proton pump inhibitors

Adverse Consequences of PPIs

Dr NazimLiaquat national hospital

karachi


• 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 .

Should PPI’s be First-Line Treatment for Newly-Diagnosed Dyspepsia or GERD?

No!!

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.

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

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

Rebound Hypersecretion of Acid on PPI’s:Basal Acid Output


6.8

3.0 3.0 1.9

Rebound Hypersecretion of Acid on PPI’s: Maximal Acid Output


6.8

3.0 3.0 1.9

32.440.441.7

29.8

PPI Therapy Induces Acid-Related Symptoms in Previously Asymptomatic Healthy

Volunteers

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)

PPI-Induced Dyspepsia: Statistically Significant but Relatively Mild

7= Very Bothersome Symptoms1= No Bothersome Symptoms

Gastroenterology 2009 ;Vol. 137, Issue 1, Pages 20-22

P <0.001

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


• 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.


• 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 .



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

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

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

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%

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.

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.

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

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

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.

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

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

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.

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.



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

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.

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.

• 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.

Clopidogrel-PPI Interactions Remain Only Observational at This Time

1) Am. Heart Journal 2009;51:258 (pantoprazole/eosmeprazole/clopidogrel)

2) J. Clinical Pharm 2008;48:475 (lansoprazole/prasugrel/clopidogrel)

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

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

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

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



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

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

PPI and Bacterial Overgrowth

0%

10%

20%

30%

40%

50%

60%

PPI IBS Control


Prevalence of SIBO

50%

25%

6%

0%

10%

20%

30%

40%

50%

60%

70%

80%

2-6 mo 7-12 mo 13-36 37-60 >60

PPI and Bacterial Overgrowth


Prevalence of SIBO by Duration of Therapy

P<0.001

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

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

Risk for Nosocomial CD Infection Increased with Increasing Acid Suppression

0.30%

0.60%

0.90%

1.40%

0.00%

0.20%

0.40%

0.60%

0.80%

1.00%

1.20%

1.40%

1.60%

No Suppression H2RA PPI x 1 PPI> 1

Arch Intern Med. 2010;170:747-748

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.

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

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

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



Beware of PPIs in Cirrhotics with Ascites

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

MECHANISMS OF BACTERIAL TRANSLOCATION (BT)

Mechanisms of Bacterial Translocation and SBP

Mechanisms of Bacterial Translocation and SBP

Intestinal Bacterial OvergrowthDysmotility Delayed transit timeNutrition?

Intestinal PermeabilityMucosal Hypoxia, AcidosisATP depletion, NO, LPS, TNF

Impaired ImmunityImpaired chemotaxis, migration, phagocytic function, complement deficiency, etc.

Aerobic bacteriaAnaerobic bacteria

Lamina propria

Enterocytes

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

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



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

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

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

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.

Health & Medicine

proton pump inhibitors