Combination Reperfusion Therapy Research Articles

Antiplatelet therapy increases symptomatic ICH risk after thrombolysis and thrombectomy.

The influence of chronic treatment by antiplatelet drug (APD) at stroke onset on the outcomes of patients with acute ischemic stroke (AIS) treated with combined intravenous thrombolysis (IVT) and endovascular therapy (EVT) is unclear. We investigated whether prior APD use influences the risk of symptomatic intracranial hemorrhage (sICH) and functional outcome in AIS patients treated with combined reperfusion therapy. A single-center retrospective analysis of AIS patients with proximal intracranial occlusion who underwent IVT and EVT between January 2015 and May 2017. The main outcomes were the incidence of sICH using the Heidelberg Bleeding Classification and patients' functional status at 90days, as defined by the modified Rankin scale (mRS). Outcomes were evaluated according to daily exposure to APD, and associations were assessed using multivariate logistic regression analysis. This study included 204 patients: 71 (34.8%) were taking APD before AIS. Patients with chronic treatment by APD at stroke onset had a higher rate of sICH (26.7% vs. 3.7%; p<.001) and worse functional outcome (mRS >2) at 90days (69% vs. 36.8%; p<.001). Prior APD use was associated with an increased likelihood of sICH (OR 9.8; 95%CI [3.6-31.3], p<.05) and of functional dependence at 90days (OR 5.72; 95%CI [2.09-1.72], p<.001), independent of confounders on multivariate analysis. Chronic treatment by APD at stroke onset in AIS patients with proximal intracranial occlusion treated using IVT and EVT increases the risk of sICH and worsens the functional prognosis. Further investigation to refine acute revascularization strategies in this population might be required.

Increased plasma levels of miR-124-3p, miR-125b-5p and miR-192-5p are associated with outcomes in acute ischaemic stroke patients receiving thrombolysis

Background and aimsCirculating microRNAs (miRNAs) have recently emerged as promising biomarkers for acute ischaemic stroke (AIS). However, the expression profiles of miRNAs in AIS patients receiving intravenous thrombolysis, and their associations with outcome have not been investigated. MethodsIn a prospective cohort study, a total of 84 AIS patients, who received intravenous thrombolysis (21.4% received combined reperfusion therapy) and completed 3 month follow-up visits, were included. Favourable and unfavourable outcomes were defined as modified Rankin Scale (mRS) scores of 0–1 and 2–6, respectively. Plasma samples were collected at 24 h after thrombolysis. We used RNA sequencing to study miRNA profiles in 5 patients with unfavourable outcomes and 5 matched patients with favourable outcomes. Differentially expressed miRNAs were further validated in all cohorts using quantitative real-time polymerase chain reaction assays. ResultsAfter identification and validation, we found that miR-124-3p, miR-125b-5p and miR-192-5p levels were higher in patients with unfavourable outcomes than in patients with favourable outcomes. Logistic regressions and receiver-operating characteristic curve analyses demonstrated that these altered miRNAs may function as predictive biomarkers for outcome in AIS patients receiving thrombolysis, whether combined with endovascular thrombectomy or not. In addition, miR-124-3p and miR-125b-5p were closely associated with stroke severity. ConclusionsA set of circulating microRNAs (miR-124-3p, miR-125b-5p and miR-192-5p) are associated with unfavourable 3 month outcomes and might have clinical utility in AIS patients receiving thrombolysis.

Specific features of reperfusion therapy for vertebrobasilar ischemic stroke

Ischemic stroke in the vertebrobasilar system (VBS) is characterized by the high rates of death and disability; reperfusion therapy in patients with a lesion focus in the VBS is safe and effective beyond the 4.5-hour therapeutic window. Actively developed current methods for the endovascular treatment of acute ischemic stroke enable one to increase recanalization rates and hence to improve the degree of functional recovery in this group of patients. Considering that there are no significant differences in the outcomes of systemic and selective thrombolytic therapy in patients with occlusion of the basilar arteries, the urgent problem is to increase the time from the onset of the disease to reperfusion therapy, therefore combined reperfusion therapy may be an optimal option. This approach would make it possible to initiate the therapy in a shorter period of time and to use the advantages of both reperfusion techniques. Intravenous thrombolysis as the rapidest and technically simplest method may be performed in the first step of therapy in the clinics unequipped with an X-ray surgical service, with the patient being further transported to a specialized endovascular center if the intravenous injection of a thrombolytic agent has no effect. Taking into account the fact that reperfusion therapy may be performed in patients with vertebrobasilar stroke in the wider therapeutic window, a similar organizational chart with multistep therapy for this disease might become the treatment of choice.

Improved speed and stability of st-segment recovery with reduced-dose tenecteplase and eptifibatide compared with full-dose tenecteplase for acute st-segment elevation myocardial infarction

ObjectivesThis sub-study of the Integrilin and Tenecteplase in Acute Myocardial Infarction (INTEGRITI) trial evaluated of the impact of combination reperfusion therapy with reduced-dose tenecteplase plus eptifibatide on continuous ST-segment recovery and angiographic results. BackgroundCombination therapy with reduced-dose fibrinolytics and glycoprotein IIb/IIIa inhibitors for ST-segment elevation myocardial infarction improves biomarkers of reperfusion success but has not reduced mortality when compared with full-dose fibrinolytics. MethodsWe evaluated 140 patients enrolled in the INTEGRITI trial with 24-h continuous 12-lead ST-segment monitoring and angiography at 60 min. The dose-combination regimen of 50% of standard-dose tenecteplase (0.27 μg/kg) plus high-dose eptifibatide (2 boluses of 180 μg/kg separated by 10 min, 2.0 μg/kg/min infusion) was compared with full-dose tenecteplase (0.53 μg/kg). ResultsThe dose-confirmation regimen of reduced-dose tenecteplase plus high-dose eptifibatide was associated with a faster median time to stable ST-segment recovery (55 vs. 98 min, p = 0.06), improved stable ST-segment recovery by 2 h (89.6% vs. 67.7%, p = 0.02), and less recurrent ischemia (34.0% vs. 57.1%, p = 0.05) when compared with full-dose tenecteplase. Continuously updated ST-segment recovery analyses demonstrated a modest trend toward greater ST-segment recovery at 30 min (57.7% vs. 40.6%, p = 0.13) and 60 min (82.7% vs. 65.6%, p = 0.08) with this regimen. These findings correlated with improved angiographic results at 60 min. ConclusionsCombination therapy with reduced-dose tenecteplase and eptifibatide leads to faster, more stable ST-segment recovery and improved angiographic flow patterns, compared with full-dose tenecteplase. These findings question the relationship between biomarkers of reperfusion success and clinical outcomes.

Combination reperfusion therapy with eptifibatide and reduced-dose tenecteplase for ST-elevation myocardial infarction results of the integrilin and tenecteplase in acute myocardial infarction (INTEGRITI) phase II angiographic trial

Combination reperfusion therapy with eptifibatide and reduced-dose tenecteplase for ST-elevation myocardial infarction results of the integrilin and tenecteplase in acute myocardial infarction (INTEGRITI) phase II angiographic trial

Combination reperfusion therapy with eptifibatide and reduced-dose tenecteplase for ST-elevation myocardial infarction: Results of the integrilin and tenecteplase in acute myocardial infarction (INTEGRITI) Phase II Angiographic urial

ObjectivesThe goal of this study was to evaluate combinations of eptifibatide with reduced-dose tenecteplase (TNK) in ST-elevation myocardial infarction (STEMI). BackgroundGlycoprotein IIb/IIIa inhibitors enhance thrombolysis. The role of combination therapy in clinical practice remains to be established. MethodsPatients (n = 438) with STEMI <6 h were enrolled. In dose-finding, 189 patients were randomized to different combinations of double-bolus eptifibatide and reduced-dose TNK. In dose-confirmation, 249 patients were randomized 1:1 to eptifibatide 180 μg/kg bolus, 2 μg/kg/min infusion, and 180 μg/kg bolus 10 min later (180/2/180) plus half-dose TNK (0.27 mg/kg) or standard-dose (0.53 mg/kg) TNK monotherapy. All patients received aspirin and unfractionated heparin (60 U/kg bolus; infusion 7 U/kg/h [combination], 12 U/kg/h [monotherapy]). The primary end point was Thrombolysis In Myocardial Infarction (TIMI) grade 3 epicardial flow at 60 min. ResultsIn dose-finding, TIMI grade 3 flow rates were similar across groups (64% to 68%). Arterial patency was highest for eptifibatide 180/2/180 plus half-dose TNK (96%, p = 0.02 vs. eptifibatide 180/2/90 plus half-dose TNK). In dose-confirmation, this combination, compared with TNK monotherapy, tended to achieve more TIMI 3 flow (59% vs. 49%, p = 0.15), arterial patency (85% vs. 77%, p = 0.17), and ST-segment resolution (median 71% vs. 61%, p = 0.08) but was associated with more major hemorrhage (7.6% vs. 2.5%, p = 0.14) and transfusions (13.4% vs. 4.2%, p = 0.02). Intracranial hemorrhage occurred in 1.0%, 0.6%, and 1.7% of patients treated with any combination, eptifibatide 180/2/180 and half-dose TNK, and TNK monotherapy, respectively. ConclusionsDouble-bolus eptifibatide (180/2/180) plus half-dose TNK tended to improve angiographic flow and ST-segment resolution compared with TNK monotherapy but was associated with more transfusions and non-cerebral bleeding. Further study is needed before this combination can be recommended for general use.

Outcome after combined reperfusion therapy for acute myocardial infarction, combining pre-hospital thrombolysis with immediate percutaneous coronary intervention and stent.

Primary therapies in acute myocardial infarction (thrombolysis and angioplasty) have inherent limitations which may be overcome by combining them. So far, no trial has demonstrated a clinical benefit in combining mechanical and pharmacological treatment strategies. From January 1995 to December 1999, out of 1010 patients admitted to our institution for acute myocardial infarction, 148 had received pre-hospital full dose thrombolysis within 12 h of onset. One hundred and thirty-one patients were included and underwent immediate angioplasty and stenting when suitable, independent of the infarct-artery patency (TIMI grade flow 0-3). In-hospital outcome was assessed and clinical information was collected for a mean (+/-SD) of 2+/-1 years. Ninety-minute angiography revealed a patent (TIMI grade 3) infarct artery in 65 patients (49%). Immediate angioplasty was performed in 119 patients (91%) with stent implantation in 114 (96%). Angioplasty achieved TIMI 2, 3 flow in 98%, and complete patency (TIMI 3 flow) in 92%. Six other patients underwent deferred revascularization (surgery in one patient, angioplasty in five) and six received medical treatment. Stent thrombosis and reinfarction occurred in three patients (2.3%). In-hospital death occurred in six patients (4.6%), including four patients presenting with cardiogenic shock. Major bleeding was observed in 2.3% of cases. No patient had emergency surgery. Freedom from death and reinfarction at 2 years was 90% and freedom from death, reinfarction and target vessel revascularization was 83%. A strategy of combined reperfusion using full dose pre-hospital thrombolysis and immediate angioplasty with stent implantation in a non-selected acute myocardial infarction population is safe and achieves high and early patency rates. This preliminary experience suggests that a combined strategy in acute myocardial infarction may have a significant impact on both early and long-term outcomes.

Combination Reperfusion Therapy with Eptifibatide and Tenecteplase for Acute Myocardial Infarction

Combination reperfusion therapy with partial-dose fibrinolytics and glycoprotein (GP) IIb/IIIa inhibitors for patients with acute myocardial infarction has been shown to accelerate and improve reperfusion compared with fibrinolytic monotherapy. Tenecteplase is a single-bolus fibrinolytic agent that has been shown to have equivalent efficacy to alteplase (the current ‘gold-standard’ fibrinolytic agent), and thus has the potential to simplify fibrinolytic dosing. Eptifibatide is a synthetic GP IIb/IIIa inhibitor that has been evaluated as an adjunct to fibrinolytic therapy. The combination of various doses of tenecteplase with eptifibatide will be evaluated in the dose-finding phase of the Integrilin and Tenecteplase for Acute Myocardial Infarction (INTEGRITI) trial to determine the optimal dose to use in the dose confirmation phase. Tenecteplase monotherapy will be compared with optimal-dose tenecteplase plus eptifibatide in the dose confirmation phase of the trial. The primary end point of both phases of the trial will be Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow in the infarct-related artery at 60 min. INTEGRITI will also evaluate other useful indicators of reperfusion efficacy, including the corrected TIMI frame count, the TIMI myocardial perfusion grade, ST segment resolution assessed with serial static electrocardiograms and continuous ST segment monitoring, and plasma/serum markers. Thus, the INTEGRITI trial will extensively evaluate the relative benefits of combination reperfusion therapy for the treatment of acute myocardial infarction, and will aid in the planning of a subsequent large-scale phase III trial.

Early Time Course of Heart Rate Variability after Thrombolytic and Delayed Interventional Therapy for Acute Myocardial Infarction

In 89 of 97 consecutive patients with myocardial infarction (MI) undergoing thrombolysis and delayed early coronary angiography with PTCA, if indicated, heart rate variability (HRV) in time domain was evaluable 40 ± 11 h after the onset of chest pain using 24-hour ECG recordings. Patients with anterior MI (n = 40) had lower values for HRV and left ventricular ejection fraction (p < 0.05). The mean of all 5-min standard deviations of RR intervals (SDNNi) and the root-mean-square difference of successive RR intervals (rMSSD) decreased significantly (p < 0.001 each), whereas the standard deviation of all normal RR intervals and the percentage of absolute differences between successive RR intervals only showed a tendency to lower values 4 weeks after MI (p = 0.20 and 0.08, respectively). The decreases in SDNNi and rMSSD were more evident in inferior than in anterior MI. The time course of HRV following MI was similar in patients with and without PTCA. These results indicate an initial vagal hyperactivity in inferior MI, which is quickly predominated by sympathetic activation and a prolonged recovery of the cardiac autonomic imbalance after MI despite a successful combined reperfusion therapy.

ST-segment resolution as a marker of epicardial and myocardial reperfusion after thrombolysis: Insights from the TIMI 14 and in TIME-II trials

Patients with persistent ST segment elevation after fibrinolysis are at high risk for death and congestive heart failure, even if normal epicardial flow has been restored. In the TIMI 14 trial, combination therapy with abciximab plus reduced-dose alteplase enhanced the speed and efficacy of epicardial reperfusion. We also found that combination therapy provided an additional benefit in terms of myocardial reperfusion, as evidenced by greater ST resolution on serial 12-lead electrocardiograms. Specifically, the proportion of patients with complete (≥70%) ST resolution was higher among patients receiving combination therapy than in those treated with alteplase alone (59% vs 37%; p<0.0001). Even among patients with normal (TIMI grade 3) epicardial blood flow, combination therapy was associated with a significantly greater likelihood of complete ST resolution than was fibrinolysis alone (69% vs 44%; p=0.0002). In conclusion, combination reperfusion therapy improved myocardial (microvascular) reperfusion, independent of epicardial flow, suggesting an additional mechanism by which abciximab may improve outcomes in patients with acute MI.