{"id":1285,"date":"2017-04-26T11:48:41","date_gmt":"2017-04-26T11:48:41","guid":{"rendered":"http:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/?p=1285"},"modified":"2017-08-21T10:18:37","modified_gmt":"2017-08-21T10:18:37","slug":"primary-care-corner-by-geoffrey-modest-md-risks-and-benefits-of-longterm-ppis","status":"publish","type":"post","link":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/2017\/04\/26\/primary-care-corner-by-geoffrey-modest-md-risks-and-benefits-of-longterm-ppis\/","title":{"rendered":"Primary Care Corner by Geoffrey Modest MD: Risks and benefits of longterm PPIs"},"content":{"rendered":"

\u200bby Dr Geoffrey Modest<\/strong><\/p>\n

The\u00a0American Gastroenterological Association (AGA) just published a\u00a0clinical practice update\u00a0on the risks and benefits of long-term use of proton pump inhibitors (see\u00a0doi.org\/10.1053\/j.gastro.2017.01.031<\/a>\u00a0\u00a0).<\/p>\n

 <\/p>\n

Details:<\/p>\n

RISKS:<\/strong> (these are the authors’ assessment of the quality of the evidence and the effect sizes)<\/p>\n

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: ?\u00a0if those on PPIs had more comorbidities which predispose them to kidney disease?<\/p>\n

dementia: retrospective observational studies finding a modest effect size\u00a0(4-80%),\u00a0with very low quality of evidence. Presumed mechanism: microglial cells use certain\u00a0ATPases\u00a0to degrade beta-amyloid, and PPIs may block these\u00a0ATPases\u00a0(which does increase\u00a0beta-amyloid in mice)<\/p>\n

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:\u00a0hypochlorhydria-related malabsorption of calcium or vitamin B12, gastrin-induced parathyroid hyperplasia, and\/or osteoclast vacuolar proton pump inhibition.<\/p>\n

myocardial infarction: though a very small effect was found in an observational study,\u00a0none found in RCTs. Presumed mechanism: omeprazole decreasing clopidogrel levels and its\u00a0anti-platelet effect, but a randomized controlled trial comparing those on\u00a0clopidogrel\u00a0versus those on\u00a0clopidogrel\u00a0plus omeprazole had no difference in cardiovascular event rates.<\/p>\n

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<\/p>\n

non-typhoidal\u00a0salmonella and Campylobacter infections: increase found in 1 study, not confirmed. modest effect size\u00a0(2-fold to 6-fold increase).\u00a0Presumed mechanism:\u00a0achlorhydria\u00a0(and studies\u00a0show that\u00a0those with pernicious anemia or gastric surgery-induced\u00a0achlorhydria\u00a0do seem to have increases in these infections)<\/p>\n

spontaneous bacterial peritonitis: observational studies suggest a 2-fold\u00a0increased\u00a0risk of SBP (50% to 3-fold increase), very low quality of evidence. Proposed mechanism:\u00a0achlorhydria\u00a0leading to gut bacteria changes, leading to changes in intestinal permeability and translocation of bacteria across the intestinal wall<\/p>\n

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),\u00a0quality of evidence: low. Proposed mechanism: downstream effects of PPIs on colonic microbiota (see comment\u00a0below)<\/p>\n

pneumonia: seems to be more frequent soon after starting PPIs than after longer-term treatment. \u00a0\u00a0Raises 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<\/p>\n

micronutrient deficiencies (overall 60-70% increase), low or very low quality of evidence:<\/p>\n

–Calcium: may be decreased absorption, but not of water-soluble calcium salts or calcium from milk or cheese.<\/p>\n

–Iron:\u00a0 inconsistent data. No association in some\u00a0Zollinger-Ellison patients on 6 years of PPIs, some association in other studies<\/p>\n

–Magnesium: rare cases of profound hypomagnesemia. Observational data on modest positive association<\/p>\n

–vitamin B12: most studies finding around 2.4-fold increased risk.<\/p>\n

gastrointestinal malignancies: data also mixed. Suggestive data of increased risk in those with untreated H pylori infections, and concern about the profound\u00a0hypergastrinemia\u00a0(which has trophic effects on colonic epithelial cells in mice and on human colorectal cancers in vitro),\u00a0 but population-based retrospective studies have failed to confirm a relationship. (No association in RCTs), modest effect size, very low quality of evidence.<\/p>\n

 <\/p>\n

BENEFITS:<\/strong><\/p>\n

In terms of benefits of PPIs, there are basically moderate to high quality studies supporting their use in:<\/p>\n

— GERD with esophagitis or structure (though may not be necessary with non-severe esophagitis, and no long-term data)<\/p>\n

— GERD without esophagitis or stricture (though may not be\u00a0necessary with relatively mild symptoms, and no\u00a0long-term data)<\/p>\n

— Barrett’s esophagus with GERD (no long-term data)<\/p>\n

— NSAID bleeding prophylaxis (no long-term data)<\/p>\n

— Barrett’s esophagus without GERD (this has\u00a0low 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\u00a0an unusual subset of patients who are asymptomatic yet have had endoscopy that\u00a0documents Barrett’s, and even observational studies are therefore a tad suspect).<\/p>\n

 <\/p>\n

Commentary:<\/p>\n

–It is not surprising that the quality of these studies on\u00a0benefit is higher than the above studies of adverse effects,\u00a0since these were designed explicitly as intervention trials to look for benefit, probably\u00a0all supported by drug companies, and controlling for co-morbidities, etc.<\/p>\n

–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). \u00a0My real concern with PPIs is that many\u00a0many\u00a0outpatients 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,\u00a0etc\u00a0etc. The issue of the above potential complications of PPIs are very probably\u00a0less 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\u00a0have many patients for whom\u00a0either I\u00a0do\u00a0not\u00a0have the time to pursue\u00a0or who are resistant to stepping down on therapy.<\/p>\n

–To me, there is also the perhaps significant general\u00a0omission in the above article of the effects of PPIs on\u00a0the microbiome (see here<\/a>). 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\u00a0Enterococcus, Streptococcus, Staphylococcus, and potentially pathogenic E coli species, as well as\u00a0oral bacteria of the genus\u00a0Rothia. And decreased\u00a0Clostridiales.\u00a0 These changes have been thought\u00a0to lead to\u00a0the association with C diff infections, but perhaps with other even unsuspected long-term harms. Though not mentioned specifically in\u00a0the above article, these microbiome changes\u00a0do add further credence to the imperative (I think) to minimize PPI\u00a0usage.<\/p>\n

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\u2026), but we should really discourage the use of PPIs unless they meet a clear criterion as above, or\u00a0try to\u00a0use\u00a0the step-up approach: start with calcium or H2 blockers, then increase to PPIs when needed, and still\u00a0try to step-down later; and try to get patients off of PPIs when they have been on them for\u00a0awhile, unless there is a clear indication to continue.\u00a0 Though a complicating factor here is that they are available OTC\u2026.<\/p>\n

for another recent blog on PPI risks and benefits and some additional concerns, see here<\/a>.<\/p>\n

 <\/p>\n","protected":false},"excerpt":{"rendered":"

Risks and benefits of longterm PPIs […]<\/p>\n

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