Is the interaction between PPI and Plavix significant and do they all have the same degree of interaction?

Comment by InpharmD Researcher

While older guidelines did not draw a definitive conclusion on the clinical significance of drug-drug interaction between clopidogrel and proton pump inhibitors (PPIs), the 2014 AHA/ASA guidelines on stroke prevention prefer ​​pantoprazole to omeprazole if use of a PPI is desired. Meta-analyses revealed conflicting results on the cardiovascular risk of combined PPI/clopidogrel therapy, depending on the study population, trial designs, individual PPI, and outcomes of interests. Specifically, pantoprazole and lansoprazole were associated with increased risk of major adverse cardiovascular endpoints. On the other hand, a pharmacodynamic study found among PPIs, omeprazole and esomeprazole were the most potent inhibitors of CYP2C19, while rabeprazole and pantoprazole had the weakest inhibitory effect and minimal drug interactions. Similarly, the prescribing information of clopidogrel also advised that dexlansoprazole, lansoprazole, and pantoprazole had less impact on the antiplatelet activity of clopidogrel in comparison with omeprazole and esomeprazole. Due to inconsistent evidence, the addition of PPI to clopidogrel should be assessed based on the risk-to-benefit ratio for individual patients.
Background

The clinical relevance of the interaction between clopidogrel and proton pump inhibitors (PPIs) has been discussed in several guidelines. The 2010 American College of Cardiology Foundation/American College of Gastroenterology/American Heart Association (ACCF/ACG/AHA) expert consensus document on the concomitant use of PPI and thienopyridines states that clinical studies that assessed the degree to which different PPIs interact with CYP2C19 (the enzyme responsible for the interaction between PPIs and clopidogrel) have yielded inconsistent results. However, a clinically relevant interaction may exist, particularly in specific subgroups, such as poor metabolizers of clopidogrel. The 2011 American College of Cardiology Foundation/American Heart Association/Society for Cardiovascular Angiography and Interventions (ACCF/AHA/SCAI) guidelines for percutaneous coronary intervention (PCI) as well as the 2012 ACCF/AHA guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction mentioned the potential drug interaction between clopidogrel and omeprazole. Given the conflicting data supporting the importance of this interaction, the panels do not prohibit use of PPIs in appropriate clinical settings. However, the risk-to-benefit ratio of administering PPI with concurrent clopidogrel should be evaluated. [1-3]

On the other hand, the 2014 guidelines from the American Heart Association/American Stroke Association (AHA/ASA) on the prevention of stroke in patients with stroke and transient ischemic attack referred to a population study that proposed PPIs alone may increase the risk of cardiovascular events. Thus, the authors recommend considering histamine-2 receptor antagonists (H2RAs) when the administration of antacid is required in a patient taking clopidogrel. It was also suggested that if a PPI is desired, ​​pantoprazole may be preferable to omeprazole because of reduced effects at the CYP2C19 cytochrome site. [4,5]

A 2021 meta-analysis evaluated the influence of individual PPIs on adverse cardiovascular events in patients receiving dual antiplatelet therapy with clopidogrel following percutaneous coronary intervention (PCI; 28 studies; N= 131,412 patients). The pooled meta-analysis revealed that the concomitant use of clopidogrel with any PPI was associated with an increased risk of ​​major adverse cardiovascular endpoints (​​MACE; relative risk [RR] 1.30; 95% confidence interval [CI] 1.15 to 1.48; p<0.001). The risk of myocardial infarction (MI) was also higher in the PPI group (RR 1.43; 95% CI 1.25 to 1.64; p <0.001). It should be noted that there was significant heterogeneity between studies for MACE and MI outcomes, limiting these findings. Inconsistent findings were obtained to analyze the specific effects of individual PPIs. Random-effects meta-analyses with individual PPIs demonstrated an increased risk of MACE in those taking pantoprazole (RR 1.31; 95% CI 1.07 to 1.61, p= 0.01) or lansoprazole (RR 1.35; 95% CI 1.19 to 1.54, p <.0001) compared with patients not on PPIs, but not for omeprazole, esomeprazole or rabeprazole. Random-effects meta-analysis of adjusted events for MACE from non-randomized controlled trials showed an increased risk of MACE for all PPIs except rabeprazole (hazard ratio [HR] 1.32; 95% CI 0.69 to 2.53; p= 0.40) and esomeprazole (HR 1.17; 95% CI 0.93 to 1.47; p= 0.19). The risk of gastrointestinal bleeding was lower when only half-dose PPI was used compared with H2RAs (RR 0.25; 95% CI 0.08 to 0.73; p= 0.01). Based on these findings, it was suggested that the concomitant use of clopidogrel with PPI in post-PCI patients is associated with an increased risk of MACE and MI. While the results of rabeprazole were not robust due to the small number of evaluated clinical trials for this agent, it was the only PPI that did not demonstrate an increased risk of MACE. [6]

A recent meta-analysis evaluated the cardiovascular risk of combined PPI/clopidogrel therapy. Co-therapy was found to heighten the risk of all-cause death (odds ratio [OR] 1.50, 95% CI 1.23 to 1.82, p <0.001). However, co-therapy did not increase the risk of MACEs, MI, stroke, target vessel revascularization (TVR), or cardiovascular disease (CVD). After performing a sensitivity analysis (heterogeneity of 0), the co-prescription of PPIs and clopidogrel was at increased risk of MACEs (p <0.001), CVD (p= 0.008), and TVR (p <0.001) but remained statistically non-significant for risk of MI (p= 0.11). Based on these results, there appears to be inconsistent evidence regarding the effects of combined PPI/clopidogrel therapy. [7]

Another 2021 meta-analysis evaluating the safety and efficacy of PPI in patients with coronary artery disease receiving dual antiplatelet therapy (DAPT) included data from 6 randomized controlled trials (RCTs; n= 6,930) and 16 observational studies (n= 183,546). Pooled analysis of RCTs found PPI users did not experience increased incidences of MACEs (risk ratio [RR] 0.89; 95% CI 0.75 to 1.05]), MI (RR 0.93; 95% CI 0.76 to 1.15), and all-cause mortality (RR 0.79; 95% CI 0.50 to 1.23) compared to the non-users. On the other hand, findings from observational studies demonstrated use of lansoprazole (RR 1.24; 95% CI 1.07 to 1.45, I2= 9%) and pantoprazole (RR 1.30; 95% CI 1.04 to 1.61], I2= 77%) led to significantly increased risk of MACEs with concomitant clopidogrel, but not omeprazole, esomeprazole, and rabeprazole. Given the lack of data for the incidence of MI and all-cause mortality in observational studies, a subgroup analysis of each PPI was not performed. As considerable heterogeneity was noticed across observational studies, results should be interpreted with caution. Additionally, actual adherence to PPI regimens in observational studies remained uncertain as the exposure to PPIs was mainly retrieved from prescription and pharmacy dispensing record databases. [8]

Another 2021 meta-analysis evaluated the efficacy and safety of PPI/clopidogrel concomitant therapy in patients undergoing PCI. A total of three randomized controlled trials and 4 cohort studies were included for analysis (N= 9,932). There was found to be a significantly lower risk of gastrointestinal bleeding events in the PPI group compared to the no PPI group (OR 3.06, 95% CI 1.89 to 4.95, p <0.00001). There was, however, no difference in MACEs between the PPI group and non-PPI group (OR 1.05, 95% CI 0.91 to 1.21, p= 0.50). Due to strict inclusion/exclusion criteria, relatively few studies were included for analysis, which may limit the impact of the results. [9]

Similarly, a 2016 meta-analysis also evaluated the effect of concomitant clopidogrel/PPI therapy on adverse cardiovascular outcomes in patients receiving PCI. A total of 12 cohort studies comprising 50,277 PCI patients were included for analysis. Concomitant therapy following PCI results in a significant increase in composite MACE (HR 1.28, 95% CI 1.24 to 1.32), MI (HR 1.51, 95% CI 1.40 to 1.62), and stroke (HR 1.46, 95% CI 1.15 to 1.86). Differences in all-cause death, cardiovascular death, and stent thrombosis were not statistically significant between concomitant therapy and clopidogrel monotherapy. Notably, the inconsistent definition of MACE outcomes may have affected the findings. [10]

A 2012 pharmacodynamic study found lansoprazole and esomeprazole to be the most potent CYP2C19 inhibitors, followed by dexlansoprazole and omeprazole. Rabeprazole and pantoprazole were observed to be the weakest inhibitors of CYP2C19. After taking plasma levels (static and dynamic), protein binding, and metabolism-dependent inhibition into consideration, it is suggested that esomeprazole and omeprazole are more likely to lead to clinically relevant inhibition of CYP2C19. [11]

References:

[1] Abraham NS, Hlatky MA, Antman EM, et al. ACCF/ACG/AHA 2010 Expert Consensus Document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the 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 Expert Consensus Documents. Circulation. 2010;122(24):2619-2633. doi:10.1161/CIR.0b013e318202f701
[2] Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions [published correction appears in Circulation. 2012 Feb 28;125(8):e412. Dosage error in article text]. Circulation. 2011;124(23):e574-e651. doi:10.1161/CIR.0b013e31823ba622
[3] Jneid H, Anderson JL, Wright RS, et al. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2012;60(7):645-681. doi:10.1016/j.jacc.2012.06.004
[4] Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association [published correction appears in Stroke. 2015 Feb;46(2):e54]. Stroke. 2014;45(7):2160-2236. doi:10.1161/STR.0000000000000024
[5] Charlot M, Ahlehoff O, Norgaard ML, et al. Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study [published correction appears in Ann Intern Med. 2011 Jan 4;154(1):76]. Ann Intern Med. 2010;153(6):378-386. doi:10.7326/0003-4819-153-6-201009210-00005
[6] Lee D, Kim JS, Kim BJ, Shin SY, Kim DB, Ahn HS. Influence of individual proton pump inhibitors on clinical outcomes in patients receiving clopidogrel following percutaneous coronary intervention. Medicine (Baltimore). 2021;100(52):e27411. doi:10.1097/MD.0000000000027411
[7] Jeridi D, Pellat A, Ginestet C, et al. The Safety of Long-Term Proton Pump Inhibitor Use on Cardiovascular Health: A Meta-Analysis. J Clin Med. 2022;11(14):4096. Published 2022 Jul 15. doi:10.3390/jcm11144096
[8] Guo H, Ye Z, Huang R. Clinical Outcomes of Concomitant Use of Proton Pump Inhibitors and Dual Antiplatelet Therapy: A Systematic Review and Meta-Analysis. Front Pharmacol. 2021;12:694698. Published 2021 Aug 2. doi:10.3389/fphar.2021.694698
[9] Han YY, Li ZX, Duan R. Efficacy and safety of proton pump inhibitors combined with clopidogrel in patients undergoing percutaneous coronary intervention: a meta-analysis. Rev Cardiovasc Med. 2021;22(1):167-174. doi:10.31083/j.rcm.2021.01.296
[10] Serbin MA, Guzauskas GF, Veenstra DL. Clopidogrel-Proton Pump Inhibitor Drug-Drug Interaction and Risk of Adverse Clinical Outcomes Among PCI-Treated ACS Patients: A Meta-analysis. J Manag Care Spec Pharm. 2016;22(8):939-947. doi:10.18553/jmcp.2016.22.8.939
[11] Zvyaga T, Chang SY, Chen C, et al. Evaluation of six proton pump inhibitors as inhibitors of various human cytochromes P450: focus on cytochrome P450 2C19. Drug Metab Dispos. 2012;40(9):1698-1711. doi:10.1124/dmd.112.045575

Relevant Prescribing Information

Clopidogrel [12]
WARNINGS AND PRECAUTIONS
Diminished Antiplatelet Activity in Patients with Impaired CYP2C19 Function: The metabolism of clopidogrel can also be impaired by drugs that inhibit CYP2C19, such as omeprazole or esomeprazole. Avoid concomitant use of clopidogrel with omeprazole or esomeprazole because both significantly reduce the antiplatelet activity of clopidogrel.

DRUG INTERACTIONS
CYP2C19 Inhibitors: Avoid concomitant use of clopidogrel bisulfate with omeprazole or esomeprazole. In clinical studies, omeprazole was shown to reduce significantly the antiplatelet activity of clopidogrel bisulfate when given concomitantly or 12 hours apart. A similar reduction in antiplatelet activity was observed with esomeprazole when given concomitantly with clopidogrel bisulfate. Dexlansoprazole, lansoprazole and pantoprazole had less effect on the antiplatelet activity of clopidogrel bisulfate than did omeprazole or esomeprazole.

Pharmacokinetics:
The effect of PPIs on the systemic exposure to the clopidogrel active metabolite following multiple doses of clopidogrel 75 mg was evaluated in dedicated drug interaction studies. Pharmacodynamic and pharmacokinetic parameters measured in these studies showed that the interaction was highest with omeprazole and least with dexlansoprazole.

References:

[12] Clopidogrel bisulfate. Prescribing information. ACI Healthcare USA, Inc.; 2021.

Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

Is the interaction between PPI and Plavix significant and do they all have the same degree of interaction?

Level of evidence

A - Multiple high-quality studies with consistent results  Read more→



Please see Table 1 for your response.


 

A randomized, 2-period, crossover design study to assess the effects of dexlansoprazole, lansoprazole, esomeprazole, and omeprazole on the steady-state pharmacokinetics and pharmacodynamics of clopidogrel in healthy volunteers

Design

Randomized, open-label, 2-period crossover study

N= 160

Objective

To assess the effects of different proton pump inhibitors (PPIs) on the steady-state pharmacokinetics and pharmacodynamics of clopidogrel

Study Groups

Lansoprazole (n= 40)

Dexlansoprazole (n= 40)

Omeprazole (n= 40)

Esomeprazole (n= 40)

Inclusion Criteria

Healthy volunteers

Exclusion Criteria

N/A

Methods

Healthy volunteers were randomized to receive clopidogrel with or without a PPI (dexlansoprazole 60 mg, lansoprazole 30 mg, esomeprazole 40 mg, or omeprazole 80 mg) daily for 9 days. Pharmacokinetic and dynamic assessments were performed on days 9 and 10. Patients then underwent crossover to receive the clopidogrel without PPI.

Duration

9 days

Outcome Measures

Time to reach peak concentration (Tmax), peak plasma concentration (Cmax), area under the plasma concentration-time curve (AUCt)

Baseline Characteristics

 

Lansoprazole (n= 40)

Dexlansoprazole (n=40)

Omeprazole (n= 40)

Esomeprazole (n= 40)

Age, years (range)

32.8 ± 6.48 (20 to 47) 35.7 ± 7.92 (22 to 53) 34.0 ± 7.40 (22 to 51) 33.3 ± 7.10 (20 to 49)

Women

20 (50%) 20 (50%) 20 (50%) 20 (50%)

White

40 (100%) 39 (97.5%) 39 (97.5%) 39 (97.5%)

Hispanic or latino

40 (100%) 38 (95.0%) 38 (95.0%) 40 (100%)

Weight, kg

Height, cm

BMI, kg/m2

70.1 ± 10.29

164.3 ± 8.91

25.9 ± 2.26

70.8 ± 9.95

165.0 ± 8.49

26.0 ± 2.41

 

68.6 ± 7.44

162.3 ± 8.40

26.1 ± 2.16

71.6 ± 10.83

164.3 ± 8.73

26.4 ± 2.50

Results

Endpoint

Lansoprazole (n= 40)

Dexlansoprazole (n= 40)

Omeprazole (n= 40)

Esomeprazole (n= 40)

Tmax, h

Clopidogrel with PPI

Clopidogrel alone



0.50 ± 0.50/4.00

0.50 ± 0.50/1.50

 

0.50 ± 0.50/1.50

0.50 ± 0.50/1.50



0.50 ± 0.50/3.00

0.50 ± 0.50/1.00



0.50 ± 0.50/1.50

0.50 ± 0.50/1.00

Cmax, ng/mL

Clopidogrel with PPI

Clopidogrel alone

Ratio (90% confidence interval)



30.01 ± 15.26

39.14 ± 12.55

0.70 (0.611 to 0.803)

 

29.33 ± 12.4

38.85 ± 15.7

0.73 (0.652 to 0.827)



22.55 ± 10.68

38.25 ± 12.46

0.56 (0.488 to 0.635)



24.69 ± 10.64

40.97 ± 22.91

0.68 (0.506 to 0.909)

AUCt, ng x h/mL

Clopidogrel with PPI

Clopidogrel alone

Ratio (90% confidence interval)



36.42 ± 10.82

41.69 ± 10.02

0.86 (0.802 to 0.916)

 

37.75 ± 13.13

41.25 ± 14.69

0.91 (0.857 to 0.967)



26.28 ± 8.80

37.78 ± 12.04

0.69 (0.644 to 0.749)



31.23 ± 9.94

42.35 ± 18.79

0.84 (0.644 to 1.093)

Values are presented as the median ± minimum/maximum for Tmax and mean ± standard deviation for Cmax and AUCt.

All PPIs decreased the peak plasma concentration of clopidogrel active metabolite. However, dexlansoprazole was the least to affect clopidogrel.

Study Author Conclusions

Generation of clopidogrel active metabolite and inhibition of platelet function were reduced less by the coadministration of dexlansoprazole or lansoprazole with clopidogrel than by the coadministration of esomeprazole or omeprazole. These results suggest that the potential of PPIs to attenuate the efficacy of clopidogrel could be minimized by the use of dexlansoprazole or lansoprazole rather than esomeprazole or omeprazole. 

InpharmD Researcher Critique

The results showed that dexlansoprazole's effect on clopidogrel activity was minimal and not significant. However, a decrease can be seen despite the drug's presumed lack of effect on CYP2C19.



References:

Frelinger AL 3rd, Lee RD, Mulford DJ, et al. A randomized, 2-period, crossover design study to assess the effects of dexlansoprazole, lansoprazole, esomeprazole, and omeprazole on the steady-state pharmacokinetics and pharmacodynamics of clopidogrel in healthy volunteers [published correction appears in J Am Coll Cardiol. 2012 Aug 7;60(6):566-7]. J Am Coll Cardiol. 2012;59(14):1304-1311. doi:10.1016/j.jacc.2011.12.024