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10
Paper / Author/ Citation
Anti-hypertensive
medications and
cardiovascular events in
older adults with multiple
chronic conditions.
Design
Competing
risk analysis
with
propensity
score
matching
Tinetti ME et al. PLoS ONE.
2014;9(3):e90733.
11
14
Withdrawal versus
continuation of chronic
antipsychotic drugs for
behavioral and
psychological symptoms in
older people with
dementia.
Declercq T et al. Cochrane
Database Syst Rev
2013;3:CD007726.
Reducing inappropriate
polypharmacy: the process
of deprescribing.
Scott IA et al. JAMA Intern
Med. 2015;175(5):827-34.
Cochrane
review of 9
trials
including a
total of 606
subjects
Clinical
review/
Expert
opinion
Results
1,247 participants (25.1%) experienced
cardiovascular events; 837 participants
(16.9%) died. Of deaths, 430 (51.4%)
occurred in participants who experienced
cardiovascular events during follow-up.
Among those who experienced
cardiovascular events, the hazard ratio for
death was 0.65 [0.48–0.87] and 0.58 [0.42–
0.80] in the moderate and high intensity
antihypertensive therapy groups,
respectively.
Results showed that long-term
antipsychotics can be withdrawn from the
majority of older nursing home residents or
outpatients with dementia without
deterioration in behaviour. Withdrawal is not
recommended in patients with severe
symptoms or psychosis/agitation who have
responded well to therapy initially.
The paper supported that deprescribing is
feasible, safe and beneficial.
A systematic review of drug withdrawal trials
in patients 65 years and older showed that
the careful withdrawal of antihypertensives,
psychotropic drugs and benzodiazepines
with close monitoring was safe and
beneficial.
Cochrane reviews showed that multidisciplinary deprescribing efforts in elderly
patients led to improvements in drug
appropriateness.
Conclusion
Anti-hypertensive
treatment was associated
with reduced mortality but
not cardiovascular events.
Translation into Practice/Key Message
Determining the amount of benefit likely
to accrue from treatment of individual
conditions and ensuring that benefits
outweigh harms is particularly important
for older adults with multiple conditions.
Chronic antipsychotics can
be withdrawn without
behavioral decline in
people with dementia,
especially when symptoms
have largely resolved.
Withdrawal of antipsyhotics can be
incorporated into routine reviews for
selected patient subgroups.
Inappropriate drug use
and the consequent risk of
drug-induced harm is a
growing problem in elderly
patients.
Consider adopting the 5-step
deprescribing protocol:
1. Ascertain all drugs the patient is
taking and the reasons for each
2. Consider overall risk of drug-induced
harm in individual patients to
determine the intensity of the
deprescribing intervention
3. Assess each drug for its eligibility to
be discontinued
4. Prioritise drugs for discontinuation
5. Implement and monitor
discontinuation regimen
Clinicians should adopt a
systematic approach in
deprescribing drugs when
the harms outweigh the
benefits.
17
17
In-hospital data 2014,
National University
Hospital
In-hospital data 2011, Tan
Tock Seng Hospital
Point
prevalence
study
Point
estimate
study
42% of non-critically ill adult patients are on
PPIs; of which, 80.9% of them are on PPIs
without an appropriate indication
There is high prevalence
(80.9%) of inappropriate
PPI use.
44.3% of patients with inappropriate PPI use
has only one risk factor such as old age
(>60yo), on antiplatelets, steroids or NSAIDs.
A commonly documented
indication for
inappropriate PPI use is
prevention of GI bleeding
in patients with ≤1 risk
factors for GI bleeding.
A total of 477 out of 1025 inpatients were on
PPI therapy.
There seem to be
widespread and
inappropriate use of PPIs
in hospital practice, and
many of these patients
were continued on PPI
upon discharge
Only 239 (50.1%) patients had appropriate
indications for PPI use. There were 10 (2.1%)
patients who had borderline indications, and
228 (47.8%) patients were inappropriately
prescribed PPI.
More than one-quarter (30.7%) of the
inappropriate use was for prophylaxis of
drug-induced gastric mucosal damage in lowrisk patients.
Of the 228 patients with inappropriate
indications for PPI use, majority (178
patients, 78.1%) were discharged with PPI.
The widespread inappropriate use of PPI
may translate to increased risk of adverse
events associated with PPI and potentially
mounting healthcare costs for the elderly
with existing multiple morbidities
Inappropriate in-hospital PPI use
promotes excessive drug consumption in
the outpatient setting subsequently,
thereby unnecessarily increasing
polypharmacy, risk of adverse events and
medical expenses.
19
ACCF/ACG/AHA 2010
Expert Consensus
Document on the
Concomitant Use of Proton
Pump Inhibitors and
Thienopyridines: A Focused
Update of the
ACCF/ACG/AHA 2008
Expert Consensus
Document on Reducing the
Gastrointestinal Risks of
Antiplatelet Therapy and
NSAID Use
Abraham NS et al. Am J
Gastroenterol. 2010 Dec;
105(12):2533-49.
Expert
Consensus
Document
PPIs are recommended to reduce GI
bleeding among patients with a history
of upper GI bleeding. PPIs are
appropriate in patients with multiple risk
factors for GI bleeding who require
antiplatelet therapy.
Routine use of either a PPI or an H2RA is not
recommended for patients at lower risk of
upper GI bleeding, who have much less
potential to benefit from prophylactic
therapy.
Advanced age,
concomitant use of
warfarin, steroids, or
NSAIDs; or H. pylori
infection all raise the risk
of GI bleeding with
antiplatelet therapy. The
risk reduction with PPIs is
substantial in patients
with risk factors for GI
bleeding and may
outweigh any potential
reduction in the CV
efficacy of antiplatelet
treatment because of a
drug–drug interaction.
Patients without these
risk factors for GI bleeding
receive little if any
absolute risk reduction
from a PPI, and the
risk/benefit balance
would seem to favor use
of antiplatelet therapy
without concomitant PPI.
The reduction of GI
symptoms by PPIs (i.e.,
treatment of dyspepsia)
may also prevent patients
from discontinuing their
antiplatelet treatment
Prior upper GI bleeding is the strongest
and most consistent risk factor for GI
bleeding on antiplatelet therapy. Patients
with ACS and prior upper GI bleeding are
at substantial CV risk, so dual antiplatelet
therapy with concomitant use of a PPI
may provide the optimal balance of risk
and benefit
19,
20,
21
ACG Guidelines for
Prevention of NSAIDRelated Ulcer
Complications
Lanza FL et al. Am J
Gastroenterol 2009;
104:728–738;
Guideline
I. Patients requiring NSAID therapy who are
at high risk (e.g., prior ulcer bleeding or
multiple GI risk factors) should receive
alternative therapy, or if antiinflammatory treatment is absolutely
necessary, a COX-2 inhibitor, and cotherapy with misoprostol or high-dose
PPI. (Level of evidence 1. Strength of
recommendation B.)
II. Patients at moderate risk can be treated
with a COX-2 inhibitor alone or with a
traditional nonselective NSAID plus
misoprostol or a PPI. (Level of evidence 1.
Strength of recommendation B.)
III. Patients at low risk, i.e., no risk factors,
can be treated with a non-selective
NSAID. (Level of evidence 1. Strength of
recommendation A.)
I. Patients requiring
NSAID therapy who are
at high risk (e.g., prior
ulcer bleeding or
multiple GI risk factors)
should receive
alternative therapy, or
if anti-inflammatory
treatment is absolutely
necessary, a COX-2
inhibitor, and cotherapy with
misoprostol or highdose PPI. (Level of
evidence 1. Strength of
recommendation B.)
II. Patients at moderate
risk can be treated
with a COX-2 inhibitor
alone or with a
traditional
nonselective NSAID
plus misoprostol or a
PPI. (Level of evidence
1. Strength of
recommendation B.)
III. Patients at low risk,
i.e., no risk factors, can
be treated with a nonselective NSAID. (Level
of evidence 1. Strength
of recommendation A.)
Patients with high GI risk should avoid
NSAIDS. Addition of PPI has not been
proven to avoid complications or prevent
rebleeding.
Patients with low GI risk should not be
given PPI for GI prophylaxis with NSAIDS
20
The use of proton pump
inhibitors in treating and
preventing NSAID-induced
mucosal damage
Review
Six randomized controlled trials (RCTs) with
1,259 participants assessed the effect of PPIs
on the prevention of NSAID-induced upper
GI injury.
PPIs significantly reduced the risk of both
endoscopic duodenal ulcers (RR 0.20, 95% CI:
0.10 - 0.39) and gastric ulcers (RR 0.39, 95%
CI: 0.31 - 0.50) compared with placebo.
Scheiman JM et al. Arthritis
Research & Therapy 2013,
15(Suppl 3):S5
PPIs reduce the risk of
ulcerations due to NSAIDs
in RCTs where endoscopic
ulcers are used as the
primary endpoint.
However, endoscopy as a
surrogate has been a
controversial endpoint for
clinical outcomes.
Large RCT outcome trials
of PPI co-therapy have not
been performed.
RCTs in high-risk patients
demonstrate that PPI +
nonselective NSAID
provide similar rates of
symptomatic ulcer
recurrence rates as a COX2 selective inhibitor.
21
Combination of a cyclooxygenase-2 inhibitor and
a proton-pump inhibitor
for prevention of recurrent
ulcer bleeding in patients
at very high risk: a doubleblind, randomised trial.
Chan FK et al. Lancet. 2007
May 12;369(9573):1621-6
Singlecentre,
prospective,
randomised
, doubleblind trial
after
admission
to hospital
with uppergastrointest
inal
bleeding
Primary endpoint was
recurrent ulcer bleeding during treatment or
within 1 month of the end of treatment
Celecoxib + PPI were more effective than
celecoxib alone
for prevention of ulcer bleeding
in patients at high risk. The 13-month
cumulative incidence of the primary
endpoint was 0% in the combined-treatment
group and 12 (8.9%) in the controls (95% CI
difference, 4.1 to 13.7; p=0.0004). The
median follow-up was 13 months (range 0.413.0).
Patients at very high risk
for
recurrent ulcer bleeding
who need antiinflammatory analgesics
should receive
combination treatment
with a COX 2 inhibitor and
a PPI.
PPIs have also shown efficacy in reducing
the risk of ulcerations due to NSAID use
compared with NSAIDs alone in
randomized controlled trials (RCTs) where
endoscopic ulcers are used as the primary
endpoint, albeit a surrogate marker for
clinical ulcers and complications.
Large RCT outcome trials comparing
patients exposed to NSAIDs with and
without PPI co-therapy have not been
performed
Large RCT outcome trials of PPI cotherapy have not been performed
(mortality outcomes, obstruction etc.)
The ONLY study, and was single centered
in high risk patients.
Does not offer supportive evidence for
routine use for COX 2 Inhibitors + PPI for
routine prescription.
22
FDA Drug Safety
Communication:
Clostridium difficileassociated diarrhea can be
associated with stomach
acid drugs known as proton
pump inhibitors (PPIs)
FDA review
Most studies found that the risk of C. difficile
infection or disease, including CDAD, ranged
from 1.40 to 2.75 times higher among
patients with PPI exposure compared to
those without PPI exposure.
http://www.fda.gov/Drugs/
DrugSafety/ucm290510.ht
m (Accessed on June 13,
2015)
22
Risk of Clostridium difficile
infection with acid
suppressing drugs and
antibiotics: meta-analysis
Kwok CS et al. Am J
Gastroenterol. 2012
Jul;107(7):1011-9. doi:
10.1038/ajg.2012.108
23
Use of acid-suppressive
drugs and risk of
pneumonia: a systematic
review and meta-analysis.
Eom CS et al. CMAJ. 2011
Feb 22; 183(3):310-9. doi:
10.1503/cmaj.092129.
Epub 2010 Dec 20.
23 out of 28 observational studies showed a
higher risk of C. difficile infection including
CDAD, associated with PPI exposure
compared to no PPI exposure.
Metaanalysis of
30 casecontrol and
12 cohort
studies
Of 313 000 patients, PPI use was significantly
associated with an increased risk of both
incident and recurrent C. difficile infection
(odds ratio [OR] 1.74, 95% CI: 1.47-2.85 and
2.51, 95% CI: 1.16-5.44, respectively).
The weight of evidence
suggests a positive
association between the
use of PPIs and C. difficile
infection and disease,
including CDAD.
A diagnosis of CDAD should be considered
for PPI users with diarrhea that does not
improve.
A probable association
exists between PPI use and
C difficile infection, both
incident and recurrent.
PPI should be used with caution in
patients who are already at risk of C
difficile infections, such as those on
antibiotics.
Use of acid suppressive
drugs is associated with
increased risk of
pneumonia
Review for optimal use of PPIs
Patients should use the lowest dose and
shortest duration of PPI therapy
appropriate to the condition being
treated.
Concomitant use of PPI and antibiotics
conferred a greater risk (OR 1.96; 95% CI:
1.03-2.70) compared to that of PPI alone.
Systematic
review,
Metaanalysis of 5
case control,
3 cohort
studies, 23
RCTs
PPI use was associated with increased risk of
pneumonia (adjusted OR 1.27, 95% CI: 1.111.46)
Higher dose of PPI was more strongly
associated with increased risk of pneumonia
(adjusted OR 1.52, 95% CI: 1.31-1.76)
compared to usual dose (adjusted OR 1.37,
95% CI: 1.08-1.74).
Strength of association decreased with
longer duration of therapy before index date
(date of pneumonia diagnosis);
within 30 days (adjusted OR 3.95, 95% CI:
2.86-5.45) compared to between 30 and 180
days (adjusted OR 1.36, 95% CI: 1.05-1.78)
24
Use of acid-suppressive
drugs and risk of fracture: a
meta-analysis of
observational studies
Eom CS et al. Ann Fam
Med. 2011 May-Jun;
9(3):257-67. doi:
10.1370/afm.1243.
Metaanalysis of 5
casecontrols, 3
nested casecontrols, 3
cohort
studies
Significant positive association between PPI
and hip fracture risk (adjusted OR 1.31, 95%
CI: 1.11-1.54) and vertebral fracture risk
(adjusted OR 1.56, 95% CI: 1.31-1.85)
PPI use longer than a year
at any dose is associated
with moderate increase in
risk of fracture
Carefully consider decision for prescribing
PPIs for patients at elevated risk of
fracture, especially women more than 65
years old.
Significant increased risk of any fracture
(adjusted OR 1.30, 95% CI: 1.15-1.48) and hip
fracture (adjusted OR 1.34, 95% CI 1.09-1.66)
with PPI use for longer than a year
H2RAs are not associated
with any increase in
fracture risk
Consider lower drug doses as it may not
be necessary to treat patients to the point
of achlorhydria.
PPIs may cause
hypomagnesaemia if taken
for prolonged periods of
time (in most cases, longer
than one year).
Healthcare professionals should be aware
of the risk of hypomagnesaemia if they
are recommending use of PPIs for longer
periods of time.
Use of PPIs predisposes
patients to
hypomagnesaemia
irrespective of the
underlying morbidity
In susceptible patient groups receiving
PPI, magnesium levels should be
frequently monitored. These patients
should be closely observed for
complications resulting from
hypomagnesaemia, or switched from a
PPI to a H2 antagonist.
Increased risk of hip fracture for both high
dose (adjusted OR 1.53, 95% CI: 1.18-1.97)
and usual dose PPI (adjusted OR 1.42, 95% CI:
1.31-1.53)
25
FDA Drug Safety
Communication: Low
magnesium levels can be
associated with long-term
use of Proton Pump
Inhibitor drugs (PPIs)
FDA review
Hypomagnesaemia has been reported in
adult patients taking PPIs for at least three
months, but most cases occurred after a year
of treatment. Approximately one-quarter of
these cases required discontinuation of PPI
treatment in addition to magnesium
supplementation.
http://www.fda.gov/Drugs/
DrugSafety/ucm245011.ht
m (Accessed on 10 March
2015)
25
Impact of proton pump
inhibitor use on
magnesium
homoeostasis: a crosssectional study in a tertiary
emergency department.
Lindner G et al. Int J Clin
Pract. 2014 Nov;
68(11):1352-7. doi:
10.1111/ijcp.12469.
FDA's review focused on 38 cases in Adverse
Effects Reporting System and 23 cases
reported in the literature.
Crosssectional
analysis
In multivariable regression analyses adjusted
for PPIs, diuretics, renal function and the
Charlson comorbidity index score, the
association between use of PPIs and risk for
hypomagnesaemia remained significant (OR
2.10; 95% CI: 1.54-2.85).
26
Association of Proton
Pump Inhibitors (PPIs) With
Risk of Dementia :A
Pharmacoepidemiological
Claims Data Analysis
Prospective
cohort
study
Observational data from 2004 -2011, were
obtained from the largest German statutory
health insurer.
Population
based
cohort
study
A total of 73679 participants 75 years or
older and free of dementia at baseline were
analyzed. This study found that regular PPI
users had a significantly increased risk of
incident dementia compared to non-users
(HR 1.44; 95% CI: 1.36-1.52)
10482 participants in the atherosclerosis risk
in communities with an estimate GFR or at
least 60 ml/min were followed from 1 Feb
1996 to 31 Dec 2011 over a 15 year period.
Willy Gomm et al. JAMA
Neurol.2016;73(4):410-41
27
Proton Pump Inhibitor Use
and the Risk of Chronic
Kidney Disease.
Lazarus B et al .JAMA
Intern Med. 2016
Feb;176(2):238-46.
Compared with non users, PPI users were
associated with incident CKD.
Unadjusted analysis (HR 1.45; 95% CI: 1.111.90)
Adjusted analysis (adjusted for demographic,
socioeconomic and clinical variables) (HR,
1.50; 95% CI: 1.14-1.96)
Twice daily PPI dosing was associated with
higher risk (adjusted HR, 1.46; 95% CI: 1.281.67) than once daily dosing (adjusted HR,
1.15; 95% CI: 1.09-1.21).
Randomized clinical trials
will be needed to examine
this association between
dementia and regular PPI
use.
Restricted and judicious prescribing of
PPIs may help prevent the development
of dementia.
Proton pump inhibitor use
is associated with a higher
risk of incident CKD.
Future research should
evaluate whether limiting
PPI use reduces the
incidence of CKD.
Although this study does not prove
causality, it certainly adds to the
overwhelming evidence that prolonged
PPI use can lead to side effects, and in this
case an increase in incident CKD.
Judicious use of PPI could possibly help
reduce development of CKD in susceptible
populations