1. Adverse Consequences of PPIs
Dr Nazim
Liaquat national hospital
karachi

2. Adverse Consequences of PPIs
• PPI-Induced Rebound Hypersecretion of Acid.
• PPI and Increased risk of pathological fracture.
• Clopidogrel -PPI Interaction.
• Gastric Acid Influences Gut Flora.
• PPIs in Cirrhotics with Ascites.
• Use of PPI and the Risk of pneumonia .

3. Should PPI’s be First-Line Treatment
for Newly-Diagnosed Dyspepsia or
GERD?
No!!

4. PPI-Induced Rebound Hypersecretion of Acid
• Since 1966, several studies have shown that as little as 2 months on
omeprazole 40 mg/day can result in marked rebound of gastric acid
secretion upon PPI withdrawal.
• The effect is most evident in Helicobacter pylori-negative individuals.
• The degree of acid rebound is proportional to the degree elevation of
intragastric pH during treatment, and fasting plasma gastrin levels during
PPI therapy.
• Presumed due to gastrin-induced increase in parietal cell mass and EC
cells.

5. Gastrin Exerts a Powerful Trophic Effect on
Enterochromaffin-like cells and Parietal cells

6. Rebound Hypersecretion of Acid on
PPI’s
• In HP-negative subjects on omeprazole 40 mg/day for 8 weeks there
was a median increase in the BAO of 82%, and a 28% increase in the
MAO 15 days after discontinuation.
• The response in HP-positive patients is similar but more highly
variable.
• Presumed due to gastrin-induced increase in parietal cell mass and EC
cells.
• The duration of the rebound acidity was not determined
Gastroenterology 1999;116:239-47

7. Rebound Hypersecretion of Acid on
PPI’s:Basal Acid Output
6.8
3.0 3.0 1.9
Gastroenterology 1999;116:239-47

8. Rebound Hypersecretion of Acid on
PPI’s: Maximal Acid Output
41.7
40.4
32.4 6.8 29.8
3.0 3.0 1.9
Gastroenterology 1999;116:239-47

9. PPI Therapy Induces Acid-Related
Symptoms in Previously Asymptomatic
Healthy Volunteers

10. PPI Therapy Induces Acid-Related Symptoms in Healthy
Volunteers After Withdrawal of Rx
• 120 subjects, without any clinically significant history of reflux
symptoms, randomized in double-blind fashion to 2 months
treatment with esomeprazole 40 mg/d or placebo, and then 4 weeks
all received placebo.
• During weeks 2, 3, and 4 post-treatment, clinically significant
symptoms of heartburn, acid reflux, or dyspepsia were reported by
44% of those who had received omeprazole versus only 15% of
those who had received placebo throughout (P < .001).
Gastroenterology 2009 ;Vol. 137(1): 20-22)

11. PPI-Induced Dyspepsia: Statistically
Significant but Relatively Mild
P <0.001
1= No Bothersome Symptoms 7= Very Bothersome Symptoms
Gastroenterology 2009 ;Vol. 137, Issue 1, Pages 20-22

12. Implications of Rebound Hypersecretion
of Acid on PPI’s
• PPI should not be first-line therapy for dyspepsia/GERD.
• The greater the acid suppression, the greater the rebound
– Acid rebound lasts for at least 2 months
• Once you start PPI’s for GERD be prepared to use as long-term therapy
– Discontinuation of PPI or switching to H2RA may be difficult

13. Implications of Rebound Hypersecretion of
Acid on PPI’s
• When treating acid-like dyspepsia or GERD, start with H2-receptor
antagonist as initial therapy.
• If H2-RA’s fail, use the lowest does PPI once a day.
• If nocturnal symptoms predominate, try PPI before dinner, or add an
evening H2RA before bid dosing of PPI.
• Never use omeprazole 40 as initial therapy.

14. Implications of Rebound Hypersecretion of
Acid on PPI’s
• Empiric PPI trials should be brief (2-4 wks)
– It is not necessary to test the efficacy of PPIs over several months
– The maximal acid suppression occurs within 2-5 days.
• Try different PPI’s before going to high-dose PPI
• Once symptoms have been controlled for several months, try to back down
to lowest effective PPI dose periodically .

15. Adverse Consequences of PPIs
• PPI-Induced Rebound Hypersecretion of Acid.
• PPI and Increased risk of pathological fracture.
• Clopidogrel -PPI Interaction.
• Gastric Acid Influences Gut Flora.
• PPIs in Cirrhotics with Ascites.
• Use of PPI and the Risk of pneumonia .

16. PPI and Hip Fractures: Overview
• Since 2006, 4 published studies have shown an association between
chronic PPI use and fractures of the hip
– 2 of the studies show greater risk with longer duration or higher intensities
of use or both.
• One study was unable to detect an effect of PPI use on the occurrence of
hip fracture in the absence of other risk factors for hip fracture
• PPI use does not affect bone density
– Association between PPIs and hip fracture may be due to the presence of
unmeasured confounders

17. Is There a Biologically Plausible
Mechanism for PPI-Induced
Fractures ?

18. Direct PPI Effect on Bone Fragility?
• Approximately 50% of low-velocity
fractures occur in patients without
osteoporotic BMD as determined by
DXA scanning.
• PPIs are capable of blocking the
osteoclast-based vacuolar proton
pump, leading to decreased bone
turnover.
• Inhibition of proton pump activity in
osteoclasts has direct inhibitory
effects on bone resorption and
release of bone calcium
• Decreased bone turnover may
promote slight increases in BMD but
may increase fracture risk by blocking
the repair of microfractures and
microarchitectural defects

19. Physiologic Mechanisms by Which use of PPI
Could Affect Bone Mineral Metabolism
• The dissociation of food calcium complexes and the liberation of Ca2+
from calcium salts is strongly dependent on pH.
• Calcium carbonate, which is the most common calcium salt found in
dietary supplements, is relatively insoluble at high pH levels, which
could potentially hinder its absorption
• PPI use may reduce absorption of inorganic calcium by as much as 60%

20. PPI and Hip Fractures
• PPI therapy 1st linked to an increased risk for hip fractures in 2006 .
• UK General Practice Research Database (1987 - 2003),
– Cases included all patients with an incident hip fracture (n = 13,556), and
135,386 controls.
• The strength of the association between hip fracture and PPI therapy
increased with increasing duration of PPI therapy.
JAMA. 2006;296:2947-2953.

21. PPI and Hip Fractures
• United Kingdom General Practice Database
• 4414 hip fractures 1995-2005 with at least 2 years of GERD therapy
• 3316 had at least one major risk factor for hip fracture
(ETOH, seizure, dementia, steroids)
• 1098 without risks factors compared to 10,923 controls
• In patients with no other risks for hip fractures, PPI use did not
increase the risk of hip fracture
Pharmacology 2008; 28:951-959.

22. PPI Use Is Not Associated With Osteoporosis or
Accelerated Bone Mineral Density Loss
• Manitoba Bone Mineral Density Database : 2000-2007.
• 2193 subjects had evidence of osteoporosis at the hip and were
matched to 5527 controls with normal hip measurements.
• A total of 3596 subjects had BMD measurements consistent with
osteoporosis at the lumbar spine and were in turn matched to 10,257
normal controls.
• The researchers found PPI use was not associated with having
osteoporosis at either the hip or the lumbar spine for proton-pump
inhibitor use over 1500 doses over the previous 5 years.
Targown, et al. Gastroenterology 2010; 138:869

23. PPI and Hip Fractures
• 2008 Canadian, retrospective, case–control study matched 15,792 cases
of osteoporosis-related fractures with 47,289 controls .
• Long-term exposure to PPI therapy, defined as 7 or more years, was
significantly associated with an increased risk of any osteoporosis-related
fractures (hip, vertebral, wrist) P = 0.011)
• Hip fracture risk was increased after only 5 years of continuous use.
Targownik et al CMAJ 2008;179(4):319

24. PPI and Hip Fractures
• Northern California Kaiser database to identify patients with a hip fracture
(cases, n = 33,752) and matched these 4:1 to controls (n = 130,471).
• PPI use > 2 years
• Cases, men and women, were 30% more likely than controls to have taken
PPIs for at least 2 years (odds ratio [OR] 1.30 [95% CI 1.21–1.39]) and 18%
more likely to have consumed H2-blockers for 2 years (1.18 [1.08–1.28]).
• The greatest relative risk of hip fractures in patient 50-59 on PPI>2 years (OR
2.31)
• Risk declines after discontinuation
Gastroenterology. 2009:136(suppl 1):A–70.

25. PPI and Fracture Risk
• 161,806 postmenopausal women aged 50 to 79 years, without a
history of hip fracture, who participated in the Women's Health
Initiative (WHI) Observational Study and Clinical Trials.
• The investigators analyzed data from 130,487 women with complete
information during mean follow-up of 7.8 ± 1.6 years.
• Primary endpoints were self-reported hip (adjudicated)
fractures, clinical spine fractures, forearm or wrist fractures, and total
fractures.
• In addition, 3-year change in BMD was determined
Arch Intern Med. 2010;170:747-748

26. PPI and Fracture Risk
• During 1,005,126 person-years of follow-up, there were
– 1500 hip fractures,
– 4881 forearm or wrist fractures,
– 2315 clinical spine fractures, and
– 21,247 total fractures identified.
• Use of PPIs was associated with only a marginal effect on 3-year BMD
change at the hip (P=.05) but not at other sites
• Multivariate-adjusted hazard ratios were 1.00 for hip fracture,
– 1.47 for clinical spine fracture,
– 1.26 for forearm or wrist fracture, and
– 1.25 for total fractures
• Use of PPIs was not associated with hip fractures but was modestly
associated with clinical spine, forearm or wrist, and total fractures.
Arch Intern Med. 2010;170:747-748

27. PPIs and Fractures
• A Japanese study 18 women with esophagitis taking PPI therapy and 57
age-matched controls without PPI.
• There was a greater risk of multiple vertebral fractures assessed by X-ray in
the esophagitis group.
• There was no statistically significant difference in bone mineral density
between the two groups
J Bone Miner Metab 2005;23:36–40.

28. PPI’s and Osteoporosis: Conclusions
• 4 of 5 case-control studies do appear to confirm an increased risk of
pathological fractures with long-term PPI use as short as 2 years, and a
lesser degree with H2RA.
• Risk appears related to dose and duration of acid suppression; possibly
reversible.
• No measurable decrease in bone density.
• Impaired absorption of calcium may be a contributing factor
– Whether additional calcium/vitamin D supplementation will offset this
risk is unknown.

29. Adverse Consequences of PPIs
• PPI-Induced Rebound Hypersecretion of Acid.
• PPI and Increased risk of pathological fracture.
• Clopidogrel -PPI Interaction.
• Gastric Acid Influences Gut Flora.
• PPIs in Cirrhotics with Ascites.
• Use of PPI and the Risk of pneumonia .

30. Clopidogrel -PPI Interaction
• Widely accepted explanation is the competitive inhibition of
cytochrome 450-2C19
– The isoenzyme responsible for conversion of clopidogrel to it’s
active form
• A PPI’s metabolized to some degree by CYP2C19
• Omeprazole, esomeprazole, lansoprazole showed the greatest
CYP2C19 inhibition, followed by pantoprazole and rabeprazole

31. Clopidogrel plus PPI After Hospitalization for ACS
Increased Risk of Adverse Outcomes
• Retrospective cohort study published in the JAMA demonstrated that
concomitant use of clopidogrel and a PPI after hospital discharge for
acute coronary syndrome (ACS) is associated with an increased risk of
all-cause mortality and rehospitalization for ACS.
• 8,205 patients with ACS were taking clopidogrel after hospital
discharge.
• 63.9% were prescribed a PPI at discharge, during follow-up, or
both, and 36.1% were not prescribed a PPI.
• The median follow-up was 521 days.
JAMA. 2009;301:937–944.

32. Clopidogrel plus PPI After Hospitalization for
ACS Increased Risk of Adverse Outcomes
• Multivariable analysis demonstrated that the use of a PPI during
clopidogrel treatment was associated with an increased risk of death
or rehospitalization for ACS (adjusted OR=1.25; 95% CI, 1.11–1.41).
• Patients taking a PPI with clopidogrel also demonstrated
– Increased rates of recurrent hospitalization for ACS (14.6% vs 6.9%;
P<.001).
– Revascularization procedures (15.5% vs 11.9%; P<.001), and
– Death (19.9% vs 16.6%; P<.001) compared with patients taking
clopidogrel without a PPI
JAMA. 2009;301:937–944.

33. Clopidogrel-PPI Interactions Remain Only
Observational at This Time
• Three randomized databases that are not subject to confounding, and all
suggest that there is no significant adverse interaction between clopidogrel
and PPIs.
– CREDO trial, presented at the AHA 2008
– TRITON trial
– PRINCIPLE 44 trial
• Several studies have also shown no difference in in vitro platelet
aggregation between eomeprazole, pantoprazole, and lasoprazole when
given with either clopidogrel or prasugrel.
1) Am. Heart Journal 2009;51:258 (pantoprazole/eosmeprazole/clopidogrel)
2) J. Clinical Pharm 2008;48:475 (lansoprazole/prasugrel/clopidogrel)

34. Two Randomized Trials of PPI/Clopidogrel
• Two double-blind trials of 202 (Principle) & 13,608 (Triton) PTCA patients
comparing clopidogrel vs prasurgrel
– Platelet functions measure day 1, 14, 28.
• PPI use was at the discretion of the treating physician
– 33% on PPI at start of study
• Mean inhibition of platelet aggregation was modestly but significantly
lower on PPIs for both clopidorgrel and prasurgrel
• No association between use of PPI and adverse cardiac events
Lancet Sept 19, 2009; 374:989

35. Outcomes With Concurrent Use of
Clopidogrel and PPI
• 20 596 patients (including 7593 concurrent users of clopidogrel and PPIs)
hospitalized for MI, coronary artery revascularization, or unstable angina
pectoris. (1999-2005) Tenn. Medicaid Database
• 65% pantoprazole 35% omeprazole
• Adjusted incidence of hospitalization for gastroduodenal bleeding in
concurrent PPI users was 50% lower than that in nonusers [95% CI, 0.39
to 0.65]).
Annals Int Med 2010; 152:337

36. Meta-analysis of Outcomes With Concurrent
Use of Clopidogrel and PPI
• Meta-analysis of 23 observational and randomized controlled trials of CV
and mortality risk in 93,278 patients on PPI and clopidogrel.
• Considerable heterogeneity in findings
– Observational studies generally showed a significant association of
PPI and CV risk
– Randomized and propensity-matched trials showed no association of
PPI with CV risk
• Meta-analysis of 13 studies showed no significant association between PPI
use and overall mortality (RR 1.09 95%CI 0.94-1.26, p=0.23)
APT 2010;31:810-23

37. Clopidogrel-PPI Interactions:
Conclusions/ Recommendations
• Three randomized, prospective databases all indicate that there is no
clinically important adverse interaction between clopidogrel and PPIs.
• There had been a recommendation that PPIs be given as blanket gastric
protection to all patients at risk of gastric problems taking dual anti-
platelet therapy,
– No longer advisable, given the possibility of an interaction
• PPIs should be prescribed to patients taking clopidogrel only if they have
increased risk of GI bleeding or dyspeptic symptoms that are not
controlled with H2 antagonists.
• Pantoprazole would appears to be default PPI

38. Adverse Consequences of PPIs
• PPI-Induced Rebound Hypersecretion of Acid.
• PPI and Increased risk of pathological fracture.
• Clopidogrel -PPI Interaction.
• Gastric Acid Influences Gut Flora.
• PPIs in Cirrhotics with Ascites.
• Use of PPI and the Risk of pneumonia .

39. Gastric Acid Influences Gut Flora
• Gastric acid < pH 4.0 is bactericidal within 15 minutes for most species of
bacteria.
• Loss of the normal stomach acidity has been associated with colonization of
the normally sterile upper gastrointestinal tract
• Profound gastric acid suppression is associated with significant increase in
total colonic bacterial count of all genera and significant changes in the mix
of dominant flora
• Acid suppression increases the risk of enteric infections
Gastroenterology 2009;136(suppl1): W2001

40. PPI and Bacterial Overgrowth
• Investigators used glucose hydrogen breath tests to look for small
intestinal bacterial overgrowth in 450 consecutive patients enrolled in
3 groups:
– 200 GERD patients treated with PPIs for a median of 36 months;
– 200 patients with irritable bowel syndrome (IBS) who had not used PPIs
for at least 3 years; and
– 50 healthy controls who had not used PPIs for at least 10 years.
• Small intestinal bacterial overgrowth in 50% of the PPI users with
GERD, 24.5% of the IBS patients, and 6% of the healthy control
Clin Gastroenterol Hepatol 2010;8(6):504

41. PPI and Bacterial Overgrowth
Prevalence of SIBO
60%
50%
50%
40%
30% 25%
20%
10% 6%
0%
PPI IBS Control
Clin Gastroenterol Hepatol 2010;8(6):504

42. PPI and Bacterial Overgrowth
Prevalence of SIBO by Duration of Therapy
80% P<0.001
70%
60%
50%
40%
30%
20%
10%
0%
2-6 mo 7-12 mo 13-36 37-60 >60
Clin Gastroenterol Hepatol 2010;8(6):504

43. Systematic Review of the Risk of Enteric
Infection in Patients Taking Acid Suppression
• Systematic review to evaluate any association between acid
suppression and enteric infections.
• 12 papers evaluating 2,948 patients with Clostridium difficile were
included in the review.
• A total of 6 studies evaluated Salmonella, Campylobacter, and other
enteric infections in 11,280 patients.
• Conclusion: Acid suppression increases risk of enteric infections (OR
2.55, 95% CI 1.53–4.26).
Am . J Gastro. 2007 :102, 2047–2056

44. Risk for Nosocomial CD Infection Increased with Increasing
Level of Acid Suppression
• Secondary analysis of prospectively collected data from 101,796 patients who
were discharged from a tertiary care medical center during a 5-year period.
• Acid suppression treatment was the primary exposure of interest, classified
by intensity.
– no acid suppression,
– histamine2-receptor antagonist [H2RA] treatment,
– daily PPI use, and
– PPI use more often than daily)
• The risk for nosocomial C difficile infection increased with increasing level of
acid suppression.
• The association persisted after adjustment for comorbid
conditions, age, antibiotics, and propensity score–based likelihood of
receiving no acid suppression treatment
Arch Intern Med. 2010;170:747-748

45. Risk for Nosocomial CD Infection Increased with
Increasing Acid Suppression
1.60%
1.40%
1.40%
1.20%
1.00% 0.90%
0.80%
0.60%
0.60%
0.40% 0.30%
0.20%
0.00%
No Suppression H2RA PPI x 1 PPI> 1
Arch Intern Med. 2010;170:747-748

46. Role of PPI on Severity of CD
• Retrospectively review 295 pts diagnoses of C. difficile-associated
diarrhea over a 12-month period at a tertiary hospital.
• The records were examined to determine duration of diarrhea, need for
treatment escalation (such as ICU care), immunoglobulin
therapy, colectomy, death related to C. difficile diarrhea, and recurrence.
• 164 of the 295 patients received PPIs
• In a multivariate analysis, PPI therapy doubled the likelihood of severe
diarrheal disease (P=0.002).
• The only other independent predictor of severe illness was male sex.
Sravinthan A, et al "Role of proton pump inhibitors on severity of outcome of
Clostridium difficile associated disease" DDW 2010; Abstract T1782.

47. Acid Suppression and CD
• The use of acid-suppressive therapy, particularly proton pump inhibitors, is
associated with an increased risk of both hospital and community-acquired
C. difficile.
• The risk appears to be independent of antibiotic use and potentially
additive
• If a patient has been treated for C. difficile, strongly consider stopping
PPI, especially if there has been a recurrence
• Frequently reassess the indications for PPI, especially in elderly
hospitalized or institutionalized patients

48. Magnitude and Economic Impact of
Inappropriate Use of Stress Ulcer Prophylaxis
• The practice of SUP has become increasingly more common in general
medicine patients, with little to no evidence to support it
• Several studies have demonstrated the inappropriate use of acid-
suppressive therapy (AST) in general medicine (non-ICU) patients, based on
current recommendations.
• AST is commonly misused in hospitals, with as many as 71% of patients in
general medicine wards receiving some sort of AST without an appropriate
indication.
American Journal of Health-System Pharmacy. 2007;64(13):1396-1400

49. Inappropriate PPI Use In Hospitals
• Prospective evaluation of IV PPI use in two Midwest community-
based teaching hospitals .
• Identify all patients for whom an IV PPI was ordered
• Fifty-six percent of patients who received IV PPIs had no acceptable
indication for their use
• Of the 126 patients who were started on PPIs for the first time during
their hospital stay, 102 (81%) were discharged on a PPI.
AJG 2004; 99:1233 - 1237

50. Adverse Consequences of PPIs
• PPI-Induced Rebound Hypersecretion of Acid.
• PPI and Increased risk of pathological fracture.
• Clopidogrel -PPI Interaction.
• Gastric Acid Influences Gut Flora.
• PPIs in Cirrhotics with Ascites.
• Use of PPI and the Risk of pneumonia .

51. Beware of PPIs in Cirrhotics with
Ascites

52. Risk Factors for Spontaneous Bacterial
Peritonitis
• Ascitic fluid total protein concentration less than 1 g/dl
• Prior episode of SBP
• Variceal hemorrhage
• Bilirubin above 2.5 mg/dl
• Malnutrition
• PPI use

53. MECHANISMS OF BACTERIAL TRANSLOCATION (BT)
Mechanisms of Bacterial
Translocation and SBP
Anaerobic
Aerobic bacteria bacteria
Intestinal Bacterial Overgrowth
Dysmotility Delayed transit time
Nutrition?
Intestinal Permeability
Enterocytes
Mucosal Hypoxia, Acidosis
ATP depletion, NO, LPS, TNF
Impaired Immunity
Impaired Lamina
propria
chemotaxis, migration, phagocytic
function, complement deficiency, etc.

54. PPIs and SBP
• Retrospective case controlled study of culture proven SBP 2002-2007
• 70 SBP patients, age and Child’s class matched, 1:1 with cirrhotics
admitted for non-SBP indications
• Pre-hospital PPI use in 69% of SBP vs 31% non-SBP admissions
(p<0.0001)
• 47% of patients on PPI had no documented indication for PPI use
Am. J. Gastro 2009;104(5):1130

55. PPI and SBP
• 2631 cirrhotics with ascites followed from 2002-2007
• PPI use strongly associated with SBP and hepatorenal syndrome
– SBP on PPI 23.7% No PPI 5.7%
– HSR on PPI 15.3% No PPI 1.9%
• Number needed to treat for harm from PPI use: 5.5 for 1 episode of SBP
Hepatology 2008;48:324A

56. Adverse Consequences of PPIs
• PPI-Induced Rebound Hypersecretion of Acid.
• PPI and Increased risk of pathological fracture.
• Clopidogrel -PPI Interaction.
• Gastric Acid Influences Gut Flora.
• PPIs in Cirrhotics with Ascites.
• Use of PPI and the Risk of pneumonia .

57. Use of PPI and the Risk of Community-Acquired
Pneumonia
• case-control study of 88,066 community-acquired pnemonia and 799,886
controls
• PPI use >30 days NOT associated with increase risk of CAP
• Short-term PPI use increased relative risk!!
– 1-2 days OR 6.5 (CI 3.9-10.8)
– 7 days OR 3.8 (CI 2.6-5.4)
– 14 days OR 3.2 (2.4-4.2)
Ann Intern Med. 2008;148:319

58. Use of PPI and the Risk of Hospital-Acquired
Pneumonia
• Cohort study of 63,878 adult patients admitted for >72 hours over a 3 year
period.
• Assess PPI and H2RA use and hospital-acquired pneumonia
• 52% (32,922) of patients placed on acid suppressive therapy
• Corrected for age , sex, race, other medications, season, and co-morbidities
• Validated result via a propensity matched analysis (whatever that is)
JAMA 2009;301(20):2120-8

59. Use of PPI and the Risk of Hospital-Acquired
Pneumonia
• PPI use associated with increased risk of pneumonia (OR = 1.3)
• Trend towards similar effect with H2RA (OR =1.2) but not stasticially significant
• The association was stronger for aspiration than non-aspiration pneumonia
JAMA 2009;301(20):2120-8

60. Conclusions
• (FDA) recommends that “ concomitant use of omeprazole with clopidogril
should be discouraged. ”
• PPI are effective in management of GERD, acute acid peptic bleeding and
stress ulcer prophylaxis but carry significant infectious risks and possible
risk of pathologic fractures.
• Up to 30-50% of acid suppression therapy may be inappropriate in
outpatients and hospital inpatients.
• Consider H2RB in mild disease or small dose of ppi.
• Do not start high dose of ppi in dyspepsia or GERD.
• Consider low dose and short duration of ppi in cirrhotics.