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

2021 ◽  
Author(s):  
Scott C. Woller ◽  
Scott M Stevens ◽  
David Kaplan ◽  
Tzu-Fei Wang ◽  
D. Ware Branch ◽  
...  
Keyword(s):  
Antiphospholipid Syndrome ◽  
Standard Treatment ◽  
Factor Xa ◽  
Data Safety Monitoring Board ◽  
Primary Efficacy ◽  
Recurrent Thrombosis ◽  
Open Label ◽  
Treatment Allocation ◽  
Primary Efficacy Outcome ◽  
Efficacy Outcome

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).

scholarly journals Therapeutic vs. prophylactic bemiparin in hospitalized patients with non-severe COVID-19 (BEMICOP): an open-label, multicenter, randomized trial

2021 ◽  
Author(s):  
María Marcos ◽  
Francisco Carmona-Torre ◽  
Rosa Vidal Laso ◽  
PEDRO RUIZ-ARTACHO ◽  
David Filella ◽  
...  
Keyword(s):  
Major Bleeding ◽  
Therapeutic Dose ◽  
Hospitalized Patients ◽  
Primary Efficacy ◽  
Open Label ◽  
Primary Efficacy Outcome ◽  
Prophylactic Dose ◽  
Efficacy Outcome ◽  
Multicenter Randomized Controlled Trial ◽  
D Dimer

Thrombophylaxis with low molecular weight heparin (LMWH) in hospitalized patients with COVID-19 is mandatory, unless contraindicated. Given the links between inflammation and thrombosis, the use of higher doses of anticoagulants could improve outcomes. We conducted an open-label, multicenter, randomized, controlled trial in adult patients hospitalized with non-severe COVID-19 pneumonia and elevated D-dimer. Patients were randomized to therapeutic-dose bemiparin (115 IU/Kg daily) vs. standard prophylaxis (bemiparin 3,500 IU daily), for 10 days. The primary efficacy outcome was a composite of death, intensive care unit admission, need of mechanical ventilation support, development of moderate/severe acute respiratory distress and venous or arterial thrombosis within 10 days of enrollment. The primary safety outcome was major bleeding (ISTH criteria). A prespecified interim analysis was performed when 40% of the planned study population was reached. From October 2020 to May 2021, 70 patients were randomized at 5 sites and 65 were included in the primary analysis; 32 patients allocated to therapeutic-dose and 33 to standard prophylactic-dose. The primary efficacy outcome occurred in 7 patients (21.9%) in the therapeutic-dose group and 6 patients (18.2%) in the prophylactic-dose (absolute risk difference 3.6% [95% CI, -16%- 24%]; odds ratio 1.26 [95% CI, 0.37-4.26]; p=0.95). Discharge in the first 10 days was possible in 66% and 79% of patients, respectively. No major bleeding event was registered. Therefore, in patients with COVID-19 hospitalized with non-severe pneumonia but elevated D-dimer, the use of a short course of therapeutic-dose bemiparin did not improve clinical outcomes compared to standard prophylactic doses.

scholarly journals Therapeutic versus Prophylactic Anticoagulation for Patients Admitted to Hospital with COVID-19 and Elevated D-dimer Concentration (ACTION): An Open-Label, Multicentre, Randomised, Controlled Trial

2021 ◽  
Vol 5 (2) ◽  
pp. 103-108
Author(s):  
Gilson Soares Feitosa-Filho ◽  
Gabriella S. Sodré ◽  
Juliane Penalva C. Serra ◽  
Rhanniel Theodorus-Villar ◽  
Tatiana Otero Mendelez ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Primary Efficacy ◽  
Therapeutic Group ◽  
Open Label ◽  
Safety Outcome ◽  
Therapeutic Anticoagulation ◽  
Efficacy Outcome ◽  
Randomised Controlled ◽  
Prophylactic Anticoagulation ◽  
D Dimer

Background. COVID-19 is associated with a prothrombotic state leading to adverse clinical outcomes. Whether therapeutic anticoagulation improves outcomes in patients hospitalised with COVID-19 is unknown. We aimed to compare the efficacy and safety of therapeutic versus prophylactic anticoagulation in this population. Methods. We did a pragmatic, open-label (with blinded adjudication), multicentre, randomised, controlled trial, at 31 sites in Brazil. Patients (aged ≥18 years) hospitalised with COVID-19 and elevated D-dimer concentration, and who had COVID-19 symptoms for up to 14 days before randomisation, were randomly assigned (1:1) to receive either therapeutic or prophylactic anticoagulation. Therapeutic anticoagulation was in-hospital oral rivaroxaban (20 mg or 15 mg daily) for stable patients, or initial subcutaneous enoxaparin (1 mg/kg twice per day) or intravenous unfractionated heparin (to achieve a 0·3–0·7 IU/mL anti-Xa concentration) for clinically unstable patients, followed by rivaroxaban to day 30. Prophylactic anticoagulation was standard in-hospital enoxaparin or unfractionated heparin. The primary efficacy outcome was a hierarchical analysis of time to death, duration of hospitalisation, or duration of supplemental oxygen to day 30, analysed with the win ratio method (a ratio >1 reflects a better outcome in the therapeutic anticoagulation group) in the intention-to-treat population. The primary safety outcome was major or clinically relevant non-major bleeding through 30 days. This study is registered with ClinicalTrials.gov (NCT04394377) and is completed. Findings. From June 24, 2020, to Feb 26, 2021, 3331 patients were screened and 615 were randomly allocated (311 [50%] to the therapeutic anticoagulation group and 304 [50%] to the prophylactic anticoagulation group). 576 (94%) were clinically stable and 39 (6%) clinically unstable. One patient, in the therapeutic group, was lost to follow-up because of withdrawal of consent and was not included in the primary analysis. The primary efficacy outcome was not different between patients assigned therapeutic or prophylactic anticoagulation, with 28.899 (34.8%) wins in the therapeutic group and 34.288 (41.3%) in the prophylactic group (win ratio 0.86 [95% CI 0.59–1.22], p=0·40). Consistent results were seen in clinically stable and clinically unstable patients. The primary safety outcome of major or clinically relevant non-major bleeding occurred in 26 (8%) patients assigned therapeutic anticoagulation and seven (2%) assigned prophylactic anticoagulation (relative risk 3.64 [95% CI 1.61–8.27], p=0.0010). Allergic reaction to the study medication occurred in two (1%) patients in the therapeutic anticoagulation group and three (1%) in the prophylactic anticoagulation group. Interpretation. In patients hospitalised with COVID-19 and elevated D-dimer concentration, in-hospital therapeutic anticoagulation with rivaroxaban or enoxaparin followed by rivaroxaban to day 30 did not improve clinical outcomes and increased bleeding compared with prophylactic anticoagulation. Therefore, use of therapeutic-dose rivaroxaban, and other direct oral anticoagulants, should be avoided in these patients in the absence of an evidence-based indication for oral anticoagulation.

scholarly journals Thrombolysis with alteplase 3–4.5 hours after acute ischaemic stroke: trial reanalysis adjusted for baseline imbalances

2020 ◽  
Vol 25 (5) ◽  
pp. 168-171 ◽  
Author(s):  
Brian Scott Alper ◽  
Gary Foster ◽  
Lehana Thabane ◽  
Alex Rae-Grant ◽  
Meghan Malone-Moses ◽  
...  
Keyword(s):  
Ischaemic Stroke ◽  
Acute Ischaemic Stroke ◽  
Intracranial Haemorrhage ◽  
Trial Data ◽  
Stroke Onset ◽  
Primary Efficacy ◽  
Nihss Score ◽  
Primary Efficacy Outcome ◽  
Efficacy Outcome ◽  
Free Status

ObjectivesAlteplase is commonly recommended for acute ischaemic stroke within 4.5 hours after stroke onset. The Third European Cooperative Acute Stroke Study (ECASS III) is the only trial reporting statistically significant efficacy for clinical outcomes for alteplase use 3–4.5 hours after stroke onset. However, baseline imbalances in history of prior stroke and stroke severity score may confound this apparent finding of efficacy. We reanalysed the ECASS III trial data adjusting for baseline imbalances to determine the robustness or sensitivity of the efficacy estimates.DesignReanalysis of randomised placebo-controlled trial. We obtained access to the ECASS III trial data and replicated the previously reported analyses to confirm our understanding of the data. We adjusted for baseline imbalances using multivariable analyses and stratified analyses and performed sensitivity analysis for missing data.SettingEmergency care.Participants821 adults with acute ischaemic stroke who could be treated 3–4.5 hours after symptom onset.InterventionsIntravenous alteplase (0.9 mg/kg of body weight) or placebo.Main outcome measuresThe original primary efficacy outcome was modified Rankin Scale (mRS) score 0 or 1 (ie, being alive without any disability) and the original secondary efficacy outcome was a global outcome based on a composite of functional end points, both at 90 days. Adjusted analyses were only reported for the primary efficacy outcome and the original study protocol did not specify methods for adjusted analyses. Our adjusted reanalysis included these outcomes, symptom-free status (mRS 0), dependence-free status (mRS 0–2), mortality (mRS 6) and change across the mRS 0–6 spectrum at 90 days; and mortality and symptomatic intracranial haemorrhage at 7 days.ResultsWe replicated previously reported unadjusted analyses but discovered they were based on a modified interpretation of the National Institutes of Health Stroke Scale (NIHSS) score. The secondary efficacy outcome was no longer significant using the original NIHSS score. Previously reported adjusted analyses could only be replicated with significant effects for the primary efficacy outcome by using statistical approaches not reported in the trial protocol or statistical analysis plan. In analyses adjusting for baseline imbalances, all efficacy outcomes were not significant, but increases in symptomatic intracranial haemorrhage remained significant.ConclusionsReanalysis of the ECASS III trial data with multiple approaches adjusting for baseline imbalances does not support any significant benefits and continues to support harms for the use of alteplase 3–4.5 hours after stroke onset. Clinicians, patients and policymakers should reconsider interpretations and decisions regarding management of acute ischaemic stroke that were based on ECASS III results.Trial registration numberNCT00153036.

scholarly journals S246. THE EFFECT OF INCORRECT SCALE ADMINISTRATION ON DATA QUALITY IN SCHIZOPHRENIA CLINICAL TRIALS

2020 ◽  
Vol 46 (Supplement_1) ◽  
pp. S132-S132
Author(s):  
Alan Kott ◽  
David Daniel
Keyword(s):  
Clinical Trials ◽  
Clinical Global Impression ◽  
Primary Outcome Measure ◽  
Primary Efficacy ◽  
Double Blind ◽  
Clinical Global Impression Scale ◽  
Primary Efficacy Outcome ◽  
Pooled Data ◽  
Efficacy Outcome ◽  
Time Stamps

Abstract Background The availability of date and time stamps of interview start times on eCOA systems permits monitoring and documentation of the order of administration of scales and instruments at each visit. The Clinical Global Impression Scale (CGI) is a holistic instrument that synthesizes all information available from the subject, caregivers, medical notes, etc. and is therefore typically required to be rated last at a particular visit. In the current retrospective analysis of double blind eCOA collected schizophrenia data pooled from multiple clinical trials we assessed the percent of visits where CGI was not administered last among other efficacy assessments. Additionally we assessed whether the inappropriate administration order of Clinical Global Impression Scale was associated with discrepancies in the data and change from baseline between the CGI and the primary efficacy outcome. Methods Available eCOA data were pooled from schizophrenia double blind, placebo controlled clinical trials. Within the data, we identified those visits where the CGI was not administered last among other efficacy assessments (inappropriate administration order). Within each trial we identified as discordant those data where the actual primary efficacy score or its change from baseline differed by at least two standard deviations from the expected score after linear regression. For this procedure the CGI- S score used as a predictor and the primary efficacy outcome as dependent variable. Logistic regression was then used on pooled data to explore whether the incorrect order of CGI administration increased the odds of discordant ratings between the CGI and primary outcome measure. Results The dataset consisted of 5,784 paired ratings of the CGI and the primary efficacy outcome. Among these, a total of 4,628 visits allowed to calculate change from baseline. Inappropriate order of CGI administration was identified in a total of 443 visits (7.7% of all visits). Discrepancies between CGI-S and the primary efficacy outcome were identified in 292 visits (5.1% of data) and discrepancies between change from baseline in CGI-S and in the primary efficacy outcome were observed in 249 cases (5.3% of data). The presence of incorrectly administered CGI increased the odds of raw score discrepancy 1.6x (95%CI 1.1–2.4), and the odds of discrepancy in change from baseline 1.8x (95%CI 1.2–2.7), both significant with p <0.01. Discussion Our data indicate a relatively large percent of visits suffer from an incorrect scale administration order. We have previously explored a number of sources of possible noise in schizophrenia clinical trials. Current analyses identified a significant effect of incorrect scale administration on the presence of between scale discordances. Such findings indicate that order of CGI administration should be mandated in schizophrenia clinical trials and enforced by eCOA platforms. Additionally, violations to correct scale administration should be monitored through analytic programs and acted upon in case of repeated occurrences at the rater or site level.

Efficacy and Safety of Edoxaban Versus Enoxaparin for the Prevention of Venous Thromboembolism Following Total Hip Arthroplasty: STARS J-V trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3320-3320 ◽  
Author(s):  
Takeshi Fuji ◽  
Satoru Fujita ◽  
Shintaro Tachibana ◽  
Yohko Kawai ◽  
Yukihiro Koretsune ◽  
...  
Keyword(s):  
Total Hip Arthroplasty ◽  
Major Bleeding ◽  
Thromboembolic Events ◽  
Primary Efficacy ◽  
Efficacy And Safety ◽  
Bleeding Events ◽  
Primary Efficacy Outcome ◽  
Treatment Groups ◽  
Efficacy Outcome ◽  
Lead Investigator

Abstract Abstract 3320 Introduction: Edoxaban is an oral, direct factor Xa inhibitor in clinical development for the prevention and treatment of thromboembolic events. The aim of this non-inferiority trial was to determine the efficacy and safety of edoxaban compared with enoxaparin sodium (enoxaparin) after total hip arthroplasty (THA) in Japan. Methods: This was a randomized, double-blind, double-dummy, enoxaparin-controlled, multicenter trial. Patients were randomized to oral edoxaban 30 mg once daily (QD) or subcutaneous enoxaparin 2,000 IU, equivalent to 20 mg, twice daily (BID) for 11 to 14 days. Edoxaban was initiated 6–24 hours after surgery and enoxaparin was initiated 24–36 hours after surgery which is the Japanese standard of care. The primary efficacy outcome was the composite of symptomatic and asymptomatic deep vein thrombosis (DVT), and pulmonary embolism (PE). The primary safety outcome was the incidence of major and clinically relevant non-major bleeding. Results: A total of 610 patients were randomized. There were no clinically relevant differences in baseline characteristics between the treatment groups. The mean age was 62.8 years and mean body weight was 57.4 kg (Efficacy analysis set). The primary efficacy outcome occurred in 6 of 255 (2.4%) patients receiving edoxaban and 17 of 248 (6.9%) patients receiving enoxaparin (relative risk reduction=65.7%; absolute risk difference -4.5%, 95% CI, -8.6% to -0.9%; P<0.001 for non-inferiority; P=0.0157 for superiority). The thromboembolic events were all asymptomatic DVT (Table). No symptomatic DVT or PE was observed in both treatment groups. The incidence of major and clinically relevant non-major bleeding events was 2.6% (8/303) vs 3.7% (11/301) in the edoxaban and enoxaparin groups, respectively (P=0.475). Major bleeding occurred in 0.7% of the edoxaban group and 2.0% of the enoxaparin group. The rates of elevated serum aminotransferase levels of more than 3 times the upper limit of normal was 2.6% with edoxaban versus 10% with enoxaparin. Conclusions: The STARS J-V trial demonstrated that oral edoxaban 30 mg QD has efficacy superior to enoxaparin 2,000 IU BID in the prevention of thromboembolic events following THA and is associated with a similar incidence of major and clinically relevant non-major bleeding events. Disclosures: Fuji: Astellas: Consultancy; Showa Ikakogyo: Consultancy; Daiichi Sankyo: Consultancy; Bayer: Consultancy. Fujita:Daiichi Sankyo: Consultancy; Astellas: Consultancy; GlaxoSmithkline: Consultancy. Tachibana:Daiichi Sankyo: Consultancy. Kawai:Daiichi Sankyo: Consultancy; Toyama Chemical: Consultancy. Koretsune:Daiichi Sankyo: Consultancy, National Lead Investigator. Yamashita:Daiichi Sankyo: Consultancy, National Lead Investigator; Otsuka Pharmaceutical: Paid instructor; Sanofi-aventis: Paid instructor; Teijin Pharma: Paid instructor. Nakamura:Daiichi Sankyo: Consultancy; GlaxoSmithkline: Consultancy; Astellas: Consultancy.

scholarly journals Dabigatran Etexilate or Warfarin in the Treatment of Acute Venous Thromboembolism in Western European Patients: A Pooled Analysis of RE-COVER® and RE-COVER II™

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4730-4730
Author(s):  
Sebastian Schellong ◽  
Henry Eriksson ◽  
Samuel Z. Goldhaber ◽  
Martin Feuring ◽  
Stefan Hantel ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Research Funding ◽  
Dabigatran Etexilate ◽  
Primary Efficacy ◽  
Bleeding Events ◽  
Primary Efficacy Outcome ◽  
Efficacy Outcome ◽  
Safety Outcomes ◽  
Western European ◽  
Acute Venous Thromboembolism

Abstract Introduction: In the RE-COVER®/RE-COVER II™ global randomized trials investigating the treatment of acute venous thromboembolism (VTE), efficacy and safety outcomes of dabigatran etexilate (dabigatran) versus warfarin were compared. This sub-analysis of pooled RE-COVER®/RE-COVER II™ data compares the safety and efficacy of dabigatran versus warfarin in the Western European sub-population. Methods: In the RE-COVER®/RE-COVER II™ trials, patients with acute VTE, initially receiving parenteral anticoagulation, were randomized to warfarin (INR 2-3) or dabigatran (150 mg twice daily) for 6 months and followed up for 30 days. The primary efficacy outcome was recurrent, symptomatic VTE/VTE-related death. Safety outcomes were major bleeding events (MBEs), a composite of MBEs or clinically relevant non-major bleeding events (MBEs/CRBEs) and any bleeding during the 6-month, oral-only treatment period. All outcomes were centrally adjudicated. Data from the Western European sub-population were analyzed using a Cox regression model with factor treatment stratified by study, assuming different baseline hazards per study. Results: This sub-analysis included 1239 patients for the efficacy analysis (dabigatran n = 613; warfarin n = 626) and 1192 patients for safety (dabigatran n = 588; warfarin n = 604) from all 13 Western European countries participating in the RE-COVER®/RE-COVER II™ trials. For the primary efficacy outcome, the rate of VTE/VTE-related death in patients receiving dabigatran was 2.1% (n = 13) compared with 2.9% (n = 18) in those receiving warfarin. However, this difference did not reach statistical significance (hazard ratio [HR] 0.74; 95% confidence interval [CI], 0.36-1.5). Of the safety outcomes, rates of MBEs were similar between both treatment groups (1.4% for dabigatran [n = 8] and 1.3% for warfarin [n = 8]; HR 1.02; 95% CI, 0.38-2.71). Rates of MBEs/CRBEs were significantly lower in patients receiving dabigatran than in those receiving warfarin at 5.1% (n = 30) and 9.4% (n = 57), respectively (HR 0.52; 95% CI, 0.34-0.82). Any bleeding events were also statistically lower in the dabigatran group (17.5%; n = 103) compared with warfarin (23.8%; n = 144) (HR 0.7; 95% CI, 0.54-0.90). Conclusions: In this Western European sub-analysis of pooled data from the RE-COVER®/ RE-COVER II™ trials, dabigatran was as effective as warfarin in the treatment of acute VTE. There was a significant reduction in MBE/CRBE and in any bleeding events in the dabigatran treatment group. Disclosures Schellong: Boehringer Ingelheim: Consultancy. Eriksson:Boehringer Ingelheim: Consultancy. Goldhaber:Boehringer Ingelheim: Consultancy, Research Funding. Feuring:Boehringer Ingelheim: Employment. Hantel:Boehringer Ingelheim Pharma GmbH and Co. KG: Employment. Kreuzer:Boehringer Ingelheim Pharma GmbH and Co. KG: Employment. Schulman:Boehringer Ingelheim: Honoraria, Research Funding; Bayer: Honoraria; Baxter: Honoraria; Octapharma: Research Funding. Kakkar:Boehringer Ingelheim: Consultancy, Honoraria, Research Funding.

Factor XI Antisense Oligonucleotide for Prevention of Venous Thrombosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. LBA-1-LBA-1
Author(s):  
Harry Roger Buller ◽  
Claudette Bethune ◽  
Sanjay Bhanot ◽  
David Gailani ◽  
Brett P. Monia ◽  
...  
Keyword(s):  
Health Care ◽  
Total Knee Arthroplasty ◽  
Knee Arthroplasty ◽  
Antisense Oligonucleotide ◽  
Research Funding ◽  
Primary Efficacy ◽  
Intrinsic Pathway ◽  
Primary Efficacy Outcome ◽  
Efficacy Outcome ◽  
Total Knee

Abstract BACKGROUND: Patients undergoing total knee arthroplasty are at risk for postoperative venous thromboembolism (VTE). The pathogenesis of postoperative VTE is incompletely understood, but tissue factor exposed at the surgical site is thought to be the major driver through the extrinsic pathway of coagulation. Experimental data indicate that reducing factor XI (FXI), a key component of the intrinsic pathway, attenuates thrombosis without causing bleeding, but the role of FXI in postoperative VTE in humans is unknown. There is evidence that patients with congenital FXI deficiency are at a reduced risk of VTE. FXI levels can be lowered with ISIS 416858 (FXI-ASO), an antisense oligonucleotide that specifically reduces human FXI mRNA expression in the liver. To determine whether lowering FXI levels prevents VTE without increasing the risk of bleeding, we compared several doses of FXI-ASO with enoxaparin on the rates of postoperative VTE and bleeding in patients undergoing total knee arthroplasty. METHODS: We randomized 300 patients to one of two FXI-ASO regimens (200 or 300 mg) or to 40 mg enoxaparin once daily in an open-label, parallel group study. FXI-ASO was administered as 9 subcutaneous injections starting 36 days before surgery with the last dose given 3 days postoperatively. Enoxaparin was to be continued for at least 8 days postoperatively. The primary efficacy outcome was the incidence of VTE detected by mandatory bilateral venography (performed on days 8 to 12 postoperatively) or symptomatic events. The principal safety outcome was major and clinically relevant nonmajor bleeding. All outcomes were adjudicated by a committee blinded to treatment allocation. RESULTS: FXI-ASO prolonged the activated partial thromboplastin time in a dose-dependent manner, but had no effect on the prothrombin time. Around the time of surgery, mean FXI activities were 0.38 ± 0.01, 0.20 ± 0.01 and 0.93 ± 0.02 units/ml in patients given the 200 and 300 mg FXI-ASO regimens and enoxaparin, respectively. In contrast, levels of FXII, FIX and FVIII, other components of the intrinsic pathway, were unaffected by FXI-ASO. The primary efficacy outcome occurred in 36 of 134 (26.9%) and 3 of 71 (4.2%) patients given the 200 and 300 mg FXI-ASO regimens, respectively, compared with 21 of 69 (30.4%) patients in the enoxaparin group. The 200 mg regimen was non-inferior, while the 300 mg regimen was superior to enoxaparin (P<0.001). Bleeding occurred in 2.8%, 2.6% and 8.3% of patients in the 200 mg, 300 mg, and enoxaparin groups, respectively. Preoperative and postoperative hemoglobin values and transfusion requirements were similar in the three treatment groups. CONCLUSIONS: This study is the first to show that FXI contributes to postoperative VTE and that lowering FXI levels is very effective for its prevention and appears to be safe. Additional studies are needed to confirm the safety of FXI-ASO, although the fact that patients receiving this therapy safely underwent major orthopedic surgery is reassuring. Our findings support the concept that thrombosis and hemostasis can be dissociated with strategies that target FXI. The profile of FXI-ASO renders it an appealing option for treatment of patients with a wide range of chronic thrombotic conditions. Disclosures Buller: Isis Pharmaceuticals Daiichi-Sankyo Bayer Health-Care Pfizer Bristol-Myers-Squibb: Consultancy, Honoraria. Bethune:Isis Pharmaceuticals: Employment. Bhanot:Isis Pharmaceuticals: Employment. Gailani:Aronora: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Dyax: Consultancy, Research Funding; Instrument Laboratory: Consultancy, Research Funding; Isis: Consultancy; Merck: Consultancy; Novartis: Consultancy. Monia:Isis Pharmaceuticals, Inc.: Employment. Raskob:Bayer Healthcare: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; ISIS Pharmaceuticals: Consultancy, Honoraria. Segers:Isis Pharmaceuticals Daiichi-Sankyo Bayer Health-Care Pfizer Bristol-Myers-Squibb: Medical Director ofAcademic Research Organization which received services fees for the scientific coordination of clinical studies Other. Weitz:Pfizer, Inc.: Consultancy, Honoraria.

scholarly journals 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

2021 ◽  
Author(s):  
Nuccia Morici ◽  
Gian Marco Podda ◽  
Simone Birocchi ◽  
Luca Bonacchini ◽  
Marco Merli ◽  
...  
Keyword(s):  
Pulmonary Artery ◽  
Major Bleeding ◽  
Primary Efficacy ◽  
Bleeding Events ◽  
Primary Analysis ◽  
Primary Efficacy Outcome ◽  
Symptomatic Pulmonary Embolism ◽  
Imaging Characteristics ◽  
Efficacy Outcome ◽  
General Wards

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.

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