Beta-Agonist Lung injury TrIal-2 (BALTI-2): a multicentre, randomised, double-blind, placebo-controlled trial and economic evaluation of intravenous infusion of salbutamol versus placebo in patients with acute respiratory distress syndrome

Gates, Simon; Perkins, Gavin D.; Lamb, Sarah E; Kelly, Cheryl; Thickett, David; Young, John; McAuley, Daniel F.; Snaith, Catherine; McCabe, Chris; Hulme, Claire; Smith, Fang Gao

doi:10.3310/hta17380

Cited by 41 publications

(32 citation statements)

References 72 publications

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“…However, we did find it difficult to achieve high rates of long-term follow-up data collection, in keeping with previous intensive care trials, 54,55 and a considerable amount of staff resource was involved in delivering this aspect of the trial. It is important to identify barriers to follow-up in these patients to inform future critical care studies.…”

Section: Economic Evaluationsupporting

confidence: 63%

“…The cost-utility analysis included only patients with complete cost and QALY data but, of those alive at 12 months, only 45% completed both the 6-and 12-month follow-up questionnaires and some data were missing from these completed questionnaires. Previous intensive care trials 54,55 have also found it difficult to achieve high rates of long-term data collection and the experience of the HARP-2 trial confirms that this is a difficult population to follow up. Furthermore, economic data are particularly likely to be missing owing to the reliance on multiple components within HRQoL and resource use questionnaires required for the calculation of QALYs and costs.…”

Section: Figure 14mentioning

confidence: 96%

“…57 This approach has been used previously in economic evaluations of therapies for patients with ARDS. 54,55 Over the course of the trial it became apparent that many patients were still in hospital at 3 months and were then not administered the EQ-5D-3L at this time point. Furthermore, the timing of the discharge questionnaire varied from patient to patient.…”

Section: Health and Social Care Service Use And Costsmentioning

confidence: 99%

“…48 QALYs were derived using the EQ-5D-3L. 53 This generic HRQoL instrument, which has been used frequently in the critically ill, [54][55][56] provides a description of health using five dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression), each with three levels of severity. Patients also place their health on a visual analogue scale (VAS), for which 0 represents the worst imaginable health state and 100 the best imaginable health state.…”

Section: Health Outcomesmentioning

confidence: 99%

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Simvastatin to reduce pulmonary dysfunction in patients with acute respiratory distress syndrome: the HARP-2 RCT

et al. 2018

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Background Acute lung injury is a common devastating clinical syndrome characterised by life-threatening respiratory failure requiring mechanical ventilation and multiple organ failure, and is a major cause of morbidity and mortality. Objective This study tested the hypothesis that treatment with simvastatin would improve clinical outcomes in patients with acute respiratory distress syndrome (ARDS). Design This was a multicentre, allocation-concealed, randomised, double-blind, parallel-group trial. Setting/participants Patients in intensive care units were eligible if they were intubated and mechanically ventilated and had ARDS as defined by a partial pressure of arterial oxygen to fraction of inspired oxygen concentration (PaO2 : FiO2) ratio of ≤ 300 mmHg, bilateral pulmonary infiltrates consistent with pulmonary oedema and no evidence of left atrial hypertension. Intervention Patients were randomised in a 1 : 1 ratio to receive enteral simvastatin 80 mg or identical placebo tablets once daily for up to 28 days. Main outcome measures The primary outcome was the number of ventilator-free days (VFDs) to day 28. Secondary outcomes included the number of non-pulmonary organ failure-free days to day 28, mortality and safety. The biological effect by which simvastatin may modify mechanisms implicated in the development of ARDS was also investigated. A cost-effectiveness analysis was also planned. Results The study was completed when 540 patients were recruited with 259 patients allocated to simvastatin and 281 patients to placebo, with 258 patients in the simvastatin group and 279 patients in the placebo group included in the analysis of the primary outcome. There was no significant difference between study groups in mean [standard deviation (SD)] VFDs [12.6 days (SD 9.9 days) with simvastatin and 11.5 days (SD 10.4 days) with placebo; mean difference 1.1, 95% confidence interval –0.6 to 2.8; p = 0.21], non-pulmonary organ failure-free days [19.4 days (SD 11.1 days) with simvastatin and 17.8 days (SD 11.7 days) with placebo; p = 0.11] or in 28-day mortality (22.0% with simvastatin and 26.8% with placebo; p = 0.23). There was no difference in the incidence of severe adverse events between the groups. Simvastatin did not significantly modulate any of the biological mechanisms investigated. Simvastatin was cost-effective at 1 year compared with placebo for the treatment of ARDS, being associated with both a small quality-adjusted life-year (QALY) gain and cost saving. Limitations One possibility for the lack of efficacy relates to the statin and dosage used. It is possible that adverse effects at the simvastatin dosage used outweighed a beneficial effect, although our data suggest that this is unlikely. The heterogenous cohort of patients with ARDS was an attempt to ensure that our findings would be generalisable; however, it may be more appropriate to target potential therapies based on their proposed biological mechanism for a specific population of patients. The assumptions underpinning the economic benefit are based on the analysis of a subgroup of responders. Conclusions High-dose enteral simvastatin, while safe and with minimal adverse effects, is not effective at improving clinical outcomes in patients with ARDS. There was a small gain in QALYs and a cost saving associated with simvastatin. Future work There is a need to confirm if ARDS endotypes that are more likely to benefit from targeted treatment with simvastatin exist. The potential role of simvastatin in the prevention of ARDS in patients at a high risk of developing ARDS has not yet been evaluated. Trial registration Current Controlled Trials ISRCTN88244364. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This study was also funded in the Republic of Ireland by the Health Research Board (HRA_POR-2010-131). In addition, the Health and Social Care Research and Development division of the Public Health Agency in Northern Ireland, the Intensive Care Society of Ireland and REVIVE provided additional funding.

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Section: Economic Evaluationsupporting

confidence: 63%

Section: Figure 14mentioning

confidence: 96%

Section: Health and Social Care Service Use And Costsmentioning

confidence: 99%

Section: Health Outcomesmentioning

confidence: 99%

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Simvastatin to reduce pulmonary dysfunction in patients with acute respiratory distress syndrome: the HARP-2 RCT

et al. 2018

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“…The authors of both studies reported satisfactory performance of these instruments in the respective patient populations. However, asking patients to complete these measures around the time of recruitment (commonly taken as the baseline measurement) into randomised controlled trials conducted within emergency and critical care settings can be problematic; patients are commonly incapacitated and unable to provide a self-assessment of their health status at or around the time of randomisation [13], [14]. Problems also arise because the event of interest is often acute in nature rather than pre-planned; the unknown timing makes it difficult to collect baseline data from participants during the occurrence of the event and at the point of recruitment into the trial.…”

Section: Introductionmentioning

confidence: 99%

Methodological Issues Surrounding the Use of Baseline Health-Related Quality of Life Data to Inform Trial-Based Economic Evaluations of Interventions Within Emergency and Critical Care Settings: A Systematic Literature Review

et al. 2017

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warwick.ac.uk/lib-publicationsOriginal citation: Dritsaki, Melina, Achana, Felix A., Mason, James and Petrou, Stavros. (2017) Methodological issues surrounding the use of baseline health-related quality of life data to inform trial-based economic evaluations of interventions within emergency and critical care settings : a systematic literature review. PharmacoEconomics. Permanent WRAP URL:http://wrap.warwick.ac.uk/85039 Copyright and reuse:The Warwick Research Archive Portal (WRAP) makes this work by researchers of the University of Warwick available open access under the following conditions. Copyright © and all moral rights to the version of the paper presented here belong to the individual author(s) and/or other copyright owners. To the extent reasonable and practicable the material made available in WRAP has been checked for eligibility before being made available.Copies of full items can be used for personal research or study, educational, or not-for profit purposes without prior permission or charge. Provided that the authors, title and full bibliographic details are credited, a hyperlink and/or URL is given for the original metadata page and the content is not changed in any way. Publisher's statement:"The final publication is available at Springer via http://dx.doi.org/10.1007/s40273-016-0485-x " A note on versions:The version presented here may differ from the published version or, version of record, if you wish to cite this item you are advised to consult the publisher's version. Please see the 'permanent WRAP url' above for details on accessing the published version and note that access may require a subscription. Results: A total of 4224 published reports were screened, 19 of which met the study inclusion criteria (mean trial size 1,670); 14 (74 %) from the UK, 4 (21%) from other European countries and 1 (5%) from India. Twelve studies (63%) were based in emergency departments and 7 (37%) in intensive care units. Only one study was able to elicit patient-reported health-related quality of life at baseline. To overcome the lack of baseline data when estimating QALYs, 8 (42%) studies assigned a fixed utility weight corresponding to either death, an unconscious health state or a country-specific norm to patients at baseline, 4 (21%) ignored baseline utilities, 3 (16%) applied values from another study, 1 (5%) generated utility values via retrospective recall and 1 (5%) elicited utilities from experts. A preliminary exploration of these methods shows that incremental QALY estimation is unlikely to be biased if balanced trial allocation is achieved and subsequent collection of health-related quality of life data occurs at the earliest possible opportunity following commencement of treatment followed by adequate number of follow-up assessments. Conclusion:Trial-based cost-utility analyses within emergency and critical illness settings have applied different methods for QALY estimation, employing disparate assumptions about the health-related quality of life of patients at baseline. Where baseline measurem...

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Pharmacological agents for adults with acute respiratory distress syndrome

Lewis

Pritchard

Thomas

et al. 2019

Cochrane Database of Systematic Reviews

140

136

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Background Acute respiratory distress syndrome (ARDS) is a life-threatening condition caused by direct or indirect injury to the lungs. Despite improvements in clinical management (for example, lung protection strategies), mortality in this patient group is at approximately 40%. This is an update of a previous version of this review, last published in 2004. Objectives To evaluate the e ectiveness of pharmacological agents in adults with ARDS on mortality, mechanical ventilation, and fitness to return to work at 12 months. Search methods We searched CENTRAL, MEDLINE, Embase, and CINAHL on 10 December 2018. We searched clinical trials registers and grey literature, and handsearched reference lists of included studies and related reviews. Selection criteria We included randomized controlled trials (RCTs) comparing pharmacological agents with control (placebo or standard therapy) to treat adults with established ARDS. We excluded trials of nitric oxide, inhaled prostacyclins, partial liquid ventilation, neuromuscular blocking agents, fluid and nutritional interventions and medical oxygen. We excluded studies published earlier than 2000, because of changes to lung protection strategies for people with ARDS since this date. Data collection and analysis Two review authors independently assessed studies for inclusion, extracted data, and assessed risks of bias. We assessed the certainty of evidence with GRADE. Main results We included 48 RCTs with 6299 participants who had ARDS; two included only participants with mild ARDS (also called acute lung injury). Most studies included causes of ARDS that were both direct and indirect injuries. We noted di erences between studies, for example the time of administration or the size of dose, and because of unclear reporting we were uncertain whether all studies had used equivalent lung protection strategies.

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Beta-Agonist Lung injury TrIal-2 (BALTI-2): a multicentre, randomised, double-blind, placebo-controlled trial and economic evaluation of intravenous infusion of salbutamol versus placebo in patients with acute respiratory distress syndrome

Cited by 41 publications

References 72 publications

Simvastatin to reduce pulmonary dysfunction in patients with acute respiratory distress syndrome: the HARP-2 RCT

Simvastatin to reduce pulmonary dysfunction in patients with acute respiratory distress syndrome: the HARP-2 RCT

Methodological Issues Surrounding the Use of Baseline Health-Related Quality of Life Data to Inform Trial-Based Economic Evaluations of Interventions Within Emergency and Critical Care Settings: A Systematic Literature Review

Pharmacological agents for adults with acute respiratory distress syndrome

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