Pharmacodynamic Properties of Antiplatelet Agents

Current Knowledge and Future Perspectives

Kallirroi I Kalantzi; Maria E Tsoumani; Ioannis A Goudevenos; Alexandros D Tselepis


Expert Rev Clin Pharmacol. 2012;5(3):319-336. 

In This Article

P2Y12 Receptor Antagonists

ADP plays an important role in the genesis of physiological platelet-rich hemostatic plugs as well as in the formation of pathological arterial thrombi.[20] ADP released from platelet dense-granules as well as injured cells binds to two platelet G-protein-coupled receptors, the P2Y1 and P2Y12 receptors. P2Y1 is a Gq-coupled receptor that initiates ADP-induced platelet aggregation through the stimulation of phospholipase C and phosphatidylinositol-signaling pathway. P2Y12 is a Gi-coupled seven-transmembrane domain receptor, which mediates platelet activation by inhibiting the adenylate cyclase-mediated signaling pathway and decreasing intracellular cAMP levels. It also inhibits PI3K and induces Akt kinase activation (Figures 3 & 4).[21] The decrease in intracellular cAMP levels reduces the rate of phosphorylation of the vasodilator-stimulated phosphoprotein, thus inducing activation of the GPIIb/IIIa receptor and platelet aggregation.[22] P2Y12 plays a central role in amplification and stabilization of ADP-induced platelet aggregation. It is also involved in platelet secretion induced by strong agonists. The important role of the P2Y12 receptor in platelet activation and stable thrombus formation has made it an important target in the management and prevention of arterial thrombosis.

Figure 3.

Chemical structures of P2Y12 antagonists.

Figure 4.

Mechanism of action of the P2Y12 antagonists. P2Y1 and P2Y12 are G-coupled receptors, which utilize ADP as an agonist. P2Y1 is a Gq-coupled receptor, which initiates ADP-induced platelet aggregation through the stimulation of PLC and phosphatidylinositol-signaling pathway. P2Y12 is a Gi-coupled 7-transmembrane domain receptor, which mediates platelet activation by inhibiting an AC-mediated signaling pathway and decreasing the cAMP intracellular levels. It also inhibits PI3K and induces Akt kinase activation. The decrease in cAMP intracellular levels reduces the rate of phosphorylation of VASP, thus inducing activation of the GPIIb/IIIa receptor and platelet aggregation. AC: Adenyl cyclase; PLC: Phospholipase C; VASP: Vasodilator-stimulated phosphoprotein; VASP-P: Vasodilator-stimulated phosphoprotein phosphorylation.

Active metabolites of the thienopyridine prodrugs (ticlopidine, clopidogrel and prasugrel) covalently bind to the P2Y12 receptor and are irreversible, indirect platelet inhibitors. The newer, direct-acting P2Y12 inhibitors (ticagrelor, cangrelor and elinogrel) change the conformation of the P2Y12 receptor, resulting in reversible, concentration-dependent inhibition of the receptor. The pharmacology of all P2Y12 antagonists is summarized in Table 1.


Clopidogrel is a second-generation thienopyridine (Figure 3) that has replaced ticlopidine owing to its equivalent efficacy, lower hematologic toxicity (neutropenia, thrombotic thrombocytopenic purpura) and for safety reasons.[23] Clopidogrel is an intestinally absorbed prodrug that is converted in vivo to its active metabolite. Intestinal absorption of clopidogrel is limited by P-glycoprotein, an efflux pump also known as multidrug resistance protein 1 (MDR1), which is encoded by the ABCB1 gene. The majority (85%) of the absorbed clopidogrel prodrug is metabolized into inactive metabolites by ubiquitous esterases (Figure 5). The remainder (15%) undergoes activation in the liver by the hepatic cytochrome P-450 (CYP) enzymatic pathway. Clopidogrel activation requires a two-step oxidative process conversion, firstly to an intermediate metabolite, 2-oxo-clopidogrel, which is still inactive, and then to its active thiol metabolite (R130964) (Figure 5). Both steps involve several hepatic CYP isoenzymes, including CYP2C19, CYP3A4/5, CYP2C9, CYPP1A2 and CYP2B6. More recently, it was demonstrated that the γ-thiobutyrolactone ring of 2-oxo-clopidogrel could be opened to the active thiol metabolite through hydrolytic cleavage catalyzed by the enzyme paraoxonase-1 (PON-1) and not by oxidation catalyzed by CYP2C19. Furthermore, it has been suggested that PON-1 is a key enzyme for clopidogrel-induced platelet inhibition,[24,25] and for the drug's clinical efficacy[25] although other studies did not support this suggestion.[20,26] The basis of this discrepancy still remains unclear.

Figure 5.

Metabolism of ADP P2Y12 antagonists. The thienopyridines clopidogrel and prasugrel are prodrugs, requiring hepatic metabolism to form their active metabolites, which irreversibly bind to P2Y12. After intestinal absorption, clopidogrel prodrug is metabolized into inactive metabolites by ubiquitous esterases. The remainder (15%) undergoes activation in the liver by the hepatic CYP450 enzymatic pathway. Clopidogrel activation requires a two-step oxidative process conversion, first to 2-oxo-clopidogrel and then to its active thiol metabolite. Both steps involve several hepatic CYP isoenzymes. PON-1 may also participate in the formation of clopidogrel's active thiol metabolite. Prasugrel is a prodrug that first undergoes a rapid de-esterification to an intermediate thiolactone, which is then converted in the liver to the active metabolite by CYP isoenzymes in a single CYP-dependent process. Clopidogrel and prasugrel are irreversible antagonists of the P2Y12 receptor. Ticagrelor is a direct-acting, reversible, noncompetitive antagonist of the P2Y12 receptor, which does not need metabolic activation. Cangrelor and elinogrel cause reversible inhibition of the P2Y12 receptor as well. Both drugs directly and competitively antagonize ADP binding to the P2Y12 receptor without the need for any metabolic activation. CYP: Cytochrome P450; PON-1: Paraoxonase-1.

The clopidogrel-active thiol metabolite irreversibly inactivates P2Y12 by forming a disulfide bond with two cysteine residues (Cys17 and Cys270) present in the extracellular domain of the P2Y12 receptor.[21] P2Y12 receptor blockade by clopidogrel-active metabolite potently inhibits ADP-induced platelet aggregation and also reduces platelet dense granule secretion. This later action may be responsible for reduction of AA-, collagen- and thrombin-induced platelet activation, since dense granule secretion is associated with amplification of such pathways. Clopidogrel also exerts anti-inflammatory effects, including a reduction in serum C-reactive protein levels as well as a decrease in platelet leukocyte conjugates, P-selectin and CD40L membrane expression, and platelet microparticle formation.[27,28] The maximum inhibiton of P2Y12 by clopidogrel is observed 4–5 days after daily administration of 75 mg clopidogrel and this delay is due to its need for metabolic activation. A higher clopidogrel dose of 150 mg has been associated with greater platelet inhibition.[29] Clopidogrel loading facilitates a more intense and rapid platelet inhibition, thus a 300-mg loading dose was originally recommended. However, a 600-mg loading dose has a faster onset of action and greater platelet inhibition. It is also associated with reduced response variability when compared with 300 mg and correlates with clinical benefit.[22,29,30]

A high interindividual variability in platelet inhibition by clopidogrel has been observed, and it has been mostly attributed to differences in the extent of clopidogrel prodrug metabolism. This variability is clinically important since many studies have demonstrated that patients exhibiting high on-treatment platelet reactivity (clopidogrel resistance or clopidogrel hyporesponsiveness) are not adequately protected from major adverse cardiac events (MACEs). It is estimated that approximately one-third of clopidogrel-treated patients exhibit a diminished ex vivo platelet response to clopidogrel.[20] Clinical, cellular and genetic factors have been associated with clopidogrel resistance. In this regard, the ABCB1 C3435T SNP significantly reduces clopidogrel absorption in both the homozygous and heterozygous form. Patients with the ABCB1 T3435T and C3435T genotypes have worse clinical outcomes than those with a C3435C genotype. Furthermore, the loss-of function CYP2C19 alleles (*2, *3, *4, *5, *6, *7 and *8), especially the CYP2C19*2 allele, can attenuate the pharmacodynamic effect and clinical efficacy of clopidogrel. In a genetic substudy of the TRITON-TIMI 38 trial, this allele was associated with an 53% increased risk of the composite ischemic end point and a threefold increase in stent thrombosis in patients receiving clopidogrel.[31] Through a collaborative meta-analysis, genomic data and clinical outcomes were extracted from nine clopidogrel trials involving nearly 10,000 patients who were treated predominantly with an invasive strategy. This retrospective analysis demonstrated a significantly increased risk of the composite end point of CV death, MI or stroke in both heterozygotes and homozygotes for reduced-function CYP2C19 alleles. Similarly, there was an increased risk of stent thrombosis in both groups with the 'hazard' alleles.[32]

However, genetic polymorphisms in CYP2C19 and ABCB1, which are involved in clopidogrel metabolism and disposition, only partially explain the correlation with suboptimal clopidogrel response. Poor compliance to treatment has been suggested as an important cause of clopidogrel resistance.[33] Obese or diabetic patients have an increased incidence of clopidogrel hyporesponsiveness and a corresponding increased sensitivity to ADP-induced platelet adhesion and aggregation. Furthermore, intracellular P2Y12-dependent and -independent pathways may also be upregulated in clopidogrel poor responders.[34]

The standard 75 mg daily maintenance dose of clopidogrel has proven to be clinically efficacious in reducing CV events in patients with an ACS and in those undergoing percutaneous coronary intervention (PCI).[35,36] We recently demonstrated that this clopidogrel dose differentially affects the platelet aggregation and platelet-derived prothrombotic and proinflammatory mediators in ACS patients undergoing PCI within the first month of the treatment, a phenomenon that is highly influenced by the drug response variability. Moreover, the platelet hyporesponsiveness to clopidogrel in these patients could be overcome within 1 month of treatment.[27,37] Other studies have addressed whether doubling the clopidogrel maintenance dose of 75 mg/day could be associated with a lower rate of hyporesponsiveness and increased clinical benefit.[29] The results of the randomized CURRENT OASIS 7 trial in ACS patients showed a nonsignificant benefit of 150 mg/day over 75 mg/day clopidogrel in the whole population. However, subgroup analysis suggested a benefit of increased maintenance dose of clopidogrel in ACS patients treated with PCI.[20] In a recent study involving patients with stable CV disease, it was demonstrated that tripling the maintenance dose of clopidogrel from 75 to 225 mg/day in CYP2C19*2 heterozygotes achieved levels of platelet reactivity similar to that seen in noncarriers receiving the standard 75 mg/day dose. By contrast, in CYP2C19*2 homozygotes clopidogrel doses as high as 300 mg/day did not result in comparable degrees of platelet inhibition.[38]

Based on the above results, recent studies have attempted to investigate whether tailored treatment of patients with clopidogrel based on the results of platelet function tests could help to overcome clopidogrel resistance. A previous study performed in ACS patients scheduled for PCI who were resistant to 600 mg loading clopidogrel dose (evaluated with the VASP phosphorylation [VASP-P] test), additional loading doses of 600 mg clopidogrel reduced the rate of MACEs[39] or stent thrombosis at 30 days.[20] However, the GRAVITAS study showed that although doubling the clopidogrel maintenance dose in poor responders may improve the measured response, it does not necessarily improve outcome.[40] Therefore, the utility of tailored treatment with clopidogrel in the daily clinical practice based on platelet function test results will have to be confirmed in larger clinical trials such as the ongoing ARCTIC trial.[41] In fact, genetic testing before starting clopidogrel therapy in high-risk patients, and platelet function testing in those who suffer adverse events, may facilitate the monitoring of clopidogrel treatment.

Several drugs that are metabolized by the CYP pathway can competitively inhibit CYP activation of clopidogrel, resulting in attenuated antiplatelet activity. Proton pump inhibitors (PPIs) are protective against gastrointestinal complications; however, several pharmacodynamic studies suggest that they may attenuate clopidogrel responsiveness when used concomitantly.[42] Observational clinical studies, evaluating the possible impact of PPIs on clopidogrel's antiplatelet efficacy, have produced controversial results.[43] The COGENT study, the only randomized trial investigating the interaction between clopidogrel and omeprazole,[44] has not shown increased CV risk with drug coadministration in patients with ACS undergoing PCI, whereas a significant reduction in gastrointestinal complications with PPIs use was observed. Since this study was terminated prematurely, it is underpowered to conclude definitive findings. Therefore, concurrent clopidogrel and PPI use appears safe, but coprescription is recommended only for patients at risk for gastrointestinal complications.[45]

Early studies suggested an interaction between lipophilic statins and clopidogrel on CYP isoforms[46] and a possible negative effect on clopidogrel's efficacy from the use of these statins,[47] possibly due to the CYP3A4 enzymatic pathway shared between statins and clopidogrel. However, we have demonstrated that clopidogrel's antiplatelet effectiveness is not influenced by atorvastatin[48] and it was subsequently supported by other studies using point-of-care methods, which indicated a lack of adverse effects during clopidogrel coadministration with lipophylic statins[46,49,50] and clinical data.[51]

All pharmacodynamic studies and clinical trials that confirmed the safety, efficacy and clinical benefit of clopidogrel (alone or in combination with aspirin) were carried out with clopidogrel bisulfate salt (hydrogen sulfate [CHS]). Last year's lower cost generic clopidogrel formulations have been introduced onto the market in an effort to increase patient compliance. One of these formulations is clopidogrel besylate (CB). Studies in healthy volunteers have demonstrated that CB has similar pharmacokinetic and pharmacodynamic properties compared with CHS.[52,53] Recently, we compared the pharmacodynamic properties of CB compared with CHS in CV disease patients. We showed that the platelet response variability, the platelet aggregation and the platelet-mediated inflammatory response in patients with a history of an ACS receiving long-term therapy with CB is similar to that of patients treated with CHS.[54] Similarly, we showed that there is no overall significant difference between CB and CHS in their antiplatelet effects in patients with ACS undergoing PCI, at 5 and 30 days post-clopidogrel loading.[55]


Prasugrel is a new thienopyridine (Figure 3), which exhibits a more rapid antiplatelet effect ex vivo compared with clopidogrel owing to its faster metabolic activation. Like clopidogrel, prasugrel is a prodrug that first undergoes a rapid de-esterification to an intermediate thiolactone, which is then converted in the liver to the active metabolite in a single CYP-dependent step involving CYP3A, CYP2B6, CYP2C9 and CYP2C19 (Figure 5).[21] Prasugrel's active metabolite appears in the circulation within 15 min after a 60-mg loading dose and reaches maximal plasma concentration at 30 min. In fact, among patients undergoing cardiac catheterization with planned PCI, loading with 60 mg prasugrel resulted in greater platelet inhibition than a 600-mg clopidogrel loading dose. Furthermore, a maintenance prasugrel dose of 10 mg/day results in a more potent and consistent inhibition of platelet activation than the standard clopidogrel maintenance doses of 75 or 150 mg/day.[56]

The TRITON-TIMI 38 trial showed that in patients with ACS with scheduled PCI, prasugrel (60 mg loading dose followed by a 10 mg/day maintenance dose) compared with clopidogrel (300 mg loading dose and a 75 mg/day maintenance dose) significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding.[20] The SWAP study evaluated the pharmacodynamic response of switching patients on maintenance clopidogrel therapy after an ACS to prasugrel. This study assessed the pharmacodynamics and tolerability of a prasugrel 10-mg/day maintenance dose administered immediately after clopidogrel 75 mg/day with or without prasugrel loading in patients treated with clopidogrel after an ACS event. Authors concluded that switching from 75 mg/day clopidogrel to 10 mg/day prasugrel did not influence the existing platelet inhibition in the first 24 h, but it significantly increased platelet inhibition 1 week later, as was determined by multiple assays including light transmission aggregometry, the VASP-P test and VerifyNow-P2Y12. Furthermore, when prasugrel was administered as a 60-mg loading dose, a rapid and marked decrease in platelet aggregation was observed within 2 h. Importantly, switching from clopidogrel to prasugrel was well tolerated without major safety events.[49] The prasugrel-induced inhibition of platelet activation is not characterized by the interindividual variability observed for clopidogrel. Recent pharmacogenetic analyses in the TRITON-TIMI 38 trial showed that individuals with the ABCB1 T3435T genotype exhibited reduced platelet inhibition and are at increased risk of recurrent ischemic events during clopidogrel treatment. By contrast, in patients treated with prasugrel, the ABCB1 C3435T polymorphisms were not significantly associated with CV outcomes. Likewise, in healthy participants no associations between the C3435T variant and pharmacokinetic and pharmacodynamic outcomes were seen with prasugrel.[57] These results suggest that although the intestinal P-glycoprotein efflux pump is involved in prasugrel absorption, the rapid metabolic activation of prasugrel may mitigate the genetic effect of ABCB1 C3435T polymorphisms. Other studies have demonstrated that the CYP2C19 polymorphism does not influence the pharmacodynamic or clinical efficacy of prasugrel.[19] A recent study determined the antiplatelet effects of prasugrel versus high-dose clopidogrel in patients with high on-treatment platelet reactivity to clopidogrel after PCI as well as their relation to CYP2C19*2 carriage. The results showed that in patients with high on-treatment platelet reactivity after PCI, prasugrel is more effective compared with high-dose clopidogrel in reducing platelet reactivity, particularly in CYP2C19*2 carriers.[58] These findings are in concert with the minor role of CYP2C19 in prasugrel metabolic activation. Indeed the main contributors to the conversion of prasugrel to its active metabolite are CYP3A4 and CYP2B6. The CYP3A4 gene is not very polymorphic, whereas no clear association has been shown with CYP2B6 variants and prasugrel function.[21]

Finally, a recent study suggested that although prasugrel significantly reduces thrombotic events in patients with ACS undergoing PCI because of its superior antiplatelet potency compared with clopidogrel, a significant number of patients exhibited high on-treatment platelet reactivity assessed with the VASP-P method. These patients have a higher risk for MACE during the 1-month follow-up period after PCI.[59] Larger trials are necessary to confirm the existence of platelet resistance to prasugrel and to describe the possible underlining mechanisms.


Ticagrelor (AZD 6140) (Figure 3) is a nonthienopyridine, direct-acting selective antagonist of the ADP P2Y12 receptor. It is a cyclopentyl-triazolo-pyrimidine, which is administered orally in its active form and does not need the metabolic activation required with thienopyridines (Figure 5).[60] Ticagrelor targets the P2Y12 receptor via a mechanism that is noncompetitive with ADP, suggesting the existence of a binding site on P2Y12 independent to that of ADP. Thus, ticagrelor may act through an allosteric mechanism preventing G-protein-mediated signal transduction following ADP binding to P2Y12.[61] Ticagrelor is administered orally twice a day, acts more rapidly and is a more potent platelet inhibitor than clopidogrel. It is rapidly absorbed in the small intestine and its plasma half-life is approximately 6–8 h following loading or maintenance dosing. Ticagrelor is eliminated in the feces, with less than 1% found in the urine, suggesting that renal dose adjustment is not necessary.[61] Ticagrelor is metabolized in the liver primarily through CYP3A4/5 isoenzymes. Some of the ticagrelor metabolites exhibit antiplatelet activity. One of them, AR-C 124910XX, is present at approximately one-third of the plasma concentration of ticagrelor and has a half-life of approximately 8–12 h. The plasma half-life of ticagrelor may be prolonged by coadministration of CYP3A4 inhibitors, such as ketoconazole (coadministration is contraindicated) or diltiazem, as well as with CYP3A4 substrates such as simvastatin (coadministration with 40 mg simvastatin is not recommended). Ticagrelor therapy overcomes nonresponsiveness to clopidogrel, and its antiplatelet effect is the same in responders and nonresponders. In addition to it being a more rapid and more potent platelet inhibitor than clopidogrel, after drug discontinuation the offset of platelet inhibition is faster for ticagrelor than for clopidogrel. Thus, in the absence of CYP3A4 inhibitors, the antiplatelet effects of ticagrelor decline rapidly over 72 h following cessation and near-normal platelet reactivity is achieved after approximately 5 days.[62]

The clinical efficacy and safety of ticagrelor was evaluated in the PLATO trial, a multicenter, double-blind randomized trial comparing ticagrelor (180-mg loading dose and 90 mg twice daily thereafter) and clopidogrel (300–600-mg loading dose and 75-mg/day maintenance dose) for the prevention of CV events in 18,624 ACS patients with or without ST-segment elevation. The PLATO trial demonstrated improved CV outcomes, including a reduction in MI and vascular events in patients receiving ticagrelor compared with those treated with clopidogrel.[63] In a genetic substudy of the PLATO trial, 10,285 genotyped patients were randomized to ticagrelor or clopidogrel treatment. No interaction of ticagrelor treatment and any loss-of-function CYP2C19 allele, gain-of-function CYP2C19*17 allele or ABCB1 C3435T genotype with regard to the primary efficacy end point (the composite of CV death, MI or stroke) during 12 months of treatment was observed, nor was any type of major bleeding was observed.[64]


Cangrelor (AR-C69931MX) belongs to a family of ATP analogs (Figure 3) that are relatively resistant to breakdown by ectonucleotidases. It is a potent antagonist of the P2Y12 receptor with a rapid onset (in a matter of seconds if a bolus is administered) and rapid offset of antiplatelet effect. The inhibitory effect of cangrelor on receptor activation by ADP is predominantly competitive and irreversible (Figure 5). With a plasma half-life of 3–9 min, cangrelor after intravenous administration achieves a high level of platelet inhibition within 5 min and reaches steady state concentration within 15–30 min of administration. Cangrelor is not a prodrug, it is administered in an active form and it is metabolized in the plasma by dephosphorylation to its nucleoside, which is inactive. In contrast to clopidogrel and prasugrel, cangrelor is rapidly reversible.[65] The combination of the very short half-life and reversible binding underlie the rapid recovery of platelet function in 1–2 h following termination of intravenous infusion of cangrelor. The onset of action of both clopidogrel and prasugrel is delayed when coadministrated with cangrelor, suggesting that cangrelor preferentially binds to the P2Y12 receptor and prevents irreversible inhibition of prasugrel's or clopidogrel's metabolite.[66]

Cangrelor showed no significant increase in major bleeding compared with clopidogrel in Phase II studies. Cangrelor subsequently underwent two Phase III trials, CHAMPION-PCI[67] and CHAMPION-PLATFORM.[68] Both trials were terminated early for lack of efficacy. The BRIDGE study assessing cangrelor usage in patients undergoing bypass surgery is ongoing.[61]


Elinogrel (PRT060128 or PRT128) (Figure 3) is a direct-acting, reversible P2Y12 antagonist (Figure 5) that can be administered both intravenously and orally. This unique dual formulation provides the potential benefit for smooth transition from short-term intravenous to long-term oral antiplatelet therapy. It has a plasma half-life of approximately 12 h, is cleared by both renal and hepatic routes, and undergoes limited CYP metabolism, resulting in low potential drug–drug interactions. When given as an intravenous bolus, immediate and full platelet inhibition of ADP-induced platelet aggregation was observed.

After intravenous infusion, elinogrel exhibits a much more rapid onset of action compared with clopidogrel and greater mean inhibition of platelet aggregation induced by 5 µM ADP either following the loading course or during maintenance therapy. Its rates of onset and offset of action have not yet been well studied in patients with coronary artery disease; results from further testing in outcome-driven clinical trials are awaited. High on-treatment platelet reactivity to ADP in patients receiving clopidogrel therapy can be reversibly overcome by elinogrel. Since elinogrel binds reversibly and competitively to the P2Y12 receptor, it could be displaced by higher concentrations of ADP.[61] This is clinically important at sites of bleeding, which are characterized by low blood flow, low shear stress and high ADP concentrations. Thus, elinogrel may provide a more favorable safety profile compared with the irreversibly acting thienopyridines. In distinction to ticagrelor and owing to the fact that elinogrel is a competitive antagonist of P2Y12 receptor, it is more effective at inhibiting platelet activation by lower, rather than higher, concentrations of ADP. By contrast, ticagrelor, as a noncompetitive P2Y12 antagonist, equally inhibits platelet activation induced with low and high ADP concentrations to the same extent.[61]

In the ERASE-MI study, patients with STEMI were randomized to several doses of intravenous elinogrel (n = 34) or placebo (n = 36) before PCI. No major bleeding events and five minor bleeding events occurred with elinogrel. All doses were well-tolerated.[69] In the randomized INNOVATE-PCI trial, 652 patients undergoing elective PCI randomized to clopidogrel (300/600 mg, followed by 75 mg) or elinogrel (80 mg intravenous followed by an oral dose of 50, 100 or 150 mg twice daily) pre-PCI. The safety end points (TIMI major and clinically relevant minor bleeding) were evaluated 24 h and 120 days after PCI.[70] Although treatment with elinogrel was associated with a more rapid and more potent inhibition of ADP-induced platelet activation ex vivo, there were no significant differences in the rates of ischemic events between the clopidogrel and elinogrel treatment arms at 24 h or 120 days. Treatment with elinogrel was associated with higher rates of bleeding requiring medical attention (defined according to the TIMI criteria), mostly occurring at the vascular access site during the periprocedural period, as well as higher rates of serious adverse events, dyspnea and a threefold elevation in liver enzymes.

According to a recent study, a single 60-mg oral dose of elinogrel overcomes high on-treatment platelet reactivity in the majority of patients on clopidogrel and aspirin therapy within 4 h of dosing and its effect is fully reversible within 24 h. Moreover, it has been observed that there is an association between the CYP 2C19*2 allele and high on-treatment platelet reactivity, whereas food may have an impact on plasma drug concentrations. Therefore, elinogrel should be preferably administrated to the patient while fasting.[71]

The clinical efficacy and safety of elinogrel will be further evaluated in an ongoing Phase III double-blind trial against placebo (ECLIPSE) involving patients with a history of MI.[70]


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