Greater Inhibition Of Platelet Aggregation Research Articles

Effects of intravenous lysine acetylsalicylate versus oral aspirin on platelet responsiveness in patients with ST-segment elevation myocardial infarction

Abstract Background Prasugrel and ticagrelor, new P2Y12-ADP receptor antagonists, are associated with greater pharmacodynamic inhibition and reduction of cardiovascular events in patients with an acute coronary syndrome. However, evidence is lacked about the effects of achieving faster and stronger cyclooxygenase inhibition with intravenous lysine acetylsalicylate (LA) compared to oral aspirin on prasugrel inhibited platelets in patients with an ST-segment elevation myocardial infarction (STEMI). Methods This is a prospective, randomized, multicenter, open platelet function study conducted. STEMI patients were randomly assigned to receive a loading dose (LD) of intravenous LA 450mg plus oral ticagrelor 180mg, or LD of aspirin 300mg plus ticagrelor 180mg orally. Platelet function was evaluated at baseline, 30 min, 1h, and 24h using multiple electrode aggregometry and vasodilator-stimulated phosphoprotein phosphorylation (VASP). The primary endpoint of the study is the inhibition of platelet aggregation after arachidonic acid (AA) 1.5mM at 30 min. Secondary endopoints are the inhibition of platelet aggregation after AA baseline and at 1h, and 24h, and measurement of aggregation with other platelet test (ADP, collagen and VASP). Results A total of 32 STEMI patients were randomized (16 LA, 16 aspirin). The inhibition of platelet aggregation after AA 1.5 mM at 30 min was greater in subjects treated with LA compared with aspirin: 166 vs. 412 respectively, p=0.001. This differential effect was observed at 1 hour (p=0.01), but not at 24 hours. Subjects treated with LA presented less variability and faster and greater inhibition of platelet aggregation with AA compared with aspirin (Figure 1). Conclusions The administration of intravenous LA resulted in a significantly reduction of platelet reactivity compared to oral aspirin on ticagrelor inhibited platelets in patients with STEMI. Loading dose of LA achieves an earlier platelet inhibition, and with less variability than aspirin. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This study was supported by the CTU-SCReN (Clinical Trial Unit – Spanish Clinical Research Network) from San Carlos University Hospital (Madrid, Spain), financed by the ISCII (Project PI16/00191)

Prasugrel in the treatment of acute coronary syndrome.

Dual antiplatelet therapy is the mainstay therapy in patients with acute coronary syndrome. The combination of aspirin and a P2Y12 inhibitor in patients who receive a coronary stent reduces the rate of stent thrombosis and the rates of major adverse cardiovascular events. The newer P2Y12 inhibitors (prasugrel and ticagrelor) have better efficacy than clopidogrel. Prasugrel provides greater inhibition of platelet aggregation and has a rapid onset of action. Current acute coronary syndrome guidelines recommend the use of both newer P2Y12 inhibitors. However, emerging data have shown that prasugrel is more efficient than ticagrelor in reducing the incidence of nonfatal myocardial infarction, stroke or cardiovascular death, without increased risk of major bleeding.

Randomized controlled trial protocol to investigate the antiplatelet therapy effect on extracellular vesicles (AFFECT EV) in acute myocardial infarction

Activated platelets contribute to thrombosis and inflammation by the release of extracellular vesicles (EVs) exposing P-selectin, phosphatidylserine (PS) and fibrinogen. P2Y12 receptor antagonists are routinely administered to inhibit platelet activation in patients after acute myocardial infarction (AMI), being a combined antithrombotic and anti-inflammatory therapy. The more potent P2Y12 antagonist ticagrelor improves cardiovascular outcome in patients after AMI compared to the less potent clopidogrel, suggesting that greater inhibition of platelet aggregation is associated with better prognosis. The effect of ticagrelor and clopidogrel on the release of EVs from platelets and other P2Y12-exposing cells is unknown. This study compares the effects of ticagrelor and clopidogrel on (1) the concentrations of EVs from activated platelets (primary end point), (2) the concentrations of EVs exposing fibrinogen, exposing PS, from leukocytes and from endothelial cells (secondary end points) and (3) the procoagulant activity of plasma EVs (tertiary end points) in 60 consecutive AMI patients. After the percutaneous coronary intervention, patients will be randomized to antiplatelet therapy with ticagrelor (study group) or clopidogrel (control group). Blood will be collected from patients at randomization, 48 hours after randomization and 6 months following the index hospitalization. In addition, 30 age- and gender-matched healthy volunteers will be enrolled in the study to investigate the physiological concentrations and procoagulant activity of EVs using recently standardized protocols and EV-dedicated flow cytometry. Concentrations of EVs will be determined by flow cytometry. Procoagulant activity of EVs will be determined by fibrin generation test. The compliance and response to antiplatelet therapy will be assessed by impedance aggregometry. We expect that plasma from patients treated with ticagrelor (1) contains lower concentrations of EVs from activated platelets, exposing fibrinogen, exposing PS, from leukocytes and from endothelial cells and (2) has lower procoagulant activity, when compared to patients treated with clopidogrel. Antiplatelet therapy effect on EVs may identify a new mechanism of action of ticagrelor, as well as create a basis for future studies to investigate whether lower EV concentrations are associated with improved clinical outcomes in patients treated with P2Y12 antagonists.

Response to clopidogrel is associated with early neurological deterioration after acute ischemic stroke.

PurposeThe relationship between response to clopidogrel and early neurological deterioration (END) after acute ischemic stroke (IS) is not well defined. The aim of present study was to evaluate the associations of clopidogrel resistance (CR) with END, and stratified analyze the effectiveness of clopidogrel alone and clopidogrel plus aspirin for the prevention of END.ResultsA total of 375 patients, 144 patients were received clopidogrel alone, 231 patients took clopidogrel plus aspirin. CR occurred in 153 patients (40.8%). 95 (25.3%) patients developed END within the first 10 days. Platelet aggregation was higher on admission, and inhibition of platelet aggregation was significantly lower in patients with END than patients without END. Diabetes mellitus, CR, and clopidogrel plus aspirin were independently associated with END. Dual antiplatelet therapy with aspirin and clopidogrel can inhibit both arachidonic acid (AA)-induced and ADP-induced platelet aggregationMethodsThis was a prospective, two-center study. A total of 375 IS patients taking clopidogrel alone or clopidogrel plus aspirin were enrolled. Platelet aggregation was measured before and after the 7–10 day treatment. CR was assessed by adenosine diphosphate (ADP)-induced platelet aggregation. The primary endpoint was END within the 10 days after admission. The secondary endpoint was a composite of recurrent ischemic stroke, myocardial infarction, and death during the 10 days after admission.ConclusionsCR and END are fairly common after acute IS. CR is associated with higher risk of END. Clopidogrel plus aspirin combination therapy provides greater inhibition of platelet aggregation, and may afford protection against END.

Comparison of half- and standard-dose ticagrelor in Chinese patients with NSTE-ACS

Ticagrelor is a novel direct-acting P2Y12 receptor antagonist used for preventing atherothrombotic events in patients with acute coronary syndromes (ACS). The current recommended dose is 90 mg bid, but a low dose of ticagrelor has not been previously studied in Chinese ACS patients. Therefore, we performed this study to observe the different effects of half- and standard-dose ticagrelor on platelet aggregation in Chinese patients with NSTE-ACS. Sixty-two NSTE-ACS subjects were assigned to half-dose ticagrelor (n = 20), standard-dose ticagrelor (n = 22) and clopidogrel (n = 20) groups. Five days after drug administration, VerifyNow P2Y12 assay was performed to test P2Y12 reaction units (PRU) and inhibition of platelet aggregation (IPA). High-platelet reactivity (HPR) was defined as a PRU > 208. The adverse events, including bleeding events and dyspnoea, were monitored throughout the study. PRU values in the half-dose (44.55 ± 32.88) and standard-dose (39.10 ± 40.02) ticagrelor were dramatically lower than those in the clopidogrel group (189.20 ± 65.22; P < 0.0001). The half-dose (84% ± 10%) and standard-dose (86% ± 13%) ticagrelor both showed greater IPA than clopidogrel (33% ± 20%; P < 0.0001). There were no significant differences in PRU and IPA between the two ticagrelor groups (P = 0.3085 and 0.4028, respectively). HPR rates were significantly lower in the two ticagrelor groups (0% for both) than those in the clopidogrel group (35%). In conclusion, half-dose ticagrelor had a similar inhibitory effect on platelet aggregation as standard-dose ticagrelor in Chinese patients with NSTE-ACS, which was significantly stronger than that of clopidogrel.

Cytochrome P450 CYP 2C19*2 Associated with Adverse 1-Year Cardiovascular Events in Patients with Acute Coronary Syndrome.

BackgroundThe cytochrome P450 (CYP450) 2C19 681 genotypes affect the antiplatelet activity of clopidogrel. We investigated the correlation of CYP 2C19 681G > A mutation with clopidogrel resistance (CR). Additionally, we studied the effect of CR on clinical prognosis of patients with acute coronary syndrome (ACS).MethodsOne hundred ten ACS patients undergoing percutaneous coronary intervention, who were followed-up for 1 year, were included in the study. The patients were co-administered aspirin 100 mg/d and clopidogrel 75mg/d following a loading dose of 300 mg. CR was assessed on the basis of polymorphism observed in the CYP2C19 subgroup.ResultsPatients in GG genotype group exhibited greater inhibition of platelet aggregation than patients in GA and AA genotype groups (16.2 ± 10.1%; 10.2 ± 9.9%; 8.0 ± 5.9%, respectively, p < 0.01). CYP2C19 681GG genotype group was associated with lower CR than CYP2C19 681A allele (GA + AA) group (9/59 vs. (12+5)/51; p = 0.009). Over a follow-up of 12 months, the incidence of recurrent angina, acute myocardial infarction, and intra-stent thrombosis in CYP2C19 681 GG carriers was significantly lower than that in CYP2C19 681A allele (GA + AA) group (2/59 vs. 8/51, 1/59 vs. 6/51, 0 vs. 4/51, respectively, p < 0.05).ConclusionCYP 2C19*2 is associated with reduced clopidogrel antiplatelet activity and might be an important marker for poor prognosis of ACS.

Impact of Intravenous Lysine Acetylsalicylate Versus Oral Aspirin on Prasugrel-Inhibited Platelets: Results of a Prospective, Randomized, Crossover Study (the ECCLIPSE Trial).

Prasugrel and ticagrelor, new P2Y12-adenosine diphosphate receptor antagonists, are associated with greater pharmacodynamic inhibition and reduction of cardiovascular events compared with clopidogrel in patients with an acute coronary syndrome. However, evidence is lacking about the effects of achieving faster and stronger cyclooxygenase inhibition with intravenous lysine acetylsalicylate (LA) compared with oral aspirin on prasugrel-inhibited platelets. This was a prospective, randomized, single-center, open, 2-period crossover platelet function study conducted in 30 healthy volunteers. Subjects were randomly assigned to receive a loading dose of intravenous LA 450 mg plus oral prasugrel 60 mg or loading dose of aspirin 300 mg plus prasugrel 60 mg orally in a crossover fashion after a 2-week washout period between treatments. Platelet function was evaluated at baseline, 30 minutes, 1 h, 4 h, and 24 h using light transmission aggregometry and vasodilator-stimulated phosphoprotein phosphorylation. The primary end point of the study, inhibition of platelet aggregation after arachidonic acid 1.5 mmol/L at 30 minutes, was significantly higher in subjects treated with LA compared with aspirin: 85.3% versus 44.3%, respectively, P=0.003. This differential effect was observed at 1 hour (P=0.002) and 4 hours (P=0.048), but not at 24 hours. Subjects treated with LA presented less variability and faster and greater inhibition of platelet aggregation with arachidonic acid compared with aspirin. The administration of intravenous LA resulted in a significant reduction of platelet reactivity compared with oral aspirin on prasugrel-inhibited platelets. Loading dose of LA achieves an earlier platelet inhibition and with less variability than aspirin. URL: http://www.clinicaltrials.gov. Unique identifier: NCT02243137.

Ticagrelor: A Review of Its Use in Adults with Acute Coronary Syndromes

Ticagrelor (Brilique™, Brilinta®), a cyclopentyl-triazolopyrimidine, is an orally active, reversible, and selective adenosine diphosphate (ADP) receptor antagonist indicated for use in patients with acute coronary syndromes (ACS). Ticagrelor has a faster onset of action and provides greater inhibition of platelet aggregation than clopidogrel. In the large well-designed, PLATO study in adult patients with ACS, 12 months' treatment with ticagrelor was more effective than clopidogrel in reducing the incidence of the primary composite endpoint of myocardial infarction, stroke, or cardiovascular (CV) death. Ticagrelor also reduced all-cause mortality relative to clopidogrel, although statistical significance of this was not confirmed in hierarchical testing. Benefit with ticagrelor was seen both in invasively and noninvasively managed patients. Ticagrelor was generally well tolerated and was not associated with an increased risk of major bleeding relative to clopidogrel. However, the incidences of non-coronary artery bypass grafting (CABG)-related bleeding, and major or minor bleeding, as well as some non-hemorrhagic adverse events, including dyspnea (usually of mild or moderate severity) and ventricular pauses (largely asymptomatic) were higher with ticagrelor. In addition, the ATLANTIC study showed that although pre-hospital administration of ticagrelor did not improve pre-percutaneous coronary intervention (PCI) coronary reperfusion in ACS patients relative to in-hospital administration, ticagrelor was safe in both instances, with no significant between-group differences in non-CABG-related major and minor bleeding events. Although further comparative studies with other antiplatelet agents, including prasugrel, are required to position it more definitively, current evidence indicates that ticagrelor is a useful option for the prevention of thrombotic CV events in ACS patients managed invasively or noninvasively.

High clopidogrel dose in patients with chronic kidney disease having clopidogrel resistance after percutaneous coronary intervention.

We evaluated the impact of clopidogrel 150 mg/d in patients with chronic kidney disease (CKD) having clopidogrel resistance (CR) after percutaneous coronary intervention (PCI); 1076 consecutive patients with coronary artery disease (CAD) having CKD were enrolled. Maximal platelet aggregation (MPA) was assessed before, 24 hours, and 30 days after a 300-mg loading dose of clopidogrel prior to PCI. After PCI, 370 patients with CR were randomized to receive clopidogrel 75 mg/d (n = 184) or 150 mg/d (n = 186) for 30 days. Stent thrombosis (ST), major adverse cardiac events (MACEs), and bleeding were analyzed after 1 month. Patients in the 150 mg group had significant lower rates of ST and MACE. There was no significant difference in major or minor bleeding. Patients in the 150 mg group had lower MPA and greater inhibition of platelet aggregation. One-month administration of 150 mg/d of clopidogrel decreases the rate of ST and MACE without increasing bleeding in patients with CKD having CR after PCI.

Short‐term Effect of Upstream Administration in Comparison to Deferred Injection of Tirofiban on Patients with Acute ST‐Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention

High bolus dose tirofiban has been demonstrated to provide greater inhibition of platelet aggregation, but the most appropriate timing of its administration remains unknown. To evaluate the efficacy of upstream vs. deferred administration of tirofiban in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention (PCI) on clinical outcomes. The 660 patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention were divided into upstream (n=330, administration of tirofiban to all patients in emergency room) and deferred groups (n=330, treatment of patients with large thrombus burden or no-reflow phenomenon in cardiac catheterization laboratory during PCI). The primary end-points were death, nonfatal myocardial infarction (MI), stent thrombosis (ST), revascularization of targeted vessels (TVR) or major adverse cardiac events (MACE) at 1 month and 6 months following PCI, with safety end-point at 7 days. Compared with that of the deferred group, there was a significant increase of left ventricular ejection fraction (LVEF) in the upstream group within 7 days (55.5 ± 6.6% vs. 54.6 ± 7.9%, P=0.011). The rates of 7-day and 1-month MACE in the upstream group were lower than those in the deferred group (1.5% vs. 4.2%, 3.3% vs. 7.0%, P=0.037 and 0.034, respectively). However, there were higher tendencies for major and minor bleedings in the upstream group (1.8% vs. 0.9%, 2.7% vs. 1.5%, P=0.315 and 0.280, respectively). To the Chinese patients with acute myocardial infarction undergoing primary PCI, upstream administration of tirofiban was slightly superior to deferred injection for short-term clinical outcomes.

Prasugrel versus Clopidogrel Antiplatelet Therapy after Acute Coronary Syndrome

Antithrombotic therapy is imperative in the management of patients presenting with an acute coronary syndrome (ACS). The combination of antiplatelet therapy in conjunction with antithrombotic therapy has become the standard of care in improving the morbidity and mortality of patients with an ACS and in reducing ischemic complications of percutaneous coronary intervention. Patients with an ACS are at increased risk for a recurrent event, both in-hospital and for several months afterward. Secondary prevention to reduce these events is accomplished through the establishment of appropriate medical therapy. Dual antiplatelet therapy with aspirin and adenosine 5'-diphosphate P2Y(12) receptor blockers such as ticlopidine or clopidogrel are integral components of this regimen; however, both of these thienopyridines have a relatively slow onset of action and variable bioavailability. Prasugrel, a third-generation thienopyridine approved by the US FDA in 2009, has a more rapid onset of platelet inhibition than clopidogrel and ticlopidine because of increased efficiency of prodrug-to-active metabolite conversion. The result is higher and less variable concentration of the active metabolite within 60 minutes following oral dosing. Phase II and III trials assessing the safety and efficacy of prasugrel have been completed, including JUMBO-TIMI 26, PRINCIPLE-TIMI 44, and TRITON-TIMI 38. These trials demonstrated greater inhibition of platelet aggregation and lower rates of the composite endpoint of death, non-fatal myocardial infarction, and stroke compared with clopidogrel. However, major bleeding occurred more frequently with prasugrel treatment than with clopidogrel. This review highlights the current state of evidence-based antiplatelet therapy and provides guidance on appropriate use of prasugrel in cardiovascular medicine.

The impact of genetic polymorphisms of P2Y12, CYP3A5 and CYP2C19 on clopidogrel response variability in Iranian patients

Clopidogrel is an inhibitor of platelet ADP P2Y12 receptors and currently used for prevention of stent thrombosis. Despite certain clinical benefit using this drug in patients undergoing percutaneous coronary intervention (PCI), some patients do not attain adequate antiplatelet effects. In this study, we investigated the role of three genetic factors (P2Y12, CYP3A5, CYP2C19), demographic characteristics, and pathologic condition on clopidogrel response variability in Iranian patients after PCI.Patients who were candidate for elective PCI were enrolled in this study. All patients had received aspirin 80–325mg daily for ≥1 week before PCI. Blood samples were taken from patients at baseline, 2h after taking a 600-mg loading dose of clopidogrel, 24h and 30 days after PCI. Platelet aggregation was measured by turbidimetric aggregation assay with two different concentrations of ADP (5 and 20μM). CYP2C19*2(rs4244285), CYP2C19*3(rs4986893), CYP3A5 (A6986G), and P2Y12 (T744C) genotypings were performed by PCR-RFLP.One hundred and twelve patients were included in this study. Maximum clopidogrel non-responsiveness (25.90%) occurred at 2h after taking 600mg of the loading dose of clopidogrel. Although there were no significant associations between clopidogrel responsiveness and polymorphisms of CYP2C19, CYP3A5, and P2Y12 (P>0.05), subjects who were CYP3A5 genotype expressor had a greater inhibition of platelet aggregation. No significant associations were observed between environmental factors and clopidogrel responsiveness (P>0.05).Our results showed that P2Y12, CYP3A5, and CYP2C19 polymorphisms along with non-genetic factors were not responsible for the interindividual variability in response to clopidogrel in Iranian population.

The Onset of Inhibition of Platelet Aggregation With Prasugrel Compared With Clopidogrel Loading Doses Using Gatekeeping Analysis of Integrated Clinical Pharmacology Data

The purpose of this analysis was to determine the time by which a prasugrel 60-mg loading dose (LD) achieved significantly greater inhibition of platelet aggregation (IPA) than the peak IPA after a clopidogrel 300-mg LD or 600-mg LD. Data were pooled from nine studies representing 587 individuals: 274 healthy subjects and 313 patients with stable coronary artery disease. The primary pharmacodynamic measure was IPA using 20 [mu]M adenosine-5'-diphosphate as the agonist. Gatekeeping analysis compared the peak IPA at 4, 6, and 24 hours after a clopidogrel 300-mg or 600-mg LD with IPA at various prior time points backwards after a prasugrel LD until a statistically nonsignificant difference was reached. Prasugrel 60-mg LD produced greater IPA by 30 minutes than the peak IPA after a clopidogrel 300-mg LD (P < 0.0001). Significantly greater IPA was achieved at 1 hour after prasugrel 60-mg LD compared with the peak IPA after 600-mg clopidogrel LD (P < 0.0001), regardless of sex, body weight, or age and as early as 30 minutes in the diabetic subgroup. A prasugrel 60-mg LD produces significantly faster onset and greater IPA compared with a clopidogrel 300-mg LD or 600-mg LD.

Inhibitory Effects of Ticagrelor Compared With Clopidogrel on Platelet Function in Patients With Acute Coronary Syndromes: The PLATO (PLATelet inhibition and patient Outcomes) PLATELET Substudy

The PLATO (PLATelet inhibition and patient Outcomes) PLATELET substudy aimed to compare the antiplatelet effects of clopidogrel and ticagrelor in patients with acute coronary syndromes.The PLATO study demonstrated superiority of ticagrelor over clopidogrel in the prevention of ischemic events in patients with acute coronary syndromes.Patients were randomized to receive either clopidogrel (300- to 600-mg loading dose [LD], 75 mg/day) or ticagrelor (180-mg LD, 90 mg twice daily). The effects of maintenance therapy were studied in 69 patients pre- and 2 to 4 h post-dose after at least 28 days. The LD effect was studied in 24 clopidogrel-naive patients. Light transmittance aggregometry (adenosine diphosphate 5 to 20 μM), VerifyNow P2Y12, and VASP phosphorylation assays were performed.During maintenance therapy, ticagrelor achieved greater suppression of platelet reactivity compared with clopidogrel. The mean maximum light transmittance aggregometry responses (adenosine diphosphate 20 μM) post-maintenance dose were 44±15% for clopidogrel and 28±10% for ticagrelor (p<0.001). High platelet reactivity was seen more frequently in the clopidogrel group. Proton pump inhibitor use was associated with higher platelet reactivity with clopidogrel but not ticagrelor. The ticagrelor LD also achieved greater inhibition of platelet aggregation compared with the clopidogrel LD.Ticagrelor achieves greater antiplatelet effect than clopidogrel in patients with acute coronary syndromes, both in the first hours of treatment and during maintenance therapy.

Potentiation of clopidogrel active metabolite formation by rifampicin leads to greater P2Y12 receptor blockade and inhibition of platelet aggregation after clopidogrel.

The thienopyridine P2Y(12) receptor antagonist clopidogrel reduces the risk of arterial thrombosis and individual pharmacodynamic responses to clopidogrel are believed to reflect the levels of active metabolite (AM) generated. Rifampicin increases the inhibitory effect of clopidogrel on platelet aggregation (PA). We studied the response to clopidogrel before and during administration of rifampicin in order to study the relationship between individual AM levels and P2Y(12) blockade. Healthy volunteers received a 600-mg loading dose of clopidogrel followed by 75 mg daily for 7 days and, after a washout period and treatment with rifampicin [300 mg twice a day (b.i.d.)], received the same regimen of clopidogrel. Clopidogrel AM levels were determined over 4 h after the clopidogrel loading dose and unblocked P2Y(12) receptor number was assessed using a (33) P-2MeSADP binding assay. PA was measured by optical aggregometry with ADP and TRAP. Rifampicin enhanced clopidogrel AM production [area-under-the-curve (AUC): clopidogrel 89±22 ng h mL(-1) , clopidogrel+rifampicin 335±86 ng h mL(-1) , P<0.0001], and P2Y(12) blockade (unblocked receptors: clopidogrel 48±24, clopidogrel+rifampicin 4±2, P<0.0001) and reduced PA (5 μmol L(-1) ADP: clopidogrel 20±4, clopidogrel+rifampicin 5±2, P<0.01). Increasing numbers of unblocked receptors were required for an aggregation response with a decreasing concentration of ADP. PA induced by ADP 2 μmol L(-1) was particularly sensitive to low levels of receptor blockade. Potentiation of clopidogrel AM production by rifampicin leads to greater P2Y(12) blockade and consequently greater inhibition of PA. PA responses to low concentrations of ADP are more sensitive to P2Y(12) blockade.

Ticagrelor: the first reversibly binding oral P2Y12 receptor antagonist.

Ticagrelor (AZD6140) is the first reversibly binding oral P2Y12 receptor antagonist that blocks ADP-induced platelet aggregation. Unlike thienopyridines, which irreversibly bind to the P2Y12 receptor for the lifetime of the platelet, ticagrelor binds reversibly to the receptor and exhibits rapid onset and offset of effect, which closely follow drug exposure levels. Animal models indicate greater separation between antithrombotic effects and bleeding effects with ticagrelor than with thienopyridines. Unlike the thienopyridines, ticagrelor does not require metabolic activation. It is quickly absorbed and exhibits a rapid antiplatelet effect, with higher and more consistent levels of inhibition of platelet aggregation (IPA) being maintained across the dosing interval than with clopidogrel. IPA levels decline with plasma drug levels after discontinuation of dosing. In the phase II DISPERSE-2 trial of 990 patients with non-ST-elevation acute coronary syndromes (ACS), ticagrelor treatment with 90 mg and 180 mg twice daily showed comparable rates of major and minor bleeding compared with clopidogrel 75 mg while there were numerically fewer myocardial infarctions. Ticagrelor resulted in greater IPA in clopidogrel-naïve patients and produced substantial additional reductions in platelet aggregation activity in patients pretreated with clopidogrel. Ticagrelor treatment was well tolerated in DISPERSE-2, and discontinuation rates were comparable to those observed for clopidogrel. An increased risk of mild to moderate dyspnea and mostly asymptomatic ventricular pauses were observed in phase II studies. The mechanisms for these effects are currently being investigated. The efficacy and safety of ticagrelor are being further evaluated in the phase III PLATO trial, involving approximately 18,000 patients with ACS, including both ST-elevation and non-ST-elevation ACS.

Abstract 5495: More Rapid and Consistent Inhibition of Platelet Aggregation is Achieved by Loading With Ticagrelor Compared to Clopidogrel in Patients With Acute Coronary Syndromes: Results From the PLATO PLATELET Substudy

Background: Ticagrelor (T) is an oral reversible P2Y 12 receptor antagonist that does not require conversion to an active metabolite for antiplatelet activity, unlike clopidogrel (C). The PLATO study compared the efficacy of T and C in patients with a broad range of acute coronary syndromes (ACS). In this substudy (PLATO PLATELET), we assessed the onset and extent of inhibition of platelet function in PLATO study patients. Methods and Results: 24 C-naive patients with NSTE ACS or STEMI undergoing primary PCI and sequentially randomised in a double blind, double dummy design to C (300mg [n=7] or 600 mg load [n=5]) or T (180mg load [n=12]) in the PLATO study in a single centre were entered into the first phase of PLATO PLATELET. Light transmittance aggregometry (LTA) with ADP (5 and 20 uM) and whole blood single platelet counting aggregometry (WBSPC) using ADP 1–100 uM was performed prior to study drug administration and 1, 2, 4, 8 and 12 hours after study drug. VerifyNow P2Y12 (VN) and VASP assays were also performed pre and 4h post study drug. Data obtained after abciximab administration was excluded except for VASP data. There was more rapid and greater inhibition of platelet aggregation with T vs C, with most T-treated patients showing a substantial effect at 1h post dose that was sustained until 12h post dose (Figure ). VN data at 4h were 273±124 and 68±97 PRU for C and T respectively (p&lt;0.01). VASP data showed a similar trend. C 300 vs 600mg doses showed the same patterns of LTA response. Conclusion: T 180mg loading dose has a faster onset of action with greater inhibition of platelet function compared to C in patients with ACS. WBSPC and VN can rapidly assess the early effects of P2Y 12 antagonists.

Interaction Between Cigarette Smoking and Clinical Benefit of Clopidogrel

The aim of this study was to examine the interaction between cigarette smoking and the clinical efficacy of clopidogrel in ST-segment elevation myocardial infarction (STEMI). Cigarette smoking induces cytochrome P450 (CYP)1A2, which converts clopidogrel into its active metabolite, and prior studies suggest greater inhibition of platelet aggregation by clopidogrel in smokers of > or =10 cigarettes/day. The effect of clopidogrel compared with placebo on angiographic and clinical outcomes was examined in 3,429 STEMI patients in the CLARITY-TIMI 28 (Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis In Myocardial Infarction 28) randomized trial stratified by smoking intensity as follows: not current smokers (n = 1,732), and smokers of 1 to 9 (n = 206), 10 to 19 (n = 354), 20 to 29 (n = 715), and > or =30 cigarettes/day (n = 422). Logistic regression was used to adjust for other baseline characteristics and interaction terms to test for effect modification. Although clopidogrel reduced the rate of the primary end point of a closed infarct-related artery or death/myocardial infarction before angiography in the CLARITY-TIMI 28 trial, the benefit was especially marked among those who smoked > or =10 cigarettes/day (adjusted odds ratio [OR]: 0.49, 95% confidence interval [CI]: 0.37 to 0.66; p < 0.0001) compared with those who did not (adjusted OR: 0.72, 95% CI: 0.57 to 0.91; p = 0.006; p(interaction) = 0.04). Similarly, clopidogrel was significantly more effective at reducing the rate of cardiovascular death, myocardial infarction, or urgent revascularization through 30 days among those who smoked > or =10 cigarettes/day (adjusted OR: 0.54, 95% CI: 0.38 to 0.76; p = 0.0004) compared with those who did not (adjusted OR: 0.98; 95% CI: 0.75 to 1.28; p = 0.87; p(interaction) = 0.006). Cigarette smoking seems to positively modify the beneficial effect of clopidogrel on angiographic and clinical outcomes. This study demonstrates that common clinical factors that influence the metabolism of clopidogrel might impact its clinical effectiveness.

Prasugrel

Prasugrel, trade name Effient, is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration. It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine. Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic P2Y12 receptor on the platelet surface. Prasugrel has been shown to be a potent antiplatelet agent with a faster, more consistent, and greater inhibition of platelet aggregation compared with clopidogrel. It is debatable, however, how effectively these pharmacologic benefits will translate to clinical benefits. The results of the large TRITON-TIMI 38 trial, which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents, demonstrated a significant reduction in ischemic events, including stent thrombosis, with prasugrel, but with an increased risk of major bleeding. The exact role of prasugrel in the management of ischemic heart disease is still being defined, but the risk:benefit ratio will likely play a major role in directing the best place for therapy with this new agent.

Optimizing platelet inhibition

The platelet P2Y12 receptor plays a critical role in sustaining ADP-mediated platelet aggregation. Drawbacks of the thienopyridine clopidogrel, a prodrug of an irreversible P2Y12 antagonist, include the need for two-step metabolism to its active form and partial hydrolysis to its inactive metabolite. Both contribute to high variability in the degree of platelet inhibition and the irreversibility of binding complicates both acute and planned invasive treatments when rapid offset of antiplatelet activity is desired. Novel P2Y12 antagonists include the thienopyridine prasugrel and the selective, direct, reversible antagonists cangrelor (iv) and AZD6140 (oral). Prasugrel, also an irreversible antagonist, requires only one-step metabolism to active form and achieves greater inhibition of platelet aggregation (IPA) than clopidogrel. Recently published data indicate that this translates into improved efficacy. Like clopidogrel, prasugrel relies on new platelet generation for offset of effect. The direct reversible antagonists bind directly to the receptor, and the degree of IPA closely follows plasma drug concentrations. In addition to permitting more rapid offset of effect and greater and more consistent IPA than clopidogrel, direct reversible antagonists may exert additional beneficial effects via blockade of P2Y12 in vascular smooth muscle cells. Reversible antagonists also appear to exhibit a wider therapeutic window, showing reduced bleeding time prolongation per given degree of antithrombotic effect in experimental models. Ongoing large-scale Phase 3 clinical trials are examining cangrelor in patients with acute coronary syndromes (ACS) also undergoing percutaneous coronary intervention (PCI) and AZD6140 in ACS patients being treated with medical therapy, PCI, or coronary artery bypass grafting.