cangrelor and Myocardial-Ischemia

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

Adenosine diphosphate (ADP)-induced platelet activation plays a pivotal role in the thrombocyte aggregation and pathogenesis of ischemic heart disease. The long-term benefit of dual anti-platelet therapy with ADP-receptor antagonists, such as clopidogrel, in combination with aspirin is well established for patients following coronary stent implantation. This review discusses latest developments in the field of ADP-receptor antagonists.

Topics: Acute Coronary Syndrome; Adenosine Monophosphate; Angioplasty, Balloon, Coronary; Aspirin; Clopidogrel; Combined Modality Therapy; Humans; Myocardial Ischemia; Platelet Aggregation Inhibitors; Pyridines; Receptors, Purinergic P2; Stents; Ticlopidine

The efficacy with aspirin and clopidogrel treatment has been demonstrated in various clinical trials. Laboratory evaluation of platelet response in recent studies revealed that a distinctive response variability and nonresponsiveness/resistance in selected patients were associated with these antiplatelet agents. Moreover, some studies have correlated this nonresponsiveness/resistance phenomenon to the occurrence of thrombotic events. At this time there are no uniformly established methods to quantify exvivo platelet reactivity after clopidogrel and aspirin treatment of the extent of platelet inhibition by clopidogrel and aspirin. Therefore, specific treatment recommendations for patients exhibiting high platelet reactivity or poor platelet inhibition during clopidogrel or aspirin therapy are not established. A higher aspirin dose and strict compliance to therapy may overcome the occurrence of "aspirin resistance" in selected patients. A higher clopidogrel dose may be considered in patients exhibiting clopidogrel nonresponsiveness.

Topics: Adenosine; Adenosine Monophosphate; Angioplasty, Balloon, Coronary; Aspirin; Clinical Trials as Topic; Clopidogrel; Coronary Restenosis; Drug Resistance; Humans; Membrane Proteins; Myocardial Ischemia; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2Y12; Thiophenes; Ticagrelor; Ticlopidine

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Animals; Drug Combinations; Humans; Myocardial Ischemia; Platelet Activation; Platelet Aggregation; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2; Thrombosis; Tissue Plasminogen Activator

In the CHAMPION PHOENIX trial, the potent, rapidly acting, intravenous platelet adenosine diphosphate receptor antagonist cangrelor reduced the 48-h incidence of major adverse cardiac events (MACE; death, myocardial infarction, stent thrombosis, or ischaemia-driven revascularization) compared with a loading dose of clopidogrel in patients undergoing percutaneous coronary intervention (PCI). We sought to determine whether the efficacy of cangrelor during PCI varies in patients with simple vs. complex target lesion coronary anatomy.. Blinded angiographic core laboratory analysis was completed in 10 854 of 10 942 (99.2%) randomized patients in CHAMPION PHOENIX (13 418 target lesions). Outcomes were analysed according to the number of angiographic PCI target lesion high-risk features (HRF) present (bifurcation, left main, thrombus, angulated, tortuous, eccentric, calcified, long, or multi-lesion treatment). The number of patients with 0, 1, 2, and ≥3 HRFs was 1817 (16.7%), 3442 (31.7%), 2901 (26.7%), and 2694 (24.8%), respectively. The 48-h MACE rate in clopidogrel-treated patients increased progressively with lesion complexity (from 3.3% to 4.4% to 6.9% to 8.7%, respectively, P < 0.0001). Cangrelor reduced the 48-h rate of MACE by 21% {4.7% vs. 5.9%, odds ratio (OR) [95% confidence interval (95% CI)] 0.79 (0.67, 0.93), P = 0.006} compared with clopidogrel, an effect which was consistent regardless of PCI lesion complexity (Pinteraction = 0.66) and presentation with stable ischaemic heart disease (SIHD) or an acute coronary syndrome (ACS). By multivariable analysis, the number of high-risk PCI characteristics [OR (95% CI) 1.68 (1.20, 2.36), 2.78 (2.00, 3.87), and 3.23 (2.33, 4.48) for 1, 2, and 3 HRFs compared with 0 HRFs, all P < 0.0001] and treatment with cangrelor vs. clopidogrel [OR (95% CI) 0.78 (0.66, 0.92), P = 0.004] were independent predictors of the primary 48-h MACE endpoint. Major bleeding rates were unrelated to lesion complexity and were not increased by cangrelor.. Peri-procedural MACE after PCI is strongly dependent on the number of treated high-risk target lesion features. Compared with a loading dose of clopidogrel, cangrelor reduced MACE occurring within 48 h after PCI in patients with SIHD and ACS regardless of baseline lesion complexity. The absolute benefit:risk profile for cangrelor will therefore be greatest during PCI in patients with complex coronary anatomy.. NCT01156571.

Topics: Adenosine Monophosphate; Aged; Clopidogrel; Coronary Angiography; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Humans; Incidence; Infusions, Intravenous; Male; Middle Aged; Myocardial Ischemia; Percutaneous Coronary Intervention; Perioperative Care; Postoperative Complications; Purinergic P2Y Receptor Antagonists; Retrospective Studies; Risk Factors; Survival Rate; Treatment Outcome; United States

To assess whether the use of the femoral or radial approach for percutaneous coronary intervention (PCI) interacted with the efficacy and safety of cangrelor, an intravenous P2Y12 inhibitor, in CHAMPION PHOENIX.. A total of 11 145 patients were randomly assigned in a double-dummy, double-blind manner either to a cangrelor bolus and 2-h infusion or to clopidogrel at the time of PCI. The primary endpoint, a composite of death, myocardial infarction, ischaemia-driven revascularization, or stent thrombosis, and the primary safety endpoint, Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) defined severe bleeding, were evaluated at 48 h. Of the patients undergoing PCI and receiving study drug treatment, a total of 8064 (74%) and 2855 (26%) patients underwent femoral or radial PCI, respectively. Among the femoral cohort, the primary endpoint rate was 4.8% with cangrelor vs. 6.0% with clopidogrel (odds ratio, OR [95% confidence interval, CI] = 0.79 [0.65-0.96]); among the radial cohort, the primary endpoint was 4.4% with cangrelor vs. 5.7% with clopidogrel (OR [95% CI] = 0.76 [0.54-1.06]), P-interaction 0.83. The rate of GUSTO severe bleeding in the femoral cohort was 0.2% with cangrelor vs. 0.1% with clopidogrel (OR [95% CI] = 1.73 [0.51-5.93]). Among the radial cohort, the rate of GUSTO severe bleeding was 0.1% with cangrelor vs. 0.1% with clopidogrel (OR [95% CI] = 1.02 [0.14-7.28]), P-interaction 0.65. The evaluation of safety endpoints with the more sensitive ACUITY-defined bleeding found major bleeding in the femoral cohort to be 5.2% with cangrelor vs. 3.1% with clopidogrel (OR [95% CI] = 1.69 [1.35-2.12]); among the radial cohort the rate of ACUITY major bleeding was 1.5% with cangrelor vs. 0.7% with clopidogrel (OR [95% CI] = 2.17 [1.02-4.62], P-interaction 0.54).. In CHAMPION PHOENIX, cangrelor reduced ischaemic events with no significant increase in GUSTO-defined severe bleeding. The absolute rates of bleeding, regardless of the definition, tended to be lower when PCI was performed via the radial artery.. http://www.clinicaltrials.gov identifier: NCT01156571.

Topics: Adenosine Monophosphate; Aged; Clopidogrel; Coronary Thrombosis; Double-Blind Method; Female; Femoral Artery; Graft Occlusion, Vascular; Hemorrhage; Humans; Infusions, Intravenous; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Myocardial Revascularization; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Radial Artery; Stents; Ticlopidine; Treatment Outcome

The intensity of antiplatelet therapy during percutaneous coronary intervention (PCI) is an important determinant of PCI-related ischemic complications. Cangrelor is a potent intravenous adenosine diphosphate (ADP)-receptor antagonist that acts rapidly and has quickly reversible effects.. In a double-blind, placebo-controlled trial, we randomly assigned 11,145 patients who were undergoing either urgent or elective PCI and were receiving guideline-recommended therapy to receive a bolus and infusion of cangrelor or to receive a loading dose of 600 mg or 300 mg of clopidogrel. The primary efficacy end point was a composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours after randomization; the key secondary end point was stent thrombosis at 48 hours. The primary safety end point was severe bleeding at 48 hours.. The rate of the primary efficacy end point was 4.7% in the cangrelor group and 5.9% in the clopidogrel group (adjusted odds ratio with cangrelor, 0.78; 95% confidence interval [CI], 0.66 to 0.93; P=0.005). The rate of the primary safety end point was 0.16% in the cangrelor group and 0.11% in the clopidogrel group (odds ratio, 1.50; 95% CI, 0.53 to 4.22; P=0.44). Stent thrombosis developed in 0.8% of the patients in the cangrelor group and in 1.4% in the clopidogrel group (odds ratio, 0.62; 95% CI, 0.43 to 0.90; P=0.01). The rates of adverse events related to the study treatment were low in both groups, though transient dyspnea occurred significantly more frequently with cangrelor than with clopidogrel (1.2% vs. 0.3%). The benefit from cangrelor with respect to the primary end point was consistent across multiple prespecified subgroups.. Cangrelor significantly reduced the rate of ischemic events, including stent thrombosis, during PCI, with no significant increase in severe bleeding. (Funded by the Medicines Company; CHAMPION PHOENIX ClinicalTrials.gov number, NCT01156571.).

Topics: Adenosine Monophosphate; Aged; Angioplasty, Balloon, Coronary; Clopidogrel; Double-Blind Method; Female; Hemorrhage; Humans; Intention to Treat Analysis; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Ischemia; Platelet Aggregation Inhibitors; Stents; Thrombosis; Ticlopidine

There is a clinical need for an intravenous P2Y(12) inhibitor in patients with acute coronary syndromes (ACS) for patients who are unable to take oral medications or might benefit from a rapidly reversible compound. As the time from admission to percutaneous coronary intervention (PCI) shortens, establishing the benefit of novel therapies impacting ischemic events is increasingly challenging. Cangrelor, an intravenous potent rapidly acting P2Y(12) inhibitor, bolus 30 μg/Kg plus infusion of 4 μg/Kg/min, was compared to a 600-mg loading dose of clopidogrel either before or early after PCI in patients with ACS undergoing PCI in The CHAMPION (Cangrelor versus standard tHerapy to Achieve optimal Management of Platelet InhibitiON) PLATFORM and PCI studies.. As both CHAMPION studies used similar inclusion/exclusion criteria and death, myocardial infarction, or ischemia-driven revascularization (including stent thrombosis) at 48 hours as their primary end points, the studies were pooled. The clinical events committee adjudicated myocardial infarction. The universal definition was used to define myocardial infarction.. A total of 13 049 patients were included. Cangrelor had no effect on the primary end point with the original MI definition (P = .646). With the use of the universal definition, the primary end point was decreased with cangrelor (odds ratio 0.82, 95% confidence interval 0.68-0.99, P = .037). Stent thrombosis was reduced from 0.4% to 0.2% (odds ratio 0.44, 95% confidence interval 0.22-0.87, P = .018). Thrombolysis in Myocardial Infarction major bleeding and transfusions were not increased with cangrelor.. With the use of the universal definition of myocardial infarction, cangrelor was associated with a significant reduction in early ischemic events when compared with clopidogrel in patients with non-ST-elevation ACS undergoing PCI.

Topics: Adenosine Monophosphate; Aged; Angioplasty, Balloon, Coronary; Coronary Angiography; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography; Female; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Postoperative Complications; Purinergic P2Y Receptor Antagonists; Survival Rate; Treatment Outcome

We compared the antiplatelet effects of clopidogrel and the intravenous platelet P2Y(12) receptor antagonist AR-C69931MX, which acts on the same receptor as clopidogrel by a different and reversible mechanism and, unlike clopidogrel, is active in vitro. Thirteen patients with acute coronary syndromes entered into a phase II study of intravenous AR-C69931MX (Group 1) and eight patients undergoing intracoronary stent implantation and treated with clopidogrel (Group 2) were studied using a whole blood single-platelet counting aggregation assay. Group 2 patients were also studied using turbidimetry with ADP and TRAP as agonists and whole blood [(14)C]5HT release to study dense granule secretion in response to ADP, collagen and TRAP. In Group 2 studies, a therapeutic concentration of AR-C69931MX was added in vitro before and after clopidogrel administration. AR-C69931MX in Group 1 achieved greater inhibition of ADP-induced platelet aggregation than clopidogrel in Group 2 and AR-C69931MX in vitro added to the effects of clopidogrel on ADP-induced aggregation. AR-C69931MX but not clopidogrel inhibited TRAP-induced aggregation and granule secretion and AR-C69931MX had a more consistent inhibitory effect on collagen-induced responses. In conclusion, therapeutic administration of clopidogrel moderately inhibits platelet P2Y(12) receptor activation and substantially greater P2Y(12) receptor blockade can be achieved with AR-C69931MX.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Aged; Clopidogrel; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Purinergic P2 Receptor Antagonists; Ticlopidine

In patients undergoing percutaneous coronary intervention (PCI), who did not receive P2Y. The CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention) double-blind randomized trial compared cangrelor with clopidogrel loading dose at the time of PCI. Pretreatment with clopidogrel before randomization was not permitted per protocol. In the clopidogrel-only group (n=5438), a loading dose was given before (early load [EL]) or after the start of PCI (late load [LL]) according to physician choice. Overall, 3442 (63.3%) patients had EL and 1997 LL (36.7%). Median times were 5 minutes before and 20 minutes after the start of PCI, respectively. EL was more frequently used among patients with ST-segment-elevation myocardial infarction (84.4%) and non-ST-segment-elevation acute coronary syndromes (71.5%) than in stable patients (53.7%). At 48 hours, rates of the primary outcome of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis were similar (6.0% versus 5.4%) for EL versus LL, respectively (odds ratio [OR], 1.11 [95% CI, 0.87-1.41]; P=0.41), and remained so after adjustment for potential confounders, including clinical presentation (OR [95% CI], 1.39 [0.90-2.15]; P=0.14). Compared with clopidogrel, cangrelor consistently reduced the primary outcome in both EL (4.8% versus 6.0%; OR [95% CI], 0.80 [0.64-0.98]) and LL (4.3% versus 5.4%; OR [95% CI], 0.79 [0.59-1.06]; interaction P=0.99). Global Use of Strategies to Open Occluded Coronary Arteries severe/moderate bleeding rates were similar between treatment arms for both EL (OR [95% CI], 1.24 [0.58-2.66]) and LL (OR [95% CI], 2.53 [0.98-6.54]; interaction P=0.25).. In a nonrandomized comparison of patients with clopidogrel loading before or after the start of PCI, the rates of periprocedural PCI complications, including bleeding, were similar, as were the benefits of cangrelor, regardless of the timing.. URL: https://www.clinicaltrials.gov . Unique identifier: NCT01156571.

Topics: Adenosine Monophosphate; Aged; Clopidogrel; Coronary Thrombosis; Drug Administration Schedule; Female; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Randomized Controlled Trials as Topic; Risk Factors; Stents; Time Factors; Treatment Outcome

Topics: Adenosine Monophosphate; Animals; Blood Platelets; Cardiotonic Agents; Diabetes Complications; Dose-Response Relationship, Drug; Humans; Male; Mice; Myocardial Ischemia; Myocardial Reperfusion Injury; Purinergic P2Y Receptor Antagonists; Rats; Rats, Inbred Strains; Receptors, Purinergic P2Y12

Topics: Adenosine Monophosphate; Angioplasty, Balloon, Coronary; Clopidogrel; Female; Humans; Male; Myocardial Ischemia; Platelet Aggregation Inhibitors; Stents; Thrombosis; Ticlopidine

Topics: Adenosine Monophosphate; Female; Humans; Male; Myocardial Ischemia; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors

Interindividual variability of the inhibitory effect of clopidogrel on platelet functions leading to clopidogrel resistance has been described in some patients with ischemic cardiovascular disease. A reliable laboratory test is therefore needed to identify patients insufficiently protected by this antiplatelet treatment. The phosphorylation of vasodilator-stimulated phosphoprotein (VASP), an intraplatelet actin regulatory protein, is dependent on the level of activation of the platelet P2Y12 receptor, which is targeted by clopidogrel. The aim of this study was to use a flow cytometric VASP phosphorylation assay to evaluate the efficacy of clopidogrel therapy. The platelet reactivity index (PRI), expressed as a percentage, is the difference in VASP fluorescence intensity between resting (+PGE1) and activated (+ADP) platelets. In vitro, the PRI was strongly correlated with the inhibition of platelet aggregation induced by specific blockade of the P2Y12 receptor by the competitive antagonist AR-C69931MX (R = 0.72, P < 0.0001). Ex vivo, the PRI was 78.3 +/- 4.6% in 47 healthy donors, 79.0 +/- 4.1% in 34 patients not receiving clopidogrel and 61.1 +/- 17.0% in 33 patients treated with clopidogrel (P < 0.0001). In the clopidogrel group, the PRI values were widely dispersed (from 6.6 to 85.8%) and more than 30% of these patients had a PRI equivalent of values in patients not receiving clopidogrel. The flow cytometric analysis of VASP phosphorylation seems to be a suitable test to evaluate the efficacy of clopidogrel treatment. This assay demonstrated a wide interindividual variability of the inhibitory response of platelets to clopidogrel and showed that one-third of the patients treated appeared to be 'unprotected' by this therapy.

Topics: Actins; Adenosine Diphosphate; Adenosine Monophosphate; Adult; Aged; Blood Platelets; Cell Adhesion Molecules; Clopidogrel; Dose-Response Relationship, Drug; Drug Resistance; Female; Flow Cytometry; Humans; Male; Membrane Proteins; Microfilament Proteins; Middle Aged; Myocardial Ischemia; Phosphoproteins; Phosphorylation; Platelet Aggregation; Platelet Aggregation Inhibitors; Receptors, Purinergic P2; Receptors, Purinergic P2Y12; Ticlopidine; Time Factors

Platelet-leukocyte interactions are recognised to have pro-inflammatory effects, which may be important in the pathophysiology of ischaemic heart disease. Clopidogrel and the novel intravenous antithrombotic agent AR-C69931MX act at the level of the platelet P2Y12 receptor, which is known to amplify platelet activation, aggregation and other responses induced by numerous platelet agonists. We studied the effects of clopidogrel and aspirin on ADP-induced platelet-leukocyte conjugate formation and P-selectin expression in healthy volunteers. The effects of clopidogrel and AR-C69931MX administered to patients with ischaemic heart disease were also assessed. AR-C69931MX and aspirin were also studied in vitro. Clopidogrel and AR-C69931MX suppressed ADP-induced platelet aggregation, P-selectin expression and platelet-leukocyte conjugate formation whereas aspirin had no inhibitory effect. These effects of clopidogrel and AR-C69931MX may confer therapeutic benefits in the management of acute coronary syndromes.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Aspirin; Blood Platelets; Cell Adhesion; Clopidogrel; Drug Therapy, Combination; Female; Humans; Leukocytes; Male; Membrane Proteins; Middle Aged; Myocardial Ischemia; P-Selectin; Platelet Aggregation; Platelet Aggregation Inhibitors; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2Y12; Stents; Ticlopidine