Based on moderate quality evidence, major guidelines have long recommended acid-suppressive therapy for patients in the intensive care unit (ICU). Several medium-sized trials have demonstrated a modestly reduced rate of gastrointestinal (GI) bleeding among patients receiving H2-blockers, antacids, and proton-pump inhibitors (PPIs) versus placebo.
Now, many major guidelines recommend PPIs for GI prophylaxis in ICU patients because of their stronger acid-suppressing potential, despite concerns related to Clostridium difficile infection, aspiration pneumonia, and other complications. Head-to-head comparisons between PPIs and other acid-suppressors, which are scant and generally of low quality, have demonstrated that PPIs are modestly more effective at preventing GI bleeding but are associated with higher rates of complications.
Furthermore, clinicians caring for patients on the general medical wards have increasingly used acid-suppressive prophylaxis, particularly PPIs, though the evidence to support acid-suppressive therapy for hospitalized patients outside of the ICU is scant.
In an important trial published recently in the New England Journal, researchers from Denmark — supported by a public grant — provide us some provocative new insights on the topic. In the study, more than 3,000 patients in ICUs at multiple European medical centers were randomized to receive 40 mg of IV pantoprazole [Protonix] or placebo daily during their ICU stay. After 90 days of follow up, 31.1% of patients in the pantoprazole group versus 30.4% in the placebo group had died (the primary endpoint), P=0.76. In the pantoprazole group, 2.5% of patients had clinically-important GI bleeding, as compared with 4.2% in the placebo group. The number of patients with infections or serious adverse reactions and the percentage of days alive without life support within 90 days were similar in the two groups.
While we don’t dismiss the observed reduction in GI bleeding with pantoprazole — certainly preventing a non-lethal GI bleed is meaningful — it’s not clear that the overall benefits of PPI prophylaxis were favorable since mortality and total complication rates did not differ between the groups. At best, PPIs appear to be a relatively low-value intervention among ICU patients. Because there was no other active treatment arm, it is not clear whether other acid-suppressing agents — such as H2 blockers — would have fared any better.
What’s the Slow Medicine conclusion? First, this trial raises questions about our longstanding practicing of using acid-suppression for all critically ill patients. Though acid suppression may modestly lower rates of GI bleeding, there are likely associated complications, and it is not clear that the overall effects are favorable. Until more compelling data are available, perhaps we should consider reserving acid suppression for those at highest risk of GI bleeding.
Furthermore, for ICU patients in whom we are providing acid-suppressive prophylactic therapy, this study might cause us to consider using H2 blockers or antacids, since these agents are associated with lower rates of adverse effects, albeit with less GI benefit. We would welcome a follow-up analysis rigorously assessing the comparative pros and cons of different acid-suppressive therapies, including PPIs, H2 blockers, and antacids.
Another important implication is that we should not initiate GI prophylaxis for hospitalized patients outside of the ICU setting unless there is another compelling indication to do so. If the net effects of GI prophylaxis in the ICU are unclear, it is likely that acid-suppression for non-critically ill patients is ineffective, or even harmful.
Finally, this important publicly-funded study reminds us of the importance of non-commercial support for pharmaceutical research. If we relied solely on industry funding, trials like this would never get completed!
Pieter Cohen, MD, is a general internist at Cambridge Health Alliance in Somerville, Massachusetts and associate professor of medicine at Harvard Medical School. Michael Hochman, MD, MPH, is a board-certified general internist who attended Harvard Medical School.