cangrelor and Coronary-Thrombosis

Dual antiplatelet therapy with aspirin and oral P2Y12-receptor inhibitors prevents ischemic events in patients undergoing Percutaneous Coronary Intervention (PCI). However, oral administration of antiplatelet drugs cause delay of onset of platelet inhibition in P2Y12-inhibitor naïve patients. Cangrelor is a novel P2Y12-receptor inhibitor which is administrated intravenously and thus allows immediate antiplatelet inhibition during PCI. Due to its unique pharmacokinetics with fast onset of platelet inhibition and very short plasma half-life it allows effective and controllable periprocedural platelet inhibition. It could reduce short-term ischemic events in large randomized clinical trials. The present article reviews the available evidence and application on cangrelor use in clinical practice.

Topics: Acute Coronary Syndrome; Adenosine Monophosphate; Administration, Intravenous; Coronary Artery Disease; Coronary Thrombosis; Hemorrhage; Humans; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Risk Factors; Treatment Outcome

Cangrelor (Kengrexal(®), Kengreal(™)) is an intravenously administered P2Y12 receptor inhibitor. It is direct-acting and reversible, with a very rapid onset and offset of action. The randomized, double-blind, multinational, phase III CHAMPION PHOENIX trial compared the efficacy of intravenous cangrelor with that of oral clopidogrel in patients requiring percutaneous coronary intervention (PCI) for stable angina pectoris, a non-ST-segment elevation acute coronary syndrome or ST-segment elevation myocardial infarction (MI). The primary composite efficacy endpoint of death from any cause, MI, ischaemia-drive revascularization or stent thrombosis in the 48 h following randomization occurred in significantly fewer cangrelor than clopidogrel recipients. The rate of severe or life-threatening non-coronary artery bypass graft-related, GUSTO-defined bleeding at 48 h did not significantly differ between cangrelor and clopidogrel recipients. In conclusion, intravenous cangrelor is an important new option for use in patients undergoing PCI who have not been treated with oral P2Y12 inhibitors.

Topics: Adenosine Monophosphate; Administration, Intravenous; Blood Platelets; Coronary Thrombosis; Drug Interactions; Hemorrhage; Humans; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Risk Factors; Treatment Outcome

Percutaneous coronary intervention (PCI) is a highly effective treatment for obstructive coronary artery disease. Oral platelet P2Y12 receptor antagonists reduce ischemic events in patients treated with PCI. However, there are several limitations to their use, including variable pharmacodynamics, a slow onset and offset, and in those patients who are pretreated but subsequently require cardiac surgery, increased bleeding. Cangrelor is an intravenous agent that provides rapid and intensive inhibition of the P2Y12 receptor that quickly dissipates after discontinuation. A recent, Phase III randomized clinical trial of PCI patients demonstrated that cangrelor bolus and infusion reduced ischemic events compared with conventional clopidogrel therapy without increasing major bleeding.. This review outlines the pharmacodynamics, pharmacokinetics, and the safety and efficacy of cangrelor for the acute treatment of patients undergoing planned PCI.. Cangrelor is an important addition to the current armamentarium of platelet inhibitors as it significantly reduces periprocedural myocardial infarction and stent thrombosis in a broad spectrum of patients, without increasing major bleeding or the need for transfusion. Cangrelor will have particular benefit in clopidogrel-naïve patients with high anatomical complexity and/or increased clinical risk (where the absolute risk for thrombotic and ischemic complications of PCI is greatest).

Topics: Adenosine Monophosphate; Coronary Artery Disease; Coronary Thrombosis; Humans; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Stents

Effective antagonism of the P2Y12 platelet receptor is central to the treatment of acute coronary syndrome (ACS) patients, especially in the setting of percutaneous coronary intervention and stenting. According to consensus guidelines, early revascularization and intensive antiplatelet therapy are key to reducing the complications that arise from myocardial ischaemia and the recurrence of cardiovascular events. Until recently, clopidogrel was the key P2Y12 antagonist advocated, but due to several limitations as an antiplatelet agent, newer drugs with more predictable, rapid and potent effects have been developed. Prasugrel and ticagrelor are now the recommended first-line agents in patients presenting with non-ST-segment elevation ACS and ST-segment elevation ACS, due to large-scale randomized trials that demonstrated net clinical benefit of these agents over clopidogrel, as stated in the European guidelines. Although no study has directly compared the two agents, analysis of the data to date suggests that certain patient types, such as diabetics, those with ST-segment elevation myocardial infarction or renal failure and the elderly may have a better outcome with one agent over the other. Further studies are needed to confirm these differences and answer pending questions regarding the use of these drugs to optimize efficacy while minimizing adverse events, such as bleeding. The aim of this review is to provide an overview of the current P2Y12 receptor antagonists in the treatment of ACS, with a focus on issues of appropriate agent selection, timing of treatment, bleeding risk and the future role of personalized treatment using platelet function and genetic testing.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Clinical Trials as Topic; Clopidogrel; Combined Modality Therapy; Coronary Artery Bypass; Coronary Thrombosis; Diabetes Complications; Hemorrhage; Humans; Multicenter Studies as Topic; Piperazines; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Prasugrel Hydrochloride; Precision Medicine; Purinergic P2Y Receptor Antagonists; Randomized Controlled Trials as Topic; Receptors, Purinergic P2Y12; Renal Insufficiency; Thiophenes; Ticagrelor; Ticlopidine; Treatment Outcome

Inhibiting platelet function is a key therapeutic principle in cardiology because platelets play a pivotal role in triggering cardiovascular events. In addition to acetylsalicylic acid, a cyclooxygenase inhibitor, ADP-receptor blockers are frequently used for anti-platelet therapy. This therapy does not abolish platelet activation and aggregation. Platelets may still be activated by alternative routes such as the thrombin receptor-mediated pathway. New, more potent inhibitors of platelet function continue to lower the risk of ischaemic events but several trials and clinical registries have also shown that this advantage was frequently offset by an increased risk of bleeding complications. As a consequence, the individual risk of ischaemia and bleeding of a patient must be taken into consideration to select the platelet inhibitor offering the best benefit-risk ratio. Modern laboratory diagnostics may help to achieve this goal by complementing functional platelet tests with pharmacogenomic analyses consistent with the idea of "personalized medicine".

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Aspirin; Clopidogrel; Coronary Thrombosis; Drug Interactions; Hemorrhage; Humans; Piperazines; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Thiophenes; Ticagrelor; Ticlopidine

Antiplatelet therapy is critical in the prevention of thrombotic complications of acute coronary syndrome and percutaneous coronary interventions. Current antiplatelet agents (aspirin, clopidogrel and glycoprotein IIb/IIIa antagonists) have demonstrated the capacity to reduce major adverse cardiac events. However, these agents have limitations that compromise their clinical utility. The platelet P2Y12 receptor plays a central role in platelet function and is a focus in the development of antiplatelet therapies. Cangrelor is a potent, competitive inhibitor of the P2Y12 receptor that is administered by intravenous infusion and rapidly achieves near complete inhibition of ADP-induced platelet aggregation. This investigational drug has been studied for use during coronary procedures and the management of patients experiencing acute coronary syndrome and is undergoing evaluation for use in the prevention of perioperative stent thrombosis.

Topics: Acute Coronary Syndrome; Adenosine Monophosphate; Animals; Clinical Trials as Topic; Coronary Thrombosis; Drug Evaluation, Preclinical; Humans; Molecular Structure; Platelet Aggregation Inhibitors; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2Y12

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

To review and assess available literature on the chemistry, pharmacology, pharmacodynamics, pharmacokinetics, clinical studies, adverse events, drug interactions, special populations, and dosing and administration for cangrelor, a product in late stage Phase II clinical trials.. A literature search of MEDLINE (1966-March 2006), International Pharmaceutical Abstracts (1970-February 2006), and Cochrane database (first quarter 2006) was conducted using key terms of cangrelor, AR-C69931MX, and P2Y12 receptor antagonist. Bibliographies of relevant articles were reviewed for additional references. The Medicines Company Web site was reviewed, and a company representative was contacted.. Available English-language literature, including abstracts, preclinical studies, clinical trials, and review articles, was reviewed.. Cangrelor is a P2Y12 antagonist under development for treatment of acute coronary syndrome. Cangrelor has been studied as an intravenous infusion in doses of 2 or 4 microg/kg/min. It inhibits platelet aggregation with rapid onset and offset and does not require metabolism for therapeutic activity. Published Phase II trials have demonstrated safety and inhibition of platelet aggregation.. Cangrelor is a promising investigational medication for inhibition of platelet aggregation in acute arterial coronary events. Phase II trials have shown safety and a greater inhibition of platelet aggregation over clopidogrel. Phase III trials will provide more definitive information on clinical efficacy and safety. Until then, the role of cangrelor is uncertain.

Topics: Adenosine Monophosphate; Animals; Clinical Trials as Topic; Coronary Thrombosis; Drug Interactions; Humans; Platelet Aggregation Inhibitors; Purinergic P2 Receptor Antagonists

Despite improvements in percutaneous coronary intervention (PCI), intraprocedural thrombotic events (IPTE) and bleeding complications occur and are prognostically important. These have not been included in prior economic studies.. PHOENIX ECONOMICS was a substudy of the CHAMPION PHOENIX trial, evaluating cangrelor during PCI. Hospital bills were reviewed from 1,171 patients enrolled at 22 of 63 US sites. Costs were estimated using standard methods including resource-based accounting, hospital billing data, and the Medicare fee schedule. Bleeding and IPTE, defined as abrupt vessel closure (transient or sustained), new/suspected thrombus, new clot on wire/catheter, no reflow, side-branch occlusion, procedural stent thrombosis or urgent need for CABG were identified. Costs were calculated according to whether a complication occurred and type of event. Multivariate analyses were used to estimate the incremental costs of IPTE and postprocedural events.. IPTE occurred in 4.3% and were associated with higher catheterization laboratory and overall index hospitalization costs by $2,734 (95%CI $1,117, $4,351; P = 0.001) and $6,354 (95% CI $4,122, $8,586; P < 0.001), respectively. IPTE were associated with MI (35.4% vs. 3.6%; P < 0.001), out-of-laboratory stent thrombosis (4.2% vs. 0.1%; 0 = 0.005), ischemia driven revascularization (12.5% vs. 0.3%; P < 0.001), but not mortality (2.1% vs. 0.2%; P = 0.12) vs. no procedural thrombotic complication. By comparison, ACUITY minor bleeding increased hospitalization cost by $1,416 (95%CI = 312, $2,519; P = 0.012). ACUITY major bleeding increased cost of hospitalization by $7,894 (95%CI $4,154, $11,635; P < 0.001).. IPTE and bleeding complications, though infrequent, are associated with substantial increased cost. These complications should be collected in economic assessments of PCI.

Topics: Adenosine Monophosphate; Aged; Clopidogrel; Coronary Thrombosis; Cost-Benefit Analysis; Double-Blind Method; Drug Costs; Female; Hemorrhage; Hospital Costs; Hospital Mortality; Humans; Length of Stay; Male; Middle Aged; Models, Economic; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Risk Factors; Time Factors; 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 Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION) PHOENIX trial demonstrated superiority of cangrelor in reducing ischemic events at 48 hours in patients undergoing percutaneous coronary intervention compared with clopidogrel.. We analyzed all patients included in the modified intention-to-treat analysis in US (n=4097; 37.4%) and non-US subgroups (n=6845; 62.6%). The US cohort was older, had a higher burden of cardiovascular risk factors, and had more frequently undergone prior cardiovascular procedures. US patients more frequently underwent percutaneous coronary intervention for stable angina (77.9% versus 46.2%). Almost all US patients (99.1%) received clopidogrel loading doses of 600 mg, whereas 40.5% of non-US patients received 300 mg. Bivalirudin was more frequently used in US patients (56.7% versus 2.9%). At 48 hours, rates of the primary composite end point were comparable in the US and non-US cohorts (5.5% versus 5.2%; P=0.53). Cangrelor reduced rates of the primary composite end point compared with clopidogrel in US (4.5% versus 6.4%; odds ratio 0.70 [95% confidence interval 0.53-0.92]) and in non-US patients (4.8% versus 5.6%; odds ratio 0.85 [95% confidence interval 0.69-1.05]; interaction P=0.26). Similarly, rates of the key secondary end point, stent thrombosis, were reduced by cangrelor in both regions. Rates of Global Use of Strategies to Open Occluded Arteries (GUSTO)-defined severe bleeding were low and not significantly increased by cangrelor in either region.. Despite broad differences in clinical profiles and indications for percutaneous coronary intervention by region in a large global cardiovascular clinical trial, cangrelor consistently reduced rates of ischemic end points compared with clopidogrel without an excess in severe bleeding in both the US and non-US subgroups.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01156571.

Topics: Adenosine Monophosphate; Aged; Brazil; Chi-Square Distribution; Clopidogrel; Coronary Thrombosis; Double-Blind Method; Europe; Female; Hemorrhage; Humans; Intention to Treat Analysis; Kaplan-Meier Estimate; Logistic Models; Male; Middle Aged; New Zealand; Odds Ratio; Percutaneous Coronary Intervention; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prospective Studies; Risk Factors; Thailand; Ticlopidine; Time Factors; Treatment Outcome; United States

The purpose of this study was to examine the safety and efficacy of cangrelor in patients with stable angina (SA) or acute coronary syndrome (ACS).. The CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention) trial demonstrated that cangrelor significantly reduced periprocedural ischemic events in all-comer percutaneous coronary intervention with a modest increase in mild and moderate bleeding. Whether this benefit is consistent across SA and ACS has not been explored fully.. The CHAMPION PHOENIX trial compared periprocedural administration of cangrelor or clopidogrel, with either a 300- or 600-mg loading dose for the prevention of periprocedural complications in patients undergoing percutaneous coronary intervention. Among the 10,942 patients in the modified intention to treat population, 6,358 patients were classified as having SA, and 4,584 patients had ACS (including unstable angina, non ST-segment elevation myocardial infarction and ST-segment elevation myocardial infarction) at randomization. The primary composite endpoint was death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 h. A key secondary endpoint was stent thrombosis, and the primary safety endpoint was GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) severe bleeding.. Cangrelor consistently reduced the primary endpoint in SA and ACS (odds ratio [OR]: 0.83 [95% confidence interval (CI): 0.67 to 1.01] and OR: 0.71 [95% CI: 0.52 to 0.96], respectively; interaction p = 0.41). Cangrelor also consistently reduced stent thrombosis in SA and ACS (OR: 0.55 [95% CI: 0.30 to 1.01] and OR: 0.67 [95% CI: 0.42 to 1.06], respectively; interaction p = 0.62). The impact of cangrelor on GUSTO severe/moderate bleeding was also similar for SA and ACS (OR: 1.49 [95% CI: 0.67 to 3.33] and OR: 1.79 [95% CI: 0.79 to 4.07], respectively; interaction p = 0.75).. The benefits and risks of cangrelor were consistent in patients with SA and ACS. (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI] [CHAMPION PHOENIX] [CHAMPION]; NCT01156571).

Topics: Acute Coronary Syndrome; Adenosine Monophosphate; Aged; Angina, Stable; Chi-Square Distribution; Clopidogrel; Coronary Thrombosis; Double-Blind Method; Female; Hemorrhage; Humans; Logistic Models; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Risk Factors; Ticlopidine; Time Factors; Treatment Outcome

The aim of this study was to examine the efficacy and bleeding outcomes of cangrelor in patients in the CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI]) who underwent percutaneous coronary intervention with bivalirudin.. Cangrelor is a potent intravenous P2Y12 inhibitor with rapid onset and offset. In the CHAMPION PHOENIX, cangrelor compared with clopidogrel significantly reduced 48-h ischemic events including stent thrombosis, without increasing major bleeding. Bivalirudin has demonstrated ischemic outcomes similar to those with heparin plus glycoprotein IIb/IIIa inhibition, with reduced bleeding but increased early stent thrombosis.. In the modified intent-to-treat population, 2,059 patients (18.8%) received bivalirudin, with 1,014 patients in the cangrelor treatment arm and 1,045 in the clopidogrel treatment arm.. At 48 h, the primary endpoint of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis was lower with cangrelor versus clopidogrel (48 [4.7%] vs. 70 [6.7%]; odds ratio [OR]: 0.68, p = 0.047). Death was similar in both arms (2 [0.2%] vs. 2 [0.2%]). Myocardial infarction was reduced by cangrelor (37 [3.6%] vs. 59 [5.6%]; OR: 0.63, p = 0.03), as was death/myocardial infarction (39 [3.8%] vs. 61 [5.8%]; OR: 0.65, p = 0.04). Cangrelor was associated with a nonsignificant trend toward less stent thrombosis (7 [0.7%] vs. 15 [1.4%]; OR: 0.48, p = 0.10), which was evident within 2 h after percutaneous coronary intervention (p = 0.057). GUSTO (Global Use of Strategies to Open Occluded Arteries) severe bleeding was similar in both arms (2 of 1,021 [0.2%] vs. 2 of 1,055 [0.2%]) as were other bleeding definitions and transfusions. Efficacy and safety results were consistent in patients with stable angina, non-ST-segment elevation acute coronary syndrome, and ST-segment elevation myocardial infarction (p for interaction: 0.62 and 0.29).. Cangrelor may offer an attractive benefit risk profile when used in combination with bivalirudin.

Topics: Adenosine Monophosphate; Aged; Anticoagulants; Chi-Square Distribution; Clopidogrel; Coronary Artery Disease; Coronary Thrombosis; Double-Blind Method; Female; Hemorrhage; Hirudins; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Peptide Fragments; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Recombinant Proteins; Risk Factors; Stents; Ticlopidine; Time Factors; Treatment Outcome

Intravenous cangrelor, a rapid-acting, reversible adenosine diphosphate (ADP) receptor antagonist, might reduce ischemic events during percutaneous coronary intervention (PCI).. In this double-blind, placebo-controlled study, we randomly assigned 5362 patients who had not been treated with clopidogrel to receive either cangrelor or placebo at the time of PCI, followed by 600 mg of clopidogrel. The primary end point was a composite of death, myocardial infarction, or ischemia-driven revascularization at 48 hours. Enrollment was stopped when an interim analysis concluded that the trial would be unlikely to show superiority for the primary end point.. The primary end point occurred in 185 of 2654 patients receiving cangrelor (7.0%) and in 210 of 2641 patients receiving placebo (8.0%) (odds ratio in the cangrelor group, 0.87; 95% confidence interval [CI], 0.71 to 1.07; P=0.17) (modified intention-to-treat population adjusted for missing data). In the cangrelor group, as compared with the placebo group, two prespecified secondary end points were significantly reduced at 48 hours: the rate of stent thrombosis, from 0.6% to 0.2% (odds ratio, 0.31; 95% CI, 0.11 to 0.85; P=0.02), and the rate of death from any cause, from 0.7% to 0.2% (odds ratio, 0.33; 95% CI, 0.13 to 0.83; P=0.02). There was no significant difference in the rate of blood transfusion (1.0% in the cangrelor group and 0.6% in the placebo group, P=0.13), though major bleeding on one scale was increased in the cangrelor group, from 3.5% to 5.5% (P<0.001), because of more groin hematomas.. The use of periprocedural cangrelor during PCI was not superior to placebo in reducing the primary end point. The prespecified secondary end points of stent thrombosis and death were lower in the cangrelor group, with no significant increase in the rate of transfusion. Further study of intravenous ADP blockade with cangrelor may be warranted. (ClinicalTrials.gov number, NCT00385138.)

Topics: Acute Coronary Syndrome; Adenosine Monophosphate; Aged; Angioplasty, Balloon, Coronary; Combined Modality Therapy; Coronary Thrombosis; Double-Blind Method; Female; Hemorrhage; Humans; Infusions, Intravenous; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Retreatment; Stents; Treatment Outcome

Topics: Adenosine Monophosphate; Coronary Thrombosis; Humans; Percutaneous Coronary Intervention; Thrombectomy; Treatment Outcome

Topics: Adenosine Monophosphate; Angioplasty, Balloon, Coronary; Coronary Angiography; Coronary Thrombosis; Drug-Eluting Stents; Humans; Male; Middle Aged; Non-ST Elevated Myocardial Infarction; Platelet Aggregation Inhibitors; Predictive Value of Tests; Tomography, Optical Coherence; Treatment Outcome

Topics: Adenosine Monophosphate; Adult; Angioplasty, Balloon, Coronary; Coronary Thrombosis; Drug-Eluting Stents; Humans; Hydroxyurea; Infusions, Intravenous; Male; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Recurrence; ST Elevation Myocardial Infarction; Thrombocythemia, Essential; Treatment Outcome

Cangrelor is an intravenous P2Y. To describe the dosing, laboratory monitoring, and clinical outcomes of a series of patients who received cangrelor as a "bridging" antiplatelet agent.. This study is a retrospective analysis of all patients within the study center with coronary stents who received cangrelor as a bridge to surgical procedure and had VerifyNow monitoring during treatment.

Topics: Adenosine Monophosphate; Administration, Oral; Aged; Aged, 80 and over; Coronary Thrombosis; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Substitution; Female; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Platelet Function Tests; Postoperative Care; Postoperative Complications; Purinergic P2Y Receptor Antagonists; Retrospective Studies; Stents; Treatment Outcome

The effect of perioperative bridging therapy on risks of ischemic cardiac events and major bleeding complications in patients on dual antiplatelet therapy (DAPT) following percutaneous coronary intervention (PCI) remains undefined.. We report on 60 consecutive patients between 2010 and 2017 who required cardiac (CS; n = 15) or non-cardiac (NCS; n = 45) surgeries following PCI at our institution. Short-acting intravenous (IV) antiplatelet (APT) bridging with eptifibatide, tirofiban and cangrelor were instituted after DAPT interruption.. All patients were men with multiple atherosclerosis risk factors. An acute coronary syndrome indication (56.7%) was the most common PCI indication in the CS and NCS groups. Drug-eluting stents were used in 93.33% and 95.56% of the above groups, respectively. The median duration from PCI to CS and NCS were 11.17 and 18.25 months, respectively and 38.33% of all surgeries were performed within 6 months of the index PCI. Most patients were on background aspirin (83.33%) and clopidogrel (81.67%) and median duration of DAPT interruption was 7 days. Median duration of perioperative IV APT bridging was 3 days for CS and 5 days for NCS groups. In the CS group, two patients (13.33%) had non-fata myocardial infarction (MI), and four (26.67%) had clinically significant bleeding. No patients had perioperative stent thrombosis. In the NCS group, one patient (2.22%) had stent thrombosis; four (6.67%) had myocardial infarction, and five (11.11%) clinically significant bleeding.. Despite using IV APT as bridging therapy during perioperative DAPT interruption in post-PCI patients, postoperative cardiac events and bleeding complications can still occur.

Topics: Adenosine Monophosphate; Administration, Intravenous; Aged; Aspirin; Cardiac Surgical Procedures; Clopidogrel; Coronary Artery Disease; Coronary Thrombosis; Drug Administration Schedule; Drug Substitution; Drug Therapy, Combination; Drug-Eluting Stents; Eptifibatide; Female; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Perioperative Care; Platelet Aggregation Inhibitors; Retrospective Studies; Risk Factors; Time Factors; Tirofiban; Treatment Outcome

This nationwide study aimed to analyse the first 2 years of routine clinical use of cangrelor in all Swedish patients undergoing percutaneous coronary intervention (PCI).. This observational Swedish Coronary Angiography and Angioplasty Registry (SCAAR) study identified 915 cangrelor-treated patients. As 899 were ST-segment elevation myocardial infarction (STEMI)-patients undergoing primary PCI, we decided to exclude all non-STEMI patients (n = 16) from the following analysis. We then identified all primary PCI patients, January 2016 to January 2018 (n = 10 816). Excluding hospitals without cangrelor use, tailoring time frames from first cangrelor use per hospital, patients treated with cangrelor (n = 899) were compared with those without cangrelor treatment (n = 4614). A separate analysis was performed for cardiac arrest STEMI patients (n = 273). Cangrelor-use in primary PCI varied greatly between hospitals (4-36%, mean 16%). At variance with randomized trials, cangrelor was used nearly exclusively in STEMI, often with cardiac arrest (19%). Cangrelor was combined with ticagrelor in two-thirds of patients, among which >50% was prehospital. Cangrelor was used more frequently in high-risk patients: left main PCI, thrombus aspiration, and cardiac arrest. Despite cangrelor being used in more high-risk patients, crude definite stent thrombosis rates at 30 days were low and similar in cangrelor (0.7%) and non-cangrelor treated patients (0.8%).. Cangrelor was used nearly exclusively in primary PCI STEMI patients, predominantly with ticagrelor. Despite being used in very high-risk patients, often with cardiac arrest, cangrelor treatment was associated with low stent thrombosis rates.

Topics: Adenosine Monophosphate; Aged; Coronary Thrombosis; Drug Utilization; Female; Hemorrhage; Humans; Male; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Practice Patterns, Physicians'; Purinergic P2Y Receptor Antagonists; Registries; Retrospective Studies; Risk Assessment; Risk Factors; ST Elevation Myocardial Infarction; Sweden; Time Factors; Treatment Outcome

Topics: Adenosine Monophosphate; Aged; Coronary Angiography; Coronary Thrombosis; Female; Follow-Up Studies; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Purinergic P2Y Receptor Antagonists; Retrospective Studies; Treatment Outcome

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

In the CHAMPION PHOENIX trial, cangrelor reduced the primary composite end point of death, myocardial infarction (MI), ischemia-driven revascularization, or stent thrombosis at 48 hours. This study aimed to explore the impact of event adjudication and the prognostic importance of MI reported by a clinical events committee (CEC) or site investigators (SIs).. Data from the CHAMPION PHOENIX trial of patients undergoing elective or nonelective percutaneous coronary intervention were analyzed. A CEC systematically identified and adjudicated MI using predefined criteria, a computer algorithm to identify suspected events, and semilogarithmic plots to review biomarker changes. Thirty-day death was modeled using baseline characteristics. Of 10 942 patients, 462 (4.2%) patients had at least 1 MI by 48 hours identified by the CEC (207 [3.8%] cangrelor; 255 [4.7%] clopidogrel; odds ratio [OR] 0.80; 95% CI, 0.67-0.97; P=0.022), and 143 patients had at least 1 MI by 48 hours reported by the SI (60 [1.1%] cangrelor; 83 [1.5%] clopidogrel; OR, 0.72; 95% CI, 0.52-1.01; P=0.053). Of the 462 MIs identified by the CEC, 92 (20%) were reported by SI, and 370 (80%) were not. Of the 143 MI reported by the SI, 51 (36%) were not confirmed by CEC. All categories were associated with an increased adjusted risk for 30-day death (CEC: OR, 5.35; 95% CI, 2.56-11.2; P<0.001; SI: 9.08 [4.01-20.5]; P<0.001; CEC and SI: 10.9 [3.23-36.6]; P<0.001; CEC but not SI: 4.69 [1.94-11.3]; P<0.001; SI but not CEC: 15.4 [5.26-44.9]; P<0.001).. In patients undergoing percutaneous coronary intervention, CEC procedures identified 3 times as many MIs as the SI reported. Compared with clopidogrel, cangrelor significantly reduced MIs identified by the CEC with a qualitatively similar relative risk reduction in MIs reported by the SI. MIs identified by CEC or reported by SI were independently associated with worse 30-day death. Central adjudication identified additional, prognostically important events.. URL: https://www.clinicaltrials.gov . Unique identifier: NCT01156571.

Topics: Adenosine Monophosphate; Coronary Artery Disease; Coronary Thrombosis; Humans; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Research Design; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome

Cangrelor is a potent intravenous adenosine diphosphate-receptor antagonist that in the CHAMPION trials reduced the 48-hour and 30-day rates of ischemic events during percutaneous coronary intervention without an increase in severe bleeding.. CHAMPION PCI (A Clinical Trial to Demonstrate the Efficacy of Cangrelor), CHAMPION PLATFORM (Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition), and CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention) were 3 randomized, double-blind, double-dummy trials in which cangrelor was compared with clopidogrel during percutaneous coronary intervention. The effect of cangrelor on ischemic events and bleeding was analyzed in the subgroup of patients with a history of cerebrovascular events at least 1 year prior to randomization; the Breslow-Day test was used to test for interaction of treatment effect in subgroups with and without such a history. The primary efficacy end point was a composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours. Among 24 910 randomized patients, 1270 patients (5.1%) had a cerebrovascular event >1 year old, including 650 assigned to cangrelor and 620 assigned to clopidogrel. Consistent with the overall trial results, the rate of the primary efficacy end point was 4.3% in the cangrelor group versus 5.3% in the clopidogrel group (odds ratio 0.80; 95% confidence interval 0.48-1.34; P=0.40; P for interaction =0.97), and the rate of GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe bleeding was 0.3% in both groups (P=0.97; P for interaction =0.81).. Among patients in the CHAMPION trials with a prior cerebrovascular event at least 1 year before the percutaneous coronary intervention, the efficacy and bleeding profile of cangrelor compared with clopidogrel was similar to that in the overall trial.

Topics: Adenosine Monophosphate; Aged; Brain Ischemia; Chi-Square Distribution; Clopidogrel; Coronary Artery Disease; Coronary Thrombosis; Female; Hemorrhage; Humans; Ischemic Attack, Transient; Logistic Models; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Stroke; Ticlopidine; Time Factors; Treatment Outcome

Unlike currently approved adenosine diphosphate receptor antagonists, the new diadenosine tetraphosphate derivative GLS-409 targets not only P2Y12 but also the second human platelet adenosine diphosphate receptor P2Y1 and may, therefore, be a promising antiplatelet drug candidate. The current study is the first to investigate the in vivo antithrombotic effects of GLS-409.. We studied (1) the in vivo effects of GLS-409 on agonist-stimulated platelet aggregation in anesthetized rats, (2) the antithrombotic activity of GLS-409 and the associated effect on the bleeding time in a canine model of platelet-mediated coronary artery thrombosis, and (3) the inhibition of agonist-stimulated platelet aggregation by GLS-409 versus selective P2Y1 and P2Y12 inhibition in vitro in samples from healthy human subjects before and 2 hours after aspirin intake. In vivo treatment with GLS-409 significantly inhibited adenosine diphosphate- and collagen-stimulated platelet aggregation in rats. Further, GLS-409 attenuated cyclic flow variation, that is, platelet-mediated thrombosis, in vivo in our canine model of unstable angina. The improvement in coronary patency was accompanied by a nonsignificant 30% increase in bleeding time. Of note, GLS-409 exerted its effects without affecting rat and canine hemodynamics. Finally, in vitro treatment with GLS-409 showed effects similar to that of cangrelor and the combination of cangrelor with the selective P2Y1 inhibitor MRS 2179 on agonist-stimulated platelet aggregation in human platelet-rich plasma and whole blood before and 2 hours after aspirin intake.. Synergistic inhibition of both P2Y1 and P2Y12 adenosine diphosphate receptors by GLS-409 immediately attenuates platelet-mediated thrombosis and effectively blocks agonist-stimulated platelet aggregation irrespective of concomitant aspirin therapy.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adult; Animals; Aspirin; Blood Coagulation; Blood Platelets; Coronary Thrombosis; Dinucleoside Phosphates; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Female; Fibrinolytic Agents; Humans; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Purinergic P2Y Receptor Antagonists; Rats, Sprague-Dawley; Receptors, Purinergic P2Y1; Receptors, Purinergic P2Y12; Time Factors; Young Adult

Topics: Acute Coronary Syndrome; Adenosine Monophosphate; Angioplasty, Balloon, Coronary; Coronary Thrombosis; Drug Approval; Humans; Infusions, Intravenous; Intraoperative Care; Platelet Aggregation Inhibitors; United States; United States Food and Drug Administration

Dual antiplatelet therapy consisting of aspirin and a P2Y12-receptor antagonist is important for preventing major adverse cardiovascular events in patients managed with percutaneous coronary intervention (PCI). The current P2Y12-receptor antagonists are only available for oral administration and exhibit a delayed onset of action. Furthermore, several days are required for platelet function to return to normal following cessation of therapy. Cangrelor is an intravenous ATP analog that directly, selectively and reversibly inhibits P2Y12 receptors on platelets. A 30-μg/kg bolus dose followed by a 4-μg/kg per minute continuous infusion of cangrelor achieves peak concentration and maximal platelet inhibition within minutes of administration. Cangrelor also demonstrates a fast offset as normal platelet function is restored 1-2 h after cessation of the infusion. Three large, double-blind, randomized trials - CHAMPION PLATFORM, CHAMPION PCI and CHAMPION PHOENIX - assessed the efficacy and safety of cangrelor compared with clopidogrel (during or immediately after PCI) or placebo in the setting of PCI. In the most recent CHAMPION PHOENIX trial, cangrelor was superior to clopidogrel for preventing adverse cardiovascular events with no significant increase in major bleeding. Based on the clinical trial results combined with unique properties such as intravenous administration and fast onset and offset, cangrelor may provide benefit in certain patients undergoing PCI.

Topics: Acute Coronary Syndrome; Adenosine Monophosphate; Aspirin; Clinical Trials as Topic; Coronary Thrombosis; Drug Interactions; Drug Therapy, Combination; Humans; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Postoperative Complications; Purinergic P2Y Receptor Antagonists; Stents

Topics: Adenosine Monophosphate; Administration, Intravenous; Administration, Oral; Blood Platelets; Clopidogrel; Coronary Thrombosis; Humans; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Ticlopidine; Treatment Outcome

Topics: Adenosine Monophosphate; Clopidogrel; Coronary Restenosis; Coronary Stenosis; Coronary Thrombosis; Double-Blind Method; Hemorrhage; Humans; Multicenter Studies as Topic; Myocardial Infarction; Myocardial Revascularization; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Randomized Controlled Trials as Topic; Stents; Ticlopidine

Topics: Acute Coronary Syndrome; Adenosine Monophosphate; Aged; Angioplasty, Balloon, Coronary; Combined Modality Therapy; Coronary Thrombosis; Double-Blind Method; Female; Hemorrhage; Humans; Infusions, Intravenous; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Retreatment; Stents; Treatment Outcome