Journal of Thrombosis and Haemostasis, 12: 2–13

DOI: 10.1111/jth.12445

REVIEW ARTICLE

Clinical implications of drug–drug interactions with P2Y12 receptor inhibitors € E N B UH € L , ‡ A . D . M I C H E L S O N § and G . D E L L E - K A R T H * J . M . S I L L E R - M A T U L A , * D . T R E N K , † S . K R AH *Department of Cardiology, Medical University of Vienna, Vienna, Austria; †Department of Clinical Pharmacology, Clinics of Cardiology and Angiology II, Universitaets-Herzzentrum Freiburg Bad Krozingen, Bad Krozingen, Germany; ‡Department of Clinical Pharmacology & Toxicology, University Hospital Basel, Basel, Switzerland; and §Center for Platelet Research Studies, Division of Hematology/Oncology, Boston Children’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

To cite this article: Siller-Matula JM, Trenk D, Kr€ahenb€ uhl S, Michelson AD, Delle-Karth G. Clinical implications of drug–drug interactions with P2Y12 receptor inhibitors. J Thromb Haemost 2014; 12: 2–14.

Summary. Polypharmacy in patients undergoing coronary artery stenting or in those presenting with an acute coronary syndrome is common. Nevertheless, the risk of drug–drug interactions in patients treated simultaneously with P2Y12 receptor inhibitors is less well considered in routine clinical practice. Whereas the irreversible P2Y12 receptor inhibitors clopidogrel and prasugrel are prodrugs requiring cytochrome P450 (CYP) enzymes for metabolic activation, such activation is not necessary for the directacting reversible P2Y12 receptor inhibitor ticagrelor. Several drugs frequently used in cardiology have been shown to interact with the metabolism of P2Y12 receptor inhibitors in pharmacodynamic studies. Whereas several drug– drug interactions have been described for clopidogrel and ticagrelor, prasugrel seems to have a low potential for drug–drug interactions. The clinical implications of these interactions have raised concern. In general, concomitant administration of P2Y12 receptor antagonists and strong inhibitors or inducers of CYP3A/CYP2C19 should be performed with caution in patients treated with clopidogrel/ticagrelor. Under most circumstances, clinicians have the option of prescribing alternative drugs with less risk of drug–drug interactions when used concomitantly with P2Y12 receptor inhibitors. Keywords: clopidogrel; drug interactions; P2Y12 purinoceptor antagonists; platelet aggregation inhibitors; prasugrel; ticagrelor.

Correspondence: Jolanta M. Siller-Matula, Department of Cardiology, Medical University of Vienna, W€ahringerg€ urtel 18-20, 1090 Vienna, Austria. Tel.: +43 1 404 004 614; fax: +43 1 404 004 216. E-mail: [email protected] Received 10 July 2013 Manuscript handled by: C. Gachet Final decision F. R. Rosendaal, 29 October 2013

P2Y12 receptor inhibitors The P2Y12 receptor on the platelet surface plays a crucial role in thrombus formation and stabilization by augmenting the signal for ADP-induced platelet aggregation and promoting platelet release reactions. The P2Y12 receptor is the target of several antagonists that have proven therapeutic value for the prevention of cardiovascular events (Fig. 1). Ticlopidine, clopidogrel, prasugrel and ticagrelor are approved P2Y12 antagonists, whereas cangrelor is still in clinical development [1]. Ticlopidine is not frequently prescribed, owing to its unfavorable safety profile, whereas clopidogrel is the most widely used P2Y12 inhibitor [2]. Prasugrel and ticagrelor are novel P2Y12 receptor inhibitors. The thienopyridines clopidogrel and prasugrel act as irreversible oral inhibitors of the P2Y12 receptor. Ticagrelor, a cyclopentyl-triazolo-pyrimidine, is the first orally available reversible antagonist of the P2Y12 receptor. Metabolism of P2Y12 receptor inhibitors Clopidogrel is a prodrug, requiring complex enteric and hepatic bioactivation. Clopidogrel is subject to efflux via P-glycoprotein (P-gp; also known as multidrug resistance protein 1 or ATP-binding cassette subfamily B member 1) in the gut. After absorption, the majority of clopidogrel (up to 90%) is metabolized by esterase-1 to an inactive carboxylic acid derivative, SR26334 (Fig. 2). The vast majority of clopidogrel metabolites circulating in plasma are its inactive metabolites, approaching peak levels that are 1000-fold higher than that of the active metabolite [3]. The conversion of clopidogrel to its active metabolite, R-130964, is a two-step process involving the formation of the intermediate metabolite 2-oxo-clopidogrel. In these two steps, cytochrome P450 (CYP)2C19 and CYP3A4 appear to have the most important roles, with CYP2B6, CYP1A2, CYP3A5 and CYP2C9 being less involved [4]. Interestingly, clopidogrel biotransformation studies in © 2013 International Society on Thrombosis and Haemostasis

Drug interactions 3

GPIbα

Thrombin Atopaxar Varopaxar

ADP GPIb–IX–V

Clopidogrel Prasugrel Ticagrelor Cangrelor

Arachidonic acid PAR-1

COX-1

Aspirin

interactions with clopidogrel [5]. In the vast majority of studies, CYP2C19 gene polymorphisms with reducedfunction alleles were associated with attenuated platelet inhibition and poor clinical outcomes under dual antiplatelet therapy with aspirin and clopidogrel [6,7], whereas some studies failed to confirm the association between CYP2C19 loss-of-function polymorphism and worse clinical outcome [8]. The maximum inhibition of platelet aggregation (40–60%) is achieved between 2 and 6 h after the administration of 600 mg of clopidogrel, mirroring the extensive hepatic metabolism of the prodrug [9]. As the inhibition of the P2Y12 receptor is irreversible, the pharmacokinetic half-life of clopidogrel does not reflect the duration of platelet inhibition. Half of the clopidogrel metabolites are excreted in the urine and half in feces. Like clopidogrel, prasugrel is a prodrug requiring bioactivation. Prasugrel is nearly completely (≥ 80%) absorbed from the intestine, and is rapidly hydrolyzed by carboxyesterases-2 to the thiolactone precursor (R-95913), primarily in the bowel and plasma (Fig. 2). As a consequence, the initial biotransformation of prasugrel to the thiolactone amounts to ~ 70%, and it is therefore much more effective in terms of proportional conversion rates than clopidogrel. Five cytochromes are involved in the generation of the active metabolite of prasugrel from the thiolactone precursor: CYP3A4/5, CYP2C19, CYP2C9, 2D6, and CYP2B6. Of these, CYP3A4 and CYP2B6 appear to be of major importance [10]. Because of these

TXA2

P2Y12 GPIIb–IIIa TP GPVI

Eptifibatide Tirofiban Abciximab

GPIIb–IIIa Fibrinogen

Collagen

Fig. 1. Receptors involved in platelet activation and aggregation, and binding sites of platelet inhibitors. COX-1, cyclooxygenase 1; GP, glycoprotein; PAR-1, protease-activated receptor 1; TP, thromboxane/prostanoid receptor; TXA2, thromboxane A2.

human liver microsomes have shown that, at clopidogrel concentrations of > 10 mM, CYP3A4 is mainly responsible for clopidogrel biotransformation, whereas CYP2C19 contributes only at clopidogrel concentrations of < 10 mM, potentially explaining the conflicting results between in vitro and in vivo investigations regarding drug

Oxidation by CYP: 2C19, 2C9, 3A4/5, 2B6

Hydrolysis by esterase-1 OCH3

O

S

Cl

O

S

Cl

Hydrolysis by esterase-2

F

CH3

Cl

2-oxoClopidogrel

Cl

Clopidogrel active metabolite

F

P2Y12 receptor

HS

F

Oxidation by CYP: Prasugrel 2C19, 2C9, 3A4/5, active metabolite 2B6, 2D6

2-oxo-Prasugrel

Prasugrel prodrug

Inactivated platelet

N

HOOC

CYP450

O S

N

HS

O

N

O C

S

O

N O

HOOC

N O

Clopidogrel inactive metabolite

Clopidogrel prodrug

OCH3

O

OCH3

O

N

N S

Oxidation by CYP: 2C19, 3A4, 1A2, 2B6

OH

O

ADP

F F

O-deethylation by CYP3A

F F

HN

OH

N N

OH

N O

N

N

S

Ticagrelor OH

N

N

N

P2Y12 receptor

HN

F

CH3 OH

N

N

S

F

CH3 HN

Ticagrelor active metabolite

OH

N

OH

OH

N

N O

N

N

S

Ticagrelor OH

Fig. 2. Metabolic pathways of P2Y12 receptor inhibitors. CYP, cytochrome P450. © 2013 International Society on Thrombosis and Haemostasis

OH

CH3

Activated platelet

4 J. M. Siller-Matula et al

differences in metabolic pathways, the active metabolite of prasugrel is generated more efficiently in vivo than the active metabolite of clopidogrel. No parent prasugrel is found in plasma. Approximately 70% of the prasugrel administered is converted into the active metabolite, which results in higher concentrations of the active metabolite, and gives a more predictable pharmacodynamic response and a faster onset of action than those obtained with clopidogrel [11]. The thiolactone precursor, 2-oxo-prasugrel (R-95913) and the active metabolite (R138727) of prasugrel appear rapidly in the blood after ingestion, showing a significant pharmacodynamic effect after 15 min [12]. Prasugrel’s metabolites are eliminated with a median half-life ranging from 3 to 9 h. Two-thirds of metabolites are excreted in the urine, and one-third in feces [11]. Ticagrelor is rapidly absorbed, with the maximum plasma concentration being obtained at 1.5 h [13]. Ticagrelor is extensively metabolized, with ~ 10 different metabolites being formed. The major active metabolite, ARC124910XX, is formed by O-deethylation (oxidative loss of the hydroxyethyl side chain) by CYP3A enzymes. In contrast to the thienopyridines, both the parent drug and the metabolite, AR-C124910XX, show antiplatelet activity (Fig. 2) [14,15]. Exposure to AR-C124910XX is between 30% and 40% of exposure to the parent drug [14]. The parent drug is responsible for the majority of the inhibition of platelet function, and the two compounds are equipotent in this respect [14]. The offset of ticagrelor effect (the end of action after discontinuation) takes up to 5 days, which is shorter than for clopidogrel (5–10 days) and prasugrel (7–10 days), but longer than expected from the pharmacokinetic half-life [16]. Ticagrelor and its active metabolite are eliminated with median half-lives of 6–9 h and 8–12 h, respectively [17]. One-third of ticagrelor metabolites are excreted in urine, and twothirds in feces. Potential sites of drug–drug interactions: drug transporters and CYPs Variability in drug response is common, and might be attributable to determinants affecting absorption, metabolism or excretion of the drug. Variability in the disposition of drugs might be related to differences in the activity of intestinal transporters or CYPs. Drug–drug interactions resulting in either inhibition or induction of transporters or CYPs can alter the efficacy or safety profile of certain medications, especially of prodrugs such as the thienopyridines. Although less well recognized than metabolizing enzymes, membrane transporters can have important effects on pharmacokinetics. Transporter-based interactions may be result from the inhibition or induction of transport proteins, such as P-gp (multidrug resistanceassociated protein), organic anion transporter, organic

cation transporter, or organic anion-transporting polypeptide [18]. P-gp is expressed in the small intestine, the blood–brain barrier, hepatocytes, and the kidney, and is responsible for the ATP-dependent active transport of drugs across biological membranes. Verapamil, diltiazem, quinidine, dronedarone, carvedilol, captopril and amiodarone, among others (Fig. 3), are important inhibitors of P-gp, which also plays an important role in the intestinal efflux of clopidogrel and ticagrelor. Moreover, in vitro studies have indicated that ticagrelor and its active metabolite, AR-C124910XX, are inhibitors of the P-gp transporter [19]. Carboxylesterases play an important role in the hydrolytic biotransformation of a large number of drugs. Carboxylesterase-1 is the primary enzyme responsible for converting clopidogrel into carboxylic acid metabolites (Fig. 2). The activity of carboxylesterases can be inhibited or induced by drugs such as dexamethasone, phenobarbital, and polycyclic aromatic hydrocarbons [20,21]. Recently, it has been shown that the expression of carboxylesterase-1 is an important determinant of clopidogrel response: carriers of the 143E allele showed a higher level of the clopidogrel active metabolite, which was reflected by an improved level of platelet inhibition by clopidogrel [22]. A superfamily of microsomal CYPs is important for the degradation of chemicals, endogenous compounds, and drugs. The liver and enterocytes of the small intestine are important sites. Cytochromes involved in the metabolism of P2Y12 receptor inhibitors belong to the CYP1, CYP2 and CYP3 families, and include CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and the CYP3A subfamily. One important feature of these CYPs is their variable genetic expression, with > 100-fold differences being seen [10]. The CYP3A subfamily accounts for more than half of the CYPs, and includes CYP3A4 and CYP3A5. CYP3As, which are abundant in the intestinal epithelium and the liver, seem to play the most important role of all drugmetabolizing enzymes, as they are involved in the oxidation of > 50% of drugs used in clinical practice. Multiple CYP3A inhibitors have been well characterized (Fig. 3). For example, grapefruit juice can cause CYP3A inhibition in the gut for 24–48 h. For patients treated with P2Y12 receptor inhibitors, concomitant intake of the following CYP3A substrates and/or inhibitors might play a role: lipophilic statins, amiodarone, and calcium channel blockers (CCBs). In vitro, ticagrelor and AR-C124910XX have been shown to weakly inhibit CYP3A activity, as both are substrates of CYP3A4 [19]. Several inducers of CYP3As (and, in most instances, also of P-gp) have been characterized: rifampin, St John’s wort, carbamazepine, and phenytoin (Fig. 3). In contrast to CYP3As, the distribution of the activity of other CYPs is polymodal, which means that people have either an extensive or a poor metabolic ability: the © 2013 International Society on Thrombosis and Haemostasis

Drug interactions 5

Ritonavir, cyclosporine, verapamil, erythromycin, ketocoanzole, itraconazole amiodarone, azithromycin, captopril, carvedilol, INHIBITORS clarithromycin, conivaptan, diltiazem, dronedarone, itraconazole, lopinavir, ritonavir, quercetin, quinidine, ranolazine, ticagrelor, voriconazole, fluconazole

Omeprazole, fluvoxamine, moclobemide

Rifampin

HI

DU CE R

IN

BI

TO

INH

IN

RS

2C19

IBI

Fluconazole, amiodarone

TO

RS

INHIBITORS

2C9 CER

Rifampin

INDU

Clopidogrel, ticlopidine, ritonavir

INH

IBI

1A2 Cytochrome P450

TO

RS

3A4/5

2B6 R

UCE

Rifampin

Rifampin, St John’s Wort, INDUCERS carbamazepine, phenytoin, tipranavir, ritonavir

P-glycoprotein (ABCB-1; MDR-1)

2D6

INHIBITORS

IND

Fluvoxamine, ciprofloxacin

Atazanavir, clarithromycin, indinavir, itraconazole, RS ITO ketoconazole, fluconazole, B I INH nelfinavir, ritonavir, saquinavir, telithromycin, grapefruit juice, diltiazem, verapamil, amlodipine, amiodarone, atorvastatin, ticagrelor, voriconazole IN DU CE RS Rifampin, carbamazepine, St John’s wort, dexamethasone, phenytoin, phenobarbital

Paroxetine, quinidine, fluoxetine Cytochrome of major importance in the metabolism of: CLOPIDOGREL 2C19

3A4

PRASUGREL 3A4

2B6

TICAGRELOR 3A

Fig. 3. Inducers and inhibitors of cytochrome P450 and p-glycoprotein (ATP-binding cassette subfamily B member 1 [ABCB-1]; multidrug resistance protein 1 [MDR-1]).

distribution is determined by genetic polymorphisms and variant alleles [23]. CYP1A2 metabolizes a number of drugs (e.g. clopidogrel, clozapine, and theophylline), procarcinogens, and endogenous compounds (e.g. steroids). CYP1A2 is subject to reversible and/or irreversible inhibition by a number of drugs (e.g. fluvoxamine and ciprofloxacin), natural sub© 2013 International Society on Thrombosis and Haemostasis

stances, and other compounds (e.g. fluvoxamine and ciproflaxacin). Large interindividual variability in the expression and activity of CYP1A2 has been observed, and is mainly caused by genetic, epigenetic and environmental factors (e.g. smoking). To date, > 15 variant alleles and a series of subvariants of the CYP1A2 gene have been identified, and some of them have been associ-

6 J. M. Siller-Matula et al

ated with altered drug clearance and response and disease susceptibility [23]. CYP2B6 accounts for 2–10% of the total hepatic CYP content. Polymorphic and ethnic variations in the range of 20–250-fold have been demonstrated. These individual differences may result in variable systemic exposure to drugs metabolized by CYP2B6, including the antiplatelet drugs clopidogrel and prasugrel, the antineoplastic cyclophosphamide, the antiretrovirals nevirapine and efavirenz, and the anesthetic propofol [24]. Rifampin is an inducer of CYP2B6 (Fig. 3). Parent clopidogrel and ticlopidine are the most potent known inhibitors of CYP2B6 [10]. CYP2D6 accounts for only 2–5% of the total hepatic CYP isoenzymes, but is involved in the metabolism of > 25% of drugs used. CYP2D6 is necessary for the metabolism of drugs used in pain and palliative medicine (opioids, neuroleptics, and antidepressants), as well as of cardiac medications and platelet inhibitors (prasugrel). Several strong inhibitors of CYP2D6 have been characterized (e.g. fluoxetine, paroxetine, and propafenone; Fig. 3) [25]. CYP2C9 metabolizes > 100 drugs, including thienopyridines, phenytoin, warfarin, and diclofenac. Large interindividual variation has been identified for CYP2C9 activity, with at least 33 variants of CYP2C9 (CYP2C9*2–CYP2C9*34) having been found [26]. Several inducers (e.g. carbamazepine and rifampin) and inhibitors (e.g. amiodarone, fluconazole, and miconazole) of CYP2C9 have been characterized (Fig. 3). CYP2C19 is important in the metabolism of thienopyridines and proton pump inhibitors (PPIs) (omeprazole, lansoprazole, rabeprazole, and pantoprazole) among other drugs. Rifampin is a moderate CYP2C19 inducer, whereas fluconazole, fluvoxamine and omeprazole are CYP2C19 inhibitors. Several genetic variants exist; CYP2C19*2 and CYP2C19*3 account for > 95% of cases of poor metabolism of the relevant medications [23]. Polymorphism of CYP2C19 is associated with a variable ability to metabolize clopidogrel; poor metabolizer (CYP2C19*2) and extensive metabolizer (CYP2C19*17) phenotypes have been defined. CYP2C19 plays an important role in the bioactivation of clopidogrel and prasugrel, as it is involved in oxidative steps (Fig. 2). CYP2C19*2 (loss-of-function allele) is common, with ~ 25% of Caucasians and up to 30% of Asians being carriers of this allele. In several studies, carriage of CYP2C19*2 has been shown to be associated with a reduced antiplatelet effect of clopidogrel and an increased risk of major adverse cardiovascular events [27–29]. In contrast, some studies have failed to demonstrate any impact of carriage of CYP2C19 loss-of-function alleles on the clinical outcomes of patients receiving clopidogrel during a long period of follow-up [8,30]. It must be considered, however, that CYP2C19*2 carriage accounts only for 5–12% of the variation in ADP-induced aggregation [7,31], suggesting that other variables, such as unknown genetic variants or dif-

ferences in baseline clinical characteristics, contribute to this phenomenon [32]. Other CYP2C19 variants (CYP2C9*3–CYP2C9*8) have also been identified. However, because of the low allele frequency (< 1%), their impact on the metabolism of clopidogrel is minor [33,34]. A gain-of-function mutation (CYP2C19*17) is responsible for increased enzyme activity via higher transcription rates of the gene, which results in accelerated bioactivation of clopidogrel. The evidence for a clinical impact of this polymorphism on bleeding risk is conflicting. Some studies showed an association of CYP2C19*17 with low platelet reactivity and hemorrhagic events [35,36]. Although some studies have postulated that the metabolism of prasugrel is not influenced by the known CYP gene polymorphisms [37], newer studies have reported that both CYP2C19*2 and CYP2C19*17 have an impact on the pharmacodynamic effect of prasugrel [38,39]. Drug–drug interactions with P2Y12 receptor inhibitors Clopidogrel

The concomitant administration of ketoconazole, a potent CYP3A inhibitor, significantly reduced the maximum plasma level of the active metabolite of clopidogrel, by ~ 50%, and impaired the inhibition of platelet aggregation by clopidogrel [40]. Similarly, other CYP3A4 inhibitors, such as erythromycin and troleandomycin, attenuated the inhibition of platelet aggregation by clopidogrel, whereas the CYP3A4 inducer rifampin increased active metabolite formation from clopidogrel, and led to greater P2Y12 receptor-mediated inhibition of platelet aggregation [41,42] (Table 1). The data concerning drug–drug interactions between CCBs and clopidogrel are inconsistent. Concomitant intake of clopidogrel and a CCB, which are moderate CYP3A inhibitors, was associated with a reduction in the pharmacodynamic effect of clopidogrel, which was mirrored by a 30–50% increase in ADP-induced platelet aggregation in patients undergoing stent implantation [31,43–45]. However, this finding could not be confirmed in a small randomized study when the interaction was studied at day 28 after administration of CCBs [46]. Therefore, the relevance of this finding remains unclear. Moreover, there is no consistent evidence that this possible pharmacokinetic interaction has an impact on patient outcome [47]. Nevertheless, as CCBs are being given to relieve angina symptoms but not to modify the disease process, clinicians might substitute CCBs with other antihypertensive drugs, such as b-blockers, angiotensin-converting enzyme (ACE) inhibitors, or angiotensin receptor blockers (ARBs). The data concerning statin–clopidogrel interactions are also inconsistent. Atorvastatin, a substrate for CYP3As, is often coprescribed for patients who require dual antiplatelet therapy. In vitro studies have indicated that the © 2013 International Society on Thrombosis and Haemostasis

Drug interactions 7 Table 1 Summary of drug–drug interactions with P2Y12 receptor inhibitors

Clopidogrel

Prasugrel Ticagrelor

Reduction in the Cmax or weaker pharmacodynamic effect of the P2Y12 receptor blocker caused by:

Increase in the Cmax or stronger pharmacodynamic effect of the P2Y12 receptor blocker caused by:

CYP3A4, CYP3A5 or CYP2C19 inhibitors: ketoconazole, intraconazole, voriconazole, fluconazole, calcium channel blockers (diltiazem and verapamil), omeprazole, esomeprazole, erythromycin, clarithromycin, troleandomycin, atazanavir, and ritonavir CYP3A4/A5 and CYP2B6 inhibitor: ritonavir CYP3A4 inducers: rifampin, dexamethasone, phenytoin, phenobarbital, carbamazepine, and St John’s wort

CYP3A4, CYP2C19 or CYP1A2 inducers: rifampin, St John’s wort, and cigarette smoking

–

–

–

CYP3A4 inhibitors: ketoconazole, itraconazole, voriconazole, fluconazole, clarithromycin, ritonavir, atazanavir, and diltiazem

Ticagrelor increases the plasma levels of the CYP3A4 substrates simvastatin and lovastatin, and of the P-glycoprotein substrates digoxin and cyclosporine

Influence on pharmacokinetics and/or action of other drugs

CYP, cytochrome P450.

metabolism of clopidogrel is inhibited by atorvastatin, but in vivo studies in healthy volunteers could not confirm an interaction between lipophilic statins and clopidogrel, especially when assessments were performed when patients were receiving maintenance therapy or after they had been given a 600-mg loading dose of clopidogrel [41,48,49]. Conflicting data on the statin–clopidogrel interaction led to further investigation of the clinical significance of this possible phenomenon. Several prospective analyses and post hoc assessments have rejected the hypothesis of a clopidogrel–statin interaction [50–53]. To date, only one pharmacoepidemiologic study has shown a negative clinical interaction between clopidogrel and statins metabolized by CYP3A4 [54]. Coumarin derivatives (vitamin K antagonists) are CYP3A4 and CYP2C9 substrates, and have been shown to reduce the antiplatelet effects of clopidogrel by 37% [55]. However, this effect is counteracted by the pharmacodynamic interaction, resulting in increased bleeding rates [56]. The concomitant use of drugs inhibiting the activity of CYP2C19 might result in reduced concentrations of the active metabolite of clopidogrel. As a precaution, the concomitant use of strong or moderate CYP2C19 inhibitors (fluvoxamine, moclobemide, omeprazole, and esomeprazole) should be discouraged. Nevertheless, the clinical relevance of this interaction is uncertain [57]. PPIs are moderate inhibitors of CYP2C19, and they are prescribed concomitantly with antiplatelet agents to reduce the risk of gastrointestinal bleeding. However, different PPIs are metabolized by CYP2C19 to varying degrees. Whereas a reduction in the antiplatelet effect of clopidogrel has been reported for omeprazole when these drugs are given concomitantly or 12 h apart [58,59], pantoprazole had minimal effects on the antiplatelet activity of clopidogrel [60]. In a randomized, open-label, two-period, crossover study of healthy subjects, the generation of clopidogrel active metabolite and the inhibition of platelet © 2013 International Society on Thrombosis and Haemostasis

function were reduced less by the coadministration of dexlansoprazole or lansoprazole with clopidogrel than by the coadministration of esomeprazole or omeprazole [61]. These results suggest that the potential of PPIs to attenuate the efficacy of clopidogrel could be minimized by the use of dexlansoprazole or lansoprazole rather than esomeprazole or omeprazole. Taken together, these studies confirm that the metabolic clopidogrel–PPI interaction is not a class effect. Omeprazole decreased exposure to the active metabolite of clopidogrel by 40%, and this was associated with a 21% decrease in inhibition of platelet aggregation [57]. Esomeprazole caused a similar interaction [61]. As a precaution, the concomitant use of omeprazole or esomeprazole with clopidogrel should be avoided. The evidence supports CYP2C19 as the mediator of the PPI–clopidogrel interaction: omeprazole is an irreversible inhibitor of CYP2C19, whereas pantoprazole has a low potential to inhibit CYP2C19 [62]. Whether PPIs negatively affect clinical outcome in patients treated with clopidogrel is unclear. Although administration of PPIs together with clopidogrel corresponded to a 29% increased risk of combined major cardiovascular events and a 31% increased risk of myocardial infarction in a meta-analysis of observational studies [63], the randomized COGENT trial did not show an increase in the risk of cardiovascular events in patients treated with the fixed combination of 75 mg of clopidogrel and 20 mg of omeprazole [64]. Nevertheless, as the COGENT trial was not powered to investigate whether concomitant use of omeprazole increases the risk of ischemic events in patients receiving clopidogrel, a negative impact of omeprazole on ischemic risk could not be ruled out. In the light of published data, the American College of Cardiology Foundation/American College of Gastroenterology/American Heart Association expert consensus document recommends PPI use only in patients at high risk of gastrointestinal bleeding (gastrointestinal symptoms, history of hospitalization for gastric bleeding, age > 65 years, and

8 J. M. Siller-Matula et al

use of anticoagulants, systemic corticosteroids and/or non-steroidal anti-inflammatory drugs [NSAIDs]) instead of blanket PPI prescription [65]. Other classes of inhibitors of gastric acid secretion, such as H2-antagonists (except cimetidine, which might have an effect, as it is a CYP2C19 inhibitor), did not modify the extent of clopidogrel absorption [57]. Coadministration of clopidogrel and the NSAID naproxen increased the risk of gastrointestinal bleeding. However, owing to the lack of further interaction studies with other NSAIDs, it is unclear whether there is a class effect. As a consequence, NSAIDs and clopidogrel should be coadministered with caution [57]. Prasugrel

Ketoconazole, a potent inhibitor of CYP3A4 and CYP3A5, did not significantly affect the area under the curve (AUC) of prasugrel active metabolite, but reduced the Cmax of prasugrel by 46%. However, ketoconazole did not affect the inhibition of platelet aggregation induced by prasugrel. Thus, other CYP3A inhibitors (verapamil, diltiazem, ciprofloxacin, clarithromycin, or grapefruit juice) are not expected to significantly affect the pharmacokinetics or pharmacodynamics of prasugrel [40]. However, ritonavir, which is a potent CYP3A and CYP2B6 inhibitor, has been shown to decrease prasugrel bioactivation substantially. As this drug–drug interaction might lead to a significant reduction of prasugrel efficacy in HIV-infected patients with acute coronary syndrome, prasugrel should not be used in this combination [66]. Rifampicin, a CYP3A4 inducer, produced only small changes in the pharmacokinetic parameter estimates of prasugrel active metabolite, suggesting that formation of the active metabolite is not influenced by CYP induction. Thus, known CYP3A inducers are not expected to significantly affect the pharmacokinetics of prasugrel. Interestingly, coadministration of rifampicin with prasugrel reduced the pharmacodynamic effect of prasugrel by 9% at 2–4 h after a loading dose [67]. However, an in vitro study showed that this apparent pharmacodynamic interaction occurs in the absence of a pharmacokinetic interaction. Therefore, this effect could not be extrapolated to other CYP3A inducers [68], suggesting that formation of active metabolite is not affected by induction of CYP3A4. Thus, known CYP3A inducers are not expected to significantly affect the pharmacokinetics of prasugrel. An interaction between HMG-CoA reductase inhibitors and prasugrel was excluded with the use of atorvastatin [49]. Atorvastatin did not significantly change the exposure to prasugrel active metabolite or levels of platelet aggregation, indicating a lack of a clinically meaningful effect on the pharmacodynamic response to prasugrel. Because the solubility of prasugrel decreases with increasing pH, two studies were conducted to examine

whether the exposure to prasugrel active metabolite was altered by H2-receptor antagonists or PPIs. Ranitidine, an H2-receptor antagonist, had no significant effect on the pharmacokinetics or pharmacodynamics of prasugrel [68]. Although the PPI lansoprazole decreased the AUC and Cmax of prasugrel active metabolite by 13% and 29%, respectively, lansoprazole coadministration did not significantly alter the inhibitory effect of prasugrel on platelets [69]. Therefore, it seems that drugs that increase gastric pH may slow the rate of formation of prasugrel active metabolite without affecting total exposure. This may result in a delayed onset of platelet inhibition after administration of a prasugrel loading dose, but not in a decrease in the antiplatelet effect during steady state. Therefore, these possible interactions are unlikely to be clinically relevant, as has been shown in post hoc analyses of randomized controlled trials [70]. Although CYP2C9 and CYP3A4 play a role in the metabolism of both (R)-warfarin and prasugrel, warfarin does not affect the pharmacodynamics of prasugrel, and prasugrel does not affect the plasma concentrations of warfarin [71]. However, the bleeding time after coadministration of prasugrel and warfarin was prolonged by 36% as compared with prasugrel alone. This might be explained by the pharmacodynamic interaction, which may lead to even higher bleeding rates than observed for the combination with clopidogrel. Therefore, the combination of prasugrel and warfarin should be avoided, if possible. Coadministration of prasugrel with digoxin, which is a substrate of P-gp, did not affect the renal clearance of digoxin. However, prasugrel slightly reduced the digoxin AUC and Cmax, which is unlikely to be clinically significant [71]. As inhibition of P-gp would be expected to increase digoxin exposure, the slight decreases in the AUC and Cmax of digoxin must result from a different mechanism. Ticagrelor

Ticagrelor is a substrate of CYP3A and P-gp; thus, on the one hand, its systemic exposure might be affected by drugs altering the activity of these systems, and on the other hand, it may affect the systemic exposure to other substrates of CYP3A and P-gp. Coadministration of ticagrelor with single-dose simvastatin (80 mg) increased the simvastatin Cmax by 81%, with a two-fold to three-fold increase in some individuals. Similar effects might be expected with lovastatin. Therefore, coadministration of ticagrelor with simvastatin doses of 40 mg could potentially exceed exposures with 80 mg of simvastatin, and similar increases might be expected with lovastatin. In contrast, ticagrelor increased the atorvastatin level only modestly (23% increase in Cmax). Therefore, no dose adjustment is needed for atorvastatin [14], whereas simvastatin doses exceeding 40 mg should be © 2013 International Society on Thrombosis and Haemostasis

Drug interactions 9

avoided in patients treated with ticagrelor. The moderate increase (20%) in the level of ethinylestradiol, which is a CYP3A4 substrate, with the use of ticagrelor is not expected to impact on oral contraceptive efficacy, but may increase the risk of venous thrombosis. Ticagrelor is a weak inhibitor of P-gp, and may therefore affect the bioavailability of other drugs that are substrates of P-gp (e.g. an increase in the digoxin Cmax of 75%). Therefore, monitoring of P-gp substrates with a narrow therapeutic window, such as digoxin and cyclosporine (which are also CYP3A4 substrates), is recommended in patients for whom ticagrelor is initiated or the dose is changed [14]. Ticagrelor appears to be a weak inducer of CYP3A5/4, whereby the bioavailability of drugs that are metabolized by CYP3A5/4 (e.g. midazolam, cyclosporine, nifedipine, testosterone, and progesterone) might be decreased during concomitant therapy. As ticagrelor is a CYP3A4 substrate, ticagrelor exposure was increased when it was administered together with the strong CYP3A4 inhibitor ketoconazole (2.4-fold increase in Cmax) [14]. Therefore, the use of ticagrelor with strong CYP3A4 inhibitors is contraindicated. More modest changes were seen with moderate CYP3A4 inhibitors (for example, diltiazem increased the ticagrelor Cmax by 69%), and ticagrelor administered in the presence of moderate CYP3A4 inhibitors was well tolerated in the Platelet Inhibition and Patient Outcomes (PLATO) trial. Coadministration of ticagrelor with the CYP3A inducer rifampicin increased ticagrelor’s clearance by 110%, decreased Cmax by 73%, and reduced the efficacy of ticagrelor. For this reason, coadministration of ticagrelor with CYP3A inducers (rifampin, dexamethasone, phenytoin, carbamazepine, and phenobarbital) is discouraged. As the use of ticagrelor with strong CYP3A4 inhibitors or inducers was an exclusion criterion in the PLATO study, it is unknown whether the interaction might be clinically relevant [72]. However, considering the extent of this interaction, a clinically relevant increase in bleeding rates could be expected. In phase II and III clinical studies, ticagrelor was commonly administered with aspirin, heparin, low molecular weight heparin, intravenous glycoprotein (GP)IIb–IIIa inhibitors, PPIs, statins, b-blockers, ACE inhibitors and/ or ARBs for concomitant conditions. These studies did not produce any evidence of clinically significant adverse interactions [19]. Aspirin did not alter the pharmacokinetics/pharmacodynamics of ticagrelor. Interestingly, in the PLATO trial, a subgroup analysis showed no beneficial effect of ticagrelor as compared with clopidogrel in North America. The most likely reason for this lack of benefit in North America was considered to be the higher aspirin maintenance dose used (≥ 300 mg) in these patients, but it may have been a chance finding. The lower risk of cardiovascular © 2013 International Society on Thrombosis and Haemostasis

death, myocardial infarction or stroke with ticagrelor than with clopidogrel was associated with a low maintenance dose of concomitant aspirin (75–100 mg) [73]. However, the definitive explanation for this so-called ‘US paradox’ is still missing. Discussion Polypharmacy including P2Y12 receptor inhibitors, aspirin, statins, glucose-lowering agents and antihypertensive drugs is recommended for the reduction of cardiovascular risk in patients suffering from an acute coronary syndrome or undergoing coronary stent implantation. Importantly, P2Y12 receptor inhibitors, lipophilic statins, omeprazole, CCBs and many other drugs used in cardiology require metabolism by CYPs, and some of these drugs are CYP inhibitors, increasing the risk of drug– drug interactions. Patients undergoing percutaneous coronary intervention are, on average, in their mid-sixties, often have comorbidities, and are, in most instances, treated with multiple drugs [74]. Registry data have shown that up to 25 drug–drug interactions are possible in patients undergoing stent implantation [75]. In contrast to the majority of cardiac drugs, which are inactivated by CYPs, clopidogrel and prasugrel require activation by certain CYPs. In the two-step activation process, no more than 10% of the clopidogrel prodrug is metabolized into the active metabolite. As clopidogrel is widely used, and insufficient platelet inhibition by clopidogrel is an independent predictor of thrombotic events [8,76–78], the implications of any drug–drug interactions could be farreaching and influence patient treatment decisions. Although the clinical significance of several proven drug– drug interactions is unclear, this issue should not be undervalued in clinical practice. Given the widespread use of P2Y12 receptor inhibitors and other drugs, such as CCBs, PPIs, statins, or digoxin, in patients with cardiovascular disease, even marginal adverse clinical effects could have far-reaching consequences. Up to 50% of all drugs, including many cardiovascular medications, are metabolized by CYP3A4, and multiple interactions and synergistic effects are therefore possible. An important point is that insufficient platelet inhibition by P2Y12 receptor inhibitors is more common in the early phases of treatment [79,80]. Therefore, any concomitant medications interacting with the metabolism of P2Y12 receptor antagonists might decrease the action of these drugs in the crucial phase of an acute coronary syndrome or shortly after stent implantation. Furthermore, the extent of drug–drug interactions may not be predictable, as it can depend on polymorphisms of the metabolizing enzymes. In addition to the timing effect and genetic effects, there are other confounding variables, such as pleiotropic effects of drugs and drug response variability, that could contribute to individual differences in the extent of drug–drug interactions.

10 J. M. Siller-Matula et al

Conclusions Polypharmacy is frequent in patients undergoing coronary artery stenting, exposing the patients to a high risk of drug interactions. Whereas various drug–drug interactions have been described for clopidogrel and ticagrelor, prasugrel seems to have a lower potential for drug–drug interactions. In general, concomitant administration of strong CYP3A4 inhibitors or inducers should be avoided in patients treated with P2Y12 receptor antagonists. Because, in most cases, these drug–drug interactions are not class effects, clinicians have the option of alternative treatment regimens with proven lack of drug–drug interactions, e.g. a hydrophilic statin such as rosuvastatin in place of atorvastatin, pantoprazole or lansoprazole in place of omeprazole, or other antihypertensive drugs instead of a CCB.

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Disclosure of Conflict of Interests J. M. Siller-Matula has received lecture or consultant fees from AstraZeneca, Daiichi Sankyo, and Eli Lilly, and a research grant from Roche Diagnostics. D. Trenk has received consulting fees, advisory board fees and lecture fees from Eli Lilly, Daiichi Sankyo, and AstraZeneca, and lecture fees from Bayer Vital, Bristol-Myers Squibb, Boehringer Ingelheim KG, and MSD Sharp & Dohme, in the previous 3 years. His institution receives grant support from Eli Lilly. A. D. Michelson has been principal investigator or co-investigator on research grants to Boston Children’s Hospital from GLSynthesis, Lilly, and Takeda, and is a member of the Data Monitoring Board of clinical trials sponsored by Lilly. G. Delle-Karth has received lecture and consultant fees from AstraZeneca and Daiichi Sankyo. S. Kr€ ahenb€ uhl states that he has no conflict of interest.

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