Risks and benefits of longterm PPIs

The American Gastroenterological Association (AGA) just published a clinical practice update on the risks and benefits of long-term use of proton pump inhibitors (see ppi risks benefits AGA2017 in dropbox, or doi.org/10.1053/j.gastro.2017.01.031  ).

Details:

RISKS: (these are the authors' assessment of the quality of the evidence and the effect sizes)

kidney disease: 2 retrospective observational studies found a modest effect size (10-20%) of CKD in those on PPIs, with very low quality of evidence. Mechanism, unclear: ? if those on PPIs had more comorbidities which predispose them to kidney disease?

dementia: retrospective observational studies finding a modest effect size (4-80%), with very low quality of evidence. Presumed mechanism: microglial cells use certain ATPases to degrade beta-amyloid, and PPIsmay block these ATPases (which does increase beta-amyloid in mice)

bone fracture: many observational studies, data inconsistent, modest effect size (39% to 4-fold increase), with low to very low quality of evidence. Presumed mechanism: hypochlorhydria-related malabsorption of calcium or vitamin B12, gastrin-induced parathyroid hyperplasia, and/or osteoclast vacuolar proton pump inhibition.

myocardial infarction: though a very small effect was found in an observational study, none found in RCTs. Presumed mechanism: omeprazole decreasing clopidogrel levels and its anti-platelet effect, but a randomized controlled trial comparing those on clopidogrel versus those on clopidogrel plus omeprazole had no difference in cardiovascular event rates.

small intestinal bacterial overgrowth: small studies have found that PPIs lead to bacterial overgrowth in the duodenum/small intestine, only some of which were symptomatic, modest effect size (2-fold to 8-fold increase), low quality of evidence. Presumed mechanism is loss of the bactericidal effects of gastric acid by taking PPIs

non-typhoidal salmonella and Campylobacter infections: increase found in 1 study, not confirmed. modest effect size (2-fold to 6-fold increase). Presumed mechanism: achlorhydria (and studies show that those with pernicious anemia or gastric surgery-induced achlorhydria do seem to have increases in these infections)

spontaneous bacterial peritonitis: observational studies suggest a 2-fold increased risk of SBP (50% to 3-fold increase), very low quality of evidence. Proposed mechanism: achlorhydria leading to gut bacteria changes, leading to changes in intestinal permeability and translocation of bacteria across the intestinal wall

C. diff infections: observational studies suggest 50% increased risk of C diff infection; and changes in bacterial taxa associated with C diff were increased in healthy volunteers after 4-8 weeks of high-dose PPIs. (the risk still pales compared to the rate of C diff with antibiotics). Risk may be higher in children, modest effect size (no increase to 3-fold increase), quality of evidence: low. Proposed mechanism: downstream effects of PPIs on colonic microbiota (see comment below)

pneumonia: seems to be more frequent soon after starting PPIs than after longer-term treatment.   Raises question of perhaps the PPIs were erroneously started for early misdiagnosed pneumonia. pneumonia is not a consistent finding in other studies, modest effect size (though no association in RCTs), very low quality of evidence. Proposed mechanism: upstream effects of PPIs on oropharyngeal microbiome

micronutrient deficiencies (overall 60-70% increase), low or very low quality of evidence:

--Calcium: may be decreased absorption, but not of water-soluble calcium salts or calcium from milk or cheese.

--Iron:  inconsistent data. No association in some Zollinger-Ellison patients on 6 years of PPIs, some association in other studies

--Magnesium: rare cases of profound hypomagnesemia. Observational data on modest positive association

--vitamin B12: most studies finding around 2.4-fold increased risk.

gastrointestinal malignancies: data also mixed. Suggestive data of increased risk in those with untreated H pylori infections, and concern about the profound hypergastrinemia (which has trophic effects on colonic epithelial cells in mice and on human colorectal cancers in vitro),  but population-based retrospective studies have failed to confirm a relationship. (No association in RCTs), modest effect size, very low quality of evidence.

BENEFITS:

In terms of benefits of PPIs, there are basically moderate to high quality studies supporting their use in:

-- GERD with esophagitis or structure (though may not be necessary with non-severe esophagitis, and no long-term data)

-- GERD without esophagitis or stricture (though may not be necessary with relatively mild symptoms, and no long-term data)

-- Barrett's esophagus with GERD (no long-term data)

-- NSAID bleeding prophylaxis (no long-term data)

-- Barrett's esophagus without GERD (this has low quality of evidence from observational studies only: no RCT, mostly mechanistic thinking that chronic inflammation may lead to esophageal adenocarcinoma and some observational data. But I would also be concerned that these data are based an unusual subset of patients who are asymptomatic yet have had endoscopy that documents Barrett's, and even observational studies are therefore a tad suspect).

Commentary:

--It is not surprising that the quality of these studies on benefit is higher than the above studies of adverse effects, since these were designed explicitly as intervention trials to look for benefit, probably all supported by drug companies, and controlling for co-morbidities, etc.

--I am also a little concerned that the AGA may be biased towards PPIs, perhaps because gastroenterologists tend to see patients with more severe conditions requiring PPIs, or perhaps financial conflicts-of-interest (as with all specialty societies, since the top academic specialists who often write the guidelines tend to be involved in drug-company-sponsored research).  My real concern with PPIs is that many many outpatients are put on PPIs for marginal reasons, and that very few patients are stepped-down to less aggressive therapy. As mentioned in prior blogs, given the limitations of time a primary care clinician has with patients, when their stomach problem is better with PPIs, it is time to deal with the myriad of other problems, keeping up with standard health maintenance issues, etc etc. The issue of the above potential complications of PPIs are very probably less important clinically than the need for PPIs for those with very clear indications (though I am a bit concerned that these studies are all short-term and it is a bit tenuous to extrapolate to long-term harms). But, the preponderance of studies finding some association of potentially serious adverse effects from PPIs, whether the studies are great or not, reinforces the imperative to avoid using PPIs unless clearly indicated, and, when appropriate, to step-down therapy as soon as possible. My experience is that patients who have endoscopy for dyspepsia are essentially invariably put on PPIs by the gastroenterologists independent of endoscopic findings. And, I have had pretty good success in getting some patients off of them, sometimes just onto prn calcium tablets or H2 blockers. But this may be a time-consuming issue to deal with. And I certainly have many patients for whom either I do not have the time to pursue or who are resistant to stepping down on therapy.

--To me, there is also the perhaps significant general omission in the above article of the effects of PPIs on the microbiome (as per prior article yesterday). My guess is that these effects do not necessarily translate clinically into disease, which is not so surprising given the complexity of this process, the multiple variables involved, and the length of time necessary to develop detectable disease (and the studies are too short). But, PPIs are associated with changes in the colonic microbiome to a less healthy one: with significant increases in Enterococcus, Streptococcus, Staphylococcus, and potentially pathogenic E coli species, as well as oral bacteria of the genus Rothia. And decreased Clostridiales.  These changes have been thought to lead to the association with C diff infections, but perhaps with other even unsuspected long-term harms. Though not mentioned specifically in the above article, these microbiome changes do add further credence to the imperative (I think) to minimize PPI usage.

So, my bottom line: PPIs are way overused for marginal indications (it is easy to jump to PPIs for dyspepsia, since they work so well…), but we should really discourage the use of PPIs unless they meet a clear criterion as above, or try to use the step-up approach: start with calcium or H2 blockers, then increase to PPIs when needed, and still try to step-down later; and try to get patients off of PPIs when they have been on them for awhile, unless there is a clear indication to continue.  Though a complicating factor here is that they are available OTC….