Tissue Plasminogen Activator Group Research Articles

Preoperative co-application of bevacizumab and tissue plasminogen activator in vitrectomy for proliferative diabetic retinopathy.

To investigate the clinical benefits of the co-application of bevacizumab and tissue plasminogen activator as adjuncts in the surgical treatment of proliferative diabetic retinopathy. Patients who underwent vitrectomy for proliferative dia-betic retinopathy complications were preoperatively given in-travitreal injection with either bevacizumab and tissue plasminogen activator (Group 1) or bevacizumab alone (Group 2). Primary outcomes were surgery time and number of intraoperative iatrogenic retinal breaks. Secondary outcomes included changes in the best-corrected visual acuity and postoperative complications at 3 months postoperatively. The mean surgery time in Group 1 (52.95 ± 5.90 min) was significantly shorter than that in Group 2 (79.61 ± 12.63 min) (p<0.001). The mean number of iatrogenic retinal breaks was 0.50 ± 0.59 (0-2) in Group 1 and 2.00 ± 0.83 (0-3) in Group 2 (p<0.001). The best-corrected visual acuity significantly improved in both groups (p<0.001). One eye in each group developed retinal detachment. Preoperative co-application of bevacizumab and tissue plasminogen activator as adjuncts in the surgical treatment of proliferative diabetic retinopathy shortens the surgery time and reduces the number of intraoperative iatrogenic retinal breaks.

Abstract Number ‐ 170: Trends for Endovascular Mechanical Thrombectomy versus Intravenous Tissue Plasminogen Activator for Vertebrobasilar Stroke Treatment

Introduction Acute vertebrobasilar artery occlusion (VBAO) represents approximately 20% of patients presenting with acute ischemic stroke. The occlusion is caused by an embolus or underlying atherosclerotic disease plaque rupture forming an acute thrombus. Without treatment, VBAO’s mortality nears 80–90%, thus, effective and timely treatment strategies become paramount in managing the patients. Herein, we analyzed the age difference and outcomes in patients that underwent either Endovascular Mechanical Thrombectomy (MT) or intravenous (IV) tissue plasminogen activator (tPA). Methods National Inpatient Sample (NIS) was queried from years 2016 to 2018 using ICD‐10 diagnosis and procedure codes for occlusion or thrombosis of vertebral artery or basilar artery (I63.21, I63.22, I63.01, and I63.02), IV tPA (3E03317), and MT (03CG3ZZ, 03CG3Z6, 03CG3Z7, 03CG4Z6, 03CG4ZZ). Chi‐square test and was used for statistical analysis. Results From 2016 to 2018, there were 37,310 patients admitted with vertebrobasilar stroke. Out of these, IV tPA was administered in 2,530 (6.8%) admissions, whereas MT was done in 2,330 (6.2%) admissions. IV tPA was used significantly more than MT in age groups 65–84 and &gt; = 85 years. MT was used significantly more than IV tPA in age groups 18–44 and 45–64 (Figure 1). There was no significant difference in their use between men and women. In large hospitals, MT was more common than IV tPA (8.1% vs 7%, p &lt; 0.0001), and in small hospitals, IV tPA usage was significantly higher (3.8% vs 2%, p &lt; 0.0001). All‐cause mortality rate was significantly higher in MT than IV tPA admissions (16.8% vs 8.1%, p &lt; 0.0001). There was no significant difference in mean length of stay (LOS) between the two modalities (Figure 1). Conclusions We saw a trend of higher rate of mechcnical thrombectomy in younger age group (18‐64 years) than older, however, no sex difference was noted. All‐cause mortality rate was higher in the mechanical thrombectomy group than intravenous tissue plasminogen activator group. In addition, there was no difference in length of hospital stay.

Bilateral lysis of aortic saddle thrombus with early tissue plasminogen activator (BLASTT): a prospective, randomized, placebo-controlled study in feline acute aortic thromboembolism.

The aim of this study was to investigate the impact of tissue plasminogen activator (TPA) on the treatment of feline aortic thromboembolism (FATE). Cats diagnosed with FATE involving ⩾2 limbs were enrolled in a prospective, multicenter, double-blinded, randomized, placebo-controlled study within 6 h of an event. Diagnosis was made by clinical findings and one confirmatory criterion. Cats received placebo or TPA (1 mg/kg/h with the first 10% by bolus). All cats received pain control and thromboprophylaxis. The primary outcome was a change from baseline in a published limb score at 48 h. Secondary outcomes included 48 h survival, survival to discharge and complication proportions. Statistical analyses included pattern-mixture models, logistic regression and Fisher's exact, Student's t- and Mann-Whitney-Wilcoxon tests. Based on a power analysis, 40 cats were enrolled; however, only 20 survived to 48 h (TPA, n = 12; placebo, n = 8 [P = 0.34]). There was a statistically significant improvement in limb scores compared with baseline for both groups (P <0.001). Limb score at 48 h was 1 point lower (better) in the TPA group (P = 0.19). Thrombolysis had no statistically significant effect on 48 h survival (P = 0.22). Lower affected limb lactate was associated with better 48 h survival (odds ratio 1.53, 95% confidence interval 1.08-2.17; P = 0.02). The survival to discharge rates were 45% (TPA) and 30% (placebo; P = 0.51). Complications in the TPA and placebo groups included acute kidney injury (22% and 19%, respectively; P = 1.00) and/or reperfusion injuries (33% and 19%, respectively; P = 0.45). Survival and complication rates of acute FATE were not different with or without thrombolysis. High in-hospital mortality decreased the statistical power to detect a statistically significant difference between treatments with regard to our primary outcome.

Treatment of submacular hemorrhage with tissue plasminogen activator and pneumatic displacement in age-related macular degeneration.

To evaluate visual and anatomic outcomes following pars plana vitrectomy and intravitreal or subretinal tissue plasminogen activator for submacular hemorrhage in patients with age-related macular degeneration. This was a retrospective study on patients with a minimum follow-up of 12 months undertaken at a tertiary referral center. Data collected include demographic details, visual and optical coherence tomography changes, surgical details, and complications. Surgical results were compared with patients who were age and lesion size matched and treated with anti-vascular endothelial growth factor injections alone. There were 36 patients in surgical and 18 patients in control group. Patients in surgical arm had pars plana vitrectomy, intravitreal tissue plasminogen activator with air 24 (67%), 6 (16%) with C3F8 gas, 1 (3%) with SF6 gas, 4 (11%) subretinal tissue plasminogen activator with air, and 1 (3%) with C2F6 as post-operative tamponade. Mean LogMAR in tissue plasminogen activator group at baseline was 1.56, and it was improved at all time points 1.06 at 1 month (p < 0.05), 0.91 at 6 months (p < 0.05), and 1.07 at 1 year (p < 0.05). Mean best corrected visual acuity in control group at baseline was 1.22LogMAR with no significant improvement at any time points: 1 month (1.27), 6 months (1.35), and 12 months (1.36). Complications included retinal detachment 5%, vitreous hemorrhage 7.5%, and cataract 19%. Pars plana vitrectomy with intravitreal (or subretinal) tissue plasminogen activator and pneumatic displacement can offer better outcome in comparison to anti-vascular endothelial growth factor alone in patients with submacular hemorrhage secondary to age-related macular degeneration.

Gender and thrombolysis therapy in stroke patients with incidence of dyslipidemia

BackgroundWhen untreated, dyslipidemia is a higher risk factor for stroke and stroke-related mortality in men than in women. However, when dyslipidemia is treated the risk reduction is the same, but men benefited from mortality reduction more than women. Whether there is a gender difference in exclusion criteria for the use of recombinant tissue plasminogen activator (rtPA) or thrombolysis therapy in an acute ischemic stroke subpopulation with dyslipidemia is yet to be investigated.MethodIn a dyslipidemic stroke population obtained from a stroke registry, gender differences in exclusion risk factors were determined using clinical and demographic variables. Univariate analysis compared the recombinant tissue plasminogen activator (rtPA) group and the no rtPA group. Multiple regression analysis was used to determine demographic and clinical factors associated with inclusion and exclusion for rtPA in the total dyslipidemic stroke population and the subsets of the male and female population. The regression model was tested using the Hosmer-Lemeshow test, for the overall correct classification percentage. Significant interactions and multicollinearity between independent variables were examined using variance inflation factors.ResultsA total of 769 patients presented with acute ischemic stroke with incidence dyslipidemia; 325 received rtPA while 444 were excluded from rtPA. Of those excluded from rtPA, 54.30% were female and 45.72% were male. In an adjusted analysis, female patients with increased age (OR = 1.024, 95% CI, 1.001–1.047, P < 0.05), with a history of carotid artery stenosis (OR = 7.063, 95% CI, 1.506–33.134, P < 0.05), and previous stroke (OR = 1.978, 95% CI, 1.136–3.442, P < 0.05) were more likely to be excluded from rtPA. Male patients with atrial fibrillation (OR = 2.053, 95% CI, 1.059–3.978, P = 0.033), carotid artery stenosis (OR = 2.400, 95% CI, 1.062–5.424, P = 0.035), and previous stroke (OR = 1.785, 95% CI, 1.063–2.998, P = 0.028) were more likely to be excluded from rtPA.ConclusionAlthough there are some similarities in the clinical risk factors for exclusion in both male and female stroke patients with incidence of dyslipidemia, there are differences as well. Elderly female stroke patients with incidence of dyslipidemia are more likely to be excluded from rtPA, even after adjustment for the effect of confounding variables. Further research should focus on how identified clinical risk factors can be targeted and managed to improve the use of rtPA in elderly female acute ischemic stroke population with incidence of dyslipidemia.

Clinical Risk Factors in Thrombolysis therapy: Telestroke Versus Nontelestroke

The objective of this study is to determine clinical risk factors associated with exclusion from thrombolysis in telestroke and nontelestroke settings. These risk factors may offer clues for optimization of thrombolysis therapy in acute ischemic stroke population. Retrospective data of patients with acute ischemic stroke via telestroke and nontelestroke assessment were analyzed. Univariate analysis was used to compare the recombinant tissue plasminogen activator (rtPA) group and the no rtPA group. A stepwise binary logistic regression identified factors associated with inclusion and exclusion from rtPA in the total telestroke population and the subsets of the telestroke population. Telestroke patients were more likely to be directly admitted rather than being initially evaluated in the emergency department (70.3% versus 9.9%) and were also substantially more likely to receive rtPA (89.5% versus 38.5%). In the nontelestroke group, patients with acute ischemic stroke were more likely to be excluded from rtPA if they possessed higher international normalized ratios (odds ratio [OR] = 4.978 [1.503-16.488]) or had a history of congestive heart failure (OR = 2.524 [1.213-5.252]), previous stroke (OR = 2.172 [1.286-3.667]), or renal dysfunction (OR = 4.204 [1.33-13.281]). The telestroke group only had 1 variable deemed statistically significant in its association with rtPA status. Patients who were directly admitted were less likely to be excluded from receipt of rtPA (OR = .322 [.112-0.927]). Factors associated with exclusion from rtPA in the nontelestroke setting did not exclude patients with acute ischemic stroke from thrombolysis therapy in the telestroke setting. Telestroke may offer methods for optimization of the risk-benefit ratio of rtPA, equipping clinicians to efficiently make treatment decisions.

Thrombolysis with tissue plasminogen activator (TPA) in feline acute aortic thromboembolism: a retrospective study of 16 cases

Thrombolytic therapy is a treatment of choice for people with acute ischemic events, but is uncommonly administered for feline aortic thromboembolism (FATE). This study reports selected clinical data and outcomes of acute FATE treated with tissue plasminogen activator (TPA). A reference group treated with current standard of care (SOC) was analyzed for comparison. This was a retrospective study of FATE in two academic hospitals. TPA-treated cats with two or more limbs (n = 16) affected were compared with a SOC-treated group with two or more limbs affected (n = 38). A limb score based on motor function and pulse quality was calculated for each group. Limb score and proportion of congestive heart failure at admission was similar in both groups. Time from FATE to admission was shorter in the TPA group, with a median of 3 h (range 0-6 h) vs 6 h (range 0-48 h; P = 0.0004). The most common regimen received for TPA was 1 mg/kg over 1 h. Other treatments were similar to those of the SOC group and included analgesia, thromboprophylaxis and furosemide. Documented complications for TPA-treated cats included reperfusion injury (5/10) and acute kidney injury (AKI; 3/10). Discharge proportion rate was 44% (TPA) vs 29% (SOC; P = 0.351). There were no differences in short-term survival rate (56.2% vs 39.5%; P = 0.369), clinical improvement (56.2% vs 31%; P = 0.122), rates of reperfusion injury (50% vs 50%; P = 1.00) or AKI (30% vs 27%; P = 1.00) between the TPA-treated and SOC groups, respectively. Survival and complication rates of TPA-treated cats and SOC-treated cats for acute FATE were similar.

Ischemia-Reperfusion Injury of Sciatic Nerve in Rats: Protective Role of Combination of Vitamin C with E and Tissue Plasminogen Activator.

An ischemia/reperfusion injury of rat's sciatic nerve was experimentally developed. In this model, we measured the in vivo production of superoxide radical, as a marker of oxidative stress and the occludin expression as an indicator of blood-nerve barrier function and we examined potential protective innervations against these abnormalities. Right sciatic nerves of the animals underwent 3h of ischemia followed by 7days of reperfusion and were divided into three groups: ischemic, pretreated with vitamin C in conjunction with vitamin E and treated with tissue plasminogen activator. Compared to measurements from left sciatic nerves used as sham, the ischemic group showed significantly increased superoxide radical and reduced expression of occludin in western blot and immunohistochemistry. No such differences were detected between sham and nerves in the vitamin or tissue plasminogen activator groups. It is suggested that the experimental ischemia/reperfusion model was suitable for studying the relationship between oxidative state and blood-nerve barrier. The reversion of abnormalities by the applied neuroprotective agents might prove to be a clinically important finding in view of the implication of vascular supply derangement in various neuropathies in humans.

Thrombolytics in VAD management — A single-center experience

BackgroundWith continued increase in the use of mechanical circulatory support, the incidence of device thrombus remains a challenge. This study is a retrospective analysis of data at a single center to assess the safety and efficacy of thrombolytic use in durable mechanical assist devices. MethodsData was analyzed retrospectively from 154 patients who underwent left ventricular assist device (LVAD) implantation from 1/1/2005 to 6/30/2014. The HMII device was implanted in 131 patients while 23 received the HVAD. LVAD thrombus was diagnosed when lactate dehydrogenase levels exceeded 1000units/l accompanied by clinical signs of hemolysis and heart failure, echocardiographic data and surges in pump power. TPA (tissue plasminogen activator) protocol consisted of a 5mg intravenous bolus followed by 3mg/h infusion in normal saline for 10h. If symptoms persisted another cycle of TPA at 1mg/h was continued up to 48h. ResultsThe TPA group had a 70% success rate. Success was defined as complete resolution of hemolysis and clinical symptoms with no requirement for LVAD exchange at 30days. 95% survival was noted at 30days and 90% were free of a hemorrhagic stroke in the TPA group. The rates of hemorrhagic strokes in the TPA group and the control group were not different (OR=0.92). ConclusionThe TPA protocol described here was successful consistently. Though this study is limited by its size and retrospective nature it leads the way for larger studies to generate more robust comparisons between different types of mechanical assist devices as well as the tailored use of thrombolytics in this patient population.

Prediction of hemorrhagic transformation after experimental ischemic stroke using MRI-based algorithms

Estimation of hemorrhagic transformation (HT) risk is crucial for treatment decision–making after acute ischemic stroke. We aimed to determine the accuracy of multiparametric MRI-based predictive algorithms in calculating probability of HT after stroke. Spontaneously, hypertensive rats were subjected to embolic stroke and, after 3 h treated with tissue plasminogen activator (Group I: n = 6) or vehicle (Group II: n = 7). Brain MRI measurements of T2, T2*, diffusion, perfusion, and blood–brain barrier permeability were obtained at 2, 24, and 168 h post-stroke. Generalized linear model and random forest (RF) predictive algorithms were developed to calculate the probability of HT and infarction from acute MRI data. Validation against seven-day outcome on MRI and histology revealed that highest accuracy of hemorrhage prediction was achieved with a RF-based model that included spatial brain features (Group I: area under the receiver-operating characteristic curve (AUC) = 0.85 ± 0.14; Group II: AUC = 0.89 ± 0.09), with significant improvement over perfusion- or permeability-based thresholding methods. However, overlap between predicted and actual tissue outcome was significantly lower for hemorrhage prediction models (maximum Dice’s Similarity Index (DSI) = 0.20 ± 0.06) than for infarct prediction models (maximum DSI = 0.81 ± 0.06). Multiparametric MRI-based predictive algorithms enable early identification of post-ischemic tissue at risk of HT and may contribute to improved treatment decision-making after acute ischemic stroke.

Intravenous Tissue Plasminogen Activator Improves the Outcome in Very Elderly Korean Patients with Acute Ischemic Stroke.

Background and PurposeIn a recent pooled analysis of randomized clinical trials (RCTs), intravenous tissue plasminogen activator (TPA) improves the outcome in patients aged ≥80 years. However, it is uncertain whether the findings are applicable to clinical practice in Asian populations.MethodsFrom a multicenter stroke registry database of Korea, we identified patients with acute ischemic stroke who were aged ≥ 80 years. Using multivariable analysis and propensity score (PS)-matched analyses, we assessed the effectiveness and safety of intravenous TPA within 4.5 hours.ResultsAmong 2,334 patients who met the eligible criteria, 236 were treated with intravenous TPA (mean age, 83±5; median NIHSS, 13 [IQR, 8-17]). At discharge, the TPA group compared to the no-TPA group had a favorable shift on the modified Rankin Scale (mRS) score (multivariable analysis, OR [95% CI], 1.51 [1.17-1.96], P=0.002; PS-matched analysis, 1.54 [1.17-2.04], P=0.002) and was more likely to achieve mRS 0-1 outcome (multivariable analysis, 2.00 [1.32-3.03], P=0.001; PS-matched analysis, 1.59 [1.04-2.42], P=0.032). TPA treatment was associated with an increased risk of symptomatic intracranial hemorrhage (multivariable analysis, 5.45 [2.80-10.59], P<0.001; PS-matched analysis, 4.52 [2.24-9.13], P<0.001), but did not increase the in-hospital mortality (multivariable analysis, 0.86 [0.50-1.48], P=0.58; PS-matched analysis, 0.88 [0.52-1.47], P=0.61).ConclusionsIn the setting of clinical practice, intravenous TPA within 4.5 hours improved the functional outcome despite an increased risk of symptomatic intracranial hemorrhage in very elderly Korean patients. The findings, consistent with those from pooled analysis of RCTs, strongly support the use of TPA for this population.

Pro-urokinase promotes angiogenesis but does not reduce neuronal apoptosis in infarcted cerebral tissue.

Ischemic stroke is most commonly caused by vascular occlusion due to thrombosis or arterial embolism. Recently, thrombolysis has been used with increasing frequency for the treatment of acute ischemic stroke. Among the drugs used for thrombolysis, only recombinant tissue plasminogen activator is widely accepted internationally (Albers et al., 2008). In China, urokinase has been widely used for thrombolysis after acute ischemic stroke. Pro-urokinase is the precursor of urokinase. Compared with urokinase, pro-urokinase has greater ability to dissolve thrombus and is safer to use. A previous study found that the recanalization rate was significantly higher after arterial thrombolysis with pro-urokinase than with recombinant tissue plasminogen activator (Fischer et al., 2005). This study compared the thrombolytic effects of pro-urokinase, recombinant tissue plasminogen activator, and urokinase in a dog model of acute cerebral embolism. For each dog used, 10 mL of arterial blood was taken and placed at room temperature for 3 hours to allow natural consolidation. Blood clots were then pressed into a 2-mm diameter cylinder and cut into 2–3 mm lengths. After general anesthesia, dogs were fixed on an operating table and the trachea was intubated. A 5F sheathing canal was placed in the right femoral artery using a modified Seldinger method (Marx et al., 1996). The sheathing canal was advanced into the internal carotid artery guided by digital subtraction angiography. Vascular traveling to the anterior and middle cerebral arteries was observed in the anteroposterior view (Figure ​(Figure1A1A–C). A mixture of autologous blood clots and physiological saline was injected into the internal carotid artery using a 5 mL syringe. If no embolization was observed on digital subtraction angiography after the first injection of blood clots, the process was repeated (Takano et al., 1998; Oureshi et al., 2004; Harris et al., 2007). When anterior or middle cerebral artery embolization was confirmed, the sheathing canal was withdrawn. Digital subtraction angiography was repeated every 30 minutes for 3 hours to confirm embolization (Figure ​(Figure1D1D–F). Figure 1 Digital subtraction angiography images before and after treatment of acute cerebral embolism in dogs using pro-urokinase, recombinant tissue plasminogen activator, or urokinase. Stroke was successfully induced in 24 dogs. These 24 dogs were randomly divided into four groups: (1) Pro-urokinase group: 1.2 × 105 U/kg pro-urokinase was administered via the femoral vein. One-third of the pro-urokinase was dissolved in physiological saline and administered over 3 minutes, and the remainder was dissolved in 100 mL of physiological saline and administered over 30 minutes. (2) Recombinant tissue plasminogen activator group: 1.37 mg/kg of recombinant tissue plasminogen activator was administered via the femoral vein. One-tenth of the recombinant tissue plasminogen activator was administered over 1 minute, and the remainder was administered over 60 minutes. (3) Urokinase group: 2.15 × 106 U/kg urokinase was dissolved in 100 mL of physiological saline and administered by intravenous infusion over 30 minutes. (4) Model group: 100 mL of physiological saline was administered by intravenous infusion over 30 minutes. Digital subtraction angiography was performed every 30 minutes for 3 hours after thrombolysis. Based on assessment of the Thrombolysis In Myocardial Infarction flow grade, the recanalization rate was higher in the urokinase group than in the model group (Table 1, Figure ​Figure1G1G–U). Hematoxylin and eosin staining showed no hematoma in the infarcted area at 3 hours after thrombolysis in any of the groups, but nerve cells in the infarcted tissues showed degeneration, coagulative necrosis, vacuole-like structures, indistinct cell borders, and pyknotic or absent nuclei. In addition, the nerve cells and glial cells were obviously reduced in number or even absent. Infiltration of neutrophilic leukocytes and microglial proliferation or phagocytosis were observed in some regions. There were no obvious differences in cell apoptosis among the groups (Figure ​(Figure2A2A–E). Hemorrhage was observed in the infarcted area in one dog from each of the pro-urokinase and urokinase groups (Figure ​(Figure2F2F–H). Table 1 Effectiveness of pro-urokinase, recombinant tissue plasminogen activator, and urokinase for the treatment of acute cerebral embolism Figure 2 Histological findings in the area of cerebral infarction at 3 hours after thrombolysis (hematoxylin and eosin staining). Previous studies reported that patients who underwent thrombolysis over 3 hours had a high incidence of hemorrhage (Camerlingo et al., 2005). Obvious hematoma was not observed in this dog model of stroke because dogs have abundant collateral cerebrovascular circulation, resulting in a limited area of infarction, and thrombolysis was performed early. The results of this study show that recanalization after thromboembolism was similar after thrombolysis with pro-urokinase and recombinant tissue plasminogen activator, and that both these drugs were more effective than urokinase (both P < 0.05). However, pro-urokinase and recombinant tissue plasminogen activator did not have any definite protective effects against neuronal injury.

Reperfusion after 4·5 Hours Reduces Infarct Growth and Improves Clinical Outcomes

The currently proven time window for thrombolysis in ischemic stroke is 4.5 h. Beyond this, the risks and benefits of thrombolysis are uncertain. To determine whether thrombolysis and reperfusion were beneficial after 4.5 h, we examined clinical and radiological outcomes in patients treated with tissue plasminogen activator or placebo within 4.5-6 h, using data from the Echoplanar Imaging Thrombolytic Evaluation Trial. In the Echoplanar Imaging Thrombolytic Evaluation Trial, ischemic stroke patients presenting three to six-hours after stroke onset were randomized to tissue plasminogen activator or placebo, without knowledge of magnetic resonance imaging results. This analysis was restricted to patients treated between 4.5 and 6 h. The effect of tissue plasminogen activator and reperfusion on infarct growth between baseline diffusion-weighted imaging and day 90 T2 imaging was assessed, along with good neurological outcome (≥8 point reduction or reaching 0-1 at 90 days on National Institutes of Health Stroke Scale) and functional outcome (modified Rankin scale). The effect of tissue plasminogen activator on reperfusion was also analyzed. Sixty-nine patients were treated 4.5-6 h after onset, and infarct growth was assessed in 63. Tissue plasminogen activator was associated with lower relative growth (94% vs. 168%, P = 0.03) and a trend to lower absolute growth (-0.17 ml versus 9.6 ml, P = 0.07). Reperfusion was increased in the tissue plasminogen activator group (58% versus 25%, P = 0.03) and was associated with increased rates of good neurological (86% versus 28% P < 0.001) and functional (modified Rankin scale 0-2 73% versus 34%, P = 0.01) outcomes. Reperfusion was strongly associated with lower relative (80% versus 189%, P < 0.001) and absolute (-2.5 ml versus 40 ml, P < 0.001) infarct growth. Thrombolysis 4.5-6 h after stroke onset reduced infarct growth and increased the rate of reperfusion, which was associated with good neurological and functional outcome.

THREE TREATMENTS FOR MACULAR EDEMA BECAUSE OF BRANCH RETINAL VEIN OCCLUSION

To evaluate the effectiveness of intravitreous bevacizumab (Avastin), intravitreous tissue plasminogen activator, and vitrectomy for the macular edema secondary to branch retinal vein occlusion. Retrospective, interventional case series. We studied 228 eyes of 228 patients. Forty-one eyes received 1.25 mg of intravitreous bevacizumab, 71 eyes received tissue plasminogen activator, and 116 eyes underwent vitrectomy. A reinjection of 1.25 mg of bevacizumab was based on the morphologic and functional findings. The main outcome measures were the best-corrected visual acuity and optical coherence tomography-determined foveal thickness. The mean postoperative follow-up period was 32.2 months with a range of 12 months to 69 months. The mean number of intravitreous bevacizumab was 2.8 with a range of 1 to 5. The mean best-corrected visual acuity and foveal thickness significantly improved after all 3 treatments, and the differences in the best-corrected visual acuity between the 3 groups were not significant at 12 months. Fourteen eyes (34%) in the intravitreous bevacizumab group and 21 eyes (30%) in the tissue plasminogen activator group required additional surgeries. The 3 treatments appear to provide similar visual outcomes at 12 months. However, in some eyes treated with intravitreous bevacizumab or tissue plasminogen activator, additional surgeries were required, and a longer follow-up period was required to determine the final outcome.

Assessment of Combined Muscarinic Antagonist and Fibrinolytic Therapy for Inhalation Injury

This study tests the hypothesis that muscarinic receptor antagonist therapy with tiotropium bromide (tiotropium; TIO), alone or in combination with tissue plasminogen activator (TPA), can attenuate pulmonary dysfunction in sheep after smoke inhalation and burn injury. The study consisted of four study groups, sham (uninjured), control (injured and untreated), TIO (injured and treated with nebulized TIO), and TIO + TPA (injured and treated with nebulized TIO and TPA). Cardiopulmonary and ventilatory parameters were monitored for 48 hours. After killing the animal, airway obstruction, submucosal gland neutrophilia, parenchyma histopathology, and lung wet to dry weight ratios were measured. PaO2/FiO2 was significantly improved in the TIO group compared with the control group at 48 hours, 301 ± 149 vs 99 ± 33, respectively, P < .05. At 48 hours, peak airway pressures in the control, TIO, and TIO + TPA groups were 35 ± 6, 24 ± 7, and 26 ± 10, respectively, with the mean of the TIO group being significantly different from that of the control group, P < .05. A trend of decreased airway obstruction was seen in the treated animals compared with controls; however, the differences were not statistically significant. The TIO and TIO + TPA groups exhibited significant decreases in gland neutrophilia compared with the control group, P < .05. No differences in parenchyma histopathology and lung edema between injured control and treated groups were observed. Nebulization of TIO was effective in improving pulmonary performance and reducing bronchial submucosal gland neutrophilia in sheep after smoke inhalation and burn injury. There was no additive benefit to the inclusion of nebulized TPA with TIO.

INTRAVITREAL TISSUE PLASMINOGEN ACTIVATOR TO TREAT REFRACTORY DIABETIC MACULAR EDEMA BY INDUCTION OF POSTERIOR VITREOUS DETACHMENT

To evaluate the effects of intravitreal injection of recombinant tissue plasminogen activator (TPA) for the treatment of refractory diabetic macular edema. A total of 27 patients with refractory diabetic macular edema with no evidence of posterior vitreous detachment were randomly assigned into follow-up (F/U) or TPA treatment groups. To control for the effects of intravitreal injection, an additional 14 patients with diabetic macular edema who were candidates for first-time intravitreal bevacizumab injection were enrolled as the IVB group. For the TPA and IVB groups, 25 μg of TPA or 1.25 mg of bevacizumab, respectively, were intravitreally injected. Fundoscopy, optical coherence tomography, and B-scan ultrasonography were performed at 1 week, 1 month, and 3 months after initiation of the study. The incidence of posterior vitreous detachment in fundoscopy over the follow-up period was 69.2% in the TPA group, which was significantly higher than that of the F/U and IVB groups (P = 0.001). Best-corrected visual acuity and changes in macular thickness did not significantly differ between the TPA and F/U groups over the 3-month period. Intravitreal TPA injection induces posterior vitreous detachment in patients with diabetic macular edema refractory to standard treatment but has no effect on macular thickness or best-corrected visual acuity within 3 months.

Comparison of Thrombolysis Versus Surgery as a First Line Therapy for Prosthetic Heart Valve Thrombosis

Prosthetic valve thrombosis (PVT) is one of the most serious long-term complications after heart valve replacement, and optimal treatment remains unclear. The investigators report clinical characteristics and outcome of all consecutive patients with PVT treated with urgent surgery or thrombolysis with recombinant tissue plasminogen activator at a single center from January 1988 to December 2008. Thirty-one patients (mean age 59 years, range 20 to 75, 19% men) were diagnosed with PVT a median of 11 years after valve replacement (range 4 months to 32 years). Affected valve positions were mitral in 17 (55%), aortic in 8 (26%), and tricuspid in 6 (19%), and all but 1 were mechanical valves. Eighteen patients underwent urgent surgery, with 2 deaths in the immediate perioperative phase and 2 recurrences (11%) of PVT over a median follow-up period of 76 months. Of 13 patients treated with thrombolysis, there was immediate clinical improvement after a single administration of recombinant tissue plasminogen activator in 12 (92%), of whom 8 (61%) showed complete response with normalization of echocardiographic findings. The only nonresponder was subsequently referred for urgent surgery. Over a median follow-up period of 18 months, recurrence of PVT was seen in 4 patients (31%), with 1 fatal event in a patient refusing further anticoagulation treatment 1 week after successful thrombolysis. Other complications in the recombinant tissue plasminogen activator group included 1 stroke, 1 transient ischemic attack, 1 hemorrhagic complication requiring surgery, and 2 peripheral embolic events with spontaneous resolution. In conclusion, thrombolysis is an attractive first-line therapy for patients with PVT, with clinical outcomes comparing favorably with the standard surgical approach.

A Comparison of Three Fibrinolytic Agents in Prevention of Intra-Abdominal Adhesions

Purpose: Three different drugs affecting the coagulation process at various stages were studied for their effectiveness in preventing intra-peritoneal adhesion formation in rats.Material and Methods: Forty female Wistar-Albino rats divided into four groups based on the drugs administered during the experimental laparotomy and caecal abrasion: the control group-no drug administered, the intra-peritoneal tissue plasminogen activator (TPA) group, the subcutaneous fondaparinux sodium (FS) group and the intra-peritoneal activated drotrecogin alfa (ADA) group. After two weeks, intra-peritoneal adhesions were macroscopically and microscopically scored.Results: The macroscopic scores of the three groups were similar but all lower than the control group (p = 0.002). Inflammation (p = 0.023) and fibrosis (p = 0.019) scores were lower in just the ADA group when compared to the control group.Conclusions: All three agents were effective in preventing adhesions when compared to the control group. Nevertheless, ADA seemed the most effective except when considering clinical applicability, in which case FS seemed to offer the greatest advantage.

Expediting MRI-Based Proof-of-Concept Stroke Trials Using an Earlier Imaging End Point

Before Phase III trials of acute stroke therapies, proof-of-concept MRI trials are increasingly used to gauge the likelihood of success. Given that animal models use infarct volume as the end point, Phase II trials have aimed to translate the findings using infarct growth. These trials could be expedited if subacute diffusion-weighted imaging lesion volume replaced late T2-weighted lesion volume as the primary end point. In the Echoplanar Imaging Thrombolytic Evaluation Trial, patients with acute ischemic stroke presenting within 3 to 6 hours were randomized to tissue plasminogen activator or placebo. We assessed correlations between acute (Day 1), subacute (Day 3 to 5) as well as late (Day 90) lesion volumes and clinical outcome (National Institutes of Health Stroke Scale). We compared lesion growth between placebo- and tissue plasminogen activator-treated patients. All 3 scans were performed in 72 of 101 patients (32 tissue plasminogen activator, 40 placebo). Median time to subacute imaging was 3 days (interquartile range, 2 to 4) and 90 days (interquartile range, 90 to 95) for the late scan. Increase in lesion volume from acute to subacute scans was smaller in the tissue plasminogen activator group compared with the placebo group (6.77 mL; interquartile range, 2.30 to 49.10; versus 30.00 mL; interquartile range, 7.19 to 85.93; P=0.03). Subsequent shrinkage did not reveal significant treatment effects. Correlation coefficient between acute and late lesion volumes was 0.81 (P<0.01). Subacute and late lesion volumes were strongly correlated (rho=0.94, P<0.01). Correlation coefficient for acute, subacute, and late lesion volume and late National Institutes of Health Stroke Scale score was 0.64 (P<0.01), 0.81 (P<0.01), and 0.77 (P<0.01), respectively. These findings suggest that subacute imaging at Day 3 after thrombolysis is an appropriate imaging end point for proof-of-concept MRI-based stroke treatment trials and can replace later MRI measurements.

Cost-Effectiveness of Thrombolytics: A Simplified Model

To construct a simple model for an internal, retrospective cost-effectiveness analysis and to calculate the incremental cost-effectiveness of tissue plasminogen activator (TPA) over streptokinase (SK) in Turkey. Koşuyolu Heart, Education and Research Hospital, Istanbul, Turkey. Among patients who were hospitalized for treatment of acute myocardial infarction (AMI), 196 were randomly selected. One-year mortality rates according to the treatment groups (TPA, SK, other) were determined. Among surviving patients, 28 from TPA and another 28 from SK group were randomly selected for the pharmacoeconomic analysis. Patient treatment data were taken from medical records while data regarding to costs were taken from hospital bills. Incremental cost-effectiveness ratio (ICER). The cost part of the ratio was considered as 'the overall-costs', while the effectiveness part was considered as 'lives saved' per treatment group. With an increased one-year survival rate of 2.37% and an increased cost of euro 1120.8 ($1165.6) per patient in the TPA group, the ICER for the use of TPA instead of SK was euro 47,289 ($49,180.6) per life saved. This model can be a guide for similar analyses. The results of our study (the incremental cost-effectiveness of TPA over SK) will be informative for the decision-makers in Turkey, by whom the medical benefit for money spent would be assessed and judged. We believe that our results make a contribution to similar studies in the literature.