Thrombolytic therapy induces faster clot dissolution than anticoagulation in patients with acute pulmonary embolism (PE) but is associated with an increased risk of haemorrhage. We reviewed the risks ...and benefits of thrombolytic therapy in the management of patients with acute PE.
We systematically reviewed randomized controlled studies comparing systemic thrombolytic therapy plus anticoagulation with anticoagulation alone in patients with acute PE. Fifteen trials involving 2057 patients were included in our meta-analysis. Compared with heparin, thrombolytic therapy was associated with a significant reduction of overall mortality (OR; 0.59, 95% CI: 0.36-0.96). This reduction was not statistically significant after exclusion of studies including high-risk PE (OR; 0.64, 95% CI: 0.35-1.17). Thrombolytic therapy was associated with a significant reduction in the combined endpoint of death or treatment escalation (OR: 0.34, 95% CI: 0.22-0.53), PE-related mortality (OR: 0.29; 95% CI: 0.14-0.60) and PE recurrence (OR: 0.50; 95% CI: 0.27-0.94). Major haemorrhage (OR; 2.91, 95% CI: 1.95-4.36) and fatal or intracranial bleeding (OR: 3.18, 95% CI: 1.25-8.11) were significantly more frequent among patients receiving thrombolysis.
Thrombolytic therapy reduces total mortality, PE recurrence, and PE-related mortality in patients with acute PE. The decrease in overall mortality is, however, not significant in haemodynamically stable patients with acute PE. Thrombolytic therapy is associated with an increase of major and fatal or intracranial haemorrhage.
Objective
The substantial clinical improvement in acute ischemic stroke (AIS) patients treated with mechanical thrombectomy (MT), combined with the poor response of proximal intracranial occlusions ...to intravenous thrombolysis (IVT), led to questions regarding the utility of bridging therapy (BT; IVT followed by MT) compared to direct mechanical thrombectomy (dMT) for AIS patients with large vessel occlusion (LVO).
Methods
We aimed to investigate the comparative safety and efficacy of BT and dMT in AIS patients. We included all observational studies and post hoc analyses from randomized controlled clinical trials that provided data on the outcomes of AIS patients with LVO stratified by IVT treatment status prior to MT.
Results
We identified 38 eligible observational studies (11,798 LVO patients, mean age = 68 years, 56% treated with BT). In unadjusted analyses, BT was associated with a higher likelihood of 3‐month functional independence (odds ratio OR = 1.52, 95% confidence interval CI = 1.32–1.76), 3‐month functional improvement (common OR cOR for 1‐point decrease in modified Rankin Scale score = 1.52, 95% CI = 1.18–1.97), early neurological improvement (OR = 1.21, 95% CI = 1.83–1.76), successful recanalization (OR = 1.22, 95% CI = 1.02–1.46), and successful recanalization with ≤2 device passes (OR = 2.28, 95% CI = 1.43–3.64) compared to dMT. BT was also related to a lower likelihood of 3‐month mortality (OR = 0.64, 95% CI = 0.57–0.73). In the adjusted analyses, BT was independently associated with a higher likelihood of 3‐month functional independence (adjusted OR = 1.55, 95% CI = 1.26–1.91) and lower odds of 3‐month mortality (adjusted OR = 0.80, 95% CI = 0.66–0.97) compared to dMT. The two groups did not differ in functional improvement (adjusted cOR = 1.24, 95% CI = 0.89–1.74) or symptomatic intracranial hemorrhage (adjusted OR = 0.87, 95% CI = 0.61–1.25).
Interpretation
BT appears to be associated with improved functional independence without evidence for safety concerns, compared to dMT, for AIS patients with LVO. ANN NEUROL 2019;86:395–406
The Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke (ESCAPE) trial used innovative imaging and aggressive target time metrics to demonstrate the benefit of endovascular ...treatment in patients with acute ischemic stroke. We analyze the impact of time on clinical outcome and the effect of patient, hospital, and health system characteristics on workflow within the trial.
Relationship between outcome (modified Rankin Scale) and interval times was modeled by using logistic regression. Association between time intervals (stroke onset to arrival in endovascular-capable hospital, to qualifying computed tomography, to groin puncture, and to reperfusion) and patient, hospital, and health system characteristics were modeled by using negative binomial regression. Every 30-minute increase in computed tomography-to-reperfusion time reduced the probability of achieving a functionally independent outcome (90-day modified Rankin Scale 0-2) by 8.3% (P=0.006). Symptom onset-to-imaging time was not associated with outcome (P>0.05). Onset-to-endovascular hospital arrival time was 42% (34 minutes) longer among patients receiving intravenous alteplase at the referring hospital (drip and ship) versus direct transfer (mothership). Computed tomography-to-groin puncture time was 15% (8 minutes) shorter among patients presenting during work hours versus off hours, 41% (24 minutes) shorter in drip-ship patients versus mothership, and 43% (22 minutes) longer when general anesthesia was administered. The use of a balloon guide catheter during endovascular procedures shortened puncture-to-reperfusion time by 21% (8 minutes).
Imaging-to-reperfusion time is a significant predictor of outcome in the ESCAPE trial. Inefficiencies in triaging, off-hour presentation, intravenous alteplase administration, use of general anesthesia, and endovascular techniques offer major opportunities for improvement in workflow.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01778335.
In adult stroke, the advent of thrombolytic therapy led to the development of primary stroke centers capable to diagnose and treat patients with acute stroke rapidly. We describe the development of ...primary pediatric stroke centers through preparation of participating centers in the Thrombolysis in Pediatric Stroke (TIPS) trial.
We collected data from the 17 enrolling TIPS centers regarding the process of becoming an acute pediatric stroke center with capability to diagnose, evaluate, and treat pediatric stroke rapidly, including use of thrombolytic therapy.
Before 2004, <25% of TIPS sites had continuous 24-hour availability of acute stroke teams, MRI capability, or stroke order sets, despite significant pediatric stroke expertise. After TIPS preparation, >80% of sites now have these systems in place, and all sites reported increased readiness to treat a child with acute stroke. Use of a 1- to 10-Likert scale on which 10 represented complete readiness, median center readiness increased from 6.2 before site preparation to 8.7 at the time of site activation (P≤0.001).
Before preparing for TIPS, centers interested in pediatric stroke had not developed systematic strategies to diagnose and treat acute pediatric stroke. TIPS trial preparation has resulted in establishment of pediatric acute stroke centers with clinical and system preparedness for evaluation and care of children with acute stroke, including use of a standardized protocol for evaluation and treatment of acute arterial stroke in children that includes use of intravenous tissue-type plasminogen activator.
http://www.clinicaltrials.gov. Unique identifier: NCT01591096.
The aim of this prospective study was to identify the most effective and safest regimen among different thrombolytic treatment strategies.
The best treatment strategies for prosthetic valve ...thrombosis have been controversial.
Transesophageal echocardiography-guided thrombolytic treatment was administered to 182 consecutive patients with prosthetic valve thrombosis in 220 different episodes (156 women; mean age, 43.2 ± 13.06 years) between 1993 and 2009 at a single center. These regimens chronologically included rapid (Group I), slow (Group II) streptokinase, high-dose (100 mg) tissue plasminogen activator (t-PA) (Group III), a half-dose (50 mg) and slow infusion (6 h) of t-PA without bolus (Group IV), and a low dose (25 mg) and slow infusion (6 h) of t-PA without bolus (Group V). The endpoints were thrombolytic success, in-hospital mortality, and nonfatal complication rates.
The overall success rate in the whole series was 83.2%; it did not differ significantly among Groups I through V (68.8%, 85.4%, 75%, 81.5%, and 85.5%, respectively; p = 0.46). The overall complication rate in the whole series was 18.6%. Although the overall complication rate was similar among Groups I through IV (37.5%, 24.4 %, 33.3%, and 29.6%, respectively; p > 0.05 for each comparison), it was significantly lower in Group V (10.5%, p < 0.05 for each). The combined rates of mortality and nonfatal major complications were also lower in Group V than in the other groups, with all differences significant except for comparison of Groups IV and V. By multivariate analysis, the predictors of combined mortality plus nonfatal major complications were any thrombolytic therapy regimen other than Group V (odds ratios for Groups I through IV: 8.2, 3.8, 8.1, and 4.1, respectively; p < 0.05 for each) and a history of stroke/transient ischemic attack (odds ratio: 3.5, p = 0.011). In addition, there was no mortality in Group V.
Low-dose slow infusion of t-PA repeated as needed without a bolus provides effective and safe thrombolysis in patients with prosthetic valve thrombosis. (Comparison of Different TRansesophageal Echocardiography Guided thrOmbolytic Regimens for prosthetIc vAlve Thrombosis; NCT01451320).
Acute stroke due to supratentorial intracerebral haemorrhage is associated with high morbidity and mortality. Open craniotomy haematoma evacuation has not been found to have any benefit in large ...randomised trials. We assessed whether minimally invasive catheter evacuation followed by thrombolysis (MISTIE), with the aim of decreasing clot size to 15 mL or less, would improve functional outcome in patients with intracerebral haemorrhage.
MISTIE III was an open-label, blinded endpoint, phase 3 trial done at 78 hospitals in the USA, Canada, Europe, Australia, and Asia. We enrolled patients aged 18 years or older with spontaneous, non-traumatic, supratentorial intracerebral haemorrhage of 30 mL or more. We used a computer-generated number sequence with a block size of four or six to centrally randomise patients to image-guided MISTIE treatment (1·0 mg alteplase every 8 h for up to nine doses) or standard medical care. Primary outcome was good functional outcome, defined as the proportion of patients who achieved a modified Rankin Scale (mRS) score of 0–3 at 365 days, adjusted for group differences in prespecified baseline covariates (stability intracerebral haemorrhage size, age, Glasgow Coma Scale, stability intraventricular haemorrhage size, and clot location). Analysis of the primary efficacy outcome was done in the modified intention-to-treat (mITT) population, which included all eligible, randomly assigned patients who were exposed to treatment. All randomly assigned patients were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01827046.
Between Dec 30, 2013, and Aug 15, 2017, 506 patients were randomly allocated: 255 (50%) to the MISTIE group and 251 (50%) to standard medical care. 499 patients (n=250 in the MISTIE group; n=249 in the standard medical care group) received treatment and were included in the mITT analysis set. The mITT primary adjusted efficacy analysis estimated that 45% of patients in the MISTIE group and 41% patients in the standard medical care group had achieved an mRS score of 0–3 at 365 days (adjusted risk difference 4% 95% CI −4 to 12; p=0·33). Sensitivity analyses of 365-day mRS using generalised ordered logistic regression models adjusted for baseline variables showed that the estimated odds ratios comparing MISTIE with standard medical care for mRS scores higher than 5 versus 5 or less, higher than 4 versus 4 or less, higher than 3 versus 3 or less, and higher than 2 versus 2 or less were 0·60 (p=0·03), 0·84 (p=0·42), 0·87 (p=0·49), and 0·82 (p=0·44), respectively. At 7 days, two (1%) of 255 patients in the MISTIE group and ten (4%) of 251 patients in the standard medical care group had died (p=0·02) and at 30 days, 24 (9%) patients in the MISTIE group and 37 (15%) patients in the standard medical care group had died (p=0·07). The number of patients with symptomatic bleeding and brain bacterial infections was similar between the MISTIE and standard medical care groups (six 2% of 255 patients vs three 1% of 251 patients; p=0·33 for symptomatic bleeding; two 1% of 255 patients vs 0 0% of 251 patients; p=0·16 for brain bacterial infections). At 30 days, 76 (30%) of 255 patients in the MISTIE group and 84 (33%) of 251 patients in the standard medical care group had one or more serious adverse event, and the difference in number of serious adverse events between the groups was statistically significant (p=0·012).
For moderate to large intracerebral haemorrhage, MISTIE did not improve the proportion of patients who achieved a good response 365 days after intracerebral haemorrhage. The procedure was safely adopted by our sample of surgeons.
National Institute of Neurological Disorders and Stroke and Genentech.
Thrombolysis for acute deep vein thrombosis Watson, Lorna; Broderick, Cathryn; Armon, Matthew P
Cochrane database of systematic reviews,
11/2016, Volume:
11
Journal Article
Peer reviewed
Open access
Standard treatment for deep vein thrombosis aims to reduce immediate complications. Use of thrombolysis or clot dissolving drugs could reduce the long-term complications of post-thrombotic syndrome ...(PTS) including pain, swelling, skin discolouration, or venous ulceration in the affected leg. This is the third update of a review first published in 2004.
To assess the effects of thrombolytic therapy and anticoagulation compared to anticoagulation alone for the management of people with acute deep vein thrombosis (DVT) of the lower limb as determined by the effects on pulmonary embolism, recurrent venous thromboembolism, major bleeding, post-thrombotic complications, venous patency and venous function.
For this update the Cochrane Vascular Information Specialist (CIS) searched the Specialised Register (February 2016). In addition the CIS searched the Cochrane Register of Studies (CENTRAL (2016, Issue 1)). Trial registries were searched for details of ongoing or unpublished studies.
Randomised controlled trials (RCTs) examining thrombolysis and anticoagulation versus anticoagulation for acute DVT were considered.
For this update (2016), LW and CB selected trials, extracted data independently, and sought advice from MPA where necessary. We assessed study quality with the Cochrane risk of bias tool. For dichotomous outcomes, we calculated the risk ratio (RR) and corresponding 95% confidence interval (CI). Data were pooled using a fixed-effect model unless significant heterogeneity was identified in which case a random-effects model was used. GRADE was used to assess the overall quality of the evidence supporting the outcomes assessed in this review.
Seventeen RCTs with 1103 participants were included. These studies differed in the both thrombolytic agent used and in the technique used to deliver it. Systemic, loco-regional and catheter-directed thrombolysis (CDT) were all included. Fourteen studies were rated as low risk of bias and three studies were rated as high risk of bias. We combined the results as any (all) thrombolysis compared to standard anticoagulation. Complete clot lysis occurred significantly more often in the treatment group at early follow-up (RR 4.91; 95% CI 1.66 to 14.53, P = 0.004) and at intermediate follow-up (RR 2.44; 95% CI 1.40 to 4.27, P = 0.002; moderate quality evidence). A similar effect was seen for any degree of improvement in venous patency. Up to five years after treatment significantly less PTS occurred in those receiving thrombolysis (RR 0.66, 95% CI 0.53 to 0.81; P < 0.0001; moderate quality evidence). This reduction in PTS was still observed at late follow-up (beyond five years), in two studies (RR 0.58, 95% CI 0.45 to 0.77; P < 0.0001; moderate quality evidence). Leg ulceration was reduced although the data were limited by small numbers (RR 0.87; 95% CI 0.16 to 4.73, P = 0.87). Those receiving thrombolysis had increased bleeding complications (RR 2.23; 95% CI 1.41 to 3.52, P = 0.0006; moderate quality evidence). Three strokes occurred in the treatment group, all in trials conducted pre-1990, and none in the control group. There was no significant effect on mortality detected at either early or intermediate follow-up. Data on the occurrence of pulmonary embolism (PE) and recurrent DVT were inconclusive. Systemic thrombolysis and CDT had similar levels of effectiveness. Studies of CDT included two trials in femoral and iliofemoral DVT, and results from these are consistent with those from trials of systemic thrombolysis in DVT at other levels of occlusion.
Thrombolysis increases the patency of veins and reduces the incidence of PTS following proximal DVT by a third. Evidence suggests that systemic administration and CDT have similar effectiveness. Strict eligibility criteria appears to improve safety in recent studies and may be necessary to reduce the risk of bleeding complications. This may limit the applicability of this treatment. In those who are treated there is a small increased risk of bleeding. Using GRADE assessment, the evidence was judged to be of moderate quality due to many trials having low numbers of participants. However, the results across studies were consistent and we have reasonable confidence in these results.
Prosthetic valve thrombosis (PVT) is one of the life-threatening complications of prosthetic heart valve replacement. Due to the lack of randomized controlled trials, the optimal treatment of PVT ...remains controversial between thrombolytic therapy (TT) and surgery.
This study aimed to prospectively evaluate the outcomes of TT and surgery as the first-line treatment strategy in patients with obstructive PVT.
A total of 158 obstructive PVT patients (women: 103 65.2%; median age 49 years IQR: 39-60 years) were enrolled in this multicenter observational prospective study. TT was performed using slow (6 hours) and/or ultraslow (25 hours) infusion of low-dose tissue plasminogen activator (t-PA) (25 mg) mostly in repeated sessions. The primary endpoint of the study was 3-month mortality following TT or surgery.
The initial management strategy was TT in 83 (52.5%) patients and surgery in 75 (47.5%) cases. The success rate of TT was 90.4% with a median t-PA dose of 59 mg (IQR: 37.5-100 mg). The incidences of outcomes in surgery and TT groups were as follows: minor complications (29 38.7% and 7 8.4%, respectively), major complications (31 41.3% and 5 6%, respectively), and the 3-month mortality rate (14 18.7% and 2 2.4%, respectively).
Low-dose and slow/ultraslow infusion of t-PA were associated with low complications and mortality and high success rates and should be considered as a viable treatment in patients with obstructive PVT.
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