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JOURNAL CLUB
DR VISHESH ROHATGI
Article
AUTHORS
• Ofke S. van Boxel, A.J.P.M. Smout, Peter D. Siersema
Department of Gastroenterology and Hepatology, University Medical Center
Utrecht , Utrecht , The Netherlands

• Martijn G.H. van Oijen
• Department of Gastroenterology and Hepatology, Radboud University
Nijmegen Medical Center , Nijmegen , The Netherlands

• Matthijs P. Hagenaars
• Achmea Health Insurance , Leiden , The Netherlands
Authors belong to the department of Gastroenterology
who are appropriate for the research topic

Although an author from the department of Cardiology

would have been beneficial
JOURNAL :
•
•
•
•
•
•

Am J Gastroenterol
November 2010
Volume 105
Issue 11
Page 2430–2436
Impact factor - 7.553
• Journal is appropriate for the research article
• Indexed journal
• Peer reviewed journal
TITLE :

Cardiovascular and gastrointestinal outcomes in
clopidogrel users on proton pump inhibitors: results of
a large Dutch cohort study
• Appropriate for the study
• Type of study – can be reframed

Reframed as
Cardiovascular and gastrointestinal outcomes in
clopidogrel users on proton pump inhibitors: results of
a retrospective study on a large Dutch cohort
ABSTRACT
• Brief and informative
• No keywords
INTRODUCTION
• Coronary artery disease is the worldwide number
one cause of mortality and a major cause of
disability: 30 % of all global deaths
• Inhibiting platelet aggregation has been shown to
decrease first and recurrent events in patients with
stroke or transient ischemic attacks, myocardial
infarction, unstable angina, or the need for vascular
bypass or angioplasty
Clopidogrel

ATP
OCH3

O

ADP

O
C

* HS

P2X1

N
Cl

15% active metabolite

Gq

CH3

N

HOOC

Ca2+ flux

O

S

Cl

“Rho”

G12

Shape change
Shape change

IP3

Gastro-intestinal absorption

PIP2

PLCβ

+ DAG

Ca2+
mobilization

PKC

αi

AC

MLCK-P

GP IIb/IIIa
receptor activation

βγ

PI3K

Granule secretion
PKB/Akt Rap1b

Hepatic CYP Biotransformation

85% inactive metabolites
(Esterases in blood)

GP IIb/IIIa receptor activation

Initiation of Platelet Aggregation
cAMP

VASP

Stabilization of Platelet Aggregation
VASP-P

cAMP

GP IIb/IIIa receptor activation

PGE1

Angiolillo DJ et al JACC 2007
Journal Club
Concurrent use of PPIs did not attenuate the clinical efficacy of
clopidogrel
• Owing to an increased incidence of gastrointestinal
(GI) bleeding events in patients using clopidogrel,
the American College of Cardiology published
guidelines recommending co-administration of a
proton pump inhibitor (PPI) as prophylaxis
Concomitant therapy of clopidogrel with PPIs was associated with
an increased risk of rehospitalization for acute coronary syndrome.
US Food and Drug Administration and
the European Medicines Agency
advice physicians to re-evaluate the
need for treatment with a PPI in
patients taking clopidogrel
• Brief and appropriate ,tells the need for the study

• Does not describe the cardiovascular outcomes
seen in various studies
METHODOLOGY
• Retrospective Cohort study
• Study aim: To investigate the association between

the co-administration of a proton pump inhibitor
(PPI) and clopidogrel, and the occurrence of
cardiovascular (CV) and gastrointestinal (GI) events
in a large cohort in the Netherland
• Ethics clearance, Informed consent – not taken
Source of
data

•2 health
Insurance
companies

- 4 million inhabitants, >18 years
- Gender, Age, Diagnosis, Prescriptions

-

Clopidogrel
and PPI use

-

•Retrospective Cohort
•18,139
-

Outcome

Inclusions: 2006-07, 1 year valid history
available
Minimum 1 prescription of clopidogrel (>= 7
daily dose)
New clopidogrel users
PPI use - 80 % overlap with clopidogrel use
or concurrent use within 7 days before or at
the time of a possible event
Exclusions: Use of clopidogrel in the 180
days before the index clopidogrel
prescription date

•Based on
ICD

- Complications occurring during
clopidogrel use or within 7 days
after ceasing it
• Primary endpoint:
• Composite of
• Myocardial infarction (ST-elevation and non-STelevation),
• Unstable angina pectoris
• Stroke and / or
• All-cause mortality

• Secondary endpoints:
• Individual components of the primary composite
endpoint.
• Occurrence of complicated and uncomplicated
peptic ulcer disease (PUD).
• Follow-up commenced at the start of the
clopidogrel index date.
• Endpoints in the study included
• The occurrence of outcome
• End of clopidogrel use or
• 31 December 2007.
• Goals & Objectives have been mentioned
• Inclusion and exclusion criteria is appropriate

• Channeling bias - allocation bias in which physicians
tend to prescribe PPIs to patients at a higher GI risk.
• Flow chart for methodology would have been better
STATISTICS
• The Pearson χ 2 and Student’s t –test were used to compare
clopidogrel users with and without concurrent PPI use.
• Survival and risk analysis - Kaplan – Meier method

• Groups were compared using - logrank test.
• Cyclo-oxygenase proportional hazard regression analysis was
used for multivariate analyses of entry variables independently
related to the endpoint.

• Level of statistical significance - 0.05
• Confidence interval – 95%
• All analyses were performed using SAS statistical software, version
9.1.
• Statistical tests are appropriate
• Power of study not mentioned
RESULTS
4 million
Dutch
Inhabitants
18,139
insured
individuals
5,734
(32%)

12,405
(68%)
Journal Club
WERE THE GROUPS SIMILAR AT
THE START OF THE TRIAL?
• No.
• There were substantial differences between the two
groups
• The concurrent PPI and clopidogrel group were

• Older
• Concomitant medications
• Medical co-morbidities (including heart failure, history of
unstable angina pectoris, chronic obstructive pulmonary
disease and renal failure)

• This is a serious threat to the internal validity of the study
WAS THE DEFINED PATIENTS
REPRESENTATIVE SAMPLE OF
OVERALL POPULATION?

• The number of subjects which formed the basis
of the study was substantial; 4 million Dutch
inhabitants
• However, as these were insured individuals
(data through insurance company database)
• Unclear.
Journal Club
Primary outcome:
• PPI + clopidogrel group: 754 (13%)
• Clopidogrel only group: 830 (7%)
• Adjusted hazard ratio (HR), PPI + clopidogrel group
vs clopidogrel-only group:
• HR = 1.75 (95% CI 1.58-1.94)
• Interpretation: the PPI + clopidogrel group were at 75%
higher risk of the primary outcome compared to the
clopidogrel-only group

• Mean time to the occurrence of cardiovascular
event was 75 days
Journal Club
• Other outcomes:
• Complicated peptic ulcer disease, PPI + clopidogrel
group vs clopidogrel-only group:
• HR = 4.76 (95% CI 1.18 – 19.17)
There was no significant difference between different types of PPI
in predicting the occurrence of cardiovascular events
DID ADJUSTMENT FOR
IMPORTANT PROGNOSTIC
FACTORS TAKE PLACE?
• Unclear, probably no.
• The authors provided results that were “adjusted for
possible confounders” but did not explain
which confounding factors. It is highly probable that
substantial residual confounding remains
• The group receiving PPIs also were also at increased risk
of PUD even with adjustment, contrary to data from
randomised controlled trials
• Inferior cardiovascular risk profile in clopidogrel and PPI group
DISCUSSION
• The occurrence of cardiovascular events in
this study (8.7 % ) was slightly higher than that
found by Juurlink et al. (5.7 % ), but
substantially lower when compared with those
of Ho et al. (26.5 % )
• Differences in the definition of the primary outcome,
as
• Juurlink et al. defined cases as patients who died or were
readmitted for myocardial infarction
• The definition of the primary outcome in this study and
that of Ho et al. also included unstable angina pectoris.
• O ’ Donoghue et al. found no association between
the concomitant use of clopidogrel and PPIs and
risk of cardiovascular death, myocardial infarction
or stroke.
• However, in that trial patients having (severe) comorbidities
were excluded.
• No difference between the various PPI types were
found predicting the possible outcome of
cardiovascular events.
• Pantoprazole primarily inhibits cytochrome P450 2C9 and
therefore causes less attenuation of the effect of
clopidogrel.
• Increased risk of an adverse event may also be attributable
to causes other than the possible competitive metabolic
effects on CYP2C19.
• GERD and cardiovascular disease have similar risk factors,
such as smoking and obesity. This could (partly) explain the
high prevalence of cardiovascular disease in the PPI group.
CONCLUSION
• New clopidogrel users on PPIs are at an increased
risk of cardiovascular and GI complications
compared with those who are not using a PPI.
• The inferior cardiovascular profile of clopidogrel
users on PPIs and the occurrence of channeling
bias may be important factors underlying this
observation
STUDY WEAKNESSES
(SUMMARY)
• Channeling bias
• Confounding Bias
• The source database used did not contain
information on important prognostic factors, e.g.,
smoking, lipoproteins and obesity
• the authors were unable to correct for these factors in
their multivariate analysis

• Over the counter medications cannot be
accounted
• Pharmacogenetics:

CYP2C19

Action

Europeans

Blacks

Asians

*1

Normal
metabolism

85%

82%

65%

*2

Poor
metabolizer

13-19%

10-25%

20-30%

*3

Poor
metabolizer

<1%

0-2%

5-13%

*17

Ultra rapid
metabolizer

18%

18%

4%
STUDY STRENGTHS
(SUMMARY)
• First European cohort study
• Patients were censored after adverse events
• Authors investigated the occurrence of GI events in this
cohort, which was not done in the other similar studies
• Large proportion (approximately 25%) of the Dutch
population was included in the database
• Recall bias not observed
EXTERNAL VALIDITY OF THE
STUDY – CLINICAL
IMPORTANCE
• No
• Older population; mean ages of 68.6 and 66.1 in the two
groups studied

• Approximately one third of patients had a history of
myocardial infarction
• Approximately one third of patients had a history of unstable
angina pectoris
• The majority of patients were receiving: anticoagulants,
NSAIDs, ACE inhibitors, or aspirin, or a combination of these
The evidence is too unreliable to be the
basis of a change in management
The risk, if any, of concurrent PPI in
clopidogrel should be a reminder that PPIs
should only be used if clinically indicated
Further studies needed.
BIAS AND CONFLICTS OF
INTERESTS
• Van Boxel OS (primary author) was funded by an
unrestricted grant from AstraZeneca
• Several other authors have served as consultants or
received grants from various pharmaceutical
companies including AstraZeneca
• The sponsors were not involved in the design,
conduct, analysis, interpretation, review or approval
of the study
REFERENCES
• Van Boxel OS, van Oijen MGH, Hagenaars MP, et al. Cardiovascular and
gastrointestinal outcomes in clopidogrel users on proton pump inhibitors:
results of a large Dutch cohort study. Am J Gastroenterol 2010; 105: 2430–
6
• 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.
• Kwok CS, Loke YK. Meta-analysis: the effects of proton pump inhibitors on
cardiovascular events and mortality in patients receiving
clopidogrel. Aliment Pharmacol Ther 2010; 31(8): 810–23
• NPS Prescribing practice review 45: proton pump inhibitors: step-down to
symptom control. National Prescribing Service Limited. 4 May 2009

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Journal Club

  • 3. AUTHORS • Ofke S. van Boxel, A.J.P.M. Smout, Peter D. Siersema Department of Gastroenterology and Hepatology, University Medical Center Utrecht , Utrecht , The Netherlands • Martijn G.H. van Oijen • Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center , Nijmegen , The Netherlands • Matthijs P. Hagenaars • Achmea Health Insurance , Leiden , The Netherlands
  • 4. Authors belong to the department of Gastroenterology who are appropriate for the research topic Although an author from the department of Cardiology would have been beneficial
  • 5. JOURNAL : • • • • • • Am J Gastroenterol November 2010 Volume 105 Issue 11 Page 2430–2436 Impact factor - 7.553
  • 6. • Journal is appropriate for the research article • Indexed journal • Peer reviewed journal
  • 7. TITLE : Cardiovascular and gastrointestinal outcomes in clopidogrel users on proton pump inhibitors: results of a large Dutch cohort study
  • 8. • Appropriate for the study • Type of study – can be reframed Reframed as Cardiovascular and gastrointestinal outcomes in clopidogrel users on proton pump inhibitors: results of a retrospective study on a large Dutch cohort
  • 10. • Brief and informative • No keywords
  • 12. • Coronary artery disease is the worldwide number one cause of mortality and a major cause of disability: 30 % of all global deaths • Inhibiting platelet aggregation has been shown to decrease first and recurrent events in patients with stroke or transient ischemic attacks, myocardial infarction, unstable angina, or the need for vascular bypass or angioplasty
  • 13. Clopidogrel ATP OCH3 O ADP O C * HS P2X1 N Cl 15% active metabolite Gq CH3 N HOOC Ca2+ flux O S Cl “Rho” G12 Shape change Shape change IP3 Gastro-intestinal absorption PIP2 PLCβ + DAG Ca2+ mobilization PKC αi AC MLCK-P GP IIb/IIIa receptor activation βγ PI3K Granule secretion PKB/Akt Rap1b Hepatic CYP Biotransformation 85% inactive metabolites (Esterases in blood) GP IIb/IIIa receptor activation Initiation of Platelet Aggregation cAMP VASP Stabilization of Platelet Aggregation VASP-P cAMP GP IIb/IIIa receptor activation PGE1 Angiolillo DJ et al JACC 2007
  • 15. Concurrent use of PPIs did not attenuate the clinical efficacy of clopidogrel
  • 16. • Owing to an increased incidence of gastrointestinal (GI) bleeding events in patients using clopidogrel, the American College of Cardiology published guidelines recommending co-administration of a proton pump inhibitor (PPI) as prophylaxis
  • 17. Concomitant therapy of clopidogrel with PPIs was associated with an increased risk of rehospitalization for acute coronary syndrome.
  • 18. US Food and Drug Administration and the European Medicines Agency advice physicians to re-evaluate the need for treatment with a PPI in patients taking clopidogrel
  • 19. • Brief and appropriate ,tells the need for the study • Does not describe the cardiovascular outcomes seen in various studies
  • 21. • Retrospective Cohort study • Study aim: To investigate the association between the co-administration of a proton pump inhibitor (PPI) and clopidogrel, and the occurrence of cardiovascular (CV) and gastrointestinal (GI) events in a large cohort in the Netherland • Ethics clearance, Informed consent – not taken
  • 22. Source of data •2 health Insurance companies - 4 million inhabitants, >18 years - Gender, Age, Diagnosis, Prescriptions - Clopidogrel and PPI use - •Retrospective Cohort •18,139 - Outcome Inclusions: 2006-07, 1 year valid history available Minimum 1 prescription of clopidogrel (>= 7 daily dose) New clopidogrel users PPI use - 80 % overlap with clopidogrel use or concurrent use within 7 days before or at the time of a possible event Exclusions: Use of clopidogrel in the 180 days before the index clopidogrel prescription date •Based on ICD - Complications occurring during clopidogrel use or within 7 days after ceasing it
  • 23. • Primary endpoint: • Composite of • Myocardial infarction (ST-elevation and non-STelevation), • Unstable angina pectoris • Stroke and / or • All-cause mortality • Secondary endpoints: • Individual components of the primary composite endpoint. • Occurrence of complicated and uncomplicated peptic ulcer disease (PUD).
  • 24. • Follow-up commenced at the start of the clopidogrel index date. • Endpoints in the study included • The occurrence of outcome • End of clopidogrel use or • 31 December 2007.
  • 25. • Goals & Objectives have been mentioned • Inclusion and exclusion criteria is appropriate • Channeling bias - allocation bias in which physicians tend to prescribe PPIs to patients at a higher GI risk. • Flow chart for methodology would have been better
  • 27. • The Pearson χ 2 and Student’s t –test were used to compare clopidogrel users with and without concurrent PPI use. • Survival and risk analysis - Kaplan – Meier method • Groups were compared using - logrank test. • Cyclo-oxygenase proportional hazard regression analysis was used for multivariate analyses of entry variables independently related to the endpoint. • Level of statistical significance - 0.05 • Confidence interval – 95% • All analyses were performed using SAS statistical software, version 9.1.
  • 28. • Statistical tests are appropriate • Power of study not mentioned
  • 32. WERE THE GROUPS SIMILAR AT THE START OF THE TRIAL? • No. • There were substantial differences between the two groups • The concurrent PPI and clopidogrel group were • Older • Concomitant medications • Medical co-morbidities (including heart failure, history of unstable angina pectoris, chronic obstructive pulmonary disease and renal failure) • This is a serious threat to the internal validity of the study
  • 33. WAS THE DEFINED PATIENTS REPRESENTATIVE SAMPLE OF OVERALL POPULATION? • The number of subjects which formed the basis of the study was substantial; 4 million Dutch inhabitants • However, as these were insured individuals (data through insurance company database) • Unclear.
  • 35. Primary outcome: • PPI + clopidogrel group: 754 (13%) • Clopidogrel only group: 830 (7%) • Adjusted hazard ratio (HR), PPI + clopidogrel group vs clopidogrel-only group: • HR = 1.75 (95% CI 1.58-1.94) • Interpretation: the PPI + clopidogrel group were at 75% higher risk of the primary outcome compared to the clopidogrel-only group • Mean time to the occurrence of cardiovascular event was 75 days
  • 37. • Other outcomes: • Complicated peptic ulcer disease, PPI + clopidogrel group vs clopidogrel-only group: • HR = 4.76 (95% CI 1.18 – 19.17)
  • 38. There was no significant difference between different types of PPI in predicting the occurrence of cardiovascular events
  • 39. DID ADJUSTMENT FOR IMPORTANT PROGNOSTIC FACTORS TAKE PLACE? • Unclear, probably no. • The authors provided results that were “adjusted for possible confounders” but did not explain which confounding factors. It is highly probable that substantial residual confounding remains • The group receiving PPIs also were also at increased risk of PUD even with adjustment, contrary to data from randomised controlled trials • Inferior cardiovascular risk profile in clopidogrel and PPI group
  • 41. • The occurrence of cardiovascular events in this study (8.7 % ) was slightly higher than that found by Juurlink et al. (5.7 % ), but substantially lower when compared with those of Ho et al. (26.5 % ) • Differences in the definition of the primary outcome, as • Juurlink et al. defined cases as patients who died or were readmitted for myocardial infarction • The definition of the primary outcome in this study and that of Ho et al. also included unstable angina pectoris.
  • 42. • O ’ Donoghue et al. found no association between the concomitant use of clopidogrel and PPIs and risk of cardiovascular death, myocardial infarction or stroke. • However, in that trial patients having (severe) comorbidities were excluded.
  • 43. • No difference between the various PPI types were found predicting the possible outcome of cardiovascular events. • Pantoprazole primarily inhibits cytochrome P450 2C9 and therefore causes less attenuation of the effect of clopidogrel. • Increased risk of an adverse event may also be attributable to causes other than the possible competitive metabolic effects on CYP2C19. • GERD and cardiovascular disease have similar risk factors, such as smoking and obesity. This could (partly) explain the high prevalence of cardiovascular disease in the PPI group.
  • 45. • New clopidogrel users on PPIs are at an increased risk of cardiovascular and GI complications compared with those who are not using a PPI. • The inferior cardiovascular profile of clopidogrel users on PPIs and the occurrence of channeling bias may be important factors underlying this observation
  • 46. STUDY WEAKNESSES (SUMMARY) • Channeling bias • Confounding Bias • The source database used did not contain information on important prognostic factors, e.g., smoking, lipoproteins and obesity • the authors were unable to correct for these factors in their multivariate analysis • Over the counter medications cannot be accounted
  • 48. STUDY STRENGTHS (SUMMARY) • First European cohort study • Patients were censored after adverse events • Authors investigated the occurrence of GI events in this cohort, which was not done in the other similar studies • Large proportion (approximately 25%) of the Dutch population was included in the database • Recall bias not observed
  • 49. EXTERNAL VALIDITY OF THE STUDY – CLINICAL IMPORTANCE • No • Older population; mean ages of 68.6 and 66.1 in the two groups studied • Approximately one third of patients had a history of myocardial infarction • Approximately one third of patients had a history of unstable angina pectoris • The majority of patients were receiving: anticoagulants, NSAIDs, ACE inhibitors, or aspirin, or a combination of these
  • 50. The evidence is too unreliable to be the basis of a change in management The risk, if any, of concurrent PPI in clopidogrel should be a reminder that PPIs should only be used if clinically indicated Further studies needed.
  • 51. BIAS AND CONFLICTS OF INTERESTS • Van Boxel OS (primary author) was funded by an unrestricted grant from AstraZeneca • Several other authors have served as consultants or received grants from various pharmaceutical companies including AstraZeneca • The sponsors were not involved in the design, conduct, analysis, interpretation, review or approval of the study
  • 52. REFERENCES • Van Boxel OS, van Oijen MGH, Hagenaars MP, et al. Cardiovascular and gastrointestinal outcomes in clopidogrel users on proton pump inhibitors: results of a large Dutch cohort study. Am J Gastroenterol 2010; 105: 2430– 6 • 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. • Kwok CS, Loke YK. Meta-analysis: the effects of proton pump inhibitors on cardiovascular events and mortality in patients receiving clopidogrel. Aliment Pharmacol Ther 2010; 31(8): 810–23 • NPS Prescribing practice review 45: proton pump inhibitors: step-down to symptom control. National Prescribing Service Limited. 4 May 2009