Tenecteplase versus alteplase for large vessel occlusion recanalization (T-FLAVOR): Trial protocol

Background Tenecteplase has higher fibrin specificity with a longer half-life and the potential to achieve higher rates of recanalization than alteplase. A critical limitation of tenecteplase is no commercial use in Japan and no experience with its administration to Japanese patients. Hypothesis Tenecteplase is superior to alteplase in achieving recanalization on the initial angiogram when administered ≤4.5-hour of stroke onset in patients planned for mechanical thrombectomy (MT) in Japan where alteplase at the unique dose of 0.6mg/kg is officially used. Methods The Tenecteplase versus alteplase For LArge Vessel Occlusion Recanalization (T-FLAVOR) trial is an investigator-initiated, phase II, multicenter, prospective, randomized, open-label, masked-endpoint, superiority study. Eligibility criteria include acute ischemic stroke with pre-stroke modified Rankin Scale score ≤3 and large vessel occlusion (internal carotid artery, middle cerebral artery, or basilar artery) eligible for intravenous thrombolysis ≤4.5-hour and MT ≤6-hour of stroke onset. After completing the safety confirmation phase involving three patients who received non-masked tenecteplase (0.25 mg/kg), 220 patients will be randomized to two groups (1:1), intravenous alteplase (0.6mg/kg, n = 110) or tenecteplase (0.25mg/kg, n = 110), prior to MT. Outcomes In the safety confirmation phase, the primary outcome is symptomatic intracranial hemorrhage (sICH) ≤24-36-hour. In the randomized, comparative phase, the primary efficacy outcome is substantial angiographic reperfusion (mTICI grade 2b/2c/3) or absence of retrievable thrombus on the initial angiogram. The primary safety outcome is sICH ≤24-36-hour and 90-day mortality. Discussion T-FLAVOR may help determine if tenecteplase should be recommended as a routine clinical strategy before MT for Japanese stroke patients. Trial registration jRCTs051210055

A novel endovascular method of atherectomy for calcified common femoral and popliteal disease using the crosser system: Crossbow and Rambow techniques

Objectives This study aims to report the efficacy and safety of new atherectomy methods using the Crosser system for calcified lesions in the common femoral and popliteal artery: the Crosser system supported by bended 0.014 wire (Crossbow) technique and retrograde approach of sheathless Crosser system supported by bended 0.014 wire (Rambow) technique. Materials and Methods This report describes a single-center, retrospective study. A total of 23 patients (mean ± SD age, 73 ± 10 years; 19 men) with symptomatic peripheral artery disease received the Crossbow technique and Rambow technique for treatment of calcified common femoral and popliteal disease; these patients were enrolled between October 2013 and October 2015. The primary efficacy outcome was acute technical success, defined as achievement of residual stenosis < 30% for stenting and < 50% for angioplasty or atherectomy. The primary safety outcome was assessed on the basis of angiographic complications. Results The Crossbow and Rambow techniques were undertaken in 100% and 17% of the patients, respectively. Acute technical success was achieved in 96% of the patients. There were two embolic events. Conclusion Crossbow and Rambow techniques could be effective atherectomy methods of calcified common femoral and popliteal disease. Regarding safety, embolic protection devices may be needed for our atherectomy methods.

Efficacy, Outcome, and Safety of Elderly Patients with Glioblastoma in the 5-ALA Era: Single Center Experience of More Than 10 Years

Background: In the next decades, the incidence of patients with glioblastoma (GBM) will increase due to the growth of the elderly population. Fluorescence-guided resection using 5-aminolevulinic acid (5-ALA) is widely applied to achieve maximal safe resection of GBM and is identified as a novel intraoperative marker for diagnostic tissue during biopsies. However, detailed analyses of the use of 5-ALA in resections as well as biopsies in a large elderly cohort are still missing. The aim of this study was thus to investigate the efficacy, outcome, and safety of surgically- treated GBM in the 5-ALA era in a large elderly cohort. Methods: All GBM patients aged 65 years or older who underwent neurosurgical intervention between 2007 and 2019 were included. Data on 5-ALA application, intraoperative fluorescence status, and 5-ALA-related side effects were derived from our databank. In the case of resection, the tumor resectability and the extent of resection were determined. Potential prognostic parameters relevant for overall survival were analyzed. Results: 272 GBM patients with a median age of 71 years were included. Intraoperative 5-ALA fluorescence was applied in most neurosurgical procedures (n = 255/272, 88%) and visible fluorescence was detected in most cases (n = 252/255, 99%). In biopsies, 5-ALA was capable of visualizing tumor tissue by visible fluorescence in all but one case (n = 91/92, 99%). 5-ALA administration did not result in any severe side effects. Regarding patient outcome, smaller preoperative tumor volume (<22.75 cm3), gross total resection, single lesions, improved postoperative neurological status, and concomitant radio-chemotherapy showed a significantly longer overall survival. Conclusions: Our data of this large elderly cohort demonstrate the clinical utility and safety of 5-ALA fluorescence in GBM for improved tumor visualization in both resections as well as biopsies. Therefore, we recommend the use of 5-ALA not only in resections, but also in open/stereotactic biopsies to optimize the neurosurgical management of elderly GBM patients.

Efficacy and safety of combination treatment of double plasma molecular adsorption system and low volume plasma exchange for patients with hepatitis B virus related acute-on-chronic liver failure: a multicentre randomised controlled clinical trial

IntroductionHepatitis B virus (HBV) related acute-on-chronic liver failure (ACLF) is still a common type of liver failure in China. Therefore, we conduct this multicentre, non-blinded, randomised controlled clinical trial to investigate the efficacy and safety of combination treatment of double plasma molecular adsorption system (DPMAS) and low volume plasma exchange (PE) for patients with HBV related ACLF.Methods and analysisA total of 200 patients with HBV related ACLF in the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou Eighth People’s Hospital, Nanfang Hospital of Southern Medical University, The Third People’s Hospital of Shenzhen, Xiangya Hospital of Central South University and The First Affiliated Hospital of Anhui Medical University, will be recruited into this trial. Eligible patients will undergo randomisation at a 1:1 ratio to two arms: the control group and the trial group. Patients in control group will receive comprehensive internal medical treatment. Patients in trial group will receive treatment of DPMAS and sequential low volume PE for three times, and comprehensive internal medical treatment. Clinical safety will be assessed by the analysis of adverse events (AEs) and laboratory tests. The primary efficacy outcome will be the incidence of unfavored events including death, liver transplantation and treatment abandonment. The secondary efficacy outcome will be the model for end-stage liver disease score variation. All evaluations will be performed at baseline, and 4, 8, 12, 24, 36, 48 weeks after enrolment. All AEs will be reported as soon as they are noted during the entire study procedure.Ethics and disseminationThis study was approved by Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University (approval no. (2020)02-173-01). The results and conclusions of this clinical trial will be published at academic conferences or in journals.Trial registration numberNCT04597164.

Enoxaparin for thromboprophylaxis in hospitalized COVID-19 patients: comparison of 40 mg o.d. vs 40 mg b.i.d. The X-COVID19 Randomized Clinical Trial

It is uncertain whether higher doses of anticoagulants than recommended for thromboprophylaxis are necessary in COVID-19 patients hospitalized in general wards. This is a multicentre, open-label, randomized trial performed in 9 Italian centres, comparing 40 mg b.i.d. vs 40 mg o.d. enoxaparin in COVID-19 patients, between April 30, 2020 and April 25, 2021. Primary efficacy outcome was in-hospital incidence of venous thromboembolism (VTE): asymptomatic or symptomatic proximal deep vein thrombosis (DVT) diagnosed by serial compression ultrasonography (CUS), and/or symptomatic pulmonary embolism (PE) diagnosed by computed tomography angiography (CTA). Secondary endpoints included each individual component of the primary efficacy outcome and a composite of death, VTE, mechanical ventilation, stroke, myocardial infarction, admission to ICU. Safety outcomes included major bleeding. The study was interrupted prematurely due to slow recruitment. We included 183 (96%) of the 189 enrolled patients in the primary analysis (91 in b.i.d., 92 in o.d.). Primary efficacy outcome occurred in 6 patients (6.5%, 0 DVT, 6 PE) in the o.d. group and 0 in the b.id. group (Sto arrivando! 6.5, 95% CI, 1.5-11.6). Absence of concomitant DVT and imaging characteristics suggest that most pulmonary artery occlusions were actually caused by local thrombi rather than PE. Statistically non-significant differences in secondary and safety endpoints were observed, with two major bleeding events in each arm. In conclusion, no DVT developed in COVID-19 patients hospitalized in general wards, independently of enoxaparin dosing used for thromboprophylaxis. Pulmonary artery occlusions developed only in the o.d. group. Our trial is underpowered and with few events.

Registration, publication, and outcome reporting among pivotal clinical trials that supported FDA approval of high-risk cardiovascular devices before and after FDAAA

Background Selective registration, publication, and outcome reporting of clinical trials distort the primary clinical evidence that is available to patients and clinicians regarding the safety and efficacy of US Food and Drug Administration (FDA)-approved medical devices. The purpose of this study is to compare registration, publication, and outcome reporting among pivotal clinical trials that supported FDA approval of high-risk (class III) cardiovascular devices before and after the FDA Amendment Act (FDAAA) was enacted in 2007. Methods Using publicly available data from ClinicalTrials.gov, FDA summaries, and PubMed, we determined registration, publication, and reporting of findings for all pivotal clinical studies supporting FDA approval of new high-risk cardiovascular devices between 2005 and 2020, before and after FDAAA. For published studies, we compared both the primary efficacy outcome with the FDA’s Premarket Approval (PMA) primary efficacy outcome and the published interpretation of findings with the FDA reviewer’s interpretation (positive, equivocal, or negative). Results Between 2005 and 2020, the FDA approved 156 high-risk cardiovascular devices on the basis of 165 pivotal trials, 48 (29%) of which were categorized as pre-FDAAA and 117 (71%) as post-FDAAA. Post-FDAAA, pivotal clinical trials were more likely to be registered (115 of 117 (98%) vs 24 of 48 (50%); p < 0.001), to report results (98 of 117 (87%) vs 7 of 48 (15%); p < 0.001) on ClinicalTrials.gov, and to be published (100 or 117 (85%) vs 28 of 48 (58%); p < 0.001) in peer-reviewed literature when compared to pre-FDAAA. Among published trials, rates of concordant primary efficacy outcome reporting were not significantly different between pre-FDAAA trials and post-FDAAA trials (24 of 28 (86%) vs 96 of 100 (96%); p = 0.07), nor were rates of concordant trial interpretation (27 of 28 (96%) vs 93 of 100 (93%); p = 0.44). Conclusions FDAAA was associated with increased registration, result reporting, and publication for trials supporting FDA approval of high-risk medical devices. Among published trials, rates of accurate primary efficacy outcome reporting and trial interpretation were high and no different post-FDAAA.

P.072 Ticagrelor vs Clopidogrel in Addition to Aspirin in Minor Ischemic Stroke/ TIA – a Systematic Review & Network Meta-Analysis (NMA)

Background: Dual antiplatelet therapy (DAPT) is recommended after minor ischemic stroke/ transient ischemic attack (TIA), but Clopidogrel/ Aspirin has never been compared directly to Ticagrelor/ Aspirin. Our objective is to compare these regimens in terms of efficacy and safety. Methods: Medline, Embase, and Cochrane were searched for randomized controlled trials (RCTs) that enrolled adults with minor stroke/ TIA and administered antiplatelets within 72 hours. The primary efficacy outcome is recurrent stroke or death at 90 days. We performed a Bayesian-approach NMA. Between group comparisons were presented as odds-ratios (OR) with 95% credible intervals (95%CI). Sucraplots were based on calculated probabilities of rankings for individual outcomes. Results: 9/4014 studies were included: 5 RCTs and 4 subgroup analyses. 22,098 patients were analyzed. At 90 days, both DAPT regimens were superior to Aspirin in the prevention of recurrent stroke/ death. There was no significant difference between Clopidogrel/ ASA compared to Ticagrelor/ ASA (OR 0.90 [95%CI 0.74 – 1.09]), although Clopidogrel/ Aspirin was ranked #1 using Sucraplots. There was no significant difference between the interventions for mortality, bleeding, or adverse events. Conclusions: DAPT was superior to ASA in the prevention of recurrent strokes/ death, but there was no difference between Clopidogrel/ ASA and Ticagrelor/ ASA.

Apixaban compared with warfarin to prevent thrombosis in thrombotic antiphospholipid syndrome: a randomized trial

Thrombotic antiphospholipid syndrome (TAPS) is characterized by venous, arterial, or microvascular thrombosis. Patients with TAPS merit indefinite anticoagulation and warfarin has historically been the standard treatment. Apixaban is an oral factor Xa inhibitor anticoagulant that requires no dose adjustment or monitoring. The efficacy and safety of apixaban compared with warfarin for TAPS patients remain unknown. This multicenter prospective randomized open-label blinded endpoint study assigned anticoagulated TAPS patients to apixaban or warfarin (target INR 2-3) for 12 months. The primary efficacy outcome was clinically overt thrombosis and vascular death. Apixaban was first given at 2.5 mg twice daily. Two protocol changes were instituted based on recommendations from the data safety monitoring board. After the 25th patient was randomized, the apixaban dose was increased to 5mg twice daily, and after the 30th patient was randomized, subjects with prior arterial thrombosis were excluded. Primary outcomes were adjudicated by independent experts blinded to treatment allocation. Patients randomized between 23 February 2015 and 7 March 2019 to apixaban (n=23) or warfarin (n=25) were similar. Among the components of the primary efficacy outcome, only stroke occurred in 6 of 23 patients randomized to apixaban compared with 0 of 25 patients randomized to warfarin. The study ended prematurely after the 48th patient was enrolled. Conclusions from our study are limited due to protocol modifications and low patient accrual. Despite these limitations, our results suggest that apixaban may not be routinely substituted for warfarin to prevent recurrent thrombosis (and especially stokes) among patients with TAPS (ClinicalTrials.gov: NCT02295475).