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GI- dyspepsia

Primary Care Corner with Geoffrey Modest MD: PPIs and increased mortality

20 Jul, 17 | by

A large longitudinal study of US veterans found a 25% increased risk of death associated with proton pump inhibitor (PPI) usage (see 10.1136/ bmjopen-2016-015735)​.


— the researchers assessed three cohorts of patients, with 5.7 years of follow-up after the first acid suppression therapy prescription was written, and all patients had at least one outpatient serum creatinine value before acid suppression therapy was chosen:

— primary cohort: new users of PPI or H2 blockers (n=349,312)

— PPI versus no PPI users (n= 3,288,092)

— PPI versus no PPI and no H2 blocker (n= 2,887,030)

— covariates assessed included age, race, gender, renal function, number of outpatient serum creatinine measurements, number of hospitalizations, diabetes, hypertension, cardiovascular disease, peripheral arterial disease, cerebrovascular disease, chronic lung disease, cancer, hepatitis C, HIV, dementia, and diseases associated with acid suppression therapy for such GI conditions as GERD, upper GI bleeding, ulcer disease, H. pylori infection, Barrett’s esophagus, achalasia, stricture, esophageal adenocarcinoma.

— Analyzing the difference between the baseline demographics of these different groups: those on PPIs were older (eight months), and had more diabetes, hypertension, cardiovascular disease, and hyperlipidemia than the overall cohort, however looking at their numbers, these differences were on the order of 1% or less. The differences between those put on H2 blockers and PPIs was somewhat more significant, more typically on the order 5%.



— overall PPI use was associated with a 25% increased risk of death vs H2 blockers, HR 1.25 (1.23-1.28)

— using high dimensional propensity scoring (see below) there was a 16% increased risk, HR 1.16 (1.13-1.18)

— comparing PPI use to no PPI use, a 15% increased mortality risk, HR 1.15 (1.14-1.15)

— comparing PPI used to neither PPI nor H2 blockers, a 23% increased risk, HR 1.23 (1.22-1.24)

— in patients without underlying gastrointestinal conditions (those conditions being the ones noted above), those on PPI had 24% increased risk of death vs H2 blocker, HR 1.24 (1.21 1.27)

— among new PPI users, there was a graded association between the duration of exposure and the risk of death (all statistically significant, as compared to those who have taken PPIs <30 days): 5% increased mortality risk for those on PPIs 31-90 days, 17% for 91-180 days, 31% for 181-360 days, 51% for 361-720 days, all of these controlled for the array of comorbidities and risk factors above.



— the above analysis included both propensity scoring, a means to statistically equalize the PPI versus non-PPI users for all of the covariates above, as well as high dimensional propensity scoring, which controlled for an additional potential 500 variables to further minimize confounding

— a recent blog reviewed the risks and benefits of PPIs from the perspective of the American Gastroenterological Association, assessing the literature on the PPI association with kidney disease, dementia, bone fractures, small intestinal bacterial overgrowth, non-typhoidal Salmonella, Campylobacter, spontaneous bacterial peritonitis, C. difficile, pneumonia, calcium/iron/magnesium deficiency, B12 deficiency, and GI malignancies.

— There is also emerging in vitro evidence that PPIs can result in inhibition of lysosomal acidification and impairment of proteostasis, potentially increasing oxidative stress, endothelial dysfunction, telomere shortening, and accelerated human endothelial senescence. In addition animal studies suggest that PPIs decrease the regenerative capacity of livers following partial hepatectomy.

— This VA study, as well as these others reviewed by the AGA, is an observational one. For observational studies, the increased risk found is on the lower side to be significant. The impressive aspects of the study include the fact that it is huge, that they have controlled for a lot of variables (though they do not have specific data on obesity, smoking, and the use of specific medications including anticoagulants, antiplatelet agents, and nonsteroidal anti-inflammatories); that the risk was independent of prior GI symptoms, and that there was a clear dose-response curve (and the 51% increase in those on PPIs for >1 year is getting more impressive). In addition, looking at survival curves for those on PPIs versus H2 blockers, the difference increases linearly over time (ie the curves are splaying apart)


— As mentioned in previous blogs, PPIs are significantly overprescribed, in part exacerbated by their availability over the counter, with studies suggesting that 53-69% are used for inappropriate indications, that the risks of PPIs are poorly understood by patients as well as perhaps some clinicians, that many patients even with severe GI symptoms respond well to H2 blockers or antacids, and that it is often difficult for an array reasons for clinicians and patients to step down therapy to H2 blockers or antacids (e.g., clinicians having relatively limited time with patients are more likely to discuss other pressing medical or psychosocial problems as opposed to spending time trying to convince a patient to step down their therapy; and patients may well be so satisfied with the effectiveness of the PPI, perhaps prescribed by a specialist which might sway them more towards taking the PPI, that they are reluctant to give H2 blockers or antacids a fair trial).

–In my experience with many patients on PPIs, often they self-titrate to use them intermittently, but in any event are usually quite willing to try H2 blockers or antacids when I express my concern about the potential long-term problems by continuing to take such a potent drug when usually a less potent and possibly less harmful one often works as well.


Primary Care Corner with Geoffrey Modest MD: Dyspepsia guidelines

18 Jul, 17 | by

by Dr Geoffrey Modest

​​The American College Of Gastroenterology and the Canadian Association of Gastroenterology updated their guidelines on the management of dyspepsia (see doi: 10.1038/ajg.2017.154​)


Recommendations (note: the recommendation is much weaker when they use the word “suggest” vs “recommend”):

— they suggest endoscopy for dyspepsia patients greater than 60 years old: conditional recommendation/very low-quality evidence. they raised the age from 55 of prior guidelines since the age-specific incidence of gastric cancer has fallen in the US, and they feel the cost of endoscopy per case of cancer detected is prohibitive. they also do suggest this guideline be individualized, so that for patients coming from areas with high upper GI malignancy rates there should be a lower threshold for endoscopy, especially those coming from Southeast Asia and some countries in South America.

— they suggest not to do endoscopy to investigate alarm features (e.g. weight loss, anemia, dysphagia, persistent vomiting) for dyspepsia patients under the age of 60 . This recommendation is based on seven studies finding that alarm features had limited value for detecting any organic pathology: conditional recommendation/moderate quality evidence

— they recommend that dyspepsia patients under the age 60 should have a noninvasive test for H. pylori, with therapy if positive: Strong recommendation/high quality evidence

— they recommend that dyspepsia patients under the age of 60 should have empiric PPI therapy if they are H. pylori negative or remain symptomatic after H. pylori eradication therapy: Strong recommendation/high quality evidence

— they suggest dyspepsia patients under the age of 60 not responding to PPI or H. pylori eradication therapy should be offered prokinetic therapy: Conditional recommendation/very low- quality of evidence.  Metoclopromide should be given for less than 12 weeks [a problem given the chronicity of dyspepsia, but this drug does have significant adverse effects such as tardive dyskinesia], and domperidone dose should be 30 mg a day or less (this medication is not available in the US).

— the recommendations for patients with functional dyspepsia mirror the above, except that those patients who fail PPI or H. pylori eradication therapy should be offered tricyclic antidepressant therapy (Conditional recommendation, moderate quality evidence), and that those not responding to any of these be offered prokinetic therapy (conditional recommendation, very low-quality evidence). Those with functional dyspepsia not responding to any drug therapy should be offered psychological therapy (conditional recommendation, very low-quality of evidence.) They do not recommend the use of complementary or alternative medicines or the routine use of motility studies, except when gastroparesis is strongly suspected (several studies have found that the relationship between dyspeptic symptoms and gastric emptying is poor). The basis of their recommendation for tricyclics is that there were 3 studies looking at patients with functional dyspepsia finding a significant effect in reducing dyspepsia symptoms. No effect has been seen with SSRIs.



— as we all know, dyspepsia is quite prevalent, approximately 20% of the population globally. More common in women, smokers, and those on NSAIDs. The cost to the US healthcare services is over for $18 billion a year, societal costs are likely double that from time away from work.

— The definitions they are using:

— dyspepsia: predominant epigastric pain lasting at least one month, can be associated with epigastric fullness, nausea, vomiting, or heartburn, provided that epigastric pain is the patient’s primary concern (they are trying to minimize the inclusion of GERD in this category)

— functional dyspepsia: patients with dyspepsia where endoscopy and other relevant tests have ruled out organic pathology that explains the symptoms


So, a few comments:

— there are a few items above which counter conventional approaches, including not doing endoscopy to investigate alarm features in those <60 years old (they do comment that studies do not suggest that the predictive value of alarm features is very good, though the quality of evidence to support this is very low)

— I personally think the flow of the above algorithm is somewhat flawed. Those either with functional dyspepsia or plain old dyspepsia who have significant life stressors or other psychosocial conditions should be appropriately treated for those, usually at the same time acid suppression therapy is used, instead of the old biomedical approach, reiterated above, that one tries to treat all medical problems first and if all else fails treat the psychological problems. There have been studies in the past which have shown, not surprisingly to those of us in clinical practice, that stress can produce dyspepsia, with other old studies also showing an increase in gastric acid production.

— The above recommendations apply to symptomatic patients and strongly recommend treating H Pylori infections. As mentioned in many prior blogs, I tend to be quite aggressive in diagnosing and treating H. pylori infections, even if asymptomatic, because of the association with gastric cancer. This is reinforced to me because I treat a population with a very high prevalence of H. pylori, and what seems to me a high incidence of gastric cancer (which in fact is prevalent in the countries from which they hail). See blog reference below.

— another issue is the potential problems with the long-term use of PPI therapy. As commented previously, many patients have been put on PPIs for inappropriate indications (and they are available OTC, to boot). Many dyspepsia patients do respond to H2 blockers or even calcium antacids, which do not put them at higher risk of the many possible complications of long-term PPIs (a blog will come out soon on the association of PPIs with increased overall mortality). In fact, in seven RCTs involving 2456 dyspepsia patients, there was no statistically significant difference between PPI and H2 blocker use in providing symptom relief. And, patients initially treated with PPIs very often can be stepped down to H2 blockers or antacids, though many of these patients do well with stepped down therapy​.



blog for a summary of risks and benefits of PPIs

blog  for a summary of the H Pylori treatment regimens

blog  for a review of H pylori eradication and decreases in gastric cancer

Primary Care Corner with Geoffrey Modest MD: PPIs and recurrent C diff infections

25 Apr, 17 | by

by Dr Geoffrey Modest

A recent systematic review and meta-analysis found that the use of protein pump inhibitors (PPIs) seems to be associated with increased recurrent Clostridium difficile infections (see doi:10.1001/jamainternmed.2017.0212)


— literature review from 1995 to 2015, specifically looking at case-control studies, cohort studies, and clinical trials, found 16 observational studies of 7703 patients with C. diff infections, 4038 (53%) were using gastric acid suppressants, and 1525 patients (20%) developed recurrent C. diff​ infections.

— These studies were performed in the United States, Korea, Israel, Europe, Japan, and Canada

— 9 studies involved PPIs alone, 5 with PPIs and H2 blockers, and one with H2 blockers alone.


— the recurrence rate for C. diff was:

–22.1% (892 of 4038 patients) in those taking gastric acid suppression

–17.3% (633 of 3665) in those not taking gastric acid suppression

an overall 38% increased risk, adjusting for age and potential confounders, OR 1.38 (1.08-1.76, p=0.02)

–subgroup analysis found that there was a 66% increased risk of C. diff recurrences with the use of PPIs, OR 1.66 (1.18-2.34), p=0.004, but not an increased risk in those they used both PPIs and H2 blockers, or H2 blockers alone (though only one study looked at H2 blockers by itself)

— the increased risk was found in both case-control studies and cohort studies


— Clostridium difficile infections are the most common cause of hospital-acquired diarrhea, and seem to be increasing in incidence, severity, morbidity, and mortality rates. At this point about 40% are community-acquired and in patients felt to be at low risk, suggesting that there may be new risk factors, including such things as gastric acid suppressants, C. difficile in the water and food, and close contacts with those with C. diff infections in the community.

— The studies are quite mixed on the relationship between gastric acid suppression and C. diff infections overall, especially when controlling for comorbid conditions and age. The connection seem to be somewhat stronger for PPIs versus H2 blockers, leading the FDA to issue a warning that PPIs are associated with an increased risk of C. diff infections ( ).

— recurrent C. diff infections happen pretty frequently, as high as 50-60% after 3 or more infections. Risk factors for recurrence include older age, concomitant antibiotic use, and comorbid conditions. About 50% of patients with C. diff infections use concomitant gastric acid suppressants. Prior analyses have found an increased risk of reinfection in those on gastric acid suppressants, but these studies were limited by being retrospective or excluding important studies.

— The current study was methodologically more sophisticated, including prospective and retrospective case-control studies, as well as post hoc analysis of 2 RCTs

— gastric acid suppressants are known to alter the distal gut microbiota, with substantial decreases in bacterial diversity, and may make the microbiota more prone to both primary and recurrent C. diff infections. And data suggest that PPIs may affect the microbiota more than H2 blockers. On the other hand, the use of antibiotics to treat C. diff infections may further change the microbiota.

— these data are still observational, limiting our ability to attribute causality. For example, those on gastric acid suppressants are perhaps more likely to be elderly, using concomitant antibiotics, or having comorbid conditions which might increase the likelihood of C. diff infections. The authors did try to control for these issues, but this is difficult in a meta-analysis of 16 studies with different criteria and baseline data on patients.

see doi: 10.1038/ajg.2012.179, which presents a meta-analysis of 300,000 patients, finding a 65% increased risk of C diff  in patients on PPIs, independent of study design (case-control vs cohort), with the unusual p-value of “p<0.000”, which on the surface seems pretty strong…..)

see here for several prior blogs on C diff infections, including the use of probiotics and fecal transplants

see here ​ for a recent review of some of the benefits and harms of PPIs, including my concerns about their being overused in general, both by being overprescribed initially, and by continuing longterm instead of “stepping down” therapy.

The blog tomorrow will review a recent American Gastroenterological Association clinical practice update on the risks and benefits of PPIs.

Primary Care Corner with Geoffrey Modest MD: PPI Harms and Benefits

29 Aug, 16 | by EBM

By Dr. Geoffrey Modest

There was a useful editorial detailing the indications for long-term proton-pump inhibitor use (see Laine L. Am J Gastroenterol 2016; 111:913). As many of you know from prior blogs, I have been very concerned that many patients are on long-term PPIs because: they work; when patients are doing better on them, we can move on to address other issues; changing them involves somewhat detailed/time-consuming discussions with patients (detracting from focusing on the other issues); changing them may not work, so we might be back to square-one; when patients see GI specialists, they are uniformly put on PPIs (at least in my experience); and, despite GI specialty recommendations to step-down therapy from PPIs to H2-blockers or antacids, studies show that this rarely happens. This review focuses on the indications for long-term PPIs, with little attention to the harms, but my guess is that most patients on long-term PPIs do not qualify for them even by these recommended indications: there are some studies finding that 70-80% of hospitalized patients put on PPIs do not have an appropriate indication. Details of the editorial:

  • The caveat: most of the studies were intervention studies with retrospective observational analysis (i.e., they were not set up as large studies comparing different therapies, and following the patients for many years to assess long-term effectiveness or adverse events)
  • GERD: for GERD symptoms, most patients do well with on-demand therapy.  In general, advice is given for long-term PPIs if erosive esophagitis, and there are studies suggesting that there is a higher risk of recurrent erosion when patients are put on placebo, H2-blockers, or intermittent PPIs. BUT, there are no data that show that recurrent esophageal erosions are harmful or that not using daily PPIs leads to Barrrett’s, and the risk of strictures is really low. Of note, many patients do use PPIs intermittently for symptoms, no matter what clinicians suggest, and most do fine, and there are observational data finding benefit of intermittent 2-4 week courses of daily therapy if twice-weekly heartburn recurs. But, I certainly do have patients who continue with their daily PPIs even if not necessary… the FDA guidelines suggest 4-8 weeks of PPIs for GERD. The editorialists in this review suggest that patients taking PPIs for GERD stop therapy 2 weeks after symptom resolution, and use H2-blockers or antacids as needed for infrequent symptoms, and if necessary, intermittent PPI courses of 2-4 weeks when symptoms recur >= 2x/week. [Given that it is often hard to do step-down therapy for GERD symptoms, I usually start with H2-blockers, step up to PPIs if necessary, and then try to step-down. In patients with mild symptoms, antacids often work just fine]
  • Barrett’s: basically, observational studies suggest PPIs may decrease neoplastic progression of Barrett’s, but the Am College of Gastroenterology and Am Gastroenterological Assn guidelines are more cautious: stating that long-term PPIs should be “considered” or discussed carefully with patients. And absolute risk of Barrett’s progression to adenocarcinoma is low (0.1%/yr). No FDA approval for this indication. The editorialists prefer using daily PPIs only if necessary to control GERD symptoms.
  • NSAIDs (my other nemesis, in terms of overuse and a plethora of adverse effects: GI, cardiovasc, renal, etc): PPIs (or misoprostol) do seem to decrease GI bleeding in those at high risk of bleeding (>65yo, high-dose NSAIDs, prior ulcers, or concurrent steroids/anti-thrombotics), and is supported in RCTs. These editorialists feel this is a clear indication for PPIs, though FDA approval is for durations up to 3-6 months. [My approach overall is to avoid long-term or high-dose NSAIDs, preferring topical treatments such as local injections, capsaicin, lidocaine gel, diclofenac gel, or oral acetaminophen. And I do have very few patients who take NSAIDs other than very intermittently]
  • Aspirin/anti-platelet agents: guidelines recommend PPIs in those at increased risk of bleeding (history of ulcers, concomitant anti-thrombotics, age>60 plus steroid therapy). Endoscopic ulcerations and recurrent ulcer bleeding have been documented in RCTs. No FDA recommendation [I do have lots of patients on low dose aspirin for cardiovascular and colorectal cancer prevention. There are some studies suggesting that low dose enteric-coated aspirin is erratically absorbed, and that the non-enteric coated aspirin has no greater incidence of gastric ulcers, so that is the one I use routinely. And with really minimal GI distress. So I do not prescribe any gastric protection routinely]
  • Dyspepsia: PPI therapy if <55yo with uninvestigated dyspepsia who are H pylori negative, or if H pylori prevalence is <10%. RCTs suggest PPIs are more effective than H2-blockers or antacids, with NNT=5. No clear guidelines on this. I did look up the Am Gastro Assn guidelines and there were no clear therapies suggested (see ). The editorialists suggest intermittent PPIs if effective to control symptoms [again, I have had considerable luck with H2-blockers or antacids, so I do try them first]


  • This editorial reviews the accepted recommendations for using PPIs, along with some of the available data. I think it is useful because so many of the patients we see in the community are on long-term PPIs for non-recommended indications.
  • And, there are substantial data in the literature on the potential adverse effects of PPIs, including the potential for gastric atrophy (a potentially premalignant lesion) especially in those with concurrent H Pylori infections, decreased mineral absorption (iron, calcium, magnesium), decreased vitamin B12, decreased bone mineral density and increased fractures, hypomagnesemia, increased enteric infections (C. difficile, C jejuni), increased pneumonia, and increased cardiovascular events. There have been more recent associations with chronic kidney disease and dementia (see blogs below).
  • And, in case you are interested, not so surprisinglyPPIs adversely affect the microbiome (after all, the acidity of the stomach probably does have some evolutionary protective effect on preventing enteric infections (and maybe much much more). see doi:10.1136/gutjnl-2015-310376 .
  • Of course, there are some patients who really do need PPIs for symptom relief/quality-of-life, but these can often be used intermittently.
  • So, I initially prescribe PPIs only in patients who have really severe presenting symptoms of GI distress (though I will often get a stool for H Pylori antigen prior to starting the PPIs). And in those already on PPIs I personally have had good success in switching people to H2-blockers, or even just intermittent antacids, though some do seem to need an occasional PPI, rarely daily long-term PPIs.

Prior blog on Barrett’s:

Relevant prior blogs on adverse effects of PPIs:

Primary Care Corner with Geoffrey Modest MD: Lifestyle Changes and GERD

8 Mar, 16 | by EBM

By Dr. Geoffrey Modest

Gastroesophageal reflux disease (GERD) is a remarkably common problem in patients presenting to primary care clinicians. Although there are an array of lifestyle interventions that have been suggested, there are somewhat limited data on their efficacy. A recent systematic review assessed the literature (see Clinical Gastroenterology and Hepatology 2016;14:175).


  • Background:
    • ​Prevalence of GERD in western populations is 30%; incidence is 5/1000 person-years
    • GERD is associated with decreased quality-of-life and work productivity, and increased risk of esophageal carcinoma (for guidelines on Barretts esophagus management, see blog: )
    • Reflux is associated with a variety of factors leading to relaxation of the lower esophageal sphincter (LES), including coffee, alcohol, chocolate, peppermint, citrus, perhaps carbonated drinks, and spicy foods), as well as obesity and cigarette smoking
  • Results:
    • Weight loss: a variety of studies:
      • Large prospective population-based cohort studies (Nurses’ Health Study and Nord-Trondelag health studies) have found that, comparing those whose weight remained stable, those with decreasing BMI had decreased reflux symptoms, in a dose-dependent fashion, with a 2-fold increased likelihood of disappearance of reflux symptoms off medications
      • A largish RCT found that those patients who lost weight had decreased prevalence of GERD symptoms
      • ​Three very small studies showed weight loss was associated with improvement or normalization of esophageal pH levels, though one small study did not find this
    • Smoking cessation:
      • The Nord-Trondelag health study of 29,610 participants found a decrease in severe reflux symptoms in normal-weight people on medications who stopped smoking, with an OR of 5.67 (1.36-23.64), vs those who continued smoking. Overweight or obese people did not derive this benefit, which the study authors thought might be related to the possibility that weight was such a strong predictor of GERD symptoms that it overwhelmed smoking’s attributable risk
    • ​Other dietary interventions: no evidence that carbonated beverages promote GERD; a small RCT (30 patients) found that an early meal (6 hours prior to bed) led to less pH-verified supine reflux vs a late meal (2 hours before bed); and another small study (30 patients) found that patients on fiber vs placebo had fewer days of and less severe symptoms of heartburn
    • Head-of-bed elevation: a small cross-over RCT of 15 GERD patients found that elevating the head of the bed by a 10-inch wedge led to less time the esophageal pH was <4.

So, a few points:

  • The best data for lifestyle changes are from the large observational studies, which of course do not confirm causation (i.e., did those who lost weight also adapt other healthier lifestyle changes which might have been the cause of the decreased symptoms?)
  • In terms of RCTs, the most compelling data showing improvement of GERD symptoms is for weight reduction in overweight/obese patients.
  • Despite some prior analyses and recommendations, it does seem that smoking cessation is useful for GERD symptom reduction, especially in non-overweight people (adding to the list of reasons to stop smoking…)
  • There are not adequate study data on other dietary interventions, though probably a high fiber diet and not eating late meals are reasonable. Though not rigorously studied, it certainly makes sense to listen to the patient: if they think spicy foods, or other items cause more symptoms, it seems prudent to reinforce that such a dietary change may be appropriate to try if not already done.
  • Raising the head of the bed does have some minimal data of support (though I must mention one of my patients from long ago who warned me that he tried this, but he slipped down uncomfortably to the bottom of the bed because he used silk bedsheets…)
  • Other recommendations may also be appropriate, in part for their other benefits (even though not so clear for GERD, for which they are untested), such as decreasing alcohol consumption (which does in fact lower LES pressure), avoiding tight-fitting corsets (which could increase the intraabdominal pressures, putting stress on the LES gradient), and for similar reasons, promoting abdominal breathing
  • So, as always, I think lifestyle changes are really important (and, of course, not just for GERD symptoms). I do find it distressing that formal recommendations from specialty societies are so grounded in the evidence-based model that they minimize potentially important recommendations for lack of data. So, for example, the 2013 recommendations of the American College of Gastroenterology (see ) has 13 treatment recommendations: one suggesting weight loss if overweight or recent weight gain, one suggesting head-of-bed elevation and avoidance of meals 2-3 hours before bed, and another unequivocally dismissing the utility of routine food elimination (including alcohol but not smoking, which is not even mentioned). And almost all of their recommendations (7 of 13) are about PPIs, 1 mentions H2-blockers, and 2 dismiss all other medical therapies (see for several blogs questioning the overuse of PPIs).​ [It turns out that drug companies do not often sponsor studies on non-drug based lifestyle interventions….]. So, because either not-great or no studies were done (e.g., There are no studies looking at cessation of chocolate, caffeine, spicy foods, citrus, or carbonated beverages and their effect on GERD), the guidelines state that these interventions should not be recommended generally, only if the patient has already tried them and they work….. Personally, I do continue to recommend trying the broad array of lifestyle changes, including those without any data/not recommended in the above guidelines (e.g. around caffeine, tobacco, alcohol, spicy foods, and, yes, even chocolate), at least for the patient to experiment to see if these help.

Primary Care Corner with Geoffrey Modest MD: PPI Use and Dementia

25 Feb, 16 | by EBM

By Dr. Geoffrey Modest

A ​pharmacoepidemiological analysis, based on claims data, found an association between taking proton pump inhibitors (PPIs) and the risk of dementia in the elderly (see doi:10.1001/jamaneurol.2015.4791).


  • An observational database from 2004-2011 from the largest Germany health insurer insuring 1/3 of the population and 50% of the elderly, was used to assess inpatient and outpatient use of PPIs
  • 73679 participants, >=75yo and free of dementia at baseline. 2950 were on regular PPIs (mean age 83.8, 78% female), compared to 70,729 patients (mean age 83.0, 73.6% female)
  • 29510 patients received a diagnosis of dementia over the course of the study period (40% of the cohort)
  • Regular PPI use was defined as a prescription for a PPI each quarter of an 18-month interval during the study period


  • Those on PPIs had a 44% increased risk of incident dementia [HR 1.44 (1.36-1.52), p<0.001]
    • For males, HR 1.52 (1.33-1.74)
    • For females, HR 1.42 (1.33-1.51)
  • Other associations with dementia included: depression (HR 1.28), stroke (HR 1.37), and to a lesser extent, female sex (HR 1.15), diabetes (HR 1.05), polypharmacy (HR 1.16); all statistically significant
  • ​But, controlling for all these potentially confounding factors actually led to a higher association of dementia with PPI use [HR 1.66 (1.57-1.76)]
  • And, controlling for use of anticholinergics, itself a risk factor for dementia with its own HR of 1.80, did not change the association with PPIs (HR was still 1.44)
  • Looking at those patients who only occasionally used PPIs, there was a lower but significant HR of 1.16 (1.13-1.19).
  • Difference by type of PPI used: omeprazole had HR 1.51, pantoprazole HR 1.58, but somewhat higher with esomeprazole with HR 2.12
  • ​There was a slight decreasing effect with age: those 75-79 had HR 1.69, those 80-84 had HR 1.49 and those >84 had HR 1.32 (all significant)

A prior study by the same group, AgeCoDe (the German Study on Aging, Cognition and Dementia in Primary Care Patients), included 3327 community-dwelling persons >= 75 yo with 18-month neuropsychological assessments similarly found incident dementia to be associated with PPI usage, and with a similar HR of 1.38 (1.04-1.83), and with somewhat more dementia in the group on esomeprazole. All PPI associations controlled for age, sex, educational level, apoE4, depression, diabetes, stroke, ischemic heart disease, and polypharmacy.

So, this was a large computer-based study finding an association between PPI use and dementia; therefore it is not confirm a causal relationship. But a few points:

  • There is biological plausibility:
    • Mouse models find that PPIs increase the levels of b-amyloid in their brains, by affecting the enzymes b- and g-secretase; PPIs also could decrease the degradation of b-amyloid by lysosomes, which are pH-dependent, in microglia (and some PPIs cross the blood-brain barrier). Also, PPIs bind to tau.
    • PPIs are associated with vitamin B12 deficiency through malabsorption, and vitamin B12 deficiency is associated with cognitive decline
  • This study adds to the potential adverse effects of PPIs (see blogs below for some other problems with PPIs)
  • Of course, this study only finds an association. As above, they tried to account for many of the covariates for dementia (stroke, polypharmacy, depression, etc.), and they also found that there was not much difference in use of the health care system (all suggesting, but not proving, that the PPI-users and non-users were pretty similar in dementia risk). But the data are not so granular: i.e., even if the level of polypharmacy is the same in both groups, did those on PPIs might have more specific drugs that could affect cognition? And what about cigarette use, alcohol, or obesity which may be over-represented in the PPI-user group and may themselves be associated with dementia?
  • So, I think there are a couple of lessons here:
    • It is always important to remember that very few drugs really are targeted specifically to a single action. One might think (as perhaps most of us did) that a drug targeting acid release from the stomach’s parietal cells would not have potential widespread effects (other than collateral damage on nutrient absorption, etc.). The finding of clear effects on b-amyloid in mice brains and the potential effects of PPIs on human brains yet again brings us to the usual conclusion: use medications in their lowest dose and only if necessary, with an emphasis on helping patients try to make lifestyle changes as the primary approach to many medical problems.
    • As mentioned in prior blogs, it is really easy to just keep refilling PPI prescriptions since they work and it is sometimes a struggle to change paths with patients, and we often are quite busy just keeping up with the other more active medical problems. I.e., the approach of step-down therapy (moving from PPI to H2-blocker or just calcium) is in reality not done much in clinical practice. Which I think supports more of a step-up approach (staring with calcium then escalating to H2 blocker prior to PPI).

For a few of the recent blogs on PPIs, see which looks at microbiome changes with gastric acid suppression which looks at the possible association of PPIs with MIs found an association of PPIs with chronic kidney disease

Primary Care Corner with Geoffrey Modest MD: Functional Dyspepsia

9 Dec, 15 | by EBM

By Dr. Geoffrey Modest

New Engl J Med just had a useful review of the remarkably common “functional dyspepsia” (see N Engl J Med 2015;373:1853-63​)​.

Their points:

  • Definition: Rome III criteria — sensation of pain or burning in epigastrium, early satiety, fullness during or after a meal, or a combo of these symptoms; lasting at least 6 months and occurring at least weekly, and no organic explanation
  • But, symptoms above to not reliably distinguish “functional” from organic cause: <10% with dyspepsia have a peptic ulcer, <1% gastroesophageal cancer, and >70% have functional dyspepsia as determined by EGD (i.e., nothing found)
  • One other overlapping diagnosis is GERD, but more than 50% of patients meeting functional dyspepsia criteria with symptoms of heartburn and regurgitation had normal 48-hour pH studies, and in these patients, heartburn/regurgitation was the predominant functional dyspepsia symptom in 30%
  • There is obvious overlap also with gastroparesis. More than 25% of patients with functional dyspepsia have evidence of delayed gastric emptying, and up to 86% of those with gastroparesis meet Rome III criteria for functional dyspepsia
  • Even looking at “alarm symptoms” (>55 yo with new-onset dyspepsia, dysphagia, vomiting, weight loss, family hx of gastric/esophageal cancer, Fe-deficiency anemia), still had low probability of finding cancer (0.8% in a large meta-analysis — Gastroenterology 2006; 131: 390)
  • Frequency of celiac disease, the great imitator, is not increased in those with dyspepsia
  • In terms of routine testing: they recommend H pylori stool antigen or breath test when the prevalence of H pylori infection is at least 10%, or, if you don’t know prevalence, it is still reasonable
  • There is a trend to distinguish 2 types of functional dyspepsia, with the hope that there may be different effective therapies:
    • Epigastric pain syndrome: intermittent pain or burning in the epigastrium occurring at least 1x/week
    • ​Postprandial distress syndrome:  bothersome postprandial fullness after normal-sized meals or early satiety preventing finishing a regular meal, several times/wk
  • Etiology of functional dyspepsia: there is a pretty clear relationship between anxiety/psychological distress and functional dyspepsia (though occasionally there is dyspepsia before onset of anxiety, leading some authors to posit a bidirectional “brain-gut pathway”, and some studies suggest a disorder in central pain processing), and there may be genetic factors. Some patients have evident disturbances of gastric physiology (e.g. slow gastric emptying, etc.), but some have none of these abnormalities. Also some question of infectious etiology (though Koch’s postulates have not been fulfilled for any microbe).  But contenders are salmonella, e coli 0157, campylobacter jejuni, giardia, norovirus (these can all induce functional dyspepsia symptoms). Duodenal inflammation is found in 40%, esp. with eosinophilia (which can be related to smoking).  H Pylori may also be associated, and a small % of patients do better after eradication of infection. Food intolerance/allergy could be involved, but this is not adequately studied. One of the new models is: in genetically-predisposed people, an allergen or infection leads to immune activation, recruitment of eosinophils (which may be protective/promote healing, but can also lead to tissue injury and symptoms perhaps because an inflamed duodenum may be more sensitive to acid. Of interest there are preliminary data in kids that montelukast reduces symptoms) [though only 40% have duodenal inflammation, so not the whole story]
  • Treatment
    • 30-40% respond to placebo (although not studied in functional dyspepsia, placebo works better than no treatment in those with irritable bowel – i.e., it is a true placebo effect)
  • ​H Pylori eradication: large meta-analysis suggested that 90% have persistent symptoms after eradication, with NNT of 15 (though this was still significant)
  • PPIs have relative risk of persistent symptoms of 87% with NNT of 10
  • H2-blockers may be better than PPIs, with relative risk of persistent symptoms of 77% with NNT of 7 (though lower quality of trials)
  • Prokinetic agents: most are too dangerous. There is a new one in Japan called acotiamide (an acetylcholinesterase inhibitor), with initial trials showing improvement in 52% (vs 35% placebo), ongoing trials in US and the West
  • Buspirone: randomized cross-over trial in 17 patients showed it was effective in relaxing the gastric fundus, decreasing bloating and postprandial fullness.
  • ​Antidepressants: some data that amitriptyline works better than escitalopram or placebo. Other studies do not find efficacy for venlafaxine or sertraline. Mirtazapine may help in those with weight loss
  • Psychological therapy: under-studied, but some data for improved quality of life and symptom score at 10 weeks which persisted after the end of treatment
  • ​Complementary/alternative meds: not much data, though some patients seem to benefit from capsaicin or STW5, a nine-herb comination product also called iberogast

So, overall approach:

  • Stress reduction, if possible
  • Dietary advice: small, regular, low-fat meals and avoiding those that precipitate symptoms
  • If alarm symptoms, get upper endoscopy (EGD)– though low yield
  • If H  Pylori prevalence is >10%, get stool antigen and treat if positive
  • Consider empirical acid suppression for 4-8 weeks. If works, try drug holiday after 3 months. may be better to try H2-blocker first
  • Consider tricyclic antidepressant for 3 months. if works, consider drug holiday
  • Consider prokinetic agent (esp. acotiamide, if you live in Japan)
  • Avoid opiates. Can consider combo therapies (e.g., some data that acid suppression and prokinetic agent combo works better). Also ?buspirone

Primary Care Corner with Geoffrey Modest MD: PPIs associated with MIs???

25 Jun, 15 | by EBM

By: Dr. Geoffrey Modest

There was a recent article published online and hitting the press regarding a possible association between the use of proton-pump inhibitors (PPIs) and subsequent MIs (see DOI:10.1371/journal.pone.0124653​). The article was unusual in that it used a new technique for medical research: data-mining.  The bottom line is that if there were a real association between PPI use and MIs, this would have profound medical implications, since over 113 million PPI scripts are filled annually around the world with over $13 billion in sales, and in the US in 2009 21 million people filled at least one PPI script (the 3rd highest seller in the US).


–they looked at over 16 million clinical documents on 2.9 million people to assess PPI use and cardiovascular risk. There were 2 large data sources for the data mining (Stanford, and Practice Fusion, Inc) and one prospective source for a survival analysis. For the data-mining, they electronically evaluated clinic notes to search for patients with a GERD diagnosis, use of meds, and subsequent notes with diagnoses of cardiovascular disease

–overall, 32,363 patients were identified (mean age 55, 44% male, 50% white/27% unknown, 6% on clopidogrel). They identified a similar number of propensity score-matched controls. Mean followup 2.1 years


–overall, patients with GERD and on PPIs had an adjusted odds ratio of 1.16 (1.09-1.24) for association with MI. H2 blockers were not associated with increased cardiovasc risk

–survival analysis in the prospective cohort followed 5.2 years found a 2-fold increased association with cardiovascular mortality [HR=2.00 (1.07-3.78, p=0.031)]. No association was found for H2-blockers

–the PPI association was independent of the concommitant use of clopidogrel (used in only 5.9% of the population)

Although this data-mining is potentially a powerful tool to look at possible real associations, it is much less persuasive than the usual organized epidemiologic studies in terms of the types and quality of the data collected.  I bring up this article for several reasons.

  1. As I have highlighted in many of my older blogs (prior to the BMJ posts), I am very concerned about the over-use of PPIs. It used to be said that treatment for GERD (the most common indication for PPIs) could be either step-up (start with calcium, then go to H2 blocker, then to PPI as needed for symptom control) or step-down therapy (hit hard with PPI, then wean down to H2 blocker or calcium as tolerated). Not so surprisingly, it is rare that we in primary care actually do the step-down (after all, the patient is doing well on the PPI, there are lots of other issues to address in the confines of a quick primary care visit, so dealing with stepping down therapy just isn’t the priority). But PPIs are very powerful drugs, and there are known and potential problems associated with their use. The documented adverse effects include those associated with infections (since neutralizing the gastric acid eliminates one of the barriers to infection), malabsorption (since stomach acidity is important for some nutrient absorption), and potentially other issues. In terms of infections, there are pretty good data that prolonged PPI use is associated with increased risk of C. difficile infections, other enteric infections (salmonella, campylobacter), and community-acquired pneumonia (though data here are a bit mixed). Malabsorption has been found for iron, vitamin B12, magnesium and calcium, and the possible association of PPIs with hip, spine and wrist fractures (and an FDA warning about this). And one of the other concerns is the profound hypergastinemia, with potential risk of colon cancer (not found so far) and atrophic gastritis (which may be more common in those who are H Pylori positive, and could potentially lead to gastric cancer). And potential drug interactions (eg with clopidogrel) or other unusual adverse effects (acute interstitial nephritis)
  2. There are many plausible explanations of an association between PPI use and MI, including:

–PPIs inhibit the activity of dimethylarginine dimethylaminohydrolase (DDAH), which is responsible for 80% of the clearance of asymmetric dimethylarginine (ADMA), which is an endogenous molecule which inhibits the activity of nitric oxide synthase (NOS), which might impair endothelial function, increase vascular resistance, and promote inflammation and thrombosis. (This is the explanation offered by the authors of  the study, though the data are based on animal studies and cultured human endothelial cells)

–perhaps there is an associated chronic inflammatory state created by the increase in GI infections from PPI use, and this inflammatory state is associated with CAD (as found with rheumatoid arthritis, in a couple of new studies on psoriasis, perhaps in HIV??)

–or, the explanation I favor, is that a small but significant proportion of patients being treated for GERD in fact have GERD-like symptoms from CAD which are falsely ascribed to GERD. I did just see a patient who epitomized this: he had GERD-like symptoms, treated by H2 blockers which did not work, augmented to a PPI which still did not work. And on further questioning, his GERD symptoms were exertional. He will be getting worked-up for this, but he presents the case of approximately 10% of angina patients present with predominantly GI symptoms, including typical GERD symptoms (even more classical than his, with postprandial and not exertional symptoms). Therefore, the relationship of PPI to MI may be really from the error of using PPIs to treat GI symptoms which really come from the heart…

So, I bring this up mostly as a means to reinforce my sense that we use too many PPIs (my other big concern is overuse of NSAIDs, but that is a side issue here…). And also to highlight a new mechanism in medical research for doing quick and dirty epidemiologic associations through data-mining.​


Primary Care Corner with Geoffrey Modest MD: Gastric Acid Suppression and the Microbiome

3 Dec, 14 | by EBM

By: Dr. Geoffrey Modest

It has been shown in several studies that gastric acid suppression puts people at risk for several infections, including pneumonia, c difficile, and gastroenteritis. In fact, one of the predisposing conditions to developing disseminated TB infection is post-gastrectomy, presumably because stomach acid inhibits TB dissemination (there are several reports in the literature, mostly case-controlled studies, finding that acid suppression also is associated with TB infections). Well, not to shock you all, but it turns out that acid suppression leads to significant changes in the gut (gastric bacterial overgrowth) as well as the lung microbiome (doi:10.1001/jamapediatrics.2014.696​). This study was a 5-year prospective one in kids aged 1-18 yo who were getting bronchoscopy and endoscopy to evaluate chronic cough, with a questionnaire about used of acid-suppressant medications. The researchers assessed the difference in concentration and prevalence of bacteria in the stomach and lung, comparing those on acid suppressants (AS) to those not. A total of 99 patients were assessed — 48 on acid suppression (45 with proton pump inhibitors, 3 with H2-blockers), and 51 not.


–Gastric bacterial growth: 46% in those on suppressants, 18% not.  specifically, more staphylococcus (prevalence ratio 12.75), streptococcus (prevalence ratio 6.91), Veillonella (prevalence ratio 9.56), Dermabacter (prevalence ratio 4.78) and Rothia (prevalence ratio 6.38)​. Those on  AS had both higher prevalence and higher concentrations of the bacteria.


–Bronchoalveolar lavage growth: no diff in % with bacterial growth (both 76%), but there was a trend to more propionibacterium, peptostreptococcus and fusobacterium in those on AS, and some more capnocytophaga in those not on AS, with higher concentrations of lactobacillus and bacilllus in those not on AS.

–Overlap of gastric/lung bacteria: significant correlation between corynebacterium and propionibacterium in both sites in those on AS.

–Specifically assessing kids with proximal nonacid reflux: there was a highly significant correlation between those with proximal nonacid reflux and lung concentrations of bacillus, dermabacter, lactobacillis, peptostreptococcus and capnocytophagia.

So, this study suggests a link between gastric bacteria and the lung microbiome in those with reflux and may offer an explanation for those studies finding an increase in pneumonia in those on AS. The increase in corynebacterium may be clinically significant, since its presence in the oropharynx has been associated with wheezing in kids. Though several of the bacteria found are not, in themselves, pathogenic, it may be that alterations in commensal bacteria may alter the microbiota in a way to increase the likelihood that pathogens could invade tissues and cause infection.

Part of the reason I bring up this study is to provide yet another example of medications which affect the microbiome and may lead to “adverse effects” (which, of course, are really just part and parcel of the the effects of the medication, just unwanted ones). This study highlights the potential infectious complications (though other literature pretty strongly supports a relationship with community-acquired pneumonia, c difficile infections, and, with less robust support, gastroenteritis, especially from campylobacter and salmonella). Other concerns are the dramatic hypergastrinemia created by proton pump inhibitors, or PPIs (carcinoid tumors in animals, though it is not clear what the human effects are, I am concerned about such high levels of gastrin for sustained periods of time), profound acid suppression (which in a couple of studies, but not all, have found atrophic gastritis, a presumptively premalignant condition, especially in the presence of h pylori infection), and malabsorption, with documented decreases in absorption of magnesium, vitamin B12, iron, and calcium (and several studies, but not all, finding increases in osteoporosis and fractures). So, the other reason I bring up this article is that my sense is that PPIs specifically are way-too-overused. And several studies corroborate my own experience: once someone with dyspepsia is doing well with a PPI, too commonly we do not think to step-down therapy to a weaker agent, either an H2-blocker or simply antacids — the path-of-least-resistance is simply to leave the patient on the PPI, so that we can attend to the multitude of other issues the patient has….​


Primary Care Corner with Geoffrey Modest MD: Belching

3 Dec, 14 | by EBM

By: Dr. Geoffrey Modest

I ran across an article on the pathophysiology, diagnosis and treatment of excessive belching, which is a pretty common primary care issue, and I have mostly been treating it as a GERD symptom. But, of course, it is more complicated than that…. (see Am J Gastroenterol 2014; 109:1196–1203​). It turns out that about 50% of the general population with dyspepsia report excessive belching. Use of manometric testing/impedance monitoring has shown that there are 2 mechanisms: the “gastric belch”, which is a vagally-mediated reflex with a relaxation of the LES (lower esophageal sphincter) and expulsion of gastric air, and a “supragastric belch”  in which pharyngeal air is sucked into the esophagus when the diaphragm contracts and causes a negative intrathoracic pressure, then is quickly expelled before it reaches the stomach through relaxation of the UES (upper esophageal sphincter) and a closed glottis.

A few comments:

–Gastric belches: increases with carbonated beverages (no big surprise). happens on average 30 times/24 hours. Air distension in the stomach leads to relaxation of LES, then triggers second reflex relaxation of UES. involved neurotransmitters include GABA and the cannabinoid receptor-1.


–Supragastric belches:  patients may be aware this is voluntary or not. the authors differentiate supragastric belching from aerophagia, which is swallowing of air and not usually identified by patients as belching, but abdominal bloating and distension. Supragastric belching is often diagnosed by lack of belching during speaking, is often a repetitive problem (vs gastric belching, where a large amount of air is expelled at one time), and is less frequent when the patient is distracted. Treatment is to explain the mechanism to the patient and the use of behavioral therapy, including speech therapy, practicing conventional breathing and vocal exercises.

–GERD: in setting of known GERD, 40-49% or patients have belching, and most are supragastric. Proton pump inhibitors (PPIs) do seem to help (confirming my experience). No study has looked at behavioral therapy in these patients. There are some patients with GERD where supragastric belches can induce reflux episodes.

So, more than you probably ever wanted to know about belching…. my sense is that if GERD is present, treat with meds (though I would start with calcium antacids, and augment as needed to H2-blockers, then PPIs). Probably also makes sense to try these even without clear GERD. and consider behavioral therapy, especially if nonresponsive to meds and the symptoms really bother the patient.

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