Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials. Lancet

TIMI Study Group, Brigham and Women's Hospital, Boston, MA 02115, USA.
The Lancet (Impact Factor: 45.22). 09/2009; 374(9694):989-97. DOI: 10.1016/S0140-6736(09)61525-7
Source: PubMed


Proton-pump inhibitors (PPIs) are often prescribed in combination with thienopyridines. Conflicting data exist as to whether PPIs diminish the efficacy of clopidogrel. We assessed the association between PPI use, measures of platelet function, and clinical outcomes for patients treated with clopidogrel or prasugrel.
In the PRINCIPLE-TIMI 44 trial, the primary outcome was inhibition of platelet aggregation at 6 h assessed by light-transmission aggregometry. In the TRITON-TIMI 38 trial, the primary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke. In both studies, PPI use was at physician's discretion. We used a multivariable Cox model with propensity score to assess the association of PPI use with clinical outcomes.
In the PRINCIPLE-TIMI 44 trial, 201 patients undergoing elective percutaneous coronary intervention were randomly assigned to prasugrel (n=102) or high-dose clopidogrel (n=99). Mean inhibition of platelet aggregation was significantly lower for patients on a PPI than for those not on a PPI at 6 h after a 600 mg clopidogrel loading dose (23.2+/-19.5% vs 35.2+/-20.9%, p=0.02), whereas a more modest difference was seen with and without a PPI after a 60 mg loading dose of prasugrel (69.6+/-13.5% vs 76.7+/-12.4%, p=0.054). In the TRITON-TIMI 38 trial, 13,608 patients with an acute coronary syndrome were randomly assigned to prasugrel (n=6813) or clopidogrel (n=6795). In this study, 33% (n=4529) of patients were on a PPI at randomisation. No association existed between PPI use and risk of the primary endpoint for patients treated with clopidogrel (adjusted hazard ratio [HR] 0.94, 95% CI 0.80-1.11) or prasugrel (1.00, 0.84-1.20).
The current findings do not support the need to avoid concomitant use of PPIs, when clinically indicated, in patients receiving clopidogrel or prasugrel.
Daiichi Sankyo Company Limited and Eli Lilly and Company sponsored the trials. This analysis had no funding.

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    • "Few studies, however, have focused on patients with cardiovascular disease at high risk of upper GI bleeding [23]. Most have excluded patients with a history of GI bleeding [14,17,18,20,24] although these patients might be at high risk of a recurrence of severe GI bleeding. Furthermore, these studies have mainly evaluated the combined use of clopidogrel and aspirin together with PPIs which might dilute or mix the real interaction between clopidogrel and PPIs [25,26]. "
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    ABSTRACT: It is unclear whether concomitant use of clopidogrel and proton-pump inhibitors (PPIs) increases the risk of recurrence of cardiovascular disease or death in patients at high risk of upper gastrointestinal (GI) bleeding. Based on the Swedish Patient Register, a cohort of cardiovascular disease (including acute myocardial infarction, stroke and angina, from 2006 to 2008) was selected from a population with any diagnosis of upper GI bleeding. Data on drug prescription was retrieved from the Prescribed Drug Register. Patients entered into the cohort after their first discharge for cardiovascular disease and were followed up to death, recurrence of cardiovascular disease, or 90 days. A Cox regression model was conducted and hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated to evaluate the risks among users of different drug prescriptions. Patients who were current users of only PPIs (HR 2.02, 95% CI 1.19-3.44), only clopidogrel (HR 1.14, 95% CI 0.53-2.45) and nonusers of both (HR 2.36, 95% CI 1.39-4.00) were at a higher risk of death compared with patients with a concomitant use. Results were similar among 1779 patients who had any history of upper GI bleeding (HR 2.05, 95% CI 1.18-3.54; HR 1.25, 95% CI 0.57-2.72; HR 2.30, 95% CI 1.33-3.98, respectively). Among patients at high risk of upper GI bleeding, those with a concomitant use of PPIs and clopidogrel were at a decreased risk of mortality, and possibly also a decreased risk of recurrence of cardiovascular disease.
    Full-text · Article · Apr 2014 · BMC pharmacology & toxicology
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    • "Furthermore, there are concerns about PPI interactions with other commonly prescribed medications, most notably clopidogrel [38]. While controversial, there are data to suggest that inhibition of platelet aggregation with clopidogrel is significantly decreased in patients on concomitant PPI therapy [39,40]. The US Food and Drug Administration has issued a public health warning on the possible interaction between clopidogrel and PPIs - specifically omeprazole and esomeprazole, the latter being the PPI component of the available prescription PPI/NSAID combination [41] This same warning applies to the H2RA cimetidine, but not to other H2RAs. "
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    ABSTRACT: Pain affects the quality of life for millions of individuals and is a major reason for healthcare utilization. As populations age, medical personnel will need to manage more and more patients suffering from pain associated with degenerative and inflammatory musculoskeletal disorders. Nonsteroidal anti-inflammatory drugs (NSAIDs) are an effective treatment for both acute and chronic musculoskeletal pain; however, their use is associated with potentially significant gastrointestinal (GI) toxicity. Guidelines suggest various strategies to prevent problems in those at risk for NSAID-associated GI complications. In this article, we review the data supporting one such strategy - the use of histamine type-2 receptor antagonists (H2RAs) - for the prevention of GI adverse events in NSAID users. Older studies suggest that high-dose H2RAs are effective in preventing upper GI ulcers and dyspepsia. This suggestion was recently confirmed during clinical trials with a new ibuprofen/famotidine combination that reduced the risk of ulcers by 50% compared with ibuprofen alone.
    Preview · Article · Jul 2013 · Arthritis Research & Therapy
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    • "Clopidogrel is an antiplatelet agent that requires cytochrome P450 2C19 enzyme to convert to its pharmacologically active form. There has been considerable controversy regarding the risk of cardiovascular events from the potential interaction between clopidogrel and proton pump inhibitors, including esomeprazole.47–49 In 2009, the FDA released warnings specifically against the concomitant use of omeprazole or esomeprazole with clopidogrel based on pharmacokinetic and platelet function data.50 "
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    ABSTRACT: Low dose aspirin therapy plays a fundamental role in both the primary and secondary prevention of cardiovascular events. Although the evidence using low dose aspirin for secondary prevention is well-established, the decision to use aspirin for primary prevention is based on an evaluation of the patient's risk of cardiovascular events compared to their risk of adverse events, such as bleeding. In addition to the risk of bleeding associated with long term aspirin administration, upper gastrointestinal side effects, such as dyspepsia often lead to discontinuation of therapy, which places patients at an increased risk for cardiovascular events. One option to mitigate adverse events and increase adherence is the addition of esomeprazole to the medication regimen. This review article provides an evaluation of the literature on the concomitant use of aspirin and esomeprazole available through February 2013. The efficacy, safety, tolerability, cost effectiveness, and patient quality of life of this regimen is discussed. A summary of the pharmacokinetic and pharmacodynamic interactions between aspirin and esomeprazole, as well as other commonly used cardiovascular medications are also reviewed. The addition of esomeprazole to low dose aspirin therapy in patients at high risk of developing gastric ulcers for the prevention of cardiovascular disease, significantly reduced their risk of ulcer development. Pharmacokinetic and pharmacodynamic studies suggested that esomeprazole did not affect the pharmacokinetic parameters or the antiplatelet effects of aspirin. Therefore, for those patients who are at a high risk of developing a gastrointestinal ulcer, the benefit of adding esomeprazole likely outweighs the risks of longer term proton pump inhibitor use, and the combination can be recommended. Administering the two agents separately may also be more economical. On the other hand, for those patients at lower risk of developing a gastrointestinal ulcer, both the additional risk and cost make the inclusion of a proton pump inhibitor unwarranted.
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