PPI and Clopidogrel Response
Condition: Drug Interaction
Study type: Interventional
Phase: Phase 1

Summary: 
      Clopidogrel, in combination with aspirin, is currently the recommended treatment for
      secondary prevention of ischemic events in high-risk patients and for prevention of coronary
      artery stent thrombosis. Patients receiving aspirin and clopidogrel are frequently treated
      with proton pump inhibitors, such as omeprazole or pantoprazole, in order to prevent the risk
      of gastrointestinal bleeding, accorded to guidelines. An interaction between proton pump
      inhibitors and clopidogrel has been suggested, which may lead to a decrease of clopidogrel
      effects. It remains unclear whether this interaction between PPIs and clopidogrel might be a
      class effect or if this may be affected by timing regimen.

      The objectives of this two-phase investigation are:

        1. to compare clopidogrel platelet inhibitory effects when taken at the same time versus
           separated at least 8 hours from omeprazole administration.

        2. to compare clopidogrel-induced inhibitory effects when taken at the same time versus
           staggered at least 8 hours from pantoprazole administration.
    

Detailed description: 
      Clopidogrel, in combination with aspirin, is currently the recommended treatment for
      secondary prevention of ischemic events in high-risk patients and for prevention of coronary
      artery stent thrombosis. Patients receiving aspirin and clopidogrel are frequently treated
      with proton pump inhibitors, such as omeprazole or pantoprazole, in order to prevent the risk
      of gastrointestinal bleeding, accorded to guidelines. An interaction between proton pump
      inhibitors and clopidogrel has been suggested, which may lead to a decrease of clopidogrel
      effects. It remains unclear whether this interaction between PPIs and clopidogrel might be a
      class effect or if this may be affected by timing regimen. The objectives of this two-phase
      investigation are: 1. to compare clopidogrel platelet inhibitory effects when taken at the
      same time versus separated at least 8 hours from omeprazole administration. 2. to compare
      clopidogrel-induced inhibitory effects when taken at the same time versus staggered at least
      8 hours from pantoprazole administration. The clopidogrel dose will be a 600mg loading dose
      followed by a 75mg daily maintenance dose, starting the next day for 7 days. Omeprazole will
      be used at a daily dose of 40mg and pantoprazole at 80mg.

      The proposed study will have a prospective, randomized, cross-over design. Subjects are
      randomized in a 1:1 fashion to take PPI concomitantly (CONC regimen) or staggered by 8-12
      hours (STAG regimen) for one-week on a background of clopidogrel therapy. In particular, in
      the CONC regimen both drugs were taken in the morning, while in the STAG regimen clopidogrel
      was taken in the morning and omeprazole in the evening. After a 2-4 week washout period,
      subjects crossed-over treatment regimen. After completing these two treatment phases,
      subjects underwent another washout period of 2-4 weeks and were treated for 1 week with
      clopidogrel alone, without receiving omeprazole therapy (CLOP regimen). The sequence with the
      PPI pantoprazole will have the same prospective, randomized, cross-over design as the
      omeprazole sequence. A CLOP regimen in the absence of pantoprazole will be collected before
      entering randomization phase with adequate wash-out period.

      Blood sampling for platelet function assessments were performed at all three phases of the
      study at the following time points: a) baseline, b) 24 hours after LD (before intake of study
      medication), and c) 7 days (24 hours after the last MD).
    

Intervention name(s): omeprazole and pantoprazole
Intervention type(s): Drug
Intervention description(s): The clopidogrel dose will be a 600mg loading dose followed by a 75mg daily maintenance dose, starting the next day for 7 days. Omeprazole will be used at a daily dose of 40mg and pantoprazole at 80mg.
Intervention MeSH terms: Omeprazole; Pantoprazole
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Keywords: proton pump inhibitor; clopidogrel; platelet function