HARP2

HARP2: Simvastatin in the Acute Respiratory Distress Syndrome

D. McAuley & HARP-2 Investigators. NEJM 2014;1-9. doi:10.1056/NEJMoa1403285

Clinical Question

  • In mechanically ventilated adults with acute respiratory distress syndrome (ARDS), does simvastatin compared to placebo reduce ventilator dependence?

Design

  • Multi-center, double-blind
  • Randomised in a 1:1 ratio using permuted blocks and stratification according to study site and vasopressor requirement
  • Designed with 80% power to detect a difference of 2.6 ventilator-free days from a baseline of 12.7 (SD 10.6), with significance level of 0.05, if 524 patients were recruited
    • Allowing for 3% withdrawal, planned to recruit 540 patients
  • Intention-to-treat statistics

Setting

  • 40 general ICUs in UK and Ireland
  • December 2010 – March 2014

Population

  • Inclusion: mechanical ventilation + onset of ARDS within previous 48 hours (PaO2:FiO2 < 300 mmHg, bilateral pulmonary infiltrates, no evidence of left atrial hypertension)
  • Exclusion: pregnancy, contraindications to statins, recent statin administration (within 2 weeks)
  • 5926 patients were screened and 540 were randomised

Intervention

  • Enteral simvastatin 80mg once daily for a maximum of 28 days

Control

  • Placebo therapy at the same frequency and duration as the intervention group
  • For both groups, ventilation strategy was not defined, but low tidal volume ventilation with plateau pressures maintained below 30 cmH2O were encouraged.

Outcome

  • Primary outcome: there was a small but not statistically significant difference in the ventilator-free days to day 28 between the groups (given as mean±SD)
    • simvastatin group 12.6±9.9 days vs placebo group 11.5±10.4
    • mean difference 1.1 days (95% CI -0.6 to 2.8; p=0.21)
  • Secondary outcome:
    • oxygenation index: no significant difference
    • SOFA score: no significant  difference
    • days free of non-pulmonary organ failure to day 28: no significant  difference
    • death within 28 days: no significant difference
    • death before discharge from hospital: no significant  difference
    • safety: significantly more adverse events in simvastatin group (raised CK and raised liver enzymes), but no difference in serious adverse events

Authors’ Conclusions

  • Simvastatin therapy did not improve clinical outcomes in patients with ARDS

Strengths

  • Builds upon carefully planned theoretical work, animal, in vitro and phase 1 clinical trials
  • Multi-centre, pragmatic study design, allowing clinicians to treat as they normally did
  • Inclusive of all causes of ARDS (c.f. SAILS trial, that focused on sepsis)
  • A priori publication of protocol and statistical plan

Weaknesses

  • Statistically significant difference between groups in baseline PaO2:FiO2 ratio, with simvastatin group having slightly worse ratios: 123 vs. 132.4 mmHg. This will bias toward null hypothesis. A post-hoc statistical adjustment was performed; the between-group difference remained statistically insignificant.

The Bottom Line

  • Simvastatin use in ARDS has no benefit, based upon these data.
  • This trial does demonstrate a good safety profile in the critically ill, although biochemical abnormalities are more likely with simvastatin.

External Links

Metadata

Summary author: @SteveMathieu75 and @DuncanChambler
Summary date: 10 December 2014
Peer-review editor: @davidslessor

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