mechanism, we identified that p.L353L can precipitate QT prolongation by itself and produce a clinically relevant interactive effect in conjunction with other LQTS variants.

Pulmonary vein isolation with incomplete antral ablation lines: Is more ablation necessary? Results of a randomized trial

Patients with ventricular tachycardia (VT) postmyocardial infarction (MI) are a higher risk group with significant morbidity and mortality. We examined the impact of prior coronary revascularization on clinical outcomes in patients with ischemic cardiomyopathy and VT.