Transcript PPI Use - CCRMC Wiki

Rational Use of Proton Pump
Inhibitors: Part II
Adverse Events
Thomas B. Hargrave III, M.D.
September 18, 2009
Adverse Consequences of PPIs
• Rebound Hypersecretion of Acid
• Osteoporosis
• Enteric infections
– Food-borne bacterial infections
– C. Difficile
– Spontaneous Bacterial Peritonitis
• Pneumonia
– Community and Hospital-Acquired
• Interactions with Plavix??
Should PPI’s be First-Line
Treatment for Newly-Diagnosed
Dyspepsia or GERD?
No!!
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.
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
of 82% in the BAO and a 28% increase in the
MAO 15 days after discontinuation
• Presumed due to gastrin-induced increase in
parietal cell mass and EC cells.
• The duration of the rebound acidity was
unknown.
• The response in HP-positive patients is similar
but more highly variable
Gastroenterology 1999;116:239-47
Rebound Hypersecretion of Acid
on PPI’s:Basal Acid Output
6.8
3.0
3.0
1.9
Gastroenterology 1999;116:239-47
Rebound Hypersecretion of Acid
on PPI’s: Maximal Acid Output
41.7
32.4
3.0
40.4
6.8 29.8
3.0
1.9
Gastroenterology 1999;116:239-47
Rebound Hyper-Secretion on PPIs
Lasts at Least 2 Months
• 12 HP(-) and 20 HP(+) tested for basal, submaximal and maximal gastric acid secretion
before and on days 7,14,28,42,56, days after
stopping omeprazole 40 mg/day for 8 weeks
• HP eradication was completed on the last week
of omeprazole therapy.
• Rebound maximal (up 40%) and sub-maximal
acid ( up 43%) secretion was observed in HP(-)
subjects at 28 days, lasting at least 56 days
(16% and 31%)
Gastro 2004;126:980-87
37%
16%
43%
31%
Gastro 2004;126:980
PPI Therapy Induces AcidRelated Symptoms in
Asymptomatic Healthy
Volunteers After Withdrawal
of Rx
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 during the subsequent 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)
Temporal Changes in the Proportion of Subjects with
Heartburn, Acid Regurgitation or Dyspepsia.
P < .001
Gastroenterology 2009 ;Vol. 137, Issue 1, Pages 20-22
Implications of Rebound
Hypersecretion of Acid on PPI’s
• The greater the acid suppression, the
greater the rebound
– Acid rebound lasts for at least 2 months
– Parietal cells have a long half-life: possibly
up to 1 year in humans
• 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
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 Nexium 40 as initial therapy
Implications of Rebound
Hypersecretion of Acid on PPI’s
• Try different PPI’s before going to high-dose
PPI
• It is not necessary to test the efficacy of PPIs
over several months: 1-2 weeks adequate
– The maximal acid suppression occurs within 2-5
days
• Once symptoms have been controlled for
several months, try to back down to lowest
effective PPI dose periodically
Adverse Consequences of PPIs
• Rebound Hypersecretion of Acid
• Osteoporosis
• Enteric infections
– C. Difficile
– Food-borne bacterial infections
• Pneumonia
• Interactions with Plavix??
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 . AOR
– 1 year, 1.22 [95% C I, 1.15 - 1.30];
– 2 years, 1.41 [95% C I, 1.28 - 1.56];
– 3 years, 1.54 [95% C I, 1.37 - 1.73]; and
– 4 years, 1.59 [95% C I, 1.39 - 1.80]; (P < .001).
JAMA. 2006;296:2947-2953.
PPI and Hip Fractures
• 2008, 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
(OR 1.92 [1.16–3.18], P = 0.011)
• Hip fracture risk was increased after only 5 years of
continuous use
Targownik et al CMAJ 2008;179(4):319
Association Between Continuous Exposure to PPI and
Osteoporosis-related Fractures (Hip, Vertebra or Wrist)
Targownik, L. E. et al. CMAJ 2008;179:319-326
Relation Between Continuous Exposure
to PPI and Risk of Hip Fractures
Targownik, L. E. et al. CMAJ 2008;179:319-326
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 Hip Fractures
• Higher dosages for longer durations increased risk
in a linear fashion
• Effect was dose dependence
– 0.01-0.75 pills/day = OR 1.2
– 0.76-1.49 pills/day = OR 1.3
– >1.49 pills/day
= OR 1.42
• Minimal durational effect beyond 2 years (risk
approximately the same at 4 years as 2)
Gastroenterology. 2009:136(suppl 1):A–70.
Physiologic Mechanisms by Which use of
PPI Could Affect Bone Mineral Metabolism
• Studies have demonstrated that the inhibition of
proton pump activity in osteoclasts has direct
inhibitory effects on bone resorption and release
of bone calcium
• 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
Effects of Proton PPI on Calcium
Carbonate Absorption in Women
• Randomized, double-blind,
placebo-controlled, crossover
clinical trial
• Mean age 76 (68-69)
• 500 mg 45Ca-carbonate
• Fractional calcium absorption
for each subject (N = 18) after
1 week of placebo and
omeprazole 20 mg. The 25th
to 75th percentile bars and
means are depicted for each
treatment period. * P = 0.003.
AJM 2005;118(7):778-83
PPI’s and Osteoporosis
• Case-control studies do appear to confirm an
increased risk of osteoporosis-related fracture
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
• Impaired absorption of calcium is the most
likely mechanism
• Whether calcium/vitamin D supplementation
will offset this risk is unknown
Adverse Consequences of PPIs
• Rebound Hypersecretion of Acid
• Osteoporosis
• Enteric infections
– Food-borne bacterial infections
– C. Difficile Colitis
– Spontaneous Bacterial Peritonitis
• Pneumonia
• Interactions with Plavix??
Gastric Acid and Colonic Flora
• Gastric acid < pH 4.0 is bactericidal within
15 minutes for most species of bacteria
• Study of colonic flora profile of Wistat rats
treated with high-doses PPI under
pathogen- free conditions and asymptomatic
adults with and without atrophic gastritis
• Profound gastric acid suppression was
associated with significant increase in total
bacterial count of all genera and significant
changes in the mix of dominant flora
Gastroenterology 2009;136(suppl1): W2001
Therapy With Gastric Acidity Inhibitors Increases the
Risk of Acute Gastroenteritis and CommunityAcquired Pneumonia in Children
• The study was performed by expert pediatric
gastroenterologists from 4 pediatric gastroenterology
centers. Children (aged 4–36 months)
– 95 healthy controls and 91 GA-inhibitor users (47 on ranitidine
and 44 on omeprazole).
• In the GA inhibitor-treated group, the rate of subjects
presenting with acute gastroenteritis (p<0.001) and
community-acquired pneumonia (p= 0.02) was increased
when comparing the 4 months before and after
enrollment
• No differences were observed between H2RA and PPI
users in acute gastroenteritis and pneumonia incidence in
the previous 4 months and during the follow-up period
PEDIATRICS Vol. 117 No. 5 May 2006, pp. e817-e820
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 six studies evaluated Salmonella,
Campylobacter, and other enteric infections in
11,280 patients.
• Acid suppression increases risk of enteric
infections (OR 2.55, 95% CI 1.53–4.26).
Am . J Gastro. 2007 :102, 2047–2056
Characteristics
Age, median, mo (IQR)
Male, n (%)
Weight, median, kg (IQR)
Length, median, cm (IQR)
Patients presenting with
Acute gastroenteritis in the previous
4 mo, n (%)
Acute gastroenteritis in the follow-up
period, n (%)
Pneumonia in the previous 4 mo, n
(%)
Pneumonia in the follow-up period,
n (%)
a
Controls (n
= 95)
10 (8–15)
50 (53)
9.3 (8–10)
74 (70–78)
GA Inhibitors
(n = 91)
10 (8–16)
48 (53)
9.1 (8–15)
74 (70–80)
17 (18)
18 (20)
19 (20)
43 (47)a,b
1 (1)
3 (3)
2 (2)
11 (12)a,b
P < .05, GA inhibitor users versus control children.
b P < .05, 4 months before versus 4 months after the enrollment.
Studies of Risk Association of Enteric
Infections with PPI and H2RA Therapy.
The association was greater for PPI use (OR 3.33, 95% CI 1.84–
6.02) compared with H2RA use (OR 2.03, 95% CI 1.05–3.92).
Am . J Gastro. 2007 :102, 2047–2056
Risk Association of C. difficile with
PPI and H2RA Therapy.
1.40, 95% CI 0.85–2.29
OR 1.96, 95% CI 1.28–3.00
Am . J Gastro. (2007) :102, 2047–2056
PPI Use: Risk for Community
and Hospital Acquired CDAD
• Case-control study 277 hospital CDAD
PPI
Yes
No
Yes
Yes
Antibiotic
Yes
Yes
No
Yes
ChemoRx
No
Yes
Yes
Yes
OR (95%)
5
17
20
43
J Hosp. Infection 2003;54:243
PPI Use: Risk for Community
and Hospital Acquired CDAD
• Prospective study of PPI prescriptions in 138
hospitalized patients diagnosed with C. difficile
infection over a 4-month period.
• Sixty-four percent (88 of 138) of all patients who
developed C. difficile infections were on PPIs
• Ninety percent of the patients were on one of these
drugs for >4 weeks, 50% for >6 months and 35% for
>12 months.
• A valid indication for PPIs therapy was not apparent in
63% of the patients.
QJM 2008 101(6):445-448
SBP: Risk Factors
• 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
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%
– HSR on PPI 15.3%
No PPI
No PPI
5.7%
1.9%
• Number needed to treat for harm from PPI
use: 5.5 for 1 episode of SBP
Hepatology 2008;48:324A
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
Adverse Consequences of PPIs
• Rebound Hypersecretion of Acid
• Osteoporosis
• Enteric infections
– Food-borne bacterial infections
– C. Difficile Colitis
– Spontaneous Bacterial Peritonitis
• Pneumonia
• Interactions with Plavix??
Use of PPI and the Risk of
Community-Acquired Pneumonia
• Population-based case-control study using data
from the County of Funen, Denmark
• Cases (n = 7642) first-discharge diagnosis of
community-acquired pneumonia from a hospital
during 2000 -2004: 34 176 control subjects
• Adjusted odds ratio (OR) associating current use
of PPIs with community-acquired pneumonia was
1.5 (95% confidence interval [CI], 1.3-1.7).
• No dose-response association demonstrated
Arch Intern Med. 2007;167(9):950-955.
Use of PPI and the Risk of
Community-Acquired Pneumonia
Arch Intern Med. 2007;167(9):950-955.
Use of PPI and the Risk of
Community-Acquired Pneumonia
• Nested case-control study of 88,066 communityacquired 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 BIMDC 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
Use of PPI and the Risk of
Pneumonia??
• No biologically plausible explanation for
short-term PPI use and increased risk of
CAP.
• Likewise no clear explanation for PPI
use and non-aspiration pneumonia in
hospitalized patients
• The jury is still out.
Adverse Consequences of PPIs
• Rebound Hypersecretion of Acid
• Osteoporosis
• Enteric infections
– Food-borne bacterial infections
– C. Difficile Colitis
– Spontaneous Bacterial Peritonitis
• Pneumonia
• Interactions with Plavix??
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.
Clopidogrel-PPI Interactions Remain
“Observational” at This Time
• Two randomized databases ,not subject to
confounding, both suggest that there is no interaction
between clopidogrel and PPIs.
– CREDO trial, presented at the AHA 2008
– Randomized database TRITON trial
• There has been a recommendation that PPIs be given
as blanket gastric protection to patients at risk of
gastric problems taking dual antiplatelet therapy: no
longer advisable, given the possibility of an interaction
• PPIs should be prescribed to patients taking
clopidogrel only if they are having stomach problems
that are not controlled with H2 antagonists.
Hospital Indications for PPI Use
• Stress Ulcer Prophylaxis
• Acute Peptic Ulcer Bleeding
• Continuation of outpatient PPI for:
– GERD
– NSAID prophylaxis
– Dyspepsia
Stress Ulcer Prophylaxis
• In 1999, the American Society of HealthSystem Pharmacists (ASHP) published
guidelines on the use of stress ulcer
prophylaxis in medical, surgical,
respiratory, and pediatric ICU patients.[6]
• In recent years, this practice has become
increasingly more common in general
medicine patients, with little to no evidence
to support it.[7]
Algorithm for Stress Ulcer Prophylaxis
Is prophylaxis needed?
(Prophylaxis is recommended for ICU patients with one or more risk factors)
Risk Factors:
•
•
•
•
•
•
•
•
•
•
Mechanical ventilation
Coagulopathy
Acute renal failure
Acute hepatic failure
Sepsis syndrome
Hypotension
Severe head trauma
History of GI bleed
Burn (>20%–30% TBSA)
Major surgery
Am J Health Syst Pharm. 1999;56:347–379; Cook DJ et al. N Engl J Med. 1994;330:377–381; Cook DJ et
al. Crit Care Med. 1999;27:2812–2817.
Clinical Presentation of SRMD
• Multiple, superficial lesions
• Continuum: erosions
ulcer
• Generally located in acidproducing areas of stomach
• Affect superficial capillaries
• No prodromal symptoms
• Usually heal spontaneously with
clinical improvement of patient
Goldin GF, Peura DA. Gastrointest Endosc Clin North Am. 1996;6:505–526. Howden CW. Am J Health Syst
Pharm. 1999;56(Suppl 4):S5–S11. Spirt MJ. Acute Care of the Abdomen. Baltimore, Md: Williams & Wilkins;
1998.
Pathophysiology Of Stress Ulcers
Underlying
Systemic Illness
Hypovolemia
Hypotension
Cytokine
release
Mechanical
Ventilation
Medications
High PEEP
 Cardiac output
 Catecholamine
 Renin-angiotensinaldosterone system (RAAS)
Splanchnic
Hypoperfusion
Mucosal protective factors
 Aggressive factors / Permeability (acid, pepsin)
?Reperfusion effect
GI Mucosal
Injury
+/- Medications
Altered GI
Motility
Threshold for Preventing SRMD
Gastric pH
Physiologic Activity
3.5
Decreased incidence of stress-induced bleeding
4.5
Pepsin inactivation
=5
<5–7
99.9% acid neutralization
Alterations in coagulation and platelet aggregation
7
Potential decrease in incidence of rebleeding
8
Pepsin destruction
• Rationale for level of acid suppression based on in vitro and animal studies
Vorder Bruegge WF, et al. J Clin Gastroenterol. 1990;12:S35–S40.
Prevention
of SRMD
Is SUP Prophylaxis Effective?
• Assume:
– Risk factors: Mechanical ventilation, coagulopathy
– Prophylaxis with H2RAs reduces risk of clinically significant
bleeding by up to 50% compared with placebo*
High Risk
Low Risk
Incidence
3.7 (2.5 – 5.2)
0.1 (0.02 – 0.5)
NNT
30
900
*Cook DJ, et al. Am J Med. 1991;91:519–527.
NNT=number needed to treat
Cook DJ, et al. N Engl J Med. 1994;330:377–380.
Therapeutic Options
• Sucralfate
– Mechanism: Unknown; improved mucosal barrier
• H2RAs
– Mechanism: H2-receptor blockade (gastrin and ACh
receptors may still be stimulated)
– Limited pH effect (cannot reach neutrality)
– Tolerance may be factor
• PPI
SRMD Prophylaxis:
Choice of Agent
• H2RAs effective for SRMD (IV cimetidine is
only FDA approved) and should probably be
first-line agent.
• PPIs may be superior to H2RAs due to
enhanced potency and lack of tolerance; but
until better evidence, should probably be
secondary agents used when H2RAs fail or
cannot be given
Algorithm for Stress Ulcer Prophylaxis
Is prophylaxis needed?
(Prophylaxis is recommended for ICU patients with one or more risk factors)
Y
Gastroprotective
Sucralfate
(only via gastric access)
Antisecretory
H2RA
PPI
OR
N
Functional GI tract?
Y
N
Consider oral
therapy
Continue periodic assessment
Discontinue when no longer appropriate
IV therapy
Magnitude and Economic Impact of
Inappropriate Use of Stress Ulcer Prophylaxis
• In recent years, the practice of stress ulcer prophylaxis
has become increasingly more common in general
medicine patients, with little to no evidence to support
it
• Several trials 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
Inapropriate 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
Magnitude and economic impact of inappropriate
use of stress ulcer prophylaxis in non-ICU
hospitalized patients.
• Retrospective chart review of adult non-ICU
admissions to one family medicine and five general
internal medicine teaching services over a consecutive
4-month period
• Of the 1769 patients screened, 391 (22.1%) were
receiving AST for stress ulcer prophylaxis without an
indication as defined by the ASHP guidelines
– Fifty-four percent of these patients were sent home
with a prescription for AST
– Est. total annualized cost for inappropriate stress
ulcer prophylaxis in the entire cohort was over
$111,000.
Am J Gastroenterol. 2006; 101:2200-5
Conclusions
• PPI are effective in management of acute acid
peptic bleeding and stress ulcer prophylaxis
but carry significant infectious risks
• Gastric acid serves as an important barrier to
gastrointestinal pathogens
• Up to 50% of acid suppression therapy may be
inappropriate in hospital inpatients
• Question the indication for PPI’s on a regular
basis