Here’s what we did in the #PEPTICtrial, what we found, and what I think it all means. #CCR20 @jama_current
We conducted an international, randomized, open-label, cluster crossover, registry-embedded trial to compare strategies of stress ulcer prophylaxis in mechanically ventilated adults implemented at the level of the ICU jamanetwork.com/journals/jama/…
The primary outcome was in-hospital all-cause mortality up to 90 days. Secondary outcomes were clinically significant upper GI bleeding, C. difficile infection, ICU and hospital length of stay.
We compared one default approach to another implemented at the level of the ICU (not PPI vs. H2RB given to every patient) in 26828 patients. Clinicians chose to give SUP to almost 90% of included patients.
A total 18.3% admitted to the ICU when PPIs were used as the default stress ulcer prophylaxis and 17.5% admitted when H2RBs were used died in hospital by day 90 (risk ratio; 1.05 95% CI 1.00 to 1.10, P=0.05).
Rates of C. difficile infection, and ICU and hospital length of stay were similar by treatment group but…
Clinically significant upper GI bleeding occurred less frequently in the PPI group patients (risk ratio; 0.73 95% CI, 0.57-0.92).
For every 1000 mechanically ventilated patients admitted when PPI was the default SUP, five fewer patients had an upper GI bleed compared to when H2RB was used as the default.
Making some assumptions based on the SUP ICU supplementary appendix data, this would equate to three fewer patients getting a transfusion and two fewer patients getting an upper GI endoscopy nejm.org/doi/full/10.10…
Both PPIs and H2RBs are cheap & adverse events with these drugs are rare
PPIs appear to do what they are supposed to do – they prevent upper GI bleeds.
Upper GI bleeds may not generally result in death or prolong ICU or hospital LOS but they can certainly:
1.Cause angst for families, patients, (& doctors)
2.Create hassles for management related to whether to scope or not and what to do with things like DVT prophylaxis & aspirin
1.Cause angst for families, patients, (& doctors)
2.Create hassles for management related to whether to scope or not and what to do with things like DVT prophylaxis & aspirin
If you want to avoid dealing with upper GI bleeds in an extra 5 out of every 1000 patients, then you may choose to go with the PPI strategy but, if you do there are some VERY important caveats...
First, in patients who had cardiac surgery, the rate of clinically significant GI bleeding was 0.7% irrespective of the strategy of stress ulcer prophylaxis chosen.
In the >6500 cardiac surgical patients, the observed risk of death was statistically significantly higher in the PPI-group (2.5%) than the H2RB-group (1.9%) corresponding to a risk ratio of 1.27 95% CI, 1.04 to 1.57.
While the increased risk of death with the PPI strategy seen in the #PEPTICtrial in cardiac surgical patients may be a chance finding, there is little to lose by adopting an H2RB strategy as the default for a subgroup where clinically significant upper GI bleeding is rare.
Second, the findings of the #PEPTICtrial were consistent with a treatment effect estimate that ranges from no effect to a 10% relative increase in mortality using the PPI strategy.
The treatment effect estimates on mortality are the narrowest ever seen in an ICU trial.
While it is now very unlikely the PPI strategy reduces mortality by a clinically important degree, the possibility of increased mortality is not excluded. How might PPIs increase mortality risk?
In ventilated ICU patients, the number of GNB in gastric aspirates increases as the gastric pH decreases. PPIs cause more profound acid suppression than H2RBs. We cannot exclude the possibility that mortality attributable to VAP is increased by using PPIs.
PPIs appear to exert a range of immunosuppressive effects they: (1) inhibit NK cell activity; (2) reduce PMN cell chemotaxis & decrease superoxide generation; & (3) reduces neutrophil bactericidal capacity.
These effects provide a mechanism by which mortality could be increased. The magnitude of the potential increase in mortality suggested is clinically important and could account for around 25000 ICU deaths per year in developed countries alone.
Weighing a potential increased risk of death with PPIs against an unequivocal reduction in clinically significant upper GI bleeding is not simple and clinicians will not necessarily all come to the same conclusion about how to do this but here’s what I think…
The PEPTIC study suggests that the NNT with a default PPI strategy to prevent clinically significant upper GI bleeding compared to a default H2RB strategy is 200
Although there is still uncertainty about whether PPIs actually increase mortality risk, I think most patients would rather not have a therapy that might kill them in order to have a 1 in 200 chance of being prevented from having an upper GI bleed that probably will not.
Remember though, PPIs are highly effective at treating upper GI bleeding. If a patient has an upper GI bleed, you should give a PPI.
Many will now ask whether SUP is required in ICU patients at all. Further clarity on the issue will likely come from the #REVISEtrial.
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