Pre-existing Arrhythmias Research Articles

QTc interval i ishod lečenja bolesnika sa COVID-19

Objective. After the beginning of the COVID-19 pandemic caused by the SARS-CoV -2 virus, enormous pressure fell on the entire health system. Since there is no adequate cure for this disease, "off-label" use of several drugs (azithromycin, chloroquine, hydroxychloroquine, etc.) was resorted to. The aim of this study was to analyse QTc interval dynamics and its relationship with other factors which could influence outcome in patients with COVID-19. Methods. Study has observational, case-control design with retrospective data collection from medical files of adult patients, with RT-PCR confirmed COVID-19. The cases (n=30) were subjects with fatal outcome and the controls (n=169) were the survivors. The QTc interval was calculated on admission, during and after initial drug treatments with presumed activity against SARS-CoV-2, mostly antimalarials. Primary independent and outcome variables were QTc interval prolongation and all-cause mortality, respectively. Results. Study population included 120 males (60.3%), the mean patients age was 57.3+-15.8 years (+-SD). The most common comorbid illnesses were hypertension (98 patients), pre-existing arrhythmias (32) and diabetes mellitus (29). The most frequently prescribed QTc prolonging drugs were azithromycin (69.8% of patients), chloroquine (50.3%) and hydroxychloroquine (42.7%). Total of 131 patients (65.8%) had QTc interval increase >60 ms from baseline, of whom 5 had QTc prolongation >500 ms (2.5%). De novo ventricular tachyarrhythmias were registered at 14 patients (7%) and 13 (92.8%) of them died. Pre-existing arrhythmias (odds ratio 9.30, 95% confidence interval 2.91-29.73, p<0.001) and furosemide (8.94, 3.27-24.41, p<0.001) were independently associated with mortality but QTc prolongation (>480 ms) did not (1.02, 0.22-4.67, p=0.974). Case fatality rate was 15.1%, as 30 patients died during hospitalization. Conclusion. Clinical importance of drug-induced QTc interval prolongation of hospitalized patients with COVID-19 should be considered primarily within the context of other risks, particularly older age, pre-existing cardiovascular disorders and major electrolyte disturbances.

Prevalence of cardiac arrhythmias in patients of obstructive sleep apnea syndrome and changes after 6 months of continuous positive airway pressure therapy

Obstructive sleep Apnoea (OSA) has generated lot of attention recently. The prevalence of OSA in adult Indian population is approximately 3.5% and the majority of these patients remain undiagnosed. OSA is associated with repeated episodes of hemoglobin desaturation and higher inspiratory effort, combined with repeated arousals during sleep. This causes repeated sympathetic and parasympathetic stimulation. This has been postulated to be associated with both electric and mechanical remodeling of the heart leading to cardiac arrhythmias. In this study, we try to find a correlation between OSA and cardiac arrhythmias and to find the type of arrhythmia as the secondary aim.This study was conducted over three year period at a tertiary care hospital in Mumbai. We screened 186 patients with proven OSA (Apnoea Hypopnea Index> 5). Among these, those with pre-existing structural heart disease or arrhythmia or those not consenting for the study were excluded. 121 subjects were taken up for the study. 01 was lost to follow up, leading to a final sample size of 120. These 120 patients with proven OSAand no pre- existing cardiac pathology were subjected to 24 hour ambulatory Holter monitoring to determine the prevalence of cardiac arrhythmias among this cohort. It was found that 30% of this population had some or the other arrhythmia. (n = 36). Various factors such as age, metabolic and endocrine ailments and others were also accounted for.In the follow up to this study, these 36 patients were advised to use CPAP. Following 06 months of effective CPAP use, these subjects underwent repeat 24 hour Holter examination. Unsurprisingly, significant reduction in prevalence of cardiac arrhythmia was noticed. Now, out of this cohort of 36 subjects, only 02 were found to have cardiac arrhythmia.

Slow Heart Rate Within 72 Hours After Cardiac Arrest Is Associated with Good Neurologic Outcome in Out-of-Hospital Cardiac Arrest Survivors Who Undergo Targeted Temperature Management with 33°C.

We aimed to verify whether slow heart rate (HR) is associated with neurologic outcome and the factors that can contribute to the development of bradycardia in out-of-hospital cardiac arrest (OHCA) survivors who underwent targeted temperature management (TTM). We extracted the data of comatose adult OHCA survivors who underwent TTM between October 2015 and December 2018 from the prospective multicenter registry. Data on HR recorded every 6 hours within 72 hours after return of spontaneous circulation and calculated minimal, mean, and maximal HR and time to the lowest HR were obtained. HR <50 bpm was defined as bradycardia. The primary outcome was a 6-month neurologic outcome based on Pittsburgh-Glasgow Cerebral Performance Category Scale. Of the 814 included patients, 508 (62.4%) had poor neurologic outcome and 197 (24.2%) had bradycardia. Bradycardia (odds ratio [OR], 0.574; 95% confidence interval [CI], 0.362-0.192), minimal HR (OR, 1.023; 95% CI, 1.008-1.037), and mean HR (OR, 1.016; 95% CI, 1.002-1.030) were independently associated with poor neurologic outcome, but not maximal HR and time to the lowest HR. Preexisting arrhythmia (OR, 2.067; 95% CI, 1.037-4.118), renal disease (OR, 2.028; 95% CI, 1.153-3.567), cardiac etiology (OR, 1.526; 95% CI, 1.045-2.228), downtime (OR, 0.985; 95% CI, 0.974-0.996), and serum lactate levels (OR, 0.936; 95% CI, 0.900-0.974) were independently associated with bradycardia. Bradycardia and decreased mean and minimal HR were independently associated with good neurologic outcomes. Bradycardia was associated with preexisting arrhythmia, renal disease, cardiac etiology, shorter downtime, and lower serum lactate level.

P1868Risk of arrhythmias after myocardial infarction in patients with left ventricular systolic dysfunction according to mode of revascularization: a CARISMA substudy

Abstract Introduction The CARISMA trial was the first study to use continuous monitoring for documentation of long-term arrhythmias in post-infarction patients with left ventricular dysfunction. During the study duration (2000–2005), primary PCI (pPCI) as treatment of acute myocardial infarction was introduced approximately midway (2002) on the enrolling centres. Purpose The aim of this study was to describe the influence of mode of revascularization after myocardial infarction (AMI) on long-term risk of risk of new onset atrial fibrillation, ventricular tachyarrhythmias and brady arrhythmias. Methods The study is a sub-study on the CARISMA study population that consisted of patients with AMI and left ventricular ejection fraction ≤40%, which received an implantable loop recorder and was followed for 2 years. After exclusion of 15 patients who refused device implantation and 26 with pre-existing arrhythmias, 268 of the 312 patients were included. Choice of revascularization was made by the treating team independently of the trial and was retrospectively divided into primary percutaneous intervention (pPCI), subacute PCI (24 hours to 2 weeks after AMI), primary thrombolysis or no revascularization. Endpoints were new-onset of arrhythmias and major cardiovascular events (MACE). The Kaplan-Meier (figure 1) and Mantel-Byar methods were used for time to first event risk analysis. Results A total of 77 patients received no revascularization, whereas 49 received thrombolysis only and 142 received PCI. At two-years follow up patients treated with any PCI had a significant lower risk (0.40, n=63) of any arrhythmia compared to patients treated with trombolysis (0.60, n=30) or no revascularization (0.68, n=16) (p&lt;0.001, unadjusted) (figure 1). Risk of MACE was significant higher in patients with any arrhythmia (0.25, n=76) compared to no arrhythmia (0.11, n=93) at two years follow-up (p=0.004, unadjusted). Figure 1 Conclusion(s) The long-term risk of new onset arrhythmias after AMI was significantly lower in patients treated with any PCI compared to patients not revascularized or treated with thrombolysis. Risk of MACE was significantly higher in patients with new onset arrhythmias compared to patients with no arrhythmias.

Drugs and life-threatening ventricular arrhythmia risk: results from the DARE study cohort

ObjectivesTo establish a unique sample of proarrhythmia cases, determine the characteristics of cases and estimate the contribution of individual drugs to the incidence of proarrhythmia within these cases.SettingSuspected proarrhythmia cases...

Does chronic exposure to high levels of nitrogen dioxide exacerbate the short-term effects of airborne particles?

BackgroundLong-term exposure to air pollutants has been hypothesised as a factor in susceptibility to short-term exposure to particulate matter (PM), but results are not coherent. We studied the short-term effects...

Management of tachyarrhythmia during pregnancy

Maternal tachyarrhythmia is a common complication during pregnancy due to hormonal changes that enhance pre-existing arrhythmias or induce new arrhythmias in the presence of congenital heart defects in pregnant females. Presence of tachyarrhythmia during pregnancy poses risk to the mother and fetus, calling for proper treatment with medications. Use of antiarrhythmic drugs in cases of maternal tachyarrhythmia must give due consideration of potential teratogenic side effects. Utilization of antiarrhythmic drugs during pregnancy has been well studied; some result in minimal fetal harm or none at all. New techniques, such as cardiac ablation, have also been implemented with minimal or no radiation exposure to the fetus or mother. Pregnant women with tachyarrhythmia have been successfully treated with little to no impact on the developing fetus as result of increasing experience with antiarrhythmic drugs and progress of new procedural techniques.

Arrhythmias in pregnancy (RCD code: VII-V)

Cardiovascular diseases in pregnancy are the most common causes of maternal mortality in developed world and an important cause of heart failure, stroke, and arrhythmia. Cardiac disease complicates 0.4–4% of all pregnancies, and arrhythmias are among the most common cardiac complications [1]. In some cases, pregnancy triggers exacerbations of pre-existing arrhythmias, whereas in others it may manifest for the first time [2]. A prior history of arrhythmias or structural heart disease and family history of sudden death are the factors that matter to risk of tachyarrhythmias during pregnancy [3]. Due to extraordinary ethical considerations in pregnant women, there are only a few randomized studies and little data on efficacy or safety of antiarrhythmic drugs applied during pregnancy [4]. Therefore, much of clinical care is guided by general knowledge about hemodynamic changes in pregnant women, universal principles of treatment of arrhythmias and finally by gained experience in that area. Multi-disciplinary approach remains the overriding principle in management of pregnant woman with arrhythmias, including collaboration with gynecological and obstetric center. JRCD 2016; 2 (6): 177–180

Prevention of Sudden Cardiac Death in Cricketers

ABSTRACT Aims Sudden death in cricketers is rare, with the most common causes being cardiac, neurological (head/neck trauma, mainly from ball impact) and environmental (e.g., lightning strike and heat stroke, the former which usually involves cardiac arrest). The aim of this study was to review possible prevention of sudden cardiac death and make recommendations. Materials and methods A literature review of possible causes of sudden cardiac death (SCD) among cricketers was performed, along with evaluation of evidence for existing preventative measures. The method for evaluation was expert panel (cardiology and sports medicine) consensus recommendations based on the published evidence base. Results Potential cardiac causes of sudden death while playing cricket can be divided into the following categories: (1) atraumatic-origin preexisting arrhythmias, cardiomyopathies and valve disorders (2) traumatic-origin arrhythmia (commotio cordis) (3) acquired coronary or valvular disease (4) viral myocarditis (5) Lightning strike. Preventive measures can be divided into pre-season (e.g., cardiovascular screening), prematch (e.g., assessment of viral illness), protective equipment (e.g., chest guards) and post-event (presence of first aid response including defibrillators). Our panel agreed that there was strong evidence that (1) trained and planned emergency response particularly with a defibrillator is effective at preventing SCD and (2) ceasing play in the presence of lightning strikes prevents lightning-related death (3) players with symptoms, risk factors or history suggestive of possible cardiac disease should undertake specific individual workup. There are other potential methods to prevent SCD, with expert level recommendations made in the absence of strong evidence. Discussion and conclusion The most controversial aspect of prevention of SCD is electrocardiogram (ECG) screening of asymptomatic players and this paper outlines the arguments both in favor and against without fully resolving the debate. The possible increase in early diagnosis of potentially life-threatening cases needs to be balanced against the risk of false positive results which may lead to discussion of exclusion from cricket. Cardiac workup is clearly of net benefit to symptomatic individuals (e.g. history of syncope, chest pain) or any player at higher than usual baseline risk (e.g., positive family history). Basic life support including access to defibrillators should be available with trained personnel wherever they can be afforded, which has strong evidence in favor of improving survival at the time of cardiac arrest. How to cite this article Orchard JW, Puranik R, Semsarian C, Orchard JJ, Samra D, Duflou J, Groenestein P, Young M, Brukner P, Kountouris A. Prevention of Sudden Cardiac Death in Cricketers. J Postgrad Med Edu Res 2016;50(2):49-58.

A Phase 2 Study of Ofatumumab in Combination with a Pan-AKT Inhibitor (Afuresertib) in Previously Treated Patients with Chronic Lymphocytic Leukemia (CLL)

Introduction: Ofatumumab is an anti-CD20 monoclonal antibody with single-agent responses of 47-58% in refractory CLL (Wierda et al 2010) and a median response duration ranging from 5.6-7.1 months. In order to improve upon these results, we combined ofatumumab with afuresertib, a pan-AKT kinase inhibitor. The AKT pathway plays a centralized role in tumor differentiation, migration, proliferation and survival and is frequently aberrantly activated in CLL (Longo et al 2007). Single agent afuresertib is very well-tolerated with minimal myelotoxicity in hematologic malignancies (Spencer et al ASH 2011). We present results from 27 of 31 planned patients (pts) in a trial of ofatumumab and afuresertib in relapsed/refractory CLL.Methods: Pts withCLL relapsed/refractory to at least one fludarabine-containing regimen were eligible. During the initial 6 month Treatment Phase, ofatumumab 2000mg IV was administered weekly for 8 doses, then once every 4 weeks for 4 doses (dose/schedule identical to the pivotal phase 2 trial) with afuresertib 125mg orally daily. An initial 10 day Lead-in Phase with afuresertib alone allowed for evaluation of pharmacodynamic (PD) and pharmacokinetic (PK) studies. Patients achieving SD, PR or CR by the end of the Treatment Phase proceeded to the Maintenance Phase with single-agent afuresertib for a maximum of 12 4-week cycles.Results:Demographics: Of the 27 patients enrolled, the median age was 63 yrs (range 43-76), absolute lymphocytes 60.4 x109 /L (range 1.0-464), β2M 5.1mg/L (range 1.1-16.6). High risk features included: FISH with del17p/del11q in 10 pts (37%), ZAP70+ in 20 pts (74%) and unmutated IgVH status in 18 pts (72%). The median number of prior therapies was 2 (range 1-6). Eleven pts (41%) were fludarabine-refractory but only 3 (11%) had received prior alemtuzumab.Toxicity:Hematologic: Gr 3-4 neutropenia occurred in 10 pts (37%) and thrombocytopenia (without bleeding) in 8 pts (30%) during at least 1 cycle of treatment. Only 1 pt (4%) developed febrile neutropenia.Nonhematologic toxicity: Most common toxicities (all grades) were infusion reactions (70%), upper respiratory infections (74%), dyspepsia (59%), cough (70%), and diarrhea (56%). Dyspepsia was temporally related to oral afuresertib and managed symptomatically. Of the 19 pts (70%) who had infusion reactions to the ofatumumab, only 3 were grade 3-4 (non-fatal, all cycle 1). Grade 3-4 non-infectious pneumonitis, attributed to ofatumumab, occurred in 3 pts (11%), with 2 pts requiring hospitalization. Two pts with preexisting atrial arrhythmias sustained exacerbation during weekly ofatumumab infusions. Most infections were mild, with grade 3 upper respiratory infections (2 pts), pneumonia (4 pts), and skin infection (1 pt). There were no grade 4 infections.Efficacy: The median number of study cycles was 8 (2-19). Of all 27 response-evaluable pts, 12 pts (44%) achieved a PR, 14 SD (52%), and 1 CR (4%) = overall response rate 48%. Response onset was rapid (median 1.4 mos). Nineteen pts did not complete treatment protocol due to: disease progression 12 pts (44%), toxicity 5 pts (19%), and patient preference 2 pts (7%). At a median follow-up of 9.5 mos, the median PFS is 8.6 mos (95% CI: 7.4-13.9) and OS not yet reached.PD Studies: CD19+ cells were assayed for phosphorylated AKT and downstream targets RAS40 and GSK3, in addition to phospho-proteins of alternative pathways including ERK and pS6 by multiplexed phospho-flow cytometry. Blood samples collected at screening demonstrated constitutive AKT phosphorylation. Partial inhibition of AKT signaling evidenced by increased phosphorylation of AKT and inhibition of GSK3 and/or RAS40 phosphorylation in response to BCR stimulation was observed post-treatment, indicating target engagement by afuresertib. PK Studies: Afuresertib exposure (Cmax and AUC) was similar when afuresertib was administered alone or in combination with ofatumumab.Conclusion: This phase 2 study of 27 previously treated CLL pts, 40% with fludarabine-refractory disease, demonstrates that the addition of an oral AKT inhibitor, afuresertib, to ofatumumab has anti-tumor activity and is generally well-tolerated with minimal myelotoxicity. Although this combination works rapidly with a response onset of 1.4 mos, the moderate response rate of 48% and PFS of 8.6 mos suggest that this combination may not provide significant benefit over single agent ofatumumab. DisclosuresChen:Glaxo Smith Kline: Honoraria; Lundbeck: Honoraria; Roche: Honoraria; Janssen: Honoraria; Sanofi: Research Funding; Celgene: Honoraria, Research Funding. Off Label Use: Afuresertib is not currently approved for use in CLL.. Trudel:BMS: Honoraria; Amgen: Honoraria, Speakers Bureau; Celgene: Consultancy, Equity Ownership, Honoraria, Speakers Bureau; GSK: Honoraria, Research Funding; Merck: Research Funding; Novartis: Consultancy, Honoraria.

Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 4: Congenital Heart Disease: A Scientific Statement From the American Heart Association and American College of Cardiology.

Congenital heart disease (CHD) is the most common form of serious birth defect, occurring in 8 per 1000 live births.1 The past several decades have seen dramatic improvements in survival with palliative or corrective heart surgery, such that there are now more adult patients than pediatric patients alive with CHD. Although restriction from competitive athletics may well be indicated for some, the great majority of patients can and should engage in some form of physical activity and should avoid a sedentary lifestyle. Clinicians should encourage their patients to engage in healthy physical activities, bearing in mind specific features in some patients, such as residual obstruction, pulmonary vascular disease, low systemic ventricular function, and preexisting arrhythmias in the presence of implanted cardiac rhythm devices such as pacemakers and implantable cardioverter-defibrillators. In addition, the physiological effects of athletic activities at high altitude should be considered for patients with elevated pulmonary vascular resistance. These issues are covered elsewhere in this document. Fortunately, although repaired CHD is clearly associated with the development of arrhythmias such as atrial flutter and ventricular tachycardia, exercise does not appear to contribute to the risk. The level of sports participation recommended includes consideration of both the training and the competitive aspects of the activity but must be individualized to the particular patient, taking into account the patient’s functional status and history of surgery. Noninvasive testing, such as formal exercise testing, Holter monitoring, echocardiography, and cardiac magnetic resonance imaging studies, is also often useful. ### Simple Shunting Lesions (Atrial Septal Defect, Ventricular Septal Defect, Patent Ductus Arteriosus), Treated and Untreated Of the 8 most common subtypes of CHD, ventricular septal defect (VSD; 34%), atrial septal defect (ASD; 13%), and patent ductus arteriosus (PDA; 10%), respectively, are the most common.2 With rare exceptions, patients with hemodynamically insignificant CHD such as VSD, ASD, and PDA may participate competitively in all sports. There are no demonstrative data …

Atrial fibrillation associated with tiotropium in patients with pre-existing arrhythmia: a case report

Atrial fibrillation associated with tiotropium in patients with pre-existing arrhythmia: a case report

Contemporary management of arrhythmias during pregnancy.

Cardiac arrhythmias are among the most common cardiac complications encountered during pregnancy.1 In some, pregnancy may trigger exacerbations of pre-existing arrhythmias, whereas in others arrhythmias may manifest for the first time.2 Fortunately, severe arrhythmias requiring aggressive or invasive therapies are rare. There are unfortunately few randomized studies, little data on the efficacy or safety of antiarrhythmic drugs (AADs), or even explicit guidelines to support decision making on pregnant women with arrhythmias. Thus, much of the clinical care is guided by knowledge of the physiology of pregnancy and educated risk/benefit decisions made in collaboration with high-risk obstetric colleagues in Maternal-Fetal Medicine, as well as with the patient. The precise mechanism of increased arrhythmia burden during pregnancy is unclear, but it is likely because of a combination of hemodynamic, hormonal, and autonomic changes. Increases in effective circulating blood volume of 30% to 50% are seen beginning at 8 weeks of gestation and peaking at ≈34 weeks. Cardiac output is increased as well, with an average of 6.7 L/min in the first trimester and ≤8.7 L/min in the third trimester. This is the result of a 35% increase in stroke volume and a 15% increase in heart rate. The increase in plasma volume causes stretching of atrial and ventricular myocytes, and this may result in early after depolarizations, shortened refractoriness, slowed conduction, and spatial dispersion through activation of stretch-activated ion channels.3,4 A larger heart can also potentially sustain re-entry more easily because of an increase in path length of potential reentrant circuits. The increase in heart rate during pregnancy, seen predominantly in the third trimester, may also predispose to arrhythmia, as a high resting heart rate has been associated with markers of arrhythmogenesis.5 Hormonal and autonomic changes may also contribute to arrhythmogenesis. Estradiol and progesterone have been …

Republished: Pro-arrhythmic and pro-ischaemic effects of inhaled anticholinergic medications

The majority of deaths in COPD are from cardiovascular causes. Several large randomized controlled trials demonstrate that inhaled anticholinergic agents ipratropium and tiotropium increase the risk of serious cardiovascular events,...

Sidestream capnographic monitoring reduces the incidence of arterial oxygen desaturation during propofol ambulatory anesthesia for surgical abortion.

BackgroundThis study investigated whether early intervention based on additional use of sidestream capnography could reduce the incidence of oxygen desaturation and hypoxic events in patients receiving propofol anesthesia during surgical abortion.Material/MethodsWe recruited 704 ASAI-III female patients, 18–52 years old and scheduled for planned painless surgical abortion, and randomized them into a control group (n=359) receiving standard monitoring and an experimental group (n=341) receiving standard monitoring and additional capnography. Exclusion criteria were preexisting cardiovascular disease, preexisting hypotension, bradycardia or arrhythmia, and drug allergy. Anesthesia was induced in all patients with propofol using target-controlled infusion at a target propofol plasma concentration of 4 μg/ml. All patients received flurbiprofen axetil 50 mg and 0.5 μg/kg fentanyl 5 min before anesthesia. Bispectral index was used and maintained between 45 and 60. Main outcome measures were apnea or abnormal ventilation status, rate of oxygen desaturation, occurrence of hypoxia and severe hypoxia, and perioperative side effects.ResultsThe experimental group had significantly higher rate of apnea or abnormal ventilation, significantly lower rate of oxygen desaturation, and significant lower occurrence of hypoxia and severe hypoxia compared to the control group. We found no statistically significant differences between the 2 groups in the rates of increased oxygen supplementation, assisted ventilation, bradycardia, hypotension, dosage of atropine, dosage of ephedrine or phenylephrine, and the amount of propofol consumed.ConclusionsSidestream capnographic monitoring improves early detection of alterations in ventilation parameters and reduces the incidence of oxygen desaturation and hypoxemia resulting from propofol anesthesia during surgical abortion.

An Open-Label Phase 2 Study Of Ofatumumab In Combination With a Novel AKT Inhibitor (Afuresertib) In Previously Treated Patients With Chronic Lymphocytic Leukemia (CLL)

IntroductionOfatumumab is a novel anti-CD20 monoclonal antibody which led to impressive single-agent responses of 47-58% in a phase 2 study of CLL patients (pts) with refractory disease (Wierda et al 2010). Unfortunately, response durations were short (median 5.6-7.1 mos). In order to improve upon these results, we combined ofatumumab with a novel pan-AKT kinase inhibitor, afuresertib (GSK2110183). The AKT pathway plays a centralized role in tumor differentiation, migration, proliferation and survival and is frequently aberrantly activated in CLL (Longo et al 2007). Single agent afuresertib is very well-tolerated with minimal myelotoxicity in relapsed/refractory hematologic malignancies (Spencer et al ASH 2011). We present an interim analysis of the initial 19 of 31 planned pts in an ongoing trial of ofatumumab and afuresertib in relapsed/refractory CLL. MethodsPreviously treated CLL pts who have received at least one prior fludarabine-containing regimen with disease progression are eligible. During the initial 6 month Treatment Phase, ofatumumab 2000mg IV is administered weekly for 8 doses, then once every 4 week cycle for 4 doses (dose/schedule identical to the pivotal phase 2 trial) with afuresertib 125mg orally daily. An initial 10 day Lead-in Phase with afuresertib alone allows for evaluation of pharmacodynamic (PD) changes in phosphoproteins and pharmacokinetic (PK) studies. Pts are assessed for safety and response on day 1 of each cycle. Pts achieving SD, PR or CR by the end of the Treatment Phase proceed to the Maintenance Phase with single-agent afuresertib for a maximum of 12 mos (12 cycles). ResultsDemographics: To date, 19 pts have been enrolled. Median age is 65 yrs (range 43-76), baseline median Hb 108g/L (range 80-145), absolute lymphocytes 29.7 x109/L (range 1.0-464.9), β2M 4.42mg/L (range 1.42-3.21), bulky nodes ≥5cm in 5 pts (32%), organomegaly in 8 pts (42%), del17p/del11q on FISH in 9 pts (47%), and ZAP70+ in 13 pts (68%). Eight pts (42%) were fludarabine-refractory; only 2 pts had received prior alemtuzumab. The median number of prior therapies was 2 (range 1-6).Toxicity: Hematologic: 4 pts (21%) developed Gr 3-4 neutropenia during at least 1 cycle; 1 pt (5%) had a febrile neutropenia event. Only 2 pts (10.5%) have developed Gr 3-4 thrombocytopenia, without bleeding. Nonhematologic toxicity: Most common related grade 3-4 toxicities were GI: dyspepsia (53%), diarrhea (37%), nausea (21%), temporally related to oral afuresertib and easily managed symptomatically. Infusion reactions to ofatumumab were frequent (12 pts; 63%) with grade 3 reactions in 3 pts. Five pts (26%) developed non-infectious pneumonitis, with 3 pts requiring hospitalization. Two pts with preexisting atrial arrhythmias sustained exacerbation with weekly ofatumumab infusions. Most infections were mild, with only 1 grade 3 cellulitis.Efficacy: Of the 19 response-evaluable pts receiving a median of 6 cycles (range 1-9), 8 pts (42%) have achieved a PR, 11 SD (58%), and no CR. Response onset was rapid at a median 0.9 mos (range 0.8-2.8). At a median follow-up of 6.8 mos (range 0.3-12.9 mos), 5 pts (26%) have progressed and one patient has died after cycle 1 on therapy due to progressive CLL.PD Studies: CD19+ cells are assayed for phosphorylated AKT and its downstream targets RAS40 and GSK3 in addition to phospho-proteins of alternative pathways including ERK and pS6 by multiplexed phospho-flow cytometry. Peripheral blood samples are collected at screening and on cycle 1 day 10, after dosing with afuresertib. Of the 7 patients evaluated thus far, 5 demonstrated constitutive AKT phosphorylation at baseline. Partial inhibition of AKT signaling evidenced by increased phosphorylation of AKT and inhibition of GSK3 and/or RAS40 phosphorylation in response to BCR stimulation was observed post-treatment, indicating target engagement by afuresertib. PK Studies: Afuresertib exposure (Cmax and AUC) was similar when afuresertib was administered alone or in combination with ofatumumab. ConclusionPreliminary results from this phase 2 study suggests that a combination of ofatumumab plus a novel oral AKT inhibitor, afuresertib, has activity in previously treated CLL and is generally well-tolerated with minimal myelotoxicity. Response data are encouraging but whether durable responses can be achieved requires more mature follow-up. Disclosures:Chen:Johnson & Johnson: Consultancy, Research Funding; Lundbeck: Consultancy; Celgene: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Roche: Honoraria. Off Label Use: Off-label use of ofatumumab and afuresertib for the treatment of relapsed/refractory CLL. Smith:GSK: Employment, Equity Ownership. Johnston:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Lundbeck: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees, Research Funding.

No benefit from perioperative intravenous lidocaine in laparoscopic renal surgery

There is evidence that perioperative intravenous lidocaine administration can reduce analgesic requirement, improve recovery of bowel function and shorten the length of hospital stay. Its effect in laparoscopic renal surgery has not been investigated. To evaluate the effect of systemic lidocaine on the length of hospital stay, readiness for discharge, opioid requirement, bowel function and inflammatory and stress response after laparoscopic renal surgery. Randomised, double-blind, placebo-controlled study. Single tertiary centre where the study was carried out between July 2009 and February 2011. Sixty-four patients completed the study. Inclusion criteria were laparoscopic renal surgery and American Society of Anesthesiologists physical status I to III. Exclusion criteria were steroid therapy, chronic opioid therapy, allergy to lidocaine, pre-existing bowel dysfunction and arrhythmia. Lidocaine was given as a 1.5 mg kg(-1) bolus during induction of anaesthesia, followed by an intraoperative infusion of 2 and 1.3 mg kg(-1) h(-1) for 24 h postoperatively. Primary outcome was the length of hospital stay. Secondary outcomes were readiness for discharge, opioid consumption, sedation, incidence of postoperative nausea and vomiting (PONV), return of bowel function and inflammatory and stress responses. Length of hospital stay. The length of hospital stay did not differ between the groups [6 days for the lidocaine group, interquartile range (IQR) 5 to 7, range 2 to 8 vs. 5 days for the placebo group, IQR 5 to 6, range 2 to 11; P = 0.24). Lidocaine had no effect on readiness for discharge [4 days for the lidocaine group (IQR 5 to 7, range 2 to 8) vs. 4 days for the placebo group (IQR 5 to 7, range 2 to 11); P = 0.26], opioid consumption, postoperative sedation, PONV, return of bowel function and plasma concentrations of C-reactive protein, procalcitonin and cortisol. Systemic perioperative lidocaine administration over 24 h did not influence the length of the hospital stay, readiness for discharge, opioid consumption, return of bowel function or inflammatory and stress responses after laparoscopic renal surgery. ClinicalTrials.gov identifier NCT00789620.

Pro-arrhythmic and pro-ischaemic effects of inhaled anticholinergic medications

The majority of deaths in COPD are from cardiovascular causes. Several large randomized controlled trials demonstrate that inhaled anticholinergic agents ipratropium and tiotropium increase the risk of serious cardiovascular events,...

Long-Term (5- to 20-Year) Outcomes After Transcatheter or Surgical Treatment of Hemodynamically Significant Isolated Secundum Atrial Septal Defect

Truly long-term follow-up data after transcatheter closure (TC) of atrial septal defects (ASDs) are scarce. We report the 5- to 20-year outcomes of TC and surgical closure (SC) for typical secundum ASD. We reviewed the records of patients with isolated secundum ASD and right ventricular volume overload who underwent TC or SC (January 1, 1986 to September 30, 2005). Follow-up was obtained through a combination of chart review, physician records, and telephone survey. We identified 375 patients (207 SC and 168 TC) and obtained follow-up data >5 years (median follow-up 10 years) for 300 (152 SC, 148 TC). Nine patients have died (3%). The New York Heart Association functional class was unchanged in 227 patients, improved in 25, and was worse in 15. Clinically significant arrhythmia was found in 28 patients (9.3%); 21% aged >40 years developed arrhythmia. On multivariate analysis, the odds of significant arrhythmia tended to be greater in the SC group, but this was statistically insignificant (95% confidence interval 0.68 to 3.9, p = 0.27). Age and preprocedure arrhythmia, but not TC or SC, were independent risk factors for late arrhythmia (p <0.001). No difference was found in the incidence of late, probably embolic, stroke in the TC (3%) versus SC (2%) groups. In conclusion, long-term outcomes after secundum ASD closure using modern methods are excellent. No significant differences were found between TC versus SC with regard to survival, functional capacity, atrial arrhythmias, or embolic neurologic events. Arrhythmia and neurologic events remain long-term risks after ASD closure, especially if the patient had pre-existing arrhythmia.

Aggravation of Arrhythmia by Antiarrhythmic Drugs (Proarrhythmia).

Arrhythmia aggravation by antiarrhythmic drugs (proarrhythmia) can be caused by worsening or a change of a preexisting arrhythmia, development of a new arrhythmia, or development of a bradyarrhythmia. Aggravation of arrhythmia usually occurs within several days of beginning an antiarrhythmic drug or increasing the dose of the drug. The time of occurrence is based on the particular drug and its pharmacokinetic properties. Although there are no ways to predict the patient at risk for developing arrhythmia aggravation with any specific agents, risk factors include QT interval prolongation, elevated serum levels of the drug, electrolyte abnormalities, presence of heart failure, a history of a sustained ventricular tachyarrhythmia, and underlying myocardial ischemia.