Reduced-dose intravenous thrombolysis for acute intermediate high-risk pulmonary embolism: Rationale and design of the PEITHO-3 trial

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.

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

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa031.312 ◽

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.

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The MARINER trial of rivaroxaban after hospital discharge for medical patients at high risk of VTE

Thrombosis and Haemostasis ◽

10.1160/th15-09-0756 ◽

2016 ◽

Vol 115 (06) ◽

pp. 1240-1248 ◽

Cited By ~ 40

Author(s):

Alex Spyropoulos ◽

Julie Zrubek ◽

Walter Ageno ◽

Gregory Albers ◽

C. Elliott ◽

...

Keyword(s):

Venous Thromboembolism ◽

High Risk ◽

Hospital Discharge ◽

Assessment Model ◽

Primary Efficacy ◽

Medical Patients ◽

Once Daily ◽

Primary Efficacy Outcome ◽

Efficacy Outcome ◽

D Dimer

SummaryHospital-associated venous thromboembolism (VTE) is a leading cause of premature death and disability worldwide. Evidence-based guidelines recommend that anticoagulant thromboprophylaxis be given to hospitalised medical patients at risk of VTE, but suggest against routine use of thromboprophylaxis beyond the hospital stay. The MARINER study is a randomised, double-blind, placebo-controlled trial to evaluate the efficacy and safety of thromboprophylaxis using rivaroxaban, begun at hospital discharge and continued for 45 days, for preventing symptomatic VTE in high-risk medical patients. Eligible patients are identified using the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE VTE) risk score, combined with a laboratory test, D-dimer. The rivaroxaban regimen is 10 mg once daily for patients with CrCl ≥ 50 ml/min, or 7.5 mg once daily for patients with CrCl ≥ 30 ml/min and < 50 ml/ min. The primary efficacy outcome is the composite of symptomatic VTE (lower extremity deep-vein thrombosis and non-fatal pulmonary embolism) and VTE-related death. The principal safety outcome is major bleeding. A blinded clinical events committee adjudicates all suspected outcome events. The sample size is event-driven with an estimated total of 8,000 patients to acquire 161 primary outcome events. Study design features that distinguish MARINER from previous and ongoing thromboprophylaxis trials in medically ill patients are: (i) use of a validated risk assessment model (IMPROVE VTE) and D-dimer determination for identifying eligible patients at high risk of VTE, (ii) randomisation at the time of hospital discharge, (iii) a 45-day treatment period and (iv) restriction of the primary efficacy outcome to symptomatic VTE events.

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Randomized Double-Blind Comparison of Apixaban with Enoxaparin for Thromboprophylaxis after Knee Replacement: The ADVANCE-1 Trial

Blood ◽

10.1182/blood.v112.11.31.31 ◽

2008 ◽

Vol 112 (11) ◽

pp. 31-31 ◽

Cited By ~ 3

Author(s):

Michael Rud Lassen ◽

Alexander S Gallus ◽

Graham F Pineo ◽

Gary E Raskob ◽

Keyword(s):

Relative Risk ◽

Knee Replacement ◽

Major Bleeding ◽

Phase Iii ◽

Primary Efficacy ◽

Double Blind ◽

Primary Efficacy Outcome ◽

Efficacy Outcome ◽

Total Knee ◽

Statistical Criteria

Abstract Thromboprophylaxis with enoxaparin after total knee replacement is an evidence-based recommended standard of care. The ADVANCE-1 clinical trial was a phase III randomized double-blind multicenter study that evaluated the efficacy and safety of apixaban, an oral direct factor Xa inhibitor, 2.5 mg orally bid compared with enoxaparin 30 mg subcutaneously every 12 hours for preventing venous thromboembolism after total knee replacement. Apixaban (or oral placebo) and enoxaparin (or subcutaneous placebo) were begun 12 to 24 hours post-operatively (mean 20 hours) and continued until mandatory bilateral venography was completed at 12± 2 days. The primary efficacy outcome was the composite of deep-vein thrombosis (DVT) by venography; symptomatic, objectively confirmed DVT or pulmonary embolism (PE); or death from any cause during the treatment period. The secondary efficacy outcome was the composite of objectively confirmed proximal DVT or PE, or death. The primary safety outcome was bleeding, including major bleeding (defined by ISTH criteria), clinically relevant non-major bleeding, and minor bleeding. All outcome events were interpreted by a central independent adjudication committee without knowledge of treatment. The study hypothesis was that apixaban would be as effective as enoxaparin based on a pre-specified non-inferiority margin in which the upper limit of the two-sided 95% CI is < 1.25 for relative risk and < 5.6% for the absolute risk difference for the primary efficacy outcome. A total of 3195 patients from 129 sites in 14 countries were randomized. The primary efficacy outcome occurred in 104 of 1157 patients (8.99%) given apixaban and in 100 of 1130 (8.85%) given enoxaparin (relative risk 1.02, 95% CI 0.78 to 1.32, one-sided p= 0.064 for non-inferiority, statistical criteria not met). The secondary efficacy outcome occurred in 26 patients (2.05%) given apixaban and in 20 patients (1.64%) given enoxaparin. Symptomatic PE occurred in 16 patients (1.0%) who received apixaban (2 fatal) and in 7 patients (0.44%) given enoxaparin (0 fatal); the majority of the PE in apixaban patients occurred within 48 hours postoperatively. Major or clinically relevant non-major bleeding occurred in 46 of 1596 patients (2.88%) given apixaban, compared with 68 patients (4.28%) given enoxaparin (absolute difference 1.46%, two-sided p=0.034). Major bleeding occurred in 11patients (0.69%) who received apixaban and in 22 patients (1.39%) who received enoxaparin (two-sided p=0.053). Elevated levels of liver transaminase enzymes were uncommon (2% to 3%) in both groups; no patient given apixaban met Hy’s criteria. Myocardial infarction or stroke occurred in only one patient who received apixaban (0.06%) and in 5 patients (0.31%) given enoxaparin. The lower-than-expected incidence of the primary efficacy outcome in the enoxaparin group resulted in an undersized study to meet the pre-defined statistical criteria for non-inferiority in spite of a similar incidence with the apixaban regimen. This is the first phase III trial to demonstrate a potential advantage of the new oral anticoagulants for bleeding. The apixaban regimen resulted in less clinically relevant bleeding than enoxaparin 30 mg given every 12 hours. Maintaining this advantage while optimizing efficacy with an altered dosing regimen, either by earlier postoperative dosing or by a slightly increased dose, would be an important advance in patient care.

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Rivaroxaban Versus Fondaparinux in the Treatment of Superficial Vein Thrombosis - the Surprise Trial

Blood ◽

10.1182/blood.v128.22.85.85 ◽

2016 ◽

Vol 128 (22) ◽

pp. 85-85 ◽

Cited By ~ 1

Author(s):

Jan Beyer-Westendorf ◽

Sebastian Schellong ◽

Horst Gerlach ◽

Katja Jersemann ◽

Eberhard Rabe ◽

...

Keyword(s):

High Risk ◽

Major Bleeding ◽

Research Funding ◽

Absolute Difference ◽

Primary Efficacy ◽

Primary Efficacy Outcome ◽

Vein Thrombosis ◽

Efficacy Outcome ◽

Superficial Vein Thrombosis ◽

Full Analysis

Abstract Background The current standard of therapy in superficial vein thrombosis (SVT) comprises subcutaneous injections of the indirect factorXainhibitorfondaparinuxfor up to 45 days, which was highlyeffectivecompared to placebo in the CALISTO trial. However,fondaparinuxis expensive, requires daily injections and cost-effectiveness in SVT therapy has been questioned. Rivaroxaban is a direct oral factorXainhibitor which has been shown to be effective in the prevention and treatment of venous thromboembolism (VTE). We hypothesizedthat SVT patientsat high risk for VTE complications may be treated as efficacious and safe with rivaroxaban as withfondaparinux. Methods The SURPRISE trial, a randomized, open-label blinded outcome event adjudication trial, compared rivaroxaban 10 mg once daily withfondaparinux2.5 mg once daily in patients with SVT at high risk of VTE complications (defined assupragenualSVT + age > 65 years, male sex, previous VTE, cancer, autoimmune disease or SVT of non-varicose veins). Treatment duration for both treatments was 45+5 days with an observational period until day 90+10. The primary efficacy outcome was a composite endpoint of deep vein thrombosis, pulmonary embolism, SVT progression towards thesaphenofemoraljunction, SVT recurrence or all cause death in the per-protocol analysis at day 45. A predefined sensitivity analysis was performed in all randomized patients (full analysis set). The primary safety outcome was the rate of ISTH major bleeding during treatment. Further outcome measures included the composite efficacy outcome up to day 90, each component of the primary efficacy outcome, rates of surgical treatment of SVT and rates of major VTE (composite of symptomatic PE or symptomatic proximal DVT or VTE-related death) at days 45 and 90. The trial was designed to test for non-inferiority of rivaroxaban compared tofondaparinuxwith respect to the primary efficacy outcome and to the rates of ISTH major bleeding. Results A total of 472 patients were randomized (mean age 60.3 years; 60.4% female) and treated with rivaroxaban (n=236) orfondaparinux(n=236). Mean treatment duration was 44.0 days for rivaroxaban and 44.8 days forfondaparinux. Until day 45+5, the primary efficacy outcome (n=435 in per-protocol analysis set) occurred in 3.3% (95%-CI 0.90; 5.73) of patients treated with rivaroxaban and 1.8% (95%-CI 0.05; 3.52) of patients receivingfondaparinux(absolute difference between rivaroxaban andfondaparinuxwas 1.53%; one-sided upper CI limit 4.03%; p-value for non-inferiority 0.025; table 1 and figure 1). Until day 90+10, the respective rates were 7.1% for rivaroxaban and 6.7% forfondaparinux(absolute difference 0.41;one-sided upper CI limit 4.41%;p-value for non-inferiority 0.047). Non-inferiority of rivaroxaban vs.fondaparinuxwas preserved in the full analysis set. No major bleeding occurred and rates of non-major, clinically relevant bleeding were 2.5 vs. 0.4% for day 45+5 and 2.5 vs. 0.9% for day 90+10 in safety set for rivaroxaban andfondaparinux, respectively (table 1).Mean±SDadherence (pill/syringe count at day 45) was 98.9±13.4% for rivaroxaban and 99.3±6.2% forfondaparinux(full analysis set). Conclusions In high-risk SVT patients, rivaroxaban was non-inferior tofondaparinuxin preventing thromboembolic complications with comparable safety. VTE events were predominantly SVT recurrence. Few cases of DVT and PE occurred, which indicates that a 45 days course of rivaroxaban 10 mg orfondaparinux2.5 mg is sufficient to prevent serious complications in this specific subset of SVT patients. As to whether oral rivaroxaban offers a better quality of life compared to 45 days of injections, this has to be investigated in future studies. We found higher SVT complications rates in both treatment arms compared to thefondaparinuxarm in the CALISTO trial. Therefore, patients at higher VTE risk can be identified by use of a simple risk factor assessment, which may help to improve cost-effectiveness of SVT therapy. However, the concept of SVT risk stratification needs to be further investigated, since patients without additional risk factors may not need anticoagulant therapy at all. (Funded by Bayer Vital GmbH, Germany, ClinicalTrials.gov NCT01499953) In response to a pre-submission enquiry, the New England Journal of Medicine indicated potential interest in the study results and a simultaneous publication/presentation is targeted. Disclosures Beyer-Westendorf: Daichii Sankyo: Consultancy, Honoraria, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; LEO: Consultancy, Honoraria, Research Funding. Schellong:Bayer: Honoraria; Pfizer: Honoraria; Boehringer-Ingelheim: Honoraria; Daichii Sankyo: Honoraria; LeoPharma: Honoraria. Gerlach:ASPEN: Honoraria; Bayer: Honoraria; Boehringer-Ingelheim: Honoraria; LeoPharma.: Honoraria. Rabe:Bayer: Honoraria; Boehringer Ingelheim: Honoraria; Daichii-Sankyo: Honoraria; LeoPharma: Honoraria; Pfizer: Honoraria. Bauersachs:Bayer: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding; BristolMyers Squibb: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; ASPEN: Honoraria, Research Funding.

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Home treatment of fragile patients with acute pulmonary embolism: a subgroup analysis of the multinational home treatment of pulmonary embolism (HoT-PE) trial

European Heart Journal ◽

10.1093/ehjci/ehaa946.2269 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

L Hobohm ◽

T Anusic ◽

S.V Konstantinides ◽

S Barco

Keyword(s):

Pulmonary Embolism ◽

Major Bleeding ◽

Acute Pulmonary Embolism ◽

Early Discharge ◽

Home Treatment ◽

Funding Source ◽

Primary Efficacy ◽

Primary Efficacy Outcome ◽

Efficacy Outcome ◽

Acute Pe

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 >75 years, a creatinine clearance level <50 ml/min, or a body mass index <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).

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Registration, Publication, and Outcome Reporting among Pivotal Clinical Trials that Supported FDA Approval of High-Risk Medical Devices Before and After FDAAA

10.1101/2021.02.28.21252619 ◽

2021 ◽

Author(s):

Matthew J. Swanson ◽

James L. Johnston ◽

Joseph S. Ross

Keyword(s):

Clinical Trials ◽

High Risk ◽

Medical Devices ◽

Primary Efficacy ◽

Cardiovascular Devices ◽

Primary Efficacy Outcome ◽

Outcome Reporting ◽

Fda Approval ◽

Efficacy Outcome ◽

Before And After

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.

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Repeated and adaptive multidisciplinary assessment of a patient with acute pulmonary embolism and recurrent cardiac arrests

BMJ Case Reports ◽

10.1136/bcr-2020-234647 ◽

2020 ◽

Vol 13 (9) ◽

pp. e234647

Author(s):

Karin Fryk ◽

Christian Rylander ◽

Kristina Svennerholm

Keyword(s):

Pulmonary Embolism ◽

Cardiac Arrest ◽

High Risk ◽

Intravenous Thrombolysis ◽

Initial Therapy ◽

Complex Case ◽

Therapeutic Decisions ◽

Threatening Condition ◽

Life Threatening ◽

Va Ecmo

High-risk pulmonary embolism (PE) is a life-threatening condition that must be recognised and treated rapidly. The importance of correct risk stratification to guide therapeutic decisions has prompted the introduction of multidisciplinary PE response teams (PERTs). The recommended first-line treatment for high-risk PE is intravenous thrombolysis. Alternatives to consider if thrombolysis has insufficient effect or may cause significant haemorrhagic complications include catheter-directed intervention (CDI) and surgical thrombectomy. For patients in deep shock or cardiac arrest, veno-arterial extracorporeal membrane oxygenation (VA-ECMO) can be instituted for cardiopulmonary rescue and support during CDI, thrombectomy or pharmacological treatment. We present a complex case of high-risk PE that illustrates the importance of an early PERT conference and repeated decision-making when the initial therapy fails. After a trial of thrombolysis with insufficient effect, VA-ECMO was used to reverse circulatory and respiratory collapse in a patient with PE and recurrent episodes of cardiac arrest.

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Dual Antiplatelet Therapy Using Cilostazol With Aspirin or Clopidogrel: Subanalysis of the CSPS.com Trial

Stroke ◽

10.1161/strokeaha.121.034378 ◽

2021 ◽

Author(s):

Haruhiko Hoshino ◽

Kazunori Toyoda ◽

Katsuhiro Omae ◽

Noriyuki Ishida ◽

Shinichiro Uchiyama ◽

...

Keyword(s):

Ischemic Stroke ◽

High Risk ◽

Dual Antiplatelet Therapy ◽

Bleeding Risk ◽

Primary Efficacy ◽

Monotherapy Group ◽

Unique Identifier ◽

Primary Efficacy Outcome ◽

Safety Outcome ◽

Efficacy Outcome

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.

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

Trials ◽

10.1186/s13063-021-05790-9 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Matthew J. Swanson ◽

James L. Johnston ◽

Joseph S. Ross

Keyword(s):

Clinical Trials ◽

High Risk ◽

Medical Devices ◽

Primary Efficacy ◽

Cardiovascular Devices ◽

Primary Efficacy Outcome ◽

Outcome Reporting ◽

Fda Approval ◽

Efficacy Outcome ◽

Before And After

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.

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Acute pulmonary embolism in COVID-19 patient: a case report of free-floating right heart thrombus successfully treated with fibrinolysis

European Heart Journal - Case Reports ◽

10.1093/ehjcr/ytaa388 ◽

2020 ◽

Author(s):

Fernando Scudiero ◽

Antonino Pitì ◽

Roberto Keim ◽

Guido Parodi

Keyword(s):

Pulmonary Embolism ◽

High Risk ◽

Retrospective Studies ◽

Right Heart ◽

Clinical Issue ◽

Systemic Thrombolysis ◽

Case Summary ◽

High Prevalence ◽

Life Threatening ◽

Complex Scenario

Abstract Background Despite the fast-growing understanding of the coronavirus disease 2019 (COVID-19), patient management remains largely empirical or based on retrospective studies. In this complex scenario, an important clinical issue appears to be represented by the high prevalence of thromboembolic events, but the data regarding high-risk pulmonary embolism (PE) is still not available. Case summary A patient with COVID-19 developed sudden shortness of breath and hypoxia. Early echocardiographic diagnosis of high-risk PE related to right heart thrombus was performed. Systemic thrombolysis was administered with excellent clinical and haemodynamic response. Discussion Pulmonary thromboembolism is a common occurrence in severe COVID-19 infection. In our experience, systemic thrombolysis proved to be effective and for this reason may be considered for life-threatening PE in COVID-19 patients.

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