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.