Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients With E coli or Klebsiella pneumoniae Bloodstream Infection and Ceftriaxone Resistance A Randomized Clinical Trial
This was a randomized, double-blinded, international multicenter pragmatic (phew! That’s a mouthful!) study to determine if piperacillin/tazobactam (pip-taz) is non-inferior to meropenem. The reason for this study is to see if there is a way to reduce carbapenems use and prevent further Carbapenem resistance acinetobacter (CRAB, not the Maryland kind). ESBL drugs are those that are by definition resistant to ceftriaxone or ceftazidime. This is a really well done trial with the trial being registered at clinicaltrials.gov and meeting all the important qualities of an RCT. The only missing item (which is probably a small one given how rigorous this trial was) is the fact that of all the 9 countries the US wasn’t one of them (Isn’t Canada close enough? Probably, still too close if you aren’t a fan of Trump). The study used a non-inferiority protocol with 30 day all cause mortality as the end point. Also a home run here with a very good patient oriented outcome. They randomized 378 patients and found an impressive 12.3% vs 3.7% mortality rate for pip-taz vs meropenem. Yikes! That is an 8.6% absolute risk reduction!!! In classic statistical phrasing using double negative: This trial found pip-tazo not non-inferior. They powered the study to find 454 patients but stopped at a predefined interim-analysis of 340 patients. Its bad form to stop a trial for “benefit” when you are looking for non-inferiority but not for harm. As such the trial enrolled 391 pts. In this cohort the patients had about 86% E. Coli and 14% Klebsiella. Most of the patients came from Singapore and Australia with only 1 patient coming from Canada (C’mon Canada!). Most of the infections were either urinary (~60%) or intra-abdominal infections (~15%). Interestingly, 60% of patients were deemed to have been treated with “appropriate” empiric therapy and EVEN MORE INTERESTING is the fact that almost 45% of patients had community associated acquisition. This is probably true world wide but maybe less so in the US? But we are likely heading that way. So to sum up in patients that have ESBL need meropenem not pip-tazo! For a number needed to treat version: If you will have one death for every 12 patients you treat if you use pip-tazo and not meropenem!!
The JC learning point
This trial was performed as a “non-inferiority” trial. These trials should be looked at with a scrutinizing eye! Drug companies love to use this because they don’t have to prove the drug is better, they just have to prove its not worse. The critical point here is to make sure that the correct significance (α level) is set. Non-inferiority is established at the α significance level if a confidence interval for the difference in efficacies (new – current) is contained within a safety margin interval. In this study they used a margin of +5%; so if the studies showed a mortality within 5% of each other then we would have said that pip-tazo is non-inferior to meropenem (but it didn’t). Normally when we compare to things we can use a α of 0.05. However, in non-inferiority testing we have to use an α of 0.025 because we are really performing TWO ONE-sided tests (think of it as needing a p-value for the +margin and the -margin so you cut the p-value in half ). Lastly, interpreting a non-inferiority trial as a superiority trial is OK and doesn’t require a multiple testing correction IF the 95% confidence interval for the treatment benefit excludes the non-inferiority margin AND zero is not in the confidence interval. However, the opposite approach is not true. If a superiority trial fails to reject the null hypothesis but the trial data appear to suggest treatment non-inferiority, you cannot default to non-inferiority
- Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients With E coli or Klebsiella pneumoniae Bloodstream Infection and Ceftriaxone Resistance A Randomized Clinical Trial. JAMA. 2018;320(10):984-994. doi:10.1001/jama.2018.12163
- Understanding noninferiority trials. Korean J Pediatr 2012;55(11):403-407. http://dx.doi.org/10.3345/kjp.2012.55.11.403