cangrelor and Coronary-Disease

Landmark clinical trials have established the benefit of P2Y12 inhibitors in the setting of acute coronary syndrome and percutaneous coronary intervention. On February 12, 2014, the Medicines Company (Sponsor) presented efficacy and safety data regarding cangrelor to the Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee. The Sponsor sought approval for 2 indications: (1) in the setting of percutaneous coronary intervention for the reduction of thrombotic cardiovascular events (including stent thrombosis) in patients with coronary artery disease and (2) in the setting of bridging therapy in patients with acute coronary syndrome or with stents who are at increased risk for thrombotic events (such as stent thrombosis) when oral P2Y12 therapy is interrupted because of surgery. The following is a summary of the data presented to the FDA by the Sponsor, the FDA's clinical review of cangrelor.

Topics: Adenosine Monophosphate; Advisory Committees; Congresses as Topic; Coronary Disease; Drug Approval; Humans; Purinergic P2Y Receptor Antagonists; United States; United States Food and Drug Administration

Cangrelor is a potent, rapid-acting, reversible intravenous platelet inhibitor that was tested for percutaneous coronary intervention (PCI) in three large, double-blind, randomised trials. We did a pooled analysis of data from three trials that assessed the effectiveness of cangrelor against either clopidogrel or placebo in PCI.. This prespecified, pooled analysis of patient-level data from three trials (CHAMPION-PCI, CHAMPION-PLATFORM, and CHAMPION-PHOENIX) compared cangrelor with control (clopidogrel or placebo) for prevention of thrombotic complications during and after PCI. Trial participants were patients undergoing PCI for ST-elevation myocardial infarction (11.6%), non-ST-elevation acute coronary syndromes (57.4%), and stable coronary artery disease (31.0%). Efficacy was assessed in the modified intention-to-treat population of 24,910 patients, with a prespecified primary efficacy composite of death, myocardial infarction, ischaemia-driven revascularisation, or stent thrombosis at 48 h. The primary safety outcome was non-coronary artery bypass graft-related GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe or life-threatening bleeding at 48 h.. Cangrelor reduced the odds of the primary outcome by 19% (3.8% for cangrelor vs 4.7% for control; odds ratio [OR] 0.81, 95% CI 0.71-0.91, p=0.0007), and stent thrombosis by 41% (0.5% vs 0.8%, OR 0.59, 95% CI 0.43-0.80, p=0.0008). Cangrelor reduced the odds of the secondary triple composite (all-cause death, myocardial infarction, or ischaemia-driven revascularisation at 48 h) by 19% (3.6% vs 4.4%, OR 0.81, 95% CI 0.71-0.92, p=0.0014). Efficacy outcomes were consistent across the trials and main patient subsets. These benefits were maintained at 30 days. There was no difference in the primary safety outcome (0.2% in both groups), in GUSTO moderate bleeding (0.6% vs 0.4%), or in transfusion (0.7% vs 0.6%), but cangrelor increased GUSTO mild bleeding (16.8% vs 13.0%, p<0.0001).. Compared with control (clopidogrel or placebo), cangrelor reduced PCI periprocedural thrombotic complications, at the expense of increased bleeding.. The Medicines Company.

Topics: Acute Coronary Syndrome; Adenosine Monophosphate; Aged; Cause of Death; Coronary Disease; Double-Blind Method; Female; Graft Occlusion, Vascular; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Myocardial Revascularization; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Stents; Treatment Outcome

Three novel nonthienopyridine antiplatelet agents--cangrelor, ticagrelor (AZD6140), and SCH 530348--are in advanced clinical testing in patients with coronary artery disease. Cangrelor and ticagrelor are direct and reversible inhibitors of the platelet adenosine 5'-diphosphate P2Y12 receptor, whereas SCH 530348 is a thrombin receptor antagonist. Clinical data available to date for each of these compounds suggest that they have safety and efficacy profiles that will be advantageous to patients with acute coronary syndromes or undergoing percutaneous intervention. We review the clinical features of these new platelet inhibition therapies.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Angioplasty, Balloon, Coronary; Aspirin; Clinical Trials as Topic; Coronary Disease; Drug Therapy, Combination; Humans; Lactones; Platelet Aggregation Inhibitors; Purinergic P2 Receptor Antagonists; Pyridines; Receptors, Thrombin; Ticagrelor

Platelets possess three P2 receptors for adenine nucleotides: P2Y1 and P2Y12, which interact with ADP, and P2X1, which interacts with ATP. The interaction of adenine nucleotides with their platelet receptors plays an important role in thrombogenesis. The thienopyridine ticlopidine, an antagonist of the platelet P2Y12 ADP receptor, reduces the incidence of vascular events in patients at risk, but it also has some important drawbacks: a relatively high incidence of toxic effects; delayed onset of action; high inter-individual variability in response. Another thienopyridine, clopidogrel, has superseded ticlopidine, because it is an efficacious antithrombotic drug and is less toxic than ticlopidine. However, the high inter-patient variability in response still remains an important issue. These drawbacks justify the continuing search for agents that can further improve the clinical outcome of patients with atherosclerosis through greater efficacy and/or safety. A new thienopyridyl compound prasugrel, which is characterized by higher potency and faster onset of action compared with clopidogrel, is currently under clinical evaluation. Two direct and reversible P2Y12 antagonists, cangrelor and AZD6140, have very rapid onset and reversal of platelet inhibition, which make them attractive alternatives to thienopyridines, especially when rapid inhibition of platelet aggregation or its quick reversal are required. Along with new P2Y12 antagonists, inhibitors of the other platelet receptor for ADP, P2Y1, and of the receptor for ATP, P2X1, are under development and may prove to be effective antithrombotic agents.

Topics: Adenosine; Adenosine Monophosphate; Angina, Unstable; Animals; Blood Platelets; Clopidogrel; Coronary Disease; Coronary Thrombosis; Drug Interactions; Fibrinolytic Agents; Humans; Myocardial Infarction; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Randomized Controlled Trials as Topic; Receptors, Purinergic P2; Receptors, Purinergic P2X; Syndrome; Thiophenes; Ticagrelor; Ticlopidine

ADP is one of the most important mediators of both physiologic hemostasis and thrombosis. Development and utilization of agents that block ADP receptors on the platelet membrane, namely thienopyridines, has represented a major advancement for treatment of patients undergoing percutaneous coronary interventions and those with acute coronary syndromes. Currently, clopidogrel, a second-generation thienopyridine that inhibits the ADP P2Y(12) receptor, represents the treatment of choice, in addition to aspirin, for the prevention of stent thrombosis. Further, long-term adjunctive use of this ADP P2Y(12) receptor antagonist is also associated with improved clinical outcomes in high-risk patients, and represents the standard of care for these patients. Despite the unambiguous clinical benefit associated with clopidogrel, accumulating experience with this drug has also led to identification of some of its drawbacks, which are related to inadequate platelet inhibition with standard dosage regimens as well as to its irreversible antiplatelet effects. This has led to the questioning of currently recommended clopidogrel dosage regimens as well as to the development of novel and more potent ADP P2Y(12) receptor antagonists, some of which are also reversible agents. Numerous studies are currently ongoing with the objective of demonstrating how more potent platelet inhibition using higher loading and maintenance dose regimens of clopidogrel or novel ADP P2Y(12) receptor antagonists - such as prasugrel, ticagrelor (AZD 6140) and cangrelor - will affect clinical outcomes. This article reviews the current knowledge of platelet ADP P2Y(12) receptor antagonism and the projected developments in this field.

Topics: Adenosine; Adenosine Monophosphate; Angioplasty, Balloon, Coronary; Blood Platelets; Clopidogrel; Coronary Disease; Humans; Membrane Proteins; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2Y12; Thiophenes; Thrombosis; Ticagrelor; Ticlopidine

AstraZeneca is developing the P2T (P2YADP) purinoceptor antagonist and platelet aggregation inhibitor, cangrelor, for the potential treatment of unstable angina and as an ultrafast-acting intravenous antithrombotic agent. It is in phase IIb clinical trials [315723]. NDA and MAA applications are planned for after 2003 [275466], [314472]. It superseded the earlier compound, ARL-67085, which also reached phase II trials [328760]. In ex vivo samples of angina patients' blood, cangrelor inhibits platelet/monocyte conjugate development, which indicate the drug has some degree of disease-modifying activity [377418]. AstraZeneca is also developing derivatives of cangrelor. Removal of the triphosphate side chain, modification of the ribose to a carbocycle and the purine to a triazolopyridine resulted in a potent (IC50 = 4 nM) orally-active P2T/P2Y12 receptor antagonist. A lead compound was scheduled to enter trials as an antithrombotic agent in July 2000 [377666]. In March 1999, Lehman Brothers predicted a 30% probability that the drug would reach world markets and would be launched in 2002 [336599].

Topics: Adenosine Monophosphate; Animals; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Contraindications; Coronary Disease; Hemodynamics; Humans; Platelet Aggregation Inhibitors; Receptors, Purinergic; Structure-Activity Relationship

This randomized trial tested whether early loading with prasugrel can provide sufficient platelet inhibition even when given at the start of a 2-h infusion of cangrelor.. Effective platelet inhibition with intravenous cangrelor reduces the risk of ischemic complications during percutaneous coronary intervention (PCI). Transitioning to oral therapy with clopidogrel or prasugrel is only recommended after discontinuation of cangrelor due to drug interactions. Given the long half-life of prasugrel, this drug could achieve effective platelet inhibition even when given early under cangrelor and thereby prevent a transient gap in platelet inhibition.. This trial randomized 110 P2Y. The 3 groups were well balanced with respect to clinical parameters. One hour following discontinuation of cangrelor, the primary endpoint was seen in 65.0% of patients on clopidogrel versus 95.6% with ticagrelor and 93.3% with prasugrel (p for superiority of prasugrel vs. clopidogrel = 0.003; p of prasugrel vs. ticagrelor = 0.65). The 30-day incidence of ischemic and bleeding events was similar in all groups.. Prasugrel 60 mg given at the start of a 2-h infusion of cangrelor can provide a sufficient platelet inhibition post-cangrelor. This approach prevents the transient gap in platelet inhibition seen with oral loading after discontinuation of cangrelor. (Impact of Extent of Clopidogrel-Induced Platelet Inhibition during Elective Stent Implantation on Clinical Event Rate - Advanced Loading Strategies [ExcelsiorLOAD2]; DRKS00009739).

Topics: Adenosine; Adenosine Monophosphate; Administration, Oral; Aged; Blood Platelets; Clopidogrel; Coronary Disease; Drug Substitution; Female; Germany; Humans; Infusions, Intravenous; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prasugrel Hydrochloride; Prospective Studies; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Stents; Ticagrelor; Ticlopidine; Time Factors; Treatment Outcome

Platelet-initiated acute thrombosis and coronary embolization are fundamental in the pathophysiology of complications during percutaneous coronary intervention (PCI). Cangrelor (formerly AR-C69931MX) is a novel, rapidly acting, intravenous, specific antagonist of platelet aggregation via binding to the adenosine diphosphate (ADP) P2Y12 receptor subtype. The primary aims of this study were to assess the initial safety and pharmacodynamics of cangrelor in patients undergoing PCI.. In part 1, patients undergoing PCI were randomized to an 18- to 24-hour of either placebo, 1-, 2-, or 4-microg/kg per minute cangrelor in addition to aspirin and heparin beginning before PCI. In part 2, patients were randomized to receive either cangrelor (4 microg/kg per minute) or abciximab before PCI. The primary end point was the composite incidence of major and minor bleeding through 7 days. Secondary end points included the occurrence of major adverse coronary events (death, MI, and unplanned repeat coronary intervention) through 30 days plus ex vivo platelet aggregation and bleeding times.. Two hundred patients (3 dosage groups and placebo) were studied in part 1, and 199 additional patients were then randomized in the second part, comparing 1 dose of cangrelor and abciximab. Combined major and minor bleeding occurred in 13% of those receiving cangrelor and in 8% in those randomized to placebo (P = non significant [NS]) during part 1 and in 7% receiving cangrelor compared with 10% randomized to abciximab (P = NS), during part 2. The 30-day composite incidence of adverse cardiac events was similar between those receiving cangrelor and those receiving abciximab during part 2 (7.6% vs 5.3%, respectively, P = NS). Mean inhibition of ex vivo platelet aggregation in response to 3 micromol/L ADP at steady state was 100% for both cangrelor 4 microg/kg per minute and abciximab groups in part 2. After termination of infusion, platelet aggregation returned to baseline response more rapidly with cangrelor compared with abciximab. There was a trend toward longer bleeding time prolongation and lower platelet count with abciximab compared with cangrelor.. This initial experience with intravenous cangrelor during PCI suggests an acceptable risk of bleeding and adverse cardiac events while achieving rapid, reversible inhibition of platelet aggregation via competitive binding to the ADP P2Y12 platelet receptor with less prolongation of bleeding time then the glycoprotein IIb/IIIa receptor antagonist abciximab.

Topics: Abciximab; Adenosine Monophosphate; Aged; Angioplasty, Balloon, Coronary; Antibodies, Monoclonal; Coronary Disease; Double-Blind Method; Female; Humans; Immunoglobulin Fab Fragments; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex

Platelet aggregation is the central process in the pathophysiology of acute coronary syndromes. ADP contributes to thrombosis by activating platelets, and AR-C69931MX is a specific antagonist of this process acting at the P2T receptor. At 5 hospitals, 39 patients with unstable angina or non-Q wave myocardial infarction, who were receiving aspirin and heparin, were administered intravenous AR-C69931MX with stepped dose increments over 3 h to a plateau of either 2 microg/kg/min for 21 h (Part 1; n = 12) or up to 69 h (Part 2; n = 13) or 4 microg/kg/min for up to 69 h (Part 3: n = 14). Safety parameters, platelet aggregation (PA) induced by ADP 3 micromol/L (impedance aggregometry), bleeding time (BT) and plasma concentrations of AR-C69931XX were assessed. AR-C69931MX was well tolerated. 33 patients completed the study. There were no deaths at 30 days and no serious adverse events attributed to AR-C69931MX. Trivial bleeding (56%) was common. At 24 h, mean inhibition of PA was 96.0 +/- 8.6, 94.9 +/- 14.4 and 98.7 +/- 2.1% and BT was 9.5 +/- 8.4, 14.0 +/- 9.7 and 16.0 +/- 11.1 min for Parts 1, 2 and 3 respectively. At 1 h post-infusion, mean inhibition of PA was 36.2 +/- 39.2, 20.7 +/- 25.9 and 40.7 +/- 36.7% respectively. 90% patients had a plasma half-life for AR-C69931XX of <9 min. In conclusion, AR-C69931MX is a potent, short-acting platelet ADP receptor antagonist suitable for further studies as an antithrombotic agent.

Topics: Acute Disease; Adenosine Monophosphate; Adult; Aged; Angina, Unstable; Aspirin; Blood Coagulation Tests; Consumer Product Safety; Coronary Disease; Dose-Response Relationship, Drug; Drug Therapy, Combination; Electrocardiography; Female; Heparin; Humans; Male; Membrane Proteins; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2Y12

Previous studies have shown that anticoagulants alter platelet reactivity and the apparent effects of antiplatelet agents. This study was conducted to identify the impact of methods of preparation of blood samples on an assay of platelet function and the effects of antiplatelet agents. The activation of platelets was identified with the use of flow cytometry in response to thrombin (1 and 10 nmol/L), adenosine diphosphate (0.2 and 1 micromol/L), platelet activating factor (1 nmol/L), and convulxin (1 and 10 ng/ml). Antiplatelet effects were assessed after the addition in vitro of tirofiban (50 ng/ml) and cangrelor (10 nmol/L). Results were compared in whole blood and platelet-rich plasma (PRP) anticoagulated with corn trypsin inhibitor (32 microg/ml, a specific inhibitor of factor XIIa). The fraction of young platelets was quantified with thiazole orange, which identifies ribonucleic acid. The activation of platelets was consistently less in PRP compared with whole blood. Activation in PRP was 23 +/- 15% that in whole blood for thrombin, 65 +/- 26% for adenosine diphosphate, 40 +/- 20% for platelet activating factor, and 49 +/- 25% for convulxin (p <0.01 for each comparison). The fraction of young platelets in PRP was 39 +/- 11% that in whole blood (p <0.001). The effects of antiplatelet agents varied with agonist and antiplatelet agent but were generally greater in PRP compared with whole blood (p <0.05). In conclusion, platelet reactivity is lower and the effects of antiplatelet agents are greater and potentially misleading in PRP compared with whole blood. The accuracy of platelet function testing may be improved by performance in whole blood.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Benzothiazoles; Blood Platelets; Coronary Disease; Crotalid Venoms; Flow Cytometry; Fluorescent Dyes; Hemostatics; Humans; Lectins, C-Type; Platelet Activating Factor; Platelet Activation; Platelet Aggregation Inhibitors; Platelet Count; Platelet Glycoprotein GPIIb-IIIa Complex; Quinolines; Thrombin; Tirofiban; Tyrosine

Thrombin induces platelet aggregation and membrane rearrangements leading to enhanced procoagulant activity and microparticle production, all of which are thought to contribute to thrombus formation in patients with acute coronary syndromes (ACS). Clopidogrel, an adenosine diphosphate (ADP) receptor antagonist acting at the P2Y(12) receptor, has been shown to provide clinical benefit in ACS. We aimed to investigate the effects of clopidogrel ex vivo and another ADP-antagonist, AR-C69931MX in vitro on thrombin receptor activating peptide (TRAP)-induced platelet aggregation, procoagulant activity, microparticle formation and [Ca(2+)]i responses in patients with ACS. Measurements were performed in platelet-rich plasma using aggregometry and flow cytometry (n = 12). Clopidogrel (300 mg loading dose plus 75 mg daily) significantly inhibited TRAP-induced aggregation, procoagulant activity (annexin V binding) and microparticle production (all P < 0.05) but not as extensively as AR-C69931MX (400 nmol/l). [Ca(2+)]i responses induced by a combination of TRAP and ADP designed to mimic the physiological effects of released ADP showed that clopidogrel partially and AR-C69931MX completely removed the ADP component of the [Ca(2+)]i responses (n = 6). The results provide new information on the mechanisms involved in the beneficial effects of P2Y(12) antagonists in patients with ACS.

Topics: Adenosine Monophosphate; Calcium Signaling; Clopidogrel; Coronary Disease; Dose-Response Relationship, Drug; Female; Humans; Male; Membrane Proteins; Platelet Aggregation; Platelet Aggregation Inhibitors; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2Y12; Receptors, Thrombin; Ticlopidine