1. Cardiovascular Outcomes and Mortality in Patients Using Clopidogrel With Proton Pump Inhibitors After Percutaneous Coronary Intervention or Acute Coronary Syndrome Liu, Jian M.D. Peking University People’s Hospital

2. Basis of the Interaction  An inert prodrug, clopidogrel is metabolized first to a thiolactone intermediate and then to an active metabolite, R-130964, which binds irreversibly to ADP receptors on the platelet surface. These 2 steps are catalyzed by multiple cytochrome (CYP) enzymes, although CYP2C19 is important to both.  Loss-off-function polymorphisms in the gene encoding for CYP2C19 are associated with a reduced response to clopidogrel and an increased risk of adverse cardiovascular events. David N. Juurlink ， Circulation. 2009;120:2310-2312.

3. Basis of the Interaction  As with most CYP enzymes, the activity of CYP2C19 can be influenced by other drugs, and CYP2C19 inhibitors can theoretically attenuate the antiplatelet effect of clopidogrel by hindering its bioactivation.  By far the most relevant drugs in this class are the PPIs. Competitive inhibition of CYP2C19 by PPIs is the theoretical basis for the interaction between these drugs and clopidogrel. David N. Juurlink ， Circulation. 2009;120:2310-2312.

4. Evidence Supporting a Meaningful Interaction Platelet Aggregation Studies  The earliest evidence suggesting an interaction between PPIs and clopidogrel involved a study of 105 patients receiving aspirin and clopidogrel after high-risk angioplasty. The platelet reactivity of each patient was assessed by vasodilator stimulated phosphoprotein in phosphorylation, and those values were 25% higher in PPI-treated patients than in patients not treated with PPIs (P=0.007).  The attenuation of the effect of clopidogrel by PPIs was confirmed in a subsequent clinical trial of 124 patients receiving acetylsalicylic acid and clopidogrel after coronary stenting who were randomized to 7 days of omeprazole (20 mg daily) or placebo. David N. Juurlink ， Circulation. 2009;120:2310-2312.

5. Evidence Supporting a Meaningful Interaction Platelet Aggregation Studies  In a recently published prospective study of 201 patients undergoing elective percutaneous coronary intervention, nonresponse to clopidogrel was 6-fold more common among patients taking a PPI compared with patients not taking a PPI (P=0.012).  Other studies have observed consistent findings with omeprazole but not with esomeprazole or pantoprazole, although variability and uncertainty regarding PPI dose are features of some studies. David N. Juurlink ， Circulation. 2009;120:2310-2312.

6. Evidence Supporting a Meaningful Interaction Observational Studies  Along with the report of Rassen and colleagues, other observational studies have explored the clinical consequences of the PPI-clopidogrel interaction. These studies use different observational approaches in distinct data sets but reach similar conclusions: specifically, that use of a PPI in combination with clopidogrel is associated with a roughly 25% increase in the risk of various adverse events, including acute myocardial infarction, death, or rehospitalization for acute coronary syndrome.  In 2 published studies, no association was seen between PPI use and adverse events among patients not receiving clopidogrel.  Two other observational studies, presented to date only as abstracts, also suggest an increased risk of adverse events, although one of these is often mischaracterized as showing no evidence of interaction. David N. Juurlink ， Circulation. 2009;120:2310-2312.

7. Background  Recent studies have raised concerns about the reduced efficacy of clopidogrel when used concurrently with proton pump inhibitors (PPIs), but those studies may have overestimated the risk. Jeremy A. Rassen,et al. Circulation. 2009;120:2322-2329.

8. Methods  Authors studied the potential for increased risk of adverse cardiovascular events among users of clopidogrel with versus without concurrent use of PPIs in 3 large cohorts of patients 65 years of age, treated between 2001 and 2005.  All patients had undergone percutaneous coronary intervention or had been hospitalized for acute coronary syndrome in Pennsylvania, New Jersey, or British Columbia, and subsequently had initiated treatment with clopidogrel.  Authors recorded myocardial infarction hospitalization, death, and revascularization among PPI users and nonusers.  Authors entered 18 565 clopidogrel users into their analysis. Jeremy A. Rassen,et al. Circulation. 2009;120:2322-2329.

9. Primary End Points  Combined MI hospitalization and death. Jeremy A. Rassen,et al. Circulation. 2009;120:2322-2329.

10. Timeline of cohort entry and study follow-up

11. Jeremy A. Rassen,et al. Circulation. 2009;120:2322-2329. Patient flowchart for the 3 study cohorts.

12. Statistical Analysis  We estimated the rate ratio (RR) comparing the incidence of the study outcomes among clopidogrel users who also used PPIs and those who were PPI nonusers. Multivariate-adjusted RRs were estimated by the use of Cox proportional-hazards regression. In this “as-treated” analysis, patients were censored at the earliest of time of outcome event, at the end of 180 days, at 5 days after stopping clopidogrel, or at death.  Because information content differed from database to database, we applied a high-dimensional propensity score (hd-PS) to further improve confounding adjustment. Jeremy A. Rassen,et al. Circulation. 2009;120:2322-2329.

13. Statistical Analysis  As a first sensitivity analysis, we matched the cohorts using 1:1 greedy matching on the hd-PS. Additionally, we performed an analysis in which we reduced the maximum duration of follow-up to 90 days. We then performed a “PPI new user” analysis in which we excluded patients who had a current PPI prescription at the time of the index event or who had filled a PPI prescription in the previous 180days.  To assess whether individual PPIs differed with respect to aninteraction with clopidogrel, we performed agent-specific analyses among omeprazole and pantoprazole users. We also performed a cumulative-risk, intention-to-treat analysis in which the PPI exposure was carried forward through a fixed 90-day follow-up period.  Finally, we tested whether PPI users were at greater risk of death or MI regardless of their use of clopidogrel. In this analysis, we allowed clopidogrel nonusers to enter the cohorts, censored patients on the day a PPI nonuser started PPI therapy or 5 days after a PPI user stopped thePPI, and adjusted for clopidogrel use. Jeremy A. Rassen,et al. Circulation. 2009;120:2322-2329.

14. Characteristics of Study Participants From 3 North American Populations, 2001 to 2005.

15. Jeremy A. Rassen,et al. Circulation. 2009;120:2322-2329. Characteristics of Study Participants From 3 North American Populations, 2001 to 2005.

16. Jeremy A. Rassen,et al. Circulation. 2009;120:2322-2329. Characteristics of Study Participants From 3 North American Populations, 2001 to 2005.

17. Jeremy A. Rassen,et al. Circulation. 2009;120:2322-2329. Patient Follow-Up, Events, and Incidence Rates in Patients Who Underwent PCI or Had ACS and Had Recorded Use of Clopidogrel

18. Jeremy A. Rassen,et al. Circulation. 2009;120:2322-2329. Analysis of Effect of Exposure to Clopidogrel Plus PPIs Versus Clopidogrel Alone PCI or ACS

19. Jeremy A. Rassen,et al. Circulation. 2009;120:2322-2329. Matched Analysis of Outcomes and Exposure to Clopidogrel and PPIs Versus Clopidogrel Alone

20. Conclusions  Although point estimates indicated a slightly increased risk of myocardial infarction hospitalization or death in older patients initiating both clopidogrel and a PPI, we did not observe conclusive evidence of a clopidogrel-PPI interaction of major clinical relevance. Our data suggest that if this effect exists, it is unlikely to exceed a 20% risk increase. Jeremy A. Rassen,et al. Circulation. 2009;120:2322-2329.

21. Evidence Against a Meaningful Interaction  Two recent studies raise legitimate questions about the clinical relevance of the PPI-clopidogrel interaction.  The first was a posthoc analysis of a large clinical trial in which 6795 patients received clopidogrel after an acute coronary syndrome; a third of these patients also received a PPI in a nonrandomized fashion. In the primary analysis, PPI use was not associated with an increased risk of the composite outcome of cardiovascular death, myocardial infarction, or stroke (adjusted hazard ratio, 0.94; 95% confidence interval, 0.80 to 1.11). Importantly, this was not a randomized trial of the effect of PPIs on clopidogrel, and patients were generally younger and healthier than those in practice. David N. Juurlink ， Circulation. 2009;120:2310-2312.

22. Evidence Against a Meaningful Interaction  Further evidence against a meaningful interaction has emerged from the preliminary findings of the Clopidogrel and the Optimization of Gastrointestinal Events (COGENT) trial, in which 3627 patients taking aspirin after an acute coronary syndrome or stent implantation were randomized to clopidogrel alone or clopidogrel plus low-dose omeprazole. Omeprazole was associated with a reduction in the risk of composite gastrointestinal events but no increase in the risk of cardiovascular events, including secondary analyses of acute myocardial infarction or revascularization.  The lack of a clinically apparent interaction in the COGENT study may reflect the active treatment, CGT-2168, which contained 75 mg clopidogrel around a core of delayed-release omeprazole. By temporally separating the absorption of clopidogrel from that of omeprazole, the formulation may have effectively circumvented any competitive inhibition of CYP2C19 by omeprazole. David N. Juurlink ， Circulation. 2009;120:2310-2312.

23. Observations on the Magnitude of Effect  The first point worth making is that in most platelet aggregation studies, PPIs attenuate rather than abolish the effect of clopidogrel. In the seminal publication of Gilard et al the mean vasodilator-stimulated phosphoprotein platelet reactivity index decreased from 83.9% at baseline to 51.4% during treatment with omeprazole and clopidogrel. In other words, some pharmacodynamic effect of clopidogrel is clearly evident despite concomitant PPI use, presumably because alternate cytochrome P450 pathways allow formation of the active metabolite. David N. Juurlink ， Circulation. 2009;120:2310-2312.

24. Observations on the Magnitude of Effect  The magnitude of the benefit of clopidogrel also warrants mention. Depending on the indication, the benefit of clopidogrel when added to aspirin is generally very modest. In the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study, for example, composite event (cardiovascular death, nonfatal myocardial, or stroke) was averted for every 47 patients treated with clopidogrel. Although clinically important, this effect is small in absolute terms, and PPI- mediated attenuation of the antiplatelet effects of clopidogrel cannot cause harm in patients who were destined to receive no benefit from clopidogrel in the first place. David N. Juurlink ， Circulation. 2009;120:2310-2312.

25. Observations on the Magnitude of Effect  Finally, the pharmacokinetics of PPIs are a particularly important consideration. Competitive inhibition of CYP2C19 is anticipated only when PPI levels are sufficient to interfere with metabolism of other substrates, including clopidogrel. Most PPIs are rapidly eliminated, with t1/2 values ranging from 30 minutes to 2 hours; consequently, any inhibition of CYP2C19 is likely to be short-lived. From a practical perspective, this means that patients taking a PPI once daily should have no difficulty metabolizing CYP2C19 substrates, including clopidogrel, for most of the day. David N. Juurlink ， Circulation. 2009;120:2310-2312.

26. Dealing With the Interaction in Practice  Evaluate the necessity of PPI therapy. Although PPIs are necessary for some patients, many others take the drugs for dubious indications. In these patients, treatment with a histamine H2 antagonist or antacid may suffice. David N. Juurlink ， Circulation. 2009;120:2310-2312.

27. Dealing With the Interaction in Practice  Consider using pantoprazole when a PPI is indicated. This suggestion stems from the observation that pantoprazole is less likely than omeprazole to inhibit CYP2C19, does not appear to attenuate the pharmacodynamic response to clopidogrel, and displayed no association with recurrent myocardial infarction in a large observational study of patients receiving clopidogrel.  Other PPIs may also be relatively safe, but more data are needed. Lansoprazole is the most potent CYP2C19 inhibitor and is probably best avoided. David N. Juurlink ， Circulation. 2009;120:2310-2312.

28. Dealing With the Interaction in Practice  Stagger the dosing of medications. This is perhaps the most important strategy and exploits the rapid metabolism of clopidogrel and the transient nature of PPI-mediated CYP2C19 inhibition. When dual therapy is necessary, taking a PPI at least 4 hours after clopidogrel should minimize the risk of interaction. David N. Juurlink ， Circulation. 2009;120:2310-2312.

29. Thank you for your kindly attention!

30. Study Population  Auhtor studied the potential for increased risk of adverse cardiovascular events among users of clopidogrel with versus without concurrent use of PPIs in 3 large cohorts of patients 65 years of age, treated between 2001 and 2005. All patients had undergone percutaneous coronary intervention or had been hospitalized for acute coronary syndrome in Pennsylvania, New Jersey, or British Columbia, and subsequently had initiated treatment with clopidogrel. Jeremy A. Rassen,et al. Circulation. 2009;120:2322-2329.

31. Results  On a pooled basis, 2.6% of those who also initiated a PPI versus 2.1% of PPI nonusers had a myocardial infarction hospitalization; 1.5% versus 0.9% died; and 3.4% versus 3.1% underwent revascularization.  The propensity score–adjusted rate ratio for the primary end point of myocardial infarction or death was 1.22 (95% confidence interval, 0.99 to 1.51); for death, 1.20 (95% confidence interval, 0.84 to 1.70); and for revascularization, 0.97 (95% confidence interval, 0.79 to 1.21). Matched analyses generally yielded similar results. Jeremy A. Rassen,et al. Circulation. 2009;120:2322-2329.

32. Proton Pump Inhibitors and Clopidogrel Putting the Interaction in Perspective David N. Juurlink ， Circulation. 2009;120:2310-2312.