primary efficacy outcome
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2021 ◽  
Author(s):  
Nuccia Morici ◽  
Gian Marco Podda ◽  
Simone Birocchi ◽  
Luca Bonacchini ◽  
Marco Merli ◽  
...  

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.


Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Matthew J. Swanson ◽  
James L. Johnston ◽  
Joseph S. Ross

Abstract 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.


Author(s):  
Scott C. Woller ◽  
Scott M Stevens ◽  
David Kaplan ◽  
Tzu-Fei Wang ◽  
D. Ware Branch ◽  
...  

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).


Author(s):  
María Marcos ◽  
Francisco Carmona-Torre ◽  
Rosa Vidal Laso ◽  
PEDRO RUIZ-ARTACHO ◽  
David Filella ◽  
...  

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.


Author(s):  
Olivier Sanchez ◽  
Anais Charles-Nelson ◽  
Walter Ageno ◽  
Stefano Barco ◽  
Harald Binder ◽  
...  

Intermediate high-risk pulmonary embolism (PE) is characterised by right ventricular (RV) dysfunction and elevated circulating cardiac troponin levels despite apparent haemodynamic stability at presentation. In these patients, full-dose systemic thrombolysis reduced the risk of haemodynamic decompensation or death but increased the risk of life-threatening bleeding. Reduced-dose thrombolysis may be capable of improving safety while maintaining reperfusion efficacy. The Pulmonary Embolism International Trial (PEITHO)-3 study (EudraCT 2018-000816-96) is a randomised, placebo-controlled, double-blind, multicentre, multinational trial with long-term follow-up. We will compare the efficacy and safety of a reduced-dose alteplase regimen with standard heparin anticoagulation. Patients with intermediate high-risk PE will also fulfil at least one clinical criterion of severity: systolic blood pressure ≤ 110 mmHg, respiratory rate >20 breaths/min, or history of heart failure. The primary efficacy outcome is the composite of all-cause death, haemodynamic decompensation or PE recurrence within 30 days of randomisation. Key secondary outcomes, to be included in hierarchical analysis, are fatal or GUSTO severe or life-threatening bleeding; net clinical benefit (primary efficacy outcome plus severe or life-threatening bleeding); and all-cause death, all within 30 days. All outcomes will be adjudicated by an independent committee. Further outcomes include PE-related death, haemodynamic decompensation, or stroke within 30 days; dyspnoea, functional limitation or RV dysfunction at 6 months and 2 years; and utilisation of healthcare resources within 30 days and 2 years. The study is planned to enrol 650 patients. The results are expected to have a major impact on risk-adjusted treatment of acute PE and inform guideline recommendations.


Stroke ◽  
2021 ◽  
Author(s):  
Haruhiko Hoshino ◽  
Kazunori Toyoda ◽  
Katsuhiro Omae ◽  
Noriyuki Ishida ◽  
Shinichiro Uchiyama ◽  
...  

Background and Purpose: Although dual antiplatelet therapy (DAPT) with aspirin and clopidogrel reduces the recurrence of ischemic stroke while significantly increasing the bleeding events compared with monotherapy, the CSPS.com trial (Cilostazol Stroke Prevention Study combination) showed that DAPT using cilostazol was more effective without the bleeding risk. In the CSPS.com trial, aspirin or clopidogrel was used as the underlying antiplatelet drug. The effectiveness and safety of each combination were examined and clarified. Methods: In the CSPS.com trial, a multicenter, open-label, randomized controlled study, patients with high-risk, noncardioembolic ischemic stroke 8 to 180 days after onset treated with aspirin or clopidogrel alone at the discretion of the physician in charge were recruited. Patients were randomly assigned to receive either monotherapy or DAPT using cilostazol and followed for 0.5 to 3.5 years. The primary efficacy outcome was first recurrence of ischemic stroke. The safety outcome was severe or life-threatening bleeding. The analysis was based on the underlying antiplatelet agents. Results: A total of 763 patients taking aspirin and 1116 taking clopidogrel were included in the intention-to-treat analysis. Although the clopidogrel group had more risk factors than the aspirin group, the primary efficacy outcome and safety outcome did not differ significantly between the 2 groups. In the aspirin group, the primary efficacy outcome and safety outcome did not differ significantly between the DAPT group and the aspirin-monotherapy group. In the clopidogrel group, the primary end point occurred at a rate of 2.31 per 100 patient-years in the DAPT group and 5.19 per 100 patient-years in the clopidogrel-monotherapy group (hazard ratio, 0.447 [95% CI, 0.258–0.774]). Safety outcome did not differ significantly between groups (0.51 per 100 patient-years versus 0.71 per 100 patient-years, respectively; hazard ratio, 0.730 [95% CI, 0.206–2.588]). Conclusions: The combination of cilostazol and clopidogrel significantly reduced the recurrence of ischemic stroke without increasing the bleeding risk in noncardioembolic, high-risk patients. REGISTRATION: URL: http://www.clinicaltrials.gov ; Unique identifier: NCT01995370. URL: https://www.umin.ac.jp/ctr/ ; Unique identifier: UMIN000012180.


2021 ◽  
Author(s):  
Matthew J. Swanson ◽  
James L. Johnston ◽  
Joseph S. Ross

ABSTRACTBackgroundSelective registration, publication, and outcome reporting of clinical trials distorts the primary clinical evidence that is available to patients and clinicians regarding the safety and efficacy of 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) medical devices before and after the U.S. Food and Drug Administration (FDA) Amendment Act (FDAAA) was enacted in 2007.MethodsUsing 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 PMA primary efficacy outcome and the published interpretation of findings with the FDA reviewer’s interpretation (positive, equivocal, or negative).ResultsBetween 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 115 (85%) vs 7 of 24 (29%); 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).ConclusionsFDAAA was associated with increased registration, results 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.


Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Alexandra Kvernland ◽  
Sara K Rostanski ◽  
Brian Mac Grory ◽  
Adam H De Havenon ◽  
Ava Liberman ◽  
...  

Background: The combination of aspirin and clopidogrel for 90 days after minor stroke or transient ischemic attack (TIA) reduced the risk of recurrent stroke in the POINT trial. The risk reduction was greater in patients with infarct on CT or MRI compared to those without infarct. Objective: To investigate the effect of DAPT on minor stroke and TIA in the POINT trial based on (1) the presence or absence of infarct attributed to the index event (“index infarct”) and (2) whether the index event was classified as stroke or TIA. Design/Methods: Patients were divided into two groups based on whether they had an “index infarct” or not. Baseline demographics and clinical variables were compared between groups using standard statistical tests. We used univariate and multivariable cox-regression models to determine associations between presence of infarct on imaging and primary and secondary outcomes, and interaction analyses to determine whether the presence of “index infarct” modifies the effect of DAPT on study outcomes. We also explored whether the association of “index-infarct” with primary and secondary outcomes varied by index diagnosis (TIA vs. minor stroke). Results: Amongst 4881 enrolled in POINT, 4876 patients had data on whether there was an “index-infarct”; 1793 (36.8%) had “index-infarct”. In adjusted cox-regression analyses, the presence of “index infarct” was associated with the primary efficacy outcome (HR 3.02 95% CI 2.34-3.89, p < 0.01) and subsequent ischemic stroke (HR 3.10 95% CI 2.39-4.02, p < 0.01). The effect of DAPT vs. aspirin on primary efficacy outcome was more pronounced in patients with “index infarct” (HR 0.58 95% CI 0.43-0.79, p <0.01) vs. those without (HR 1.16 95% CI 0.79-1.71, p=0.44) (p for interaction = 0.01). In a secondary analysis based on final diagnosis, the effect of “index infarct” on primary outcome was only significant in those with minor stroke at the time of randomization (p for interaction=0.01) but not TIA at the time of randomization (p for interaction=0.36). Conclusions: In the POINT trial, efficacy of DAPT was greater in patients with infarct on imaging attributed to the index event. Future work should focus on determining clinical factors associated with this group to help identify patients most likely to benefit from acute DAPT.


2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
L Hobohm ◽  
T Anusic ◽  
S.V Konstantinides ◽  
S Barco

Abstract Background and aims Subgroup analyses of randomized trials and cohort studies on direct oral anticoagulants (DOACs) suggested that single direct drug treatment may be effective and safe in elderly and “fragile” patients with acute pulmonary embolism (PE). In a post-hoc analysis of HoT-PE, a prospective multicenter management trial, we studied whether early discharge and home treatment of acute PE is effective and safe in these patients. Methods HoT-PE enrolled patients with acute PE classified as being at low risk based on the modified Hestia criteria and the absence of right ventricular dysfunction. The primary efficacy outcome was symptomatic recurrent VTE, or PE-related death within 3 months of enrolment. The safety outcome included major bleeding. Fragility was defined as age &gt;75 years, a creatinine clearance level &lt;50 ml/min, or a body mass index &lt;18.5 kg/cm2. Results A total of 524 patients were included; of these, 112 (21.4%) were fragile. Mean age was 77 (range 74–80) years. A total of 104 (92.9%) fragile and 372 (90.3%) non-fragile patients spent two nights or less in hospital corresponding to a median hospital stay of 42 (Q1-Q3: 25–47) and 32 (Q1-Q3: 23–46) hours, respectively. The primary efficacy outcome occurred in one (0.9%) fragile and one (0.5%) non-fragile patient (absolute risk difference [ARD] +0.4%; 95% CI: −1.1%; +4.4%). Major bleeding occurred in three (2.7%) fragile and three (0.7%) non-fragile patients; ARD +2.0% (+0.3%; +6.9%). All-cause 3-month mortality was low in both groups (0.9% vs. 0.2%; ARD +0.7%, −0.7%; +4.7%). Conclusion Early discharge and home treatment of fragile patients with acute PE appears to be feasible and acceptably safe. The HoT-PE trial supports the notion that these patients should not be a priori excluded from early discharge, but caution is warranted due to a possibly higher risk of major bleeding on DOAC treatment. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): This study was supported by the German Federal Ministry of Education and Research (BMBF 01EO1503).


2020 ◽  
Vol 25 (5) ◽  
pp. 168-171 ◽  
Author(s):  
Brian Scott Alper ◽  
Gary Foster ◽  
Lehana Thabane ◽  
Alex Rae-Grant ◽  
Meghan Malone-Moses ◽  
...  

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.


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