Best ablation strategy in patients with premature ventricular contractions with multiple morphology: a single-centre experience.

AIMS: This study aimed to examine the clinical benefits of targeted ablation of all Premature ventricular complex (PVC) morphologies vs. predominant PVC only. METHODS AND RESULTS: A total of 171 consecutive patients with reduced left ventricular ejection fraction (LVEF) and ≥2 PVC morphology with high burden (>10%/day) undergoing their first ablation procedure were included in the analysis. At the initial procedure, prevalent PVC alone was ablated in the majority. However, at the redo, all PVC morphologies were targeted for ablation. : At the first procedure, 152 (89%) patients received ablation of the dominant PVC only. In the remaining 19 (11%) patients, all PVC morphologies were ablated. At two years, high PVC burden was detected in 89 (52%) patients. Repeat procedure was performed in 78 of 89, where all PVC morphologies were ablated. At 5 years after the repeat procedure, 71 (91%) had PVC burden of <5% [3.8 ± 1.1% vs. 15.4 ± 4.3% in successful vs. failed subjects (P < 0.001)]. In patients with low PVC burden after the initial procedure, LVEF improved from 37.5% to 41.6% [mean difference (MD): 3.39 ± 2.9%, P < 0.001], whereas a reduction in LVEF from 39.8% to 34.5% (MD: 6.45 ± 4.7%, P < 0.001) was recorded in patients with high PVC burden. One year after the repeat procedure, LVEF improved from 36.2% to 41.7% (MD: 5.5 ± 4.3%, P < 0.001) in patients with successful ablation. CONCLUSION: In this observational series, ablation of all PVC morphologies was associated with significantly lower PVC burden and improvement of LVEF at long-term follow-up, compared with ablation of the dominant morphology only.

Cavotricuspid isthmus line in patients undergoing catheter ablation of atrial fibrillation with or without history of typical atrial flutter: A meta-analysis.

BACKGROUND: Pulmonary vein isolation (PVI) is the mainstay of catheter ablation (CA) for paroxysmal atrial fibrillation (AF). However, for persistent and long-standing persistent AF, there are no established strategies to improve the success rate of CA. Despite studies indicating that prophylactic cavotricuspid isthmus (CTI) ablation provides no or limited incremental benefit in patients with AF, it is still routinely performed worldwide. OBJECTIVE: We sought to examine whether CTI ablation for AF is associated with improvement in recurrence of all-atrial arrhythmias, compared with PVI alone in patients with and without typical atrial flutter (AFL). METHODS: A systematic review of PubMed, Cochrane, and Embase was performed for clinical studies including AF patients, reporting outcomes of CTI + PVI versus PVI alone. The primary efficacy endpoint was recurrence of all-atrial arrhythmias. RESULTS: Five studies comprising 1400 patients undergoing CTI + PVI versus PVI alone were included; 1110 patients had AF without AFL, and 290 patients had coexistent AF and AFL. After a mean follow-up of 14.4 ± 4.8 months, CTI + PVI was not associated with improvement in recurrence of all-atrial arrhythmias when compared with PVI alone (risk ratio [RR]: 1.29; 95% confidence interval [CI]: 0.93-1.79;p = .13). In the subgroup analysis, there were no differences between both groups in patients with AF without AFL (RR: 1.55; 95% CI: 0.96-2.48; p = .07), and in patients with AF and AFL (RR: 0.91; 95% CI: 0.6-1.39; p = .68). CONCLUSION: In AF patients, irrespective of the presence of typical AFL, additional CTI ablation is not associated with improvement in recurrence of all-atrial arrhythmias, compared with PVI alone.

Long-term outcomes of catheter ablation in patients with longstanding persistent atrial fibrillation lasting less than 2 years.

INTRODUCTION: Outcome data after catheter ablation (CA) for longstanding persistent atrial fibrillation (LSPAF) lasting less than 2 years are limited and highly variable with different ablation approaches. We aimed to assess the long-term outcomes in patients with LSPAF lasting less than 2 years undergoing extended pulmonary vein antrum isolation (PVAI) versus those with additional non-pulmonary vein (PV) trigger ablation. METHODS AND RESULTS: In this prospective analysis, 381 consecutive patients with LSPAF lasting less than 2 years (age: 64 ± 9 years, 76% male, atrial fibrillation duration: 19 ± 5 months) undergoing their first CA were classified into two groups: Group 1 (n = 104) received PVAI extended to PW plus isolation of superior vena cava (SVC) and Group 2 ( n = 277) received PVAI + PW + SVC + non-PV-trigger ablation. All patients were followed-up for at least 2 years. In case of recurrence, repeat procedure was offered and non-PV triggers were targeted for ablation in all. After a single procedure, 26 (25%) patients in Group 1 and 172 (62.1%) in Group 2 remained arrhythmia-free (P < 0.001). A second procedure was performed in 58 of 78 (74.4%) patients in Group 1 and 77 of 105 (73.3%) patients in Group 2. Non-PV triggers were identified in 52 (89.6%) and 54 (70.1%) patients in Groups 1 and 2, respectively, and targeted for ablation. Overall, 72 (69.2%) patients in Group 1 and 238 (86%) in Group 2 remained arrhythmia-free ( P < 0.001). CONCLUSION: In patients with LSPAF lasting less than 2 years, extended PVAI plus SVC isolation was less likely to achieve long-term sinus rhythm. In the majority of patients, recurrence was due to non-PV triggers and ablation of those resulted in better outcome.

Impact of weight loss on ablation outcome in obese patients with longstanding persistent atrial fibrillation.

AIMS: This study investigated the impact of weight loss in longstanding persistent (LSPAF) patients undergoing catheter ablation (CA). METHODS: Ninety consecutive obese LSPAF patients were approached; 58 volunteered to try weight loss interventions for up to 1 year (group 1), while 32 patients declined weight loss interventions and were included as a control (group 2). Both groups remained on antiarrhythmic drugs. If they continued to experience AF, CA was performed. Body weight was measured at 6-month intervals and arrhythmia status was assessed by event recorder, electrocardiogram (ECG), and Holter monitoring. Symptom severity and quality of life (QoL) were evaluated by AFSS and SF-36 survey, respectively. A scoring algorithm with two summary measures, physical component score (PCS) and mental component score (MCS), was prepared for QoL analysis. RESULTS: Significant reduction in body weight (median -24.9 (IQR -19.1 to -56.7) kg, P < 0.001) was observed in the group 1 patients, while no such change was seen in group 2. The PCS and MCS scores improved significantly in group 1 only, with a change from baseline of 8.4 ± 3 (P = 0.013) and 12.8 ± 8.2 (P < 0.02). However, AF symptom severity remained unchanged from baseline in both groups (P = 0.84). All 90 patients eventually underwent CA and received PVAI+ posterior wall+ non-PV triggers ablation. At 1-year follow-up after single procedure, 37 (63.8%) in group 1 and 19 (59.3%) patients in group 2 remained arrhythmia-free off AAD (P = 0.68). CONCLUSION: In this prospective analysis, in LSPAF patients weight loss improved QoL but had no impact on symptom severity and long-term ablation outcome.

Catheter ablation of ventricular tachycardia in nonischemic cardiomyopathy: A propensity score-matched analysis of in-hospital outcomes in the United States.

INTRODUCTION: Monomorphic ventricular tachycardia (VT) is an important cause of morbidity and mortality. Use and outcome data of catheter ablation for VT in nonischemic cardiomyopathy (NICM) are limited. METHODS AND RESULTS: We obtained data from the 2003-2014 National Inpatient Sample databases. We used propensity score matching to compare patients undergoing catheter ablation versus medical therapy of VT related to NICM, and described the temporal trends in utilization and in-hospital outcomes of catheter ablation of VT in patients with NICM in the United States. From 2003 to 2014, of 133,529 patients hospitalized with the principal diagnosis of VT in NICM, 14,651 (11.0%) underwent catheter ablation. In this period, there was an increasing trend in utilization of catheter ablation (9.3% in 2003-2004 to 12.1% in 2003-2014, adjusted OR [per year], 1.12; 95% CI, 1.08-1.16; Ptrend  < 0.001). After propensity score matching, in-hospital mortality occurred in 172 of 14,318 (1.2%) patients in the catheter ablation group, compared with 297 of 14,156 (2.1%) of patients undergoing medical therapy (47% lower; 43% relative difference [adjusted OR, 0.53; 95% CI, 0.43-0.66]). CONCLUSIONS: In patients with NICM, catheter ablation of VT is associated with lower in-hospital mortality compared with those managed medically. The utilization rates of CA for VT related to NICM have increased in the past decade. Adequately powered randomized trials will be necessary to confirm these findings.

Long-term outcomes of different ablation strategies for ventricular tachycardia in patients with structural heart disease: systematic review and meta-analysis.

Aims: To compare the long-term outcomes of standard ablation of stable ventricular tachycardia (VT) vs. substrate modification, and of complete vs. incomplete substrate modification in patients with structural heart disease (SHD) presenting with VT. Methods and results: An electronic search was performed using major databases. The main outcomes were a composite of long-term ventricular arrhythmia (VA) recurrence and all-cause mortality of standard ablation of stable VT vs. substrate modification, and long-term VA recurrence in complete vs. incomplete substrate modification. Six studies were included for the comparison of standard ablation of stable VT vs. substrate modification, with a total of 396 patients (mean age 63 ± 10 years, 87% males), and seven studies were included to assess the impact of extensive substrate modification, with a total of 391 patients (mean age 64 ± years, 90% males). More than 70% of all the patients included had ischaemic cardiomyopathy. Substrate modification was associated with decreased composite VA recurrence/all-cause mortality compared to standard ablation of stable VTs [risk ratio (RR) 0.57, 95% confidence interval (CI) 0.40-0.81]. Complete substrate modification was associated with decreased VA recurrence as compared to incomplete substrate modification (RR 0.39, 95% CI 0.27-0.58). Conclusion: In patients with SHD who had VT related mainly to ischaemic substrates, there was a significantly lower risk of the composite primary outcome of long-term VA recurrence and all-cause mortality among those undergoing substrate modification compared to standard ablation. Long-term success is improved when performing complete substrate modification.

MABp1 as a novel antibody treatment for advanced colorectal cancer: a randomised, double-blind, placebo-controlled, phase 3 study.

BACKGROUND: MABp1, an antibody that targets interleukin 1α, has been associated with antitumour activity and relief of debilitating symptoms in patients with advanced colorectal cancer. We sought to establish the effect of MABp1 with a new primary endpoint in patients with advanced colorectal cancer. METHODS: Eligible patients for the double-blind phase of this ongoing, placebo-controlled, randomised, phase 3 trial, had metastatic or unresectable disease, Eastern Cooperative Oncology Group performance status score 1 or 2, systemic inflammation, weight loss, and other disease-related morbidities associated with poor prognosis, and were refractory to oxaliplatin and irinotecan. Patients were randomly assigned 2:1 to receive either MABp1 or placebo. Randomisation codes were obtained from a centrally held list via an interactive web response system. Patients received an intravenous infusion of 7·5 mg/kg MABp1 or placebo given every 2 weeks for 8 weeks. The primary endpoint was assessed in patients who received at least one dose of MABp1 or placebo (modified intention-to-treat population), and was a composite of stable or increased lean body mass and stability or improvement in two of three symptoms (pain, fatigue, or anorexia) at week 8 compared with baseline measurements. This study is registered with ClinicalTrials.gov, number NCT02138422. FINDINGS: Patients were enrolled between May 20, 2014, and Sept 2, 2015. The double-blind phase of the study was completed on Nov 3, 2015. Of 333 patients randomly assigned treatment, 207 received at least one dose of MABp1 and 102 at least one dose of placebo. 68 (33%) and 19 (19%) patients, respectively, achieved the primary endpoint (relative risk 1·76, 95% CI 1·12-2·77, p=0·0045). The most common grade 3-4 adverse events in the MABp1 group compared with in the placebo group were anaemia (eight [4%] of 207 vs five [5%] of 102 patients), increased concentration of alkaline phosphatase (nine [4%] vs two [2%]), fatigue (six [3%] vs seven [7%]), and increased concentration of aspartate aminotransferase (six [3%] vs two [2%]). After 8 weeks, 17 (8%) patients in the MABp1 group and 11 (11%) in the placebo group had died, but no death was judged to be related to treatment. The incidence of serious adverse events was not significantly different in the MABp1 group and placebo groups (47 [23%] vs 33 [32%], p=0·07). INTERPRETATION: The primary endpoint was a useful means of measuring clinical performance in patients. MABp1 might represent a new standard in the management of advanced colorectal cancer. FUNDING: XBiotech.

Ablation Versus Amiodarone for Treatment of Persistent Atrial Fibrillation in Patients With Congestive Heart Failure and an Implanted Device: Results From the AATAC Multicenter Randomized Trial.

BACKGROUND: Whether catheter ablation (CA) is superior to amiodarone (AMIO) for the treatment of persistent atrial fibrillation (AF) in patients with heart failure is unknown. METHODS AND RESULTS: This was an open-label, randomized, parallel-group, multicenter study. Patients with persistent AF, dual-chamber implantable cardioverter defibrillator or cardiac resynchronization therapy defibrillator, New York Heart Association II to III, and left ventricular ejection fraction <40% within the past 6 months were randomly assigned (1:1 ratio) to undergo CA for AF (group 1, n=102) or receive AMIO (group 2, n=101). Recurrence of AF was the primary end point. All-cause mortality and unplanned hospitalization were the secondary end points. Patients were followed up for a minimum of 24 months. At the end of follow-up, 71 (70%; 95% confidence interval, 60%-78%) patients in group 1 were recurrence free after an average of 1.4±0.6 procedures in comparison with 34 (34%; 95% confidence interval, 25%-44%) in group 2 (log-rank P<0.001). The success rate of CA in the different centers after a single procedure ranged from 29% to 61%. After adjusting for covariates in the multivariable model, AMIO therapy was found to be significantly more likely to fail (hazard ratio, 2.5; 95% confidence interval, 1.5-4.3; P<0.001) than CA. Over the 2-year follow-up, the unplanned hospitalization rate was (32 [31%] in group 1 and 58 [57%] in group 2; P<0.001), showing 45% relative risk reduction (relative risk, 0.55; 95% confidence interval, 0.39-0.76). A significantly lower mortality was observed in CA (8 [8%] versus AMIO (18 [18%]; P=0.037). CONCLUSIONS: This multicenter randomized study shows that CA of AF is superior to AMIO in achieving freedom from AF at long-term follow-up and reducing unplanned hospitalization and mortality in patients with heart failure and persistent AF. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00729911.

Long-term follow-up of patients with paroxysmal atrial fibrillation and severe left atrial scarring: comparison between pulmonary vein antrum isolation only or pulmonary vein isolation combined with either scar homogenization or trigger ablation.

AIMS: Left atrial (LA) scarring, a consequence of cardiac fibrosis is a powerful predictor of procedure-outcome in atrial fibrillation (AF) patients undergoing catheter ablation. We sought to compare the long-term outcome in patients with paroxysmal AF (PAF) and severe LA scarring identified by 3D mapping, undergoing pulmonary vein isolation (PVAI) only or PVAI and the entire scar areas (scar homogenization) or PVAI+ ablation of the non-PV triggers. METHODS AND RESULTS: Totally, 177 consecutive patients with PAF and severe LA scarring were included. Patients underwent PVAI only (n = 45, Group 1), PVAI+ scar homogenization (n = 66, Group 2) or PVAI+ ablation of non-PV triggers (n = 66, Group 3) based on operator's choice. Baseline characteristics were similar across the groups. After first procedure, all patients were followed-up for a minimum of 2 years. The success rate at the end of the follow-up was 18% (8 pts), 21% (14 pts), and 61% (40 pts) in Groups 1, 2, and 3, respectively. Cumulative probability of AF-free survival was significantly higher in Group 3 (overall log-rank P <0.01, pairwise comparison 1 vs. 3 and 2 vs. 3 P < 0.01). During repeat procedures, non-PV triggers were ablated in all. After average 1.5 procedures, the success rates were 28 (62%), 41 (62%), and 56 (85%) in Groups 1, 2, and 3, respectively (log-rank P< 0.001). CONCLUSIONS: In patients with PAF and severe LA scarring, PVAI+ ablation of non-PV triggers is associated with significantly better long-term outcome than PVAI alone or PVAI+ scar homogenization.

Differential Association of Exercise Intensity With Risk of Atrial Fibrillation in Men and Women: Evidence from a Meta-Analysis.

BACKGROUND: Despite widespread interest and extensive research, the association between different levels of physical activity (PA) and risk of atrial fibrillation (AF) is still not clearly defined. Therefore, we systematically evaluated and summarized the evidences regarding association of different intensity of PA with the risk of AF in this meta-analysis. METHODS AND RESULTS: An extensive literature search was performed on databases for studies showing association of exercise with AF risk. Twenty-two studies were identified that included 656,750 subjects. Meta-analytic estimates were derived using random-effects models and pooled odds ratio estimates were obtained. Potential sources of heterogeneity were examined in sensitivity analyses, and publication biases were estimated. Pooled analysis of 7 studies with 93,995 participants reported high risk of incident AF with sedentary lifestyle (pooled OR 2.47 [95% CI 1.25-3.7], P = 0.005). In 3 trials, 149,048 women involved in moderate PA were 8.6% less likely to develop AF compared to women with sedentary life (OR 0.91 [95% CI 0.78-0.97], P = 0.002). Women performing intense exercise were found to have 28% lower risk of AF (OR 0.72 [95% CI 0.57-0.88], P < 0.001). The overall pooled estimate indicated a protective impact of moderate PA in men (pooled OR 0.8133 [95% CI 0.26-1.004], P = 0.06) whereas vigorous PA was associated with a significantly increased AF risk (pooled OR 3.30 [1.97-4.63], P = 0.0002). CONCLUSION: Sedentary lifestyle significantly increases and moderate amount of physical activity reduces the risk of AF in both men and women. However, intense exercise has a gender-specific association with AF risk.

A randomized phase II study of Xilonix, a targeted therapy against interleukin 1α, for the prevention of superficial femoral artery restenosis after percutaneous revascularization.

OBJECTIVE: The purpose of this study was to evaluate an anti-interleukin 1α antibody for its ability to reduce acute postprocedural inflammation, thereby reducing neointimal hyperplasia and restenosis after superficial femoral artery (SFA) angioplasty. Restenosis of the SFA after endovascular intervention is a common problem leading to 1-year primary patency as low as 40%. These failures are primarily due to the development of neointimal hyperplasia, resulting from arterial wall inflammation. METHODS: This was a randomized, phase II trial examining SFA restenosis in patients after percutaneous revascularization. Randomization occurred after successful revascularization, and patients were assigned to either the standard of care arm or the Xilonix (XBiotech USA, Inc, Austin, Tex) plus standard of care arm (N = 43). Xilonix was administered immediately after revascularization, every 2 weeks intravenously for four doses, and monthly subcutaneously until month 12. The major efficacy end points were target vessel event-free survival and incidence of major adverse cardiovascular events (MACEs). RESULTS: At 12 months of follow-up, MACE (43% vs 36%; P = .76) and target vessel restenosis (24% vs 27%; log-rank, P = .79) rates were not significantly different between the groups. At 3-month follow-up, which covers the intravenous dosing period, a trend toward lower incidence of restenosis (0 of 22 [0%] vs 2 of 21 [10%]; P = .14) and MACE (2 of 22 [9%] vs 5 of 21 [24%]; P = .22) was observed in the Xilonix cohort. Adverse events were equally distributed in both arms. CONCLUSIONS: Xilonix was well tolerated. Observed tendency to improved vessel patency with intravenous dosing suggests Xilonix could potentially represent a safe and effective therapeutic approach to preserving vessel patency.

Periprocedural stroke and bleeding complications in patients undergoing catheter ablation of atrial fibrillation with different anticoagulation management: results from the Role of Coumadin in Preventing Thromboembolism in Atrial Fibrillation (AF) Patients Undergoing Catheter Ablation (COMPARE) randomized trial.

BACKGROUND: Periprocedural thromboembolic and hemorrhagic events are worrisome complications of catheter ablation for atrial fibrillation (AF). The periprocedural anticoagulation management could play a role in the incidence of these complications. Although ablation procedures performed without warfarin discontinuation seem to be associated with lower thromboembolic risk, no randomized study exists. METHODS AND RESULTS: This was a prospective, open-label, randomized, parallel-group, multicenter study assessing the role of continuous warfarin therapy in preventing periprocedural thromboembolic and hemorrhagic events after radiofrequency catheter ablation. Patients with CHADS2 score ≥1 were included. Patients were randomly assigned in a 1:1 ratio to the off-warfarin or on-warfarin arm. The incidence of thromboembolic events in the 48 hours after ablation was the primary end point of the study. The study enrolled 1584 patients: 790 assigned to discontinue warfarin (group 1) and 794 assigned to continuous warfarin (group 2). No statistical difference in baseline characteristics was observed. There were 39 thromboembolic events (3.7% strokes [n=29] and 1.3% transient ischemic attacks [n=10]) in group 1: two events (0.87%) in patients with paroxysmal AF, 4 (2.3%) in patients with persistent AF, and 33 (8.5%) in patients with long-standing persistent AF. Only 2 strokes (0.25%) in patients with long-standing persistent AF were observed in group 2 (P<0.001). Warfarin discontinuation emerged as a strong predictor of periprocedural thromboembolism (odds ratio, 13; 95% confidence interval, 3.1-55.6; P<0.001). CONCLUSION: This is the first randomized study showing that performing catheter ablation of AF without warfarin discontinuation reduces the occurrence of periprocedural stroke and minor bleeding complications compared with bridging with low-molecular-weight heparin. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01006876.

Pulmonary Vein Isolation to Reduce Future Risk of Atrial Fibrillation in Patients Undergoing Typical Flutter Ablation: Results from a Randomized Pilot Study (REDUCE AF).

BACKGROUND: This study examined incidence of AF following cavotricuspid isthmus (CTI) ablation alone or CTI plus prophylactic pulmonary vein isolation (PVI) in patients presenting with isolated atrial flutter (AFL) with no history of AF. METHODS AND RESULTS: We enrolled 216 patients with isolated typical atrial flutter and randomized them to CTI alone (group 1, n = 108, 61.2 ± 9.7 year, 75% male) or CTI+PVI ablation (group 2, n = 108, 62.4 ± 9.3 year, 73% male). Insertible loop recorder (ILR) was implanted in 21 and 19 patients from groups 1 and 2, respectively. Remaining patients were monitored with event recorders, ECG, 7-day Holter. Follow-up period was for 18 ± 6 months. Compared to group 1, group 2 had significantly longer procedural duration (75.9 ± 33 min vs. 161 ± 48 min [P < 0.001]) and fluoroscopy time (15.9 ± 12.3 min vs. 56.4+21 min [P < 0.001]). At the end of follow-up, 65 (60.2%) in group 1 and 77 (71.3%) in group 2 were arrhythmia free off-AAD (log-rank P = 0.044). A subgroup analysis was performed with 55 year age cut-off. In the <55 age group the CTI only population had similar success as in CTI+PVI, (21 of 24 [83.3%] vs. 19 of 22 [86.4%], respectively, log-rank P = 0.74). In the ≥55 group, having CTI+PVI showed significantly higher success compared to CTI only; 45 of 84 (53.6%) were AF/AT free in CTI only group versus 58 of 86 (67.4%) with CTI+PVI (log-rank P = 0.029). CONCLUSION: Prophylactic PVI reduced new-onset AF in patients with lone atrial flutter.

Xilonix, a novel true human antibody targeting the inflammatory cytokine interleukin-1 alpha, in non-small cell lung cancer.

BACKGROUND: Advanced non-small cell lung cancer (NSCLC) patients were treated as part of a Phase I dose escalation and expansion study evaluating a true human monoclonal antibody targeting IL-1α (Xilonix), which is intended to modulate the malignant phenotype-inhibiting tumor growth, spread and offering relief of symptoms. METHODS: Sixteen NSCLC patients were included. Patients failed a median of 4 chemotherapy regimens, including 10/16 failing anti-EGFR therapy. Disease progression was evaluated using a multi-modal approach: tumor response, patient reported outcomes (EORTC-QLQC30), and lean body mass (LBM). Patients received infusions every 2 or 3 weeks until progression, and were followed 24 months to assess survival. RESULTS: There were no infusion reactions, dose-limiting toxicities, or deaths due to therapy. Albeit not statistically significant, there was a trend in IL-6 (-2.6 ± 18.5 (0.1 [-2.8-2.4]), platelet counts (-11 ± 54 (-4[-36.0-1.0]), CRP (-3.3 ± 30.2 (0.4 [-10.7-1.8]) and LBM (1.0 ± 2.5 (0.4 [-0.5-2.6]). Self-reported outcomes revealed reductions in pain, fatigue and improvement in appetite. Median survival was 7.6 (IQR 4.4-11.5) months, stratification based on prior anti-EGFR therapy revealed a median survival of 9.4 months (IQR 7.6-12.5) for those pretreated (N = 10) versus a survival of 4.8 months (IQR 4.3-5.7) for those without (N = 6, logrank p = 0.187). CONCLUSION: Xilonix was well tolerated, with gains in LBM and improvement in symptoms suggesting a clinically important response. Although not statistically significant, the survival outcomes observed for patients with and without prior anti-EGFR therapy raises intriguing questions about the potential synergy of IL-1α blockade and anti-EGFR therapy. Further study for this agent in NSCLC is warranted.

MABp1, a first-in-class true human antibody targeting interleukin-1α in refractory cancers: an open-label, phase 1 dose-escalation and expansion study.

BACKGROUND: Inflammation is an important feature of the malignant phenotype and promotes angiogenesis, tumour invasiveness, metastases, and cachexia. We used a first-in-class, monoclonal antibody (MABp1) cloned from a human being to target interleukin-1α, a mediator of chronic inflammation. We aimed to assess the safety and tolerability of MABp1 for interleukin-1α blockade in a refractory cancer population. METHODS: We did an open-label, dose-escalation, and phase 1 study of MABp1 in adults with metastatic cancer at the MD Anderson Clinical Center for Targeted Therapy (Houston, TX, USA). We used a standard 3+3 design to identify the maximum tolerated dose. Patients received MABp1 intravenously once every 3 weeks through four dose levels: 0.25 mg/kg, 0.75 mg/kg, 1.25 mg/kg, and 3.75 mg/kg. After the dose-escalation phase, a second dosing arm was started with dosing every 2 weeks at the maximum tolerated dose. The primary objectives were safety, tolerability, characterisation of the pharmacokinetic profile, and identification of the recommended phase 2 dose. Secondary endpoints included pharmacodynamic effects and antitumour activity. All patients who received at least one dose of MABp1 were included in the safety analyses. This trial is registered with ClinicalTrials.gov, NCT01021072. FINDINGS: Between March 15, 2010, and July 30, 2012, 52 patients with metastatic cancer (18 tumour types) received anti-interleukin-1α monotherapy in dose-escalation and expansion groups. MABp1 was well tolerated, with no dose-limiting toxicities or immunogenicity. Thus, the recommended phase 2 dose was concluded to be 3.75 mg/kg every 2 weeks. Pharmacokinetic data were consistent at all dose levels and showed no evidence of accumulation or increased clearance of MABp1 at increasing doses. For 42 assessable patients, median plasma interleukin-6 concentrations had decreased from baseline to week 8 by a median of 2.7 pg/mL (IQR -12.6 to 3.0; p=0.08). Of the 34 patients restaged, one patient had a partial response and ten had stable disease. 30 patients were assessable for change in lean body mass, which increased by a mean of 1.02 kg (SD 2.24; p=0.02) between baseline and week 8. The most common adverse events possibly related to the study drug were proteinuria (n=11; 21%), nausea (7; 13%), and fatigue (7; 13%). The most frequent grade 3-4 adverse events (regardless of relation to treatment) were fatigue (3; 6%), dyspnoea (2; 4%), and headache (2; 4%). Two patients (4%) had grade 5 events (death due to disease progression), which were unrelated to treatment. INTERPRETATION: MABp1 was well tolerated, no dose-limiting toxicities were experienced in this study, and disease control was observed. Further study of MABp1 anti-interleukin-1α antibody therapy for advanced stage cancer is warranted.

Results from a single-blind, randomized study comparing the impact of different ablation approaches on long-term procedure outcome in coexistent atrial fibrillation and flutter (APPROVAL).

BACKGROUND: This study examined the impact of different ablation strategies on atrial fibrillation (AF) recurrence and quality of life in coexistent AF and atrial flutter (AFL). METHODS AND RESULTS: Three-hundred sixty enrolled patients with documented AF and AFL were blinded and randomized to group 1, AF±AFL ablation (n=182), or group 2, AFL ablation only (n=178). AF recurrence was evaluated with event recording and 7-day Holter at 3, 6, 9, and 12-month follow-ups. Quality of life was assessed at baseline and at the 12-month follow-up with 4 questionnaires: the Medical Outcome Study Short Form, the Hospital Anxiety and Depression Score, the Beck Depression Inventory, and the State-Trait Anxiety Inventory. Of the 182 patients in group 1, 58 (age, 63±8 years; 78% male; left ventricular ejection fraction, 59±8%) had AF+AFL ablation and 124 (age, 61±11 years; 72% male; left ventricular ejection fraction, 59±7%) had AF ablation only. In group 2 (age, 62±9 years; 76% male; left ventricular ejection fraction, 58±10%), only AFL was ablated by achieving bidirectional isthmus conduction block. Baseline characteristics were not different across groups. At 21±9 months of follow-up, 117 in group 1 (64%) and 34 in group 2 (19%) were arrhythmia free (P<0.001). In group 1, scores on most quality-of-life subscales showed significant improvement at follow-up, whereas group 2 patients derived relatively minor benefit. CONCLUSIONS: In coexistent AF and AFL, lower recurrence rate and better quality of life are associated with AF ablation only or AF+AFL ablation than with lone AFL ablation. Furthermore, quality of life directly correlates with freedom from arrhythmia, as shown in this study for the first time in patients blinded to the procedure. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrial.gov/. Unique identifier: NCT01439386.

Outcomes of atrioesophageal fistula following catheter ablation of atrial fibrillation treated with surgical repair versus esophageal stenting.

INTRODUCTION: Atrioesophageal fistula (AEF) is a rare but devastating complication of radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF). Surgical repair and esophageal stents are available treatment options for AEF. We report outcomes of these 2 management strategies. METHODS: Nine patients with AEF post-RFCA for AF were included in this study. AEF was diagnosed based on symptoms and chest CT imaging. Of the 9 patients, 5 received stents and 4 underwent surgical repair of fistula. RESULTS: AF ablation was performed under general anesthesia (n = 4) or conscious sedation (n = 5). During ablation, RF power was maintained between 25 and 35 Watts in areas close to the esophagus and energy delivery discontinued when esophageal temperature reached 38 °C. Seven patients underwent ablation with 3.5-mm open-irrigated catheter, 1 with 8-mm nonirrigated catheter, and 1 had surgical epicardial ablation. Seven patients received proton pump inhibitor and sucralfate before and after procedure. AEF symptoms developed within 2­6 weeks from ablation. Esophageal stenting was performed in 5 patients (median age 58 years, median time from RFCA 4 weeks) and 4 underwent surgical repair (median age 54 years, median time from RFCA 4 weeks) within 2­4 hours from diagnosis. All 5 patients receiving stents died within 1 week of the procedure due to cerebral embolism, septic shock, or respiratory failure. On the other hand, the 4 patients that received surgical repair were alive at median follow-up of 2.1 years (P = 0.005). CONCLUSIONS: Esophageal stenting should be discouraged and prompt surgical repair is crucial for survival in patients with atrioesophageal fistula.

Catheter ablation of asymptomatic longstanding persistent atrial fibrillation: impact on quality of life, exercise performance, arrhythmia perception, and arrhythmia-free survival.

BACKGROUND: Impact of catheter ablation on exercise performance, quality of life (QoL) and symptom perception in asymptomatic longstanding persistent AF (LSP-AF) patients has not been reported yet. METHODS AND RESULTS: Sixty-one consecutive patients (mean age 62 ±13 years, 71% males) with asymptomatic LSP-AF undergoing first catheter ablation were enrolled. Extended pulmonary vein antrum isolation plus ablation of complex fractionated atrial electrograms and nonpulmonary vein triggers was performed in all. QoL survey was taken at baseline and 12-months postablation, using Short Form-36 (SF-36). Information on arrhythmia perception was obtained using a standard questionnaire and corroborating symptoms with documented evidence of arrhythmia. Exercise tests were performed on 38 patients at baseline and 5 months after procedure. Recurrence was assessed using event recorder, cardiology evaluation, electrocardiogram, and 7-day holter monitoring. After 20 ± 5 months follow-up, 36 (57%) patients remained recurrence-free off-AAD. Of the 25 patients experiencing recurrence, 21 (84%) were symptomatic. Compared to baseline, follow-up SF-36 scores improved significantly in many measures. For patients with successful ablation, physical component summary (PCS) and mental component summary (MCS) demonstrated substantial improvement ( MCS: 64.2 ± 22.3 to 70.1 ± 18.6 [P = 0.041]; PCS: 62.6 ± 18.4 to 70.0 ± 14.4 [P = 0.032]). Postablation exercise study in recurrence-free patients showed significant reduction in resting and peak heart rate (75 ± 11 vs. 90 ± 17 and 132 ± 20 vs. 154.5 ± 36, respectively, P < 0.001), increase in peak oxygen pulse (13.4 ± 3 vs. 18.9 ± 16 mL/beat, Δ5.5 ± 15, P = 0.001), peak VO2 /kg (19.7 ± 5 to 23.4 ± 13 mL/kg/min [Δ 3.7 ± 10, P = 0.043]), and corresponding MET (5.6 ± 1 to 6.7 ± 4 [Δ1.1 ± 3, P = 0.03]). No improvement was observed in patients with failed procedures. CONCLUSION: Successful ablation improves exercise performance and QoL in asymptomatic LSP-AF patients.

Long-term outcome of catheter ablation in atrial fibrillation patients with coexistent metabolic syndrome and obstructive sleep apnea: impact of repeat procedures versus lifestyle changes.

INTRODUCTION: Metabolic syndrome (MS) and obstructive sleep apnea (OSA) are well-known independent risk factors for atrial fibrillation (AF) recurrence. This study evaluated ablation outcome in AF patients with coexistent MS and OSA and influence of lifestyle modifications (LSM) on arrhythmia recurrence. METHODS AND RESULTS: We included 1,257 AF patients undergoing first catheter ablation (30% paroxysmal AF). Patients having MS + OSA were classified into Group 1 (n = 126; 64 ± 8 years; 76% male). Group 2 (n = 1,131; 62 ± 11 years; 72% male) included those with either MS (n = 431) or OSA (n = 112; no CPAP users) or neither of these comorbidities (n = 588). Patients experiencing recurrence after first procedure were divided into 2 subgroups; those having sporadic events (frequency < 2 months) remained on previously ineffective antiarrhythmic drugs (AAD) and aggressive LSM, while those with persistent arrhythmia (incessant or ≥2 months) underwent repeat ablation. After 34 ± 8 months of first procedure, 66 (52%) in Group 1 and 386 (34%) in Group 2 had recurrence (P < 0.001). Recurrence rate in only-MS, only-OSA, and without MS/OSA groups were 40%, 38%, and 29%, respectively. Patients with MS + OSA experienced substantially higher recurrence compared to those with lone MS or OSA (52% vs. 40% vs. 38%; P = 0.036). Of the 452 patients having recurrence, 250 underwent redo-ablation and 194 remained on AAD and LSM. At 20 ± 6 months, 76% of the redo group remained arrhythmia-free off AAD whereas 74% of the LSM group were free from recurrence (P = 0.71), 33% of which were off AAD. CONCLUSIONS: MS and OSA have additive negative effect on arrhythmia recurrence following single procedure. Repeat ablation or compliant LSM increase freedom from recurrent AF.