PPIs: way overprescribed!!
The American Gastroenterological Association developed a clinical practice guideline on de-prescribing proton pump inhibitors (PPIs), unless there are clear indications for continuing them (see ppi deprescribing Gastro2022 in dropbox, or https://doi.org/10.1053/j.gastro.2021.12.247
Recommendations:
--BEST PRACTICE ADVICE 1: all patients taking PPIs should have a regular review of the ongoing indications for use, with documentation of the indication
--and this should mostly be done by the primary care clinicians (their rationale for adding more stuff for us guys to do: we do prescribe most of the PPIs; we are more likely to uncover that the patient has been buying them over-the-counter; and, when gastroenterologists are involved, the patients are usually subsequently followed by us)
--BEST PRACTICE ADVICE 2: all patients without a definitive indication for chronic PPIs should be considered for a trial of de-prescribing
--BEST PRACTICE ADVICE 3: most patients with an indication for chronic PPI use who take twice-daily dosing should be considered for step-down therapy to once-daily PPI
-- double-dose PPIs (standard dose twice-daily or double strength dose once daily) have not been studied in any RCT and are not FDA approved. However, 15% of PPI users are on higher than standard doses.
-- and observational studies have found that there is a stronger association between higher dose PPI use and several complications, including community-acquired pneumonia, hip fracture, and C. difficile infection
-- there are no studies showing that high dose PPIs are beneficial for Barrett’s esophagus, an often appropriate indication for long-term PPIs
-- high dose PPIs had been advocated for long-term (eg 3-month trial) for the treatment of laryngopharyngeal reflux (LPR), though relatively recent studies have undercut this use, with one suggesting that alkaline water and a Mediterranean diet worked at least as well (see http://gmodestmedblogs.blogspot.com/2017/09/lpr-treatment-by-diet.html
--BEST PRACTICE ADVICE 4: patients with complicated GERD, such as those with a history of severe erosive esophagitis, esophageal ulcer, or peptic stricture, should generally not be considered for PPI discontinuation
-- about 20% of patients with untreated GERD have erosive esophagitis, and continuing PPIs in this group is effective in healing erosive esophagitis and in preventing the development and recurrence of GERD complications in longtime PPI users
-- erosive esophagitis is also more common in people who have Barrett’s esophagus
--BEST PRACTICE ADVICE 5: patients with known Barrett’s esophagus, eosinophilic esophagitis, or idiopathic pulmonary fibrosis should generally not be considered for a trial of deprescribing
-- PPIs have been shown to decrease the risk of esophageal adenocarcinoma in those with Barrett’s esophagus
-- about half the patients with symptomatic esophageal eosinophilia respond to PPI therapy, but not everyone requires a PPI since topical steroids or nonpharmacologic therapy may help
-- PPI use in those with idiopathic pulmonary fibrosis has been found to reduce the likelihood of disease progression, though in low quality studies
--BEST PRACTICE ADVICE 6&7: PPI users should be assessed for risk of upper GI bleeding and should not be considered for PPI de-prescribing if at high risk, using an evidence-based strategy
-- though they comment on evidence-based strategies, they also have a table of guidelines from many different organizations which actually have different recommendations, e.g. some suggesting that patients on NSAIDs should have a PPI if they have moderate to high risk of upper GI bleeding (with at least 1 more risk factor, including prior ulcer, >65yo, high-dose NSAID therapy, concurrent use of aspirin/ steroids/ anticoagulants)
-- one of the guidelines also included H. pylori infection (eg, a Lancet article from about 30 years ago found that people with H. pylori who are put on long-term NSAIDs have a 3-fold higher risk of major GI bleeding unless the H. pylori is treated ….). And about 1/2 of the world has H Pylori infections, with substantial numbers in the US (see http://gmodestmedblogs.blogspot.com/2019/12/h-pylori-in-us-veterans.html )
-- other guidelines have much less stringent criteria (eg patients on 2 or mote antithrombotic agents)
--BEST PRACTICE ADVICE 8: patients who discontinue long-term PPI therapy should be advised that they may develop transient upper GI symptoms due to rebound acid hypersecretion (RAHS)
-- this is related to the astronomically high gastrin levels in those on PPIs, which lead to proliferation of parietal cells and enterochromaffin-like cells, leading to increased acid production.
-- one study found that PPI withdrawal after an 8-week course led to higher incidence of upper GI symptoms
-- use of H2 receptor antagonists or calcium antacids, or on-demand PPIs are useful strategies to de-prescribing PPIs
-- which all means that patients should be aware that they could have recurrent GI symptoms if they just stopped the PPIs (though, those with persistent symptoms for >2 months after stopping the PPI may need to continue PPIs). for example, these patients may well have erosive esophagitis or Barrett's.
--BEST PRACTICE ADVICE 9: when de-prescribing PPIs, either dose tapering or abrupt discontinuation can be considered
-- but regression of parietal cells and enterochromaffin-like cells may take 2 to 6 months
--BEST PRACTICE ADVICE 10: the decision to discontinue PPIs should be based solely on the lack of an indication for PPI use and not because of concern for PPI associated adverse events
-- see below for comments on this
Commentary:
--PPIs are used remarkably often: overall 7%-15% of people use them over time, 40% of those >70yo take them
-- one quarter of those taking PPIs continue to use them for >1 year
-- a large observational study from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey found the PPIs were used in 4.0% of ambulatory visits in 2002, increasing to 9.9% in 2009. And, 62.9% of patient visits did not have gastrointestinal complaints, gastrointestinal diagnoses, or other indicated reason for their use (see Proton Pump Inhibitor Use in the U.S. Ambulatory Setting, 2002–2009 | PLOS ONE )
-- these numbers of PPI users have likely increased dramatically, but with difficulty assessing actual use of PPIs since they have been over-the-counter in the United States since 2003
-- there are lots of potential serious adverse effects of PPIs documented in observational studies, including chronic kidney disease, increased risk of osteoporosis and bone fractures, increased risk of dementia, and even increased risk of Covid-19 (see below for longer list). However, randomized controlled trials comparing PPIs to placebo have not found higher rates of any of these events. [Observational trials are certainly easier to do, and they have the benefit of longer-term assessment of adverse effects, whereas randomized controlled trials are pretty short-term, per this article “the vast majority of trials demonstrating [PPI] efficacy have tested durations of 4-12 weeks, or no more than 6-12 months for maintenance therapy”, likely too soon for many of these adverse effects to present themselves....}
-- an interesting study from Hong Kong found that people who were taking PPIs after a successful H. pylori treatment had an increased risk of gastric cancer, not so for H2 blockers (see http://gmodestmedblogs.blogspot.com/2017/11/ppi-post-hpylori-rx-and-gastric-cancer.html )
-- a claims-based study found that PPI use in the elderly was related to an increased risk of dementia (see http://gmodestmedblogs.blogspot.com/2019/04/ppi-use-and-dementia.html )
-- unfortunately, as noted above, PPIs are prescribed at a much higher rate in elderly patients, and being >65yo is in fact considered a risk factor for bleeding in those on NSAIDs (ie, lots of older people have musculoskeletal or other pain problems and are prescribed NSAIDs, which would bump them up into high GI bleeding risk and per these recommendations would subject them to PPIs… I guess this adds to the litany of suggestions to try nonpharmacologic approaches first, then acetaminophen, and then perhaps a COX-2 inhibitor as the NSAID of choice)
-- a large study of patients in the Atherosclerosis Risk in Communities database found increased risk of chronic kidney disease in those on PPIs (see http://gmodestmedblogs.blogspot.com/2016/01/ppis-and-chronic-kidney-dz.html )
-- another study found increased risk of subsequent MIs on those on PPIs (see http://gmodestmedblogs.blogspot.com/2015/06/ppis-associated-with-mis_13.html )
-- a recent systematic review found that gastric acid suppression by PPIs was associated with highly adverse gut microbiota changes, and specifically with increased odds of intestinal carriage of multiple bacteria that were multi-drug resistant and pretty lethal (see http://gmodestmedblogs.blogspot.com/2020/03/gastric-acid-suppression-and-adverse.html ); there also are many studies finding a positive association between PPIs and C. diff infections (see ppi and cdiff review PharmPract2021 in dropbox, or https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102963/pdf/21550417-12-01-3439.pdf )
-- there may be an increased risk of osteoporosis and fracture risk (see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540255/ )
-- there was a case-control study in Taiwan finding that PPIs were associated with increased risk of pulmonary tuberculosis. This is perhaps not so surprising given that gastric resection in the past and gastric bypass in more recent studies have found an increased risk of tuberculosis, likely from eliminating gastric acidity as a barrier to inhaled/swallowed pathogens from reaching the intestines.
-- there may also be increased risks of obesity and allergy in kids on PPIs (see http://gmodestmedblogs.blogspot.com/2018/12/antibiotics-ppish2ras-increase-obesity.html )
so, bottom line:
-- PPIs are really strong
-- as noted in the BEST PRACTICE ADVICEs, these significant multiple adverse effects have not been borne out in randomized controlled trials. However, as mentioned above, RCTs only looked at really short-term, mostly several months or up to 1 year, and there may well have been a statistically significant increased risk of several of these multitude of potential adverse events from PPIs if these trials were extended to 10 years for example. The advantage of many of the observational studies is that they are long-term, though are not in of themselves as rigorous as RCTs. The RCTs were designed to assess benefit (which drug companies like) and not long-term harms (which they don't like), and many of the harms may take much longer to reveal themselves (as noted above, some are clearly cumulative dose-dependent). so, the AGA guidelines to ignore the potential adverse effects (their last BEST PRACTICE ADVICE) and focus only on whether PPIs are necessary is a tad misleading (though, of course, meds should only be taken if actually needed). But patients should know what they are getting into: both the benefits and potential adverse effects.
-- PPIs work really well for many upper GI symptoms and they are very easy to get over-the-counter (though, H2 blockers and OTC calcium antacids also work well for many people)
-- I suspect that many people on PPIs are unaware of the multitude of potentially bad adverse effects (similar to other OTC drugs, such as NSAIDs, which also have an array of largely unknown adverse effects to patients, such as chronic kidney disease, hypertension, heart failure, GI bleeds, etc.). this represents a problem in our country with OTC drugs, since these are marketed directly to consumers without clinicians being able to review potential adverse effects. And, when these meds are bought OTC, patients do not get the multi-page list of potential adverse effects that they get when these same meds are prescribed.
-- and all of this means yet another task for us primary care types to deal with: asking about PPI use and spending the precious, limited time we have with patients trying to de-prescribe them
-- and, another important acknowledgment is that we in primary care are dealing with a host of problems even if we prescribe the PPIs; if the patient is doing better, we may not have the time in our short visits to de-prescribe them. We often need to move on to other active problems, leading to perhaps inappropriately just refilling the prescription
--My concern with PPIs is basically the very large potential for lots of adverse effects. I am personally very hesitant to prescribe PPIs largely based on this concern, but also a feeling that there was likely an important evolutionary reason for us to have acid in our stomachs. Perhaps that is to destroy potentially harmful bacteria that are swallowed from food, or inhaled and then swallowed? Perhaps stomach acid is useful to help our bodies breakdown foods so that we can absorb the important nutrients? And, I have found on many occasions that people do well with de-prescribing, with the not infrequent patient finding that over-the-counter calcium supplements were even better than H2 blockers...
-- And, given the rebound acid hypersecretion from stopping the PPIs, I have successfully used the strategy of spacing PPIs out or making the PPIs as PRN; or in those reluctant to stop the PPI, moving them to an H2 blocker or calcium supplement with PPIs to be taken only if needed
geoff
If you would like to be on the regular email list for upcoming blogs, please contact me at gmodest@uphams.org
to get access to all of the blogs (2 options):
1. go to http://gmodestmedblogs.blogspot.com/ to see them in reverse chronological order
2. click on 3 parallel lines top left, if you want to see blogs by category, then click on "labels" and choose a category
3. or you can just click on the magnifying glass on top right, then type in a name in the search box and get all the blogs with that name in them
or: go to https://www.bucommunitymedicine.org/ , a website from the Community Medicine section at Boston Medical Center. This site does have a very searchable and accessible list of my blogs (though there have been a few that did not upload over the last year or two). but overall it is much easier to view blogs and displays more at a time.
please feel free to circulate this to others. also, if you send me their emails, i can add them to the list
Comments
Post a Comment
if you would like to receive the near-daily emails regularly, please email me at gmodest@uphams.org