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Controversy of proton pump inhibitor and clopidogrel interaction: a review

Tan HJ

J Dig Dis, 2010 Dec;11(6):334-42.
PMID: 21091895 DOI: 10.1111/j.1751-2980.2010.00466.x

A proton pump inhibitor (PPI) is often co-prescribed with clopidogrel to reduce the gastrointestinal risk of bleeding ulcers in patients following acute coronary syndrome or a stent implant. However, the safety issue of such practice has been scrutinized after some studies reporting an increased incidence of cardiovascular events and mortality, although there have also been contrary research reports. This has lead to a warning statement from the US Food and Drug Administration cautioning the concomitant use of PPI and clopidogrel. This review examines the evidence of PPI as gastroprotective agent, histamine H(2) antagonists as an alternative therapy, the influence of PPI on the antiplatelet effect of clopidogrel, and the controversies of various studies.

Matched MeSH terms: Ticlopidine/administration & dosage
Fulltext Malaysia-ACute CORonary syndromes Descriptive study (ACCORD): evaluation of compliance with existing guidelines in patients with acute coronary syndrome

Ahmad WA, Ramesh SV, Zambahari R

Singapore Med J, 2011 Jul;52(7):508-11.
PMID: 21808962

The ACute CORonary syndromes Descriptive study (ACCORD) is a prospective observational study that evaluates the management of acute coronary syndrome (ACS) in clinical practice and the use of antiplatelet agents in acute settings and after discharge. The secondary objective of this study was to obtain information on risk factors in a large cohort of patients with ACS.
Comment in: Sachithanandan A. Malaysia-ACCORD study: tip of the cardiovascular iceberg--we must do better. Singapore Med J, 2011 Sep;52(9):702;

Matched MeSH terms: Ticlopidine/administration & dosage
CYP2C19 genotypes and their impact on clopidogrel responsiveness in percutaneous coronary intervention

Mejin M, Tiong WN, Lai LY, Tiong LL, Bujang AM, Hwang SS, et al.

Int J Clin Pharm, 2013 Aug;35(4):621-8.
PMID: 23661171 DOI: 10.1007/s11096-013-9783-y

BACKGROUND: Cytochrome P450 2C19 (CYP2C19) loss-of-function polymorphisms are more common in Asian populations and have been associated with diminished antiplatelet response to clopidogrel. In this era of 'personalised medicine', combining genotyping and phenotyping as a strategy to personalise antiplatelet therapy warrants further exploration.
OBJECTIVE: This study aimed to investigate the prevalence and impact of CYP2C19*2, *3 and *17 genotypes on clopidogrel responsiveness in a multiethnic Malaysian population planned for percutaneous coronary intervention.
SETTING: Between October 2010 and March 2011, a total of 118 consecutive patients planned for percutaneous coronary intervention were enrolled in Sarawak General Hospital, Borneo. All patients received at least 75 mg aspirin daily for at least 2 days and 75 mg clopidogrel daily for at least 4 days prior to angiography.
METHOD: Genotyping for CYP2C19*2 (rs4244285, 681G > A), *3 (rs4986893, 636G > A) and *17 (rs11188072, -3402C > T) alleles were performed by polymerase chain reaction-restriction fragment linked polymorphism method. Whole blood ADP-induced platelet aggregation was assessed with multiple electrode platelet aggregometry (MEA) using the Multiplate Analyzer.
MAIN OUTCOME MEASURES: The distribution of CYP2C19*2, *3 and *17 among different ethnic groups and the association between genotype, clopidogrel responsiveness and clinical outcome were the main outcome measures.
RESULTS: The highest prevalence of poor metabolisers (carriers of at least one copy of the *2 or *3 allele) was among the Chinese (53.7 %), followed by the Malays (26.9 %), Ibans (16.4 %) and other races (3.0 %). Poor metabolisers (PMs) had the highest mean MEA (303.6 AU*min), followed by normal metabolisers (NMs) with 270.5 AU*min and extensive metabolisers (EMs) with 264.1 AU*min (p = 0.518). Among poor responders to clopidogrel, 65.2 % were PMs and NMs, respectively, whereas none were EMs (p = 0.350). Two cardiac-related deaths were reported.
CONCLUSION: There was a diverse inter-ethnic difference in the distribution of CYP2C19 polymorphism. The findings of this study echo that of other studies where genotype appears to have a limited impact on clopidogrel responsiveness and clinical outcome in low-risk patients.

Matched MeSH terms: Ticlopidine/administration & dosage
CYP2C19 and PON1 polymorphisms regulating clopidogrel bioactivation in Chinese, Malay and Indian subjects

Chan MY, Tan K, Tan HC, Huan PT, Li B, Phua QH, et al.

Pharmacogenomics, 2012 Apr;13(5):533-42.
PMID: 22462746 DOI: 10.2217/pgs.12.24

AIM, MATERIALS & METHODS: We investigated the functional significance of CYP2C19*2, *3, *17 and PON1 Q192R SNPs in 89 consecutive Asian patients on clopidogrel treatment and the prevalence of functionally significant polymorphisms among 300 Chinese, Malays and Asian Indians.

Matched MeSH terms: Ticlopidine/administration & dosage
East Asian perspective on the interaction between proton pump inhibitors and clopidogrel

Zou D, Goh KL

J Gastroenterol Hepatol, 2017 Jun;32(6):1152-1159.
PMID: 28024166 DOI: 10.1111/jgh.13712

Both proton pump inhibitors (PPIs) and clopidogrel are widely prescribed in the Asia-Pacific population. PPIs are the mainstay therapeutic agents for prophylaxis against aspirin gastropathy and for acid-related disorders including gastroesophageal reflux disease. They are also co-prescribed with oral anticoagulant agents and with dual-antiplatelet therapy for the treatment and prevention of gastrointestinal bleeding. Clopidogrel belongs to the drug class of thienopyridines and is currently the most widely prescribed oral anticoagulant agent either alone or in combination with aspirin. Platelet inhibition by clopidogrel is prone to significant inter-individual variability and is believed to be affected by several factors such as genetics and drug-drug interactions. Since it was first reported in 2009, the potential for drug-drug interactions between PPIs and clopidogrel has remained headline news, and its significance in clinical practice is the subject of an ongoing debate. For East Asian patients in particular, the clinical relevance of the interaction between PPIs and clopidogrel remains unclear because of conflicting data, as well as underrepresentation of East Asian subjects in landmark trials. Increased CYP2C19 genetic polymorphisms in individuals from Asia-Pacific countries only fuel the confusion. Recent studies in East Asian cohorts suggests that the potential of PPIs to attenuate the efficacy of clopidogrel could be minimized by the use of newer PPIs with weaker affinity for the CYP2C19 isoenzyme, namely, pantoprazole, dexlansoprazole, and rabeprazole. This review aims to help clinicians choose the most appropriate PPI for co-prescription with clopidogrel in patients from Asia-Pacific countries.

Matched MeSH terms: Ticlopidine/administration & dosage