A #tweetorial on proton pump inhibitors (PPIs)

Just for fun, which drug class is archetypal of a gastroenterologist?

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PPIs would be my pick!

The advent of these potent and effective acid suppression medications led to a paradigm shift in the mx of many GI conditions

The market for PPIs is MASSIVE! Just the projected 5 year growth from 2018 - 2023 estimated to be $3.24 billion!

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So how do #PPIs work?

A reminder on physiology: this class of drug acts on the gastric parietal cells by irreversibly blocking the hydrogen/potassium adenosine triphosphatase enzyme system (the H+/K+ ATPase, aka the gastric proton pump), hence the elegant name

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Do they work? YES THEY DO!

They are great meds and essential for:
Erosive esophagitis / Barrett's
Peptic ulcer / prophylaxis for pts taking NSAIDs/aspirin / ZE
H. pylori eradication

They are also prescribed for symptoms such as non-erosive reflux +/- dyspepsia

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The AspECT trial in @TheLancet showed that a chemoprevention strategy of aspirin + high dose #PPI offered the best event-free survival in patients with Barrett's

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31388-6/fulltext

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Acute treatment of peptic ulcers has been covered in a previous thread on #UGIB https://twitter.com/RashidLui/status/1383817746010435592?s=20

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As for prophylaxis, our Dean Prof @FrancisKLChan @CUHKMedicine led a RCT in @NEJM of pts with Hx of #UGIB + H pylori infection + low dose aspirin or NSAIDs, showing that prophylaxis with PPI is better than eradication alone in preventing recurrent bleeding for NSAIDs

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How about H pylori infection?
From the latest Maastricht V/Florence, Toronto & AP consensus, most if not all eradication regimens contain PPIs

https://gut.bmj.com/content/66/1/6 

https://www.sciencedirect.com/science/article/abs/pii/S0016508516301081

https://onlinelibrary.wiley.com/doi/full/10.1111/j.1440-1746.2009.05982.x

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PPIs also work for certain conditions to relief symptoms such as reflux in the absence of esophagitis +/- dyspepsia

This great tweet on the NNT for esophageal symptoms highlights that the stronger the indication, the more effective PPIs are https://twitter.com/EsophagusDoc/status/1388141322632974342?s=20

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So PPIs are great, but are they safe?

Being one of the most frequently prescribed around the, my take is that PPIs are largely safe

The problem actually stems from its relative safety. Many a time they are prescribed far too carefree and liberally

A discussion below:

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These are some of the reported adverse events associated with long term PPI use with their proposed mechanisms from a great review by Vaezi et al. @AGA_Gastro @AmerGastroAssn

https://pubmed.ncbi.nlm.nih.gov/28528705/ 

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This is all very scary, but what are the effect sizes?

Another excellent review by @UofT_GI_Head in @AmJGastro @AmCollegeGastro summarizes some of the recent estimates
- Enteric infections OR 2.55
- Other reported associations effect size < 2

https://pubmed.ncbi.nlm.nih.gov/29557943/ 

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@UofT_GI_Head also did a robust study that refuted the causal association between PPI use and fractures with no differences shown using BMD, markers of bone metabolism or measures of bone strength for PPI users

https://pubmed.ncbi.nlm.nih.gov/27845341/ 

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Recently, several observational studies have reported arisk of stomach cancer in long term PPI users, summarized expertly here:
likely limited to pts with current or past Hx of HP
probably already had underlying precancerous lesions

https://pubmed.ncbi.nlm.nih.gov/30886648/ 

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Last but not least, the potential for drug-drug interactions (DDI)

Clopidogrel (prodrug)cytochrome P450 2C19active metabolite

But PPIs may interfere with this which led to FDA drug label change for clopidogrel

(dex)lansoprazole & pantoprazole have less effect on this

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A brief recap:
PPIs are great, effective and largely safe!

Though there are some safety signals
- Infections: enteric, C. difficile, pneumonia
- GI: fundic gland polyps, CA stomach
- Micronutrient
- Dementia
- Renal failure
- Drug-drug interactions with clopidogrel

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We should stop PPIs if not indicated/helping!

from @UofT_GI_Head on deprescribing PPIs:
look out for rebound gastric acid hypersecretion
mindful of rebound symptoms
take PPIs every other day for 2 weeks, 2x/week for 2 weeks, then stop https://pubmed.ncbi.nlm.nih.gov/29557943/ 

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In some circumstances H2RA can perform quite well too

Though pts on low-dose aspirin (LDA) + PPI had a slightly lower proportion of recurrent bleeding or ulcer compared with H2RA this was not statistically significant in this study

Reasonable to switch to LDA + H2RA?

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To conclude, good practice when prescribing PPIs:
- Discuss on indications and potential SEs
- risks and benefits
- Consideracid suppressants
- possible dose to control symptoms
- Deprescribe PPIs, not just abruptly stop them

P.S great algorithm by @grepmeded

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I had a great time preparing this and I hope you enjoyed this thread too! Don't be shy to share/re-tweet!