Limb Outcomes With Ticagrelor Plus Aspirin in Patients With Diabetes Mellitus and Atherosclerosis.

BACKGROUND: Ticagrelor reduced major adverse cardiovascular events (MACE) and increased bleeding in patients with type 2 diabetes mellitus (T2DM) and coronary artery disease. Limb events including revascularization, acute limb ischemia (ALI), and amputation are major morbidities in patients with T2DM and atherosclerosis. OBJECTIVES: This study sought to determine the effect of ticagrelor on limb events. METHODS: Patients were randomized to ticagrelor or placebo on top of aspirin and followed for a median of 3 years. MACE (cardiovascular death, myocardial infarction, or stroke), limb events (ALI, amputation, revascularization), and bleeding were adjudicated by an independent and blinded clinical events committee. The presence of peripheral artery disease (PAD) was reported at baseline. RESULTS: Of 19,220 patients randomized, 1,687 (8.8%) had PAD at baseline. In patients receiving placebo, PAD was associated with higher MACE (10.7% vs 7.3%; HR: 1.48; P < 0.001) and limb (9.5% vs 0.8%; HR: 10.67; P < 0.001) risk. Ticagrelor reduced limb events (1.6% vs 1.3%; HR: 0.77; 95% CI: 0.61-0.96; P = 0.022) with significant reductions for revascularization (HR: 0.79; 95% CI: 0.62-0.99; P = 0.044) and ALI (HR: 0.24; 95% CI: 0.08-0.70; P = 0.009). The benefit was consistent with or without PAD (HR: 0.80; 95% CI: 0.58-1.11; and HR: 0.76; 95% CI: 0.55-1.05, respectively; Pinteraction = 0.81). There was no effect modification of ticagrelor vs placebo based on PAD for MACE (Pinteraction = 0.40) or TIMI major bleeding (Pinteraction = 0.3239). CONCLUSIONS: Patients with T2DM and atherosclerosis are at high risk of limb events. Ticagrelor decreased this risk, but increased bleeding. Future trials evaluating the combination of ticagrelor and aspirin would further elucidate the benefit/risk of such therapy in patients with PAD, including those without coronary artery disease. (A Study Comparing Cardiovascular Effects of Ticagrelor Versus Placebo in Patients With Type 2 Diabetes Mellitus [THEMIS]: NCT01991795).

Pharmacokinetic and pharmacodynamic profiles of a novel phospholipid-aspirin complex liquid formulation and low dose enteric-coated aspirin: results from a prospective, randomized, crossover study.

Low dose enteric-coated aspirin (EC-ASA) is routinely used for secondary cardiovascular event prevention. However, absorption of EC tablets is poor, which can result in subtherapeutic antiplatelet effects. Phospholipid-aspirin liquid filled capsules (PL-ASA) are a novel FDA-approved immediate-release formulation designed to reduce gastrointestinal (GI) injury by limiting direct contact with the stomach lining. We compared the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of PL-ASA versus EC-ASA at a low dose. This randomized, open-label, crossover study assessed PK and PD following a single 81-mg dose of PL-ASA versus EC-ASA under fasting conditions in 36 volunteers without cardiovascular disease between 18 and 75 years of age. Volunteers were randomly assigned 1:1 to either PL-ASA then EC-ASA or vice versa with a minimum 14-day washout. Assessments included PK parameters for acetylsalicylic acid and salicylic acid, platelet aggregation in response to arachidonic acid (AA), and serum thromboxane B2 (TxB2) assessments over 24 h. PL-ASA was rapidly absorbed. PL-ASA reached Tmax 3 h earlier (1.01 vs. 4.00 h, p < 0.0001), with almost double the Cmax (720 vs. 368 ng/mL, p < 0.0001) and overall 44% higher exposure of acetylsalicylic acid (AUC0-t: 601 vs. 416 h*ng/mL, p = 0.0013) compared with EC-ASA. Within 1 h of dosing, PL-ASA achieved significantly lower residual platelet aggregation, which persisted for the full 24 h (median AA-LTA was 47% with PL-ASA vs. 80.5% with EC-ASA; p = 0.0022 at hour-24). Treatment with PL-ASA also resulted in significantly lower serum TxB2 concentrations at each time point compared with EC-ASA (all p-values < 0.05). PL-ASA resulted in faster and more complete aspirin absorption paralleled by more prompt and potent platelet inhibition compared with EC-ASA after a single 81 mg dose. PL-ASA represents an attractive novel aspirin formulation for the secondary prevention of cardiovascular events.Clinical Trial Registration ClinicalTrials.gov identifier: NCT04811625.

Effect of Platelet Inhibition by Cangrelor Among Obese Patients Undergoing Coronary Stenting: Insights From CHAMPION.

BACKGROUND: In randomized trials, cangrelor reduced periprocedural ischemic events related to percutaneous coronary intervention without increasing GUSTO severe bleeding. However, some antiplatelet agents have shown a differential treatment effect by body mass index (BMI). METHODS: Patients from the 3 CHAMPION trials (Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition) who were randomized to cangrelor versus clopidogrel during percutaneous coronary intervention were stratified by BMI. The primary efficacy end point was a composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis within 48 hours. The principal safety outcome was GUSTO moderate or severe bleeding at 48 hours, although more sensitive bleeding measures such as Thrombolysis in Myocardial Infarction major bleeding were also assessed. We examined obese patients (defined as BMI≥30) versus nonobese patients. RESULTS: There were 24 893 patients, with 8979 (36.1%) having BMI of ≥30. There was no significant difference in the primary efficacy end point among obese versus nonobese patients (4.3% versus 4.2%; rate ratio, 1.01 [95% CI, 0.89-1.15]; P=0.82). There was a consistent benefit in the primary efficacy end point in patients who received cangrelor versus placebo who were obese (3.9% versus 4.7%, rate ratio, 0.83 [95% CI, 0.68-1.02]; P=0.07) and not obese (3.8% versus 4.7%; rate ratio, 0.81 [95% CI, 0.69-0.94]; P=0.0053); interaction P=0.77. There was no difference in GUSTO moderate or severe bleeding among patients who received cangrelor versus placebo who were obese (0.6% versus 0.6%; rate ratio, 0.99 [95% CI, 0.58-1.67]; P=0.96). CONCLUSIONS: Cangrelor at the time of percutaneous coronary intervention is effective and safe in obese and nonobese patients. There was no difference in short-term efficacy between obese and nonobese patients. Periprocedural cangrelor is an effective and safe antiplatelet agent, irrespective of BMI. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01156571, NCT00385138, NCT00305162.

Pharmacokinetic and Pharmacodynamic Profile of a Novel Phospholipid Aspirin Formulation.

Aspirin is one of the most widely used medicines. Although aspirin is commonly utilized for the treatment of several medical conditions, its broadest uptake is for the prevention of recurrent ischemic events in patients with atherosclerotic disease. Its mechanism of action of inhibiting platelet activation via blockade of thromboxane A2 production is unique and is not covered by any other antiplatelet agents. While plain, uncoated, immediate-release aspirin is used in acute settings to help assure rapid absorption, enteric-coated aspirin formulations dominate current chronic use, particularly in North America, including for secondary prevention of cardiovascular events. The unmet needs with current aspirin formulations include a high risk of gastrointestinal (GI) adverse events with plain aspirin, which enteric-coated formulations are not able to overcome, and subject to erratic absorption leading to reduced drug bioavailability. These observations underscore the need for aspirin formulations with a more favorable safety and efficacy profile. Phospholipid-aspirin complex (PL-ASA) is a novel formulation designed to address these needs. It is associated with reduced local acute GI injury compared with plain aspirin, and predictable absorption resulting in more reliable platelet inhibition compared with enteric-coated tablets. This review explores the rationale and pharmacologic profile of PL-ASA intended to address the unmet needs for aspirin therapy.

Ischemic Events Occur Early in Patients Undergoing Percutaneous Coronary Intervention and Are Reduced With Cangrelor: Findings From CHAMPION PHOENIX.

BACKGROUND: Thrombotic events are reduced with cangrelor, an intravenous P2Y12 inhibitor. We sought to characterize the timing, number, and type of early events (within 2 hours of randomization) in CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention). METHODS: CHAMPION PHOENIX was a double-blind, placebo-controlled trial that randomized patients undergoing percutaneous coronary intervention to cangrelor or clopidogrel. For this analysis, we evaluated the efficacy of cangrelor in the first 2 hours postrandomization with regards to the primary end point (death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis). Sensitivity analyses were performed evaluating a secondary, post hoc end point (death, Society of Coronary Angiography and Intervention myocardial infarction, ischemia-driven revascularization, or Academic Research Consortium definite stent thrombosis). RESULTS: The majority of events (63%) that occurred in the trial occurred within 2 hours of randomization. The most common early event was myocardial infarction; next were stent thrombosis, ischemia driven revascularization, and death. In the first 2 hours after randomization, cangrelor significantly decreased the primary composite end point compared with clopidogrel (4.1% versus 5.4%; hazard ratio, 0.76 [95% CI, 0.64-0.90], P=0.002). Similar findings were seen for the composite end point of death, Society of Coronary Angiography and Intervention myocardial infarction, ischemia-driven revascularization, or Academic Research Consortium stent thrombosis at 2 hours (0.9% versus 1.6%; hazard ratio, 0.57 [95% CI, 0.40-0.80], P=0.001). Between 2 and 48 hours, there was no difference in the primary composite end point (0.6% versus 0.5%; odds ratio, 1.17 [95% CI, 0.71-1.93]; P=0.53). Early (≤2 hours of randomization) GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) moderate or severe bleeding events were infrequent, and there was no significant difference with cangrelor compared with clopidogrel (0.2% [n=10] versus 0.1% [n=4]; adjusted odds ratio, 1.41 [95% CI, 0.37-5.40]; P=0.62). CONCLUSIONS: The reductions in ischemic events and overall efficacy seen with cangrelor in CHAMPION PHOENIX occurred early and during the period of time in which patients were being actively treated with cangrelor. These findings provide evidence that supports the importance of potent platelet inhibition during percutaneous coronary intervention. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01156571.

Cost-Consequence Analysis of Using Cangrelor in High Angiographic Risk Percutaneous Coronary Intervention Patients: A US Hospital Perspective.

OBJECTIVES: The objective of this study was to evaluate a US hospital's cost implications and outcomes of cangrelor use in percutaneous coronary intervention (PCI) patients with two or more angiographic high-risk features (HRFs), including avoidance of oral P2Y12 inhibitor pretreatment in patients requiring cardiac surgery. Intravenous cangrelor provides direct, immediate onset and rapid-offset P2Y12 inhibition, which may reduce the necessity for oral P2Y12 pretreatment. METHODS: A decision analytic model was developed, estimating the annual impact over 3 years of cangrelor availability. Ischemic and bleeding events (48 h) from randomized clinical trial data were extrapolated to 30 days. Event costs were from the CHAMPION PHOENIX Economics substudy. Rates of coronary artery disease (CAD) presentation, PCI, oral P2Y12 pretreatment, and inpatient hospitalization costs were from published literature and clinical experts. Scenario analyses evaluated the impact of cangrelor availability on potential reduced P2Y12 pretreatment rates by 50-100%. Drug costs were 2019 wholesale acquisition costs and, where necessary, all costs were adjusted to 2019 dollars. RESULTS: In a hospital treating 1000 CAD PCI inpatients annually, increasing cangrelor use from 11 to 32% resulted in a reduction in 48-h ischemic events/year by 5.7%, while bleeding events increased by 2.9%. Total costs of $1,135,472 declined 12.8%, with a 50% reduction in P2Y12 pretreatment or 30% with no pretreatment. Savings were driven by a decrease in ischemic events, decrease in glycoprotein IIb/IIIa inhibitor use, and less need for and shorter oral P2Y12 inhibitor washout period for surgery patients. CONCLUSION: Use of cangrelor in patients with two or more angiographic HRFs may improve outcomes and lower hospital budgets, mainly from avoiding surgery delays necessitated by oral P2Y12 inhibitor pretreatment.

Diabetes-Related Factors and the Effects of Ticagrelor Plus Aspirin in the THEMIS and THEMIS-PCI Trials.

BACKGROUND: THEMIS (The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study) (n = 19,220) and its pre-specified THEMIS-PCI (The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study-Percutaneous Coronary Intervention) (n = 11,154) subanalysis showed, in individuals with type 2 diabetes mellitus (median duration 10.0 years; HbA1c 7.1%) and stable coronary artery disease without prior myocardial infarction (MI) or stroke, that ticagrelor plus aspirin (compared with placebo plus aspirin) produced a favorable net clinical benefit (composite of all-cause mortality, MI, stroke, fatal bleeding, and intracranial bleeding) if the patients had a previous percutaneous coronary intervention. OBJECTIVES: In these post hoc analyses, the authors examined whether the primary efficacy outcome (cardiovascular death, MI, stroke: 3-point major adverse cardiovascular events [MACE]), primary safety outcome (Thrombolysis In Myocardial Infarction-defined major bleeding) and net clinical benefit varied with diabetes-related factors. METHODS: Outcomes were analyzed across baseline diabetes duration, HbA1c, and antihyperglycemic medications. RESULTS: In THEMIS, the incidence of 3-point MACE increased with diabetes duration (6.7% for ≤5 years, 11.1% for >20 years) and HbA1c (6.4% for ≤6.0%, 11.8% for >10.0%). The relative benefits of ticagrelor plus aspirin on 3-point MACE reduction (hazard ratio [HR]: 0.90; p = 0.04) were generally consistent across subgroups. Major bleeding event rate (overall: 1.6%) did not vary by diabetes duration or HbA1c and was increased similarly by ticagrelor across all subgroups (HR: 2.32; p < 0.001). These findings were mirrored in THEMIS-PCI. The efficacy and safety of ticagrelor plus aspirin did not differ by baseline antihyperglycemic therapy. In THEMIS-PCI, but not THEMIS, ticagrelor generally produced favorable net clinical benefit across diabetes duration, HbA1c, and antihyperglycemic medications. CONCLUSION: Ticagrelor plus aspirin yielded generally consistent and favorable net clinical benefit across the diabetes-related factors in THEMIS-PCI but not in the overall THEMIS population.

Influence of Lipid Excipients on Platelet Function and the Pharmacodynamic Effects of Aspirin.

ABSTRACT: The combination of pharmaceutical lipid excipients with aspirin in a novel liquid oral formulation (Vazalore) limits gastrointestinal toxicity of aspirin. This study was performed to determine whether the lipid excipients influence the pharmacodynamic effects of aspirin and whether the excipients directly affect platelet function. The pharmacodynamic effects of aspirin were assessed over a range of concentrations designed to exert limited to maximal inhibition of cyclooxygenase-1 (COX1) necessary for thromboxane A2 production. Platelet aggregation induced by arachidonic acid and assessed with the use of light transmission aggregometry was used as a direct measure of the inhibition of COX1 by aspirin. Flow cytometry was used to assess the direct effect of excipients on platelet function. Twice the ratio of lipid excipient to aspirin used in the formulation of the novel oral agent was used. Blood was taken from 20 healthy subjects and anticoagulated with trisodium citrate (3.2%, 1:10 vol/vol). Aspirin and excipients were added in vitro and incubated for 10 minutes before performance of light transmission aggregometry and flow cytometry. The excipients did not limit the pharmacodynamic effects of aspirin. When the extent of inhibition of platelet aggregation was limited, the excipients tended to enhance pharmacodynamic effects. The excipients did not activate platelets in the absence of agonist and did not alter activation of platelets in response to adenosine diphosphate, arachidonic acid, thrombin, or convulxin (a collagen mimetic). Lipid excipients used in an oral formulation of aspirin do not impair the pharmacodynamic effects of aspirin and do not alter platelet function.

Efficacy and safety of cangrelor in patients with peripheral artery disease undergoing percutaneous coronary intervention - Insights from the CHAMPION program.

Background: Peripheral artery disease (PAD) is associated with an increased risk of ischemic events following percutaneous coronary intervention (PCI). More aggressive antiplatelet therapy may mitigate this risk. The present study evaluates the efficacy of cangrelor in patients with PAD undergoing PCI. Methods and results: This is a pooled analysis from the CHAMPION PCI, CHAMPION PLATFORM, AND CHAMPION PHOENIX trials, evaluating cangrelor versus either clopidogrel or placebo in PCI patients. The occurrence of the primary endpoint of death, myocardial infarction, or ischemia-driven revascularization (IDR) was assessed in patients with and without PAD. GUSTO severe bleeding at 48 h was also evaluated. There were 1720 (7%) patients with PAD and 22,802 (93%) without PAD. After adjustment for differences in baseline variables, PAD patients, compared with those without PAD, experienced increased odds of the primary endpoint (OR [95% CI] = 1.27 [0.91, 1.77], P = 0.16) and GUSTO severe bleeding (OR [95% CI] = 3.24 [1.28, 8.21], P = 0.01). In PAD patients, the primary endpoint was 4.7% with cangrelor vs. 7.2% with clopidogrel (OR [95% CI] = 0.64 [0.42,0.96]); in patients without PAD the primary endpoint was 3.5% with cangrelor vs. 4.2% with clopidogrel (OR [95% CI] = 0.83 [0.72,0.95]), P-interaction 0.23. Among patients with or without PAD, there was no significant difference in the rate of GUSTO severe bleeding with cangrelor compared with control, P-interaction 0.86. Conclusions: In a pooled analysis of the CHAMPION studies, PAD was associated with increased rates of ischemic and bleeding complications. Cangrelor reduced the odds of ischemic events, without increasing GUSTO severe bleeding. Clinical trial registration: clinicaltrials.gov identifiers: CHAMPION PCI (NCT00305162), CHAMPION PLATFORM(NCT00385138), CHAMPION PHOENIX (NCT01156571).

Bioavailability of aspirin in fasted and fed states of a novel pharmaceutical lipid aspirin complex formulation.

Dyspeptic symptoms are common with aspirin and clinicians frequently recommend that it be taken with food to reduce these side effects. However, food can interfere with absorption, especially with enteric-coated aspirin formulations. We evaluated whether food interferes with the bioavailability of a new, pharmaceutical lipid-aspirin complex (PL-ASA) liquid-filled capsule formulation. In this randomized, open label, crossover study, 20 healthy volunteers fasted for ≥ 10 h and then randomized as either "fasted", receiving 650 mg of PL-ASA, or as "fed", with a standard high-fat meal and 650 mg of PL-ASA 30 min later. After a washout of 7 days, participants crossed over to the other arm. The primary outcome was comparison of PK parameters of the stable aspirin metabolite salicylic acid (SA) between fasted and fed states. Mean age of participants was 36.8 years and 55% were male. The ratios for the fed to fasted states of the primary SA PK parameters of AUC0-t and AUC0-∞ were 88.7% and 88.8% respectively, with 90% confidence intervals between 80 and 125%, which is consistent with FDA bioequivalence guidance. Mean peak SA concentration was about 22% lower and occurred about 1.5 h later in the fed state. Food had a modest effect on peak SA levels and the time required to reach them after PL-ASA administration, but did not impact the extent of exposure (AUC) compared with intake in a fasted state. These data demonstrate that PL-ASA may be co-administered with food without significant impact on aspirin bioavailability.Clinical Trial Registration:http://www.clinicaltrials.gov Unique Identifier: NCT01244100.

Pharmacokinetic/pharmacodynamic assessment of a novel, pharmaceutical lipid-aspirin complex: results of a randomized, crossover, bioequivalence study.

Aspirin (acetylsalicylic acid, ASA) can lead to gastrointestinal mucosal injury through disruption of its protective phospholipid bilayer. A liquid formulation of a novel pharmaceutical lipid-aspirin complex (PL-ASA) was designed to prevent this disruption. We sought to determine the pharmacokinetic (PK)/pharmacodynamic (PD) characteristics of PL-ASA compared with immediate release aspirin (IR-ASA). In this active-control crossover study, 32 healthy volunteers were randomized to receive 1 of 2 dose levels (a single dose of 325 mg or 650 mg) of either PL-ASA or IR-ASA. After a 2-week washout period between treatment assignments, subjects received a single dose of the alternative treatment, at the same dose level. The primary objectives of the study were to assess, for PL-ASA and IR-ASA at 325 mg and 650 mg dose levels, PK and PD bioequivalence, and safety, over a 24-h period after administration of both drugs. PK parameters were similar for PL-ASA and IR-ASA, and met FDA-criteria for bioequivalence. Regarding PD, both drugs also showed Cmin TxB2 values below 3.1 ng/mL (cut-off associated with decreased cardiovascular events) and > 99% inhibition of serum TxB2 ( ≥ 95% inhibition represents the cut-off for aspirin responders) along with similar results in several secondary PK/PD parameters. There were no serious adverse events or changes from baseline in vital signs or laboratory values in either of the 2 treatment groups. PL-ASA's novel liquid formulation has similar PK and PD performance compared with IR-ASA, supporting functional and clinical equivalence. These data coupled with the improved gastric safety of PL-ASA suggest that this novel formulation may exhibit an improved benefit-risk profile, warranting evaluation in future trials.Clinical trial registration: http://www.clinicaltrials.gov . Unique Identifier: NCT04008979.

Central Adjudication Identified Additional and Prognostically Important Myocardial Infarctions in Patients Undergoing Percutaneous Coronary Intervention.

BACKGROUND: 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). METHODS AND RESULTS: 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). CONCLUSIONS: 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. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01156571.

The efficacy and safety of cangrelor in single vessel vs multivessel percutaneous coronary intervention: Insights from CHAMPION PHOENIX.

BACKGROUND: The intravenous, rapidly acting P2Y12 inhibitor cangrelor reduces the rate of ischemic events during PCI with no significant increase in severe bleeding. However, the efficacy and safety of cangrelor compared with clopidogrel in patients treated with single vessel (SV)-percutaneous coronary intervention (PCI) or multivessel (MV)-PCI remains unexplored. METHODS: We studied the modified intention-to-treat population of patients from the CHAMPION PHOENIX trial who were randomized to either cangrelor or clopidogrel. We used logistic regression and propensity score matching to evaluate the effect of cangrelor compared with clopidogrel on the primary efficacy outcome (composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis) at 48 hours. The safety outcome was moderate or severe Global Utilization of Streptokinase and tPA for Occluded Arteries bleeding at 48 hours. HYPOTHESIS: Cangrelor is as efficacious and safe as clopidogrel in both SV and MV PCI. RESULTS: Among 10 854 patients, 9204 (85%) underwent SV- and 1650 (15%) MV-PCI. After adjustment, cangrelor was associated with similar reductions vs clopidogrel in the primary efficacy outcome in patients undergoing SV-PCI (4.5% vs 5.2%; odds ratio [OR] 0.81 [0.66-0.98]) or MV-PCI (6.1% vs 9.8%, OR 0.59 [0.41-0.85]; Pint 0.14). Similar results were observed after propensity score matching (SV-PCI: 5.5% vs 5.9%, OR 0.93 [0.74-1.18]; MV-PCI: 6.2% vs 8.9%, OR 0.67 [0.44-1.01]; Pint 0.17). There was no evidence of heterogeneity in the treatment effect of cangrelor compared with clopidogrel for the safety outcome. CONCLUSIONS: In patients undergoing SV- or MV-PCI, cangrelor was associated with similar relative risk reductions in ischemic complications and no increased risk of significant bleeding compared with clopidogrel, which highlights the expanding repertoire of options for use in complex PCI.

Periprocedural Outcomes According to Timing of Clopidogrel Loading Dose in Patients Who Did Not Receive P2Y12 Inhibitor Pretreatment.

BACKGROUND: In patients undergoing percutaneous coronary intervention (PCI), who did not receive P2Y12 inhibitor pretreatment, the optimal timing of P2Y12 inhibitor loading dose remains debated. We sought to examine whether the choice of administration of the clopidogrel loading dose before or after the start of PCI had an impact on periprocedural complications, including bleeding. METHODS AND RESULTS: 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). CONCLUSIONS: 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. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01156571.

Characteristics and outcomes of patients requiring bailout use of glycoprotein IIb/IIIa inhibitors for thrombotic complications of percutaneous coronary intervention: An analysis from the CHAMPION PHOENIX trial.

AIMS: To describe the characteristics and outcomes of patients receiving bailout glycoprotein IIb/IIIa inhibitors (GPI) for thrombotic complications of percutaneous coronary intervention (PCI) in a large, contemporary trial. METHODS AND RESULTS: In the CHAMPION PHOENIX trial, the use of GPI was restricted to bailout for thrombotic complications. We describe the characteristics and outcomes of patients requiring bailout GPI compared to patients not receiving GPIs, with adjustment through propensity-score. A multivariable model was constructed to identify independent correlates associated with bailout GPI use. A total of 380 out of 10,942 patients received GPI (3.5%); GPI patients were younger, more frequently male, more likely to present with ST segment elevation myocardial infarction and less frequently treated with cangrelor. At 48 h, GPI patients experienced higher rates of the primary composite outcome of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis (ST) (19.2% vs 4.8%; adjusted OR: 5.65(4.08, 7.82), p < 0.0001) and a higher rate of GUSTO severe or moderate bleeding (2.6% vs 0.4% adjusted OR: 4.90 (1.98, 12.18), p = 0.0006) compared with non GPI patients. Independent correlates of GPI use were STEMI, use of unfractionated heparin, drug-eluting stents and longer procedure duration. CONCLUSIONS: In a large contemporary trial, patients receiving bailout GPI for thrombotic complications of PCI experienced very high risks of both ischemic and bleeding complications, suggesting that prevention of periprocedural complications rather than bailout GPI may be preferable. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov identifier: NCT01156571.

Impact of lesion complexity on peri-procedural adverse events and the benefit of potent intravenous platelet adenosine diphosphate receptor inhibition after percutaneous coronary intervention: core laboratory analysis from 10 854 patients from the CHAMPION PHOENIX trial.

Aims: 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. Methods and results: 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. Conclusion: 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. Clinicaltrials.gov identifier: NCT01156571.

Correction to: A Novel Bridging Strategy for Patients Undergoing Emergent Non-Cardiac Surgery with a Recent Coronary Stent.

In the original publication, the abstract text, informed consent and disclosure text have been published incorrectly.

A Novel Bridging Strategy for Patients Undergoing Emergent Non-Cardiac Surgery with a Recent Coronary Stent.

INTRODUCTION: Not infrequently, patients undergoing dual antiplatelet therapy for a recent cardiac stent develop a need for a non-cardiac surgery. Most of these surgeries can be delayed while the antiplatelet treatment is stopped and normal platelet function returns in order to avoid potential surgical complications and excessive bleeding. However, there are a number of patients who require urgent surgery where the procedure cannot be postponed. To date, no agents have been proven to bridge the patient off dual-antiplatelet therapy. METHODS: A 46-year-old man was admitted to the hospital with an acute anterior wall myocardial infarction. He was urgently taken to the catheterization lab where he was found to have a totally occluded proximal left anterior descending coronary artery (LAD). He was successfully stented with a drug-eluting stent of the LAD, but subsequently developed a sarcoma 2 months later that required urgent surgery. The novel direct-acting, reversible P2Y12 receptor inhibitor cangrelor was used to bridge this patient followed by ongoing antiplatelet treatment, allowing surgery for the removal of a soft tissue sarcoma. RESULTS: Cangrelor was successfully used to bridge a patient with a recent stent placement and current antiplatelet treatment undergoing the removal of a soft tissue sarcoma. CONCLUSION: This case report demonstrates the use of a novel, now currently available, short-acting antiplatelet agent that can be used for bridging patients undergoing non-cardiac surgery who had a recent myocardial infarction and stent placement.

Incidence, Predictors, and Outcomes of Acquired Thrombocytopenia After Percutaneous Coronary Intervention: A Pooled, Patient-Level Analysis of the CHAMPION Trials (Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition).

BACKGROUND: The influence of cangrelor on the incidence and outcomes of post-percutaneous coronary intervention (PCI) thrombocytopenia is not defined. We aimed to explore the incidence, predictors, and clinical impact of thrombocytopenia after PCI in cangrelor-treated patients. METHODS AND RESULTS: This was a pooled, patient-level analysis of the CHAMPION trials (Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition), which compared cangrelor with clopidogrel for prevention of thrombotic complications during and after PCI. Acquired thrombocytopenia was defined as either a drop in platelet count to <100 000 after PCI or a drop of >50% between baseline and a follow-up. The main efficacy outcome was major adverse cardiac events. The primary safety outcome was noncoronary artery bypass grafting-related Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries-defined severe bleeding at 48 hours. Patients (23 783) were enrolled, and 3009 (12.7%) received a GPI (glycoprotein IIb/IIIa inhibitor). Acquired thrombocytopenia occurred in 200 patients (0.8%). The adjusted rate of major adverse cardiovascular events at 48 hours was significantly higher in patients who developed thrombocytopenia compared with those who did not (odds ratio, 3.00; 95% confidence interval, 1.89-4.69; P<0.001), as was major bleeding (odds ratio, 14.71; 95% confidence interval, 5.96-36.30; P<0.001). GPI use was the strongest independent predictor of acquired thrombocytopenia (odds ratio, 2.93; 95% confidence interval, 2.15-3.97; P<0.0001). There was no difference in the rate of acquired thrombocytopenia in patients randomized to cangrelor or clopidogrel. CONCLUSIONS: Acquired thrombocytopenia after PCI is strongly associated with substantial early morbidity and mortality, as well as major bleeding. GPI use is a significant predictor of thrombocytopenia. Cangrelor is not associated with acquired thrombocytopenia, and its clinical efficacy and safety is consistent irrespective of thrombocytopenia occurrence. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT00305162, NCT00385138, and NCT01156571.