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Is intravenous recombinant tissue plasminogen activator (r-tPA) safe in patients on Dabigatran?

ABSTRACT: Dabigatran etexilate is a newly approved oral anticoagulant indicated for stroke prevention in nonvalvular atrial fibrillation. There are no reliable, rapidly available laboratory markers to assess its anticoagulant activity. There is no data on the safety of r-tPA on patients who are on dabigatran and it is not known whether r-tPA is safe in patients who are on dabigatran with a normal activated partial thromboplastin time (aPTT).We report the case of a 59-year-old male who is reported with right hemiparesis and global aphasia. Two days prior to admission he underwent elective cardioversion for atrial fibrillation. He had begun dabigatran at 150 mg BID 3 days before cardioversion. Five days after commencing dabigatran, and 10 h after the last oral dose he presented with these symptoms. Patient fulfilled the criteria for r-tPA including a normal aPTT (30 s), normal prothrombin time (INR = 1.0) and a normal creatinine clearance (glomerular filtration rate >60 mL/min/1.73 m(2)). A brain CT without contrast was normal. After extensive discussion with the family, with clear understanding of the risks and benefits of such an approach in a patient who has been on dabigatran, consent was obtained, and r-tPA (0.9 mg/kg alteplase) was given. Patient's hospital course remained uncomplicated and he was discharged 4 days after the initial symptoms to an acute rehabilitation facility and is currently on coumadin with INR therapeutic goal between 2 and 3.More studies are needed to asses whether r-tPA might be safe in patients who are on dabigatran with a normal activated partial thromboplastin time and more than 10 h after the last dose.

SUBMITTER: Govindarajan R

PROVIDER: S-EPMC4051900 | biostudies-other | 2014 May

REPOSITORIES: biostudies-other

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Is intravenous recombinant tissue plasminogen activator (r-tPA) safe in patients on Dabigatran?

Govindarajan Raghav R Galvez Nestor N

Journal of vascular and interventional neurology 20140501 1

<h4>Introduction</h4>Dabigatran etexilate is a newly approved oral anticoagulant indicated for stroke prevention in nonvalvular atrial fibrillation. There are no reliable, rapidly available laboratory markers to assess its anticoagulant activity. There is no data on the safety of r-tPA on patients who are on dabigatran and it is not known whether r-tPA is safe in patients who are on dabigatran with a normal activated partial thromboplastin time (aPTT).<h4>Case report</h4>We report the case of a ...[more]

PMID: 24920984

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Project description:Background and Purpose- Telemedicine is increasingly utilized for intravenous tPA (tissue-type plasminogen activator) delivery. The comparative safety of leaving tPA-treated patients at a presenting (spoke) hospital (drip-and-stay) or transferring patients to a central treating (hub) hospital (drip-and-ship) is not established. We sought to compare outcomes between drip-and-ship and drip-and-stay patients treated with tPA via telemedicine. We hypothesized that there would be no differences in short-term outcomes of in-hospital mortality, length of stay, or discharge disposition or in 90-day outcomes between groups. Methods- We retrospectively identified patients treated with tPA at 17 spoke hospitals between September 2015 and December 2016. Demographic, clinical, and outcome data were obtained from a prospective telemedicine registry. We used negative binomial, multinomial, and logistic regression analyses to evaluate length of stay, discharge disposition, and inpatient mortality, respectively. We compared the proportion of patients with 90-day modified Rankin Scale score <2 by group. Results- Among 430 tPA-treated patients, 232 (53.9%) were transferred to the hub after treatment. The median arrival National Institutes of Health Stroke Scale score was higher for drip-and-ship (10; interquartile range, 5-18) compared with drip-and-stay patients (6; interquartile range, 4-10; P<0.001). Unadjusted length of stay was longer in drip-and-stay patients (incidence rate ratio, 0.82; 95% CI, 0.71-0.95). There were no significant differences in adjusted length of stay, hospital mortality, or discharge disposition. Among the 64% of patients with complete 90-day modified Rankin Scale score, the proportion with good outcomes (modified Rankin Scale score <2) did not differ between groups. Conclusions- We found no differences in measured outcomes between drip-and-ship and drip-and-stay patients treated in our network, although our study may be underpowered to detect small differences.

Project description:Background and Purpose- Although there are no trials or large cohorts to inform clinical care, current guidelines caution against giving intravenous tPA (tissue-type plasminogen activator) to patients with acute ischemic stroke who are taking non-vitamin K antagonist oral anticoagulants (NOACs). We performed a literature review of intravenous tPA in patients treated with NOACs preceding stroke. Methods- A literature search of PubMed was performed encompassing January 2010 to March 2018. Patient characteristics, timing of last medication intake, laboratory testing, use of reversal, and outcomes ?3 months after discharge were summarized. Results- We identified 55 studies with 492 NOAC patients receiving tPA (dabigatran, 181; rivaroxaban, 215; apixaban, 40; and unspecified NOAC, 56). Among patients with complete data, the median time from the last NOAC intake to symptom onset was 8 hours (interquartile range, 2.5-14.5), with 55.2% (80/145) within 12 hours. Few patients underwent sensitive laboratory tests, such as thrombin time, diluted thrombin time, or anti-Xa assays before tPA administration. The overall observed rates of symptomatic intracranial hemorrhage, mortality, and favorable outcomes (National Institutes of Health Stroke Scale score, ?1; modified Rankin Scale score, 0-2; or neurological improvement in the National Institutes of Health Stroke Scale score, ?8 points) were 4.3% (20/462), 11.3% (48/423), and 43.7% (164/375), respectively. Among dabigatran-treated patients, reversal with idarucizumab was associated with fewer symptomatic intracranial hemorrhage (4.5% [2/44] versus 7.4% [8/108]; unadjusted odds ratio, 0.60; 95% CI, 0.12-2.92), death (4.5% [2/44] versus 12.0% [13/108]; unadjusted odds ratio, 0.35; 95% CI, 0.08-1.61), and more favorable outcomes (79.1% [34/43] versus 39.2% [29/74]; unadjusted odds ratio, 5.86; 95% CI, 2.45-14.00), although the differences were not statistically significant for symptomatic intracranial hemorrhage and death. Conclusions- These preliminary observations suggest that tPA may be reasonably well tolerated without prohibitive risks of bleeding complications in selected patients on NOACs. Reversal of anticoagulant effects by idarucizumab for dabigatran-treated patients before tPA is an emerging strategy that was associated with more favorable outcomes.

Project description:BACKGROUND:The necessity for rapid evaluation and treatment of acute ischemic stroke with intravenous tPA (tissue-type plasminogen activator) may increase the risk of administrating tPA to patients presenting with noncerebrovascular conditions that closely resemble stroke (stroke mimics). However, there are limited data on thrombolysis safety in stroke mimics. METHODS AND RESULTS:Using data from the Get With The Guidelines-Stroke Registry, we identified 72?582 patients with suspected ischemic stroke treated with tPA from 485 US hospitals between January 2010 and December 2017. We documented the use of tPA in stroke mimics, defined as patients who present with stroke-like symptoms, but after workup are determined not to have suffered from a stroke or transient ischemic attack, and compared characteristics and outcomes in stroke mimics versus those with ischemic stroke. Overall, 3.5% of tPA treatments were given to stroke mimics. Among them, 38.2% had a final nonstroke diagnoses of migraine, functional disorder, seizure, and electrolyte or metabolic imbalance. Compared with tPA-treated true ischemic strokes, tPA-treated mimics were younger (median 54 versus 71 years), had a less severe National Institute of Health Stroke Scale (median 6 versus 8), and a lower prevalence of cardiovascular risk factors, except for a higher prevalence of prior stroke/transient ischemic attack (31.3% versus 26.1%, all P<0.001). The rate of symptomatic intracranial hemorrhage was lower in stroke mimics (0.4%) as compared with 3.5% in ischemic strokes (adjusted odds ratio, 0.29; 95% CI, 0.17-0.50). In-hospital mortality rate was significantly lower in stroke mimics (0.8% versus 6.2%, adjusted odds ratio, 0.31; 95% CI, 0.20-0.49). Patients with stroke mimics were more likely to be discharged to home (83.8% versus 49.3%, adjusted odds ratio, 2.97; 95% CI, 2.59-3.42) and to ambulate independently at discharge (78.6% versus 50.6%, adjusted odds ratio, 1.86; 95% CI, 1.61-2.14). CONCLUSIONS:In this large cohort of patients treated with tPA, relatively few patients who received tPA for presumed stroke were ultimately not diagnosed with a stroke or transient ischemic attack. The complication rates associated with tPA in stroke mimics were low. Despite the potential risk of administering tPA to stroke mimics, opportunity remains for continued improvement in the rapid and accurate diagnosis and treatment of ischemic stroke.

Project description:Background and purposeIn spite of the advent of thrombolytic therapy, CT-perfusion imaging is currently not fully used for clinical decision-making and not included in published clinical guidelines for management of ischemic stroke. We investigated whether lesion volumes on cerebral blood volume (CBV), cerebral blood flow (CBF), and mean transit time (MTT) maps predict final infarct volume and whether all these parameters are needed for triage to intravenous recombinant tissue plasminogen activator (rtPA). We also investigated the effect of intravenous rtPA on affected brain by measuring salvaged tissue volume in patients receiving intravenous rtPA and in controls.Materials and methodsForty-four patients receiving intravenous rtPA and 19 controls underwent CT perfusion (CTP) studies in the emergency department within 3 hours of stroke onset. Lesion volumes were measured on MTT, CBV, and CBF maps by region-of-interest analysis and were compared with follow-up CT volumes by correlation and regression analysis. The volume of salvaged tissue was determined as the difference between the initial MTT and follow-up CT lesion volumes and was compared between intravenous rtPA-treated patients and controls.ResultsNo significant difference between the groups was observed in lesion volume assessed from the CTP maps (P > .08). Coefficients of determination for MTT, CBF, and CBV versus follow-up CT lesion volumes were 0.3, 0.3, 0.47, with intravenous rtPA; and 0.53, 0.55, and 0.81 without intravenous rtPA. Regression of MTT on CBF lesion volumes showed codependence (R(2) = 0.98, P < .0001). Mean salvaged tissue volumes with intravenous rtPA were 21.8 +/- 17.1 and 13.2 +/- 13.5 mL in controls; these were significantly different by using nonparametric (P < .03) and Fisher exact tests (P < .04).ConclusionsWithin 3 hours of stroke onset, CBV lesion volume does not necessarily represent dead tissue. MTT lesion volume alone can be used to identify the upper limit of the size of abnormally perfused brain. More brain is salvaged in patients with intravenous rtPA than in controls.

Project description:ObjectivesThe benefit of intravenous recombinant tissue plasminogen activator (rt-PA) therapy for very old patients with acute ischemic stroke remains unclear. The aim of this study was to elucidate the efficacy and safety of intravenous rt-PA therapy for patients over 80 years old.MethodsOf 13,521 stroke patients registered in the Fukuoka Stroke Registry in Japan from June 1999 to February 2013, 953 ischemic stroke patients who were over 80 years old, hospitalized within 3 h of onset, and not treated with endovascular therapy were included in this study. Among them, 153 patients were treated with intravenous rt-PA (0.6 mg/kg). For propensity score (PS)-matched case-control analysis, 148 patients treated with rt-PA and 148 PS-matched patients without rt-PA therapy were selected by 1:1 matching with propensity for using rt-PA. Clinical outcomes were neurological improvement, good functional outcome at discharge, in-hospital mortality, and hemorrhagic complications (any intracranial hemorrhage [ICH], symptomatic ICH, and gastrointestinal bleeding).ResultsIn the full cohort of 953 patients, rt-PA use was associated positively with neurological improvement and good functional outcome, and negatively with in-hospital mortality after adjustment for multiple confounding factors. In PS-matched case-control analysis, patients treated with rt-PA were still at lower risk for unfavorable clinical outcomes than non-treated patients (neurological improvement, odds ratio 2.67, 95% confidence interval 1.61-4.40; good functional outcome, odds ratio 2.23, 95% confidence interval 1.16-4.29; in-hospital mortality, odds ratio 0.30, 95% confidence interval 0.13-0.65). There was no significant association between rt-PA use and risk of hemorrhagic complications in the full and PS-matched cohorts.ConclusionsIntravenous rt-PA therapy was associated with improved clinical outcomes without significant increase in risk of hemorrhagic complications in very old patients (aged>80 years) with acute ischemic stroke.

Project description:Background and Purpose- Thrombolytic treatment of acute ischemic stroke with tPA (tissue-type plasminogen activator) is hampered by its narrow therapeutic window and potential hemorrhagic complication. Vepoloxamer is a nonionic surfactant that exerts potent hemorheologic and antithrombotic properties in various thrombotic diseases. The current study investigated the effect of vepoloxamer on tPA treatment in a rat model of embolic stroke. Methods- Male Wistar rats subjected to embolic middle cerebral artery occlusion were treated with the combination of vepoloxamer and tPA, vepoloxamer alone, tPA alone, or saline initiated 4 hours after middle cerebral artery occlusion. Results- Monotherapy with tPA did not reduce infarct volume, and adversely potentiated microvascular thrombosis and vascular leakage compared with the saline treatment. Vepoloxamer monotherapy reduced infarct volume by 25% and improved brain perfusion. However, the combination treatment with vepoloxamer and tPA significantly reduced infarct volume by 32% and improved neurological function, without increasing the incidence of gross hemorrhage. Compared with vepoloxamer alone, the combination treatment with vepoloxamer and tPA robustly reduced secondary thrombosis and tPA-augmented microvascular leakage and further improved brain perfusion, which was associated with substantial reductions of serum active PAI-1 (plasminogen activator inhibitor-1) level and tPA-upregulated PAI-1 in the ischemic brain. Mechanistically, exosomes derived from platelets of ischemic rats treated with tPA-augmented cerebral endothelial barrier permeability and elevated protein levels of PAI-1 and TF (tissue factor) in the endothelial cells, whereas exosomes derived from platelets of rats subjected to the combination treatment with vepoloxamer and tPA diminished endothelial permeability augmented by tPA and fibrin and reduced PAI-1 and TF levels in the endothelial cells. Conclusions- The combination treatment with vepoloxamer and tPA exerts potent thrombolytic effects in rats subjected to acute ischemic stroke. Vepoloxamer reduces tPA-aggravated prothrombotic effect of platelet-derived exosomes on cerebral endothelial cells, which may contribute to the therapeutic effect of the combination treatment.

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Is intravenous recombinant tissue plasminogen activator (r-tPA) safe in patients on Dabigatran?

Publications

Is intravenous recombinant tissue plasminogen activator (r-tPA) safe in patients on Dabigatran?

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