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What is the clinical relevance of the clopidogrel/proton pump inhibitor (PPI) interaction?

Background

Clopidogrel is a thienopyridine that prevents platelet aggregation by irreversibly binding the adenosine diphosphate (ADP) P2Y12 receptors on platelets.1,2  The Food and Drug Administration (FDA) has approved clopidogrel for decreasing the rate of myocardial infarction (MI) and stroke in patients with acute coronary syndrome (ACS) and those with a recent MI, stroke, or established peripheral arterial disease (PAD).3  Clopidogrel may be used as an alternative to or with aspirin in dual antiplatelet therapy (DAPT) for a variety of cardiovascular indications including ACS and the prevention of thrombosis following percutaneous intervention (PCI).2,4-7

Proton pump inhibitors (PPIs) inhibit the H+/K+-ATPase enzyme in gastric parietal cells leading to decreased gastric acid secretion.8  This drug class includes dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole.  Proton pump inhibitors are indicated for several gastrointestinal (GI) indications such as gastroesophageal reflux disease (GERD) and ulcer bleeding.9,10

The inhibitory effects of clopidogrel on platelets may lead to bleeding of pre-existing lesions from esophagitis or peptic ulcer disease due to aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) usage or H. pylori infection.2  This bleeding may be indirectly decreased by suppressing gastric acid production, which in turn allows for gastric ulcer healing and thrombi stabilization.  Proton pump inhibitors may be recommended as an adjunct to clopidogrel therapy in order to prevent GI bleeding.  Table 1 summarizes various guideline recommendations for prevention of GI bleeding in patients taking antiplatelet therapy with clopidogrel.

Table 1. Guideline recommendations for prevention of GI bleeding in patients taking antiplatelet therapy with clopidogrel.2,5-7,10

Guideline Recommendation
2010 ACCF/ACG/AHA expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines2 ·         Recommends PPIs in patients taking antiplatelet therapy with multiple risk factors for a GI bleed and in patients with a history of upper GI bleeding
2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention6 ·         Recommends PPIs in patients who require DAPT with a history of prior GI bleed

·         PPI use is reasonable in patients with an increased risk of GI bleed (older age, concomitant warfarin, steroids, or NSAIDs, H. pylori infection) who require DAPT
2012 ACG guideline for the management of patients with ulcer bleeding10 ·         For secondary cardiovascular disease prevention, recommends long-term PPI use in patients with a bleeding ulcer from aspirin or other antiplatelet agents
2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes (NSTE-ACS)5 ·         Recommends PPIs in patients with a history of GI bleed and NSTE-ACS taking triple antithrombotic therapy with a vitamin K antagonist, aspirin, and P2Y12 receptor inhibitor

·         PPI use is reasonable in patients with NSTE-ACS without a history of GI bleed and taking antithrombotic therapy with a vitamin K antagonist, aspirin, and P2Y12 receptor inhibitor
2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease7 ·         References the same recommendations from the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention
Abbreviations: ACC=American College of Cardiology; ACCF=American College of Cardiology Foundation; ACG=American College of Gastroenterology; AHA=American Heart Association; DAPT=dual antiplatelet therapy; GI=gastrointestinal; NSAID=non-steroidal anti-inflammatory drug; NSTE-ACS=non-ST-elevation acute coronary syndrome; PPI=proton pump inhibitor; SCAI= Society for Cardiovascular Angiography and Interventions.

Clopidogrel/PPI drug interaction

Although the concurrent administration of clopidogrel and PPIs is recommended by guidelines in various situations, a major concern of co-administration is the potential for a CYP450-mediated drug interaction.  Clopidogrel is a prodrug that requires biotransformation via CYP2C19 oxidation to an active thiol metabolite.3  Proton pump inhibitors are inhibitors of CYP2C19 with varying degrees of potency.2  Therefore, PPIs may inhibit activation of clopidogrel to its active metabolite via CYP2C19 leading to decreased serum concentrations of the active metabolite and potentially reducing the antiplatelet effect of clopidogrel.2,3  Within the class, omeprazole and esomeprazole are considered the most potent inhibitors of CYP2C19 while rabeprazole and pantoprazole have the weakest inhibitory effect on CYP2C19.11

Several guidelines have discussed the clinical relevance of the clopidogrel/PPI interaction.  The 2010 ACCF/ACG/AHA expert consensus document on the concomitant use of PPIs and thienopyridines explains that there is conflicting scientific evidence regarding the effects on cardiovascular outcomes when these agents are used together; however, a clinically relevant interaction may exist, especially in poor metabolizers of clopidogrel.2  Guidelines following this publication, such as the 2011 ACCF/AHA/SCAI guideline for PCI and 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction, mention the potential drug interaction between clopidogrel and omeprazole.4,6  However, these guidelines state that there is not definitive evidence supporting a clinically important drug-drug interaction and that concurrent administration of clopidogrel and PPIs does not seem to worsen cardiovascular outcomes.  In contrast, the 2014 AHA/ASA guideline for the prevention of stroke in patients with stroke and transient ischemic attack discusses that there is evidence supporting the reduced effectiveness of clopidogrel with PPI administration, but other clinical data propose that PPIs alone may also be associated with an increased risk of cardiovascular events.12  This guideline recommends that patients taking clopidogrel should be administered either a H2 blocker or pantoprazole, if a PPI is desired.

Review of clopidogrel/PPI drug interaction literature

To date, the available literature has not provided compelling evidence on whether a clinically significant drug interaction exists between clopidogrel and PPIs.  Several observational studies have demonstrated conflicting results regarding the relationship between this interaction and an increased risk of cardiovascular events.13-30  The following section focuses on results from meta-analyses and systematic reviews that evaluate whether the concomitant use of clopidogrel and PPIs may or may not lead to an increased risk of cardiovascular events.

Clopidogrel/PPI interaction is associated with an increased risk of cardiovascular events

Table 2 is a summary of 7 meta-analyses reporting an increased risk of cardiovascular events with the concomitant use of PPIs and clopidogrel as compared to clopidogrel monotherapy in patients with certain cardiovascular conditions.31-37  The majority of the studies included in these meta-analyses were observational with significant heterogeneity and varying definitions of outcomes such as major adverse cardiovascular events (MACE).

Table 2. Clinical evidence supporting the association between the clopidogrel/PPI interaction and an increased risk of cardiovascular events.31-37

Citation Design Population Interventions Outcome(s)
Hu 201831 MA

4 RCTs and 8 cohort studies

 N=33,492 patients with ACS, PCI, or coronary stenting and taking the combination of aspirin and clopidogrel with or without a PPI PPIs

·         Rabeprazole

·         Omeprazole

·         Lansoprazole

·         Pantoprazole

Clopidogrel

Placebo

 ·         PPIs increased the occurrence of MACE (defined as ACS, stent thrombosis, revascularization, stroke, and all-cause mortality) [OR, 1.17; 95% CI, 1.07-1.28; p=0.001]

·         A higher occurrence of stent thrombosis in the PPI vs. placebo group was observed [OR, 1.30; 95% CI, 1.01-1.68; p=0.041]

·         A higher occurrence of revascularization in the PPI vs. placebo group was also seen [OR, 1.20; 95% CI, 1.04-1.38; p=0.011]

·         PPI and placebo groups had similar occurrences of MI [OR, 1.03; 95% CI, 0.87-1.22; p=0.724] and cardiogenic death [OR, 1.09; 95% CI, 0.83-1.43; p=0.526]
Bundhun 201732 SR/MA

2 RCTs and 9 cohort studies

 N=84,729 patients with coronary stenting treated with clopidogrel and a PPI or clopidogrel alone PPIs

·         Omeprazole

·         Esomeprazole

·         Lansoprazole

·         Pantoprazole

·         Rabeprazole

Clopidogrel

 Short-term follow-up period (<1 year)

·         Higher occurrence of TVR in the PPI users vs. non-PPI-users [OR, 1.26; 95% CI, 1.06-1.49; p=0.009]

·         Occurrence of MI was similar in both the PPI users and non-PPI users [OR, 1.17; 95% CI, 0.86-1.58; p=0.32]

Long-term follow-up period (≥1 year)

·         Higher occurrence of MACE (defined as death, MI, and repeated revascularization) in the PPI users vs. non-PPI-users [OR, 1.37; 95% CI, 1.23-1.53; p<0.00001]

·         Higher occurrence of MI in the PPI-users vs. non-PPI users [OR, 1.41; 95% CI, 1.26-1.57; p<0.00001]

·         Higher occurrence of stent thrombosis in the PPI-users vs. non-PPI users [OR, 1.38; 95% CI, 1.13-1.70; p=0.002]

·         Higher occurrence of TVR in the PPI-users vs. non-PPI users [OR, 1.28; 95% CI, 1.01-1.61; p=0.04]
Serbin 201633 SR/MA

10 cohort studies and 2 retrospective analyses of RCTs

 N=50,277 patients taking clopidogrel and aspirin following PCI with or without a PPI PPIs

·         Omeprazole

·         Esomeprazole

·         Pantoprazole

·         Rabeprazole

·         Lansoprazole

Clopidogrel

 ·         Significant increase of composite MACE (defined as MI, stroke, and/or cardiovascular death) in PPI users vs. non-PPI users [HR, 1.28; 95% CI, 1.24-1.32]

·         Increased risk of MI in PPI users vs. non-PPI users [HR, 1.51; 95% CI, 1.40-1.62]

·         Increased risk of stroke in the PPI-users vs. non-PPI users [HR, 1.46; 95% CI, 1.15-1.86]

·         Both PPI-users and non-PPI users had similar risk of cardiovascular death [HR, 0.85; 95% CI, 0.7-1.04] and stent thrombosis [HR, 1.23; 95% CI, 0.96-1.58]
Sherwood 201534 SR/MA

6 observational studies

 N=>41,000 patients with ACS or PCI receiving clopidogrel with DAPT with or without a PPI PPIs

·         Omeprazole

·         Pantoprazole

·         Lansoprazole

·         Esomeprazole

·         Rabeprazole

Clopidogrel

 Omeprazole

·         Similar risk of the composite endpoint of cardiovascular or all-cause mortality, nonfatal MI, and stroke at 1 year [HR, 1.16; 95% CI, 0.93-1.44] as compared to the non-PPI users

Pantoprazole

·         Increased risk of the composite endpoint of cardiovascular or all-cause mortality, nonfatal MI, and stroke at 1 year [HR, 1.38; 95% CI, 1.12-1.70] as compared to the non-PPI users

Lansoprazole

·         Increased risk of the composite endpoint of cardiovascular or all-cause mortality, nonfatal MI, and stroke at 1 year [HR, 1.29; 95% CI, 1.09-1.52] as compared to the non-PPI users

Esomeprazole

·         Increased risk of the composite endpoint of cardiovascular or all-cause mortality, nonfatal MI, and stroke at 1 year [HR, 1.27; 95% CI, 1.02-1.58] as compared to the non-PPI users

Rabeprazole

·         Excluded from analysis due to insufficient data
Kwok 201335 SR/MA

19 cohort studies, 2 post-hoc analyses of clinical trials, and 2 RCTs

 N=222,311 subjects following a MI or PCI and receiving clopidogrel with or without a PPI PPIs

·         Omeprazole

·         Esomeprazole

·         Lansoprazole

·         Pantoprazole

·         Rabeprazole

Clopidogrel

 Omeprazole

·         Increased risk of adverse cardiovascular outcomes as compared to the non-PPI users [OR, 1.24; 95% CI, 1.07-1.43]

Esomeprazole

·         Increased risk of adverse cardiovascular outcomes as compared to the non-PPI users [OR, 1.32; 95% CI, 1.09-1.60]

Omeprazole or Esomeprazole

·         Sensitivity analysis of the 2 RCTs: Similar risk of MACE (variable definitions among the studies) [OR, 1.04; 95% CI, 0.72-1.51; p=0.83] and MI [OR, 0.94; 95% CI, 0.47-1.87; p=0.87] as compared to the non-PPI users

Lansoprazole

·         Increased risk of adverse cardiovascular outcomes as compared to the non-PPI users [OR, 1.39; 95% CI, 1.23-1.57]

Pantoprazole

·         Increased risk of adverse cardiovascular outcomes as compared to the non-PPI users [OR, 1.41; 95% CI, 1.21-1.64]

Rabeprazole

·         Similar risk of adverse cardiovascular outcomes as compared to the non-PPI users [OR, 1.38; 95% CI, 0.78-2.45]

The authors also noted that PPI therapy alone without concurrent clopidogrel was associated with an increased OR of 1.28 (95% CI, 1.14-1.44) as compared to no clopidogrel/no PPI exposure
Huang 201236 SR/MA

23 cohort studies, 4 case-control studies, 1 post-hoc analysis of a RCT, and 4 RCTs

 N=159,998 subjects with CAD taking clopidogrel with or without a PPI PPIs

·         Esomeprazole

·         Omeprazole

·         Pantoprazole

·         Rabeprazole

·         Lansoprazole

Clopidogrel

 ·         PPIs were associated with an increased risk of MACE (defined as death, ACS, cerebrovascular accident, stent thrombosis, revascularization, etc.) as compared to the non-PPI users [HR, 1.40; 95% CI, 1.19-1.64; OR, 1.27; 95% CI, 1.13-1.42]

·         PPIs were associated with an increased risk of ACS as compared to the non-PPI users [HR, 1.42; 95% CI 1.14-1.77; OR, 1.42; 95% CI, 1.08-1.87]

·         There was a similar risk of cardiovascular death [HR, 1.21; 95% CI, 0.60-2.43] and stent thrombosis [HR, 1.52; 95% CI, 0.87-2.65] for the PPI-users and the non-PPI users

·         Out of the individual PPIs, only pantoprazole was associated with an increased risk of MACE [HR, 1.52; 95% CI, 1.18-1.94]
Siller-Matula 201037 SR/MA

20 cohort studies, 2 case-control studies, 2 post-hoc analyses of RCTs, and 1 RCT

 N=159,138 subjects with established cardiovascular disease receiving clopidogrel with or without a PPI PPIs

·         Omeprazole

·         Esomeprazole

·         Pantoprazole

·         Lansoprazole

·         Rabeprazole

Clopidogrel

 ·         PPIs were associated with an increased risk of MACE (variable definitions among the studies) as compared to the non-PPI users [RR, 1.29; 95% CI, 1.15-1.44; p<0.001]

·         Similar risk of MACE (variable definitions among the studies) for pantoprazole [RR, 1.23; 95% CI, 0.95-1.59; p=0.11] and omeprazole [RR, 1.05; 95% CI, 0.79-1.40; p=0.72] as compared to the non-PPI users

·         PPIs were associated with an increased risk of MI as compared to the non-PPI users [RR, 1.31; 95% CI, 1.12-1.53; p<0.001]

·         PPIs were associated with an almost 2-fold increased risk of stent thrombosis; however, this failed to reach significance [RR, 1.88; 95% CI, 0.97-3.62; p=0.06]
Abbreviations: ACS=acute coronary syndrome; CAD=coronary artery disease; CI=confidence interval; DAPT=dual antiplatelet therapy; HR=hazards ratio; MA=meta-analysis; MACE=major adverse cardiovascular events; MI=myocardial infarction; OR=odds ratio; PCI=percutaneous coronary intervention; PPI=proton pump inhibitor; RCT=randomized controlled trial; RR=risk ratio; SR=systematic review; TVR=target vessel revascularization

Clopidogrel/PPI interaction is not associated with an increased risk of cardiovascular events

Table 3 is a summary of 3 meta-analyses and systematic reviews that do not support an association between an increased risk of cardiovascular outcomes and the concomitant use of clopidogrel and PPIs as compared to clopidogrel monotherapy in patients with certain cardiovascular conditions.38-40  The majority of the included studies were also observational in nature with substantial heterogeneity.
Table 3. Clinical evidence supporting the lack of association between the clopidogrel/PPI interaction and an increased risk of cardiovascular events.38-40

Citation Design/Duration Population Interventions Outcome(s)
Farhat 201938 SR/MA

38 cohort studies, 4 case-control studies, 1 case crossover study, 4 post-hoc analyses of RCTs, and 3 RCTs

 Subjects with ACS receiving clopidogrel and/or aspirin for DAPT with or without a PPI PPIs

·         Omeprazole

·         Esomeprazole

·         Pantoprazole

·         Rabeprazole

·         Lansoprazole

Clopidogrel

 ·         In the observational studies, PPIs were associated with an increased risk of MI as compared to the non-PPI users [RR, 1.23; 95% CI, 1.04-1.47], but the risk was not significant in the propensity score matched studies and post-hoc analyses of RCTs [RR, 1.15; 95% CI, 1.00-1.32]

·         There was a similar risk of MI for omeprazole [RR, 0.97; 95% CI, 0.76-1.22], esomeprazole [RR, 1.18; 95% CI, 0.83-1.68], and pantoprazole [RR, 1.18; 95% CI, 0.72-1.95] as compared to the non-PPI users

·         In the observational studies, PPIs were associated with an increased risk of cardiovascular mortality as compared to the non-PPI users [RR, 1.21; 95% CI, 1.09-1.34], but the risk was not significant in the propensity score matched studies and post-hoc analyses of RCTs [RR, 1.17; 95% CI, 0.80-1.71]

·         In the observational studies, the risk of stroke was similar between the PPI-users and non-PPI users [RR, 1.05; 95% CI, 0.85-1.29]; however, the propensity score matched cohort studies showed an association of increased risk of stroke with PPIs vs. the non-PPI users [RR, 1.75; 95% CI, 1.45-2.11]
Focks 201339 SR

26 cohort studies, 2 case-control studies, 3 post-hoc analyses of RCTs, and 2 RCTs

 Subjects with ACS or following coronary stenting for stable coronary disease receiving clopidogrel with or without a PPI PPIs

·         Omeprazole

·         Pantoprazole

·         Lansoprazole

·         Rabeprazole

·         Esomeprazole

Clopidogrel

 ·         PPIs increased the risk of MI as compared to the non-PPI users in 11 out of 25 studies [RR, 1.19-4.58], with the other 14 studies reporting no difference

·         PPIs increased the risk of MACE (undefined) as compared to the non-PPI users in 12 out of 25 studies [HR, 1.20-4.58] with the other 13 studies reporting no difference
Gerson 201240 MA

14 cohort studies and 2 RCTs

 Subjects with MI, ACS, and/or PCI receiving clopidogrel with or without a PPI PPIs (individual PPIs are not specified)

Clopidogrel

 ·         In the 2 RCTs, there was a similar risk for the primary outcomes (death, MI, stent thrombosis, and/or stroke) and secondary outcomes (re-hospitalization for cardiac symptoms or revascularization) in the PPI users and the non-PPI users [RD, 0.0; 95% CI, -0.01-0.01]

·         When combining data from the 2 RCTs with the 14 cohort studies, PPI users showed a minimally increased risk of the primary endpoints [RD, 0.02; 95% CI, 0.01-0.03] and secondary endpoints [RD, 0.02; 95% CI, 0.01-0.04] as compared to the non-PPI users
Abbreviations: ACS=acute coronary syndrome; CI=confidence interval; DAPT=dual antiplatelet therapy; HR=hazard ratio; MA=meta-analysis; MACE=major adverse cardiovascular events; MI=myocardial infarction; PPI=proton pump inhibitor; RCT=randomized controlled trial; RD=risk difference; RR=risk ratio; SR=systematic review

Conclusion

Overall, the clinical significance of the clopidogrel and PPI interaction remains unclear.  Meta-analyses and systematic reviews have failed to demonstrate consistent outcomes regarding the clinical relevance of this interaction potentially due to the heterogeneous and primarily observational nature of the data.31-40  Current guidelines note the potential drug interaction, but also state that evidence for clinical relevance is not convincing and that PPIs alone may be the culprit of negative cardiovascular outcomes versus the effects from an interaction involving clopidogrel and PPIs.2,4,6,12  Firm conclusions cannot be drawn from the currently available literature and the addition of a PPI to a clopidogrel regimen should be assessed on a case-by-case basis to determine benefits and risks to the individual patient.

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Prepared by:
Katie Miles, PharmD
PGY2 Drug Information Resident
University of Illinois at Chicago College of Pharmacy

October 2019

The information presented is current as July 24, 2019. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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