Journal Club
DR.ZEESHAN TARIQ
PGY 1
Clinical Scenario
• A 69 years old male is getting discharged from
the hospital where he was admitted for an
acute MI. In addition to other medications he
is also getting discharged on Aspirin and
Plavix. Should he get a PPI for GI side
effects???
What are the recommendations?
• Compared with ASA alone, the combination of
Clopidogrel and ASA significantly reduces the
incident of recurrent coronary events
following acute MI.
•
Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in
patients with acute coronary syndromes without ST-segment elevation. N Engl J
Med 2001;345:494-502
What are the recommendations?
• Recent guidelines published by the American Heart
Association, the American College of
Gastroenterology and the American College of
Cardiology advocate proton pump inhibitor therapy
for the majority of patients receiving ASA after
myocardial infarction, including all patients aged 60
years or older.
•
Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/AHA 2008 expert consensus document
on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the
American College of Cardiology Foundation Task Force on Clinical Expert Consensus
Documents. Circulation 2008;118:1894-909
Interaction between
Clopidogrel and PPI
Mechanism of Action of
Clopidogrel
• Clopidogrel is a prodrug that is converted in the
liver to an active thiol metabolite.
• Irreversibly inhibits the platelet P2Y12 adenosine
diphosphate receptor.
• Bioactivation mediated by hepatic cytochrome
P450 isoenzymes, 2C19
• Cytochrome P450 2C19 dramatically influences
the antiplatelet effect .
Effect of PPI on Cytochrome
P450 2C19
• Drugs that inhibit this enzyme may reduce
the antiplatelet effect of clopidogrel.
• Emerging evidence suggests that some PPI can
inhibit cytochrome P450 2C19.
• Influencing clopidogrel's pharmacokinetics.
Effect of PPI on Cytochrome P450 2C19
• Small DS, Farid NA, Payne CD, et al. Effects of the proton pump inhibitor
lansoprazole on the pharmacokinetics and pharmacodynamics of
prasugrel and clopidogrel. J Clin Pharmacol 2008;48:475-84
• Li XQ, Andersson TB, Ahlstrom M, et al. Comparison of inhibitory effects of
the proton pump-inhibiting drugs omeprazole, esomeprazole,
lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450
activities. Drug Metab Dispos 2004;32:821-7
• Gilard M, Arnaud B, Cornily JC, et al. Influence of omeprazole on the
antiplatelet action of clopidogrel associated with aspirin: the randomized,
double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll
Cardiol 2008;51:256-60
Published at www.cmaj.ca on Jan. 28, 2009
Methods
Setting
• A population-based nested case–control study
among Ontario residents aged 66 years or older who
were discharged from hospital between Apr. 1, 2002,
and Dec. 31, 2007, after treatment for acute MI.
• These individuals had universal access to hospital
care, physicians' services and prescription drug
coverage.
• The study was approved by the Research Ethics
Board of Sunnybrook Health Sciences Centre.
Data Sources
• Computerized prescription records of the Ontario
Public Drug Program.
• Hospital admissions using the Canadian Institute for
Health Information Discharge Abstract Database.
• Ontario Health Insurance Plan database.
Figure 1: Study design
Juurlink, D. N. et al. CMAJ 2009;180:713-718
Copyright ©2009 Canadian Medical Association or its licensors
Identification of Patients
• A cohort of patients aged 66 years or older who filled
a prescription for clopidogrel within 3 days after
hospital discharge following treatment for acute
myocardial infarction.
• The date of discharge from hospital served as the
date of cohort entry.
Exclusion Criteria
• Patients who had received clopidogrel, ticlopidine or
dipyridamole in the year before admission to
hospital.
• Patients in long-term care facilities.
• Those who received, within 90 days before or after
the index date,PPI to eradicate Helicobacter pylori.
Cases
• Patients who died or were readmitted for myocardial
infarction within 90 days after the initial hospital
discharge.
Controls
• Random sampling with replacement was used from
the same cohort of patients to identify the controls.
• These individuals were at risk but were not
readmitted because of myocardial infarction before
the index date.
• Controls were matched to cases on age , receipt of
PCI in hospital, date of hospital discharge and
predicted probability of short-term mortality.
Exposure to PPIs
• Current (within 30 days before the index date)
• Previous (31–90 days before the index date)
• Remote (91–180 days before the index date)
Statistical Analysis
• Conditional logistic regression was used to estimate
the odds ratio (OR) for the association between reinfarction and exposure to a PPI, using as the
reference group patients with no prescription for a
PPI in the previous year
Statistical Analysis
Adjustments were made for:
•
•
•
•
•
•
Age
Sex
Income quintile
Charlson comorbidity index
Length of stay in hospital
Medical conditions previously shown to correlate with short-term
mortality following acute myocardial infarction
• Other commonly used cardiovascular medications
• Other cytochrome P450 2C19 and cytochrome P450 3A4 inhibitors
or inducers
• Use of H2-receptor antagonists
Statistical Analysis
• Stratified analysis of the risk of recurrent MI
with pantoprazole or with other PPI.
• Pantoprazole does not inhibit cytochrome P450
2C19 and therefore should not interfere with the
metabolic activation of clopidogrel.
• Other PPI do inhibit cytochrome P450 2C19 and
can be expected to attenuate clopidogrel's
beneficial effects.
Table 1
Juurlink, D. N. et al. CMAJ 2009;180:713-718
Copyright ©2009 Canadian Medical Association or its licensors
Results
Results
• A significant association between readmission
because of MI and current use of a PPI (adjusted OR
1.27, 95% confidence interval [CI] 1.03–1.57) but not
with earlier use of these drugs.
• No association between recurrent myocardial
infarction and use of histamine H2-receptor
antagonists.
• No such association among patients not treated with
clopidogrel.
Results
• In the stratified analysis of the type of PPI used,
pantoprazole was not associated with recurrent MI
among patients receiving clopidogrel.
• In contrast, compared with no treatment, other PPI
were collectively associated with a 40% increase in
the risk of recurrent MI within 90 days of hospital
discharge (OR 1.40, 95% CI 1.10–1.77)
Figure 2: Association between acid-reducing therapies and adverse outcomes
Juurlink, D. N. et al. CMAJ 2009;180:713-718
Copyright ©2009 Canadian Medical Association or its licensors
Table 2
Juurlink, D. N. et al. CMAJ 2009;180:713-718
Copyright ©2009 Canadian Medical Association or its licensors
Interpretation
• In older patients taking clopidogrel following MI,
concomitant use of a PPI was associated with a
significantly increased short-term risk of reinfarction.
• It was estimated that 5% to 15% of early
readmissions because of MI among patients taking
clopidogrel could be the result of this drug
interaction.
Interpretation
• No association was found with more remote use of a
proton pump inhibitor or current use of histamine
H2-receptor antagonists.
• As predicted from its basic pharmacology,
pantoprazole displayed no such association in a
stratified analysis, whereas other proton pump
inhibitors did.
Interpretation
• Indiscriminate treatment with PPI could result
in thousands of additional cases of recurrent
MI each year.
• Potentially be avoided by preferentially using
pantoprazole in patients taking clopidogrel.
Cost Effectiveness
• With annual sales of US$7.3 billion in 2007,
clopidogrel is the drug with the second-largest
sales volume worldwide.
Top ten global products — 2007. IMS Midas Monthly. London (UK): IMS Health Inc.;
December 2007.
Conclusion of the Study
• Among patients taking clopidogrel following acute
MI, the concomitant use of a PPI that inhibits
cytochrome P450 2C19 was associated with an
increased risk of recurrent MI.
• Pending further data, concomitant treatment with
clopidogrel and PPI other than pantoprazole should
be minimized when possible.
• H2-receptor antagonist may be an alternative for
patients who require acid-lowering therapy.
Are the Results Valid?
1. Study Design
• Population-based nested case-control study
• RCTs can also demonstrate harm
• Reasons that we usually do not find RCTs in Harm
studies:
1. Unethical
2. Concern about rare and serious adverse effects
Did Investigators Demonstrate Similarity in All
known Determinants of Outcome?
Did They Adjust for Differences in the
Analysis?
1. No data on important cardiac risk factors such as
smoking status, blood pressure and lipoproteins.
2. Data sets included only drugs listed on the provincial
formulary, we can not identify use of nonprescription
medications, particularly over-the-counter ASA.
3. Although cases and controls were matched on
important predictors of outcome, some imbalance
was evident in their measured characteristics.
4. Patients who either developed reinfarction or were
prescribed PPI were sicker cohorts and with higher prevalence
of such distinctive factors as diabetes, renal failure, and heart
failure
5. Case group had a significantly higher percentage of
diabetic patients compared to the matched control
group (28.3% vs. 19.9%, p<0.001)
a. Diabetic patients demonstrate poorer outcome post MI
b. Diabetics have also been shown to have an attenuated
response to clopidogrel mediated platelet inhibition
6. The study did not account for ethnicity, potentially
relevant since genetic polymorphisms of cytochrome
P450 2C19 leading to insufficient enzymatic activity are
not equally distributed among individuals of white,
Asian and African descent
7. It is also possible that by analyzing the Pantoprazole
data separately a Type II error could have occurred.
Were Exposed Patients Equally Likely
to Be Identified in the Two Groups?
• Because some patients take proton pump
inhibitors intermittently, misclassification of
exposure status is possible.
Were the Outcomes Measured in the
Same Way in the Groups Being
Compared?
• Ascertainment of exposure is not an issue unless
effected by misclassification of exposure.
• It was not addressed whether all three of the
implicated proton pump inhibitors (omeprazole,
lansoprazole, and rabeprazole) equally
contributed to the reported odds ratio of 1.40.
( In vitro studies on Rabeprazole )
Was Follow-up Sufficiently Complete?
• 69 month study period
• Follow up not an issue in this study
How Strong is the Association Between
Exposure and Outcome?
• Given the flaws inherent in a case-control
design, higher odds ratios (e.g. >2) are
generally required before the results can be
seen as indicative of real risk.
•
Levine M, Waiter S, Lee H: et al. Users Guides to the Medical Literature IV. How to
use an article about harm. JAMA 1994;271:1615-1619.
FINAL CONCLUSION
• The study suffers from the limitation inherent in
any observational study: that exposed and
unexposed patients may differ in prognosis at
baseline.
• No amount of adjustment and sensitivity analyses
will overcome the impact of unmeasured
confounders, and thus these studies could still be
considered hypothesis-generating.
FINAL CONCLUSION
• Since the CURE trial showed a 20% relative risk reduction in
vascular events with clopidogrel:
1. Is it reasonable to expect to accurately detect a lessening of
that effect in observational studies, given the unavoidable
confounding?
2. Is it plausible that there is truly an odds ratio of 1.27 for risk
for reinfarction as seen in this study, which suggests that PPIs
would more than completely negate the benefits of
clopidogrel?
Fox KA, Mehta SR, Peters R, et al. Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical
revascularization for non-ST-elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic
Events (CURE) Trial. Circulation. 2004;110:1202-8.
FINAL CONCLUSION
• Despite the limitations, this careful study based on
a biologically plausible explanation should prompt
avoidance of unnecessary PPI use with clopidogrel
and further study of potentially important
interaction in future randomized trials.
• If a PPI is required, pantoprazole should be used
preferentially in patients who are also receiving
clopidogrel.
THANK YOU ALL