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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. A clinically relevant interaction between clopidogrel and PPI?
  5. Pharmacological basis of a clopidogrel-PPI interaction
  6. Clinical evidence – evidence of an interaction
  7. Clinical evidence – evidence against a clinically relevant interaction
  8. Does bleeding have an impact?
  9. Further controversy for PPIs?
  10. Conclusion
  11. Acknowledgement
  12. References

Aliment Pharmacol Ther 2011; 33: 758–767

Summary

Background  The treatment of acute coronary syndromes involves a combination of antiplatelet therapies. Proton pump inhibitors are frequently recommended for patients receiving clopidogrel in addition to aspirin, to minimise the risk of bleeding. Several studies have shown that proton pump inhibitors can affect the platelet inhibitory effects of clopidogrel. However, the data on whether this has an effect on clinical outcomes are conflicting and a definitive answer is still awaited.

Aim  To provide an overview of the evidence for the pharmacological interaction between proton pump inhibitors and clopidogrel and to discuss whether this interaction translates into adverse clinical outcomes. Despite recent developments, clear consensus is lacking.

Methods  A search of the published literature combined with the authors’ knowledge of the field.

Results  There is evidence to show that proton pump inhibitors can influence the pharmacodynamics of clopidogrel, but the data suggesting clinical effects are weak and conflicting. Supporting a clinically important interaction are four retrospective studies including over 11 000 patients prescribed both clopidogrel and a proton pump inhibitor. Evidence against a clinically important interaction is derived from over 18 000 patients from seven studies, including the only prospective trial to examine the potential interaction. Confounding variables are relevant and prospective clinical evidence is lacking.

Conclusions  Proton pump inhibitors offer clear protection and the concern over clinically relevant interactions with clopidogrel is biologically plausible, but not yet proven.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. A clinically relevant interaction between clopidogrel and PPI?
  5. Pharmacological basis of a clopidogrel-PPI interaction
  6. Clinical evidence – evidence of an interaction
  7. Clinical evidence – evidence against a clinically relevant interaction
  8. Does bleeding have an impact?
  9. Further controversy for PPIs?
  10. Conclusion
  11. Acknowledgement
  12. References

The treatment of Acute Coronary Syndromes (ACS) with dual antiplatelet therapy (i.e. aspirin plus clopidogrel) reduces recurrent cardiovascular events.1 However, with the advent of dual antiplatelet therapy comes an inevitable increased risk of bleeding as a side effect. With regard to gastrointestinal bleeding, this occurs in 1.3–2.7% of patients treated for ACS with aspirin, clopidogrel and enoxaparin.2, 3 Even patients on low-dose aspirin have an incidence of gastrointestinal peptic ulcer bleeding of 0.5% per year.4

In the context of ACS, gastrointestinal bleeding should be regarded as a serious condition that is independently associated with increases in both mortality and ischaemic complications.3 Co-prescription with a proton pump inhibitor (PPI) could significantly reduce the risk of bleeding.2 As a result, the near-universal use of a PPI is recommended to reduce the incidence of gastrointestinal bleeding in patients taking clopidogrel, most of whom are taking aspirin in addition.5 In addition to these guidelines, gastroenterologists frequently prescribe PPIs to prevent drug-induced upper gastrointestinal bleeding, supported by a Cochrane meta-analysis of PPI use to prevent NSAID-induced peptic ulcers.6

The aim of this review article was to provide an overview of the evidence for the pharmacological interaction between proton pump inhibitors and clopidogrel and its impact on clinical outcomes.

A clinically relevant interaction between clopidogrel and PPI?

  1. Top of page
  2. Abstract
  3. Introduction
  4. A clinically relevant interaction between clopidogrel and PPI?
  5. Pharmacological basis of a clopidogrel-PPI interaction
  6. Clinical evidence – evidence of an interaction
  7. Clinical evidence – evidence against a clinically relevant interaction
  8. Does bleeding have an impact?
  9. Further controversy for PPIs?
  10. Conclusion
  11. Acknowledgement
  12. References

The possibility of a clinically relevant interaction between clopidogrel and PPIs was first noted in 2008.7 This came on the background of an observational study from 2006, which found clopidogrel activity on platelets to be diminished in patients receiving PPI treatment.8

In response to studies suggesting that PPIs could diminish the effects of clopidogrel,9 the European Medicines Agency (EMEA) released a statement in May 2009,10 and the FDA also in 2009,11 warning of the potential interaction. Since then, clinicians have faced difficult and uncertain decisions regarding patient care. Various suggestions have been made for prescribing, such as evening dosing of a PPI to ensure a 12-h gap after a morning clopidogrel dose or the preferential use of pantoprazole.12 However, there appears to be little evidence to back these approaches. Any potential interaction between PPIs and clopidogrel needs to be clarified due to the increased risk of poor cardiovascular outcomes in potentially large numbers of patients.

Pharmacological basis of a clopidogrel-PPI interaction

  1. Top of page
  2. Abstract
  3. Introduction
  4. A clinically relevant interaction between clopidogrel and PPI?
  5. Pharmacological basis of a clopidogrel-PPI interaction
  6. Clinical evidence – evidence of an interaction
  7. Clinical evidence – evidence against a clinically relevant interaction
  8. Does bleeding have an impact?
  9. Further controversy for PPIs?
  10. Conclusion
  11. Acknowledgement
  12. References

Clopidogrel, a thienopyridine, is a prodrug which is metabolised in the liver via the cytochrome p450 (mainly CYP2C19) pathway to its active metabolite.13, 14 This compound targets and irreversibly inhibits the ADP P2Y12 receptor on circulating platelets, which prevents platelet aggregation. CYP2C19, which has a major role in the metabolism of clopidogrel, also metabolises the PPIs. Reduced conversion of clopidogrel to its active metabolite by the CYP450 system could be in part responsible for clopidogrel resistance15 and clopidogrel resistance is associated with adverse cardiovascular events.16 In addition to this, reduced intestinal absorption may play a role.15, 17

As mentioned above, clopidogrel is metabolised to its active metabolite by various cytochrome p450 enzymes, the key enzyme being CYP2C19.18, 19 Approximately 15% of the absorbed dose is converted to an active thiol metabolite, R-130964.20 The extent of platelet inhibition by clopidogrel varies between patients and reduced platelet inhibition is associated with poor cardiovascular outcomes.21–24

The activity of CYP2C19 can have a profound effect on the conversion of clopidogrel to its active metabolite. In healthy volunteers, those with CYP2C19 loss-of-function polymorphisms have impaired responsiveness to clopidogrel demonstrated by platelet aggregation and higher vasodilator-stimulated phosphoprotein (VASP) phosphorylation.13 It is thought that approximately 90% cases of poor metabolism is accounted for by the CYP2C19*2 allele.13, 25 In patients suffering myocardial infarction who received clopidogrel, those with CYP2C19 loss-of-function alleles have lower levels of the active metabolite of clopidogrel and a higher rate of subsequent cardiovascular events than those who do not have.17, 26–28 The common polymorphisms of CYP2C19 are present in approximately 3–30% of whites, 3–40% of blacks and 12–100% of various Asian populations.29, 30 In the study by Mega et al., 30% of healthy recruits had a loss-of-function allele for CYP2C19, which resulted in a relative reduction of 32.4% of the active metabolite of clopidogrel compared to noncarriers, and a 9% reduction in platelet aggregation.26 This resulted in an increase in death from cardiovascular cause, myocardial infarction and stroke.26 These effects are most notable in patients undergoing percutaneous coronary intervention with a HR of 3.58 (CI 1.71–7.51) for recurrent cardiovascular events.17 The CYP2C19 loss-of-function polymorphism is also associated with stent thrombosis with rates as high as a factor of 3 as compared with noncarriers.26, 31 Thus, any medication that reduces the conversion of clopidogrel to its active metabolite may reduce the platelet inhibition caused by clopidogrel.

Indeed, clopidogrel has been at the centre of controversy previously, with a reported possible interaction with atorvastatin, which competes for CYP3A4 (see Figure 1).32 Atorvastatin was found to attenuate the antiplatelet activity of clopidogrel in a dose-dependent manner in vitro.33 However, this observation has since been refuted and was not found to be associated with worse clinical outcomes.34–37

image

Figure 1.  Metabolism of clopidogrel. Following intestinal absorption, clopidogrel undergoes a two-step process to form its active metabolite. These processes are dependent on various cytochrome P450 (CYP450) enzymes.

Download figure to PowerPoint

The potential mechanism of interaction lies in the fact that both clopidogrel and the PPIs, in varying degrees, are both metabolised by the same cytochrome p450 enzyme – CYP2C19.13, 38 PPIs have the potential to inhibit competitively the metabolism of clopidogrel to its active metabolite. This leads to reduced circulating concentrations of the active metabolite.

The earliest evidence of a pharmacological interaction between clopidogrel and PPIs is from platelet aggregation studies. One study of 105 patients found PPI users (omeprazole, = 24) had higher VASP phosphorylation levels than none PPI users and suggested an interaction.8 In the OCLA study,7 which was a double-blind placebo-controlled trial, measurements of VASP expressed as platelet reactivity index (PRI) were measured in 124 patients undergoing coronary stent insertion. Patients receiving aspirin and clopidogrel were treated with omeprazole 20 mg or placebo for 7 days. By day seven, 26.7% of placebo-treated patients and 60.9% of omeprazole-treated patients were classified as poor responders to clopidogrel (PRI > 50%) indicating a significantly decreased effect of clopidogrel in the presence of a PPI.

As all PPIs are metabolised by CYP2C19 to varying degrees and share the ability to inhibit CYP2C19, do all PPIs have negative effects on clopidogrel? Several studies have tried to answer this question.

One small study showed that lansoprazole 30 mg given in addition to clopidogrel 300 mg diminished the inhibition of platelet aggregation when compared with clopidogrel alone.39 However, no effect was seen with regard to PPIs interacting with prasugrel. Another study found that the inhibitory profiles for all PPIs were similar, but with some heterogenicity; for example, lansoprazole is the most potent in vitro inhibitor of CYP2C19 with pantoprazole exhibiting more of an effect on CYP2C9.40

Although lansoprazole has been shown to be the most potent inhibitor of CYP2C19,40 other evidence reports that in patients prescribed clopidogrel, concomitant treatment with lansoprazole does not alter the pharmacokinetics or pharmacodynamics of clopidogrel.39

Data from 1000 patients on clopidogrel undergoing angiography examined the effect the various PPIs had on platelet aggregation.41 Platelet aggregation was significantly greater in patients prescribed omeprazole (= 64) than in those without PPI therapy. It was observed that platelet aggregation was similar in patients taking clopidogrel and pantoprazole (= 162), esomeprazole (= 42) or no PPI.

Another study found that omeprazole (= 3132) was associated with adverse cardiovascular outcomes (e.g. death or rehospitalisation for ACS).42 In the same study, similar results were found with rabeprazole (= 151); however, small numbers weaken this finding. Results from 300 patients looking at clopidogrel responsiveness by VASP phosphorylation and platelet aggregometry, in patients with coronary artery disease undergoing PCI found no difference between esomeprazole (= 74) and pantoprazole (= 152), and indeed no suggestion that either was associated with impaired response to clopidogrel.43 Unfortunately, omeprazole was not included in the analysis.

Other evidence suggests that pantoprazole has less of a deleterious effect on clopidogrel than omeprazole.44 PRI VASP was measured in 104 patients undergoing PCI who were randomised to either omeprazole (= 52) or pantoprazole (= 52) in addition to both aspirin and clopidogrel. After 1 month, patients receiving pantoprazole had significantly better platelet response to clopidogrel as assessed with the PRI VASP (36% vs. 48%).

These observations have led authors to put forward the case that pantoprazole is the preferred PPI in the context of concomitant clopidogrel use.45–47 Some data suggest that pantoprazole is less likely to inhibit CYP2C19 than omeprazole and does not attenuate the pharmacodynamic response to clopidogrel.40, 43, 44, 47 However, recently updated guidelines suggest that no one PPI should be used preferentially over another. This is due to the lack of head-to-head trials and that studies showing a difference between PPIs were in different populations using different methods.48

Although drug–drug interactions of omeprazole for CYP2C19 are thought to be one of competitive inhibition, the issue of its short plasma half-life (<1 h) has been brought up to refute this argument.45 However, omeprazole has a high affinity for CYP2C19 and its binding is extensive and it is unknown how long this inhibition persists. Omeprazole has a short half-life; however, separating the dose of omeprazole and clopidogrel is not a way of overcoming the interaction as some CYP2C19 may still be bound by omeprazole metabolism.45 In addition, there has been no obvious dose–response relationship found between PPI dose and adverse outcomes, which one would expect from competitive inhibition.42, 45

At present, there is insufficient evidence to suggest that one particular PPI (e.g. pantoprazole) should be prescribed in preference to another to avoid an interaction. The ongoing SPICE (Evaluation of the Influence of Statins and Proton Pump Inhibitors on Clopidogrel Antiplatelet Effects) trial directly compares the effect of all PPIs on platelet aggregation and VASP and should help answer the question of which PPI is preferable. In addition, the trial will examine clopidogrel resistance, CYP2C19 polymorphism and its effect on PPI on the antiplatelet activity of clopidogrel, mortality and the need to stop medication due to peptic ulcer disease or GI bleeding.49

Clinical evidence – evidence of an interaction

  1. Top of page
  2. Abstract
  3. Introduction
  4. A clinically relevant interaction between clopidogrel and PPI?
  5. Pharmacological basis of a clopidogrel-PPI interaction
  6. Clinical evidence – evidence of an interaction
  7. Clinical evidence – evidence against a clinically relevant interaction
  8. Does bleeding have an impact?
  9. Further controversy for PPIs?
  10. Conclusion
  11. Acknowledgement
  12. References

From the evidence above, there is no doubt that PPIs have an effect on the pharmacokinetics and pharmacodynamics of clopidogrel, as evidenced by laboratory assays, but these are surrogate markers of clinical effect. The question has to be asked, does a pharmacokinetic or pharmacodynamic effect have any impact on clinical outcomes?

Several studies suggest a link between co-prescription of a PPI and clopidogrel, and an increased risk of adverse clinical outcomes (see Table 1).

Table 1.   Summary of studies examining the interaction between a PPI and clopidogrel
AuthorRef.PPINo. of patients on PPI and clopidogrelStudy designResults and conclusion
  1. P, pantoprazole; O, omeprazole; E, esomeprazole; L, lansoprazole; R, rabeprazole; OR, odds ratio; HR, hazard ratio; AHR, adjusted hazard ratio; MACE, major adverse cardiac event; ARR, adjusted rate ratio; NA, not available; MI, myocardial infarction.

  2. * Composite of cardiovascular death, nonfatal MI or nonfatal stroke.

Ho42NA5244RetrospectiveOR 1.25 for death or rehospitalisation for PPI group Positive link
Juurlink9POLR734RetrospectiveOR1.4 (CI 1.1–1.77) for OLR for reinfarction. OR 1.02 (CI 0.7–1.47) for P for reinfarction Positive link
Aubert50NA4521RetrospectiveOR 1.86 (CI 1.63–2.12) for PPI group Positive link
Pezalla51NA712Retrospective5% rate of MI at 1 year in high PPI exposure group (1.38% in controls) Positive link
Dunn54NA176RetrospectiveOR 1.63 (CI 1.01–2.63) for PPI group No link
O’Donoghue55POEL4529RetrospectiveAHR 0.94 for primary endpoint* No link
Rassen53POELR3996RetrospectiveARR for MI/death 1.22 (CI 0.99–1.51) No link
Zairis57O340RetrospectiveHR for MI/death 1.1 (CI 0.6–1.8) No link
Simon17POELRNARetrospectivePPI had no effect on clinical response to clopidogrel No link
Ray58POELR7593RetrospectiveHR for CVS events 0.99 (CI 0.82–1.19)
Bhatt59O1876ProspectiveHR 0.99 (CI 0.68–1.44) No link

Data from 14383 patients in the Medco Integrated database were presented in abstract format at the AHA Scientific Sessions 2008 Symposium. The study population comprised patients who had undergone PCI and were prescribed clopidogrel alone or clopidogrel plus a PPI. Patients with no preceding cardiovascular disease taking PPIs had a 32.5% incidence of a major cardiovascular event within 1 year vs. 21.2% of patients not taking a PPI (adjusted OR 1.79, 95% CI 1.62–1.97). Effects were more pronounced in patients with a preceding cardiovascular event (adjusted OR 1.86, 95% CI 1.63–2.12). However, confounding may be an issue and the study did not have information on valuable cardiovascular risk factors, such as smoking, blood pressure and serum cholesterol levels.50

Data retrospectively analysed from 4800 patients admitted with acute myocardial infarction and subsequently receiving clopidogrel classified patients as no PPI exposure, low PPI exposure and high PPI exposure based upon adherence rates to PPIs.51 One-year event rates for acute myocardial infarction were 1.38% for no PPI, 3.08% in the low exposure and 5.03% in the high exposure group. However, patients prescribed PPIs may be older with greater co-morbidity, and indeed this is the case in this study which limits the applicability of the results; after adjustment, the high exposure group still had a relative risk of 337% compared with the no exposure group.

Further evidence suggests a clinically relevant interaction comes from the retrospective analysis of 8205 patients from Veteran Affairs hospitals between 2003 and 2006 who had been admitted with ACS.42 Of these patients, 63.9% were prescribed PPI at discharge, during follow-up or both: omeprazole = 3132, rabeprazole = 151, lansoprazole = 22, pantoprazole = 15, more than one PPI = 1924. Death or rehospitalisation for ACS occurred in 20.8% of patients prescribed clopidogrel without PPI, and 29.8% of patients prescribed clopidogrel plus a PPI. The use of a PPI during any point was associated with an increased risk of death or rehospitalisation with ACS – Odds Ratio (OR) 1.25 (95% CI 1.11–1.41). Adjusted OR for all-cause mortality revealed no difference between the two groups. The authors, however, conclude that concomitant use of clopidogrel and a PPI may be associated with an attenuation of the benefits of clopidogrel, but stop short of confirming a causal relationship. Again, one limitation of this study is the difference in baseline characteristics – those prescribed a PPI tended to be older with more comorbidity (e.g. diabetes, prior MI, heart failure, CVA, COPD, renal and liver disease) and may therefore represent a population with a higher risk of adverse outcomes, rather than PPIs being the problem.

One Canadian population-based study examined patients admitted with acute myocardial infarction between 2002 and 2007.9 PPI prescribing was common – 31% of patients receiving a PPI within 90 days of discharge. The authors report a significant association between readmission due to MI and current use of a PPI (adjusted OR 1.27, 95% CI 1.03–1.57) and a 40% increase in recurrent MI within 90 days (OR 1.4, 95% CI 1.10–1.77). Pantoprazole and histamine receptor antagonists were not associated with adverse outcomes. Unfortunately, the number of prescriptions and breakdown of which PPI was prescribed are not given. As with the previous study,42 the baseline characteristics varied considerably. Those on a PPI had greater comorbidity with higher rates of renal failure, diabetes and congestive cardiac failure. The study also lacked data on smoking status and blood pressure. Again, because of these differences, it is unclear if the adverse outcomes observed are related to PPI use or to confounding factors such as comorbidity.52

Thus, the results seen from these observational studies may simply reflect a greater tendency to prescribe prophylactic PPIs to patients at higher risk of cardiovascular events.12, 53

Clinical evidence – evidence against a clinically relevant interaction

  1. Top of page
  2. Abstract
  3. Introduction
  4. A clinically relevant interaction between clopidogrel and PPI?
  5. Pharmacological basis of a clopidogrel-PPI interaction
  6. Clinical evidence – evidence of an interaction
  7. Clinical evidence – evidence against a clinically relevant interaction
  8. Does bleeding have an impact?
  9. Further controversy for PPIs?
  10. Conclusion
  11. Acknowledgement
  12. References

The first data against an interaction were presented in abstract format at the AHA Scientific Sessions 2008 Symposium was in direct conflict with Medco data presented at the same meeting.50, 54 In this retrospective analysis of the Clopidogrel for the Reduction of Events During Observation (CREDO) Trial, no increase in cardiovascular or cerebrovascular events was seen in the clopidogrel-PPI group at 1 year.

Perhaps the most definitive data on whether mechanistic changes translate into clinical data come from over 13 000 patients participating in the Prasugrel In Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation–Thrombolysis in Myocardial Infarction (PRINCIPLE-TIMI) 44 and Trial to Assess Improvement in Therapeutic Outcomes by Optimising Platelet Inhibition with Prasugrel-TIMI (TRITON-TIMI) 38 studies. Both studies were sub-analysed to look at individual PPI use and showed no association between PPI and adverse cardiovascular outcomes. The authors found no independent association between any of the PPIs and the risk of MI or cardiovascular death.55 These two randomised trials studied over 13 000 patients. There was no difference among the PPIs used: omeprazole (= 1675), lansoprazole (= 441), esomeprazole (= 613), pantoprazole (= 1844). As with previous studies, patients taking PPIs were older and sicker, with a more frequent history of peptic ulcer disease and lower baseline haemoglobin. After adjustment for confounders, no significant association was observed between use of a PPI and risk of primary endpoint (composite of cardiovascular death, nonfatal MI, or nonfatal stroke) with HR 0.94 (95% CI 0.80–1.11, = 0.46). Consistent PPI use (i.e. use of PPI for the whole duration of follow-up) was not associated with an increased risk of cardiovascular death, MI or stroke in patients treated with clopidogrel (HR 1.05, 95% CI 0.85–1.30). An accompanying editorial commended the work, but highlighted that the patients included in the TRITON-TIMI trial were much younger, with less diabetes or renal failure than those in the previously highlighted observational studies.56

Rassen et al. analysed data of 64 561 patients who underwent PCI or hospitalisation for ACS between 2001 and 2005.53 Crude rates of MI hospitalisation or death were higher in the PPI group with a relative risk of 1.74 (CI 1.44–2.10). However, after multivariable adjustment, the RR fell to 1.32 (CI 1.08–1.61). With high-dimensional propensity score (hd-PS) adjustment, an RR of 1.22 (CI 0.99–1.51) for MI hospitalisation or death was seen. Thus, no statistically significant clopidogrel-PPI interaction was seen.

The study of Zairis et al. on 588 patients undergoing PCI showed no difference in cardiovascular outcomes in the PPI (omeprazole only = 340) group at 1 year.57 The primary endpoint was defined as cardiac death or rehospitalisation for a nonfatal MI. This endpoint was reached by 10% in PPI group and 9.7% in the no PPI group – hazard ratio 1.1 (95% CI 0.6–1.8). The study groups were well matched in terms of baseline characteristics. This is in contrast to other studies where patients on a PPI were older and with more comorbidity.9, 42

The genetic determinants of response to clopidogrel have been evaluated and the use of omeprazole, or any other PPI, had no effect on the clinical response to clopidogrel.17 A large retrospective analysis of 20 596 Medicare patients again drew negative results with regard to the effect any drug interaction had on clinical events. Those patients receiving both clopidogrel and a PPI (pantoprazole = 4707, omeprazole = 683) had an HR 0.99 (CI 0.82–1.19) for serious cardiovascular disease (ACS or revascularisation). The study also raises the importance of PPIs in this group of patients with regard to reducing the incidence of gastrointestinal bleeding. In those patients receiving concurrent PPI, the incidence of hospitalisation with gastrointestinal bleeding was 50% lower than those not prescribed a PPI.58

The recently published Clopidogrel and the Optimisation of Gastrointestinal Events (COGENT) trial is the first and the only prospective study of the potential interaction.59 The study was well designed specifically to address the issue of a clinically relevant interaction. Unfortunately, the trial was halted early due to bankruptcy of its sponsor with 3873 of 5000 patients enrolled. The study groups were well matched. With respect to cardiovascular outcomes, 109 patients had an event (MI, stroke, coronary artery bypass graft, PCI, CV death), 4.9% and 5.7% with omeprazole and placebo respectively (HR 0.99, 95% CI 0.68–1.44). In addition, overt upper gastrointestinal bleeding was reduced in those patients prescribed a PPI (HR 0.13, 95% CI 0.03–0.56). The authors err on the side of caution, however, stating ‘that the results do not rule out a clinically meaningful difference in cardiovascular events due to use of a PPI’. This is due to a low number of clinical events during follow-up and, as a result, wide confidence intervals.

It should be highlighted that confounding can have a significant effect on results and their subsequent interpretation. Work by Valkhoff et al. has highlighted the problems with confounding by indication when analysing data retrospectively collected regarding the use of PPIs with clopidogrel.60 This analysis examined 23 655 patients admitted with MI, with 1247 readmitted with recurrent MI. All PPIs were included in the analysis. PPI users were noted to be older, with more co-morbidity and co-medication. With current users of clopidogrel, current PPI use was associated with recurrent MI (OR 1.62, 95% CI 1.15–2.27). However, when applying past PPI use as the reference category, rather than PPI non-use, no association between recurrent MI and current PPI use was noted (OR 0.95, 95% CI 0.38–2.41). The authors suggest that the observed association between current PPI use and recurrent MI when PPI non-use was the reference may be the result of residual confounding.

Does bleeding have an impact?

  1. Top of page
  2. Abstract
  3. Introduction
  4. A clinically relevant interaction between clopidogrel and PPI?
  5. Pharmacological basis of a clopidogrel-PPI interaction
  6. Clinical evidence – evidence of an interaction
  7. Clinical evidence – evidence against a clinically relevant interaction
  8. Does bleeding have an impact?
  9. Further controversy for PPIs?
  10. Conclusion
  11. Acknowledgement
  12. References

An alternative hypothesis is that bleeding per se in the ACS setting is bad. Indeed, bleeding in the context of ACS is an independent risk for poor short and long term clinical outcomes.61–64 Therefore, it may not be that PPIs are associated with adverse clinical outcomes, but that patients taking them may have had a history of bleeding resulting in PPI prescription or may be deemed at high risk of bleeding. A bleeding episode could lead to a prolonged prothrombotic state, which in turn leads to increased adverse clinical events. This is an area that requires further studies to clarify.

Other possibilities include that PPIs do have a direct effect on cardiovascular risk, or that PPIs interact with clopidogrel, but it is individuals with genetic polymorphism of the gene encoding CYP2C19 leading to loss-of-function who may be more susceptible to this interaction. The TRITON-TIMI 38 study examined those patients with a loss-of-function CYP2C19 polymorphism and current PPI use in patients prescribed clopidogrel. The study was underpowered to address this specific point; however, no association of increased adverse events was observed (HR 0.76, CI 0.39–1.48).55

Ultimately, however, the association between clopidogrel and PPIs is likely to suffer from channelling bias – which is that physicians tend to prescribe PPIs to patients with more severe underlying illness.65

Further controversy for PPIs?

  1. Top of page
  2. Abstract
  3. Introduction
  4. A clinically relevant interaction between clopidogrel and PPI?
  5. Pharmacological basis of a clopidogrel-PPI interaction
  6. Clinical evidence – evidence of an interaction
  7. Clinical evidence – evidence against a clinically relevant interaction
  8. Does bleeding have an impact?
  9. Further controversy for PPIs?
  10. Conclusion
  11. Acknowledgement
  12. References

In addition to the concerns regarding clopidogrel, there are conflicting reports on the use of PPIs with aspirin. Studies have shown that omeprazole has the ability to reduce the absorption and bioavailability of aspirin in animals66 and by doing so has the ability to reduce the analgesic and antipyretic effects.67

However, with respect to aspirin, the interaction is thought to lie in the PPIs’ ability to increase intragastric pH and thereby reduce the absorption and thus bioavailability of aspirin, rather than inhibit the enzymes that metabolise it, as is the mechanism with clopidogrel. Aspirin is normally absorbed in a lipid-soluble state by diffusion. By increasing intragastric pH above the pKa of aspirin, absorption is reduced.66, 68

Unfortunately, as with the clopidogrel interaction, there is ongoing debate as to the importance and accuracy of the aspirin-PPI interaction in humans. Two studies on small numbers of patients report that PPIs do not interfere with the antiplatelet effects of aspirin; one studied omeprazole69 and the other lansoprazole70 in 14 and 24 patients respectively. One study, however, reported enhanced antiplatelet activity of aspirin when co-administered with pantoprazole.71 The largest study examining this interaction which enrolled 418 patients with stable coronary disease found that the antiplatelet effect of aspirin was reduced by PPIs.72

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. A clinically relevant interaction between clopidogrel and PPI?
  5. Pharmacological basis of a clopidogrel-PPI interaction
  6. Clinical evidence – evidence of an interaction
  7. Clinical evidence – evidence against a clinically relevant interaction
  8. Does bleeding have an impact?
  9. Further controversy for PPIs?
  10. Conclusion
  11. Acknowledgement
  12. References

Although the current data are conflicting, much concern has been raised in the medical press regarding the potential negative effects of PPIs on the efficacy of clopidogrel. There is extensive evidence demonstrating that PPIs do have an effect on the pharmacokinetics and pharmacodynamics of clopidogrel, but it is important to highlight that abnormal laboratory indices do not always translate into clinically relevant interactions.

Patients who have a GI bleed have increased mortality, and the protection PPIs offer against such events is not to be underestimated.73 Based on the available evidence, the decision to prescribe a PPI to a patient on clopidogrel should be made after an individual risk assessment balancing gastrointestinal bleeding risk against thrombotic risk. Further prospective randomised clinical trials are needed, but in the meantime, we must be careful not to jump to the wrong conclusions, and deny our patients the protection that PPIs clearly offer, compared with a concern about cardiovascular outcomes that has not yet been proven. However, a clinically important interaction cannot be excluded in certain groups such as those patients with loss-of-function polymorphisms and further work should be aimed at this area.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. A clinically relevant interaction between clopidogrel and PPI?
  5. Pharmacological basis of a clopidogrel-PPI interaction
  6. Clinical evidence – evidence of an interaction
  7. Clinical evidence – evidence against a clinically relevant interaction
  8. Does bleeding have an impact?
  9. Further controversy for PPIs?
  10. Conclusion
  11. Acknowledgement
  12. References
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    Yusuf S, Zhoa 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: 494502.
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    Ng F, Wong S, Lam K, et al. Gastrointestinal bleeding in patients receiving a combination of aspirin, clopidogrel, and enoxaparin in acute coronary syndrome. Am J Gastro 2008; 103: 86571.
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    Nikolsky E, Stone GW, Kirtane AJ, et al. Gastrointestinal bleeding in patients with acute coronary syndromes: incidence, predictors, and clinical implications: analysis from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) Trial. J Am Coll Cardiol 2009; 54: 1293302.
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