Understanding Protopathic Bias and Safety of Proton Pump Inhibitors & COVID-19 Worldwide Nadir

C-H Lo et al. Gastroenterol 2022; 163: 852-861. Open Access! Association of Proton Pump Inhibitor Use With All-Cause and Cause-Specific Mortality

Background: “A major challenge that pharmacoepidemiologic studies often face is the susceptibility to protopathic bias. Protopathic bias occurs when a pharmaceutical agent is prescribed for an early manifestation of a disease and then appears to cause the disease when it is eventually diagnosed…Here, we used a modified lag-time approach to investigate the association between PPI use and all-cause and cause-specific mortality”

Methods: This was a prospective cohort study using data collected from the Nurses’ Health Study (2004–2018) and the Health Professionals Follow-up Study (2004–2018). Study participants: 50,156 women and 21,731 men followed for 831,407 person-years and a median of 13.8 years.

Key findings:

Upon applying lag times of up to 6 years, the mortality associations were attenuated and no longer statistically significant:

  • All-cause mortality: HR, 1.04; 95% CI, 0.97–1.11
  • Cancer: HR, 1.07; 95% CI, 0.89–1.28
  • Cardiovascular diseases: HR, 0.94; 95% CI, 0.81–1.10
  • Respiratory diseases: HR, 1.20; 95% CI, 0.95–1.50
  • Digestive diseases: HR, 1.38; 95% CI, 0.88–2.18

Longer duration of PPI use did not confer higher risks for all-cause and cause-specific mortality.

My take: This study provides convincing evidence that PPI use does not increase the risk of mortality. Protopathic bias can make PPI use appear to increase the risk of mortality (HR, 1.19 in this study) compared to PPI non-users. It is still a good idea to use these agents for appropriate indications and at appropriate doses.

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Beached Fishing Boats Jules Achille Noel. The Art Institute of Chicago.

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition

Also, worldwide COVID-19 deaths are at a low point since the beginning of the pandemic (both reported and estimated excess deaths).

More Good News for PPIs: NO Increased Risk of Dementia

From ACG SmartBrief (thanks to Ben Gold for this):

A study published in The American Journal of Gastroenterology found no link between the use of proton-pump inhibitors and increased dementia risk. The study, led by Muhammad Ali Khan, MD, examined 11 studies with a combined 642,949 participants, and researchers said “PPI use among patients who have a valid indication for it, should not be curtailed because of concerns about dementia risk.”

The American Journal of Gastroenterology: January 2, 2020 – Volume Publish Ahead of Print – Issue – p doi: 10.14309/ajg.0000000000000500



Long-term use of proton pump inhibitors (PPIs) has been associated with a wide variety of potentially serious adverse effects including a possible increased risk of dementia. Studies evaluating this association have reached divergent conclusions. We aimed to evaluate this proposed association further and to assess the quality of the evidence in its support.


We searched MEDLINE, EMBASE, ISI Web of Science, and Cochrane databases for studies examining a link between PPI use and dementia, up to February 2019. Studies reporting summary results as hazard ratio (HR) or odds ratio (OR) were pooled using the DerSimonian and Laird random-effects model for meta-analyses. Methodological quality of individual observational studies was assessed using the Newcastle-Ottawa scale and the overall quality of evidence rated as per the GRADE approach.


We identified and included 11 observational studies comprising 642,949 subjects; 64% were women. Most studies were short-term ranging from 5 to 10 years. There were 158,954 PPI users and 483,995 nonusers. For studies summarizing data as adjusted HR, pooled HR for all causes of dementia was 1.10 (0.88–1.37); for Alzheimer dementia only, it was 1.06 (0.72–1.55). For studies summarizing data as adjusted OR, pooled OR for all causes of dementia was 1.03 (0.84–1.25) and for Alzheimer dementia only 0.96 (0.82–1.11). Per Newcastle-Ottawa scale assessment, 10 studies were of high quality and 1 was of moderate quality. By applying GRADE methodology, quality of evidence for both outcomes was very low.


We found no evidence to support the proposed association between PPI use and an increased risk of dementia. PPI use among patients who have a valid indication for it, should not be curtailed because of concerns about dementia risk.

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How Long Should Be PPIs Be Used in Patients with Esophageal Atresia?

A recent study (FR Grunder et al. JPGN 2019; 69: 45-51) examines the use of proton pump inhibitor use after surgical repair of esophageal atresia; this involved a longitudinal cohort (n=73) with prospectively collected data over 11 years.

Background: While PPIs have been used for long-term treatment due to the high frequency of reflux and concerns regarding anastomotic strictures, the authors note that data on long-term outcomes/natural history and benefits/risks of this approach are lacking.

Key findings:

  • 48% of patients had PPIs discontinued at followup.
  • Among the 43 with PPI discontinuation, 40 had endoscopy results available.  Histologic abnormalities were noted in 8 (19%) which was lower than in the group receiving ongoing PPI use (n=19, 63%).. These 8 patients had PPI restarted.
  • Among patients unable to discontinue PPI therapy, there was a higher rate of prior anti-reflux surgical procedure, 27% compared to 5% who had anti-reflux procedure among group who were able to discontinue PPI therapy.
  • Patients more likely to remain on PPIs more frequently had a prior anastomotic leak and/or moderate to severe tracheomalacia.
  • The authors state that among patients receiving PPIs, there was more frequent recurrent pneumonia as well as more frequent use of inhaled beta-adrenergic agonists and steroids. However, this was not shown to be a causal association.  It is unclear whether these patients had more severe esophageal dysfunction or whether PPI use contributed to this outcome.

In their discussion, the authors note that PPIs have not been shown to reduce the rate of anastomotic strictures.  They argue that “PPI could be used more selectively in the following: in children with long-gap EA or anastomotic tension or anastomotic leak; after a first dilatation for anastomotic stricture rather than systematically, given the lack of preventive effect of PPI; and in children whose esophagoscopy demonstrates peptic esophagitis, eosinophilic esophagitis, or gastric metaplasia.”

My take: The authors are probably right that a large fraction of EA patients may not need long-term PPI use.  Selecting which patients will benefit will remain a challenge. Published guidelines recommend monitoring for GERD complications in EA, especially after stopping PPIs.

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University of Virginia


PPIs: Good News on Safety

When someone gets bitten by a shark, it often makes the news.  Yet, the frequency of shark attacks is rare and it is probably much more dangerous driving to the beach than getting into the water.

For proton pump inhibitors, it seems that they get similar press coverage as shark bites.  Many times potential adverse effects are covered heavily by the media even though many of these effects are unproven or very infrequent.

A recent study (“Safety of Proton Pump Inhibitors Based on a Large, Multi-year, Randomized Trial of Patients Receiving Rivaroxaban or Aspirin” Moayyedi, Paul et al. Gastroenterology DOI: https://doi.org/10.1053/j.gastro.2019.05.056) shows that 3 years of pantoprazole had an excellent safety profile.

Here is the abstract:

Background & Aims

Proton pump inhibitors (PPIs) are effective at treating acid-related disorders. These drugs are well tolerated in the short term, but long-term treatment was associated with adverse events in observational studies. We aimed to confirm these findings in an adequately powered randomized trial.


We performed a 3×2 partial factorial double-blind trial of 17,598 participants with stable cardiovascular disease and peripheral artery disease randomly assigned to groups given pantoprazole (40 mg daily, n=8791) or placebo (n=8807). Participants were also randomly assigned to groups that received rivaroxaban (2.5 mg twice daily) with aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg) alone. We collected data on development of pneumonia, Clostridium difficile infection, other enteric infections, fractures, gastric atrophy, chronic kidney disease, diabetes, chronic obstructive lung disease, dementia, cardiovascular disease, cancer, hospitalizations, and all-cause mortality every 6 months. Patients were followed up for a median of 3.01 years, with 53,152 patient years of follow up.


There was no statistically significant difference between the pantoprazole and placebo groups in safety events except for enteric infections (1.4% vs 1.0% in the placebo group; odds ratio, 1.33; 95% CI, 1.01–1.75). For all other safety outcomes, proportions were similar between groups except for C difficile infection, which was approximately twice as common in the pantoprazole vs the placebo group, although there were only 13 events, so this difference was not statistically significant.

Does PPI Use Increase Pneumonias in Otherwise Healthy Infants?

A recent study (M-L Blank, et al. JPGN 2018; 67: 335-40) showed that proton pump inhibitors (PPIs) do not appear to increase the risk of pneumonia in otherwise healthy infants.

This study used a cohort of 21,991 patients (2005-2012) in New Zealand and examined the use of a PPI (omeprazole, lansoprazole, or pantoprazole) and its association with lower respiratory tract infections (566 validated cases) and 65 cases of radiography-confirmed community acquired pneumonia (CAP).  For each LRTI and each CAP, there were 10 matched controls.

Key findings:

  • Neither current nor recent use of a PPI was associated with an increased risk of CAP or LRTI resulting in hospitalization or death.
  • The matched odds ratio for CAP with current or past use of PPI was 0.88 and for all LRTI cases the matched odds ratio was 1.13.

My take: This study indicates that PPIs are unlikely to contribute to respiratory infections in otherwise healthy infants.  The larger question is how many of these infants really should be receiving PPIs and what other adverse consequences that may occur.

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More on PPIs and Kidney Disease & Brain Disease

The most recent information and perspective on proton pump inhibitors and kidney disease:

From AGA: More Data on PPI Use and Kidney Disease

An excerpt:

The most recent study related to PPIs and CKD was a meta-analysis by Wijarnpreecha et al. presented at the American Society of Nephrology annual meeting and published in Digestive Diseases and Sciences. They found that any use of PPIs was associated with a 33 percent relative increase in risk for CKD/ESRD whereas no such risk was seen with H2RAs.

Talking to Your Patients
  1. Inform patients that, while this study does raise some concern about long-term PPI use and the potential contributions to kidney disease, the study does not show that PPI use causes kidney disease. No decisions should be made in haste as a reaction to this study. A brief explanation of the meta-analysis may also be helpful. 
  2. Reassure patients that the benefits of using PPIs often outweigh the possible risks. Let them know that you prescribed a PPI for a clear-cut indication, in the lowest possible dose, and for an appropriate period of time (lowest dose, shortest time). 

From the published abstract:

Results: five studies (three cohort studies and two case-control studies) with 536,902 participants met the eligibility criteria and were included in the meta-analysis. We found that individuals with PPIs use had significantly increased the risk of CKD or ESRD when compared with non-PPIs users (pooled RR of 1.33, 95% CI, 1.18-1.51). There was no publication bias of overall included studies assessed by the funnel plots.

My take: (borrowed from the AGA) This is an association, not proof of a causal relationship. Patients who use PPIs differ at baseline than those who do not. For example, patients who use PPIs are more likely to have diabetes or hypertension than patients who do not use PPIs, and are more likely to use additional nephrotoxic medications. Large retrospective studies are unable to completely adjust for these baseline differences. These differences, rather than PPIs themselves, may explain the observed association.

Related study: DCF Klatte et al. Gastroenterol 2017; 153: 702-10.  In this retrospective analysis with more than 100,000 new PPI users (Swedish cohort), PPI users (compared to H2 blocker users) had an increased risk for doubled levels of creatinine with a HR of 1.26, and an increased risk of end-stage renal disease with HR of 2.40. The risk of chronic kidney disease was increased with higher cumulative PPI exposures.

Related study: Effects of PPI on dementia –recent large study shows no association: H Taipale et al. The American Journal of Gastroenterology(2017) 112, 1802–1808 (2017) doi:10.1038/ajg.2017.196.  (Thanks to Ben Gold for this reference. This study examined more than 70,000 Finnish patients with Alzheimer’s disease (AD) (2005-2011) and 280,000 controls.  Results: PPI use was not associated with risk of AD with 3-year lag window applied between exposure and outcome (adjusted odds ratio (OR) 1.03, 95% confidence interval (CI) 1.00–1.05). Similarly, longer duration of use was not associated with risk of AD (1–3 years of use, adjusted OR 1.01 (95% CI 0.97–1.06); ≥3 years of use adjusted OR 0.99 (95% CI 0.94–1.04)). Higher dose use was not associated with an increased risk (≥1.5 defined daily doses per day, adjusted OR 1.03 (95% CI 0.92–1.14)).

Sunrise over the South Rim at the Grand Canyon

Clostridium difficile Risk Factors in Children

From J Pediatr -full text: Risk Factors for Community-Associated Clostridium difficile Infection in Children  (DJ Adams J Pediatr 2017; 186: 105-9)

Methods: We performed a case-control study using billing records from the US military health system database

Results (from abstract):

A total of 1331 children with CA-CDI were identified and 3993 controls were matched successfully. Recent exposure to fluoroquinolones, clindamycin (OR 73.00; 95% CI 13.85-384.68), third-generation cephalosporins (OR 16.32; 95% CI 9.11-29.26), proton pump inhibitors (OR 8.17; 95% CI 2.35-28.38), and to multiple classes of antibiotics, each was associated strongly the subsequent diagnosis of CA-CDI. Recent exposure to outpatient healthcare clinics (OR 1.35; 95% CI 1.31-1.39) or to a family member with CDI also was associated with CA-CDI.

Table 2 lists other medications and their risks; for example, corticosteroids had adjusted OR of 1.22 and H2-receptor antagonists had adjusted OR of 3.33.  The OR of fluoroquinolone could not be calculated as 51 cases were exposed compared with 0 controls

In their discussion, the authors note the following:

Our study supports the occurrence of CDI among a population of children who were never hospitalized previously and provides a broad characterization of the medication and epidemiologic exposures associated with pediatric CA-CDI cases. Recent exposure to fluoroquinolones, clindamycin, third-generation cephalosporins, and to multiple classes of antibiotics was associated strongly with the subsequent diagnosis of CA-CDI in children; however, a sizeable minority had no preceding antibiotic exposure.

My take: This large study shows that CDI is more frequent after antibiotic usage and after usage of acid suppression (particularly with proton pump inhibitor) therapy.

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