Journal club - Cardiovascular outcomes in Clopidogrel and PPI users

1. JOURNAL CLUB
DR VISHESH ROHATGI

2. Article

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

9. ABSTRACT

10. • Brief and informative
• No keywords

11. INTRODUCTION

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

20. METHODOLOGY

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

26. STATISTICS

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

29. RESULTS

30. 4 million
Dutch
Inhabitants
18,139
insured
individuals
5,734
(32%)
12,405
(68%)

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

40. DISCUSSION

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.

44. CONCLUSION

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

47. • 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%

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