Austin Bradford Hill, PPIs and IBD

KH Allin, P Moayyedi. Gastroenterol 2021; 161: 1789-191 (editorial). Open Access: Proton Pump Inhibitor Use: A Risk Factor for Inflammatory Bowel Disease or an Innocent Bystander?

This editorial helps provide needed context on the associated observational study by Xia et al (B Xia, M Yang et al. Gastroenterol 2021; 161: 1842-1852. Open Access. Regular use of proton pump inhibitor and the risk of inflammatory bowel disease: pooled analysis of 3 prospective cohorts) which showed a mild increase risk of IBD among PPI users. While the PPI users were at 42% increased risk of IBD compared to nonusers, if correct, “the absolute risk associated with PPI use is modest. Number needed to harm is 3770, meaning that when 3770 individuals are treated with PPIs for 1 year, 1 additional case of IBD is observed.”

Despite the efforts of the study authors to minimize confounders, the editorial focuses on the work of Austin Bradford Hill (Proc R Soc Med. 1965; 58: 295-300. The environment and disease: association or causation?) who “realized making causal inferences on observational data was challenging and outlined a list of factors that would make this interpretation more or less likely….strength of association, dose response, and consistency are important and often not commented on in observational studies.”

In a previous “a double-blind, randomized clinical trial comparing pantoprazole with placebo over 3 years with more than 53,000 patient years follow-up found there was no association” with IBD identified…Interestingly, this trial reported a slightly higher risk of enteric infections, and this is the underlying mechanism proposed for how PPI therapy may increase the risk of IBD.”

My take (borrowed from editorial): “Most associations for PPI and harm are likely to be residual or unmeasured confounding, whether this is also true for IBD will only be determined by further study.”

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Long-term Use of Proton Pump Inhibitors for Eosinophilic Esophagitis

A prospective pediatric eosinophilic esophagitis (EoE) study (C Gutierrez-Junquera et al. JPGN 2018; 67: 210-6) examines the use of proton pump inhibitors (PPIs) for long-term management for this disorder.

After diagnosis of EoE, children received esomeproazole (1 mg/kg/dose BID).  For those with a response (<15 eos/hpf), they were maintained on 1 mg/kg/day for one year.

Key findings:

  • Of the initial cohort of 109, 72 (66%) had response to esomeprazole.
  • 57 of these responders were subsequently followed in this study.  At the lower daily esomeprazole dose, 70.1% (n=40) continued with <15 eos/hpf and 29.9% (n=17) had relapse.
  • Maintaining response was more common among those who achieved an initial response (with BID esomeprazole) of <5 eos/hpf compared to those who had achieved an initial response of 6-14 eos/hpf.  At 1 year, in those with who had a more complete response, 81% maintained eosinophil count <15/hpf compared with only 50% in those with a lesser initial response.
  • Adverse events with prolonged treatment were uncommon and included self-resolving diarrhea in three, headache in one and urticaria in one; the latter two adverse effects responded to change to lansoprazole

My takes: 

  1. PPI treatment is effective in probably 40-50% of individuals with EoE (though higher response in this study)
  2. Some individuals need higher doses of PPIs
  3. Due to the high response rate, this underscores the need to diagnose EoE prior to using PPIs or after they have been discontinued.

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Which Proton Pump Inhibitor is the Most Potent?

A recent study (DY Graham, A Tansel. Clin Gastroenterol Hepatol 2018; 16: 800-808) analyzed 56 randomized trials to determine relative potency of proton pump inhibitors (PPIs) based on time in which intragastric pH was 4 or less (pH4time).

Key findings:

  • Pantoprazole 20 mg was equivalent to 4.5 mg of omeprazole
  • Lansoprazole 15 mg was equivalent to 13.5 mg of omeprazole
  • Esomeprazole 20 mg was equivalent to 32 mg of omeprazole
  • Rabeprazole 20 mg was equivalent to 36 mg of omeprazole

The authors note that peak effectiveness for PPIs was at ‘approximately 70 mg of omeprazole equivalents’.  In addition, they state that twice a day dosing was more effective than increasing once a day dosing; however, three times a day dosing was not more effective than twice a day. “Dexlansoprazole, a quasi-twice-a-day formulation produced similar acid suppression to the lowest twice-daily PPI regimen and 20 mg vonoprazan once daily provided similar efficacy aas high-dose twice-daily PPI.” The authors also compare costs; generics of pantoprazole, omeprazole, and esomeprazole cost as little as $0.02-0.04 per omeprazole equivalent.  Thus, 20 mg of omeprazole would be as little as 40 cents.

My take: Using the lowest effective dose of a PPI is recommended.  In patients needing higher dosing or with suboptimal response to acid suppression, this data can be very helpful.


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PPI and Poor Outcomes

A large observation study provides some bad publicity for proton pump inhibitors (PPI):

BMJ Open Access: Risk of death among users of Proton Pump Inhibitors: a longitudinal
observational cohort study of United States veterans (Y Xie et al BMJ Open
2017;7:e015735. doi:10.1136/bmjopen-2016-01573) Thanks to Ben Enav for this reference.

This study selected ~350,000 patients from a database which identified more than 1.7 million PPI users. These patients were ‘new’ PPI users.

Key finding:  Over a median follow-up of 5.71 years, PPI use was associated with increased risk of death compared with H2 blockers use (HR 1.25, CI 1.23 to 1.28).

The authors note the limitations of this observational study; however, they suggest that the findings cannot be fully explained by residual confounders.  They recommend limiting PPI use to “instances and durations where it is medically indicated.”

My take: As noted in a recent post (see below), some risks attributed to PPIs in observational studies do not pan out.  Yet, PPI therapies need to be better-targeted to those who will truly benefit from them.

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Two for the PPI Team

Medicine safety is not nearly as straight-forward as most people would expect.  Virtually all medicines have the potential for adverse reactions.  In addition, there are often conflicting reports on how frequent adverse reactions occur; furthermore, negative studies demonstrating safety may be published less frequently due to publication bias.

This problem is compounded by the frequent misunderstanding of statistics.  Frequently, risks of medications are expressed as an odds ratio.  So, if an adverse reaction occurs twice as often with the medication than without the medication, the odds ratio would 2.0.  Yet, if the adverse reaction is rare (eg. one in a million), then the absolute increase in risk remains minuscule.

Proton pump inhibitors have received a lot of press, often about rare increases in adverse reactions. But, there are many potential benefits to these medications and numerous studies demonstrating fairly good safety profiles.  A few more studies (thanks to Ben Gold for these references) on their safety have recently been published:

  • 1. “Long-term Proton Pump Inhibitor Use is Not Associated with Changes in Bone Strength and Structure” LE Targownik et al. Am J Gastroenterol 2017; 112: 95: 101.
  • 2. “Proton Pump Inhibitors Do Not Increase Risk for Clostridium difficile Infection in the Intensive Care Unit.” DM Faleck et al. Am J Gastroenterol 2016; 111: 1641-8.

In the first study, the authors examined 52 PPI-users (>5 yrs) and 52 non-PPI users with mean age of 65 years.  They underwent quantitative CT , DXA, and markers of bone metabolism. “There were no differences detected..between the two groups.”  The conclude that PPIs were not associated with changes that increase a risk of fracture and “provide further evidence that the association between PPI use and fracture is not causal.”

In the second study, the authors analyzed data from 14 ICUs 2010-2013 and identified 18,134 patients (mean age 66-67 yrs) who met inclusion criteria.  271 (1.5%) developed Clostridium difficile infection (CDI) in the ICU.  The main risk factor for CDI was antibiotics with adjusted Hazard Ratio (aHR) of 2.79.  “There was no significant increase in risk for CDI associated with PPIs in those who did not receive antibiotics (aHR 1.56; 95% CI, 0.72-3.35).”  “PPIs were actually associated with a decreased risk for CDI in those who received antibiotics (aHR 0.64; 95% CI 0.48-0.83).”  The authors also noted that even those who received the highest doses of PPIs, “there was no risk for health-care facility-onset CDI.”

My take: PPIs can be life-saving medications and can alleviate a lot of suffering.  These studies pushback on some of the concerns about PPI risk.

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Piling on PPIs -Now Concerns about Dementia

A recent study (see abstract below -from Mike Hart) indicates the possibility that proton pump inhibitors (PPIs) could increase the risk of dementia to a small degree.  Despite the big numbers, this study cannot adequately control for numerous factors that could influence these results.  As is often said, association does not prove causation.  Nevertheless, this study is another reminder to use PPIs when indicated and to use them for the appropriate length of therapy.

Here’s NBC News Narrative: Popular Heartburn Drugs Linked to Dementia


Association of Proton Pump Inhibitors With Risk of Dementia: A Pharmacoepidemiological Claims Data Analysis

Willy Gomm, PhD1; Klaus von Holt, MD, PhD1; Friederike Thomé, MSc1; Karl Broich, MD2; Wolfgang Maier, MD1,3; Anne Fink, MSc1,4; Gabriele Doblhammer, PhD1,4,5,6; Britta Haenisch, PhD1

JAMA Neurol
. Published online February 15, 2016. doi:10.1001/jamaneurol.2015.4791

Importance  Medications that influence the risk of dementia in the elderly can be relevant for dementia prevention. Proton pump inhibitors (PPIs) are widely used for the treatment of gastrointestinal diseases but have also been shown to be potentially involved in cognitive decline.

Objective  To examine the association between the use of PPIs and the risk of incident dementia in the elderly.

Design, Setting, and Participants  We conducted a prospective cohort study using observational data from 2004 to 2011, derived from the largest German statutory health insurer, Allgemeine Ortskrankenkassen (AOK). Data on inpatient and outpatient diagnoses (coded by the German modification of the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision) and drug prescriptions (categorized according to the Anatomical Therapeutic Chemical Classification System) were available on a quarterly basis. Data analysis was performed from August to November 2015.

Exposures  Prescription of omeprazole, pantoprazole, lansoprazole, esomeprazole, or rabeprazole.

Main Outcomes and Measures  The main outcome was a diagnosis of incident dementia coded by the German modification of the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision. The association between PPI use and dementia was analyzed using time-dependent Cox regression. The model was adjusted for potential confounding factors, including age, sex, comorbidities, and polypharmacy.

Results  A total of 73 679 participants 75 years of age or older and free of dementia at baseline were analyzed. The patients receiving regular PPI medication (n = 2950; mean [SD] age, 83.8 [5.4] years; 77.9% female) had a significantly increased risk of incident dementia compared with the patients not receiving PPI medication (n = 70 729; mean [SD] age, 83.0 [5.6] years; 73.6% female) (hazard ratio, 1.44 [95% CI, 1.36-1.52]; P < .001).

Conclusions and Relevance  The avoidance of PPI medication may prevent the development of dementia. This finding is supported by recent pharmacoepidemiological analyses on primary data and is in line with mouse models in which the use of PPIs increased the levels of β-amyloid in the brains of mice. Randomized, prospective clinical trials are needed to examine this connection in more detail.

Related blog post: Proton Pump Inhibitors Webinar

Unrelated article (from Ben Gold): J Molina-Infante et al. Am J Gastroenterol 2015; 110: 1567-1575.  This study examined 75 patients (mean age 38 years) with proton-pump inhibitor responsive esophageal eosinophilia (PPI-REE).  55 (73%) had long-term sustained histologic remission with low-dose PPI therapy (20 mg once or twice daily). In addition, the article noted that 9 of 10 relapsers with distal eosinophilia were noted to have a CYP2C19 rapid metabolizer genotype and regained histologic remission with dose intensification.

Briefly noted: AI Sharara et al. Clin Gastroenterol Hepatol 2016; 14: 317-21.  Among 414 who met inclusion criteria (at least 6 months of PPI usage and at least 1 serum magnesium level), 57 (13.8%) had at least 1 low serum magnesium –44 of these patients had recognizable causes (eg. diuretics, chronic diarrhea).  Of the remainder who continued with PPI therapy, the level was normal at final measurement and only mildly low levels were noted previously.  Thus, in patients without other reasons for low magnesium, the authors found that use of a PPI does not appear to be associated with hypomagnesemia.


Good Press for PPIs

A lot of medical publications focus on infrequent complications of medications.  This is problematic for many who have trouble understanding absolute risks and relative risks.  If a medication increases the relative risk of a rare problem, the absolute risk to the individual remains quite low.

For proton pump inhibitors, there has been a fair amount of focus on potential complications.  In my view, some of this is due to the fact that there are many taking these medications who may not be receiving much benefit.   Many of the adverse effects for most patients would result in a low absolute risk. In fact, stopping PPIs in those who have indications for their usage could result in significantly greater harm.

For those who’ve been thinking that proton pump inhibitors (PPIs) have been getting a ‘bum rap,’ here are a few publications have highlighted their success in problems other than ulcers and gastroesophageal reflux disease.

  • AJ Lucendo et al. Clin Gastroenterol Hepatol 2016; 14: 13-22.
  • RMM van Aerts et al.  Clin Gastroenterol Hepatol 2016; 14: 147-52.

The first study, a systemic review and meta-analysis of PPIs in inducing remission for eosinophilic esophagitis (EoE).  In all 33 studies (11 prospective) of adults and children were included with 619 patients. Key findings:

  • Clinical response was noted in 60.8%
  • Histologic remission (<15 Eos/hpf in this study) in 50.5%
  • In prospective studies, once-daily therapy had similar effectiveness to twice daily (55.9% vs. 49.7%)
  • pH monitoring did not predict response to PPI therapy

My take: While the conclusion from this study (by the authors) is that PPIs should be considered a first-line therapy for EoE, they also indicate that the findings need to interpreted cautiously due to poor-quality evidence, heterogeneity of the studies, and publication bias.  Despite these limitations, most experts agree that PPI therapy should be undertaken prior to use of other treatments like diets or topical steroids for EoE.

The second study showed that patients with hereditary hemochromatosis needed less phlebotomy if they were taking PPIs.  The study was a retrospective study which divided patients into 3 groups, including a paired group of 12 patients who had ferritin levels and number of phlebotomies compared for 3 years prior and 3 years after the start of PPI therapy.  In this group, phlebotomies were needed 3.16 times per year prior to PPI and only 0.5 per year subsequently (to keep ferritin less than 100 mcg/L).  The authors note that studies have shown that PPIs reduced postprandial iron absorption.  PPIs effect on iron metabolism “acts at cellular level in the endosomes and in the stomach, and it seems to have no influence on the hepcidin regulation.”  For PPI fans, the editorial (pgs 153-55) comments that “an attractive aspect of this strategy is the safety of PPIs, which has been shown even with long-term use.’ [Aliment Phamacol Ther 2015; 41: 1162-74]

My take: While this study is not recommending that patients with hereditary hemochromatosis start PPI therapy, those who are taking PPI therapy may need less frequent phlebotomy.

So, in addition to patients with gastroesophageal reflux disease and peptic ulcer disease, patients with eosinophilic esophagitis and those with hereditary hemochromatosis often benefit from PPI therapy.

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NEJM: Functional Dyspepsia

A recent NEJM had a concise review of functional dyspepsia (Talley NJ, Ford AC. NEJM 2015; 373: 1853-63).

With regard to functional dyspepsia in adults, the authors note that using the Rome III criteria, the global prevalence is between 5% and 11%.

While symptoms do not reliably distinguish organic and functional dyspepsia, they note that “with a relatively low rate of identification of organic disease, it is neither desirable nor realistic to perform this test [upper gastrointestinal endoscopy] in all patients with dyspepsia.”

Their review suggests several criteria to consider to help determine who needs endoscopy including age >55 yrs, GI bleeding, dysphagia, persistent vomiting, unintentional weight loss, family history of gastric or esophageal cancer, and iron-deficiency anemia.

With regard to workup, they suggest testing for H pylori non invasively with either breath testing or stool antigen testing.  The review covers treatment approaches including acid suppression (“effect is modest”), antidepressants (“tricyclic antidepressants…should be preferred over selective serotonin-reuptake inhibitors”), prokinetic agents, psychological treatments, and complementary approaches.  Figure 3 provides a helpful algorithm.

With regard to prognosis, “approximately 15 to 20% of people with functional dyspepsia have persistent symptoms and 50% have resolution of symptoms; in the remaining 30 to 35% of patients symptoms will fluctuate and meet the criteria for another functional gastrointestinal disorder.”

Briefly noted: “Acute Anxiety and Anxiety Disorders are Associated with Impaired Gastric Accommodation in Patients with Functional Dyspepsia” HG Ly et al. Clin Gastroenterol Hepatol 2015; 13: 1584-91.

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PPIs and Associated Heart Risk

A NY Times review PPIs and Heart Attacks of PLos One study showing an association between PPI usage (eg. prilosec, prevacid, and nexium) and heart attacks -this study does not prove any causality, but is likely to spark some questions. Excerpt:

The widely used drugs known as proton pump inhibitors, or P.P.I.’s — gastric reflux preventives like Prilosec and Prevacid — may increase the risk for heart attack, according to analysis of data involving almost three million people.

A significant limitation of the study, in PLOS One, is that P.P.I. usage may be a marker of a sicker patient population, more subject to heart disease in any case.

Here’s NPR’s take on the same study: Data Dive -Possible Link Between PPIs and Heart Attacks

“The increase in risk is about 16 to 20 percent, depending on the particular drug involved”…

Someone with a low risk of heart attack doesn’t have much to worry about. “If your risk of a cardiovascular event or a heart attack is one in a million, now it is 1.2 in a million,” [Nigham] Shah [one of the authors] says.

“The problem is, it’s very easy to do studies of this sort that lead to conclusions that can be misleading,” says Dr. David Juurlink, a drug-safety researcher at the University of Toronto…

“Having a bad diet, drinking too much alcohol, smoking and all sorts of other things … might lead people to be on a PPI,” Juurlink says. One would expect those people to be at higher risk of heart attack, which leads Juurlink to think the medicine is likely not to blame.”


Also noted:

No Effect of Proton Pump Inhibitors and Irritability on Crying in Infants

While the title of this blog will come as no surprise to most pediatric gastroenterologists, many parents would be surprised that a systemic review of randomized controlled trials (RCTs) showed` that proton pump inhibitors (PPI) are ineffective for crying infants (J Pediatr 2015; 166: 767-70).

In this review, only five trials (with 430 infants) met the prespecified inclusion criteria.  While some trials showed a decrease in crying/irritability form baseline to the end of the intervention, a similar effect was evident in the control group.  The authors found that one trial reported a higher risk of lower respiratory tract infections in the PPI group and note that “administration of PPIs is not without risk.”

Take-home message: “the limited data available suggest that PPIs are not effective for the management of crying/irritability in infants.”

Another PPI citation: Rosen R et al. J Pediatr 2015; 166: 917-23.  In this study, the authors prospectively showed that PPI use was associated with differences in gastric, lung, and oropharyngeal microflora (n=116 children with 59 receiving PPIs)

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