Thienopyridines and Statins: Assessing a Potential Drug-Drug Interaction

Neubauer, H.; Mügge, Andreas

doi:10.2174/138161206776361354

Cited by 24 publications

(11 citation statements)

References 45 publications

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“…Indeed, clopidogrel has been at the centre of controversy previously, with a reported possible interaction with atorvastatin, which competes for CYP3A4 (see Figure 1). 32 Atorvastatin was found to attenuate the antiplatelet activity of clopidogrel in a dose-dependent manner in vitro. 33 However, this observation has since been refuted and was not found to be associated with worse clinical outcomes.…”

Section: -24mentioning

confidence: 98%

Review article: proton pump inhibitors with clopidogrel - evidence for and against a clinically-important interaction

Disney

Watson

Blann

et al. 2011

Alimentary Pharmacology &Amp; Therapeutics

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Aliment Pharmacol Ther 2011; 33: 758–767 Summary Background The treatment of acute coronary syndromes involves a combination of antiplatelet therapies. Proton pump inhibitors are frequently recommended for patients receiving clopidogrel in addition to aspirin, to minimise the risk of bleeding. Several studies have shown that proton pump inhibitors can affect the platelet inhibitory effects of clopidogrel. However, the data on whether this has an effect on clinical outcomes are conflicting and a definitive answer is still awaited. Aim To provide an overview of the evidence for the pharmacological interaction between proton pump inhibitors and clopidogrel and to discuss whether this interaction translates into adverse clinical outcomes. Despite recent developments, clear consensus is lacking. Methods A search of the published literature combined with the authors’ knowledge of the field. Results There is evidence to show that proton pump inhibitors can influence the pharmacodynamics of clopidogrel, but the data suggesting clinical effects are weak and conflicting. Supporting a clinically important interaction are four retrospective studies including over 11 000 patients prescribed both clopidogrel and a proton pump inhibitor. Evidence against a clinically important interaction is derived from over 18 000 patients from seven studies, including the only prospective trial to examine the potential interaction. Confounding variables are relevant and prospective clinical evidence is lacking. Conclusions Proton pump inhibitors offer clear protection and the concern over clinically relevant interactions with clopidogrel is biologically plausible, but not yet proven.

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Section: -24mentioning

confidence: 98%

Review article: proton pump inhibitors with clopidogrel - evidence for and against a clinically-important interaction

Disney

Watson

Blann

et al. 2011

Alimentary Pharmacology &Amp; Therapeutics

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“…Importantly, an interaction with the lipophilic statin atorvastatin that competes for CYP 3A4 has also been demonstrated (8 -10). The clinical significance of the lipophilic statin-clopidogrel interaction has not been definitively demonstrated and remains controversial (11). In a recent study, co-administration of ketoconazole (a CYP3A4 inhibitor) did not affect prasugrel (a third-generation thienopyridine) active metabolite generation or prasugrel-induced platelet inhibition.…”

Section: See Page 256mentioning

confidence: 99%

Omeprazole

Gurbel¹,

Lau²,

Tantry³

2008

Journal of the American College of Cardiology

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Clopidogrel is a prodrug activated in the liver to a metabolite that is a specific and irreversible inhibitor of the platelet P2Y 12 receptor. The P2Y 12 receptor mediates the amplification of aggregation induced by adenosine diphosphate (ADP) and also other agonists. In addition, P2Y 12 inhibition also affects coagulation and inflammation (1). These mechanisms serve as the rationale for P2Y 12 blockade in high-risk cardiovascular disease. Indeed, following significant clinical benefits reported in major clinical trials, clopidogrel, along with aspirin therapy, is now widely used around the world to prevent thrombotic events in patients with acute coronary syndromes and after coronary artery stenting (2). See page 256In 2003, we first reported (3) evidence of a nonuniform antiplatelet effect of clopidogrel therapy in patients undergoing coronary stenting by serially measuring ADP-induced platelet aggregation and expression of activation-dependent receptors. Platelet inhibition and after-treatment reactivity were normally distributed. Of great potential concern was the observation of nonresponsiveness ("resistance"), defined as Յ10% absolute change in ADP-induced platelet aggregation in a substantial percentage of patients. Our data suggested that clopidogrel nonuniformly inhibited its target and that in some patients the lack of inhibition was profound (3). Other investigators confirmed these results (2). These data served as the rationale for the development of new P2Y 12 receptor blockers with superior pharmacodynamic profiles (2).The mechanisms responsible for clopidogrel response variability and resistance are incompletely defined. Several lines of evidences indicated that clopidogrel nonresponsiveness is a pharmacokinetic problem associated with insufficient active metabolite generation that is influenced by limitations in intestinal absorption, as well as functional and genetic variability in the hepatic cytochrome (CYP) P450 isoenzymes (4 -7).Only ϳ15% of the absorbed clopidogrel dose is converted to an active thiol metabolite (R-130964), mainly by the hepatic CYP isoenzymes (6). Studies by our group (8 -10) demonstrated the inverse relation between after-clopidogrel platelet reactivity and CYP3A4 metabolic activity. Stimulation of CYP3A4 activity by rifampin or St. John's wort enhanced platelet inhibition by clopidogrel, whereas agents that competed with clopidogrel for CYP3A4 (e.g., erythromycin or troleandomycin) attenuated platelet inhibition. Importantly, an interaction with the lipophilic statin atorvastatin that competes for CYP 3A4 has also been demonstrated (8 -10). The clinical significance of the lipophilic statin-clopidogrel interaction has not been definitively demonstrated and remains controversial (11). In a recent study, co-administration of ketoconazole (a CYP3A4 inhibitor) did not affect prasugrel (a third-generation thienopyridine) active metabolite generation or prasugrel-induced platelet inhibition. Prasugrel is metabolized by other cytochromes in addition to CYP3A4. However, clopidogr...

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“…20 Dose-dependent atorvastatin inhibitory effect on clopidogrel biotransformation was shown in an ex vivo experiment by Lau et al 21 In one later study about the influence of statin on the clopidogrel antiplatelet effect in vivo, it was revealed that the interference between statins and clopidogrel was best seen during the loading phase (5 h), but in the maintenance phase (48 h) it was marginal, although still significant. 22 Although the experimental data in vitro and ex vivo showed that statins can influence clopidogrel biotransformation, these results cannot be directly integrated into clinical practice. Nowadays, there are no statistically significant results about the influence of statin on clopidogrel therapy in different clinical studies.…”

Section: Clopidogrel and Lipophilic Statins Co-medicationmentioning

confidence: 99%

Clopidogrel and the possibility of drug–drug interaction in primary health care

Urtane¹,

Aitullina²,

Pukite³

2013

Journal of Young Pharmacists

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a b s t r a c tIntroduction: Clopidogrel ineffectiveness is a serious problem in antiplatelet therapy. Many factors may contribute to this phenomenon. One of them is clopidogrel drugedrug interaction with CYP2C19 and CYP3A4 enzyme inhibitors. The main goal of this descriptive study was to assess the prevalence of cases of clopidogreledrug interactions in the primary health care physicians' practices. Materials and methods: During 2010e2011, 80 patients receiving clopidogrel antiplatelet therapy from primary care physicians' clinical practices were involved in this study. By using questionnaires and case histories, the following information was collected: Age, gender, clinical diagnoses, and medications used.Results: In the current study, drugs were used that could potentially influence the effect of clopidogrel: Omeprazole, lipophilic statins, calcium channel blockers (CCB). There was a different use of the abovementioned drugs before and after the initiation of the clopidogrel therapy, e.g., 12 (15.0%) and 44 (55.0%) patients used proton pump inhibitors (PPI) before and after the clopidogrel therapy accordingly (P ¼ 0.16; c 2 ¼ 1.91). However, pantoprazole was recommended more often than other PPI. The use of the potential CYP3A4 inhibitors e lipophilic statins and CCB e was increased after the prescription of clopidogrel too. Concomitant use of statins (mainly atorvastatin) with clopidogrel was observed in 75 (93.8%) patients and the use of CCB (mainly amlodipine) e in 33 (41.3%) patients. Conclusion: In the primary health care practices, it is revealed that there is co-medication of clopidogrel with weak CYP3A4 inhibitors, such as lipophilic statins and amlodipine, and with the moderate CYP2C19 inhibitor e omeprazole. The latter co-medication is potentially harmful and it is very important to inform the first care professionals about the opportunity to change omeprazole to pantoprazole, which does not influence clopidogrel biotransformation.

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Thienopyridines and Statins: Assessing a Potential Drug-Drug Interaction

Cited by 24 publications

References 45 publications

Review article: proton pump inhibitors with clopidogrel - evidence for and against a clinically-important interaction

Review article: proton pump inhibitors with clopidogrel - evidence for and against a clinically-important interaction

Omeprazole

Clopidogrel and the possibility of drug–drug interaction in primary health care

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