SAFER: pulse methylprednisolone did not improve survival in acute exacerbation of fibrosis

Design

multicentre, open-label, randomised controlled trial, 1:1 allocation

Population

100 adults with acute exacerbation of idiopathic pulmonary fibrosis at eight South Korean university hospitals

Primary outcome

all-cause mortality at 28 and 90 days

Effect

28-day 10.0% vs 14.6% (risk difference -4.6, 95% CI -18.8 to 9.1); 90-day 24.5% vs 29.8% (-5.3, -23.1 to 12.6)

Guidelines recommend corticosteroids in acute exacerbation of idiopathic pulmonary fibrosis weakly and without specifying dose or duration, and pulse methylprednisolone became standard on that silence rather than on evidence. SAFER tested it: 100 adults at eight South Korean university hospitals randomised to intravenous pulse methylprednisolone 10 mg/kg for three days or a non-pulse regimen of 1 mg/kg for seven days, each followed by protocolised tapering and low-dose maintenance prednisolone.

Mortality at 28 days was 10.0% with pulse against 14.6% without, a risk difference of -4.6 percentage points (95% CI -18.8 to 9.1, p = 0.549). At 90 days, 24.5% against 29.8% (-5.3, -23.1 to 12.6, p = 0.648). A Fine-Gray analysis treating transplantation as a competing event found no difference either. No secondary outcome separated the groups.

Read this carefully rather than triumphantly. With 100 patients the confidence intervals are wide enough to contain a benefit worth having in either direction, so this is not proof that pulse dosing is useless. What it is, is the first randomised comparison, and it removes the basis for treating pulse dosing as established. A ten-fold higher steroid dose that has not shown a survival benefit needs a reason each time it is given, particularly in patients who are frequently diabetic, frail and at risk of the infection that may have triggered the exacerbation. The non-pulse regimen is now a defensible default.

• Pulse dosing is no longer the evidence-supported default in acute exacerbation of fibrosis.
• A non-pulse regimen of 1 mg/kg for seven days is a defensible choice.
• Confidence intervals are wide - this does not prove the regimens are equivalent.
• Weigh hyperglycaemia, infection risk and delirium against a benefit not demonstrated.
• Exclude infection and heart failure before attributing deterioration to the exacerbation itself.

Why it matters

A tenfold difference in steroid dose has been decided by habit for years, and this is the first randomised evidence in either direction.

Don't overread it

A 100-patient trial with wide confidence intervals - it does not establish that the two regimens are equivalent.

The statistics, in plain English

A risk difference of -4.6 percentage points with an interval from -18.8 to 9.1 means the trial is compatible with pulse dosing saving nearly one in five patients or harming about one in eleven - which is the honest reading of 100 patients. A non-significant result in a small trial is an absence of evidence, not evidence of absence. The value here is that it shifts the burden of justification onto the higher dose, where it belongs.

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