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Pro/con clinical debate: It is acceptable to stop large multicentre randomized controlled trials at interim analysis for futility
David A Schoenfeld, Maureen O Meade
Critical Care , 2004, DOI: 10.1186/cc3013
Abstract: You are a clinician in an intensive care unit and you have recently heard that some very large trials have been stopped at interim analysis for futility. Although you have not yet seen the results, this cessation concerns you because you were anxiously awaiting the results of these trials since you felt they were very relevant clinical questions that would impact on your treatment decisions. Your concern is based on the fact that you are uncertain whether clinical trials should ever be stopped for futility.David A SchoenfeldA futility-stopping rule for a clinical trial is a plan in which the results of a clinical trial are periodically reviewed and the clinical trial is stopped if the treatment difference is smaller than some predetermined value. The idea is to stop trials that would not have shown statistical significance had they gone on to completion. A futility-stopping rule can drastically reduce the time and money spent on clinical trials, and can more rapidly find effective treatments. In the present paper I describe the available methods used for futility stopping. I then quantify the advantages of futility stopping in a drug development programme. Finally, I will discuss some of the problems of futility stopping and how clinicians should interpret trials that stop early for futility.There are two methods of futility stopping. The method that was used in early trials was based on the principal of stochastic curtailment [1]. A review committee would analyse the results of a trial and calculate the probability that the trial will give a significant result if it is completed. If this probability was small, say less than 25%, then the trial would be stopped. This probability calculation depends on an assumption about the actual success rates of the treatments. The safest assumption is to use the original difference that was used to calculate the sample size.The second method is to use asymmetric stopping boundaries [2,3]. The futility boundary can be based on ho
Drotrecogin alfa (activated) in patients with severe sepsis and a high risk of death
Jan O Friedrich, Neill KJ Adhikari, Maureen O Meade
Critical Care , 2006, DOI: 10.1186/cc5117
Abstract: We also support the pooling of individual patient data from these trials to generate hypotheses regarding appropriate patient selection for drotrecogin alfa (activated) that could be tested in subsequent trials [5]. Furthermore, we encourage public release of these data for the purposes of a meta-analysis of individual patient data to be undertaken by an independent group, using appropriate statistical methods that incorporate random effects, and that is subject to peer review.The authors declare that they have no competing interests.
Drotrecogin alfa (activated): down and not out, but not really in either
Jan O Friedrich, Neill KJ Adhikari, Maureen O Meade
Critical Care , 2006, DOI: 10.1186/cc5022
Abstract: Agarwal and Nath's letter highlights the surprising degree of statistical heterogeneity that remains between the Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) trial [3] and the Recombinant Human Activated Protein C Worldwide Evaluation of Severe Sepsis (PROWESS) trial [4] results despite minimal methodologic differences between these trials and further minimization of clinical heterogeneity by selecting a more uniform subgroup of patients with severe sepsis and a high risk of death. In particular, for the subgroup with an APACHE II score of 25 or more, I2 (the percentage of total variation in results across studies that is due to heterogeneity rather than chance [5]) is very high (84%). Given this degree of heterogeneity, we feel that one should account for, rather than ignore, its effects when pooling results.The APACHE II subgroup effect in PROWESS was one of about 80 prospectively defined subgroup comparisons [6].Using other definitions of high risk, the difference in treatment effect between high-risk and low-risk subgroups in PROWESS was not statistically significant (for example, patients with multiple organ failure) and in some cases not even directionally consistent (for example, patients requiring mechanical ventilation or vasopressor support) [7]. If the APACHE II high-risk and low-risk subgroup effect in PROWESS is due to chance, then the best estimate of the effect of DrotAA for any patient is the overall pooled result incorporating all patients. Interestingly, although the degree of between-study heterogeneity is significant when the overall data from all four trials presented in Figure 1 [2] are pooled (I2 = 59%), it disappears if PROWESS is excluded (I2 = 0%).Is there a role for DrotAA in severe sepsis? The inconsistent trial results and increased risk of serious bleeding highlight the importance of identifying patients for whom the benefits of DrotAA outweigh the risks. The high variability and very low proport
Drotrecogin alfa (activated): does current evidence support treatment for any patients with severe sepsis?
Jan O Friedrich, Neill KJ Adhikari, Maureen O Meade
Critical Care , 2006, DOI: 10.1186/cc4947
Abstract: Severe sepsis is a condition with important public health ramifications because it is common and has a high case-fatality rate [1]. Drotrecogin alfa (activated) (DrotAA), more commonly known as recombinant human activated protein C, is the first specific therapy for sepsis to show an important survival benefit. On the basis of the favourable results of the Recombinant Human Activated Protein C Worldwide Evaluation of Severe Sepsis (PROWESS) trial [2], DrotAA was approved for patients with severe sepsis and at high risk of death. However, regulatory approval for DrotAA was controversial [3,4], and the recently published Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) trial [5] has heightened this controversy. The results of this study demonstrated no evidence of benefit for DrotAA in patients with severe sepsis and at low risk of death, and unexpectedly raised concerns regarding its efficacy among patients at high risk of death [6]. In this commentary we argue that the cumulative evidence for a survival benefit in DrotAA-treated patients with severe sepsis and at high risk of death is weaker than originally believed. We also suggest methodological explanations for discrepant results of these two rigorous multicentre trials. These findings have important implications not only for clinicians treating patients with severe sepsis but also for the interpretation of other single, seemingly pivotal, randomised controlled trials.Figure 1 shows the effect of DrotAA therapy on 28-day survival, as observed in all three published trials (a phase II trial [7], PROWESS [2], and ADDRESS [5]) and in an additional unpublished trial in children with severe sepsis [8]. (A recent systematic review and health technology assessment of DrotAA [9] found no additional trials.) PROWESS suggested a survival benefit for all severely septic patients who received DrotAA. This survival benefit seemed to be concentrated in patients at high risk of death, define
Partial Ventilatory Support Modalities in Acute Lung Injury and Acute Respiratory Distress Syndrome—A Systematic Review
Sarah M. McMullen,Maureen Meade,Louise Rose,Karen Burns,Sangeeta Mehta,Robert Doyle,Dietrich Henzler
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0040190
Abstract: The efficacy of partial ventilatory support modes that allow spontaneous breathing in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is unclear. The objective of this scoping review was to assess the effects of partial ventilatory support on mortality, duration of mechanical ventilation, and both hospital and intensive care unit (ICU) lengths of stay (LOS) for patients with ALI and ARDS; the secondary objective was to describe physiologic effects on hemodynamics, respiratory system and other organ function.
Wean Earlier and Automatically with New technology (the WEAN study): a protocol of a multicentre, pilot randomized controlled trial
Karen EA Burns, Maureen O Meade, Martin R Lessard, Sean P Keenan, Francois Lellouche
Trials , 2009, DOI: 10.1186/1745-6215-10-81
Abstract: A pilot weaning randomized controlled trial (RCT) is underway in the ICUs of 8 Canadian hospitals. We will randomize 90 critically ill adults requiring invasive ventilation for at least 24 hours and identified at an early stage of the weaning process to either Automated Weaning (SmartCare?) or Protocolized Weaning. The results of a National Weaning Survey informed the design of the Protocolized Weaning arm. Both weaning protocols are operationalized in Pressure Support mode, include opportunities for Spontaneous Breathing Trials, and share a common sedation protocol, oxygen titration parameters, and extubation and reintubation criteria. The primary outcome of the WEAN study is to evaluate compliance with the proposed weaning and sedation protocols. A key secondary outcome of the pilot RCT is to evaluate clinician acceptance of the weaning and sedation protocols. Prior to initiating the WEAN Study, we conducted a run-in phase, involving two patients per centre (randomizing the first participant to either weaning strategy and assigning the second patient to the alternate strategy) to ensure that participating centres could implement the weaning and sedation protocols and complete the detailed case report forms.Mechanical ventilation studies are difficult to implement; requiring protocols to be operationalized continuously and entailing detailed daily data collection. As the first multicentre weaning RCT in Canada, the WEAN Study seeks to determine the feasibility of conducting a large scale future weaning trial and to establish a collaborative network of ICU clinicians dedicated to advancing the science of weaning.ISRCTN43760151Weaning is the process during which mechanical ventilation is gradually or abruptly withdrawn. In addition, it is the time during which work of breathing is transferred from the ventilator back to the patient until fully autonomous breathing is resumed. Weaning accounts for approximately 40% of the total time spent on mechanical ventilation [1,
Red blood cell transfusion and increased length of storage are not associated with deep vein thrombosis in medical and surgical critically ill patients: a prospective observational cohort study
Christina Katsios, Lauren Griffith, Philip Spinella, Jacques Lacroix, Mark Crowther, Paul Hebert, Maureen Meade, William Geerts, Christian Rabbat, Deborah Cook
Critical Care , 2011, DOI: 10.1186/cc10526
Abstract: Using a database which prospectively enrolled 261 patients over the course of 1 year with an ICU stay of at least 3 days, we analyzed DVT and RBC transfusions using Cox proportional hazards regression. Transfusions were analyzed with 4 thresholds, and storage age using 3 thresholds. DVTs were identified by twice-weekly proximal leg ultrasounds. Multivariable analyses were adjusted for 4 significant DVT predictors in this population (venous thrombosis history, chronic dialysis, platelet transfusion and inotropes).Of 261 patients, 126 (48.3%) had at least 1 RBC transfusion; 46.8% of those transfused had ≥ 5 units in ICU. Patients receiving RBCs were older (68.8 vs 64.1 years), more likely to be female (47.0 vs 30.7), sicker (APACHEII 26.8 vs 24.4), and more likely to be surgical (21.4 vs 8.9) (P < 0.05). The total number of RBCs per patient was 1-64, mean was 6.3 (SD 7.5), median was 4 (IQR 2,8). In univariate analyses, there was no association between DVT and RBC exposure (1 day earlier, 3 days earlier, 7 days earlier, or ever) or RBC storage (≤ 7 or > 7 days, ≤ 14 or > 14 days, ≤ 21 or > 21 days). Among patients transfused, no multivariable analyses showed that RBC transfusion or storage age predicted DVT. Trends were counter to the hypothesis (e.g., RBC storage for ≤ 7 days suggested a higher DVT risk compared to > 7 days (HR 5.3; 95% CI 1.3-22.1).We were unable to detect any association between RBC transfusions or prolonged red cell storage and increased risk of DVT in medical or surgical ICU patients. Alternate explanations include a lack of sufficient events or patients' interaction, between patient groups, a mixing of red cell storage times creating differential effects on DVT risk, and unmeasured confounders.Over 24 million units of packed red blood cells (RBCs) were transfused in the US in 2004. More than 40% of critical care patients receive RBC transfusions while in the intensive care unit (ICU) [1,2]. Numerous studies demonstrate that RBC transfusions are
Clinically important deep vein thrombosis in the intensive care unit: a survey of intensivists
Deborah Cook, Maureen Meade, Gordon Guyatt, Lauren Griffith, John Granton, William Geerts, Mark Crowther, the Canadian Critical Care Trials Group
Critical Care , 2004, DOI: 10.1186/cc2859
Abstract: Our definition of clinically important DVT was a DVT likely to result in short-term or long-term morbidity or mortality if left untreated, as opposed to a DVT that is unlikely to have important consequences. We asked respondents to indicate the likelihood that patient factors and ultrasonographic features make a DVT clinically important using a five-point scale (from 1 = much less likely to 5 = much more likely).Of the 71 Canadian intensivists who responded, 70 (99%) rated three patient factors as most likely to make a DVT clinically important: clinical suspicion of pulmonary embolism (mean score 4.6), acute or chronic cardiopulmonary morbidity that might limit a patient's ability to tolerate pulmonary embolism (score 4.5), and leg symptoms (score 4.2). Of the ultrasound features, proximal (score 4.7), large (score 4.2), and totally occlusive (score 3.9) thrombi were considered the three most important.When labeling a DVT as clinically important, intensivists rely on different patient specific factors and thrombus characteristics than are used to assess the clinical importance of DVT outside the ICU. The clinical importance of DVT is influenced by unique factors such as cardiopulmonary reserve among mechanically ventilated patients.Venous thromboembolism (VTE), which includes both deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common complication of critical illness [1,2]. Critically ill patients harbor many coincident risk factors for DVT, such as the need for surgery, catheters, immobility, and use of sedatives and paralytic agents [3-5]. As in the noncritically ill population, it is likely that most episodes of DVT are asymptomatic and confined to the deep veins of the calf. However, with time, 20–30% of untreated calf vein thrombi extend proximally into the thigh, where they pose a 40–50% risk for PE [6]. Early studies of the natural history of PE suggest that untreated PE has a mortality rate of at least 25% [7].One large study found PE at autopsy
An Explanatory Model to Guide Assessment, Risk and Diagnosis of Psychological Distress after Abortion  [PDF]
Maureen Curley
Open Journal of Obstetrics and Gynecology (OJOG) , 2014, DOI: 10.4236/ojog.2014.415133
Abstract: Background: Emerging data report 30% of women worldwide who obtain elective abortion experience negative and persistent psychological distress afterward. Studies find higher rates of psychological stress, depressive, substance, and anxiety disorders as well as suicidal behaviors, among some populations after abortion as compared to other reproductive events. Of concern, is that currenttheory and practice which promote abortion to relieve the stress of an unwanted pregnancy do not reflect new evidence. Moreover, the controversy on abortion inhibits research and treatment on its impact on women’s mental health. Thus, clinicians do not identify adverse psychological outcomes to abortion leaving many women untreated. Indeed, this knowledge-practice gap among healthcare providers may be the major reason that the incidence of adverse psychological outcomes after abortion continues to rise. Method: This paper proposes a theoretical understanding of psychological distress after abortion based on new data. A bio-psychosocial framework, including a psychological and biological theory, as well as a conceptual model is presented to explain the development of psychological distress after abortion. A comparison of risk factors between postpartum and post-abortion disorders is presented. Conclusion: A new theoretical model of psychological distress after abortion deepens understanding of the range of women’s responses to abortion and promotes evidence based practice. A scientific framework provides a much needed understanding of abortion aftermath as opposed to a political one. By providing assistance to clinicians in the identification, screening, and treatment of psychological disorders after abortion, this thesis aims to close the practice gap, and increase services after abortion to women who need them.
Clinical review: Intra-abdominal hypertension: does it influence the physiology of prone ventilation?
Andrew W Kirkpatrick, Paolo Pelosi, Jan J De Waele, Manu LNG Malbrain, Chad G Ball, Maureen O Meade, Henry T Stelfox, Kevin B Laupland
Critical Care , 2010, DOI: 10.1186/cc9099
Abstract: Patients with acute respiratory failure frequently require mechanical ventilation (MV). Unfortunately MV can further damage the lungs and worsen respiratory failure through a variety of mechanisms [1,2]. Prone ventilation (PV) by means of prone positioning (PP) has been proposed as a strategy that may rescue the sickest patient from refractory hypoxemia [1,3-6], although identifying a survival benefit has proven difficult [4,7-12]. PV may also ameliorate the underlying physical strain and generation of inflammatory mediators that compound ventilator-induced lung injury [13-16]. Further, as a technologically simple intervention, PV could conceivably benefit patients in countries where more expensive respiratory technologies are unavailable. There is therefore reason to further explore specific mechanisms and patient groups who might benefit [5,7,17-19].One of the most frequent causes of acute respiratory failure requiring MV is acute respiratory distress syndrome (ARDS), reflecting the more severe spectrum of acute lung injury (ALI) [20,21]. The initial consensus definitions recognized two inciting pathways for ALI/ARDS: pulmonary and extrapulmonary - reflecting either direct lung injury or indirect injuries to the pulmonary endothelium as mediated by the systemic inflammatory response [20,21]. In particular, the influence of the abdomen appears to differ between pulmonary and extrapulmonary causes, differently affecting chest wall mechanics [21-28] - with higher intra-abdominal pressure (IAP) in extrapulmonary ALI/ARDS often related to greater and more recruitable lung collapse [24,26].The World Society of the Abdominal Compartment Syndrome defines intra-abdominal hypertension (IAH) as sustained IAP ≥12 mmHg, and defines the abdominal compartment syndrome (ACS) as IAP >20 mmHg with new organ failure [29]. IAH is a condition that can complicate virtually any critical condition, greatly influences the respiratory system and associates with adverse clinical outcomes [3
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