Pharmacokinetic basis of the antiplatelet action of prasugrel

Prasugrel is the most recent development of thienopyridine-type antiplatelet drugs. Like the earlier-generation thienopyridines, i.e. ticlopidine and clopidogrel, prasugrel is also an inactive prodrug that requires metabolic processing in vivo to generate the active antiplatelet metabolite. The efficacy of this bioactivation is the key determinant for the pharmacodynamic potency of the compound, i.e. the irreversible blockade of the platelet P2Y12-ADP receptor. Prasugrel is rapidly absorbed from the gut. After oral administration of standard-loading doses of 60 mg, maximum plasma levels of the active metabolite are achieved within 1 h, effective, maximum inhibition of platelet aggregation at 1-2 h. Bioconversion of prasugrel into the active metabolite requires two metabolic steps that occur in sequence. The first is the generation of a thiolactone-intermediate, mainly by carboxyesterases-2 in the intestine, the second the cytochrome (CYP)-dependent conversion of the thiolactone into the active metabolite. This second step involves several cytochromes, most notably CYP3A4, CYP2C19, CYP2B6, and CYP2C9. The enzymatic generation of the active metabolite of prasugrel is much more effective than that of clopidogrel where only about 5% of oral clopidogrel is transformed into the active compound by two-step CYP-dependent procedures. About 70% of prasugrel metabolites are excreted in the urine and 30% in the feces. The molar potency of the respective active metabolites of prasugrel and clopidogrel is identical. Thus, the more rapid onset, higher potency and lower interindividual variability of antiplatelet effects of prasugrel as compared to clopidogrel in vivo are entirely because of its more efficient pharmacokinetics.     

Dissecting the activation of thienopyridines by cytochromes P450 using a pharmacodynamic assay in vitro

The thienopyridine antiplatelet drugs, such as ticlopidine, clopidogrel, and prasugrel, require activation by cytochromes P450 in vivo to effectively block platelet aggregation. The study of the metabolic activation of these compounds has been hampered by the lability and reactivity of the ring-opened active metabolite (AM) and by the numerous metabolites that can be formed in such a transformation. We have developed a novel method whereby platelets are incubated with the cytochrome P450 and the thienopyridine of interest for various amounts of time, and the effects on ADP-driven platelet aggregation are directly examined. In this way, the platelet is used as a biosensor for detection of the AM. Using this method, cytochromes P450 capable of converting clopidogrel, prasugrel, and 2-oxo-clopidogrel to metabolites that inhibit ADP-induced platelet aggregation were identified as well as which cytochromes P450 were capable of catalyzing partial reactions (e.g., conversion of 2-oxo-clopidogrel to the AM). These studies show that, in vitro, CYP3A4/5, 2C19, and 2B6 are individually capable of converting clopidogrel and prasugrel to the AM and that the cytochrome P450 preference for these two thienopyridines is very similar.     

Aggressive chronic platelet inhibition with prasugrel and increased cancer risks: revising oral antiplatelet regimens?

The TRITON-TIMI 38 was a head-to-head trial to assess the efficacy and safety of the experimental antiplatelet agent prasugrel vs. standard care with clopidogrel on top of aspirin. Besides some ischemic protection at expense of overwhelming bleeding disadvantage, prasugrel treated patients experienced three times higher rate of colonic neoplasms then after clopidogrel, and this difference was significant. Importantly, known gastrointestinal bleeding preceded the diagnosis of colonic neoplasms only in half of the patients. Three potential mechanisms responsible for such harmful association are reviewed, namely: (i) direct hazard of the experimental drug on cancer occurrence and progression; (ii) indirect modulation of tumor growth; and (iii) enhanced metastatic dissemination due to instability of platelet-tumor cell aggregates, or/and inability to keep the disease locally due by much more potent long-term platelet inhibition should be considered. Significant excess of cancer after prasugrel is alarming, and can be reasonably explained, with critical clinical implications not only for prasugrel further development, but also for existing and future chronic antiplatelet strategies. If the hypothesis that oral aggressive platelet inhibition cause higher cancer risks will turn out to be true, then intensity of platelet inhibition, and especially duration of chronic antiplatelet therapy should be reconsidered. More delicate platelet inhibition, and shorter exposure to oral antiplatelet agents will prevail.     

Prasugrel, a new thienopyridine

The introduction of thienopyridines, specifically of clopidogrel, offered for the first time an orally active therapeutic alternative to acetylsalicylic acid (ASA) as an antiplatelet agent. Despite of established clinical efficacy, it became also evident with increasing clinical use that the antiplatelet actions of clopidogrel are subject of considerable interindividual variations of its antiplatelet efficacy (clopidogrel resistance) in laboratory tests which might also be clinically relevant. Prasugrel is a new, orally active thienopyridine with an expected spectrum of biological activities similar to clopidogrel. Prasugrel, like clopidogrel, is also an inactive prodrug that has to be transformed into the active metabolite by the liver cytochrome P450 system. However, different cytochromes appear to be involved for different extent in the generation of the active metabolite. The active metabolite of prasugrel, R-138727, inhibits irreversibly the platelet P2Y(12) ADP receptor. In contrast to ASA, neither clopidogrel nor prasugrel inhibit the arachidonic acid metabolism. This allows synergistic interactions with ASA as thromboxane inhibitor and PGI(2) as stimulator of cAMP-formation in platelets. Prasugrel is orally more potent and acts more rapidly than clopidogrel, allowing lower oral dosing despite of similar in vitro activity of the active metabolites. These pharmacological advantages of prasugrel are probably due to its improved pharmacokinetics, i.e. the higher conversion rate of the prodrug into the active metabolite. In case of clopidogrel, only about 10-15% of the prodrug is converted into the active metabolite. This higher conversion rate possibly also explains the more rapid onset of platelet inhibition, the lower interindividual variability and higher oral potency with apparently less "resistance" than clopidogrel. Clinically, this might result in an improved efficacy. Whether this is associated with an increased risk of bleeding will be seen from the first phase III clinical trial in PCI-patients. The first results are expected at the end of the year.     

The active metabolite of prasugrel inhibits adenosine diphosphate- and collagen-stimulated platelet procoagulant activities

Summary.  Background : Prasugrel is a novel antiplatelet prodrug of the same thienopyridine class as clopidogrel and ticlopidine. Metabolism of prasugrel generates the active metabolite R-138727, an antagonist of the platelet P2Y₁₂ adenosine diphosphate (ADP) receptor, leading to inhibition of ADP-mediated platelet activation and aggregation. ADP also enhances the platelet response to collagen, and these two agonists contribute to the generation of platelet procoagulant activity. We therefore examined whether R-138727 inhibits ADP- and collagen-triggered platelet procoagulant activities. Methods and results : As shown by whole blood flow cytometry, R-138727 inhibited surface phosphatidylserine expression on ADP plus collagen-stimulated platelets and tissue factor (TF) expression on ADP-, collagen-, and ADP plus collagen-stimulated monocyte–platelet aggregates. R-138727 reduced monocyte–platelet aggregate formation, thereby further inhibiting TF expression. ADP, collagen, and ADP plus collagen accelerated the kinetics of thrombin generation in recalcified whole blood and R-138727 significantly inhibited this acceleration. Clot strength in a modified thromboelastograph system was also inhibited by R-138727 (IC₅₀ 0.7 ± 0.1 μ m ). Conclusions : In addition to its previously known inhibitory effects on platelet activation and aggregation, the active metabolite of prasugrel, R-138727, inhibits platelet procoagulant activity in whole blood (as determined by phosphatidylserine expression on platelets and TF expression on monocyte–platelet aggregates), resulting in the functional consequences of delayed thrombin generation and impaired clot development.     

Antiplatelet options for secondary prevention in acute coronary syndromes

Current guidelines recommend dual antiplatelet therapy, a combination of aspirin and a P2Y(12) inhibitor, for 6?12 months after percutaneous coronary intervention with drug-eluting stent implantation in all patients and for 1 year in all patients after an acute coronary syndrome (ACS), irrespective of revascularization strategy. Clopidogrel has a pharmacokinetic and pharmacodynamic profile that results in a delayed and/or subtherapeutic antiplatelet effect, and wide variability in antiplatelet response. New P2Y(12) inhibitors, such as prasugrel and ticagrelor, have favorable pharmacodynamics and clinical efficacy over clopidogrel and offer an alternative antiplatelet treatment strategy in specific patients. Prasugrel has more potent, rapid, and consistent effects on inhibiting ADP-induced platelet aggregation than clopidogrel. Ticagrelor also appears to have more rapid and consistent antiplatelet effects than clopidogrel. The higher levels of antiplatelet inhibition provided by prasugrel and ticagrelor compared with standard-dose clopidogrel result in improved ischemic outcomes in patients with ACS. Despite an increase in bleeding risk, prasugrel and ticagrelor appear to have a better net clinical benefit, especially in higher-risk patients with ACS.     

Antiplatelet options for secondary prevention in acute coronary syndromes

Current guidelines recommend dual antiplatelet therapy, a combination of aspirin and a P2Y₁₂ inhibitor, for 6–12 months after percutaneous coronary intervention with drug-eluting stent implantation in all patients and for 1 year in all patients after an acute coronary syndrome (ACS), irrespective of revascularization strategy. Clopidogrel has a pharmacokinetic and pharmacodynamic profile that results in a delayed and/or subtherapeutic antiplatelet effect, and wide variability in antiplatelet response. New P2Y₁₂ inhibitors, such as prasugrel and ticagrelor, have favorable pharmacodynamics and clinical efficacy over clopidogrel and offer an alternative antiplatelet treatment strategy in specific patients. Prasugrel has more potent, rapid, and consistent effects on inhibiting ADP-induced platelet aggregation than clopidogrel. Ticagrelor also appears to have more rapid and consistent antiplatelet effects than clopidogrel. The higher levels of antiplatelet inhibition provided by prasugrel and ticagrelor compared with standard-dose clopidogrel result in improved ischemic outcomes in patients with ACS. Despite an increase in bleeding risk, prasugrel and ticagrelor appear to have a better net clinical benefit, especially in higher-risk patients with ACS.     

The reversible P2Y12 antagonist cangrelor influences the ability of the active metabolites of clopidogrel and prasugrel to produce irreversible inhibition of platelet function

Summary.  Background:  Agents that act as antagonists at P2Y₁₂ ADP receptors on platelets are in use (clopidogrel), and in development for use (cangrelor and prasugrel), in patients with cardiovascular disease. Cangrelor is a direct-acting reversible antagonist being developed for short-term infusion; clopidogrel and prasugrel are oral prodrugs that provide irreversible inhibition via transient formation of active metabolites. At the cessation of cangrelor infusion, patients are likely to receive clopidogrel or prasugrel as a means of maintaining antiplatelet therapy. Objectives:  To apply an experimental in vitro approach to investigate the possibility that cangrelor influences the ability of the active metabolites of clopidogrel and prasugrel to inhibit ADP-mediated platelet function. Methods:  The effects of cangrelor and the active metabolites of clopidogrel (C-AM) and prasugrel (P-AM) on platelet function were assessed by ADP-induced platelet P-selectin expression in whole blood. The method involved rapid removal of the antagonists by dilution, and measurement of residual platelet inhibition. Results:  Cangrelor, C-AM and P-AM markedly inhibited P-selectin expression. The effect of cangrelor, but not of C-AM and P-AM, was reversible following antagonist removal. Preincubation of blood with cangrelor prior to addition of C-AM or P-AM reduced the ability of metabolites to irreversibly antagonize P2Y₁₂. Irreversible inhibition was maintained when blood was preincubated with metabolites prior to cangrelor. Conclusions:  Cangrelor influences the ability of the active metabolites of clopidogrel or prasugrel to inhibit platelet function irreversibly. Careful consideration should be given to the timing of administration of an oral P2Y₁₂ antagonist following cangrelor infusion.     

The future of platelet function testing to guide therapy in clopidogrel low and enhanced responders

Dual oral antiplatelet therapy with aspirin and clopidogrel is the therapy of choice in patients with acute coronary syndromes and in patients undergoing coronary stent placement to lower the risk of thrombotic events. Responsiveness to aspirin and especially to clopidogrel is not uniform and is subject to considerable interindividual variability. Furthermore, there is a broad consensus that clopidogrel low response or so-called high on-treatment platelet reactivity is linked to the occurrence of ischemic events. On the other hand, evidence is accumulating that enhanced clopidogrel responders are at increased risk of bleeding. Newer antiplatelet drugs, such as prasugrel and ticagrelor, are more potent and produce more consistent inhibition of platelet aggregation via the P2Y(12) ADP platelet receptor. A variety of methods of platelet function testing are available for evaluating platelet inhibition in percutaneous coronary intervention-treated patients in order to help determine the individual risk for ischemic and bleeding complications. Although not yet routinely undertaken, platelet function testing offers the potential to tailor antiplatelet therapy for individual patients. Whether alteration of therapy based on platelet function testing improves patients' outcomes remains unclear and is currently under investigation. This article reviews the impact of antiplatelet drug responsiveness on clinical outcomes with a focus on P2Y(12) receptor inhibition as well as on current and future concepts for personalized antiplatelet strategies.     

Bioactive peptides and proteins as alternative antiplatelet drugs

Antiplatelet drugs reduce the risks associated with atherothrombotic events and show various applications in diverse cardiovascular diseases including myocardial infarctions. Efficacy of the current antiplatelet medicines including aspirin, clopidogrel, prasugrel and ticagrelor, and the glycoprotein IIb/IIIa antagonists, are limited due to their increased risks of bleeding, and antiplatelet drug resistance. Hence, it is important to develop new effective antiplatelet drugs, with fewer side-effects. The vast repertoire of natural peptides can be explored towards this goal. Proteins and peptides derived from snake venoms and plants represent exciting candidates for the development of novel and potent antiplatelet agents. Consequently, this review discusses multiple peptides that have displayed antiplatelet aggregation activity in preclinical drug development stages. This review also describes the antiplatelet mechanisms of the peptides, emphasizing the signaling pathways intervened by them. Also, the hurdles encountered during the development of peptides into antiplatelet drugs have been listed. Finally, hitherto unexplored peptides with the potential to prevent platelet aggregation are explored.     

Monitoring of antiplatelet therapy. Current limitations, challenges, and perspectives

Screening of platelet function can be performed by point-of-care testing followed by platelet aggregometry in response to agonists such as collagen, adenosine diphosphate, epinephrine, and arachidonic acid. Despite in use for decades, this technique is not well standardized. Monitoring of antiplatelet therapy is increasingly applied in patients at high risk for re-thrombosis or bleeding. To assess pharmacological inhibition of platelet function, agonist-induced platelet aggregation, thromboxane B2 (TxB2) and vasodilator-stimulated protein phosphorylation (VASP) are being measured. While serum TxB2 levels of < 2 ng/ml reflect aspirin-induced inhibition of cyclo-oxygenase-1 activity with high sensitivity, VASP exhibits a wide variability upon treatment with clopidogrel or prasugrel. Multiple studies reveal an association between high residual platelet reactivity and adverse cardiovascular events in patients on antiplatelet therapy. However, despite the plethora of platelet function assays currently under investigation, their use in daily practice cannot be recommended. This is due to several reasons: (i) there is no consensus on the method and a respective cut-off value associated with clinical adverse outcome, and (ii) data demonstrating any benefit of tailored antiplatelet therapy and its monitoring (based on assessment of platelet functions) are still limited. Thus, appropriate identification of 'resistant' or 'poor responders' to antiplatelet agents remains challenging in clinical practice.     

Platelet reactivity tests for assessing antiplatelet drug response: what the clinician needs to know

Antiplatelet therapy is a cornerstone in the treatment of cardiovascular disease to prevent ischemic events. Various tests have become clinically available to measure platelet function after antiplatelet treatment. A wide interpatient variability in the magnitude of platelet inhibition has been demonstrated in numerous studies, especially in response to clopidogrel. Several reasons including clinical, pharmacological and genetic factors have been identified. High on-clopidogrel platelet reactivity has been linked to adverse clinical outcome, in particular to stent thrombosis after percutaneous coronary interventions. New antiplatelet drugs including prasugrel and ticagrelor have been advocated to overcome the limitations of clopidogrel. Several studies addressed the concept of tailored antiplatelet treatment according to the results of platelet function testing. Within this review, we summarize the current status of personalized antiplatelet therapy for cardiovascular disease.     

A novel nitric oxide-releasing statin derivative exerts an antiplatelet/antithrombotic activity and inhibits tissue factor expression.

BACKGROUND: NO-releasing statins are new chemical entities, combining HMG-CoA reductase inhibition and slow NO release, that possess stronger anti-inflammatory and antiproliferative activities than the native statins. OBJECTIVE: We evaluated the antithrombotic effects of nitropravastatin (NCX-6550) by assessing its activity on platelet activation and tissue factor (TF) expression by mononuclear cells in vitro and in vivo. METHODS AND RESULTS: In vitro, NCX-6550 inhibited (1) U46619- and collagen-induced platelet aggregation in buffer and plasma; (2) collagen-induced P-selectin expression in whole blood and (3) platelet adhesion to collagen-coated coverslips under high shear stress. These effects were displayed at concentrations of NCX-6550 ranging from 25 to 100 mum, and were totally reverted by the guanylylcyclase inhibitor ODQ (10 microm). Equimolar concentrations of pravastatin had no influence on these parameters of platelet function. LPS- and PMA-induced TF expression by blood mononuclear cells was also inhibited by NCX-6550 (IC50 13 microm), but not by pravastatin, as assessed by functional and immunological assays and by real-time PCR. In a mouse model of platelet pulmonary thromboembolism, induced by the i.v. injection of collagen plus epinephrine, pretreatment with NCX-6550 (24-48 mg kg(-1)) significantly reduced platelet consumption, lung vessel occlusion and mortality. Moreover, nitropravastatin markedly inhibited the generation of procoagulant activity by spleen mononuclear cells and peritoneal macrophages in mice treated with LPS. In these in vivo models too, pravastatin failed to affect platelet activation and monocyte/macrophage procoagulant activity. CONCLUSIONS: Our results show that nitropravastatin exerts strong antithrombotic effects in vitro and in vivo, and may represent an interesting antiatherothrombotic agent for testing in acute coronary syndromes.     

How to get from antiplatelet to antithrombotic treatment.

Despite undisputed clinical benefit of platelet inhibitors in an acute interventional setting, chronic antiplatelet treatment with aspirin and clopidogrel have shown a moderate reduction of approximately 18% in the prevention of myocardial infarction and stroke. More recent data on the effect of combining the two compounds leading to an irreversible blockade of cyclooxygenase as well as the adenosine diphosphate receptor showed increased protection from cardiac events in patients with unstable angina and no significant protection from stroke. This improvement did come with the price of a significant increase in major bleeding, requiring hospitalization or transfusion. Furthermore, the most potent inhibition of platelet aggregation by blocking the binding of fibrinogen to activated platelets did not further improve the clinical outcome. All major clinical investigations of the effect of chronic administration have been recently terminated owing to an overall increased mortality rate for the entire class of drugs of orally active fibrinogen receptor antagonists. This poses the question of whether measuring platelet aggregation in vitro and ex vivo can serve as an adequate surrogate parameter to select antithrombotic therapy, particularly in the chronic setting. When evaluating the importance of other endogenous antithrombotic defense systems, the test for inhibition of platelet aggregation must fail. The importance of the endogenous defense systems is easily demonstrated by in vivo studies of thrombus formation in smaller vessels. The rapid and well-balanced interaction of local prothrombotic as well as antithrombotic factors is key in keeping the process confined. By carefully shifting this balance with antiplatelet therapy in combination with therapy to amplify the endogenous antithrombotic defense systems, a far more pronounced overall antithrombotic therapeutic effect can be demonstrated. By employing more complex antithrombotic tests performed in vivo, this balance can be studied. These studies confirm the importance of the ratio of two independent antithrombotic treatments when given together, which was not reflected in in vitro tests but was found to correlate with clinical outcome data. The attention in selecting antithrombotic treatment is to be shifted from approaches only directed toward the inhibition of platelets to an antithrombotic treatment, which includes amplification of the local therapeutic effects often mediated through the vessel wall.     

Clinical and preclinical pharmacology of KC-764, a novel antiplatelet agent]

Preclinical pharmacological studies showed that KC-764 was more potent and more selective in inhibiting platelet aggregation than aspirin. The concentration of KC-764 for inhibiting PGI2 production in the aorta was 70 times higher than that for inhibiting TXA2 in platelets. Antiplatelet action of KC-764 was augmented by plasma components. This augmentation by plasma may lead to selective antiplatelet activity. KC-764 has been investigated for platelet function in patients with chronic cerebral infarction. KC-764 at 10, 20 and 40 mg b i d, inhibited platelet aggregation induced by arachidonic acid, collagen, and ADP, and its potency was almost equal to aspirin at 100-330 mg daily. Plasma TXB2 levels were markedly depressed by KC-764 but plasma 6-keto-PGF1 alpha levels were not influenced. On the contrary, aspirin depressed both plasma prostanoids. These findings suggest that KC-764 can overcome the 'aspirin dilemma'.     

Dual antiplatelet therapy in patients with diabetes mellitus: special considerations

Diabetes mellitus (DM) is associated with higher rates of ischemic events in patients suffering from an acute coronary syndrome and/or undergoing percutaneous coronary intervention, thereby underscoring the need to develop more effective and specific strategies toward mitigation of the cardiovascular burden associated with DM. Platelet hyper-reactivity associated with DM is a central contributor to this high risk, since platelets are the key players in the processes underpinning atherothrombotic complications, thereby representing a specific therapeutic target. Oral dual antiplatelet therapy comprising the combination of aspirin (75–100 mg) and clopidogrel (75 mg) has been, for years, the standard antithrombotic treatment for patients with acute coronary syndrome and/or undergoing percutaneous coronary intervention. However, despite the use of this therapy, high rates of cardiovascular events continue to occur, especially within the cohort of patients with DM. These observations could be in part explained by an inadequate clopidogrel-induced platelet inhibition, which has been associated with impaired clinical outcomes. In particular, DM is associated with a higher prevalence of reduced responsiveness to standard dual antiplatelet therapy, which may contribute to the higher rates of ischemic events seen in this population. These findings have prompted the identification of alternative dual antiplatelet treatment regimens to optimize platelet inhibition. The present review aims to describe benefits and limitations of oral dual antiplatelet therapy with aspirin and clopidogrel (75 mg) and to appraise the evidence regarding alternative oral dual antiplatelet therapy regimens, which include higher doses of aspirin and clopidogrel or the combination of prasugrel or ticagrelor with aspirin, focusing on patients with DM.     

Unmet needs in oral antiplatelet therapy with ADP receptor blocking agents

Antiplatelet agents like aspirin and clopidogrel are treatment cornerstones for acute coronary syndromes (ACS). Drawbacks of dual therapy with these agents include slow onset and offset of effect and wide response variability. Clopidogrel may provide little benefit if administered too close to percutaneous coronary intervention (PCI) and increase major bleeding risk if given too close to coronary artery bypass grafting (CABG) or other surgery. It may not provide sufficient antiplatelet coverage prior to CABG if stopped too long before intervention and leave patients without antiplatelet coverage due to hyporesponsiveness. Prasugrel has made steps towards addressing these limitations by exhibiting more efficient metabolism, more rapid onset of effect, and greater and more consistent platelet inhibition than clopidogrel. The TRITON-TIMI38 trial in ACS patients undergoing PCI showed prasugrel produced greater ischemic event protection than clopidogrel but significantly increased major bleeding risk. AZD6140, the first reversible oral P2Y₁₂ inhibitor, provides more rapid onset of effect and greater and more consistent platelet inhibition than clopidogrel. In DISPERSE2, a phase II trial in ACS patients, AZD6140 did not increase bleeding risk, reduced bleeding risk among CABG patients, and produced numerical reductions in myocardial infarction risk. AZD6140 is being compared with clopidogrel in PLATO, a phase III trial in approximately 18000 ACS patients.     

Prasugrel in acute coronary syndrome patients undergoing percutaneous coronary intervention

Currently, dual antiplatelet therapy with aspirin and clopidogrel represents the key treatment strategy for the prevention of ischemic events in patients with acute coronary syndrome (ACS) and/or undergoing percutaneous coronary intervention (PCI). However, there is a broad inter-individual response variability to such treatment strategy, and a considerable number of patients persist with inadequate platelet inhibition, which has been associated with an increased risk of ischemic events. Overall, these findings underscore the need for novel antiplatelet agents able to achieve greater platelet inhibition; this can potentially reduce ischemic event rates. Prasugrel (CS-747; LY 640315), a novel third-generation oral thienopyridine, is a specific, irreversible antagonist of the platelet adenosine diphosphate P2Y₁₂ receptor. Laboratory studies have shown prasugrel to be associated with more prompt, potent and predictable degrees of platelet inhibition compared with clopidogrel. In a large-scale clinical study, which was comprised of high-risk ACS patients undergoing PCI, prasugrel was shown to significantly reduce the short- and long-term risk of ischemic events, including stent thrombosis. However, such significant reduction in ischemic events occurred at the expense of a higher risk of bleeding. Recent clinical trial data analyses have led to a better understanding of the efficacy and safety of prasugrel. This article reviews the currently available data regarding the efficacy and safety of prasugrel in ACS patients.     

Enhanced antiplatelet effect of clopidogrel in patients whose platelets are least inhibited by aspirin: a randomized crossover trial

Summary. Objective: We aimed to determine whether adding clopidogrel to aspirin in patients at high risk of future cardiovascular events would suppress laboratory measures of the antiplatelet effects of aspirin; and have greater platelet inhibitory effects in patients with the least inhibition of platelets by aspirin. Methods: We performed a randomized, double‐blind, placebo‐controlled, crossover trial, comparing clopidogrel 75 mg day^?1 versus placebo, in 36 aspirin‐treated patients with symptomatic objectively confirmed peripheral arterial disease. Results: The addition of clopidogrel to aspirin did not suppress platelet aggregation induced by arachidonic acid, urinary 11 dehydro thromboxane B₂ concentrations, or soluble markers of platelet activation markers (P‐selectin, CD40‐ligand) and inflammation (high sensitivity serum C‐reactive protein, interleukin‐6). Clopidogrel significantly inhibited platelet aggregation induced by ADP (reduction 26.2%; 95% CI: 21.3–31.1%, P < 0.0001) and collagen (reduction 6.2%; 95% CI: 3.2–9.3%, P = 0.0003). The greatest inhibition of collagen‐induced platelet aggregation by clopidogrel was seen in patients with the least inhibition of arachidonic acid induced aggregation by aspirin [lower tertile of arachidonic acid‐induced platelet aggregation: 2.8% (95% CI: ?0.8 to 6.3%) reduction in mean collagen‐induced aggregation by clopidogrel; middle tertile: 4.0% (95% CI: 0.4–7.6%); upper tertile 12.6% (95% CI: 4.5–20.8%); P‐value for interaction 0.01]. Conclusions: The greatest platelet inhibitory effect of clopidogrel occurs in patients with the least inhibition of arachidonic acid‐induced platelet aggregation by aspirin. This raises the possibility that the clinical benefits of adding clopidogrel to aspirin may be greatest in patients whose platelets are least inhibited by aspirin. Confirmation in clinical outcome studies may allow these patients to be targeted with antiplatelet drugs that inhibit the ADP receptor, thereby overcoming the problem of laboratory aspirin resistance.     

MRS2500 [2-iodo-N6-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphate], a potent, selective, and stable antagonist of the platelet P2Y1 receptor with strong antithrombotic activity in mice

The platelet P2Y(1) ADP receptor is an attractive target for new antiplatelet drugs. However, because of the lack of strong and stable antagonists, only a few studies have suggested that pharmacological inhibition of the P2Y(1) receptor could efficiently inhibit experimental thrombosis in vivo. Our aim was to determine whether the newly described potent and selective P2Y(1) receptor antagonist MRS2500 [2-iodo-N(6)-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphate] could inhibit platelet function ex vivo and experimental thrombosis in mice in vivo. MRS2500 was injected intravenously into mice, and its effect on ex vivo platelet aggregation and in several models of thrombosis in vivo was determined. MRS2500 displayed high potency and stable and selective P2Y(1) receptor inhibition ex vivo. Although MRS2500 injection resulted in only moderate prolongation of the bleeding time, it provided strong protection in systemic thromboembolism induced by infusion of a mixture of collagen and adrenaline. MRS2500 also potently inhibited localized arterial thrombosis in a model of laser-induced vessel wall injury with two degrees of severity. Moreover, combination of MRS2500 with clopidogrel, the irreversible inhibitor of the platelet P2Y(12) receptor for ADP, led to increased antithrombotic efficacy compared with each alone. These results add further evidence for a role of the P2Y(1) receptor in thrombosis and validate the concept that targeting the P2Y(1) receptor could be a relevant alternative or complement to current antiplatelet strategies.