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Journal club - Cardiovascular outcomes in Clopidogrel and PPI users

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  2. 2. Article
  3. 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. 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. 5. JOURNAL : • • • • • • Am J Gastroenterol November 2010 Volume 105 Issue 11 Page 2430–2436 Impact factor - 7.553
  6. 6. • Journal is appropriate for the research article • Indexed journal • Peer reviewed journal
  7. 7. TITLE : Cardiovascular and gastrointestinal outcomes in clopidogrel users on proton pump inhibitors: results of a large Dutch cohort study
  8. 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. 9. ABSTRACT
  10. 10. • Brief and informative • No keywords
  12. 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. 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
  14. 14. Concurrent use of PPIs did not attenuate the clinical efficacy of clopidogrel
  15. 15. • 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
  16. 16. Concomitant therapy of clopidogrel with PPIs was associated with an increased risk of rehospitalization for acute coronary syndrome.
  17. 17. 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
  18. 18. • Brief and appropriate ,tells the need for the study • Does not describe the cardiovascular outcomes seen in various studies
  20. 20. • 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
  21. 21. 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
  22. 22. • 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).
  23. 23. • 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.
  24. 24. • 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
  25. 25. STATISTICS
  26. 26. • 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.
  27. 27. • Statistical tests are appropriate • Power of study not mentioned
  28. 28. RESULTS
  29. 29. 4 million Dutch Inhabitants 18,139 insured individuals 5,734 (32%) 12,405 (68%)
  30. 30. 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
  31. 31. 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.
  32. 32. 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
  33. 33. • Other outcomes: • Complicated peptic ulcer disease, PPI + clopidogrel group vs clopidogrel-only group: • HR = 4.76 (95% CI 1.18 – 19.17)
  34. 34. There was no significant difference between different types of PPI in predicting the occurrence of cardiovascular events
  35. 35. 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
  36. 36. DISCUSSION
  37. 37. • 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.
  38. 38. • 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.
  39. 39. • 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.
  40. 40. CONCLUSION
  41. 41. • 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
  42. 42. 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
  43. 43. • 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%
  44. 44. 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
  45. 45. 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
  46. 46. 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.
  47. 47. 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
  48. 48. 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