More ethical and more efficient clinical research:multiplex trial design

BACKGROUND: Today's clinical research faces challenges such as a lack of clinical equipoise between treatment arms, reluctance in randomizing for multiple treatments simultaneously, inability to address interactions and increasingly restricted resources. Furthermore, many trials are biased by extensive exclusion criteria, relatively small sample size and less appropriate outcome measures. FINDINGS: We propose a 'Multiplex' trial design that preserves clinical equipoise with a continuous and factorial trial design that will also result in more efficient use of resources. This multiplex design accommodates subtrials with appropriate choice of treatment arms within each subtrial. Clinical equipoise should increase consent rates while the factorial design is the best way to identify interactions. CONCLUSION: The multiplex design may evolve naturally from today's research limitations and challenges, while principal objections seem absent. However this new design poses important infrastructural, organisational and psychological challenges that need in depth consideration

Preferences for thromboprophylaxis in the intensive care unit: An international survey

Intensive care unit; Survey; ThromboprophylaxisUnidades de cuidados intensivos; Encuesta; TromboprofilaxisUnitat de cures intensives; Enquesta; TromboprofilaxiBackground Venous thromboembolism (VTE) is a frequent complication in critically ill patients, who often have multiple risk factors. Pharmacological thromboprophylaxis is widely applied to lower this risk, but guidelines lack dosing recommendations. Objective This survey aims to assess current thromboprophylaxis preferences and willingness to participate in future randomized clinical trials (RCTs) on this topic. Method We conducted an international online survey between February and May 2023 among intensive care unit (ICU) physicians, including 16 questions about preferences in relation to thromboprophylaxis and preferences on topics for a future RCT. The survey was distributed through the network of the Collaboration for Research in Intensive Care. Results A total of 715 physicians from 170 ICUs in 23 countries contributed information, with a mean response rate of 36%. In most ICUs, both pharmacological (n = 166, 98%) and mechanical thromboprophylaxis (n = 143, 84%) were applied. A total of 36 pharmacological thromboprophylaxis regimens were reported. Use of low-molecular-weight heparin (LMWH) was most common (n = 149 ICUs, 87%), followed by subcutaneous unfractionated heparin (n = 44 ICUs, 26%). Seventy-five percent of physicians indicated that they used enoxaparin 40 mg (4000 IU), dalteparin 5000 IU, or tinzaparin 4500 IU once daily, whereas 25% reported the use of 16 other LMWH type and dose combinations. Dose adjustment according to weight was common (78 ICUs, 46%). Participants perceived high variation in the application of thromboprophylaxis and were willing to consider an alternative LMWH type (n = 542, 76%) or dose (n = 538, 75%) in the context of an RCT. Conclusion LMWH was the preferred agent for thromboprophylaxis in critically ill patients. There was considerable variation in the application of LMWH for prophylaxis, reflected by the use of different types, doses, and dosing strategies. Most physicians would be willing to participate in an RCT on thromboprophylaxis. Editorial comment This survey demonstrates current patterns in implementation preferences for critically ill patients. While there is one approach and drug that is commonly preferred, these findings show that there is some variation in practice

Carotid endarterectomy with patch angioplasty versus primary closure in patients with symptomatic and significant stenosis:a systematic review with meta-analyses and trial sequential analysis of randomized clinical trials

Background: Patch angioplasty in conventional carotid endarterectomy is suggested to reduce the risk of restenosis and recurrent ipsilateral stroke compared with primary closure. A systematic review of randomized clinical trials is needed to compare outcomes (benefits and harms) of both techniques. Methods: Searches (CENTRAL, PubMed/MEDLINE, EMBASE, and other databases) were last updated 3rd of January 2021. We included randomized clinical trials comparing carotid endarterectomy with patch angioplasty versus primary closure of the arterial wall in patients with a symptomatic and significant (> 50%) carotid stenosis. Primary outcomes are defined as all-cause mortality and serious adverse events. Results: We included 12 randomized clinical trials including 2187 participants who underwent 2335 operations for carotid stenosis comparing carotid endarterectomy with patch closure (1280 operations) versus carotid endarterectomy with primary closure (1055 operations). Meta-analysis comparing carotid endarterectomy with patch angioplasty versus carotid endarterectomy with primary closure may potentially decrease the number of patients with all-cause mortality (RR 0.53; 95% CI 0.26 to 1.08; p = 0.08, best-case scenario for patch), serious adverse events (RR 0.73; 95% CI 0.56 to 0.96; p = 0.02, best-case scenario for patch), and the number of restenosis (RR 0.41; 95% CI 0.23 to 0.71; p < 0.01). Trial sequential analysis demonstrated that the required information sizes were far from being reached for these patient-important outcomes. All the patient-relevant outcomes were at low certainty of evidence according to The Grading of Recommendations Assessment, Development, and Evaluation. Conclusions: This systematic review showed no conclusive evidence of a difference between carotid endarterectomy with patch angioplasty versus primary closure of the arterial wall on all-cause mortality, < 30 days mortality, < 30 days stroke, or any other serious adverse events. These conclusions are based on data from 15 to 35 years ago, obtained in trials with very low certainty according to GRADE, and should be interpreted cautiously. Therefore, we suggest conducting new randomized clinical trials patch angioplasty versus primary closure in carotid endarterectomy in symptomatic patients with an internal carotid artery stenosis of 50% or more. Such trials ought to be designed according to the Standard Protocol Items: Recommendations for Interventional Trials statement (Chan et al., Ann Intern Med 1:200–7, 2013) and reported according to the Consolidated Standards of Reporting Trials statement (Schulz et al., 7, 2010). Until conclusive evidence is obtained, the standard of care according to guidelines should not be abandoned. Systematic review registration: PROSPERO CRD42014013416. Review protocol publication 2019 DOI: https://doi.org/10.1136/bmjopen-2018-026419

Carotid endarterectomy with primary closure versus patch angioplasty in patients with symptomatic and significant stenosis:protocol for a systematic review with meta-analyses and trial sequential analysis of randomised clinical trials

Introduction Use of patch angioplasty in carotid endarterectomy (CEA) is suggested to reduce the risk of restenosis and recurrent ipsilateral stroke. The objective is to conduct a systematic review with meta-analysis and trial sequential analysis as well as Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessments comparing the benefits and harms of CEA with primary closure of the arterial wall versus CEA with patch angioplasty in patients with a symptomatic and significant carotid stenosis.Methods and analysis The review shall be conducted according to this published protocol following the recommendations of the ` Cochrane' and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Randomised clinical trials comparing CEA with primary closure of the arterial wall versus CEA with patch angioplasty (regardless of used patch materials) in human adults with a symptomatic and significant carotid stenosis will be included. Primary outcomes are all-cause mortality at maximal follow-up, health-related quality of life and serious adverse events. Secondary outcomes are symptomatic or asymptomatic arterial occlusion or restenosis, and non-serious adverse events. We will primarily base our conclusions on meta-analyses of trials with overall low risk of bias. However, if pooled point estimates of all trials are similar to pooled point estimates of trials with overall low risk of bias and there is lack of a statistical significant interaction between estimates from trials with overall high risk of bias and trials with overall low risk of bias we will consider the precision achieved in all trials as the result of our meta-analyses.Ethics and dissemination The proposed systematic review will collect and analyse secondary data from published studies therefor ethical approval is not required. The results of the systematic review will be disseminated by publication in a peer-review journal and submitted for presentation at relevant conferences.</p

Intermediate Dose Low-Molecular-Weight Heparin for Thrombosis Prophylaxis:Systematic Review with Meta-Analysis and Trial Sequential Analysis

Different doses of low-molecular-weight heparin (LMWH) are registered and used for thrombosis prophylaxis. We assessed benefits and harms of thrombosis prophylaxis with a predefined intermediate-dose LMWH compared with placebo or no treatment in patients at risk of venous thromboembolism (VTE). We performed a systematic review with meta-analyses and trial sequential analyses (TSA) following The Cochrane Handbook for Systematic Reviews of Interventions . Medline, Cochrane CENTRAL, Web of Science, and Embase were searched up to December 2018. Trials were evaluated for risk of bias and quality of evidence was assessed following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Seventy randomized trials with 34,046 patients were included. Eighteen (26%) had overall low risk of bias. There was a small statistically significant effect of LMWH on all-cause mortality (risk ratio [RR]: 0.96; TSA-adjusted confidence interval [TSA-adjusted CI]: 0.94-0.98) which disappeared in sensitivity analyses excluding ambulatory cancer patients (RR: 0.99; TSA-adjusted CI: 0.84-1.16). There was moderate-quality evidence for a statistically significant beneficial effect on symptomatic VTE (odds ratio [OR]: 0.59; TSA-adjusted CI: 0.53-0.67; number needed to treat [NNT]: 76; 95% CI: 60-106) and a statistically significant harmful effect on major bleeding (Peto OR: 1.66; TSA-adjusted CI: 1.31-2.10; number needed to harm [NNH]: 212; 95% CI: 142-393). There were no significant intervention effects on serious adverse events. The use of intermediate-dose LMWH for thrombosis prophylaxis compared with placebo or no treatment was associated with a small statistically significant reduction of all-cause mortality that disappeared in sensitivity analyses excluding trials that evaluated LMWH for anticancer treatment. Intermediate-dose LMWH provides benefits in terms of VTE prevention while it increases major bleeding

Clinical examination for diagnosing circulatory shock

Purpose of review: In the acute setting of circulatory shock, physicians largely depend on clinical examination and basic laboratory values. The daily use of clinical examination for diagnostic purposes contrasts sharp with the limited number of studies. We aim to provide an overview of the diagnostic accuracy of clinical examination in estimating circulatory shock reflected by an inadequate cardiac output (CO). Recent findings: Recent studies showed poor correlations between CO and mottling, capillary refill time or central-to-peripheral temperature gradients in univariable analyses. The accuracy of physicians to perform an educated guess of CO based on clinical examination lies around 50% and the accuracy for recognizing a low CO is similar. Studies that used predefined clinical profiles composed of several clinical examination signs show more reliable estimations of CO with accuracies ranging from 81 up to 100%. Summary: Single variables obtained by clinical examination should not be used when estimating CO. Physician's educated guesses of CO based on unstructured clinical examination are like the flip of a coin'. Structured clinical examination based on combined clinical signs shows the best accuracy. Future studies should focus on using a combination of signs in an unselected population, eventually to educate physicians in estimating CO by using predefined clinical profiles

Cost-minimization analysis in a blind randomized trial on small-incision versus laparoscopic cholecystectomy from a societal perspective: sick leave outweighs efforts in hospital savings

Background: After its introduction, laparoscopic cholecystectomy rapidly expanded around the world and was accepted the procedure of choice by consensus. However, analysis of evidence shows no difference regarding primary outcome measures between laparoscopic and small-incision cholecystectomy. In absence of clear clinical benefit it may be interesting to focus on the resource use associated with the available techniques, a secondary outcome measure. This study focuses on a difference in costs between laparoscopic and small-incision cholecystectomy from a societal perspective with emphasis on internal validity and generalisability Methods: A blinded randomized single-centre trial was conducted in a general teaching hospital in The Netherlands. Patients with reasonable to good health diagnosed with symptomatic cholecystolithiasis scheduled for cholecystectomy were included. Patients were randomized between laparoscopic and small-incision cholecystectomy. Total costs were analyzed from a societal perspective. Results: Operative costs were higher in the laparoscopic group using reusable laparoscopic instruments (difference 203 euro; 95% confidence interval 147 to 259 euro). There were no significant differences in the other direct cost categories (outpatient clinic and admittance related costs), indirect costs, and total costs. More than 60% of costs in employed patients were caused by sick leave. Conclusion: Based on differences in costs, small-incision cholecystectomy seems to be the preferred operative technique over the laparoscopic technique both from a hospital and societal cost perspective. Sick leave associated with convalescence after cholecystectomy in employed patients results in considerable costs to society

Barriers That Obstruct Return to Work After Coronary Bypass Surgery:A Qualitative Study

Coronary artery bypass grafting is the most frequently performed cardiac surgical procedure. Despite its benefits on survival and quality of life, it is associated with a considerable financial burden on society including sick leave. Our study aimed to explore the barriers that obstruct return to work after coronary artery bypass grafting. We performed a qualitative study with in-depth interviewing of patients 6 months after their surgery. We included ten working patients and interviewed them and their spouses at home. The interviews were transcribed and two investigators independently searched the transcriptions for barriers that had obstructed return to work. Based on the interviews we were able to distinguish four main groups of barriers: 'personal', 'healthcare', 'work' and 'law & regulation.' The personal barriers were subgrouped in affective, physical, cognitive, social and individually determined factors. Conclusion In a qualitative study we showed that personal barriers as well as barriers regarding healthcare, work and law & regulation, were perceived by patients as important factors obstructing return to work after coronary artery bypass grafting. To overcome the identified barriers, the process of return to work could preferably be initiated during the hospital phase, started during cardiac rehabilitation, and coordinated by a case-managing professional

Does postoperative cognitive decline after coronary bypass affect quality of life?

OBJECTIVE: This study aimed to explore the influence of coronary artery bypass grafting (CABG) on both postoperative cognitive dysfunction and quality of life (QoL) and the association between the two patient-related outcomes. METHODS: In a prospective, observational cohort study, patients with elective, isolated CABG were included. Cognitive function was assessed using the Cogstate computerised cognitive test battery preoperatively, 3 days and 6 months after surgery. QoL was measured preoperatively and at 6 months using the RAND-36 questionnaire including the Physical Component Score (PCS) and the Mental Component Score (MCS). Regression analysis, with adjustment for confounders, was used to evaluate the association between postoperative cognitive dysfunction and QoL. RESULTS: A total of 142 patients were included in the study. Evidence of persistent cognitive dysfunction was observed in 33% of patients after 6 months. At 6 months, the PCS had improved in 59% and decreased in 21% of patients, and the MCS increased in 49% and decreased in 29%. Postoperative cognitive changes were not associated with QoL scores. CONCLUSIONS: Postoperative cognitive dysfunction and decreased QoL are common 6 months after surgery, although cognitive function and QoL were found to have improved in many patients at 6 months of follow-up. Impaired cognitive function is not associated with impaired QoL at 6 months. TRIAL REGISTRATION NUMBER: NCT03774342