Nebulised heparin for patients with or at risk of acute respiratory distress syndrome: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial

B. Dixon. Lancet Respiratory Medicine; 2021 Jan 22;S2213-2600(20)30470-7. doi: https://doi.org/10.1016/S2213-2600(20)30470-7

Clinical Question

• In patients with or at risk of Acute Respiratory Distress Syndrome (ARDS), can nebulised heparin compared to placebo, accelerate recovery of physical function?

Background

• ARDS affects 23% of mechanically ventilated patients and has a mortality of up to 46%
• A large proportion of survivors of ARDS have significant limitations in physical function, which can persist for several years
• Most studied pharmaceutical agents (including statins, aspirin, ketoconazole and vitamin D amongst others) have yielded disappointing results in phase 3 trials, despite often showing promise in early phase trials
• A key part of the inflammatory response in ARDS is fibrin accumulation in pulmonary capillaries and venules, which can lead to microvascular thrombosis, the extent of which correlates with the severity of acute lung injury. This could theoretically be mitigated by heparin and is supported by improvements in pulmonary dead space, coagulation activation and microvascular thrombosis in phase 1 and 2 studies
• Heparin may confer other benefits that make it an appealing therapeutic option in patients with or at risk of ARDS such as binding of bacterial and viral pathogens, inhibition of inflammatory pathways, reduced mucus tenacity, and prevention of bronchospasm

Design

• Multicentre, double-blind, randomised, placebo-controlled trial
• Randomisation in a 1:1 ratio to nebulised heparin (intervention group) or placebo (control group), using variable block sizes and stratification by site
• To detect a clinically important 10-point improvement in the primary outcome (SF-36 Health Survey Physical Function Score) from 45 to 55 with SD 25, 80% power, and a two-sided significance level of 0·05, a sample of 198 patients was required. To account for the anticipated loss of data due to death assuming a mortality rate of 30% up to day 60, a further 58 patients were required, giving a final target sample size of 256
• Intention-to-treat analysis
• Planned interim analyses by the DSMB after the 50th, 100th and 200th enrolments.
• Registered with the Australian and New Zealand Clinical Trials Register

Setting

• 256 patients were recruited (n=131 to the intervention group; n=125 to the control group) in nine hospitals in Australia between September 4, 2012 and August 23, 2018

Population

• Inclusion: Mechanically ventilated adult patients (age 18 or older) who met all of the following criteria:
  • Mechanical ventilation commenced on the day before or day of recruitment
  • Expected to require invasive ventilation until the end of the next day
  • P:F ratio <300 or SpO2:FiO2 ratio <315 at any time since commencing invasive ventilation
  • Active ventilator circuit humidification
• Exclusion: The main exclusion criteria were as follows:
  • Allergy to heparin
  • History of heparin induced thrombocytopaenia
  • Platelet count <50 or APTT >80 seconds
  • Uncontrolled bleeding or pulmonary bleeding during current hospital admission
  • History of intracranial, spinal or epidural hemorrhage
  • Hepatic encephalopathy, history of gastrointestinal bleeding due to portal hypertension or cirrhosis with portal hypertension
  • Pre-existing tracheostomy, oxygen or assisted ventilation at home
  • Neurological diagnosis impacting on respiratory function (such as cervical spinal cord injury, MND, GBS)
  • Treatment limitations (including RRT, vasoactive medications), dementia or death considered imminent
  • Pregnancy
• 256 patients were randomised, 131 to nebulised heparin and 125 to placebo
• Data were analysed for 128 participants assigned to heparin and 124 to placebo after three participants withdrew consent and another was ineligible due to thrombocytopenia
• Volume of scheduled dose delivered was 94.7% in the intervention group and 98.1% in the control group
• Similar concomitant low molecular weight heparin use (any; 73% vs 70%) and therapeutic dose unfractionated or low molecular weight heparin use (25% vs 18%) between groups
• Baseline demographics (intervention group vs placebo group)
  • Median age: 58 vs 59 years
  • Male sex: 65% vs 60%
  • Major comorbidities:
    • COPD: 25% vs 26%
    • Asthma: 16% vs 16%
    • Other respiratory disease: 11% vs 14%
  • Risk factors for ARDS:
    • Pneumonia: 68% vs 73%
    • Sepsis, non-pulmonary: 16% vs 15%
    • Inhalation of food/gastric contents: 13% vs 16%
  • APACHE II score: 23 vs 24
  • Therapies:
    • Inotropes/vasopressors: 81% vs 75%
    • Renal replacement therapy: 12% vs 10%
    • Corticosteroid: 48% vs 49%
  • Respiratory rescue therapies:
    • Neuromuscular blocker: 46% vs 49%
    • Recruitment manoeuver: 7% vs 8%
    • Nitric oxide or prostaglandin: 6% vs 8%
    • Prone positioning: 1% vs 2%
  • Respiratory characteristics:
    • P:F ratio (unit): 185 vs 184
    • Tidal volume (ml/kg pbw): 7.6 vs 7.8
    • PEEP (cmH2O): 10.2 vs 10
    • Ppeak (cmH2O): 25.1 vs 24.5
  • Acute lung injury assessments:
    • ARDS
      • At risk: 49% vs 57%
      • Present: 51% vs 43%
    • ARDS severity
      • Mild: 15% vs 13%
      • Moderate: 31% vs 24%
      • Severe: 5% vs 6%
    • Murray lung injury score:
      • If at risk of ARDS: 1.91 vs 1.95
      • If ARDS present: 2.63 vs 2.50

Intervention

• Unfractionated heparin sodium
  • 25 000 IU in 5 mL, administered using a vibrating mesh membrane nebuliser every 6 hours to day 10 while invasively ventilated

Control

• Placebo
  • (sodium chloride 0·9% 5 mL), administered identically

Management common to both groups

• Standard of care, including the administration of intravenous and subcutaneous heparin

Outcome

• Primary outcome: SF-36 Physical Function Score (patient or proxy reported limitations across ten physical activities) of survivors at day 60 – no significant difference
  • Intervention group vs control group: (95% CI): 53.6 vs 48.7, MD 4.9 (-4.8 to 14.5) – a lower score indicates worse limitation
• Secondary outcomes: Fewer patients in the intervention group developed ARDS and deterioration in Murray Lung Injury Score at day 5. At day 60 there were more survivors residing at home in the intervention group
  • At day 5 – intervention group vs control group (95% CI):
    • Developed new ARDS: 15% vs 30%, HR 0.46 (0.22 to 0.98), p=0.04
    • Deterioration in Murray Lung Injury Score: -0.05 vs 0.09, MD -0.14 (-0.26 to -0.02), p=0.02
  • At day 28:
    • New respiratory therapies:
      • Neuromuscular blocker: 24% vs 29%, OR 0.78 (0.36 to 1.72)
      • Recruitment manoeuver: 12% vs 9%, OR 1.44 (0.61 to 3.39)
      • Nitric oxide or nebulised prostacyclin: 6% vs 9%, OR 0.66 (0.24 vs 1.80)
      • Prone positioning: 2% vs 2%, OR 0.96 (0.19 to 4.85)
    • Time to ventilator separation: 9.9 days vs 10.2 days, HR 1.01 (0.77 to 1.33)
    • Time to ICU separation: 11.9 days vs 12.6 days, HR 1.08 (0.82 to 1.42)
    • ICU readmission: 1% vs 9%, OR 0.10 (0.01 to 0.81), p=0.03
    • Deceased: 17% vs 13%, OR 1.39 (0.69 to 2.79)
  • At day 60:
    • Survivors residing at home: 87% vs 73%, OR 2.45 (1.18 to 5.08), p=0.02
    • Deceased: 18% vs 15%, OR 1.29 (0.66 to 2.53)
• Adverse events: Serious adverse events were similar in each group; 5% in the intervention group vs 2% in the control group, OR 2·33 (0·59–9·24), although APTT peak for patients who received concomitant systemic prophylactic or therapeutic anticoagulation was 69s in the intervention group and 51s in the control group; MD 18 (6-30), p=0.0037. There was no difference between groups in APTT peak for patients who did not receive concomitant anticoagulation
  • Red cell transfusion: 26% vs 25%, OR 1.03 (0.58 to 1.83)
  • Major non-pulmonary bleeding: 2% vs 2%, OR 0.97 (0.13 to 6.98)
  • Haemoptysis: 1 (1%) vs 0
• Post-hoc analysis
  • significantly fewer patients in heparin group had a very low SF-36 Physical function score (<20)
    • 16 vs 31% OR 0.44 95% C.I. 0.22-0.88, p=0.02

Authors’ Conclusions

• “The CHARLI study found that nebulised heparin therapy, compared with placebo, in invasively ventilated intensive care patients with impaired oxygenation and the expectation of invasive ventilation beyond the next calendar day, did not improve the SF-36 Physical Function of survivors at day 60”

Strengths

• Investigator-initiated, multi-centre, randomised, controlled trial
• Patients, clinicians, and investigators were masked to treatment allocation
• Variable block sizes ensured allocation concealment
• Biological plausibility and a particularly relevant clinical question in the context of COVID-19, which has been associated with profound pulmonary microvascular thrombi at post-mortem
• Intention to treat analysis
• Overall good internal validity; baseline demographics, use of other medications (antimicrobials, sedatives, steroids, systemic anticoagulation) and time to randomisation similar between groups. Good adherence to protocol in both groups
• Another study demonstrating that nebulised heparin was easy to administer and well tolerated alongside concomitant systemic low molecular weight and unfractionated heparin

Weaknesses

• The statistical analysis plan was not published apriori
• Heterogeneous population with a range of lung injury severity
• External validity threatened by enrolment of nearly 50% of patients from 1 centre and exclusion of nearly 90% of patients screened
• The primary outcome of choice may have been problematic as only survivors could be assessed. Additionally a physical performance score at day 60 may not be the best way to assess the efficacy of such a targeted single organ intervention and may be susceptible to confounding
• Nebulised heparin moderately increased the peak APTT in patients receiving concomitant systemic anticoagulation. It is plausible that this could have led to inadvertent unmasking of some patients assigned to the intervention
• Excluding deceased patients there was close to 10% loss to follow-up. The direction of any bias associated with this is not possible to infer, although it is plausible that this could be a consequence of poor functional status that was not captured by the primary outcome measure
• Although some secondary outcomes suggested benefit of the intervention, without correction for multiple comparisons these are susceptible to type 1 error and should be considered hypothesis generating only

The Bottom Line

• This study did not show an improvement in the physical function of survivors of critical illness with or at risk of ARDS at day 60
• Given the improvement in certain physiological parameters in previous studies and secondary outcomes supporting the attenuation of lung injury in this study, it is possible that the wrong outcome measure or population was studied
• Further studies should focus on more clinically important outcomes such as mortality or duration of mechanical ventilation, ideally in a more homogenous population
• Aside from corticosteroids there is still no proven efficacious pharmaceutical prevention or treatment for ARDS, and there is currently insufficient evidence to begin using nebulised heparin in this setting

External Links

• [article] Nebulised heparin for patients with or at risk of acute respiratory distress syndrome: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial

Metadata

Summary author: Andrew Achilleos
Summary date: 18/02/2021
Peer-review editor: david slessor

Picture by: Gerd Altmann from Pixabay