Predictors of Major Atrial Fibrillation Endpoints in the National Heart, Lung, and Blood Institute HCMR.

OBJECTIVES: This study sought to identify predictors of major clinically important atrial fibrillation endpoints in hypertrophic cardiomyopathy. BACKGROUND: Atrial fibrillation (AF) is a common morbidity associated with hypertrophic cardiomyopathy (HCM). The HCMR (Hypertrophic Cardiomyopathy Registry) trial is a prospective natural history study of 2,755 patients with HCM with comprehensive phenotyping. METHODS: All patients received yearly telephone follow-up. Major AF endpoints were defined as requiring electrical cardioversion, catheter ablation, hospitalization for >24 h, or clinical decisions to accept permanent AF. Penalized regression via elastic-net methodology identified the most important predictors of major AF endpoints from 46 variables. This was applied to 10 datasets, and the variables were ranked. Predictors that appeared in all 10 sets were then used in a Cox model for competing risks and analyzed as time to first event. RESULTS: Data from 2,631 (95.5%) patients were available for analysis after exclusions. A total of 127 major AF endpoints events occurred in 96 patients over 33.3 ± 12.4 months. In the final model, age, body mass index (BMI), left atrial (LA) volume index, LA contractile percent (active contraction), moderate or severe mitral regurgitation (MR), and history of arrhythmia the most important. BMI, LA volume index, and LA contractile percent were age-dependent. Obesity was a stronger risk factor in younger patients. Increased LA volume, reduced LA contractile percent, and moderate or severe MR put middle-aged and older adult patients at increased risk. CONCLUSIONS: The major predictors of major AF endpoints in HCM include older age, high BMI, moderate or severe MR, history of arrhythmia, increased LA volume, and reduced LA contractile percent. Prospective testing of a risk score based on these parameters may be warranted.

Distinct Subgroups in Hypertrophic Cardiomyopathy in the NHLBI HCM Registry.

BACKGROUND: The HCMR (Hypertrophic Cardiomyopathy Registry) is a National Heart, Lung, and Blood Institute-funded, prospective registry of 2,755 patients with hypertrophic cardiomyopathy (HCM) recruited from 44 sites in 6 countries. OBJECTIVES: The authors sought to improve risk prediction in HCM by incorporating cardiac magnetic resonance (CMR), genetic, and biomarker data. METHODS: Demographic and echocardiographic data were collected. Patients underwent CMR including cine imaging, late gadolinium enhancement imaging (LGE) (replacement fibrosis), and T1 mapping for measurement of extracellular volume as a measure of interstitial fibrosis. Blood was drawn for the biomarkers N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (cTnT), and genetic analysis. RESULTS: A total of 2,755 patients were studied. Mean age was 49 ± 11 years, 71% were male, and 17% non-white. Mean ESC (European Society of Cardiology) risk score was 2.48 ± 0.56. Eighteen percent had a resting left ventricular outflow tract (LVOT) gradient ≥30 mm Hg. Thirty-six percent had a sarcomere mutation identified, and 50% had any LGE. Sarcomere mutation-positive patients were more likely to have reverse septal curvature morphology, LGE, and no significant resting LVOT obstruction. Those that were sarcomere mutation negative were more likely to have isolated basal septal hypertrophy, less LGE, and more LVOT obstruction. Interstitial fibrosis was present in segments both with and without LGE. Serum NT-proBNP and cTnT levels correlated with increasing LGE and extracellular volume in a graded fashion. CONCLUSIONS: The HCMR population has characteristics of low-risk HCM. Ninety-three percent had no or only mild functional limitation. Baseline data separated patients broadly into 2 categories. One group was sarcomere mutation positive and more likely had reverse septal curvature morphology, more fibrosis, but less resting obstruction, whereas the other was sarcomere mutation negative and more likely had isolated basal septal hypertrophy with obstruction, but less fibrosis. Further follow-up will allow better understanding of these subgroups and development of an improved risk prediction model incorporating all these markers.

New-Onset Atrial Fibrillation in the Critically Ill.

OBJECTIVE: To determine the association of new-onset atrial fibrillation with outcomes, including ICU length of stay and survival. DESIGN: Retrospective cohort of ICU admissions. We found atrial fibrillation using automated detection (≥ 90 s in 30 min) and classed as new-onset if there was no prior diagnosis of atrial fibrillation. We identified determinants of new-onset atrial fibrillation and, using propensity matching, characterized its impact on outcomes. SETTING: Tertiary care academic center. PATIENTS: A total of 8,356 consecutive adult admissions to either the medical or surgical/trauma/burn ICU with available continuous electrocardiogram data. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: From 74 patient-years of every 15-minute observations, we detected atrial fibrillation in 1,610 admissions (19%), with median burden less than 2%. Most atrial fibrillation was paroxysmal; less than 2% of admissions were always in atrial fibrillation. New-onset atrial fibrillation was subclinical or went undocumented in 626, or 8% of all ICU admissions. Advanced age, acute respiratory failure, and sepsis were the strongest predictors of new-onset atrial fibrillation. In propensity-adjusted regression analyses, clinical new-onset atrial fibrillation was associated with increased hospital mortality (odds ratio, 1.63; 95% CI, 1.01-2.63) and longer length of stay (2.25 d; CI, 0.58-3.92). New-onset atrial fibrillation was not associated with survival after hospital discharge (hazard ratio, 0.99; 95% CI, 0.76-1.28 and hazard ratio, 1.11; 95% CI, 0.67-1.83, respectively, for subclinical and clinical new-onset atrial fibrillation). CONCLUSIONS: Automated analysis of continuous electrocardiogram heart rate dynamics detects new-onset atrial fibrillation in many ICU patients. Though often transient and frequently unrecognized, new-onset atrial fibrillation is associated with poor hospital outcomes.

Clinical Implications of Brief Device-Detected Atrial Tachyarrhythmias in a Cardiac Rhythm Management Device Population: Results from the Registry of Atrial Tachycardia and Atrial Fibrillation Episodes.

BACKGROUND: The RATE Registry (Registry of Atrial Tachycardia and Atrial Fibrillation Episodes) is a prospective, outcomes-oriented registry designed to document the prevalence of atrial tachycardia and/or fibrillation (AT/AF) of any duration in patients with pacemakers and implantable cardioverter defibrillators (ICDs) and evaluate associations between rigorously adjudicated AT/AF and predefined clinical events, including stroke. The appropriate clinical response to brief episodes of AT/AF remains unclear. METHODS: Rigorously adjudicated electrogram (EGM) data were correlated with adjudicated clinical events with logistic regression and Cox models. Long episodes of AT/AF were defined as episodes in which the onset and/or offset of AT/AF was not present within a single EGM recording. Short episodes of AT/AF were defined as episodes in which both the onset and offset of AT/AF were present within a single EGM recording. RESULTS: We enrolled 5379 patients with pacemakers (N=3141) or ICDs (N=2238) at 225 US sites (median follow-up 22.9 months). There were 359 deaths. There were 478 hospitalizations among 342 patients for clinical events. We adjudicated 37 531 EGMs; 50% of patients had at least one episode of AT/AF. Patients with clinical events were more likely than those without to have long AT/AF (31.9% vs. 22.1% for pacemaker patients and 28.7% vs. 20.2% for ICD patients; P<0.05 for both groups). Only short episodes of AT/AF were documented in 9% of pacemaker patients and 16% of ICD patients. Patients with clinical events were no more likely than those without to have short AT/AF (5.1% vs. 7.9% for pacemaker patients and 11.5% vs. 10.4% for ICD patients; P=0.21 and 0.66, respectively). CONCLUSIONS: In the RATE Registry, rigorously adjudicated short episodes of AT/AF, as defined, were not associated with increased risk of clinical events compared with patients without documented AT/AF. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00837798.

Hypertrophic Cardiomyopathy Registry: The rationale and design of an international, observational study of hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common monogenic heart disease with a frequency as high as 1 in 200. In many cases, HCM is caused by mutations in genes encoding the different components of the sarcomere apparatus. Hypertrophic cardiomyopathy is characterized by unexplained left ventricular hypertrophy, myofibrillar disarray, and myocardial fibrosis. The phenotypic expression is quite variable. Although most patients with HCM are asymptomatic, serious consequences are experienced in a subset of affected individuals who present initially with sudden cardiac death or progress to refractory heart failure. The Hypertrophic Cardiomyopathy Registry study is a National Heart, Lung, and Blood Institute-sponsored 2,750-patient, 44-site, international registry and natural history study designed to address limitations in extant evidence to improve prognostication in HCM (NCT01915615). In addition to the collection of standard demographic, clinical, and echocardiographic variables, patients will undergo state-of-the-art cardiac magnetic resonance for assessment of left ventricular mass and volumes as well as replacement scarring and interstitial fibrosis. In addition, genetic and biomarker analyses will be performed. The Hypertrophic Cardiomyopathy Registry has the potential to change the paradigm of risk stratification in HCM, using novel markers to identify those at higher risk.

Catheter Ablation of Arrhythmia During Pregnancy.

Cardiac arrhythmia as a complication of pregnancy can be problematic to maternal health and fetal life and development. Catheter ablation of tachyarrhythmias during pregnancy has been successfully performed in selected patients with limited experience. Techniques to limit maternal and fetal radiation exposure, including intracardiac echo and electroanatomic mapping systems, are particularly important in this setting. Specific accommodations are necessary in the care of the gravid patient during catheter ablation.

A placebo-controlled, double-blind, randomized, multicenter study to assess the effects of dronedarone 400 mg twice daily for 12 weeks on atrial fibrillation burden in subjects with permanent pacemakers.

PURPOSE: Dronedarone is a benzofuran derivative with a pharmacological profile similar to amiodarone but has a more rapid onset of action and a much shorter half-life (13-19 h). Our goal was to evaluate the efficacy of dronedarone in atrial fibrillation (AF) patients using dual-chamber pacemakers capable of quantifying atrial fibrillation burden. METHODS: Pacemakers were adjusted to optimize AF detection. Patients with AF burden >1% were randomized to dronedarone 400 mg twice daily (BID) or placebo. Pacemakers were interrogated after 4 and 12 weeks of treatment. The primary endpoint was the change in AF burden from baseline over the 12-week treatment period. Patients with permanent AF, severe/recently decompensated heart failure, and current use of antiarrhythmic drugs were excluded. AF burden was assessed by a core laboratory blinded to treatment assignment. RESULTS: From 285 patients screened, 112 were randomized (mean age 76 years, 60% male, 84% hypertensive, 65% with sick sinus syndrome, 26% with diabetes mellitus type II, 15% with heart failure). Baseline mean (SEM) AF burden was 8.77% (0.16) for placebo and 10.14% (0.17) for dronedarone. Over the 12-week study period, AF burden compared to baseline decreased by 54.4% (0.22) (P = 0.0009) with dronedarone and trended higher by 12.8% (0.16) (P = 0.450) with placebo. The absolute change in burden was decreased by 5.5% in the dronedarone group and increased by 1.1% in the placebo group. Heart rate during AF was reduced to approximately 4 beats/min with dronedarone (P = 0.285). Adverse events were higher with dronedarone compared to placebo (65 vs 56%). CONCLUSIONS: Dronedarone reduced pacemaker-assessed the relative AF burden compared to baseline and placebo by over 50% during the 12-week observation period.

Major complications and mortality within 30 days of an electrophysiological procedure at an academic medical center: implications for developing national standards.

BACKGROUND: Despite growing attention to performance and quality measures, national standards for reporting of outcomes after all electrophysiology (EP) procedures have not yet been developed. We sought to characterize the incidence and timing of adverse events up to 30 days after EP procedures at a tertiary academic medical center. METHODS AND RESULTS: We prospectively followed all patients undergoing EP procedures between January 2010 and September 2012. All were followed for 30 days postprocedure either in clinic or by telephone. Major complications were defined as events related to the procedure that led to prolongation of hospital stay or readmission, required additional procedural intervention, or resulted in death or significant injury. These were further categorized as intraprocedure, postprocedure, or postdischarge events. Seven EP physicians collectively adjudicated whether complications were directly related to the procedure. A total of 3,213 procedures were performed. Major complications occurred in 2.2% of patients; 49% of these events occurred after discharge. Death occurred in 0.6% of patients; 73% of these deaths were found to be secondary to worsening of the patient's underlying comorbid conditions and unrelated to the procedure. CONCLUSIONS: When considering national standards for reporting outcomes of all EP procedures, continued follow-up after discharge is important. In our cohort, half of major complications occurring within 30 days occurred after discharge. In addition, three-quarters of deaths within 30 days were not directly related to the procedure and caution should be used in using all-cause mortality as an outcome measure for EP procedures.

Effectiveness of implantation of a subcutaneous implantable cardioverter-defibrillator in a patient with complete heart block and a pacemaker.

The subcutaneous implantable cardioverter-defibrillator (S-ICD) represents an important alternative to traditional ICD therapy. The major limitation of this technology is the inability to provide pacing. Here, we present a case of a patient with complete heart block and a pacemaker who underwent placement of an S-ICD. Special considerations had to be taken with regards to evaluation and implantation of the S-ICD because of the pacemaker. In conclusion, implantation of an S-ICD can be done in patients with pacemaker effectively with appropriate electrocardiographic screening, device testing, and programming.

Cost of a recall of a single-center experience managing the Riata defibrillator lead.

Riata and Riata ST defibrillator leads (St. Jude Medical, Sylmar, California) were recalled in 2011 due to increased risk of insulation failure leading to externalized cables. Fluoroscopic screening can identify insulation failure, although the relation between mechanical failure and electrical failure is unclear. At the time of the recall, the University of Virginia developed a screening program, including fluoroscopic evaluation, education sessions, device interrogation, and remote monitoring for patients with this defibrillator lead. The aim of this study was to review the outcomes of the screening program, including costs, which were absorbed by our institution. Costs were calculated using Medicare reimbursement estimates. Forty-eight patients participated in the screening program. At initial screening, 31% were found to have evidence of insulation failure but electrical function was normal in all leads. The cost of this program was $35,358.72. The cost per diagnosis of mechanical lead failure was $2,357.25. During 2 years of follow-up, 1 patient experienced Riata lead electrical failure without fluoroscopic evidence of insulation failure. Patients were more likely to have a lead revision if there was evidence of insulation failure. Lead revisions occurred at the time of generator change in 88% of patients with insulation failure but in only 14% of patients with a fluoroscopically normal lead (p = 0.04). The cost of recall-related defibrillator lead revisions was $81,704.55. In conclusion, our Riata screening program added expense without clear benefit to patients. In fact, patients may have been put at more risk by undergoing defibrillator lead revisions based solely on the results of the fluoroscopic screening.

Left atrial appendage devices for stroke prevention in atrial fibrillation.

Atrial fibrillation (AF) is the most commonly encountered clinical arrhythmia, and stroke prevention remains an integral part of management of AF. Long-term therapy with oral anticoagulants, though effective, has many limitations, and these limitations have encouraged the search for device-based alternatives. In patients with non-valvular AF, approximately 90% of thrombi are thought to arise from the left atrial appendage (LAA). The LAA can be obliterated surgically or percutaneously, and this should reduce the incidence of systemic thromboembolic events in AF, ideally without the need for further anticoagulation. We explore the currently available LAA occlusion devices and the evidence behind these devices. Although additional evidence from randomized trials is required to fully characterize the safety and efficacy of all of these devices, LAA occlusion has the potential to offer an attractive alternative for those at high stroke risk but are under-protected because of contraindications to anticoagulant therapy.

First-dose effects of fingolimod: Pooled safety data from three phase 3 studies.

Fingolimod treatment initiation is associated with a transient slowing of heart rate and atrioventricular conduction. This report presents first-dose fingolimod effects (0.5mg or 1.25mg) on cardiac parameters using phase 3 FREEDOMS, FREEDOMS II and TRANSFORMS pooled study data (n=3635 patients). Vital signs were recorded hourly for ≥6h; 12-lead electrocardiogram (ECG) was obtained at baseline and at 6h post-dose. Clinical events were graded at the first-dose administrator׳s discretion. At screening, on day 1 and at month 3, 1073 patients underwent 24-h ambulatory electrocardiogram monitoring. A transient decrease in mean measured heart rate occurred 4-5h after the first dose, with a maximum reduction of 8 (fingolimod 0.5mg) and 11 beats per minute (fingolimod 1.25mg) below baseline. Symptomatic bradycardia at treatment initiation was reported in 0.6% (fingolimod 0.5mg) and 2.1% (fingolimod 1.25mg) of patients; events were typically mild or moderate in severity, and most resolved spontaneously. Atrioventricular (AV) conduction delays were observed in a few patients (Wenckebach (Mobitz type I) second-degree AV block, fingolimod 0.5mg, 0.2%; 1.25mg, 1%: 2:1 AV block fingolimod, 0.5mg, 0%; 1.25mg, 0.2% on ECG 6-h post-dose). These were usually well tolerated and first occurred within 6h of dosing. Consistent with its effects on atrial myocytes, fingolimod treatment initiation induced a transient slowing of heart rate and AV conduction. However, symptomatic bradycardia and second-degree AV block were uncommon and did not require intervention.

Usefulness of pharmacologic conversion of atrial fibrillation during dofetilide loading without the need for electrical cardioversion to predict durable response to therapy.

Conversion of persistent atrial fibrillation (AF) to sinus rhythm is frequently seen during the 3-day in-hospital loading period required during dofetilide initiation, but it is not known whether pharmacologic conversion (PC) without the need for electrical cardioversion (EC) is a predictor of long-term maintenance of sinus rhythm during continued therapy with dofetilide. We sought to test the hypothesis that PC predicts durable maintenance of sinus rhythm and determine additional predictors of long-term maintenance of sinus rhythm on dofetilide. We retrospectively reviewed all elective inpatient admissions for dofetilide loading from 2003 to 2011 at the University of Virginia. A multivariate Cox proportional hazards model was used to assess predictors of maintenance of sinus rhythm after in-hospital dofetilide loading. In all, 101 patients with a current duration of AF lasting for a median of 1.86 months (interquartile range 0.47 to 6.03) were included in the analysis. Forty-seven patients were in the PC group, whereas 54 patients were in the EC group. Patients in the PC group remained longer in sinus rhythm compared with the patients in the EC group (log-rank p = 0.032). The seventy-fifth percentile for the current episode duration in the PC group was 5.77 months, indicating that even long-standing persistent AF frequently converted pharmacologically. Hypertension and a longer duration of the current AF episode were also predictors of recurrence in the multivariate model. In conclusion, PC during in-hospital dofetilide loading is an important predictor of durable response even in long-standing persistent patients, which has important public health implications for choice of therapy.

The disconnect between the guidelines, the appropriate use criteria, and reimbursement coverage decisions: the ultimate dilemma.

Recently, the American College of Cardiology Foundation in collaboration with the Heart Rhythm Society published appropriate use criteria (AUC) for implantable cardioverter-defibrillators and cardiac resynchronization therapy. These criteria were developed to critically review clinical situations that may warrant implantation of an implantable cardioverter-defibrillator or cardiac resynchronization therapy device, and were based on a synthesis of practice guidelines and practical experience from a diverse group of clinicians. When the AUC was drafted, the writing committee recognized that some of the scenarios that were deemed "appropriate" or "may be appropriate" were discordant with the clinical requirements of many payers, including the Medicare National Coverage Determination (NCD). To charge Medicare for a procedure that is not covered by the NCD may be construed as fraud. Discordance between the guidelines, the AUC, and the NCD places clinicians in the difficult dilemma of trying to do the "right thing" for their patients, while recognizing that the "right thing" may not be covered by the payer or insurer. This commentary addresses these issues. Options for reconciling this disconnect are discussed, and recommendations to help clinicians provide the best care for their patients are offered.

Acute decompensated heart failure: update on new and emerging evidence and directions for future research.

Acute decompensated heart failure (ADHF) is a complex clinical event associated with excess morbidity and mortality. Managing ADHF patients is challenging because of the lack of effective treatments that both reduce symptoms and improve clinical outcomes. Existing guideline recommendations are largely based on expert opinion, but several recently published trials have yielded important data to inform both current clinical practice and future research directions. New insight has been gained regarding volume management, including dosing strategies for intravenous loop diuretics and the role of ultrafiltration in patients with heart failure and renal dysfunction. Although the largest ADHF trial to date (ASCEND-HF, using nesiritide) was neutral, promising results with other investigational agents have been reported. If these findings are confirmed in phase III trials, novel compounds, such as relaxin, omecamtiv mecarbil, and ularitide, among others, may become therapeutic options. Translation of research findings into quality clinical care can not be overemphasized. Although many gaps in knowledge exist, ongoing studies will address issues around delivery of evidence-based care to achieve the goal of improving the health status and clinical outcomes of patients with ADHF.

Independent multicenter study of Riata and Riata ST implantable cardioverter-defibrillator leads.

BACKGROUND: Riata and Riata ST leads (St Jude Medical, Sylmar, CA) are prone to failure. There are no independent multicenter reports regarding Riata or Riata ST lead performance. OBJECTIVE: To conduct a retrospective multicenter study of Riata and Riata ST leads that were implanted and followed at 7 centers. METHODS: The study included adults who received St Jude Medical Riata or Riata ST leads. Data for Quattro Secure leads were obtained from an earlier study. RESULTS: From 2002 to 2010, 1081 patients received a Riata (n = 774) or Riata ST (n = 307) lead. Follow-up was longer for Riata than Riata ST leads (4.2 ± 2.4 years vs 3.3 ± 1.7 years; P<.0001). During the study, 67 leads failed (6.2%), including 62 of 774 Riata (8.0%) and 5 of 307 Riata ST (1.6%) leads. Forty-seven of 67 lead failures (70.1%) were caused by electrical malfunction, and 20 lead failures (29.9%) were due to externalized conductors (ECs) that were electrically intact. Of 110 leads examined fluoroscopically, ECs were found in 26 of 81 Riata (32%) and 1 of 29 Riata ST (3.4%) leads. Of 26 Riata leads with ECs, 7 (27%) were malfunctioning. Riata leads had lower overall and malfunction free survival compared to Quattro leads (P<.0001), while Riata ST lead survival was not different (P = .422). CONCLUSIONS: The survival of Riata (but not Riata ST) leads was lower than Quattro leads; however, Riata ST leads had significantly shorter follow-up than Riata leads. ECs were common in Riata leads, and more than a quarter of Riata leads that had ECs were malfunctioning. Our observations suggest that systematic fluoroscopic examination of patients with Riata leads is appropriate.

Increasing lead burden correlates with externalized cables during systematic fluoroscopic screening of Riata leads.

PURPOSE: Riata and Riata ST defibrillator leads (St. Jude Medical, Sylmar, CA, USA) have been recalled due to increased risk of insulation failure leading to externalized cables. As this mechanical failure does not necessarily correlate with electrical failure, it can be difficult to diagnose. Fluoroscopic screening can identify insulation failure. Studies have suggested that insulation failure is predominantly seen in 8-Fr, single-coil models. Our patients have exclusively dual-coil leads and a high proportion of 7-Fr leads. METHODS: Fluoroscopic screening was performed in 48 patients with recalled Riata leads. Twenty-three patients had 8-Fr Riata leads and 25 patients had 7-Fr Riata ST leads. Images were recorded in at least three projections and studies were reviewed by seven attending electrophysiologists. RESULTS: Externalized cables were seen in ten patients (21 %), and another five patients (10 %) had abnormal cable spacing. All device interrogations showed normal parameters. Patients with abnormal leads had more leads in situ (2.5 ± 0.7 vs. 1.6 ± 0.8 leads; P = 0.002) and a higher rate of nonischemic cardiomyopathy (80 vs. 24 %; P = 0.03). There were no differences between the groups with regards to patient age, body mass index, lead age, lead parameters, or vascular access site. There was no difference with regard to lead size (P = 0.76). CONCLUSIONS: The Riata family of leads has a high incidence of mechanical failure, as demonstrated on fluoroscopic screening. In this study, the 7-Fr models were just as likely to mechanically fail as the 8-Fr models. Increasing lead burden and a diagnosis of nonischemic cardiomyopathy correlated with insulation failure.