Dose Of rt-PA Research Articles

Efficacy of Solitaire Stent Arterial Embolectomy in Treating Acute Cardiogenic Cerebral Embolism in 17 Patients.

BackgroundThrombolysis with rtPA is the only accepted drug therapy for acute ischemic stroke. Since acute cerebral stroke is so pervasive, newly developed recanalization methods have the potential for wide-ranging impacts on patient health and safety. We explored the efficacy and safety of Solitaire stent arterial embolectomy in the treatment of acute cardiogenic cerebral embolism.Material/MethodsBetween October 2012 and June 2015, 17 patients underwent Solitaire stent arterial embolectomy, either alone or in combination with rtPA intravenous thrombolysis, to treat acute cardiogenic cerebral embolism. Sheath placement time, vascular recanalization time, number of embolectomy attempts, and IV rtPA dose and time were recorded. Success and safety of the recanalization procedure, as well as clinical outcomes, were assessed. These results were compared to 16 control patients who were treated using only rtPA IV thrombolysis.ResultsFull recanalization of the occluded arteries was achieved in 15 (88.2%) of the Solitaire stent patients. NIH Stroke Scale scores of embolectomy patients improved by an average of 12.59±8.24 points between admission and discharge, compared to 5.56±5.96 in the control group (P<0.05). Glasgow Coma Score improvement between admission and discharge was also significantly higher in the embolectomy group (P<0.05). There was no significant difference in symptomatic intracerebral hemorrhage, high perfusion encephalopathy, incidence of hernia, or mortality between the 2 groups (P>0.05).ConclusionsSolitaire stent embolectomy is a safe and effective alternative to simple venous thrombolytic therapy, and it can significantly improve short-term neurological function and long-term prognosis in acute cardiogenic cerebral embolism.

Abstract TMP5: Secondary Analysis of Eptifibatide Plus Full Dose rt-PA in Ischemic Stroke

Background: The Phase 2 Combined approach to Lysis utilizing Eptifibatide And Rt-PA in Acute Ischemic Stroke - Full Dose Regimen (CLEAR-FDR) trial was a single arm trial that demonstrated the safety of full dose (0.9mg/kg) rt-PA plus eptifibatide in AIS patients treated with rt-PA within three hours of symptom onset. Interventional Management of Stroke (IMS) III randomized AIS patients to rt-PA plus endovascular therapy versus standard r-tPA. Albumin in Acute Stroke (ALIAS) Part 2 randomized patients to albumin±rt-PA versus saline±rt-PA. We compared outcomes in CLEAR-FDR patients to propensity score-matched rt-PA only subjects in ALIAS Part 2 and IMS. Methods: All datasets were restricted to subjects with baseline modified Rankin score (mRS) of 0 or 1. Controls were selected using propensity score matching of CLEAR-FDR subjects and rt-PA only subjects from both IMS III and ALIAS. Age, gender, race, baseline mRS, baseline NIHSS score, and time from stroke onset to rt-PA were included in the logistic model used to generate a propensity score for each subject. The greedy matching algorithm was then used to match 1:3. The primary outcome was 90-day severity-adjusted mRS dichotomization based on baseline NIHSS. Secondary outcomes were 90-day mRS dichotomized as excellent (mRS 0-1); favorable (mRS 0-2); and, nonparametric analysis of the ordinal mRS. Results: Eighteen CLEAR-FDR subjects were matched with 52 controls. Median age in CLEAR-FDR and control subjects was 67 and 68 years respectively. Median NIHSS in both CLEAR-FDR and control subjects was 11. At 90 days, CLEAR-FDR subjects had a nonsignificant greater proportion of patients with a favorable primary outcome (61% versus 38%; unadjusted RR 1.59; 95%CI 0.96-2.63; P=0.10). Secondary outcomes also favored CLEAR-FDR subjects: excellent outcomes - 67% versus 38% (RR 1.73; 95%CI 1.08-2.79; P=0.04); favorable outcomes - 67% versus 58% (RR 1.16; 95%CI 0.77-1.73; P=0.50); and ordinal Cochran-Mantel-Haenszel, P=0.13. Conclusion: The outcomes for combination of full dose rt-PA plus eptifibatide showed a consistent direction of effect in favor of the combination over rt-PA alone. A trial to establish the efficacy of rt-PA plus eptifibatide for improving AIS outcomes is warranted and in the planning stages.

Abstract 182: The CLEAR Trials: A Pooled Analysis of rt-PA plus Eptifibatide for Treatment of Acute Ischemic Stroke

Background: The Combined approach to Lysis utilizing Eptifibatide And Rt-PA in Acute Ischemic Stroke (CLEAR), CLEAR-Enhanced Regimen (CLEAR-ER) and CLEAR-Full Dose Regimen (CLEAR-FDR) trials were phase 2 trials that examined escalating doses of recombinant tissue-type plasminogen activator (rt-PA) combined with eptifibatide in acute ischemic stroke (AIS). We pooled data from these trials and compared outcomes of the escalating doses of rt-PA plus eptifibatide to rt-PA alone. Methods: The combination arms of the CLEAR trial were: tier 1 - 0.3mg/kg of rt-PA and tier 2 - 0.45mg/kg both combined with eptifibatide 75mcg/kg bolus and 0.75mcg/kg/min for 2 hours. CLEAR-ER combined 0.6mg/kg of rt-PA and 135mcg/kg bolus of eptifibatide and 0.75mcg/kg/min for 2 hours. CLEAR-FDR combined full dose rt-PA (0.9mg/kg) and 135mcg/kg bolus of eptifibatide and 0.75mcg/kg/min for 2 hours. The control groups for both CLEAR and CLEAR-ER received full dose rt-PA only. The primary outcome was 90-day modified Rankin score (mRS) of 0-1 or return to baseline. Logistic regression was used for the analysis. Results: A total of 247 subjects were available for analysis; 69 from the combination arm of CLEAR (29 in tier 1 and 40 in tier 2), 101 from the combination arm of CLEAR-ER, and 27 from CLEAR-FDR. Fifty rt-PA only subjects (25 from CLEAR and 25 from CLEAR-ER) served as controls. Characteristics and outcomes adjusted for age, sex, race, NIHSS and time to IV rt-PA are shown in the Table. Conclusion: In the CLEAR trials, eptifibatide added to rt-PA showed a progressive increase in odds of a favorable outcome, without safety concerns. A phase 3 trial of full dose rt-PA plus the eptifibatide dose used in CLEAR-ER and CLEAR-FDR is warranted to establish the efficacy of the combination for improving AIS outcome.

Combined administration of the GPVI-Fc fusion protein Revacept with low-dose thrombolysis in the treatment of stroke.

Thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) remains the only approved medication for acute ischemic stroke, but incurs significant bleeding risks. Therefore, approaches to combine lower doses of thrombolytic therapy with other effective drugs aim at improving efficacy and reducing bleeding rates. We examined the safety and therapeutic effects of various dosings of rtPA, either alone or combined with glycoprotein VI-Fc fusion protein (GPVI-Fc, Revacept) on experimental stroke in mice. The effect of filament-induced intracerebral thrombus formation and embolization was investigated after a one-hour occlusion of the middle cerebral artery. In accordance with previous studies, treatment with 10 mg/kg rtPA significantly improved functional outcome, cerebral infarct size and edema, but also resulted in markedly increased intracranial bleeding volumes. In contrast, low doses of rtPA (0.1 or 0.35 mg/kg body weight) did not change outcome parameters. However, addition of 1 mg/kg Revacept to 0.35 mg/kg rtPA led to improved reperfusion compared to rtPA alone. Moreover, these combined treatments resulted in improved grip strength, compared to the respective dose of rtPA alone. Infarct-surrounding edema improved after combined treatments, but not after respective single rtPA dosings. Intracranial bleeding volumes were below controls after all low-dose rtPA therapies, given either alone or combined with Revacept. In contrast to using the equally effective full dose of rtPA, intracranial bleeding was not increased by low-dose rtPA combined with Revacept. Therefore, addition of Revacept to low-dose rtPA does not incur safety risks, but improves efficacy of treatment.

Feasibility and efficacy of thrombolysis in acute ischemic stroke: A study from National Institute of Neurological and Allied Sciences, Kathmandu, Nepal.

Background:Stroke is the major cause of morbidity and mortality worldwide. The number of stroke patients receiving recombinant tissue plasminogen activator (rt-PA), also known as Alteplase, in the developing world is extremely low. We aim to study the feasibility and efficacy of thrombolysis for the 1st time in our country.Materials and Methods:In this retrospective study (July 2012-August 2015), acute ischemic stroke patients who were thrombolyzed within 3 h of stroke onset were included. Their demographic profiles, clinical profiles, risk factors, type of thrombolytic used, and outcomes were systematically recorded and analyzed.Results:A total of 9 patients were thrombolyzed. The mean time from the onset of stroke symptoms to first dose of rt-PA (onset to treatment) was 1.2 h. Six patients had good neurological outcome as measured by modified Rankin Scale (mRS). The median mRS at discharge was 3. Thrombolysis-related post treatment complication was noted in 44.4%, of which nonfatal intracranial bleed occurred only in 2 patients (22.2%). None of the patients receiving intravenous tenecteplase had thrombolysis-related complications, and none of the patients had fatal intracranial bleed.Conclusion:This study clearly demonstrates the beginning of a feasible and effective thrombolysis in the treatment of acute ischemic stroke in Nepal.

Magnetically controlled release of recombinant tissue plasminogen activator from chitosan nanocomposites for targeted thrombolysis.

Ionic cross-linking of water-soluble chitosan with sodium tripolyphosphate in the presence of recombinant tissue plasminogen activator (rtPA) and magnetite (Fe3O4) nanoparticles could produce rtPA-encapsulated magnetic chitosan nanoparticles (MCNPs-rtPA). MCNPs do not elicit cytotoxicity and hemolysis in vitro. MCNPs-rtPA showed a negligible release of the rtPA protein when stored in phosphate buffer for 28 days. In contrast, the burst release of rtPA from MCNPs-rtPA was found in the serum with 60% of the original activity released in 30 min. The drug release into the serum is also magnet-sensitive; the release could be turned down with a magnetic field when MCNPs-rtPA was pelleted and reversibly turned on after removing the magnetic field when MCNPs-rtPA was dispersed. An in vitro thrombolytic study by thromboelastometry indicated a controlled release of rtPA from MCNPs-rtPA. In a rat embolic model where a preformed blood clot lodged in the left iliac artery upstream of the pudic epigastric branch, MCNPs-rtPA (0.2 mg kg-1 rtPA) was administered and guided magnetically to the clot, followed by mobile magnetic guidance for 60 min. Iliac blood flow increased immediately in response to the treatment, and reached a stable level ∼50 min after drug administration and the hind limb perfusion rate was restored from 53% to 75% of the basal level. Effective thrombolysis was therefore successfully demonstrated at an rtPA dose equivalent to 20% of the regular dose when the MCNPs-rtPA pellet was magnet-guided to the blood clot, followed by a triggered release of rtPA when switched to mobile magnetic guidance.

Assessment of Anti-Tissue Type Plasminogen Activator Antibodies in Patients With Prosthetic Heart Valve Thrombosis: The ATA Trial.

Thrombolysis is an effective treatment strategy for prosthetic valve thrombosis (PVT). Recombinant tissue-type plasminogen activator (rt-PA) is widely used as a thrombolytic agent. Infusion of rt-PA may trigger the production of anti-tissue plasminogen activator (tPA) antibodies (ATAs). We aimed to evaluate the possible relationship between ATA levels and PVT formation, and the role of baseline ATA levels on outcomes of thrombolytic therapy in patients with PVT. This prospective, single-center cohort study included 28 patients with PVT undergoing thrombolysis and 31 controls with normal prostheses. Plasma samples were collected from patients with PVT at baseline and at 15th, 30th, 90th, and 180th days after thrombolysis and from controls at baseline only. The ATA levels were assessed in human plasma by an enzyme-linked immunosorbent assay. Baseline ATA-immunoglobulin (Ig) G and IgM were significantly higher in patients with PVT than in controls. The levels of IgM and IgG peaked at 15th and 30th days after rt-PA infusion, respectively. Subtherapeutic international normalized ratio and baseline ATA-IgM were independent predictors of PVT. Thrombolysis failed in 6 patients (21%) in whom baseline IgM levels were significantly higher than successfully lysed patients. Rethrombosis occurred in 9 patients (32%) in whom baseline IgG levels were significantly higher than those without rethrombosis. There was a moderate positive correlation between baseline and 15th-day IgM levels and the dose of rt-PA needed for successful lysis. The ATA levels tended to be higher in patients with PVT at the time of initial diagnosis compared to controls without PVT. In addition, such patients with PVT and high ATA levels may be at high risk for failed thrombolysis or rethrombosis.

Pharmacist Impact on Ischemic Stroke Care in the Emergency Department

BackgroundThe Froedtert Acute Stroke Team (FAST) is composed of various health professionals who respond to stroke calls, but it does not formally include a pharmacist at this time. However, emergency department (ED) pharmacists have been actively involved in patient evaluation and facilitation of i.v. recombinant tissue plasminogen activator (rtPA) preparation and administration in the ED. ED pharmacists are qualified to dose and prepare rtPA, as well as screen for contraindications to therapy. ObjectiveThe primary objective was to compare the accuracy of rtPA dosing, mean door-to-rtPA time, and identification of contraindications to rtPA therapy when a pharmacist was present vs. absent in the ED. MethodsThis is a retrospective study of 105 patients who received rtPA for acute ischemic stroke in the ED at a comprehensive stroke center from January 1, 2008 to October 1, 2012. ResultsA total of 105 patients were included in this study. Dosing accuracy was similar when a pharmacist was present vs. absent (96.6% vs. 95.6%; p = 0.8953). The median door-to-rtPA time when a pharmacist was present was statistically significantly shorter than when a pharmacist was absent (69.5 vs. 89.5 min; p = 0.0027). When a pharmacist was present, a door-to-rtPA time of < 60 min was achieved 29.9% of the time, as compared with 15.8% in the pharmacist-absent group (p = 0.1087). ConclusionsPharmacist involvement on stroke teams may have a beneficial effect on door-to-rtPA time and patient care in the ED.

The Use of Recombinant Tissue Plasminogen Activator (rTPA) in The Treatment of Fibrinous Pleuropneumonia in Horses: 25 Cases (2007-2012).

BackgroundInformation about treatment protocols, adverse effects and outcomes with intrapleural recombinant tissue plasminogen activator (rTPA) use in horses with fibrinous pleuropneumonia is limited.Hypothesis/ObjectivesDescribe factors that contribute to clinical response and survival of horses treated with rTPA intrapleurally.AnimalsHorses with bacterial pneumonia and fibrinous pleural effusion diagnosed by ultrasonography, that were treated with rTPA intrapleurally.MethodsRetrospective multicenter case series from 2007–2012. Signalment, history, clinical and laboratory evaluation, treatment, and outcome obtained from medical records. Regression analysis used to identify associations between treatments and outcomes.ResultsThirty three hemithoraces were treated in 25 horses, with 55 separate treatments. Recombinant tissue plasminogen activator (375–20,000 μg/hemithorax) was administered 1–4 times. Sonographically visible reduction in fibrin mat thickness, loculations, fluid depth, or some combination of these was seen in 32/49 (65%) treatments. Response to at least 1 treatment was seen in 17/20 (85%) horses with sonographic follow‐up evaluation after every treatment. Earlier onset of rTPA treatment associated with increased survival odds. No association was found between cumulative rTPA dose or number of rTPA doses and survival, development of complications, duration of hospitalization or total charges. Clinical evidence of hypocoagulability or bleeding was not observed. Eighteen horses (72%) survived to discharge.Conclusions and clinical importanceTreatment with rTPA appeared safe and resulted in variable changes in fibrin quantity and organization within the pleural space. Recombinant tissue plasminogen activator could be a useful adjunct to standard treatment of fibrinous pleuropneumonia, but optimal case selection and dosing regimen remain to be elucidated.

Rationale, design, and progress of the ENhanced Control of Hypertension ANd Thrombolysis strokE stuDy (ENCHANTED) trial: An international multicenter 2 × 2 quasi-factorial randomized controlled trial of low- vs. standard-dose rt-PA and early intensive vs. guideline-recommended blood pressure lowering in patients with acute ischaemic stroke eligible for thrombolysis treatment.

Controversy exists over the optimal dose of intravenous (i.v.) recombinant tissue plasminogen activator (rt-PA) and degree of blood pressure (BP) control in acute ischaemic stroke (AIS). Asian studies suggest low-dose (0·6 mg/kg) is more efficacious than standard-dose (0·9 mg/kg) i.v. rt-PA, and guidelines recommend reducing systolic BP to <185 mmHg before and <180 mmHg after use of i.v. rt-PA, despite observational studies indicating better outcomes at much lower (<140 mmHg) systolic BP levels in this patient group. The study aims to assess in thrombolysis-eligible AIS patients whether: (i) low-dose (0·6 mg/kg body weight; maximum 60 mg) i.v. rt-PA has non-inferior efficacy and lower risk of symptomatic intracerebral haemorrhage (sICH) compared to standard-dose (0·9 mg/kg body weight; maximum 90 mg) i.v. rt-PA; and (ii) early intensive BP lowering (systolic target 130-140 mmHg) has superior efficacy and lower risk of any ICH compared to guideline-recommended BP control (systolic target < 180 mmHg). The ENhanced Control of Hypertension And Thrombolysis strokE stuDy (ENCHANTED) trial is an independent,2 × 2 quasi-factorial, active-comparison, prospective, randomized, open blinded endpoint (PROBE), clinical trial that is evaluating Arm [A] 'rt-PA dose' and/or Arm [B] 'BP control', using central Internet randomization and data collection in patients fulfilling local criteria for thrombolysis and clinician uncertainty over the study treatments. The treatment arms will be analyzed separately. The primary study outcome in both trial Arms is death or disability according to the modified Rankin scale (mRS, scores 2-6) assessed at 90 days. Secondary outcomes include sICH, any ICH, a shift ('improvement') in function across mRS scores, separately on death and disability, early neurological deterioration, recurrent major vascular events, health-related quality of life, length of hospital stay, need for permanent residential care, and health care costs. Following launch of the trial in February 2012, the study has recruited more than 2500 patients across a global network of approximately 100 sites in 15 countries. The required sample sizes are 3300 for Arm [A] and 2300 for Arm [B], which will provide >90% power to detect non-inferiority of low-dose i.v. rt-PA and superiority of intensive BP lowering on the primary clinical outcome, respectively. Low-dose i.v. rt-PA and early intensive BP lowering could provide more affordable and safer use of thrombolysis treatment for patients with AIS worldwide.

Abstract W MP74: Development And Validation Of A Modified Stroke Thrombolytic Predictive Instrument To Improve Implementation And Ease Of Use

Introduction: The Stroke Thombolytic Predictive Instrument (Stroke TPI), derived on data from the first 5 randomized clinical trials of standard dose rtPA, predicts the probability of good and bad outcomes with and without rtPA. We sought to rebuild and externally validate a simpler Stroke TPI to support implementation in routine clinical care. Methods: Using a derivation cohort of 1,983 patients from a combined database of randomized clinical trials (NINDS 1 and 2; ATLANTIS A and B; ECASS 2), we simplified the Stroke TPI by: 1) removing lower credibility interaction terms; and 2) exploring reduced stroke severity scores, including previously developed 8-item and 3-item measures. Additionally, we included alternative thresholds of a good 90-day functional outcome (i.e. prediction of both modified Rankin Score [mRS] ≤ 1 and mRS ≤ 2). Bootstrapping methods were used for internal validation. External validation was performed on the ECASS 3 trial (n=821). Results: The following 6 variables were included to predict good outcomes: age, systolic blood pressure (SBP), diabetes, stroke severity, symptom onset to treatment time (OTT) and rtPA therapy. Treatment effect modifiers (interaction terms) included OTT and SBP. For the models predicting a bad outcome (mRS ≥ 5), significant variables included: age, stroke severity, and serum glucose. rtPA therapy did not change the risk of a poor outcome. As compared to models using the full NIHSS, models employing the 3-item severity score showed similar discrimination, with c-statistics on bootstrap (internal) validation of: 0.76 (mRS ≤ 1); 0.78 (mRS ≤ 2); and 0.76 (mRS ≥ 5), and with excellent calibration. External validation on ECASS 3 showed similar performance (c-statistics 0.75 [mRS ≤ 1] and 0.80 [mRS ≤ 2]), with good calibration. Conclusion: A simpler prediction model using a 3-item, instead of the 15-item NIHSS stroke severity score, has similar prognostic value and may be easier to use in routine care. Future studies are needed to test whether the reduced model can improve treatment rates, time to treatment, and outcomes.

Safety of thrombolytic therapy with rt-PA and transcranial color Doppler ultrasound (TCCS) combined with microbubbles: A histopathologic study on rabbit brain tissues

ObjectiveTo evaluate effect of thrombolytic therapy with rt-PA (recombinant tissue plasminogen activator) and transcranial color Doppler ultrasound (TCCS) combined with microbubbles on histology of brain tissue. MethodsNew Zealand rabbits were subjected to TCCS based thrombolytic therapy, in 8 groups depending on dose of rt-PA, exposure duration of TCCS and presence of attenuation by skull bone window, 2 animals/group: (1) skull+1/2 rt-PA+TCCS+MBs, 10min, (2) skull+rt-PA+TCCS+MBs, 10min, (3) skull+1/2 rt-PA+TCCS+MBs, 20min, (4) skull+rt-PA+TCCS+MBs, 20min, (5) skull+1/2 rt-PA+TCCS+MBs, 30min, (6) skull+rt-PA+TCCS+MBs, 30min, (7) 1/2 rt-PA+TCCS+MBs, 10min, (8) 1/2 rt-PA+TCCS+MBs, 20min. The brain tissues were harvested after therapies and submitted for microscopic, electronic microscope and immunohistochemical examination. The histological changes were scored. ResultsTCCS caused exposure duration dependent brain tissue damage. With attenuation by bone window, TCCS based therapies for 10–20min caused minimal tissue damage. However, significant tissue damage was observed upon TCCS for 30min in presence of skull bone window, presenting as hemorrhage, misdistribution of organelles, demyelination of nerve fibers, and thinning of basement membrane in blood–brain barrier, which was milder than that after 20min of exposure to TCCS in absence of bone window. Dose of rt-PA did not affect brain histology in all groups. ConclusionShort treatment of brain tissue with TCCS through a bone window is relative safe. And skull bone window protected brain tissue from TCCS induced damage.

Double Bolus Thrombolysis for Suspected Massive Pulmonary Embolism during Cardiac Arrest.

More than 70% of cardiac arrest cases are caused by acute myocardial infarction (AMI) or pulmonary embolism (PE). Although thrombolytic therapy is a recognised therapy for both AMI and PE, its indiscriminate use is not routinely recommended during cardiopulmonary resuscitation (CPR). We present a case describing the successful use of double dose thrombolysis during cardiac arrest caused by pulmonary embolism. Notwithstanding the relative lack of high-level evidence, this case suggests a scenario in which recombinant tissue Plasminogen Activator (rtPA) may be beneficial in cardiac arrest. In addition to the strong clinical suspicion of pulmonary embolism as the causative agent of the patient's cardiac arrest, the extremely low end-tidal CO2 suggested a massive PE. The absence of dilatation of the right heart on subxiphoid ultrasound argued against the diagnosis of PE, but not conclusively so. In the context of the circulatory collapse induced by cardiac arrest, this aspect was relegated in terms of importance. The second dose of rtPA utilised in this case resulted in return of spontaneous circulation (ROSC) and did not result in haemorrhage or an adverse effect.

Effects of a TAFI-Inhibitor Combined with a Suboptimal Dose of rtPA in a Murine Thromboembolic Model of Stroke

Background: Since thrombolysis is the only approved intervention for ischemic stroke, improving its efficacy and safety is a therapeutic aim of considerable interest. The activated form of thrombin activatable fibrinolysis inhibitor (TAFI) has antifibrinolytic effects, and inhibition of TAFI might thus favor recanalization. The present study compared efficacy between TAFI inhibition alone and TAFI inhibition in combination with rtPA at a suboptimal dose, in a murine model of thromboembolic stroke. Methods: Focal ischemia was induced in mice by thrombin injection in the middle cerebral artery. Animals were placed within the magnet immediately after surgery for baseline MRI (H0). MRI examination comprised diffusion-weighted imaging (DWI), perfusion-weighted imaging (PWI), and T2-weighted imaging (T2-WI). Animals were randomly assigned to 1 of 5 treatment groups: saline, rtPA 5 mg/kg (tPA⁵: suboptimal or low dose), rtPA 10 mg/kg (tPA¹⁰: standard dose), TAFI-I 100 mg/kg (TAFI-I), and rtPA 5 mg/kg + TAFI-I 100 mg/kg (tPA⁵ + TAFI-I). Treatments were administered inside the magnet, via a catheter placed in the tail vein, using a power injector, as 10% bolus and 90% infusion over a period of 20 min. MRI examination was repeated at 3 h (H3) and 24 h (H24) after surgery. Therapeutic benefit was evaluated by: (1) improvement of reperfusion and (2) reduction in final lesion size. Microhemorrhages were assessed as black spots on T2-WI at H24. Animals were sacrificed after the last MR examination. The surgeon and all investigators were blinded to treatment allocation. Results: A total of 104 mice were operated on. Forty four of these were excluded from the study and 27 from the analysis, according to a priori defined criteria (no lesion or no mismatch), leading to the following distribution: saline (n = 6), tPA⁵ (n = 8), tPA¹⁰ (n = 7), TAFI-I (n = 7), and TAFI-I + tPA⁵ (n = 5). Standard-dose rtPA treatment (tPA¹⁰) significantly improved lesion regression between H0 and H24 compared to saline (-57 ± 18% vs. -36 ± 21%, p = 0.03), which treatment with rtPA⁵ or TAFI-I alone did not. On the other hand, combined treatment with tPA⁵ + TAFI-I showed only a trend toward lesion regression (-49 ± 26%), similarly to treatment with tPA¹⁰, but not significantly different from saline (p = 0.46). Nine animals showed microhemorrhage on T2-WI at H24. These animals were evenly distributed between groups. Conclusions: The present study showed that the combination of TAFI-I with a suboptimal dose of rtPA is not as effective as the standard dose of rtPA, while TAFI inhibition alone is not effective at all. The thromboembolic model is of particular interest in assessing rtPA association to improve thrombolysis, especially when coupled with longitudinal MRI assessment.

Different doses of recombinant tissue-type plasminogen activator for acute stroke in Chinese patients.

The relationship between the dose of recombinant tissue-type plasminogen activator (r-tPA) and its safety/efficacy for ischemic stroke has not been well evaluated in the East Asian population. We assessed the safety/efficacy of different doses of r-tPA for acute ischemic stroke in Chinese patients. A total of 1004 eligible patients were classified according to the dose of r-tPA received for managing acute ischemic stroke: 0.9 mg/kg (n=422), 0.8 mg/kg (n=202), 0.7 mg/kg (n=199), and 0.6 mg/kg (n=181). The safety outcome was symptomatic intracerebral hemorrhage and death within 3 months. The efficacy outcome was good functional outcome (modified Rankin Scale ≤1) at 3 months. There was a significant trend for symptomatic intracerebral hemorrhage with age (P=0.002). With multivariate logistic regression analysis, a dose of 0.9 mg/kg was a predictor of symptomatic intracerebral hemorrhage (P=0.0109), and a dose ≤0.65 mg/kg was a predictor of good functional outcome (P=0.0369). In patients aged 71 to 80 years, there was a significant trend of increasing symptomatic intracerebral hemorrhage (P=0.0130) and less good functional outcome (P=0.0179) with increasing doses of r-tPA. There was also a trend of increasing mortality (P=0.0971) at 3 months in these patients. These results did not support the dose of 0.9 mg/kg of r-tPA being optimal for all patients in the East Asian population. In elderly patients (71-80 years), a lower dose of 0.6 mg/kg is associated with a better outcome. Confirmation of the results through randomized trial is required.

O-006 Analysis of Screened Patients from the Penumbra THERAPY Trial: Correlations of Clot Length Assessed by Thin-Section CT in a Sequential Series of Acute Stroke Patients

PurposeThin-section (≤2.5 mm) NCCT is a dependable method for measurement of clot length in documented anterior circulation occlusions. A majority of clots in the proximal anterior circulation are ≥8 mm,...

Outcome and complications after intra-arterial thrombolysis for lower limb ischaemia with or without continuous heparin infusion.

BackgroundThrombolysis is a common treatment for acute leg ischaemia. The purpose of this study was to evaluate different thrombolytic treatment strategies, and risk factors for complications.MethodsThis was a retrospective analysis of prospective databases from two vascular centres. One centre used a higher dose of heparin and recombinant tissue plasminogen activator (rtPA).ResultsSome 749 procedures in 644 patients of median age 73 years were studied; 353 (47·1 per cent) of the procedures were done in women. The aetiology of ischaemia was graft occlusion in 38·8 per cent, acute arterial thrombosis in 32·2 per cent, embolus in 22·3 per cent and popliteal aneurysm in 6·7 per cent. Concomitant heparin infusion was used in 63·2 per cent. The mean dose of rtPA administered was 21·0 mg, with a mean duration of 25·2 h. Technical success was achieved in 80·2 per cent. Major amputation and death within 30 days occurred in 13·1 and 4·4 per cent respectively. Bleeding complications occurred in 227 treatments (30·3 per cent). Blood transfusion was needed in 104 (13·9 per cent). Three patients (0·4 per cent of procedures) had intracranial bleeding; all were fatal. Amputation-free survival was 83·6 per cent at 30 days at both centres. In multivariable analysis, preoperative severe ischaemia with motor deficit was the only independent risk factor for major bleeding (odds ratio (OR) 2·98; P <0·001). Independent risk factors for fasciotomy were severe ischaemia (OR 2·94) and centre (OR 6·50). Embolic occlusion was protective for major amputation at less than 30 days (OR 0·30; P = 0·003). Independent risk factors for death within 30 days were cerebrovascular disease (OR 3·82) and renal insufficiency (OR 3·86).ConclusionBoth treatment strategies were successful in achieving revascularization with acceptable complication rates. Continuous heparin infusion during intra-arterial thrombolysis appeared to offer no advantage.

Catheter-Directed Thrombolytic Intervention Is Effective for Patients with Massive and Submassive Pulmonary Embolism

Massive pulmonary embolism (MPE) is a significant cause of mortality and, with submassive pulmonary embolism (SPE), is associated with chronic thromboembolic pulmonary hypertension, resulting in ongoing patient morbidity. Standard treatment is anticoagulation, although systemic thrombolytic therapy has been shown to reduce early mortality in patients with MPE and improve cardiopulmonary hemodynamics in patients with SPE. However, systemic lysis is associated with significant bleeding risk. Early reports of catheter-directed techniques (CDT) suggest favorable outcomes in patients with MPE and SPE with reduced risk of hemorrhage. The purpose of this study is to evaluate efficacy and safety outcomes in MPE and SPE patients treated with CDT. Seventeen patients treated with CDT for MPE and SPE were clinically and hemodynamically evaluated. Patients were grouped by severity of pulmonary embolism: MPE (n=5) or SPE (n=12). Pre- and post-interventional measures were assessed, including pulmonary artery pressures (PAPs), cardiac biomarkers, tricuspid regurgitation, right ventricular (RV) dilatation, and systolic function. Nine patients had contraindications to systemic thrombolytic therapy. PAP was elevated in 94% at presentation. The average dose of recombinant tissue plasminogen activator (rt-PA) was 31mg; 44mg in MPE and 26mg in SPE. Pre- and post-intervention PAPs were recorded in 13 patients. All demonstrated an acute reduction in posttreatment PAP, averaging 37%. At presentation, all MPE and 10 (83%) SPE patients showed both RV dilatation and reduced function on echocardiography, which normalized in 76% (13/17) and improved in 24% (4/17) after CDT. Patients who demonstrated left ventricle underfilling before CDT (2 [40%] MPE and 2 [20%] SPE) normalized after CDT. All MPE and 11 (92%) SPE patients had tricuspid regurgitation on echocardiography pretreatment, which resolved in 60% and 58% of MPE and SPE patients, respectively. One delayed mortality occurred in an MPE patient who was hypotensive and hypoxic at presentation. There was one puncture site bleed. CDT was successful in the acute management of patients with MPE and SPE. CDT rapidly restores cardiopulmonary hemodynamics using reduced doses of rt-PA. These observations suggest that CDT should be considered in MPE and SPE patients to rapidly restore cardiopulmonary hemodynamics, reduce acute morbidity and mortality, reduce bleeding complications, and potentially avoid long-term morbidity.

Efficacy of short-term catheter-directed thrombolysis used with rt-PA combined with endovascular interventional therapy in patients with lower limb ischemia

To evaluate the performance effect of short-term catheter-directed thrombolysis with different dosage of rt-PA allied with endovascular interventional therapy for patients with acute lower limb ischemia. To separate 84 consecutive patients suffered from acute lower limb ischemia into two groups at random, then adopt catheter-directed thrombolysis for each group of patients injected 20 mg (Group A) or 10 mg (Group B) rt-PA into the occlusive lesion correspondingly, and subsequently perform endovascular intervention on significant underlying lesions on the base of angiography results. Adopt statistical methods to assess treatment effectiveness, rates of complication and amputation rates within 30 days, 6 months or 12 months. The statistic analysis was performed under SPSS 16.0 format, and adopts t test and χ(2) test. There was no statistical difference on patient characteristics and lesions between both groups (P > 0.05). Procedural success rates as well clinical success rates were all 100%. Not incur any diversity on thrombolysis effectiveness between both groups injected different dosage of rt-PA (P > 0.05). Not found major differences on ratios of PTA or implant stent between both groups (P > 0.05). During the follow-up period of 30-day, 6-, 12- months, there were no statistical differences on the amputation-free survival rates and complication rates between both groups. Whereas short-term catheter-directed thrombolysis combined with endovascular interventional therapy won good operation effectiveness on patients with acute lower limb ischemia, moreover the dosage of rt-PA did not impact on thrombolysis, it is worthy to be applied in the clinical practice.

Intraclot recombinant tissue-type plasminogen activator reduces perihematomal edema and mortality in patients with spontaneous intracerebral hemorrhage

The study aimed to investigate the impact of intraclot recombinant tissue-type plasminogen activator (rt-PA) on perihematomal edema (PHE) development in patients with intracerebral hemorrhage (ICH) treated with minimally invasive surgery (MIS) and the effects of intraclot rt-PA on the 30-day survival. We reviewed the medical records of ICH patients undergoing MIS between October 2011 and July 2013. A volumetric analysis was done to assess the change in PHE and ICH volumes at pre-MIS (T1), post-MIS (T2) and day 10-16 (T3) following diagnostic computed tomographic scans (T0). Forty-three patients aged 52.8±11.1 years with (n=30) or without rt-PA (n=13) were enrolled from our institutional ICH database. The median rt-PA dose was 1.5 (1) mg, with a maximum dose of 4.0 mg. The ratio of clot evacuation was significantly increased by intraclot rt-PA as compared with controls (77.9%±20.4% vs. 64%±15%; P=0.046). From T1 to T2, reduction in PHE volume was strongly associated with the percentage of clot evacuation (ρ=0.34; P=0.027). In addition, PHE volume was positively correlated with residual ICH volume at the same day (ρ ranging from 0.39-0.56, P<0.01). There was no correlation between the cumulative dose of rt-PA and early (T2) PHE volume (ρ=0.24; P=0.12) or delayed (T3) PHE volume (ρ=0.19; P=0.16). The 30-day mortality was zero in this cohort. In the selected cohort of ICH patients treated with MIS, intraclot rt-PA accelerated clot removal and had no effects on PHE formation. MIS aspiration and low dose of rt-PA seemed to be feasible to reduce the 30-day mortality in patients with severe ICH. A large, randomized study addressing dose titration and long-term outcome is needed.