STATS AND TRIALS STUFF

Anthony Delaney MBBS MSc FACEM FCICM

Staff Specialist Malcolm Fisher Department of Intensive Care Medicine

Disclaimer

I ain’t a statistician More of an enthusiastic amateur

So…..

Difference between mortality and survival? How to interpret a “negative” trial result?

Mortality or survival?

Mortality: Number of deaths/number at risk at the end of a period

of time 28 day mortality Rate

Survival: Time to event analysis How long it takes for the event to happen If you have survived for x time, what are your chances of

dying in x+1 time Hazard

Population: >18 yo Source of infection Temperature >38.3oC or <35.6oC Heart rate > 90bpm SBP <90 mmHg for 1 hour if adequate fluids and some pressors Urine output <0.5 ml/kg/hr for > 1 hr or PaO2/FiO2 <280 Lactate >2 mmol/L Ventilated Excluded:

pregnant, contra/indication to steroids, advanced cancer, AMI, PE, AIDS,

Intervention: Hydrocortisone mg q6h ivi Fludrocortisone 50mg po daily For 7 days

Comparison: Placebo For 7 days

Outcome: The primary endpoint was the 28-day survival

distribution from randomisation in non-responders to the short corticotropin test

Point one Post-randomisation sub groups are dubious

Is the subgroup variable a characteristic measured at baseline or after randomisation?

“The credibility of subgroup hypotheses based on post-randomisation characteristics is severely compromised, and can be rejected simply on this criterion”

Subdivision of patients in ISIS-2 with respect to birth signs

Gemini and Libra shows an adverse effect on mortality

Results: 300 participants In non-responders

Placebo 73/115 (63%) Steroids 60/114 (53%) Hazard ratio 0.67 95% CI 0.47-0.95; P=0.02

Conclusion: Treatment with hydrocortisone and

fludrocortisone significantly reduced the risk of death in patients with septic shock and adrenal insufficiency

Date of download: 9/11/2013Copyright © 2012 American Medical Association.

All rights reserved.

From: Effect of Treatment With Low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patients With Septic Shock

JAMA. 2002;288(7):862-871. doi:10.1001/jama.288.7.862

Results are according to the response to the short corticotropintest. In nonresponders, the median time to death was 12 days in the placeboand 24 days in the corticosteroid groups; in responders, 14 days in the placeboand 16.5 days in the corticosteroid groups; and in all patients, 13 days inthe placebo and 19.5 in the corticosteroid groups.

Figure Legend:

In nonresponders, the median time to death was 12 days in the placebo and 24 days in the corticosteroid groups;

in responders, 14 days in the placebo and 16.5 days in the corticosteroid groups;

and in all patients, 13 days in the placebo and 19.5 in the corticosteroid groups.

Mortality or Survival

Time (days)28

Survival

1.0

0.5

i

How big a difference in mortality do you think putting a tracheostomy in at Day 4 compared to Day 10 would make on 30 day mortality?

50% RRR (15% ARR) 25% RRR (7.5% ARR) 10% RRR (3% ARR) 5% RRR (1.5% ARR)

“Negative trials”

n

Population: Mechanically ventilated adults Had been ventilated for 4 days and thought to

require at least 7 more days of ventilation Excluded:

Those requiring a tracheostomy, contraindication to tracheostomy, respiratory failure due to chronic neurological disease

Intervention: Trachesotomy by Day 4

Comparison: Tracheostomy after Day 10 if still required

Outcome: All cause mortality 30 days from randomisation

Sample Size Calculation: Baseline mortality of 30% Absolute risk reduction 6.3% (21% RRR) Power 80% Alpha 5% 4% loss to follow up

N=1692

Due to study fatigue and exhaustion of funding

N=899

“Tracheostomy within 4 days of critical care admission was not associated with an improvement in 30 day mortality”

We are 95% certain that early tracheostomy might be between

5.4% worse to 6.7% better in absolute risk About 20% better or worse in terms of relative

risk

6.3% of patients had a complication of tracheostomy

53% of patients who were randomised to delayed trache didn’t need one

2 year mortality was 52.3% Only 5 lost to follow up

Conclusions: Unable to rule out a clinically important difference

between early and late trache It probably doesn’t make a big difference to

mortality Unknown about patient perspective

Useful information about the patient cohort

Not really a “negative trial”

QUESTIONS??