Very early versus early referral for ablation in young patients with newly diagnosed paroxysmal atrial fibrillation.

BACKGROUND: Catheter ablation (CA) has emerged as an effective therapy for the treatment of paroxysmal atrial fibrillation (AF); however it is unclear whether proceeding expeditiously to CA improves clinical outcomes in a real-world population. This study compares outcomes of CA for new AF within 6 months of diagnosis (very early) 6 to 12 months after diagnosis (early) and 12 to 24 months after diagnosis (later). METHODS: A large nationally-representative sample of patients ages 18 to 64 who underwent CA from January 2011 to June 2019 was studied using the IBM MarketScan Database. The primary outcome was a composite of healthcare utilization over the following 24 months. Propensity score-matching was used to match patients in each cohort. Risk difference in outcomes were compared between matched patients. RESULTS: Two thousand six hundred thirty one patients were identified postmatching, with 1649 in the very early cohort and 982 in the early cohort. The very early referral group was less likely to experience the primary composite outcome postablation (Absolute risk difference [ARD]: -3.9%; 95% Confidence interval [CI]: -5.8%, -2.0%), with the difference driven by fewer cardioversions (ARD: -2.9%, 95% CI: -5.3%, -0.5%) and outpatient visits (ARD: -6.6%, 95% CI: -10.5%, -2.7%). There was no difference in outcomes between early and later referral groups, with only very early referral showing decreased healthcare utilization. CONCLUSIONS: Patients who underwent ablation within 6 months of diagnosis had lower healthcare utilization in the ensuing 24 months, driven by fewer outpatient visits and cardioversions, supporting expeditious referral for ablation for symptomatic AF.

Site-specific cancer risk following cobalt exposure via orthopedic implants or in occupational settings: A systematic review and meta-analysis.

In 2020, the European Commission up-classified metal cobalt as Class 1B Carcinogen (presumed to have carcinogenic potential) based primarily on data from rodent inhalation carcinogenicity studies. This up-classification requires an assessment under the Medical Device Regulations of cobalt cancer risk from medical devices. We performed a systematic review and meta-analysis to evaluate site-specific cancer risks with cobalt exposure from either total joint replacement (TJR) or occupational exposure (OC). Results were stratified by exposure type (OC or TJR), exposure level (metal-on-metal (MoM) or non-MoM), follow-up duration (latency period: <5, 5-10 or >10 years), and cancer incidence or mortality (detection bias assessment). From 30 studies (653,104 subjects, average 14.5 years follow-up), the association between TJR/OC and cancer risk was null for 22 of 27 cancer sites, negative for 3 sites, and positive for prostate cancer and myeloma. Significant heterogeneity and large estimate ranges were observed for many cancer sites. No significant increase in estimates was observed by exposure level or follow-up duration. The current evidence, including weak associations, heterogeneity across studies and no increased association with exposure level or follow-up duration, is insufficient to conclude that there exists an increased risk for people exposed to cobalt in TJR/OC of developing site-specific cancers.

Carcinogenic assessment of cobalt-containing alloys in medical devices or cobalt in occupational settings: A systematic review and meta-analysis of overall cancer risk from published epidemiologic studies.

In 2020, the European Commission up-classified pure cobalt metal to a Category 1B hazard, based primarily on data from rodent inhalation carcinogenicity studies of metallic cobalt. The European Commission review did not evaluate cobalt-containing alloys in medical devices, which have very different properties vs. pure cobalt metal and did not include a systematic epidemiologic review. We performed a systematic review and meta-analysis of published, peer-reviewed epidemiologic studies evaluating the association between overall cancer risk and exposure to orthopedic implants containing cobalt alloys or cobalt particulates in occupational settings. Study-specific estimates were pooled using random-effects models. Analyses included 20 papers on orthopedic implants and 10 occupational cohort papers (~1 million individuals). The meta-analysis summary estimates (95% confidence intervals) for overall cancer risk were 1.00 (0.96-1.04) overall and 0.97 (0.94-1.00) among high-quality studies. Results were also similar in analyses stratified by type of exposure/data sources (occupational cohort, implant registry or database), comparators (general or implant population), cancer incidence or mortality, follow-up duration (latency period), and study precision. In conclusion, meta-analysis found no association between exposure to orthopedic implants containing cobalt alloys or cobalt particulates in occupational settings and overall cancer risk, including an analysis of studies directly comparing metal-on-metal vs. non-metal-on-metal implants.

A hazard evaluation of the reproductive/developmental toxicity of cobalt in medical devices.

Cobalt (Co) is an essential element with human exposure occurring from the diet, supplement ingestion, occupational sources, and medical devices. The European Chemical Agency (ECHA) recently voted to classify Co metal as a Reproductive Hazard Category 1B; presumed human reproductive toxicant due to adverse testicular effects in male rodents. A weight of evidence evaluation of the preclinical reproductive and developmental toxicity studies and available clinical data was performed to critically evaluate the relevance of this proposed classification for Co in medical devices. Reproductive responses to Co are limited to the male testes and sperm function following high systemic exposure in rodents, only at Co concentrations/doses that result in overt toxicity (i.e., above the maximum tolerable dose (MTD)). The potential mechanisms of Co reproductive/developmental toxicity, including its indirect mode of action in the testes and relevance to humans, are discussed. The available preclinical and clincial evidence suggests that it would be more appropriate to classify Co as a Reproductive Hazard Category 2 compound: suspected human reproductive toxicant and, in the case of Co-containing medical devices, it should not be considered a reproductive hazard.

An integrated benefit-risk assessment of cobalt-containing alloys used in medical devices: Implications for regulatory requirements in the European Union.

In 2017, the European Union (EU) Committee for Risk Assessment (RAC) recommended the classification of metallic cobalt (Co) as Category 1B with respect to its carcinogenic and reproductive hazard potential and Category 2 for mutagenicity but did not evaluate the relevance of these classifications for patients exposed to Co-containing alloys (CoCA) used in medical devices. CoCA are inherently different materials from Co metal from a toxicological perspective and thus require a separate assessment. CoCA are biocompatible materials with a unique combination of properties including strength, durability, and a long history of safe use that make them uniquely suited for use in a wide-range of medical devices. Assessments were performed on relevant preclinical and clinical carcinogenicity and reproductive toxicity data for Co and CoCA to meet the requirements under the EU Medical Device Regulation triggered by the ECHA re-classification (adopted in October 2019 under the 14th Adaptation to Technical Progress to CLP) and to address their relevance to patient safety. The objective of this review is to present an integrated overview of these assessments, a benefit-risk assessment and an examination of potential alternative materials. The data support the conclusion that the exposure to CoCA in medical devices via clinically relevant routes does not represent a hazard for carcinogenicity or reproductive toxicity. Additionally, the risk for the adverse effects that are known to occur with elevated Co concentrations (e.g., cardiomyopathy) are very low for CoCA implant devices (infrequent reports often reflecting a unique catastrophic failure event out of millions of patients) and negligible for CoCA non-implant devices (not measurable/no case reports). In conclusion, the favorable benefit-risk profile also in relation to possible alternatives presented herein strongly support continued use of CoCA in medical devices.

Carcinogenic hazard assessment of cobalt-containing alloys in medical devices: Review of in vivo studies.

Cobalt (Co) alloys have been used for over seven decades in a wide range of medical devices, including, but not limited to, hip and knee implants, surgical tools, and vascular stents, due to their favorable biocompatibility, durability, and mechanical properties. A recent regulatory hazard classification review by the European Chemicals Agency (ECHA) resulted in the classification of metallic Co as a Class 1B Carcinogen (presumed to have carcinogenic potential for humans), primarily based on inhalation rodent carcinogenicity studies with pure metallic Co. The ECHA review did not specifically consider the carcinogenicity hazard potential of forms or routes of Co that are relevant for medical devices. The purpose of this review is to present a comprehensive assessment of the available in vivo preclinical data on the carcinogenic hazard potential of exposure to Co-containing alloys (CoCA) in medical devices by relevant routes. In vivo data were reviewed from 33 preclinical studies that examined the impact of Co exposure on local and systemic tumor incidence in rats, mice, guinea pigs, and hamsters. Across these studies, there was no significant increase of local or systemic tumors in studies relevant for medical devices. Taken together, the relevant in vivo data led to the conclusion that CoCA in medical devices are not a carcinogenic hazard in available in vivo models. While specific patient and implant factors cannot be fully replicated using in vivo models, the available in vivo preclinical data support that CoCA in medical devices are unlikely a carcinogenic hazard to patients.

Trends and predictors of early ablation for Atrial Fibrillation in a Nationwide population under age 65: a retrospective observational study.

BACKGROUND: Catheter ablation (CA) has emerged as an effective treatment for symptomatic atrial fibrillation (AF). However practice patterns and patient factors associated with referral for CA within the first 12 months after diagnosis are poorly characterized. This study examined overall procedural trends and factors predictive of catheter ablation for newly-diagnosed atrial fibrillation in a young, commercially-insured population. METHODS: A large nationally-representative sample of patients age 20 to 64 from years 2010 to 2016 was studied using the IBM MarketScan® Commercial Database. Patients were included with a new diagnosis of AF in the inpatient or outpatient setting with continuous enrollment for at least 1 year pre and post index visit. Patients were excluded if they had prior history of AF or had filled an anti-arrhythmic drug (AAD) in the pre-index period. RESULTS: Early CA increased from 5.0% in 2010 to 10.5% in 2016. Patients were less likely to undergo CA if they were located in the Northeast (OR: 0.80, CI: 0.73-0.88) or North Central (OR: 0.91, CI: 0.83-0.99) regions (compared with the West), had higher CHA2DS2-VASc scores, or had Charlson Comorbidity Index (CCI) score of 3 or greater (OR: 0.61; CI: 0.51-0.72). CONCLUSIONS: CA within 12 months for new-diagnosed AF increased significantly from 2010 to 2016, with most patients still trialed on an AAD prior to CA. Patients are less likely to be referred for early CA if they are located in the Northeast and North Central regions, have more comorbidities, or higher CHA2DS2-VASc scores.

Predictors of Cardiac Perforation With Catheter Ablation of Atrial Fibrillation.

OBJECTIVES: This study identified factors associated with risk for cardiac perforation in the setting of atrial fibrillation (AF) ablation in contemporary clinical practice. BACKGROUND: Cardiac perforation is an uncommon but potentially fatal complication of AF ablation. An improved understanding of factors associated with cardiac perforation could facilitate improvements in procedural safety. METHODS: Logistic regression models were used to assess predictors of cardiac perforation among Medicare beneficiaries who underwent AF ablation from July 1, 2013 and December 31, 2017. Cardiac perforation was defined as a diagnosis of hemopericardium, cardiac tamponade, or pericardiocentesis, within 30 days of AF ablation. RESULTS: Of 102,398 patients who underwent AF ablation, 0.61% (n = 623) experienced cardiac perforation as a procedural complication. Rates of cardiac perforation decreased over time. In adjusted analyses of the overall population, female sex (odds ratio [OR]: 1.34; 95% confidence interval [CI]: 1.14 to 1.58; p = 0.0004), obesity (OR: 1.35; 95% CI: 1.09 to 1.68; p = 0.0050), and absence of intracardiac echocardiography (ICE) (OR: 4.85; 95% CI: 4.11 to 5.71; p < 0.0001) were associated with increased risk for cardiac perforation, whereas previous cardiac surgery (OR: 0.14; 95% CI: 0.07 to 0.26; p < 0.0001) was associated with a lower risk for perforation. Patient risk factors for cardiac perforation were identical in the subset of patients in whom ICE was used (n = 76,134). A risk score was generated with the following point assignments: female sex (1 point); obesity (1 point); nonuse of ICE (5 points); and previous cardiac surgery (-6 points). CONCLUSIONS: Cardiac perforation is a rare complication of AF ablation; incidence has decreased over time. One of the strongest predictors of cardiac perforation in the contemporary era is a modifiable factor, use of intraprocedural ICE.

Asymptomatic or "silent" atrial fibrillation: frequency in untreated patients and patients receiving azimilide.

BACKGROUND: Asymptomatic, or "silent" atrial fibrillation could increase the risk of stroke. Little is known about the frequency of asymptomatic atrial fibrillation in patients who also have symptomatic atrial fibrillation; similarly, little is known about the effect of antiarrhythmic drug therapy on asymptomatic atrial fibrillation. METHODS AND RESULTS: Patients in sinus rhythm with a history of symptomatic atrial fibrillation or atrial flutter received placebo or azimilide (35 to 125 mg) once daily for 6 or 9 months in 4 similar double-blind trials. The end point was the first recurrence of a symptomatic ECG-documented supraventricular arrhythmia. Routine transtelephonic electrocardiograms, in the absence of symptoms, were recorded for 30 seconds every 2 weeks until patients completed follow-up or documented a symptomatic supraventricular arrhythmia. Of the 1380 patients, 489 received placebo. Among these patients receiving placebo, 303 transmitted at least one routine ECG while asymptomatic. Asymptomatic atrial fibrillation was recorded in 50 (17%) within 6 months and before recurrence of symptomatic supraventricular arrhythmia. In the 3 trials evaluating azimilide in therapeutic doses (100 and 125 mg), asymptomatic atrial fibrillation occurred in 49 of 382 (13%) receiving azimilide and 43 of 233 (18%) receiving placebo. Although drug effect on time to first asymptomatic event was not statistically significant (hazard ratio, 0.70; P=0.09), there was a 40% reduction in asymptomatic atrial fibrillation on azimilide compared with placebo (P=0.03) when repeated observations were considered. CONCLUSIONS: Asymptomatic atrial fibrillation is common in untreated patients with a history of symptomatic atrial fibrillation (and is likely underestimated by this analysis). Azimilide may reduce the occurrence of this silent arrhythmia.

The efficacy of azimilide in the treatment of atrial fibrillation in the presence of left ventricular systolic dysfunction: results from the Azimilide Postinfarct Survival Evaluation (ALIVE) trial.

OBJECTIVES: The purpose of this study was to assess the effect of oral azimilide dihydrochloride (AZ) 100 mg versus placebo on the onset, termination, and prevalence of atrial fibrillation (AF) in a subpopulation of patients in the Azimilide Postinfarct Survival Evaluation (ALIVE) trial. BACKGROUND: Previous clinical trials have demonstrated the antiarrhythmic effects of AZ in patients with AF. Azimilide was investigated for its effects on mortality in patients with depressed left ventricular (LV) function after recent myocardial infarction (MI) and in a subpopulation of patients with AF. METHODS: A total of 3,381 post-MI patients with depressed LV function were enrolled in this randomized, placebo-controlled, double-blind study of AZ 100 mg on all-cause mortality. A total of 93 patients had AF on the baseline 12-lead electrocardiogram (ECG). An additional 27 patients developed AF after initially being in sinus rhythm at randomization. These patients were identified through 12-lead ECGs obtained during routine visits at week 2, months 1, 4, 8, and 12. RESULTS: Patients with AF at baseline had a higher mortality than those without AF (p = 0.0006). Among AF patients, there was no difference in mortality between AZ patients and placebo patients (p = 0.82). Fewer AZ patients developed AF than placebo patients (p = 0.04). More AZ patients than placebo patients converted to sinus rhythm, but this difference did not achieve statistical significance (p = 0.076). Over one-year follow-up, more AZ patients were in sinus rhythm than placebo patients (p = 0.04). CONCLUSIONS: Azimilide was safe and effective AF therapy in patients with depressed LV function after an MI.

Symptoms at the time of arrhythmia recurrence in patients receiving azimilide for control of atrial fibrillation or flutter: results from randomized trials.

BACKGROUND: Azimilide is a new antiarrhythmic agent being developed for the management for atrial fibrillation and flutter (AF). Four randomized, placebo-controlled, double-blind trials have been performed that investigated the effect of azimilide on time to first recurrence of symptomatic AF. This paper examines the data collected during those studies regarding the symptoms reported by patients at the time of AF recurrence METHODS: At the time that patients reported their first documented symptomatic recurrence of arrhythmia, they were systematically asked whether or not they were experiencing any of the following 6 symptoms: palpitation, fatigue, chest pain, shortness of breath, dizziness, or sweating. Patients were required to answer yes or no. A symptom score was created varying from 0 to 6, in increasing order of number of symptoms reported. This was compared for patients receiving either of 2 doses of azimilide or placebo. The relationship between the number of symptoms, heart rate at time of arrhythmia recurrence and treatment was analyzed. RESULTS: In 2 separate studies, azimilide at a dose of 125 mg/day significantly reduced the number of symptoms at the time of arrhythmia recurrence compared to placebo. On the other hand, in 2 studies, the dose of 100 mg/day did not significantly reduce symptom burden. The individual symptoms significantly reduced by azimilide125 mg/day were fatigue, shortness of breath, chest pain and dizziness. Palpitations and sweating were not significantly reduced. Modeling of heart rate at the time of arrhythmia recurrence, symptoms and treatment indicated that a small reduction in heart rate with azimilide accounted for only a small part of the symptom reduction. There was another effect of azimilide: an average reduction of 0.38 symptoms (P <.01) that was independent of heart rate. CONCLUSION: Azimilide (125 mg/day) reduces the number of symptoms reported at the time of AF recurrence.

Antiarrhythmic effects of azimilide in paroxysmal supraventricular tachycardia: efficacy and dose-response.

BACKGROUND: Azimilide is a novel classification III antiarrhythmic agent that blocks both I(Kr)and I(Ks)and shows evidence of efficacy in patients with atrial fibrillation or flutter. Its effect on paroxysmal supraventricular tachycardia (PSVT) has not been reported. METHODS AND RESULTS: One hundred ninety-three patients with symptomatic PSVT were enrolled in 4 double-blind, randomized, placebo-controlled clinical trials with almost identical trial design (supraventricular arrhythmia-1 [SVA-1], SVA-2, SVA-3, and SVA-4), performed as a separate stratum of studies that also included a stratum of patients with atrial fibrillation or flutter. Patients received oral azimilide (100 mg in SVA-1 and SVA-3, 35 or 75 mg in SVA-2, and 125 mg in SVA-4) or matching placebo twice daily for 3 days (loading period), followed by once-daily dosing (maintenance period). The primary outcome variable was the first recording of a symptomatic supraventricular arrhythmia (either PSVT, atrial fibrillation, or atrial flutter) recorded on a transtelephonic electrocardiographic event recorder. The duration of study was 270 days in SVA-1 and SVA-2 and 180 days in SVA-3 and SVA-4. Combined analysis results of the PSVT stratum from the 4 studies showed a dose-response relationship in prolongation of time to recurrence (P =.02). In the combined 100-mg daily dose, the hazard ratio (placebo:azimilide) was 2.35 (P =.023). The hazard ratio for the 125-mg daily dose measured 1.28 (P = not significant). However, the time to recurrence was prolonged when the patients receiving 100 and 125 mg daily were combined and compared with placebo (P =.02). There were no deaths and 1 case of torsades de pointes. CONCLUSION: These trial results suggest a significant dose-related suppression of PSVT with azimilide, with a low risk of serious adverse events.

Effects of azimilide on heart rate and ECG conduction intervals during sinus rhythm in patients with a history of atrial fibrillation.

The purpose of this study was to assess the effect of azimilide, a Class III antiarrhythmic drug, on ECG conduction intervals recorded during sinus rhythm in patients with a history of symptomatic atrial fibrillation or atrial flutter. In Phase I clinical pharmacology studies, azimilide was associated with prolongation of the QT and QTc intervals on electrocardiograms recorded during sinus rhythm in normal subjects, but the effect of azimilide on the target population of patients with atrial fibrillation has not been reported in detail previously. Patients with a history of atrial fibrillation, atrial flutter, or both were randomly assigned to receive placebo or azimilide twice daily for 3 days and then qd thereafter. Azimilide doses of 50 mg, 100 mg, or 125 mg were tested. The RR, PR, QRS, QT, QTc(Bazett), and QTc(Fridericia) intervals were measured from electrocardiograms recorded at baseline and on Day 4 of test therapy. Increasing azimilide doses were associated with significant increases in the RR, QT, QTc(Bazett), and QTc(Fridericia) compared with changes in the placebo group based on the F-test for differences among treatment groups and the test for a dose response. In the azimilide 125 mg dose group, the mean change in RR was significantlygreater than the mean change in the placebo group (+61.4 ms in the azimilide 125 mg group vs. -14.1 ms in the placebo group). The mean change in QT was significantly greater in the azimilide 125 mg group than the mean change in the placebo group (+44.2 ms in the azimilide 125 mg group vs. -1.0 ms in the placebo group). The mean change in QTc using both correction methods was significantly greater in the azimilide 125 mggroup than the mean change in the respective placebo group: QTc(Bazett) +31.6 ms in the azimilide 125 mg group versus +2.1 ms in the placebo group and QTc(Fridericia) +35.8 in the azimilide 125 mg group versus +1.0 ms in the placebo group. It was concluded that in patients with a history of atrial fibrillation or flutter, azimilide was associated with statistically significant increases in RR, QT, QTc(Bazett), and QTc(Fridericia) when patients were in sinus rhythm.

Cumulative experience of azimilide-associated torsades de pointes ventricular tachycardia in the 19 clinical studies comprising the azimilide database.

OBJECTIVES: The purpose of this study was to assess the incidence, temporal characteristics, and risk factors associated with azimilide-associated torsades de pointes (TdP) ventricular tachycardia. BACKGROUND: Azimilide dihydrochloride is a class III antiarrhythmic drug possessing Ikr and Iks channel-blocking properties. METHODS: Oral azimilide (75 to 125 mg/day) was taken by 5,375 patients in 19 clinical trials conducted at 775 international centers. Of 3,964 patients in double-blind studies, 1,427 had a history of atrial fibrillation or other supraventricular arrhythmia, 510 had an implantable cardioverter-defibrillator, and 2,027 were post-myocardial infarction patients with a left ventricular ejection fraction < or =35%. RESULTS: The TdP occurred in 56 patients assigned to azimilide, was dose-related, and tended to occur earlier with an azimilide-loading regimen. Forty-three percent of TdP patients had a QT interval corrected by Bazett's formula, for heart rate, (QTc) > or =500 ms at the time of or before the TdP occurrence. Significant risk factors using logistic regression were increasing age, female gender, diuretic use, and lack of aspirin use. CONCLUSIONS: Azimilide-associated TdP has characteristics and risk factors similar to other Ikr blockers. However, there is a distinctive temporal profile. The TdP events are not concentrated in the first week. The azimilide-associated TdP rate is 1% (95% confidence interval 0.78 to 1.35) and is not increased in patients with low left ventricular ejection fraction, even in women.

Azimilide for atrial fibrillation: clinical trial results and implications.

Azimilide dihydrochloride (or azimilide) is a class III antiarrhythmic drug currently under investigation that has been tested in atrial fibrillation in four randomized, placebo-controlled clinical trials to assess efficacy and dose range. These investigational trials showed that doses of azimilide 100 and 125 mg once daily prolonged the time to symptomatic arrhythmia recurrence in patients with a history of symptomatic atrial fibrillation, atrial flutter or both. Doses of 75 mg or less were not useful in this indication. Safety of azimilide has been examined in several different types of studies. In a large randomized clinical trial of post-infarct patients, azimilide neither increased nor decreased mortality risk. In patients with supraventricular arrhythmias, the most common adverse effects reported by patients on azimilide were approximately equal in frequency with those on placebo: headache, asthenia, infection, diarrhea and dizziness. Infrequent cases of torsade de pointes and severe neutropenia were reported in patients taking azimilide. Azimilide is an investigational antiarrhythmic drug that has shown efficacy in patients with atrial fibrillation.