Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocol

Background: Abiraterone acetate plus prednisolone (herein referred to as abiraterone) or enzalutamide added at the start of androgen deprivation therapy improves outcomes for patients with metastatic prostate cancer. Here, we aimed to evaluate long-term outcomes and test whether combining enzalutamide with abiraterone and androgen deprivation therapy improves survival. Methods: We analysed two open-label, randomised, controlled, phase 3 trials of the STAMPEDE platform protocol, with no overlapping controls, conducted at 117 sites in the UK and Switzerland. Eligible patients (no age restriction) had metastatic, histologically-confirmed prostate adenocarcinoma; a WHO performance status of 0–2; and adequate haematological, renal, and liver function. Patients were randomly assigned (1:1) using a computerised algorithm and a minimisation technique to either standard of care (androgen deprivation therapy; docetaxel 75 mg/m2 intravenously for six cycles with prednisolone 10 mg orally once per day allowed from Dec 17, 2015) or standard of care plus abiraterone acetate 1000 mg and prednisolone 5 mg (in the abiraterone trial) orally or abiraterone acetate and prednisolone plus enzalutamide 160 mg orally once a day (in the abiraterone and enzalutamide trial). Patients were stratified by centre, age, WHO performance status, type of androgen deprivation therapy, use of aspirin or non-steroidal anti-inflammatory drugs, pelvic nodal status, planned radiotherapy, and planned docetaxel use. The primary outcome was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who started treatment. A fixed-effects meta-analysis of individual patient data was used to compare differences in survival between the two trials. STAMPEDE is registered with ClinicalTrials.gov (NCT00268476) and ISRCTN (ISRCTN78818544). Findings: Between Nov 15, 2011, and Jan 17, 2014, 1003 patients were randomly assigned to standard of care (n=502) or standard of care plus abiraterone (n=501) in the abiraterone trial. Between July 29, 2014, and March 31, 2016, 916 patients were randomly assigned to standard of care (n=454) or standard of care plus abiraterone and enzalutamide (n=462) in the abiraterone and enzalutamide trial. Median follow-up was 96 months (IQR 86–107) in the abiraterone trial and 72 months (61–74) in the abiraterone and enzalutamide trial. In the abiraterone trial, median overall survival was 76·6 months (95% CI 67·8–86·9) in the abiraterone group versus 45·7 months (41·6–52·0) in the standard of care group (hazard ratio [HR] 0·62 [95% CI 0·53–0·73]; p<0·0001). In the abiraterone and enzalutamide trial, median overall survival was 73·1 months (61·9–81·3) in the abiraterone and enzalutamide group versus 51·8 months (45·3–59·0) in the standard of care group (HR 0·65 [0·55–0·77]; p<0·0001). We found no difference in the treatment effect between these two trials (interaction HR 1·05 [0·83–1·32]; pinteraction=0·71) or between-trial heterogeneity (I2 p=0·70). In the first 5 years of treatment, grade 3–5 toxic effects were higher when abiraterone was added to standard of care (271 [54%] of 498 vs 192 [38%] of 502 with standard of care) and the highest toxic effects were seen when abiraterone and enzalutamide were added to standard of care (302 [68%] of 445 vs 204 [45%] of 454 with standard of care). Cardiac causes were the most common cause of death due to adverse events (five [1%] with standard of care plus abiraterone and enzalutamide [two attributed to treatment] and one (<1%) with standard of care in the abiraterone trial). Interpretation: Enzalutamide and abiraterone should not be combined for patients with prostate cancer starting long-term androgen deprivation therapy. Clinically important improvements in survival from addition of abiraterone to androgen deprivation therapy are maintained for longer than 7 years. Funding: Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas

Defibrillation, the coronary venous system and the passive electrode affect

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Defibrillation Threshold Testing for Right-sided Device Implants: A Review to Inform Shared Decision-making, in Association with the British Heart Rhythm Society

Prevention of sudden death using ICDs requires the reliable delivery of a high-energy shock to successfully terminate VF. Until more recently, the device implant procedure included conducting defibrillation threshold (DFT) testing involving VF induction and shock delivery to ensure efficacy. Large clinical trials, including SIMPLE and NORDIC ICD, have subsequently demonstrated that this is unnecessary, with a practice of omitting DFT testing having no impact on subsequent clinical outcomes. However, these studies specifically excluded patients requiring devices implanted on the right side, in whom the shock vector is significantly different and smaller studies suggest a higher DFT. In this review, the data regarding the use of DFT testing, focusing on right-sided implants, and the results of a survey of current UK practice are presented. In addition, a strategy of shared decision-making when it comes to deciding on the use of DFT testing during right-sided ICD implant procedures is proposed

Determination of human ventricular repolarization by noncontact mapping: validation with monophasic action potential recordings

Background: Noncontact mapping (NCM) has not been validated as a clinical technique to measure ventricular repolarization. We used NCM to determine repolarization characteristics by analysis of reconstructed unipolar electrograms (UEs) at the same sites as monophasic action potential (MAP) recordings in the human ventricle.Methods and Results: MAPs were recorded from a total of 355 beats at 46 sites in the left or right ventricle of 9 patients undergoing ablation of ventricular tachycardia guided by NCM (EnSite system). Measurements were made during sinus rhythm, constant right ventricular pacing, and ventricular extrastimuli during restitution-curve construction. The EnGuide locator signal was used to document MAP catheter locations on the endocardial geometry. UE-determined activation-recovery interval (ARI) measured at the maximum derivative of the T wave (Wyatt method) and the minimum derivative of the positive T wave (alternative method) was correlated with MAP measured at 90% repolarization (MAP90%) at the same sites. ARI correlated with MAP90% during steady state by the Wyatt method (r=0.83, P<0.001) and the alternative method (r=0.94, P<0.001). Restitution curves constructed from MAP and UE data exhibited the same characteristics, with a mean correlation coefficient of 0.95 (range, 0.90 to 0.99, P<0.001). The error between ARI and MAP90% was greater over a shorter diastolic coupling interval but was not influenced by distance of the sampling site from the multielectrode array.Conclusions: NCM accurately determines steady-state and dynamic endocardial repolarization in humans. Global, high-density, NCM data could be used to characterize abnormalities of human ventricular repolarization

Establishing safe, effective ablation in the diseased human ventricle: an analysis of generator impedance and electrogram attenuation

Funding acknowledgements: type of funding sources: Private company. Main funding source(s): Biosense Webster IncBackground: predictors of effective and safe lesion delivery in the human left ventricle have not been established. Generator impedance (GI) drop and electrogram (EGM) attenuation are indices which can be used as surrogates for ablation lesion parameters. Tissue pops are a complication of myocardial overheating preceded by a rise in GI and can have adverse consequences.Purpose: to establish the relationships between Ablation Index (AI), Force Time Integral (FTI) and contact force with GI and EGM attenuation. To establish factors early in ablation that are predictive of a GI rise.Methods: patients undergoing ventricular tachycardia ablation were recruited. All ablations were performed with contact force sensing surround flow catheters. Electrograms were collected pre and post ablation, with GI, AI, FTI measured during. Ablations were divided into low (LVM, &lt; 0.50mV), intermediate (IVM, 0.51 – 1.50mV) and normal voltage (NVM, &gt; 1.50mV) based upon pre-ablation bipolar EGM amplitude. Ablations with a 5% rise in GI from maximal drop were noted and predictors of this explored.Results: in 15 patients, 402 ablations were analysed. Filtered percentage GI drop correlated with AI and FTI, (p &lt; 0.0005, Spearman’s ρ = 0.522 and 0.524) and reached a plateau at 763AI and 713gs, a filtered GI drop of 7.5% (Figure 1). Shallower curves occurred progressively from NVM to IVM to LVM, (p &lt; 0.0005), (Figure 2)The bipolar EGM significantly attenuated with ablation, (median attenuation 0.14mV, [29.3%], p Parameters associated with a GI rise during ablation were greater mean CF to maximum GI drop, (p = 0.002), greater initial percentage GI drop at 5 seconds, (p &lt; 0.0005), power of 50W (p = 0.005), and perpendicular orientation, (p = 0.006). Percentage GI drop at 5 seconds was the best predictor of ablations with a GI rise, (AUCROC 0.773; 95% CI 0.708 – 0.838; optimal cut-off 2.44%). Mean contact force to maximum GI drop was a poor predictor of a GI rise (AUCROC 0.647; 95% CI 0.577 – 0.718, optimal cut-off 14.7g).Conclusion: during left ventricular ablation, AI of 763 and FTI of 713gs should be targeted, with a lower impedance drop observed for more scarred myocardium. A GI drop of <br/

Radiofrequency ablation of the diseased human left ventricle

Background: predictors of effective ablation lesion delivery in the human left ventricle are not established, particularly in scar. Impedance drop and electrogram (EGM) attenuation are potential surrogates to assess this.Objectives: this study sought to establish the relationships between ablation index (AI) and force-time integral (FTI) with impedance drop and EGM attenuation in the human left ventricle.Methods: patients undergoing ventricular tachycardia ablation were recruited. EGMs were collected preablation and postablation, with impedance, AI, and FTI measured during. Based on preablation bipolar voltage, myocardium was adjudged a low-voltage myocardium (LVM) (1.50 mV). Relationships between these parameters were explored.Results: a total of 402 ablations were analyzed in 15 patients. The percent impedance drop correlated with AI and FTI (P &lt; 0.0005; repeated-measures correlation coefficient: 0.54 and 0.44, respectively), a relationship that became weaker with increased myocardial fibrosis, (repeated-measures correlation coefficient for NVM, IVM, and LVM, AI: 0.67, 0.60, and 0.52, respectively; FTI: 0.59, 0.51, and 0.42, respectively). The curve between AI/FTI and impedance drop plateaued at 763 AI and 713 gram-seconds, an impedance drop of 7.5%. Shallower curves occurred progressively from NVM to LVM (P &lt; 0.0005). Mixed models demonstrated that AI and FTI had a greater effect on impedance drop than myocardial fibrosis, drift, or orientation, (standardized β: 0.54 and 0.48, respectively). EGMs were attenuated with ablation (29.3%; IQR: 4.4%-53.3%; P &lt; 0.0005), but attenuation did not correlate with AI or FTI.Conclusions: on biophysical analysis, ablation beyond an AI of 763 and FTI of 713 gs offers minimal additional efficacy on average. Fibrosis blunts ablation efficacy. AI is a stronger correlate with impedance drop than FTI. EGM attenuation does not correlate with ablation parameters. (Late Potentials and Ablation Index in Ventricular Tachycardia Ablation; NCT03437408

Passive electrode effect reduces defibrillation threshold in bi-filament middle cardiac vein defibrillation

AIMS: To investigate whether a passive electrode effect decreases defibrillation threshold (DFT) in multi-filament middle cardiac vein (MCV) defibrillation. METHODS AND RESULTS: Twelve pigs underwent active housing (AH) insertion, with defibrillation coils placed transvenously in right ventricular apex and superior vena cava. The MCV was cannulated, and 1.12F, 50 mm coil electrodes (Ela Medical SA, France) were deployed in its right and left branches. Lead placement was possible in 11 of 12 animals. DFT (J, mean +/- SD) was determined by three-reversal binary search and compared between the MCV monofilament (single filament deployed) and the AH (25.9 +/- 10.9) and the MCV mono + passive filaments (both filaments deployed, one connected) and the AH (19.9 +/- 11.4); 24% DFT reduction P = 0.008. CONCLUSION: A bystander electrode adjacent to a monofilament electrode in the MCV reduces DFT by 24% when compared with monofilament MCV alone. Microfilament electrodes decrease DFT as auxiliary anode but not as sole anode

Comparison of voltages between atria: differences in sinus rhythm and atrial fibrillation

Background: ultra high-density mapping systems allow for comparison of atrial electroanatomical maps in unprecedented detail. Atrial scar determined by voltages and surface area between atria, rhythm and atrial fibrillation (AF) types was assessed.Methods: left (LA) and right atrial (RA) maps were created using Rhythmia HDx in patients listed for ablation for paroxysmal (PAF, sinus rhythm (SR) maps only) or persistent AF (PeAF, AF and SR maps). Electrograms on corresponding SR/AF maps were paired for direct comparison. Percentage surface area of scar was assigned low- (LVM, ≤ 0.05 mV), intermediate- (IVM, 0.05–0.5 mV) or normal voltage myocardium, (NVM, &gt; 0.5 mV).Results: thirty-eight patients were recruited generating 96 maps using 913,480 electrograms. Paired SR-AF bipolar electrograms showed fair correlation in LA (Spearman’s ρ = 0.32) and weak correlation in RA (ρ = 0.19) and were significantly higher in SR in both (LA: 0.61 mV (0.20–1.67) vs 0.31 mV (0.10–0.74), RA: 0.68 mV (0.19–1.88) vs 0.47 mV (0.14–1.07), p Significantly more IVM/LVM surface areas were seen in AF over SR (LA only, p Conclusions: ultra high-density mapping shows paired electrograms correlate poorly between SR and AF. SR electrograms are typically (but not always) larger than those in AF. Patients with PeAF have a lower global electrogram voltage than those with PAF. Electrogram voltages are similar between atria within individual patients

Non-contact mapping guided cardiac resynchronization therapy for a failing systemic right ventricle

AIMS: Progressive systemic right ventricular (sRV) dysfunction, atrial and ventricular arrhythmias and sudden cardiac death are well-recognized late sequelae of atrial redirection surgery in which the right ventricle is left connected to the systemic circulation. Although cardiac resynchronization therapy (CRT) poses an attractive therapeutic option, little is known about indications, patient selection, and technical aspects of best lead placement. METHODS AND RESULTS: We undertook CRT in a 27-year-old female patient post-Mustard correction for d-transposition (d-TGA) with New York Heart Association (NYHA) grade III disability with QRS duration measuring 130 ms. There was also echocardiographic (TTE) evidence of severe sRV dysfunction. Non-contact mapping (NCM) was used to define sites of late activation within the sRV and the acute intra-arterial blood pressure (BP) response was assessed during implantation of a 4 french (F) lead onto the endocardial surface of the sRV. At 4 weeks post-implant sRV lateral wall motion had improved and the ejection fraction (EF) rose from 23 to 33%. The patient has been successfully anticoagulated and improved to NYHA II status after 6 months. CONCLUSION: The use of NCM proved safe and effective and provided a qualitative assessment of electrical viability of the sRV complimenting the measurement of mechanical function provided by TTE. The favourable clinical response in the above case justifies a prospective evaluation of this strategy