Efficacy and safety of a targeted-release formulation of budesonide in patients with primary IgA nephropathy (NefIgArd): 2-year results from a randomised phase 3 trial.

BACKGROUND: IgA nephropathy is a chronic immune-mediated kidney disease and a major cause of kidney failure worldwide. The gut mucosal immune system is implicated in its pathogenesis, and Nefecon is a novel, oral, targeted-release formulation of budesonide designed to act at the gut mucosal level. We present findings from the 2-year, phase 3 NefIgArd trial of Nefecon in patients with IgA nephropathy. METHODS: In this phase 3, multicentre, randomised, double-blind, placebo-controlled trial, adult patients (aged ≥18 years) with primary IgA nephropathy, estimated glomerular filtration rate (eGFR) 35-90 mL/min per 1·73 m2, and persistent proteinuria (urine protein-creatinine ratio ≥0·8 g/g or proteinuria ≥1 g/24 h) despite optimised renin-angiotensin system blockade were enrolled at 132 hospital-based clinical sites in 20 countries worldwide. Patients were randomly assigned (1:1) to receive 16 mg/day oral capsules of Nefecon or matching placebo for 9 months, followed by a 15-month observational follow-up period off study drug. Randomisation via an interactive response technology system was stratified according to baseline proteinuria (<2 or ≥2 g/24 h), baseline eGFR (<60 or ≥60 mL/min per 1·73 m2), and region (Asia-Pacific, Europe, North America, or South America). Patients, investigators, and site staff were masked to treatment assignment throughout the 2-year trial. Optimised supportive care was also continued throughout the trial. The primary efficacy endpoint was time-weighted average of eGFR over 2 years. Efficacy and safety analyses were done in the full analysis set (ie, all randomly assigned patients). The trial was registered on ClinicalTrials.gov, NCT03643965, and is completed. FINDINGS: Patients were recruited to the NefIgArd trial between Sept 5, 2018, and Jan 20, 2021, with 364 patients (182 per treatment group) randomly assigned in the full analysis set. 240 (66%) patients were men and 124 (34%) were women, and 275 (76%) identified as White. The time-weighted average of eGFR over 2 years showed a statistically significant treatment benefit with Nefecon versus placebo (difference 5·05 mL/min per 1·73 m2 [95% CI 3·24 to 7·38], p<0·0001), with a time-weighted average change of -2·47 mL/min per 1·73 m2 (95% CI -3·88 to -1·02) reported with Nefecon and -7·52 mL/min per 1·73 m2 (-8·83 to -6·18) reported with placebo. The most commonly reported treatment-emergent adverse events during treatment with Nefecon were peripheral oedema (31 [17%] patients, vs placebo, seven [4%] patients), hypertension (22 [12%] vs six [3%]), muscle spasms (22 [12%] vs seven [4%]), acne (20 [11%] vs two [1%]), and headache (19 [10%] vs 14 [8%]). No treatment-related deaths were reported. INTERPRETATION: A 9-month treatment period with Nefecon provided a clinically relevant reduction in eGFR decline and a durable reduction in proteinuria versus placebo, providing support for a disease-modifying effect in patients with IgA nephropathy. Nefecon was also well tolerated, with a safety profile as expected for a locally acting oral budesonide product. FUNDING: Calliditas Therapeutics.

Atrial pacing minimization in sinus node dysfunction and risk of incident atrial fibrillation: a randomized trial.

BACKGROUND AND AIMS: High percentages of atrial pacing have been associated with an increased risk of atrial fibrillation. This study is aimed at evaluating whether atrial pacing minimization in patients with sinus node dysfunction reduces the incidence of atrial fibrillation. METHODS: In a nationwide, randomized controlled trial, 540 patients with sinus node dysfunction and an indication for first pacemaker implantation were assigned to pacing programmed to a base rate of 60 bpm and rate-adaptive pacing (DDDR-60) or pacing programmed to a base rate of 40 bpm without rate-adaptive pacing (DDD-40). Patients were followed on remote monitoring for 2 years. The primary endpoint was time to first episode of atrial fibrillation longer than 6 min. Secondary endpoints included longer episodes of atrial fibrillation, and the safety endpoint comprised a composite of syncope or presyncope. RESULTS: The median percentage of atrial pacing was 1% in patients assigned to DDD-40 and 49% in patients assigned to DDDR-60. The primary endpoint occurred in 124 patients (46%) in each treatment group (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.76-1.25, P = .83). There were no between-group differences in atrial fibrillation exceeding 6 or 24 h, persistent atrial fibrillation, or cardioversions for atrial fibrillation. The incidence of syncope or presyncope was higher in patients assigned to DDD-40 (HR 1.71, 95% CI 1.13-2.59, P = .01). CONCLUSIONS: Atrial pacing minimization in patients with sinus node dysfunction does not reduce the incidence of atrial fibrillation. Programming a base rate of 40 bpm without rate-adaptive pacing is associated with an increased risk of syncope or presyncope.

Severity of Brugada syndrome disease manifestation and risk of new-onset depression or anxiety: a Danish nationwide study.

AIMS: Reduced psychological health is associated with adverse patient outcomes and higher mortality. We aimed to examine if a Brugada syndrome (BrS) diagnosis and symptomatic disease presentation were associated with an increased risk of new-onset depression or anxiety and all-cause mortality. METHODS AND RESULTS: All Danish patients diagnosed with BrS (2006-2018) with no history of psychiatric disease and available for ≥6 months follow-up were identified using nationwide registries and followed for up to 5 years after diagnosis. The development of clinical depression or anxiety was evaluated using the prescription of medication and diagnosis codes. Factors associated with developing new-onset depression or anxiety were determined using a multivariate Cox proportional hazards regression model. Disease manifestation was categorized as symptomatic (aborted cardiac arrest, ventricular tachycardia, or syncope) or asymptomatic/unspecified at diagnosis. A total of 223 patients with BrS and no history of psychiatric disease were identified (72.6% male, median age at diagnosis 46 years, 45.3% symptomatic). Of these, 15.7% (35/223) developed new-onset depression or anxiety after BrS diagnosis (median follow-up 5.0 years). A greater proportion of symptomatic patients developed new-onset depression or anxiety compared with asymptomatic patients [21/101 (20.8%) and 14/122 (11.5%), respectively, P = 0.08]. Symptomatic disease presentation (HR 3.43, 1.46-8.05) and older age (lower vs. upper tertile: HR 4.41, 1.42-13.63) were significantly associated with new-onset depression or anxiety. All-cause mortality in this group of patients treated according to guidelines was low (n = 4, 1.8%); however, 3/4 developed depression or anxiety before death. CONCLUSION: Approximately, one-sixth of patients with BrS developed new-onset depression or anxiety following a diagnosis of BrS. Symptomatic BrS disease manifestation was significantly associated with new-onset depression or anxiety.

Long-term follow-up of selective and non-selective His bundle pacing leads in patients with atrioventricular block.

BACKGROUND: His bundle pacing (HBP) is a novel treatment with limited knowledge on long-term outcome. We aimed to assess long-term safety and effectiveness of HBP in patients with atrioventricular block treated with HBP and a back-up right ventricular pacing (RVP) lead. METHODS: We included 38 patients from a completed single-center, randomized controlled cross-over trial designed to compare left ventricular (LV) function after 12 months of HBP vs. RVP conducted between September 2007 and August 2011. Lead performance beyond the 2-year study period was assessed based on a retrospective review of capture thresholds, sensing, impedance, energy consumption, and rate of HBP interruption. RESULTS: Patients were followed for a mean of 7 ± 4 years. Both at baseline and during follow-up, HBP leads displayed significantly higher capture thresholds than RVP leads (P < 0.001), multifold higher energy consumption (P < 0.001), and lower sensing amplitudes (P < 0.001). During follow-up, 17 (53%) HBP leads were deactivated or abandoned. The principal cause for HBP interruption was high pacing thresholds in patients with preserved LVEF during RVP. Device longevity was shorter than that of contemporary cohorts treated with dual-chamber pacing or CRT, and time to first device exchange was 6.8 ± 1.5 years. No lead dislodgements occurred, but four patients (10%) developed device-related infections requiring device extraction. CONCLUSION: HBP was interrupted in > 50% of patients during long-term follow-up. The principal cause was unacceptably high capture thresholds and no significant difference in LV function with HBP compared with RVP. Device longevity was shorter, and infection rates were higher than anticipated.

Cardiac surgery in patients with cardiac implantable electronic devices and risk of device infections: a nationwide nested case-control study.

PURPOSE: Cardiac surgery in patients with cardiac implantable electronic devices (CIEDs) has been associated with a higher risk of infective endocarditis, but how it influences risk of CIED-specific infections is not known. Our aim was to examine risk of systemic CIED infections after cardiac surgery in patients with CIEDs. METHODS: Based on data obtained from Danish administrative registries and the Danish Pacemaker and ICD Register, we conducted a case-control study nested within a nationwide cohort of patients who underwent a de novo CIED implantation in Denmark between 1998 and 2017. We defined cases as incident systemic CIED infections resulting in device system extraction. Controls were sampled 1:100 on time, age, sex and device type using risk set sampling. Exposure was defined as coronary artery bypass graft, or cardiac heart valve replacement or repair surgery. RESULTS: From a study cohort comprising 67,621 patients, we identified 170 cases and 16,788 controls. In the minimally adjusted model, the incidence rate ratio (IRR) for systemic CIED infection was 6.4 (95% confidence interval (CI) 3.8-10.7) with cardiac surgery, and after additional confounder adjustment, 5.4 (95% CI 3.2-9.2). IRRs were higher with restriction to heart valve replacement surgery (adjusted IRR 7.5, 95% CI 4.0-16.6), and when limiting our exposure time window to one year (adjusted IRR 10.1, 95% CI 4.5-22.3). CONCLUSION: Cardiac surgery in patients with de novo CIEDs was associated with a high risk of systemic CIED infections. Highest risk was observed after heart valve replacement surgery and within the first year of surgery.

Results from part A of the multi-center, double-blind, randomized, placebo-controlled NefIgArd trial, which evaluated targeted-release formulation of budesonide for the treatment of primary immunoglobulin A nephropathy.

The therapeutic potential of a novel, targeted-release formulation of oral budesonide (Nefecon) for the treatment of IgA nephropathy (IgAN) was first demonstrated by the phase 2b NEFIGAN trial. To verify these findings, the phase 3 NefigArd trial tested the efficacy and safety of nine months of treatment with Nefecon (16 mg/d) versus placebo in adult patients with primary IgAN at risk of progressing to kidney failure (ClinicalTrials.gov: NCT03643965). NefIgArd was a multicenter, randomized, double-blind, placebo-controlled two-part trial. In Part A, 199 patients with IgAN were treated with Nefecon or placebo for nine months and observed for an additional three months. The primary endpoint for Part A was 24-hour urine protein-to-creatinine ratio (UPCR) after nine months. Secondary efficacy outcomes evaluated included estimated glomerular filtration rate (eGFR) at nine and 12 months and the UPCR at 12 months. At nine months, UPCR was 27% lower in the Nefecon group compared with placebo, along with a benefit in eGFR preservation corresponding to a 3.87 ml/min/1.73 m2 difference versus placebo (both significant). Nefecon was well-tolerated, and treatment-emergent adverse events were mostly mild to moderate in severity and reversible. Part B is ongoing and will be reported on later. Thus, NefIgArd is the first phase 3 IgA nephropathy trial to show clinically important improvements in UPCR and eGFR and confirms the findings from the phase 2b NEFIGAN study.

Magnetic resonance imaging in patients with temporary external pacemakers.

AIMS: To describe safety and feasibility of magnetic resonance imaging (MRI) in patients with transvenous temporary external pacemakers and whether artefacts affect the diagnostic image quality during cardiac MRI. METHODS AND RESULTS: We reviewed records of all patients treated with temporary external pacing between 2016 and 2020 at a tertiary centre. Temporary pacing was established using a transvenous standard active fixation pacing lead inserted percutaneously and connected to a MRI-conditional pacemaker taped to the skin. All patients undergoing cardiac or non-cardiac MRI during temporary transvenous pacing were identified. Before MRI, devices were programmed according to guidelines for permanent pacemakers, and patients were monitored with continuous electrocardiogram during MRI. Of 827 consecutive patients receiving a temporary external pacemaker, a total of 44 (5%) patients underwent MRI (mean age 71 years, 13 [30%] females). Cardiac MRI was performed in 22 (50%) patients, while MRI of cerebrum, spine, and other regions was performed in the remaining patients. Median time from implantation of the temporary device to MRI was 6 (3-11) days. During MRI, we observed no device-related malfunction or arrhythmia. Nor did we detect any change in lead sensing, impedance, or pacing threshold. We observed no artefacts from the lead or pacemaker compromising the diagnostic image quality of cardiac MRI. MRI provided information to guide the clinical management in all cases. CONCLUSION: MRI is feasible and safe in patients with temporary external pacing established with a regular MRI-conditional pacemaker and a standard active fixation lead. No artefacts compromised the diagnostic image quality.

Lead complications after cardiac surgery in patients with cardiac implantable electronic devices.

OBJECTIVES: Manipulation of the heart during cardiac surgery in patients with cardiac implantable electronic devices (CIEDs) may result in lead damage or displacement, but whether cardiac surgery truly infers an excess risk of lead failure is not known. The objective of this study was to examine the risk of lead complications after cardiac surgery in patients with CIEDs. METHODS: We conducted a nationwide nested case-control study. The source population comprised all Danish patients ≥18 of age who underwent a de novo CIED implantation during 1998-2017. For inclusion, patients had to be alive and event free 6 months after implantation. Cases were matched 1:30 to controls on time, age, sex, and device type using risk set sampling. We used conditional logistic regression to estimate incidence rate ratios (IRRs) for the association between cardiac surgery and lead-related reoperation. RESULTS: Our final population consisted of 67 621 patients. We identified 1437 (2.1%) incident cases of lead-related reoperations and 42 698 controls. Risk of lead complications was highest within 6 months of cardiac surgery [IRR 9.7, 95% confidence interval (CI) 6.3-14.8, adjusted IRR 9.6, 95% CI 6.2-14.7], and at 1 year, the relative risk of lead-related reoperation was close to unity (adjusted IRR 1.2, 95% CI 0.8-1.7). CONCLUSIONS: Cardiac surgery was associated with a considerable risk of lead complications in patients with de novo CIEDs.

Troubleshooting the difficult left ventricular lead placement in cardiac resynchronization therapy: current status and future perspectives.

INTRODUCTION: Cardiac resynchronization therapy (CRT) is an important option in modern cardiac implantable electronic device (CIED) treatment. Techniques for left ventricular (LV) lead placement in the coronary sinus and its tributaries are neither well described nor studied systematically, despite attention regarding where to place the LV lead. AREAS COVERED: This review presents specialized tools and techniques to overcome some of the most common problems encountered in LV lead placement in CRT. These tools and techniques are termed Interventional CRT (I-CRT), as they share technology with other interventional procedures. The main principle in I-CRT, compared to the traditional over-the-wire technique, is to add better support for delivery of the LV lead through dedicated inner catheters that also allows more flexibility with the use of more guidewires and better imaging with direct venography in the target vein. EXPERT OPINION: Even though CRT is an established therapeutic option, there are still many challenges in the implementation of the therapy. The cornerstone should be an ease of delivering the CRT and specifically implantation of the LV lead. Therefore, knowledge of the principles in I-CRT is necessary, as I-CRT could make implantation simpler in general and easier to reach the optimal LV pacing site.

Rate of permanent cardiac implantable electronic device infections after active fixation temporary transvenous pacing: A nationwide Danish cohort study.

BACKGROUND: Temporary transvenous pacing (TP) has been associated with an increased risk of cardiac implantable electronic device (CIED) infections, but there is little data to document this in contemporary populations. OBJECTIVE: To investigate the impact of active fixation TP on rate of CIED infections in a nationwide cohort of Danish patients. METHODS: We identified all patients who underwent a first-time CIED implantation between 2009 and 2017. Patients were categorized according to TP status at implantation and followed for 1 year. The primary outcome was local or systemic CIED infection resulting in device system removal. The secondary outcomes were systemic CIED infections and hospitalization for infective endocarditis (IE). RESULTS: We included a total of 40,601 CIED patients. A total of 2952 were treated with active fixation TP. The primary outcome was met in 246 patients. Risk of CIED infection at 1 year was 0.61% for patients not treated with TP and 0.65% for patients who were, HR of 1.28 (95% CI 0.80-2.05) and adjusted HR 0.85 (95% CI 0.51-1.42). More systemic CIED infections and IE hospitalizations occurred in TP patients; however, these differences did not persist after confounder adjustment. Cumulative mortality at 1 year was 16.8% in patients with TP vs 8.4% in patients without. CONCLUSION: Active fixation TP was not associated with a higher rate of CIED infections. Patients treated with TP had higher mortality, more systemic CIED infections, and more IE hospitalizations within first year of implantation. Most was attributable to an accumulation of risk factors for infection among TP patients.

Cardiac computed tomography-verified right ventricular lead position and outcomes in cardiac resynchronization therapy.

PURPOSE: To evaluate the association between different right ventricular (RV) lead positions as assessed by cardiac computed tomography (CT) and echocardiographic and clinical outcomes in patients receiving cardiac resynchronization therapy (CRT). METHODS: We reviewed patient records of all 278 patients included in two randomized controlled trials (ImagingCRT and ElectroCRT) for occurrence of heart failure (HF) hospitalization or all-cause death (primary endpoint) during long-term follow-up. Outcomes were compared between RV lead positions using adjusted Cox regression analysis. Six months after CRT implantation, we estimated left ventricular (LV) reverse remodeling by measuring LV end-systolic and end-diastolic volumes by echocardiography. Changes from baseline to 6 months follow-up were compared between RV lead positions. Device-related complications were recorded at 6-month follow-up. RESULTS: During median (interquartile range) follow-up of 4.7 (2.9-7.1) years, the risk of meeting the primary endpoint was similar for patients with non-apical vs. apical RV lead position (adjusted hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.54-1.12, p = 0.17) and free wall vs. septal RV lead position (adjusted HR 1.03, 95% CI 0.72-1.47, p = 0.86). Changes in LV ejection fraction and dimensions were similar with the different RV lead positions. We observed no differences in device-related complications relative to the RV lead position. CONCLUSIONS: In patients receiving CRT, the risk of HF hospitalization or all-cause death during long-term follow-up, and LV remodeling and incidence of device-related complications after 6 months are not associated with different anatomical RV lead position as assessed by cardiac CT.

Recurrent atrial arrhythmia in a randomised controlled trial comparing contact force-guided and contact force-blinded ablation for typical atrial flutter.

BACKGROUND: Contact force (CF)-guided catheter ablation (CA) is a novel technology developed to improve efficacy and reduce complications. In a randomised controlled trial (RCT), we previously documented that after 3 months, rate of persistent conduction block was similar with and without using CF while performing CA for typical atrial flutter (AFL). Clinical effect of CF on recurrent arrhythmia is unknown. Our objective is to study recurrent atrial arrhythmia during 12-month follow-up in a RCT investigating whether CF-guided CA for typical AFL is superior to CF-blinded CA. METHODS: Patients were randomised 1:1 to CA guided by CF (intervention group) or blinded to CF (control group). After 12 months, patients attended clinical check-up preceded by a 5-day ambulatory Holter monitor recording. Primary outcome was any recurrent atrial arrhythmia ≥ 30 s within 12 months and documented in 12-lead ECG or Holter monitor recording. RESULTS: We included 156 patients, four patients withdrew consent and two died during follow-up. Thus, 150 patients were included in final analysis. Recurrent arrhythmia was detected in 36 of 77 (47%) patients in the intervention group, and 32 of 73 patients (44%) in the control group (p = 0.51). Atrial fibrillation was detected in 23 (30%) and 29 (40%) patients in the intervention and control groups respectively. AFL was detected in 11 (14%) and 5 (7%) patients in the intervention and control groups respectively. CONCLUSIONS: Contact force-guided ablation for typical atrial flutter does not reduce recurrent atrial arrhythmia after 12-month follow-up as compared with ablation blinded for contact force.

Long-term outcomes in a randomized controlled trial of multimodality imaging-guided left ventricular lead placement in cardiac resynchronization therapy.

AIMS: This study aims to investigate the long-term occurrence of the composite endpoint of heart failure (HF) hospitalization or all-cause death (primary endpoint) in patients randomized to cardiac resynchronization therapy (CRT) using individualized multimodality imaging-guided left ventricular (LV) lead placement compared with a routine fluoroscopic approach. Furthermore, this study aims to evaluate whether inter-lead electrical delay (IED) is associated with improved response rate of this endpoint. METHODS AND RESULTS: We reviewed follow-up data until November 2020 for all 182 patients included in the ImagingCRT trial for the occurrence of HF hospitalization and all-cause death. During median (inter-quartile range) time to primary endpoint/censuring of 6.7 (3.3-7.9) years, the rate of the primary endpoint was 60% (n = 53) in the imaging group compared with 52% (n = 48) in the control group [hazard ratio (HR) 1.22, 95% confidence interval (CI) 0.83-1.81, P = 0.31]. Neither the risk of HF hospitalization (HR 1.11, 95% CI 0.62-1.99, P = 0.72) nor of all-cause death differed between treatment groups (HR 1.23, 95% CI 0.82-1.85, P = 0.32). The risk of the primary endpoint was significantly reduced among those with IED ≥100 ms when compared with those with IED <100 ms (HR 0.62, 95% CI 0.39-0.98, P = 0.04). CONCLUSIONS: In this study, an individualized multimodality imaging-guided strategy targeting LV lead placement towards the latest mechanically activated non-scarred myocardial segment during CRT implantation did not reduce HF hospitalization or all-cause death when compared with routine LV lead placement during long-term follow-up. Targeting the latest electrical activation should be studied as an alternative individualized strategy for optimizing LV lead placement in CRT recipients.

Non-infective left ventricular lead complications requiring re-intervention following cardiac resynchronization therapy: prevalence, causes and outcomes.

PURPOSE: Left ventricular (LV) lead complications in cardiac resynchronization therapy are challenging and poorly reported. We aimed to establish prevalence, causes and outcomes of LV lead complications requiring re-intervention. METHODS: We analysed the rate of complications in 2551 consecutive patients who received a transvenous de novo LV lead as part of a cardiac resynchronization therapy device between 2000 and 2018. LV lead complications requiring re-intervention were identified; those due to infection were excluded. Patient, procedural and device characteristics, and outcomes were examined for non-infective LV lead complications requiring re-intervention. RESULTS: During a median of 4.7 years, 142 (5.6%) patients required re-intervention for non-infective LV lead complications with a decrease from 10.7% between 2000 and 2004, 8.7% between 2005 and 2009, 3.2% between 2010 and 2014 to 3.2% after 2014. The most common complications were LV lead displacement (50%), high pacing threshold (28%) and phrenic nerve stimulation (15%). Of the complications, 79 (56%) occurred within 90 days post-implant and 63 (44%) later. At the end of the study period, 132/142 patients (93%) had a functional LV lead. Lead re-intervention was associated with higher risk of complications (20%), but no increase in mortality (P = 0.19). Quadripolar leads had longer longevity and lower risk of complications compared with unipolar and bipolar LV leads. CONCLUSIONS: A small but significant proportion of patients required LV lead re-intervention for complications following de novo implant. Lead displacement accounted for half of the re-interventions. Re-intervention was associated with a higher complication rate, but 92% of these patients had functional LV leads at the end of follow-up.

Sevuparin for the treatment of acute pain crisis in patients with sickle cell disease: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: There are no approved treatments for vaso-occlusive crises in sickle cell disease. Sevuparin is a novel non-anticoagulant low molecular weight heparinoid, with anti-adhesive properties. In this study, we tested whether sevuparin could shorten vaso-occlusive crisis duration in hospitalised patients with sickle cell disease. METHODS: We did a multicentre, double-blinded, placebo-controlled, phase 2 study in 16 public access clinical hospitals in the Netherlands, Lebanon, Turkey, Bahrain, Oman, Saudi Arabia, and Jamaica. Patients aged 12-50 years with a diagnosis of sickle cell disease (types HbSS, HbSC, HbSß0-thalassaemia, or HbSß+-thalassaemia) on a stable dose of hydroxyurea, hospitalised with vaso-occlusive crisis for parenteral opioid analgesia with a projected stay of more than 48 h were included in the study. Patients were randomly assigned (1:1) using a computer-generated randomisation scheme to receive sevuparin (18 mg/kg per day) or placebo (NaCl, 0·9% solution) intravenously for 2-7 days until vaso-occlusive crisis resolution. All individuals involved in the trial were masked to treatment allocation. The analysis was done in the intention-to-treat population. The primary endpoint was time to vaso-occlusive crisis resolution defined as freedom from parenteral opioid use (in preceding 6-10 h); and readiness for discharge as judged by the patient or physician. The trial is registered with ClinicalTrials.gov, NCT02515838. FINDINGS: Between Oct 7, 2015, and Feb 10, 2019, 144 patients were randomly assigned and administered sevuparin (n=69) or placebo (n=75). The median age was 22·2 years (range 12·2-33·6), 104 (72%) 144 were adults (18 years or older), and 90 (63%) were male and 54 (37%) were female. The intention-to-treat analysis for the primary endpoint showed no significant difference in median time to vaso-occlusive crisis resolution between the sevuparin and placebo groups (100·4 h [95% CI 85·5-116·8]) vs 86·4 h [70·6-95·1]; hazard ratio 0·89 [0·6-1·3]; p=0·55). Serious adverse events occurred in 16 (22%) of 68 patients in the sevuparin group and in 21 (22%) of patients in the placebo group. The most frequent treatment-emergent adverse events were pyrexia (17 [25%] in the sevuparin group vs 17 [22%] in the placebo group), constipation (12 [18%] vs 17 [22%]), and decreased haemoglobin (18 [26%] vs 9 [12%]). There were no deaths in the sevuparin group and there was one (1%) death in the placebo group after a hyper-haemolytic episode due to alloimmunisation. INTERPRETATION: This result, as well as the results seen in other clinical studies of inhibitors of adhesion in sickle cell disease, suggest that selectin-mediated adhesion might be important in the initiation, but not maintenance of vaso-occlusion, indicating that strategies to treat vaso-occlusive crises differ from strategies to prevent this complication. FUNDING: Modus Therapeutics.

Discontinuation of oral anticoagulation and risk of stroke and death after ablation for typical atrial flutter: A nation-wide Danish cohort study.

INTRODUCTION: Oral anticoagulation (OAC) is indicated for patients with atrial fibrillation (AF) and atrial flutter (AFL) with a CHA2DS2-VASc score ≥ 2 for men and ≥3 for women. This is regardless of successful catheter ablation for their arrhythmia. Studies have mainly focused on AF, and little is known regarding use of OAC in AFL patients following catheter ablation. PURPOSE: To describe discontinuation of OAC in a national cohort of patients who have undergone first-time cavo-tricuspid isthmus ablation (CTIA) for AFL. METHODS: We identified patients undergoing first-time CTIA during the period 2010-2016 using the Danish National Ablation Registry. Information on comorbidities and OAC use were gathered using the Danish National Patient Registry and the Danish National Prescription Registry. Patients were followed until March 1st, 2018. RESULTS: We identified 2409 consecutive patients. Median age was 66 (IQR 58-72) years, and 1952 (81%) were men. During mean follow-up of 4 ± 1.7 years, 723 (30%) patients discontinued OAC. Patients discontinuing OAC were younger, had less comorbidity, and a lower CHA2DS2-VASc score. During follow-up, 252 (10%) patients died, and 112 (5%) patients had a stroke. Incidence of both these events increased with increasing age and CHA2DS2-VASc score. In adjusted analysis, we observed higher mortality (p < 0.0001) in patients discontinuing OAC, while stroke rate was not significantly higher (p = 0.21). CONCLUSION: In this national cohort of patients who have undergone first-time CTIA, patients discontinuing OAC treatment were younger and had less comorbidities. Patients remain at elevated risk of death and stroke/TIA, increasing with their age and CHA2DS2-VASc score.

Repeat pulmonary vein isolation in patients with atrial fibrillation: low ablation index is associated with increased risk of recurrent arrhythmia.

OBJECTIVES: We aimed to investigate the predictors of recurrent arrhythmia after repeated pulmonary vein isolation (PVI) performed in the era of contact force without additional substrate ablation. One of the predictors studied, ablation index (AI), incorporates power, contact force, and time in a weighted formula and is reported to predict lesion size in animals. Design. Consecutive patients (n = 108) undergoing repeat PVI without additional substrate modification using a contact force sensing catheter were included retrospectively at a tertiary center. All ablation points were analyzed offline. A new variable, normalized AI (AI corrected for the location of the lesion-anterior vs. posterior) was calculated. The patients were systematically followed with clinical visit and 12-lead ECG as well as review of the regional electronic patient files at 3 and 12 months after the procedure with 5-day Holter at 12 months. Results. Electrical reconnection to at least one pulmonary vein (PV) was seen in 97% of the patients. The recurrence rate was 35%. There was no recurrence in patients with nAI above 1.15 (n = 26). Patients with electrical reconnection of up to two PVs had a higher risk of recurrence compared with patients having electrical reconnection of three or four PVs (p = .003), and this risk was especially high in patients with persistent atrial fibrillation (69 [39-91]%). Conclusions. The risk of recurrence is higher in patients with ablations performed with low levels of AI and in patients with reconnection to up to two PVs. Our data may indicate the need for higher target levels of AI during repeat PVI than normally used during de-novo PVI.

Reproducibility and repeatability of identifying the latest electrical activation during mapping of coronary sinus branches in CRT recipients.

INTRODUCTION: Studies have shown an association between the outcome in cardiac resynchronization therapy (CRT) and longer interventricular delay at the site of the left ventricular (LV) lead. Targeted LV lead placement at the latest electrically activated segment increases LV function further as compared with standard treatment. We aimed to determine reproducibility and repeatability of identifying the latest electrically activated segment during mapping of all available coronary sinus (CS) branches in patients receiving CRT. METHODS: We included 35 patients who underwent CRT implantation with protocolled mapping guided LV lead implantation aiming for the site of the latest electrical activation. Three different doctors experienced in electrophysiology and implantation of CRT devices independently measured time interval from the local bipolar right ventricular (RV) electrogram (EGM) to the local unipolar LV EGM at all mapped sites (RV-LV). The segment with the latest electrical activation was defined as the target segment (TS) and the CS tributary containing TS was defined as the target vein (TV). Weighted κ statistics with 95% confidence intervals were computed to assess intra- and interobserver agreement for TS and TV. RESULTS: We mapped 258 segments within 131 veins. Weighted κ values for repeatability were 0.85 (0.81-0.89) for TS and 0.92 (0.89-0.93) for TV, and weighted κ values of interobserver agreement ranged from 0.70 (0.61-0.73) to 0.80 (0.76-0.83) for TS and 0.73 (0.64-0.78) to 0.86 (0.83-0.89) for TV among all three observers. CONCLUSION: The reproducibility and repeatability of identifying the latest electrically activated segment during mapping of all available CS branches in patients receiving CRT range from good to very good.