Adjunctive Intravenous Argatroban or Eptifibatide for Ischemic Stroke.

BACKGROUND: Intravenous thrombolysis is a standard treatment of acute ischemic stroke. The efficacy and safety of combining intravenous thrombolysis with argatroban (an anticoagulant agent) or eptifibatide (an antiplatelet agent) are unclear. METHODS: We conducted a phase 3, three-group, adaptive, single-blind, randomized, controlled clinical trial at 57 sites in the United States. Patients with acute ischemic stroke who had received intravenous thrombolysis within 3 hours after symptom onset were assigned to receive intravenous argatroban, eptifibatide, or placebo within 75 minutes after the initiation of thrombolysis. The primary efficacy outcome, the utility-weighted 90-day modified Rankin scale score (range, 0 to 10, with higher scores reflecting better outcomes), was assessed by means of centralized adjudication. The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours after randomization. RESULTS: A total of 514 patients were assigned to receive argatroban (59 patients), eptifibatide (227 patients), or placebo (228 patients). All the patients received intravenous thrombolysis (70% received alteplase, and 30% received tenecteplase), and 225 patients (44%) underwent endovascular thrombectomy. At 90 days, the mean (±SD) utility-weighted modified Rankin scale scores were 5.2±3.7 with argatroban, 6.3±3.2 with eptifibatide, and 6.8±3.0 with placebo. The posterior probability that argatroban was better than placebo was 0.002 (posterior mean difference in utility-weighted modified Rankin scale score, -1.51±0.51) and that eptifibatide was better than placebo was 0.041 (posterior mean difference, -0.50±0.29). The incidence of symptomatic intracranial hemorrhage was similar in the three groups (4% with argatroban, 3% with eptifibatide, and 2% with placebo). Mortality at 90 days was higher in the argatroban group (24%) and the eptifibatide group (12%) than in the placebo group (8%). CONCLUSIONS: In patients with acute ischemic stroke treated with intravenous thrombolysis within 3 hours after symptom onset, adjunctive treatment with intravenous argatroban or eptifibatide did not reduce poststroke disability and was associated with increased mortality. (Funded by the National Institute of Neurological Disorders and Stroke; MOST ClinicalTrials.gov number, NCT03735979.).

Eptifibatide use following emergent carotid stenting in acute anterior circulation ischemic stroke with tandem occlusion.

BACKGROUND: Early revascularization of the extracranial internal carotid artery in acute anterior circulation ischemic stroke (ACIS) is feasible and may improve clinical outcome. When a stent is deployed, antithrombotic agents should be administered peri-procedurally to ensure stent patency. Our institution implemented a protocol for the use of eptifibatide as a means of maintaining stent patency in the treatment of ACIS associated with cervical internal carotid artery occlusion. METHODS: Our internal database was queried for patients who received emergent endovascular therapy (ET) for ACIS with stent placement and eptifibatide administration between July 2016 and 2019. RESULTS: Twenty nine patients met the study criteria. The etiology was large artery atherosclerosis in 26 cases. Two patients had a dissection (7%), and one had a carotid occlusion related to a recent carotid endarterectomy. Mean NIHSS was 14. Sixteen patients received IVrtPA. Extracranial-intracranial tandem occlusion (TO) was present in 21 of cases. All patients received an eptifibatide bolus followed by an infusion for approximately 24 hours post stent deployment. Head CT was obtained prior to initiation of oral dual antiplatelet therapy with aspirin and clopidogrel. Successful recanalization was achieved in all patients with no evidence of downstream embolization. Symptomatic intracerebral hemorrhage occurred in one patient. Stent occlusion occurred in two patients, only one of which was symptomatic. Favorable clinical outcome with mRS ≤ 2 at 3 months was achieved in seventeen patients. CONCLUSIONS: The use of eptifibatide post procedure was associated with low risk of symptomatic intracranial hemorrhage, including in patients treated with rtPA.

Prolonged use of eptifibatide as a bridge to maintain drug-eluting stent patency in a patient receiving extracorporeal membrane oxygenation.

BACKGROUND: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) has been used as a bridge to cardiac recovery in patients following a major cardiac event. There is a lack of literature surrounding prolonged use of eptifibatide and optimal dosing during ECMO. This case report describes our experience with extended durations and standard dosing of eptifibatide in the setting of ECMO. CASE: A 40-year-old male with a history of Marfan's syndrome, aortic root and ascending aortic aneurysm status post a modified Bentall with a St. Jude mechanical aortic valve conduit and hemi-Cabrol with a Dacron graft to the left main coronary artery presented with exertional chest pain and was found to have an anastomotic narrowing to the left main which occluded while awaiting surgical revision. A rescue percutaneous coronary intervention at the anastomotic site was performed. Due to hemodynamic instability, he was placed on femoral VA-ECMO. The patient was started on anticoagulation for the ECMO circuit and eptifibatide to maintain stent patency. The patient experienced several bleeding episodes for which he received supportive care, endoscopic intervention and left gastric artery embolization. Eptifibatide was maintained at standard dosing and the heparin infusion was withheld. A coronary angiogram revealed no thrombus within the Cabrol graft a patent stent previously placed at the site of the distal graft-coronary anastomosis. The patient was decannulated from ECMO and underwent coronary artery bypass grafting and division of the hemi-Cabrol graft. CONCLUSION: While eptifibatide was effective in maintaining stent patency, our patient experienced several bleeding episodes during ECMO. Thus, the risks and benefits of concurrent antiplatelet and anticoagulant therapy must be appropriately weighed in this patient population. Additionally, as the need for dual antiplatelet therapy due to coronary stent implantation is increasing, further studies are needed to validate optimal dosing of eptifibatide in patients at a high risk of bleeding during ECMO.

A Double-Blinded Randomized Controlled Trial Comparing Eptifibatide Bolus Only Versus Bolus Plus Infusion In Patients Undergoing Primary Percutaneous Coronary Intervention For ST-Elevation Myocardial Infarction.

BACKGROUNDS: The use of eptifibatide combined with heparin during percutaneous coronary intervention (PCI) in patients presenting with ST-elevation myocardial infarction (STEMI) is recommended to be followed by continuous infusion. Recently, there are some suggestions that using bolus only may be sufficient and cost-effective but randomized trials are lacking. AIMS: The goal of this study was to evaluate these two approaches in a double-blinded randomized control trial. METHODS: The primary PCI patients who received bolus eptifibatide were randomized to 75 mg IV eptifibatide infusion or placebo blindly. The patients were followed up for the primary outcome of vascular or bleeding complications and secondary outcome of ischemic complications. RESULTS: 330 patients (165 from each group) completed the study. The mean age was 57.67 ± 11.53 years and 77.3 % were male. Major bleeding was seen in 1 patient in each group. Hematoma occurred in 8.5 %. The relative risk of hematoma and ecchymosis in bolus plus infusion group to bolus only group were 0.988 (95 % CI: 0.486-2.006) and 1.032 (95 % CI: 0.729-1.459). Multivariate analysis confirmed no significant differences in the bleeding event. Furthermore, there was no significant difference in in-hospital death or any ischemic events. (Cath lab death: 1.4 % in bolus only vs zero % in the control group, p = 0.217, stent thrombosis was seen in one patient in each group). CONCLUSION: There were no differences in the risk of access site ecchymosis, hematoma or major bleeding. Ischemic events and stent thrombosis rates were also similar. Our study suggests that using eptifibatide bolus only during PCI of patients with STEMI is safe and can be cost-saving.

Efficacy and Safety of Abbreviated Eptifibatide Treatment in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention.

The glycoprotein IIb/IIIa inhibitor eptifibatide, administered as bolus followed by infusion, is an adjunctive antithrombotic treatment during primary percutaneous coronary intervention (PCI) in selected patients with ST-segment elevation myocardial infarction (STEMI). Whether both bolus and infusion are necessary to improve outcomes is unknown. We hypothesized that primary PCI with eptifibatide bolus only is non-inferior to the conventional treatment (bolus and infusion) with regard to infarct size, while reducing bleeding complications. We analyzed 720 consecutive STEMI patients receiving eptifibatide bolus only or conventional treatment in an observational case-control study utilizing propensity score matching of clinical and intervention-specific confounders. Infarct size was estimated based on myocardial bound creatine kinase, creatine kinase (CK), and CK area under the curve values, with a prespecified non-inferiority margin of 20%. Major bleeding was defined as type 2, 3, or 5 on the Bleeding Academic Research Consortium classification. Eptifibatide bolus only was administered to 147 patients (20%), which were matched 1:1 to patients receiving conventional treatment. Based on peak myocardial bound creatine kinase, CK and CK area under the curve values, infarct size was -8.4% (95% CI [-31.2%, 14.4%]), -11.6% (95% CI [-33.5%, 10.3%]), and -13.9% (95% CI [-34.1%, 6.2%]) after eptifibatide bolus, respectively, reaching prespecified noninferiority compared with conventional treatment. Bolus treatment significantly reduced major bleeding complications (OR 0.48, 95% CI [0.30, 0.79]). In conclusion, eptifibatide given as abbreviated bolus only to selected STEMI patients who underwent primary PCI was noninferior regarding infarct size and resulted in less bleeding complications compared with conventional bolus and infusion treatment.

Intra-arterial thrombolytic therapy for acute anterior spinal artery stroke.

BACKGROUND AND IMPORTANCE: Spinal cord infarction is rare but can be extremely disabling. Prompt diagnosis and treatment of these infarcts is important for patient outcomes. While intravenous thrombolytic therapy is a well-established form of treatment in circumstances of cerebral stroke, it has only recently been successfully used in a few incidents of spinal cord ischemia. We present a case of anterior spinal artery (ASA) territory ischemia treated with ASA intra-arterial thrombolytic therapy. CLINICAL PRESENTATION: A 52-year-old male presented with acute onset of severe lumbar pain, rapidly progressing paraplegia and loss of pain and temperature sensation, with preservation of proprioception and vibratory sensation at the L1 level and below on the right and at the L3 level and below on the left. MRI showed restricted diffusion involving the cord at and below L1 level, with normal cord T2 signal. Digital subtraction spinal angiography showed ASA cutoff in the descending limb at the level of L1. Intra-arterial tissue plasminogen activator (t-PA) combined with verapamil and eptifibatide was administered within the ASA and the patient had significant neurological improvement immediately postoperatively and at 8-month clinical follow-up. CONCLUSION: Direct ASA intra-arterial thrombolysis is feasible, and this drug combination might be an effective therapy for spinal stroke.

Antiplatelet agents'-ticagrelol and eptifibatide-safety in experimental colitis in mice.

BACKGROUND/AIMS: To evaluate the side effects of two antiplatelet agents - ticagrelor and eptifibatide - in mice with experimentally-induced inflammatory bowel disease. METHODS AND MATERIAL: This study was designed as a controlled, animal, drug safety investigation. C57Bl/6 mice were used to establish the ulcerative colitis model by exposure to dextran sulfate sodium (DSS), and divided into three experimental groups: eptifibatide-treated (150 µg/day intraperitoneally; n = 10), ticagrelol-treated (1 mg/day via gastric tube; n = 10), and DSS-control (plain drinking water; n = 10). An unmodeled non-DSS group served as the experimental control. Complete blood count was taken for all mice at baseline (day 0, treatment initiation) and after four days of treatment. On day 4, all animals were sacrificed for autopsy. The primary outcome measure was bleeding, and the secondary outcomes were change in platelet count, hemoglobin level, and hematocrit level. RESULTS: Neither ticagrelor nor eptifibatide treatment produced a significant effect on DSS colitis mice for the safety parameters measured. Platelet count and hemoglobin and hematocrit levels were statistically similar between the three DSS groups and the non-DSS control group (P > 0.05). Autopsy found no evidence of recent bleeding in liver, spleen, central nervous system or serous cavities. CONCLUSION: The antiplatelet agents ticagrelor and eptifibatide were safe in DSS colitis mice, suggesting their potential in humans suffering from ulcerative colitis, and supporting future safety studies.

Clinical Evaluation of the Tolerability, Pharmacokinetics, and Inhibition of Platelet Aggregation of Eptifibatide in Healthy Chinese Subjects.

The present study aimed to evaluate the pharmacokinetic properties and antiplatelet aggregation activity of eptifibatide in healthy Chinese subjects. Eptifibatide (180 µg/kg) was administrated by 2 bolus injections 10 minutes apart, followed by a 2.0 µg/kg/min infusion for 24 hours. The eptifibatide pharmacokinetic and antiplatelet aggregation activities were evaluated using nonlinear mixed-effects modeling and noncompartmental analysis. Safety assessments included adverse events, hematology, and biochemistry tests. Twelve Chinese healthy subjects were enrolled and completed the study. Steady-state concentrations were achieved at 0.5 to 24 hours after dosing. The median time to maximum concentration was 13 minutes, and the mean terminal elimination half-life was 148.19 minutes. The effective inhibition of platelet aggregation (<20% platelet aggregation) occurred by 3 minutes after starting dosing to 4 hours after termination of the infusion. Eptifibatide concentrations were fitted with a 3-compartment model, and the typical value of clearance was 0.11 L/min, with no significant covariates found. Three mild adverse events were detected in the study. Eptifibatide displays high sensitivity and excellent tolerability in healthy Chinese subjects. The dosage of eptifibatide recommended on the label for whites can effectively inhibit platelet aggregation.

Comparison of In-Hospital Bleeding and Cardiovascular Events with High-Dose Bolus Tirofiban and Shortened Infusion to Short-Duration Eptifibatide as Adjunctive Therapy for Percutaneous Coronary Intervention.

Potent platelet inhibition is one of the most important medical interventions to prevent ischemic complications during and after percutaneous coronary intervention (PCI). Practice has evolved with the introduction of potent oral P2Y12 inhibitors that provide quick, effective platelet inhibition, and the need for routine glycoprotein IIb/IIIa inhibitors (GPIs) has decreased. Additionally, a shorter duration of GPI infusion has been shown to be safe with adequate oral antiplatelet loading, but clinical outcome data are limited to eptifibatide. This single-center, retrospective cohort study analyzed in-hospital outcomes for patients who received adjunctive GPI therapy for PCI before and after an institution-wide switch to high-dose bolus tirofiban with shortened infusion from short-duration eptifibatide. The primary end point was a composite in-hospital outcome of major and minor bleeding and cardiovascular events (death, myocardial infarction, coronary artery bypass grafting, ischemic stroke, and target vessel revascularization). Secondary end points included bleeding and cardiovascular event types. A total of 357 and 446 patients received eptifibatide and tirofiban, respectively, from February 1, 2014 through September 30, 2017. Thirty five eptifibatide and 46 tirofiban patients experienced an in-hospital composite event (9.8% vs 10.3%, p = 0.81). There was no difference found between in-hospital bleeding (6.4% vs 5.4%, p = 0.52) or cardiovascular events (5.6% vs 6.5%, p = 0.60) with the use of eptifibatide or tirofiban, respectively. Multivariable analysis showed that patients with transradial access or an indication of unstable angina were less likely to experience an in-hospital composite event (OR 0.30 and 0.19, respectively, p <0.001 for both). In conclusion, the use of high-dose bolus tirofiban with shortened infusion versus short-duration eptifibatide was not associated with an increase of in-hospital bleeding or cardiovascular events.

Novel Antiplatelet Perioperative Bridging Protocol for Lung Lobectomy: A Case Report.

INTRODUCTION: Some patients with cardiac stents will need thoracic surgery during the dual antiplatelet therapy (DAPT) period. When surgery cannot be safely delayed to allow 1 year of uninterrupted DAPT, appropriate perioperative management of anticoagulation is critical. CASE PRESENTATION: A patient treated with new drug-eluting stents and DAPT was concomitantly diagnosed with lung cancer and required a lobectomy. We describe the novel addition of ticagrelor (a short-acting oral antiplatelet agent) to eptifibatide (a short-acting intravenous antiplatelet agent) to bridge DAPT for surgery. DISCUSSION: This ticagrelor-eptifibatide perioperative bridge resulted in decreased preoperative hospitalization compared with eptifibatide alone. There were no associated perioperative cardiac or bleeding complications.

Effects of Crushed Ticagrelor Versus Eptifibatide Bolus Plus Clopidogrel in Troponin-Negative Acute Coronary Syndrome Patients Undergoing Percutaneous Coronary Intervention: A Randomized Clinical Trial.

Background After a loading dose of ticagrelor, the rate of high on-treatment platelet reactivity remains elevated, which increases periprocedural myocardial infarction and injury. This indicates that faster platelet inhibition with crushed ticagrelor (CTIC) or eptifibatide is needed to reduce high on-treatment platelet reactivity. The efficacy of CTIC versus eptifibatide bolus plus clopidogrel is unknown. Methods and Results A total of 100 P2Y12 naïve, troponin-negative patients with acute coronary syndrome were randomized to CTIC (180 mg) versus eptifibatide bolus (180 µg/kg×2 intravenous boluses) plus clopidogrel (600 mg) at the time of percutaneous coronary intervention. High on-treatment platelet reactivity was markedly higher with CTIC versus eptifibatide bolus plus clopidogrel (42% versus 0%; P<0.001) at 30 minutes and persisted up to 2 hours (12% versus 0%; P=0.01, respectively). Platelet aggregation by adenosine diphosphate dropped faster from baseline with eptifibatide bolus plus clopidogrel versus CTIC (0.5 versus 2 hours, respectively) and was higher with CTIC versus eptifibatide bolus plus clopidogrel at 0.5, 2, and 4 hours after loading dose (53±12% versus 1.3±2%; 35±11% versus 0.34±1.0%; and 23±9% versus 3.5±2%, respectively; P<0.001). Eptifibatide bolus plus clopidogrel, but not CTIC, significantly inhibited platelet aggregation induced by thrombin-receptor activating peptide. Periprocedural myocardial infarction and injury was higher with CTIC versus eptifibatide bolus plus clopidogrel (48% versus 28%, respectively; P=0.035). Post-percutaneous coronary intervention hemoglobin levels were not different between groups. Conclusions Eptifibatide bolus plus clopidogrel led to faster and more potent platelet inhibition than CTIC and reduced periprocedural myocardial infarction and injury in troponin-negative acute coronary syndrome patients undergoing percutaneous coronary intervention, with no significant hemoglobin drop after percutaneous coronary intervention. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02925923.

Intravenous Antiplatelet Therapy Bridging in Patients Undergoing Cardiac or Non-Cardiac Surgery Following Percutaneous Coronary Intervention.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Despite using IV APT as bridging therapy during perioperative DAPT interruption in post-PCI patients, postoperative cardiac events and bleeding complications can still occur.

Acute Carotid Stent Thrombosis in an Ultrarapid Clopidogrel Metabolizer: Case Report and Literature Review.

INTRODUCTION: Carotid angioplasty and stenting (CAS) represents an effective procedure for treating carotid artery disease. The acute in-stent thrombosis is an extremely rare complication of CAS especially when it occurs postprocedurally during the first 24 hours. Improper antiplatelet therapy or poor response to antiplatelet medications is known to be associated with a higher risk of in-stent thrombosis during early postprocedural period following a successful intervention. MATERIAL AND METHODS: A patient who experienced acute carotid in-stent thrombosis in early postprocedural period is described. He had been taking dual antiplatelet therapy for 2 weeks before undergoing a successful CAS. Moreover, pharmacogenetics studies showed the patient to be a clopidogrel ultrarapid metabolizer, which theoretically confers hyperresponsivity to medication. Alongside the report itself, a brief literature review of relevant sources pertinent to the case has been conducted. RESULTS: According to the available literature, this is the first case report describing an ultrarapid clopidogrel metabolizer who underwent an uneventful CAS but experienced acute carotid in-stent thrombosis in early postprocedural period. A rescue procedure included an endovascular intervention consisting of thrombectomy and local alteplase application, followed by postprocedural administration of intravenous eptifibatide. At discharge, patient's dual antiplatelet therapy included ticagrelor instead of clopidogrel. CONCLUSION: Acute carotid in-stent thrombosis is a highly unexpected complication of CAS and can occur despite ultrarapid clopidogrel metabolism trait.

Activated Clotting Time to Guide Heparin Dosing in Non-ST-Segment-Elevation Acute Coronary Syndrome Patients Undergoing Percutaneous Coronary Intervention and Treated With IIb/IIIa Inhibitors: Impact on Ischemic and Bleeding Outcomes: Insights From the TAO Trial.

BACKGROUND: Monitoring anticoagulation with activated clotting time (ACT) has been proposed to reduce ischemic or bleeding events. However, the value of using ACT to improve outcomes is uncertain. This study sought to determine the relationship between ACT and outcomes during percutaneous coronary intervention in patients with non-ST-segment-elevation acute coronary syndrome (NSTE-ACS) treated by unfractionated heparin with GPIs (glycoprotein IIb/IIIa inhibitors). METHODS AND RESULTS: From the randomized TAO trial (Treatment of Acute Coronary Syndromes With Otamixaban), we analyzed the value of ACT to predict ischemic and bleeding outcomes in the 3275 patients receiving unfractionated heparin plus eptifibatide. Ischemic and safety outcomes were analyzed according to ACT to determine the best threshold. Median peak ACT was 225 s. There was no correlation (r=-0.02; P=0.24) between the unfractionated heparin dose received and the ACT value before percutaneous coronary intervention. There was no evidence of a nonlinear association between ACT and either ischemic or bleeding events (P=0.66; P=0.07). No threshold was found to predict ischemic complications. Conversely, increased bleeding was observed with ACT >230 s with an optimal threshold of ACTs ≥250 s (4.53% versus 6.17%; odds ratio, 1.46; 95% confidence interval, 1.04-2.06; P=0.028). This optimal threshold varied according to access site: ≥250 s (6.86% versus 10.18%; odds ratio, 1.57; 95% confidence interval, 1.00-2.45; P=0.047) by femoral approach and ≥290 s (2.86% versus 5.43%; odds ratio, 2.24; 95% confidence interval, 1.05-4.44; P=0.027) by radial approach. CONCLUSIONS: In the TAO trial, peak procedural ACT ≥250 s was associated with increased bleeding risk in non-ST-segment-elevation acute coronary syndrome patients treated with unfractionated heparin plus GPIs. This threshold was increased to 290 s when performing radial approach. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01076764.