Proton Pump Inhibitors And Clopidogrel Association - PACA

Sep 21, 2009
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Trial Sponsor:
Grants from the Assistance Publique Hôpitaux de Marseille.
Date Published:
01/01/2009
Date Updated:
09/21/2009
Original Posted Date:
09/21/2009
References

Description:

Clopidogrel has been shown to have a broad variability in its response, partly related to the activity of the CYP450 system, specifically the isoform 2C19. A number of proton pump inhibitors (PPIs) are also metabolized by the same system, and so a few small studies have indicated that PPIs may attenuate the antiplatelet efficacy of clopidogrel. The PACA trial sought to assess the relative influences of omeprazole and pantoprazole on the antiplatelet efficacy of high-dose clopidogrel in patients presenting with non–ST-elevation acute coronary syndrome (NSTE-ACS).

Hypothesis:

Pantoprazole would be associated with less attenuation of antiplatelet efficacy of high-dose clopidogrel compared with omeprazole.

Study Design

Study Design:

Patients Enrolled: 104
Mean Follow Up: 1 month
Mean Patient Age: 63.5 years
Female: 14

Patient Populations:

  • NSTE-ACS within 12 hours before admission

Exclusions:

  • History of bleeding diathesis
  • Persistent STE-ACS
  • New York Heart Association functional class IV
  • Percutaneous intervention or coronary artery bypass grafting within 3 months
  • Contraindications to antiplatelet therapy
  • Platelet count <100 g/L
  • Creatinine clearance <25 ml/min
  • Use of glycoprotein IIb/IIIa antagonist before the procedure
  • Prior use of PPI or clopidogrel

Primary Endpoints:

  • Clopidogrel response 1 month after hospital discharge assessed with PRI VASP

Secondary Endpoints:

  • Post-treatment platelet reactivity assessed with ADP-Ag

Drug/Procedures Used:

Patients were randomized 1:1 to either omeprazole 20 mg or pantoprazole 20 mg.

Concomitant Medications:

Patients received oral loading doses of 250 mg aspirin and 600 mg clopidogrel at least 12 hours before stenting. Anticoagulation was obtained with enoxaparin when possible, or unfractionated heparin when contraindicated. All patients were discharged on 75 mg aspirin and 150 mg clopidogrel daily. Other discharge medications included statins (73%) and beta-blockers (77.9%).

Principal Findings:

A total of 104 patients were randomized, 52 to omeprazole and 52 to pantoprazole. Baseline characteristics were fairly similar between the two groups, except for hypertension, which was more prevalent in the omeprazole arm (65% vs. 42%). About 21% were diabetic, and 43% were smokers. Drug-eluting stents were used in 34% of the patients. Baseline platelet studies, including maximal intensity of adenosine diphosphate (ADP)–induced aggregation for platelet reactivity (ADP-Ag) (39.7%) and platelet reactivity index vasoactive stimulated phosphoprotein (PRI VASP) (33%) were similar between the two arms.

One month after treatment, patients receiving pantoprazole had significantly lower PRI VASP (indicating better platelet response), compared with those receiving omeprazole (36% vs. 48%, p = 0.007). No difference was noted for platelet reactivity with ADP-Ag between the omeprazole and pantoprazole arms (52% vs. 50%, p = 0.29). Clopidogrel nonresponders (defined as PRI VASP >50%) were also significantly higher in the omeprazole arm (44% vs. 23%, p = 0.04).

Interpretation:

The results of this small clinical trial indicate that pantoprazole is not associated with a reduction in antiplatelet efficacy when taken along with clopidogrel, as compared with omeprazole, although a third comparison arm with no PPIs would be needed to definitively make this statement. No clinical endpoints were measured in this trial.

Platelet studies had shown a similar reduction in antiplatelet efficacy with atorvastatin when taken along with clopidogrel, although this did not result in clinically significant differences in randomized trials focusing on outcomes. Similar trials are needed with PPIs before recommending one PPI versus the other. Currently, the use of PPIs should be restricted only to situations where they are definitively indicated, in the setting of concomitant usage of clopidogrel.

References:

Cuisset T, Frere C, Quilici J, et al. Comparison of omeprazole and pantoprazole influence on a high 150-mg clopidogrel maintenance dose: The PACA (Proton Pump Inhibitors And Clopidogrel Association) Prospective Randomized Study. J Am Coll Cardiol 2009;54:1149-53.

Keywords: Acute Coronary Syndrome, Platelet Aggregation Inhibitors, Drug-Eluting Stents, Hydroxymethylglutaryl-CoA Reductase Inhibitors, 2-Pyridinylmethylsulfinylbenzimidazoles, Ticlopidine, Heptanoic Acids, Proton Pump Inhibitors, Purinergic P2Y Receptor Antagonists, Pyrroles, Phosphoproteins, Omeprazole, Hypertension, Diabetes Mellitus


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