Clinical overview of promising nonthienopyridine antiplatelet agents

Ticagrelor (AZD6140) 

In phase I dose-dependency studies in healthy volunteers, single oral doses of AZD6140 100 to 400 mg were rapidly absorbed with linear and dose-dependent pharmacokinetics.1 Complete platelet inhibition was achieved 2 hours after dosing.1 Inhibition approaching 100% was seen with 300- and 400-mg/d doses, and approximately 90% inhibition was maintained with these doses over a 24-hour period. However, there was a lessening of effect over 24 hours with AZD6140 100 mg/d: at 4, 12, and 24 hours, inhibition of platelet aggregation (IPA) was 99%, 89%, and 57%, respectively.

The phase II DISPERSE trial was an early dose-confirmation study assessing the antiplatelet effects of AZD6140 plus aspirin against those of clopidogrel plus aspirin.2 In this study, 200 patients with atherosclerotic disease were randomized to receive AZD6140 50, 100, or 200 mg twice a day (BID) or 400 mg/d, or clopidogrel 75 mg/d for 28 days in addition to aspirin 75 to 100 mg. AZD6140 ≥100 mg BID produced a more rapid and greater platelet inhibition (>90%) than did clopidogrel, which produced ∼60% platelet inhibition. It is notable that there was less interpatient variability in response to AZD6140 than to clopidogrel, and all bleeding events except one (a major, nonfatal hemorrhage reported in a patient receiving AZD6140 400 mg once a day [QD]) were considered minor. Overall, AZD6140 was well tolerated, with an adverse event profile comparable with that of clopidogrel. Only minor bleeding events and dyspnea increased with dose; and in all cases, these adverse effects were considered minor or moderate.

In the phase II DISPERSE-2 trial, 990 patients with non–ST-segment elevation acute coronary syndromes (NSTE ACS) were randomly assigned to receive AZD6140 90 or 180 mg BID or clopidogrel 75 mg QD for up to 12 weeks; half of the patients receiving AZD6140 were subrandomized to receive a loading dose of 270 mg, whereas the other half started therapy with the maintenance dose.3 All patients received aspirin 75 to 100 mg/d. Outcome measures included the incidence of bleeding events (the primary end point) and cardiac events (cardiovascular death, myocardial infarction [MI], and stroke). Ex vivo platelet inhibition was also assessed. No significant differences in bleeding events occurred between the AZD6140 and clopidogrel treatment groups, and major and minor bleeding events through 4 weeks occurred at similar rates in all patient groups.3 In particular, the Kaplan-Meier rate of major or minor bleeding through 4 weeks was 8.1% in the clopidogrel group, 9.8% in the AZD6140 90-mg group, and 8.0% in the AZD6140 180-mg group (P = .43 and P = .96, respectively, vs clopidogrel); the major bleeding rates were 6.9%, 7.1%, and 5.1%, respectively (P = .91 and P = .35, respectively, vs clopidogrel). Of note, favorable trends were seen in the incidence of MI (5.6%, 3.8%, and 2.5%, respectively; P = .41 and P = .06, respectively, vs clopidogrel). Although treatment with AZD6140 was generally well tolerated, several adverse events observed in the DISPERSE-2 study, including dyspnea and bradycardia, need further evaluation in a phase III testing. These findings were dose dependent, were self-limiting, and did not lead to discontinuation of therapy. With regard to dyspnea, physical examination of the patients with symptoms was unremarkable; and evaluation of respiratory function showed no definitive changes. Bradycardia was manifested by an increased frequency of sinus pauses or atrioventricular block. The overall significance of the bradycardia will be evaluated in phase III trials.

A pharmacodynamic/pharmacokinetic substudy in DISPERSE-2 was also conducted. In this substudy, 45 patients were clopidogrel naïve and 44 patients were clopidogrel pretreated. In the first group, 45 patients with NSTE ACS were randomized to receive AZD6140 90 or 180 mg BID, or clopidogrel 75 mg QD. Half of both AZD6140 groups received a 270-mg loading dose, and the patients in the clopidogrel group received a 300-mg loading dose. Plasma levels of AZD6140 peaked at 2 hours and at 4, 8, and 12 weeks; and both AZD6140 doses yielded consistently higher levels of IPA than did clopidogrel (4 weeks, 4 hours postdose: AZD6140 90 mg 79% ± 22%, AZD6140 180 mg 95% ± 8%, clopidogrel 64% ± 22%). No statistical difference was noted between the patients who received the 180- and 270-mg doses of AZD6140.4 Thus, AZD6140 suppressed platelet aggregation in clopidogrel-naïve patients more rapidly and consistently than did clopidogrel. In the second group, 44 patients with NSTE ACS were randomized to receive AZD6140 90 or 180 mg BID, or clopidogrel 75 mg QD. Half of both AZD6140 groups received a 270-mg loading dose. All AZD6140 groups (90, 180, and 270 mg BID) showed a marked IPA at 4 hours after the initial dose, whereas the clopidogrel-treated patients showed no fall in platelet aggregation (AZD6140 270 mg: predose 43% ± 22%, postdose 2% ± 4%). Plasma levels of AZD6140 peaked at 2 hours, and the highest individual platelet aggregation response at 4 hours was 66% in the clopidogrel group and 19% in the 3 AZD6140 groups combined.

AZD6140 has the potential to overcome some of the limitations of clopidogrel with superior potency, more rapid onset and offset of activity, and less interpatient response variability. The property of rapid offset of antiplatelet effects has been a source of concern with long-term use, particularly in patients who are inconsistent in taking their medication, similar to previous experiences with the oral glycoprotein IIb/IIIa antagonists. However, functional studies have shown that, in patients who miss a dose of AZD6140 at 12 hours, the degree of IPA is greater than that seen after clopidogrel. Further insights into the clinical profile of AZD6140 will be provided by the PLATO, an ongoing head-to-head phase III trial comparing AZD6140 (180-mg loading dose, 90-mg BID maintenance dose) and clopidogrel (300-mg loading dose, 75-mg QD maintenance dose). This study is being conducted in 40 countries through 1,000 investigational centers and will include 18,000 patients with ACS. The primary composite end point is cardiovascular death, MI, and stroke at a mean follow-up of 11 months.

Cangrelor (ARC-69931MX) 

A phase I study conducted in healthy volunteers who received 4 overlapping 1-hour infusions of cangrelor 10 to 4,000 ng/kg per minute demonstrated a dose-dependent inhibition of ADP-induced platelet aggregation that was completely reversed within 20 minutes of discontinuation of the drug without the presence of a rebound effect on platelet activity.5 Cangrelor achieved a steady state rapidly, with a clearance of 50 L/h and a short half-life of 2.6 minutes; and there was a separation between antiplatelet activity and bleeding times, similar to the effect seen in animal studies. The pharmacokinetic profile of cangrelor was similar in male and female subjects. Overall, cangrelor was well tolerated and associated with only minor increases in petechiae and bruising.

In a subsequent phase I study, 8 healthy male subjects received cangrelor or clopidogrel 75 mg/d; and ADP-induced ex vivo platelet aggregation was measured over 11 days.6 The antiplatelet effects of clopidogrel slowly increased during this time, but there was large interindividual variability. However, no subject demonstrated complete IPA (ie, by day 11, inhibition of ADP-induced platelet aggregation was 46% ± 10% of baseline). Thus, cangrelor did not lead to complete inhibition of the P2Y12 receptor; but rapid and complete platelet inhibition could be achieved when cangrelor was added in vitro.

The STEP-AMI trial studied the continuous infusion of cangrelor in combination with tissue plasminogen activator (t-PA) in 101 patients with ST-segment elevation MI (STEMI).7 Patients were randomized to receive cangrelor alone (280 μg/min), a full dose of t-PA alone, or a reduced dose of t-PA (50 mg) plus 1 of 3 doses of cangrelor: 35, 140, or 280 μg/kg per minute. The primary end point, Thrombolysis in Myocardial Infarction (TIMI)–3 flow, did not differ significantly in the presence or absence of cangrelor. Cangrelor administered alone had no beneficial effect on reperfusion. However, patients with >70% ST-segment elevation who received cangrelor showed trends toward improved ST-segment recovery. Cangrelor was well tolerated in all treatment groups and was not associated with major adverse clinical events or non–coronary artery bypass graft-related TIMI major bleeding. Thus, reduced doses of a fibrinolytic agent combined with cangrelor might have beneficial effects on reperfusion without causing serious hemorrhagic events.

A phase II study with cangrelor was conducted in patients with unstable angina (UA) and non–Q wave MI.8 Patients received ascending-dose infusions of cangrelor combined with aspirin, nitrate therapy (as required), and anticoagulation therapy. As an intravenous agent with a short half-life (terminal half-life ∼3 to 5 minutes) cangrelor caused a rapid inhibition of ex vivo platelet aggregation within minutes of initiation of infusion and a rapid reversal of inhibition within 1 hour of cessation of infusion. Steady-state plasma concentrations were achieved within 30 minutes of continuous infusion, and the average level of inhibition was similar among doses ranging from 0.2 to 2.0 μg/kg per minute. An increase of the cangrelor dose to >2 μg/kg per minute was needed for all patients to achieve >80% inhibition, with less variability in platelet inhibition being observed with doses of 2 to 4 μg/kg per minute. At this dosing range, 74% of patients demonstrated 100% IPA. Adverse events were commonly seen in this study, especially at the injection site; but no severe bleeding was reported by TIMI minor or major criteria, and there was no correlation between bleeding times and cangrelor plasma levels. Notably, there was no placebo arm for a safety comparison. Overall, cangrelor was well tolerated as an adjunct to aspirin and heparin.

In a phase II trial designed to assess the safety and tolerability of cangrelor, 91 patients with UA and non-STEMI were randomized to receive a continuous infusion of cangrelor 4 μg/kg per minute or placebo for 72 hours, plus aspirin or low–molecular weight heparin.9 Cangrelor achieved a calculated steady-state plasma concentration of 401 ng/mL and was rapidly cleared from the circulation (44.3 ± 6.4 L/h). The adverse effect profile of cangrelor was similar to that of placebo, including rates of adverse bleeding events. Statistically significantly lower rates of angina were reported in the patients receiving cangrelor than in those receiving placebo, although UA occurred in 1 patient 27 hours after infusion, perhaps related to platelet reactivation.

Phase II clinical trials have also examined the safety and efficacy of cangrelor in patients undergoing percutaneous coronary interventions (PCI). In a clinical study comparing cangrelor and clopidogrel in patients with ischemic heart disease during PCI, a small group of 13 patients with non-STEMI received open-label cangrelor 2 μg/kg per minute (n = 8) or 4 μg/kg per minute (n = 5). Cangrelor caused near-complete IPA at 4 minutes after infusion, whereas clopidogrel exerted only a 60% inhibition.10 Normal platelet aggregation was restored within 1 hour after cangrelor therapy was stopped. Another group of patients undergoing coronary stenting received a loading dose of clopidogrel 300 mg at implantation and a maintenance dose of 75 mg/d. Consistent with its potent P2Y12 receptor inhibitory properties, cangrelor, when added to the blood of clopidogrel-treated patients, caused nearly complete IPA; and the antiplatelet effect was additive (P < .05).

The results of a 2-part study of the safety and tolerability of cangrelor in patients undergoing PCI have been reported.11 Patients received aspirin 325 mg and weight-adjusted unfractionated heparin. In the first part of the study, 200 patients were randomized to receive a continuous infusion of cangrelor 1, 2, or 4 μg/kg per minute or placebo, which was initiated before the coronary intervention and continued for 18 to 24 hours. Four patients (8%) receiving the highest dose of cangrelor experienced major bleeding, compared with no patients receiving placebo (P = .052). At lower doses of cangrelor, no relationship was observed between dose and rates of minor bleeding. It is notable that other patient bleeding risks confounded the association of an increased rate of major bleeding with cangrelor, including concurrent glycoprotein inhibitor therapy and surgical revascularization. Patients in the placebo group had a higher rate of reintervention between week 1 and the end of the study, an observation that may indicate a delayed benefit from the inhibition of proinflammatory mediators.

The second part of this study involved 199 patients undergoing PCI who were randomized to receive cangrelor 4 μg/kg per minute or abciximab throughout the PCI. Overall, cangrelor was well tolerated in both parts of the study; and there was no TIMI major or minor bleeding. Bleeding times in the patients receiving cangrelor were almost double what they were in the patients receiving placebo, and those in the patients receiving abciximab were almost triple what they were in the placebo group. Thrombocytopenia occurred in 1% of patients receiving cangrelor compared with 7% of patients receiving abciximab (P = .025). Rapid IPA ex vivo was seen in both parts of the study, with a return to normal levels of platelet aggregation within 15 minutes of discontinuation of cangrelor therapy. Patients receiving abciximab demonstrated persistent inhibition of mean platelet aggregation beyond 24 hours.

Cangrelor will be studied further in 2 prospective, randomized, double-blind, controlled phase III trials.12, 13 The objective of the CHAMPION-PLATFORM trial will be to evaluate whether the efficacy of cangrelor plus usual care is superior to placebo plus usual care in >4,000 clopidogrel-naïve patients undergoing PCI. A 600-mg loading dose of clopidogrel followed by a 75-mg/d maintenance dose will be used in this study, which will randomize patients to a 30-μg/kg bolus and 4-μg/kg per minute infusion of cangrelor. A clinical composite end point of death, MI, or ischemia-driven revascularization will be evaluated within 48 hours of cangrelor infusion. The second phase III trial, CHAMPION-PCI, will evaluate whether the efficacy of cangrelor is superior, or at least noninferior, to that of clopidogrel in patients requiring PCI.13, 14 Approximately 9,000 patients will be randomized to receive a bolus dose of cangrelor 30 μg/kg and maintenance infusion of 4 μg/kg per minute for a maximum of 4 hours given immediately before the index procedure, or a bolus dose and maintenance infusion of placebo and a loading dose of clopidogrel during the PCI. The study drug will be infused for the duration of the procedure. Combined death, MI, and urgent revascularization at 48 hours will be the primary end point.

Overall, cangrelor is a potent, short-acting P2Y12 ADP receptor antagonist that may be useful when surgical coronary revascularization procedures are needed. During a pharmacodynamic comparison, cangrelor demonstrated superior platelet inhibition to clopidogrel even when an effective loading dose of clopidogrel was used.10 However, when both drugs were administered simultaneously, clopidogrel was unable to mitigate platelet aggregation and activation. Thus, defining the potential pharmacologic interaction between clopidogrel and cangrelor is paramount for optimizing antiplatelet function when transitioning from acute to chronic settings. The results of several studies suggest that the high affinity of cangrelor for the P2Y12 receptor prohibits the active metabolite of clopidogrel from forming the necessary bond with its cognate receptor during the 2-hour cangrelor infusion used in this study.14 In addition, it should be noted that the active metabolite of cangrelor is unstable; hence, it might not be expected to be available for binding to the P2Y12 receptor >2 hours after the administration of a 600-mg loading dose.14 These findings may have important clinical implications as cangrelor advances into phase III testing. Parenterally administered cangrelor seems to be most useful in the acute setting.

SCH 530348 (thrombin receptor antagonist) 

A pharmacokinetic study in healthy individuals indicated that single-dose oral SCH 530348 was well tolerated and caused a significant dose-related inhibition of thrombin receptor–activating, peptide-induced platelet aggregation, with maximum effects (>90% inhibition) achieved as early as 1 hour after administration.15 SCH 530348 was rapidly absorbed and slowly eliminated (terminal half-life >72 hours). In the phase II TRA-PCI trial, 1,031 patients scheduled for angiography and possible elective stenting were randomized equally to receive 1 of 3 oral loading doses of SCH 530348 (10, 20, or 40 mg) or placebo. The loading doses were increased in sequential fashion based on a blinded review by an independent safety review committee. The patients who subsequently underwent PCI (n = 573) or coronary artery bypass graft (n = 382) were randomized to receive 1 of 3 oral daily maintenance doses of SCH 530348 (0.5, 1.0, or 2.5 mg) if they received an SCH 530348 loading dose, or to placebo if they received a placebo loading dose. Patients received standard of care therapies, including aspirin, clopidogrel, and an antithrombin agent of the investigator's choice (heparin or bivalirudin). The total duration of treatment was 60 days, and patients were followed for an additional 60 days after treatment.16 Results showed that, in the primary cohort (ie, patients who had PCI), the incidence of TIMI major bleeding (ie, any intracranial hemorrhage or overt sign of bleeding requiring intervention, and associated with a decrease in hemoglobin concentration of >5 g/dL) and minor bleeding (ie, any overt sign of bleeding requiring intervention that did not meet the requirements for TIMI major bleed and associated with a decrease in hemoglobin concentration of 3 to ≤5 g/dL) in the collective SCH 530348 treatment arms was 2.8% compared with 3.3% with standard of care alone. There was no statistically significant difference in TIMI bleeding across all doses. Thus, this trial met its primary end point of demonstrating no increase in TIMI major and minor bleeding when SCH 530348 was added to standard dual antiplatelet therapy (including aspirin and clopidogrel) among patients undergoing PCI. Although not powered to establish efficacy, the study reported a non–statistically significant 46% reduction in cardiovascular events at the highest SCH 530348 dose tested compared with standard antiplatelet therapy. Such trend toward a reduction in cardiovascular events is inversely related to the degree of IPA.

A substudy of TRA-PCI assessed IPA of SCH 530348 in response to several different agonists, including thrombin receptor–activating peptide, a potent thrombin analog that can activate protease-activated receptor–1 ( PAR-1). A significant reduction compared with placebo emerged as early as 0.5 hour with the 40-mg loading dose and by 1 hour with the 10- and 20-mg doses; by 2 hours, there was still greater inhibition (>80%) with the 40-mg dose, which was clearly the most effective. An IPA of >80% was sustained at 30 and 60 days with the 1.0- and 2.5-mg maintenance doses. On the other hand, there was no relevant inhibition of ADP- or collagen-induced platelet aggregation, which attests to the relative specificity of SCH 530348 for PAR-1. The effects appear to be long lasting, with only a 50% or 60% return of platelet function 3 weeks after termination of dosing. This may be related to the long half-life of SCH 530048 (≥2 weeks).

Importantly, SCH 530348 is being investigated to determine whether it has the potential to provide clinical benefit through the inhibition of thrombin-mediated platelet activation without the liability of increased bleeding, a tendency associated with drugs that block thromboxane or ADP pathways. Specifically, this compound is being investigated as an oral antiplatelet agent for patients with established vascular disease, with the intent to demonstrate incremental benefit on top of standard antiplatelet and other antithrombotic therapies, with no significant increase in bleeding. Clinical studies to date have shown no increase in bleeding time or prolongation in coagulation times (activated partial thromboplastin time or prothrombin time) with SCH 530348, indicative of a selective antiplatelet effect of this agent.

The phase III clinical development program will include 2 large clinical trials to evaluate the risk reduction provided by SCH 530348 plus standard antiplatelet therapy compared with placebo plus standard antiplatelet therapy. The trials will be conducted in approximately 30 countries at >800 sites for each trial. The phase III TRACER trial will be a multinational, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of SCH 530348 in addition to standard of care. In this study, a loading dose of 40 mg and a maintenance dose of 2.5 mg will be evaluated in approximately 10,000 patients with ACS for ≥1 year of follow-up. The primary end point is the composite of cardiovascular death, MI, stroke, rehospitalization for ACS, and urgent revascularization; and the secondary end point is the composite of cardiovascular death, MI, and stroke. The phase III TRA-2P–TIMI 50 trial will be a multinational, randomized, double-blind, placebo-controlled study in approximately 19,500 patients with prior MI or stroke, or who have existing peripheral arterial disease. Patients will receive a 2.5-mg maintenance dose of SCH 530348 or placebo as secondary prevention in addition to their standard medical care, including aspirin and/or clopidogrel. The primary end point of the trial is the composite of cardiovascular death, MI, urgent coronary revascularization, or stroke. The key secondary end point is cardiovascular death, MI, or stroke. Patients will be followed for a minimum of 1 year.

Conclusions 

Despite the beneficial effects of dual clopidogrel and aspirin therapy in patients who have ACS or are undergoing PCI, these antiplatelet agents have a number of significant limitations that have prompted the search for new therapies. As described here, novel nonthienopyridine platelet inhibitors that target the P2Y12 and thrombin receptors are currently in advanced clinical testing. The pharmacology and clinical profiles of these emerging platelet inhibition therapies suggest that they have the potential to provide more consistent, more rapid, and more potent antiplatelet effects than do antiplatelet agents currently used in clinical practice. Results to date of phase II studies have shown favorable safety profiles. Ongoing large-scale phase III trials will further evaluate their clinical efficacy.