Reversal Agents in the Era of NOACs.

The incidence and prevalence of atrial fibrillation (AF) is expected to more than double between 2010 and 2030. Accordingly, the use of non-vitamin K oral anticoagulant (NOAC) agents for thromboembolic stroke prevention is anticipated to increase. The development of effective and safe antidotes is needed to address the unmet need for rapid anticoagulation reversal. The immediate role for these novel antidotes is for reversal of NOAC activity in life threatening bleeding and urgent surgical intervention. In addition, reversal agents may play an important role in simplifying bridging protocols in the peri-procedural period for catheter ablation of AF and elective surgery. Currently, novel reversal agents are either decoy drug receptors or small molecule non-specific anticoagulant activity inhibitors. These agents are at various stages of FDA investigation and approval, with emerging prospective data for safety and efficacy. The purpose of this review is to outline the currently developed NOAC molecular antagonists, their potential clinical roles and future directions.

Periprocedural Management of Novel Oral Anticoagulants During Atrial Fibrillation Ablation: Controversies and Review of the Current Evidence.

Oral anticoagulation (OAC) has been the cornerstone for the prevention of thromboembolic complications in patients with atrial fibrillation (AF) at significant risk of stroke. Catheter ablation is an established efficacious technique for the treatment of AF. Ameliorating the risk of stroke or transient ischaemic attack (TIA) in patients with AF undergoing ablation requires meticulous planning of pharmacotherapy. The advent of non-vitamin K oral anticoagulants (NOACs) has broadened the therapeutic scope, representing a viable alternative to traditional vitamin K antagonists (VKA) in non-valvular AF. Potential advantages of NOACs include greater pharmacokinetic predictability, at least comparable efficacy as compared to VKA and a superior haemorrhagic complication profile. However, robust evidence for the safety and efficacy of periprocedural NOAC use for AF ablation remains uncertain with a non-uniform clinical approach between and within institutions. The following review will summarise the current and emerging evidence on periprocedural management of NOACs in patients undergoing catheter ablation of AF. An overview of NOAC pharmacology will provide a foundation for the review of reversal agents in the context of catheter ablation of AF. The purpose of the review is to outline key studies and identify key areas for further critical research with the ultimate aim of developing evidence-based guidelines for optimal care.

Systematic Review of Defibrillation Threshold Testing at De Novo Implantation.

BACKGROUND: Recent results from the largest multicenter randomized trial (Shockless IMPLant Evaluation [SIMPLE]) on defibrillation threshold (DFT) testing suggest that while shock testing seems safe, it does not reduce the risk of failed shocks or prolong survival. A contemporary systematic review of DFT versus no-DFT testing at the time of implantable cardioverter-defibrillator implantation was performed to evaluate the current evidence and to assess the impact of the SIMPLE study. METHODS AND RESULTS: Electronic searches were performed using 6 databases from their inception to March 2014. Relevant studies investigating implant DFT were identified. Data were extracted and analyzed according to predefined clinical end points. Predefined outcomes for interrogation were all-cause mortality, composite end point of implantable cardioverter-defibrillator efficacy (arrhythmic deaths and ineffective shocks), and composite safety end point (the sum of complications recorded at 30 days). Meta-analysis was performed including 13 studies and 9740 patients. No significant differences between DFT versus no-DFT cohorts were found in terms of all-cause mortality (risk ratio, 0.90; 95% confidence interval, 0.71-1.15; P=0.41), composite efficacy outcome (risk ratio, 1.24; 95% confidence interval, 0.65-3.37; P=0.51), and 30-day postimplant complications (risk ratio, 1.18; 95% confidence interval, 0.87-1.60; P=0.29). No significant difference was found in the trends observed when the results of the SIMPLE study were excluded or included. CONCLUSIONS: This systematic review of contemporary data suggests a modest average effect of DFT, if any, in terms of mortality, shock efficacy, or safety. Therefore, DFT testing should no longer be compulsory during de novo implantation. However, DFT testing may still be clinically relevant in specific patient populations.

Hypoglycaemia and QT interval prolongation: Detection by simultaneous Holter and continuous glucose monitoring.

This study using simultaneous Holter and continuous glucose monitoring demonstrates that prolongation of QT interval can occur with hypoglycaemia in an ambulatory setting in people with type 1 and type 2 diabetes treated with insulin. This highlights the potential proarrhythmic harms associated with hypoglycaemia.

Interventions for prevention of post-operative atrial fibrillation and its complications after cardiac surgery: a meta-analysis.

AIMS: Atrial fibrillation (AF) is the most common complication after cardiac surgery. We aimed to evaluate, by meta-analysis, all randomized trials testing interventions for preventing AF. METHODS AND RESULTS: Ninety-four trials of prevention of post-operative AF were identified, by standard search methods, and analysed by standard meta-analysis techniques. All five commonly tested interventions, beta-blockers (BBs), sotalol, amiodarone, magnesium, and atrial pacing, were effective in preventing AF. The odds ratio (OR) for the effect of BB on the incidence of AF was 0.36 (95% CI 0.28-0.47, P<0.001), but after trials confounded by post-operative non-study BB withdrawal were excluded was 0.69 (95% CI 0.54-0.87, P=0.002). Sotalol reduced AF, compared with placebo (OR 0.34, 95% CI 0.26-0.45, P<0.001) and compared with conventional BB (OR 0.42, 95% CI 0.26-0.65, P<0.001). Amiodarone reduced AF (OR 0.48, 95% CI 0.40-0.57, P<0.001). Magnesium (Mg) also had an effect (OR 0.57 95% CI 0.42-0.77) but there was significant heterogeneity (P<0.001), partly explained by concomitant BB. The effect of Mg with BB was less (OR 0.83, 95% CI 0.60-1.16). Pacing reduced AF (OR 0.60, 95% CI 0.47-0.77, P<0.001), despite wide variations in techniques. Only amiodarone and pacing significantly reduced length of stay, average -0.60 days (95% CI -0.92 to -0.29) and -1.3 days (95% CI -2.55 to -0.08), respectively. Collectively, all treatments analysed together reduced stroke (OR 0.63, 95% CI 0.41-0.98). Amiodarone was the only intervention that alone significantly reduced stroke rate (OR 0.54, 95% CI 0.30-0.95). CONCLUSION: All five interventions reduced the incidence of AF, though the effect of BBs is less than previously thought. The significant reductions in length of stay and stroke in meta-analysis suggest that there are worthwhile benefits from aggressive prevention. Larger studies to confirm these clinical benefits and evaluate their cost-effectiveness would be worthwhile.

Sudden death in the young.

BACKGROUND: Sudden death is rare in young people, but it has a disproportionate impact on the community. OBJECTIVES: The purpose of this study was to determine the causes of sudden, natural death in persons aged 5-35 years. METHODS: All autopsies conducted at a forensic medicine facility in the years 1995-2004 (inclusive) were reviewed. This facility serves more than 2.5 million people in the eastern part of Sydney, Australia. Data collected included subject age, height, weight, gender, circumstances of death, and pathologic findings at autopsy. Deaths caused by trauma, accidental causes, drowning, and drug toxicity were excluded from analysis. RESULTS: There were 427 nontraumatic, sudden deaths in the 10-year period (70.7% male). Cardiac causes accounted for 56.4%, noncardiac causes 39.3%, and undetermined cause 4.3%. The most common cardiac cause of sudden death was presumed arrhythmia in those with no or minimal structural heart disease (29.0%). Other cardiac causes were acute myocardial infarction (24.5%), myocarditis (11.6%), hypertrophic cardiomyopathy (5.8%), aortic dissection (5.4%), and dilated cardiomyopathy (5.4%). More than two thirds of deaths caused by acute myocardial infarction occurred in the age group from 30-35 years. Sudden cardiac death occurred during physical activity in 10.8% of cases. Sudden cardiac death was reported in a first-degree relative in 4.5% of decedents. The most common noncardiac causes of sudden death were epilepsy (23.8%), intracerebral hemorrhage (23.8%), asthma (16.1%), and pulmonary embolism (12.5%). CONCLUSION: Presumed cardiac arrhythmia is the most common cause of sudden, natural death in the young. There was no reported history of sudden death among the relatives of most decedents.

QTc interval prolongation associated with intravenous methadone.

Numerous medications prolong the rate-corrected QT (QTc) interval and induce arrhythmias by blocking ionic current through cardiac potassium channels composed of subunits expressed by the human ether-a-go-go-related gene (HERG). Recent reports suggest that high doses of methadone cause torsades de pointes. To date, no controlled study has described an association between methadone and QTc prolongation. The only commercial formulation of parenteral methadone available in the United States contains the preservative chlorobutanol. The objectives of this study are to determine: (1) whether the administration of intravenous (i.v.) methadone causes QTc prolongation in humans; (2) whether methadone and/or chlorobutanol block cardiac HERG potassium currents (IHERG) in vitro. Over 20 months, we identified every inpatient with at least one electrocardiogram (ECG) performed on i.v. methadone. For each patient, we measured QTc intervals for every available ECG performed on and off i.v. methadone. Concurrent methadone doses were also recorded. Similar data were collected for a separate group of inpatients treated with i.v. morphine. In a separate set of experiments IHERG was evaluated in transfected human embryonic kidney cells exposed to increasing concentrations of methadone, chlorobutanol, and the two in combination. Mean difference (+/- standard error) per patient in QTc intervals on and off methadone was 41.7 (+/- 7.8)ms, p<0.0001. Mean difference in QTc intervals on and off morphine was 9.0 (+/- 6.1)ms, p=0.15. The approximately linear relationship between QTc measurements and log-dose of methadone was significant (p<0.0001). Methadone and chlorobutanol independently block IHERG in a concentration-dependent manner with IC50 values of 20 +/- 2 microM and 4.4 +/- 0.3 mM, respectively. Chlorobutanol potentiates methadone's ability to block IHERG. Methadone in combination with chlorobutanol is associated with QTc interval prolongation. Our data strongly suggest that methadone in combination with chlorobutanol is associated with QTc interval prolongation.

Amiodarone and mortality among elderly patients with acute myocardial infarction with atrial fibrillation.

BACKGROUND: Amiodarone has been shown to be safe in patients with acute myocardial infarction (AMI) who are at risk for sudden cardiac death. However, there is limited data concerning the safety of amiodarone in patients who experience AMI complicated by atrial fibrillation. METHODS: To determine the safety of amiodarone therapy, we conducted a retrospective analysis of elderly patients hospitalized with AMI who experienced atrial fibrillation and had survived to hospital discharge (n = 17,597). Amiodarone prescribed at discharge was evaluated for its association with short-term and long-term mortality in crude and adjusted analyses employing propensity score methods. RESULTS: Of the 17,597 patients, 550 patients (3.1%) were prescribed amiodarone, 2317 patients (13.2%) were prescribed other antiarrhythmic agents (excluded from analysis), and 14,730 (83.7%) were prescribed no antiarrhythmic medication at discharge. Thirty-day mortality rates were similar for patients prescribed amiodarone and those not prescribed amiodarone (6.8% amiodarone vs 5.4% no amiodarone, P =.21), but mortality at 1 year was higher among patients prescribed amiodarone (35.6% vs 31.6%, P =.001). However, amiodarone was not associated with mortality at 30 days (odds ratio 0.80, 95% CI 0.53-1.20) or at long-term follow-up (mean duration 612 days, hazard ratio 1.04, 95% CI 0.92-1.18) after multivariable modeling. CONCLUSIONS: Amiodarone was not independently associated with short-term or long-term mortality in elderly patients discharged after a hospitalization for AMI complicated by atrial fibrillation. Although our data suggest that amiodarone may be safe to use in this population, randomized controlled trial data are needed to confirm this finding.

Influence of opioid agonists on cardiac human ether-a-go-go-related gene K(+) currents.

We have evaluated the ability of various opioid agonists, including methadone, L-alpha-acetylmethadol (LAAM), fentanyl, meperidine, codeine, morphine, and buprenorphine, to block the cardiac human ether-a-go-go-related gene (HERG) K(+) current (I(HERG)) in human cells stably transfected with the HERG potassium channel gene. Our results show that LAAM, methadone, fentanyl, and buprenorphine were effective inhibitors of I(HERG), with IC(50) values in the 1 to 10 microM range. The other drugs tested were far less potent with respect to I(HERG) inhibition. Compared with the reported maximal plasma concentration (C(max)) after administration of therapeutic doses of these drugs, the ratio of IC(50)/C(max) was highest for codeine and morphine (>455 and >400, respectively), thereby indicating that these drugs have the widest margin of safety (of the compounds tested) with respect to blockade of I(HERG). In contrast, the lowest ratios of IC(50)/C(max) were observed for LAAM and methadone (2.2 and 2.7, respectively). Further investigation showed that methadone block of I(HERG) was rapid, with steady-state inhibition achieved within 1 s when applied at its IC(50) concentration (10 microM) for I(HERG) block. Results from "envelope of tails" tests suggest that the majority of block occurred when the channels were in the open and/or inactivated states, although approximately 10% of the available HERG K(+) channels were apparently blocked in a closed state. Similar results were obtained for LAAM. These results demonstrate that LAAM and methadone can block I(HERG) in transfected cells at clinically relevant concentrations, thereby providing a plausible mechanism for the adverse cardiac effects observed in some patients receiving LAAM or methadone.