This document discusses long-term use of proton pump inhibitors (PPIs) and potential risks and conditions for use. It notes that long-term PPI use has been associated with chronic kidney disease (CKD) and dementia, though the relationships are uncertain. For conditions like GERD, NSAID use, and Barrett's esophagus, the benefits of PPIs usually outweigh the small and uncertain risks. The document provides guidance on what to tell patients about risk/benefit assessments and recommends the lowest effective dose and intermittent use when possible to reduce potential side effects.

1. Kurdistan Board GEH J Club
Supervised by:
Dr. Mohamed Alshekhani
Professor in Medicine
MBChB-CABM-FRCP-EBGH 2016
1

2. Introduction:
• The possible side effects of Long-term PPIs include:
• Gastric carcinoids
• Gastric carcinoma
• Decreased absorption of minerals (e.g., iron, calcium)/ vitamin B-
12,magnesium.
• Fractures.
• Enteric infections (e.g., C . difficile.)
• Pneumonia.
• CV events.
• Recently associations with (CKD) &dementia.

3. Long-term PPI side effects : CVD,CKD,Dementia:
• Hazard ratios for PPI use & dementia or CKD were ≤1.5 &when
hazard ratio<2 , it is not possible to determine whether the
association is valid or the result of residual bias.
• if a true cause-&-effect exists, even small effect sizes can result in
meaningful risk for common interventions&conditions.

4. CONDITIONS WITH POTENTIAL LONG-TERM PPI USE:GERD
• Most GERD patients (2/3 with erosive esophagitis) who stopped
therapy after heartburn resolution did well with intermittent 2–4-
week courses of daily therapy reinstituted if twice-weekly
heartburn recurred: 70% had 0–1 relapses& 30% changed to daily
PPI during almost 1-year follow-up.
• 80–100% are willing to continue on-demand therapy, with 60–80%
decrease in PPI consumption compared with daily therapy.
• Guidelines recommend erosive esophagitis to remain on daily
maintenance PPI due to the higher risk of recurrent erosions, but no
data document that lack of daily PPI are harmful or increases the
risk of developing Barrett’s &complications as stricture,so
improvement in symptoms &QOL is the primary goal.
• Even when PPIs are prescribed daily, patients commonly stop &
start therapy, defining their own adequate symptom control.

5. CONDITIONS WITH LONG-TERM PPI USE: Barrett’s
• PPIs may decrease progression to neoplastic Barrett’s esophagus
• ACG guidelines recommend that patients with Barrett’s esophagus
receive once-daily PPI but this “deserve consideration” without refl
ux symptoms .
• AGA guidelines recommend that risks&potential benefits of long-
term PPI be discussed carefully with Barrett’s patients given the
0.1% annual risk for progression of non-dysplastic Barrett’s
esophagus to adenocarcinoma ,any absolute beneft will be small.

6. CONDITIONS WITH LONG-TERM PPI USE: NSAIDs
• Guidelines recommend PPI or misoprostol co-therapy in NSAID
users with increased risk for bleeding:
• Age >65 years
• High dose/ multiple NSAIDs.
• Prior ulcer
• Concurrent anti-thrombotics or corticosteroids.
• RCTs document that PPI co-therapy decreases endoscopic ulcers
&recurrent ulcer bleeding.

7. CONDITIONS WITH LONG-TERM PPI USE: Anti-platelets
• Guidelines recommend PPIs in patients with increased risk of
bleeding:
• H/O ulcer or GIB.
• Concomitant anti-thrombotic.
• Age>60 years plus corticosteroid therapy.
• In low-dose aspirin users PPIs reduce endoscopic ulcers ( 20 ),
recurrent ulcer bleeding &in those taking concomitant clopidogrel,
UGIB.

8. CONDITIONS WITH LONG-TERM PPI USE: Dyspepsia
• PPI therapy is recommended for patients ≤55 years of age with
uninvestigated dyspepsia who are H . pylori negative or in
populations with H. pylori prevalence <10% & it is more effective
than placebo, antacids, or H2RAs.
• A 4–8-week course is suggested, with another course if symptoms
recur.
• Guidelines do not specifically recommend long-term daily PPIs but
patients who respond can be managed without further
investigation & long-term self-directed therapy may be considered.
• PPI has a smaller benefit for functional dyspepsia: number-needed-
to-treat=10–15.

9. LONG-TERM PPI USE: what to tell patients
• Dementia &CKD
• We cannot conclude that these associations are valid&patients
should not accept these reports as fact,but we cannot conclude that
risks do not exist.
• But benefits outweigh potential risk.
• If PPIs are indicated, using the lowest effective dose &if possible,
intermittent rather than daily therapy hopefully should decrease
the risk of potential side effects.
• NSAIDs/anti-platelets

10. LONG-TERM PPI USE: what to tell patients
• NSAIDs/anti-platelets
• The benefi t of daily PPI in high-risk patients taking NSAIDs&/or
anti-platelet agents is well documented and exceeds the small &
uncertain risks.

11. LONG-TERM PPI USE: what to tell patients
• GERD:
• We suggest that patients taking PPIs for GERD stop therapy >2
weeks after symptoms resolve, use H2RAs or antacids for
infrequent symptoms, employ adjunctive life-style modifications, &
institute intermittent PPI courses of ≥2–4 weeks for symptom
recurrence (≥2 episodes per week)& On-demand therapy is also
reasonable.
• If patients require daily PPI to control symptoms, we reassure them:
the gain in quality-adjusted-life-years with long-term symptom
control in all such patients should far exceed any decrease due to
possible rare, serious adverse events.
• In patients greatly concerned about side effects, the reduced quality
of life due to worry about side effects may exceed the gain achieved
with symptom control& patients may choose to accept symptoms
or try other therapies (e.g., surgery).

12. LONG-TERM PPI USE: what to tell patients
• Barrett’s esophagus
• In Barrett’s patients not requiring daily PPI for GERD symptoms, we
suggest that the absolute risk reduction in cancer with daily trt is
uncertain & low (1% in 15–20 years assuming 50–67% relative risk
reduction), as is the risk of serious adverse events.
• Patient preference is key in decisions regarding long-term PPIs in
patients with GERD or Barrett’s esophagus.

13. LONG-TERM PPI USE: what to tell patients
• Dyspepsia
• If PPIs are effective we use intermittent therapy, although some
patients may require long-term daily PPIs to control symptoms.

14. LONG-TERM PPI USE: what to tell patients
• Inappropriate/unstated indications:
• The most important intervention we perform is stopping PPIs in the
many patients without appropriate indications.
• For example, many hospitalized patients receive PPIs, which are
then continued as outpatient treatment& PPI use is inappropriate in
~70–80% of these patients.
• Even uncertain rare risk is unacceptable if a medication provides no
clear benefit.

16. Complementary/ Alternative Medicine Induced ALF:
• CAM-induced DILI is at least as severe in presentation as that
observed due to PM with higher rates of transplantation &
lower transplant-free survival in those who progress to ALF.
• There is increasing incidence of CAM-induced liver injury &
emphasizes the importance of early referral /evaluation for
liver transplantation when CAM-induced liver injury is
suspected.