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NIHR Signal Statins are of no benefit in acute respiratory distress syndrome

Published on 13 March 2018

doi: 10.3310/signal-00571

Giving statins to patients with acute respiratory distress syndrome made no difference to the number of days they spent on a ventilator. It also had no effect on mortality or the length of time spent in intensive care or in hospital compared with placebo.

In acute respiratory distress syndrome, the lungs become severely inflamed, fill with fluid (pulmonary oedema) and can no longer function. The person needs mechanical ventilation and is at high risk of multiple organ failure and mortality. This serious condition has high impact on both patients and NHS resources.

Early studies had suggested statins may help to reverse the inflammatory process and could be a potential treatment to explore. This large, multicentre trial, funded by the NIHR, found no evidence that simvastatin (80mg daily) improved these outcomes.

No practice change seems indicated.

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Why was this study needed?

Acute respiratory distress syndrome (ARDS) is a severe form of respiratory failure where the lungs cannot exchange gases normally, resulting in low blood oxygen (hypoxaemia) and high blood carbon dioxide. ARDS is diagnosed on the basis of acute onset; pulmonary oedema on chest X-ray (not caused by a heart problem); and a ratio of arterial oxygen to inspired oxygen concentration (PaO2/FiO2) of less than 200. When hypoxaemia is less severe (PaO2/FiO2 less than 300), it’s termed acute lung injury (ALI).

ARDS/ALI has various causes including severe infection or trauma. The mortality rate is 30-50%, mostly due to the underlying cause. It requires prolonged intensive care treatment, hospital stays and community rehabilitation with high resource use. A single intensive care bed day costs over £1,400.

Prior laboratory and animal studies had suggested statins may help to reduce lung inflammation and pulmonary oedema. This is the first human trial aimed to see if simvastatin has any effect.

What did this study do?

HARP-2 was a randomised controlled trial carried out in 40 intensive care units in the UK. It involved 540 adults who were being mechanically ventilated and met the above criteria for ALI or ARDS. The main causes were pneumonia and sepsis.

Participants were assigned to 80mg of simvastatin daily (in two divided doses) or identical placebo given by mouth (or feeding tube) for up to 28 days. Adults with a clinical indication for statins (for example, high cholesterol) were excluded.

The patient group was overall mixed, though this was expected to reflect the real-life situation. The economic evaluation involved only those with complete quality of life data available at six to 12 months. This represented only 45% of those alive at this point.

What did it find?

  • Simvastatin had no effect on the main outcome of the number of ventilator-free days by 28 days. This was on average 12.6 days in the simvastatin group and 11.5 days in the placebo group (mean difference 1.4, 95% confidence interval [CI] -0.3 to +3.2; adjusted for baseline level of lung function).
  • There was no effect on mortality by 28 days (22.0% with simvastatin vs 26.8% with placebo), or when separately analysing mortality before intensive care or before hospital discharge. Neither did simvastatin have any effect on organ failure assessments at any time-point.
  • Among survivors, simvastatin made no difference to the average duration of stay in intensive care (13.9 days vs 14.4 with placebo) or total duration of hospital stay (37.7 vs 35.4 days).
  • There was no difference between groups in the total number of adverse effects, but more of those in the simvastatin group were thought to be directly caused by the study drug such as elevated creatinine levels (45 vs 30 attributed to placebo; odds ratio 2.2, 95% CI 1.1 to 4.2). However, simvastatin didn’t increase the number of serious adverse events.
  • Surviving patients who took simvastatin had slightly higher quality of life scores at three, six and 12 months, though these differences fell short of statistical significance. However, this did result in a slightly higher number of quality-adjusted life years (QALYs) of 0.17 with simvastatin vs 0.06 with placebo (QALY gain 0.064, 95% CI 0.002 to 0.127, equivalent to about 23 days of health). It was also associated with cost savings of £3,601. This made simvastatin technically cost effective.

What does current guidance say on this issue?

The British Thoracic Society and Intensive Care Society provide guidelines on the type of mechanical ventilation and other supplementary interventions to use in acute respiratory failure. They do not make any recommendations regarding the use of statins.

What are the implications?

The findings of this large multicentre trial seem clear: statins do not have a role in the management of people with acute lung injury or respiratory distress syndrome.

It made no difference to the most important outcomes for both patients and hospital resources: intensive care stay, ventilator use and mortality.

Given these results, the finding that statins were cost-effective seems slightly spurious. However, caution is needed given that this finding is based on only a subsample of surviving patients who completed quality of life assessments.

Citation and Funding

McAuley DF, Laffey JG, O'Kane CM et al. Simvastatin to reduce pulmonary dysfunction in patients with acute respiratory distress syndrome: the HARP-2 RCT. Efficacy Mech Eval. 2018;5(1).

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.

Bibliography

British Thoracic Society/Intensive Care Society Acute Hypercapnic Respiratory Failure Guideline Development Group. Guidelines for the ventilatory management of acute hypercapnic respiratory failure in adults. Thorax. 2016;71:Supplement 2.

NHS Choices. Acute respiratory distress syndrome. London: Department of Health; reviewed 2017.

Patient. Acute (adult) respiratory distress syndrome. Leeds: Patient Platform Ltd; 2014.

Laycock H and Rajah A. Acute lung injury and acute respiratory distress syndrome: a review article. Br J Med Pract. 2010;3(2):324.

Why was this study needed?

Acute respiratory distress syndrome (ARDS) is a severe form of respiratory failure where the lungs cannot exchange gases normally, resulting in low blood oxygen (hypoxaemia) and high blood carbon dioxide. ARDS is diagnosed on the basis of acute onset; pulmonary oedema on chest X-ray (not caused by a heart problem); and a ratio of arterial oxygen to inspired oxygen concentration (PaO2/FiO2) of less than 200. When hypoxaemia is less severe (PaO2/FiO2 less than 300), it’s termed acute lung injury (ALI).

ARDS/ALI has various causes including severe infection or trauma. The mortality rate is 30-50%, mostly due to the underlying cause. It requires prolonged intensive care treatment, hospital stays and community rehabilitation with high resource use. A single intensive care bed day costs over £1,400.

Prior laboratory and animal studies had suggested statins may help to reduce lung inflammation and pulmonary oedema. This is the first human trial aimed to see if simvastatin has any effect.

What did this study do?

HARP-2 was a randomised controlled trial carried out in 40 intensive care units in the UK. It involved 540 adults who were being mechanically ventilated and met the above criteria for ALI or ARDS. The main causes were pneumonia and sepsis.

Participants were assigned to 80mg of simvastatin daily (in two divided doses) or identical placebo given by mouth (or feeding tube) for up to 28 days. Adults with a clinical indication for statins (for example, high cholesterol) were excluded.

The patient group was overall mixed, though this was expected to reflect the real-life situation. The economic evaluation involved only those with complete quality of life data available at six to 12 months. This represented only 45% of those alive at this point.

What did it find?

  • Simvastatin had no effect on the main outcome of the number of ventilator-free days by 28 days. This was on average 12.6 days in the simvastatin group and 11.5 days in the placebo group (mean difference 1.4, 95% confidence interval [CI] -0.3 to +3.2; adjusted for baseline level of lung function).
  • There was no effect on mortality by 28 days (22.0% with simvastatin vs 26.8% with placebo), or when separately analysing mortality before intensive care or before hospital discharge. Neither did simvastatin have any effect on organ failure assessments at any time-point.
  • Among survivors, simvastatin made no difference to the average duration of stay in intensive care (13.9 days vs 14.4 with placebo) or total duration of hospital stay (37.7 vs 35.4 days).
  • There was no difference between groups in the total number of adverse effects, but more of those in the simvastatin group were thought to be directly caused by the study drug such as elevated creatinine levels (45 vs 30 attributed to placebo; odds ratio 2.2, 95% CI 1.1 to 4.2). However, simvastatin didn’t increase the number of serious adverse events.
  • Surviving patients who took simvastatin had slightly higher quality of life scores at three, six and 12 months, though these differences fell short of statistical significance. However, this did result in a slightly higher number of quality-adjusted life years (QALYs) of 0.17 with simvastatin vs 0.06 with placebo (QALY gain 0.064, 95% CI 0.002 to 0.127, equivalent to about 23 days of health). It was also associated with cost savings of £3,601. This made simvastatin technically cost effective.

What does current guidance say on this issue?

The British Thoracic Society and Intensive Care Society provide guidelines on the type of mechanical ventilation and other supplementary interventions to use in acute respiratory failure. They do not make any recommendations regarding the use of statins.

What are the implications?

The findings of this large multicentre trial seem clear: statins do not have a role in the management of people with acute lung injury or respiratory distress syndrome.

It made no difference to the most important outcomes for both patients and hospital resources: intensive care stay, ventilator use and mortality.

Given these results, the finding that statins were cost-effective seems slightly spurious. However, caution is needed given that this finding is based on only a subsample of surviving patients who completed quality of life assessments.

Citation and Funding

McAuley DF, Laffey JG, O'Kane CM et al. Simvastatin to reduce pulmonary dysfunction in patients with acute respiratory distress syndrome: the HARP-2 RCT. Efficacy Mech Eval. 2018;5(1).

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.

Bibliography

British Thoracic Society/Intensive Care Society Acute Hypercapnic Respiratory Failure Guideline Development Group. Guidelines for the ventilatory management of acute hypercapnic respiratory failure in adults. Thorax. 2016;71:Supplement 2.

NHS Choices. Acute respiratory distress syndrome. London: Department of Health; reviewed 2017.

Patient. Acute (adult) respiratory distress syndrome. Leeds: Patient Platform Ltd; 2014.

Laycock H and Rajah A. Acute lung injury and acute respiratory distress syndrome: a review article. Br J Med Pract. 2010;3(2):324.

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

Published on 5 February 2018

McAuley D F, Laffey J G, O’Kane C M, Perkins G D, Mullan B, Trinder T J, Johnston P, Hopkins P A, Johnston A J, Murphy L, McNally C, Agus A M, McDowell C & Jackson C

Efficacy and Mechanism Evaluation Volume 5 Issue 1 , 2018

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. 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 Randomized Exploratory Clinical Trial to Evaluate the Safety and Effectiveness of Stem Cell Product in Alcoholic Liver Cirrhosis Patient (REVIVE) provided additional funding.

Expert commentary

HARP-2 has shown that simvastatin 80mg can safely be administered to critically ill adults, and hence therapy does not need to be routinely discontinued in most patients admitted to ICU who are receiving the medication for appropriate clinical indications.

While the study did not meet the primary end-point in a heterogeneous population of patients with acute respiratory distress syndrome (ARDS), there may be a sub-group of patients who may derive benefit, and further research is required to explore this.

Further research is also needed to explore the mechanisms by which simvastatin may act to modify ARDS.

Dr Charlotte Summers, University Lecturer in Intensive Care Medicine, Department of Medicine; Director of Academic Clinical Fellow Programme, Deputy Director of Clinical Academic Training, University of Cambridge School of Clinical Medicine