Intravenous Tissue-type Plasminogen Research Articles

Abstract WMP117: Patterns of All Bleeding Complications Associated with r-tPA Use-experience of an Acadamic Center in China

Background and objective: Rapid administration of intravenous recombinant tissue-type plasminogen activator (rt-PA) is the standard treatment for patients with acute ischemic stroke (AIS). While hemorrhage represents as an important and unpredictable complication of thrombolytic treatment, few studies have specifically assessed the prevalence and predictors of bleeding complications among AIS patients in Asia. We assessed characteristics of hemorrhagic complications after intravenous thrombolysis in Chinese AIS patients. Methods: This single-academic-center study retrospectively evaluated 351 acute ischemic stroke patients who received rt-PA intravenously from April 2011 to April 2016. The occurrence and characteristics of any hemorrhagic complications, as well as their associated risk factors were recorded and summarized. Multivariate logistic regression was conducted to analyze significant predictors of bleeding. Results: 134 (38.1%) patients experienced one hemorrhagic event in one or more locations The top seven common sites were gingiva (49.3%), skin (18.3%), urinary system (10.4%), digestive tract (7.5%), intra-cranial cavity (7.5%), mouth (4.4%) and nasal cavity (2.2%). All the gingival bleeding occurred during 1 to 24 hours after thrombolysis and was the first sign of bleeding. Intracranial hemorrhage (both symptomatic and asymptomatic) occurred in 16 patients, of whom 4 presented first with gingival bleeding. Multivariate analysis showed that high systolic blood pressure (SBP) and National Institutes of Health Stroke Scale (NIHSS) score were independent risk factors for hemorrhage post thrombolysis (P<0.05). Conclusions: One out of three AIS patients in this study had a bleeding complication. The most common site of initial hemorrhage after intravenous thrombolysis was gingival, which frequently occurred as the initial bleeding site within 24 hours after thrombolysis. Consistent with literature, elevated SBP and higher NIHSS were the two key predictors of bleeding risk.

Abstract TMP19: Intravenous Recombinant Tissue-type Plasminogen Activator Use in Young Adults With Acute Ischemic Stroke

Background: Intravenous recombinant tissue-type plasminogen activator (rt-PA) administration improves outcomes in acute ischemic stroke. However, young patients (<40 years old) presenting with stroke symptoms may experience delays in treatment due to misdiagnosis or a reluctance to treat since they do not fit the profile of a typical stroke patient. Methods: We analyzed data from the large national Get With The Guidelines–Stroke registry for acute ischemic stroke patients hospitalized between January 2009 and September 2015. Multivariable models with generalized estimating equations (GEE) were used to test for differences between younger (age 18-40) and older (age > 40) acute ischemic stroke patients, controlling for patient and hospital characteristics including stroke severity. Results: Of 1,320,965 AIS patients admitted to participating hospitals, 2.3% (30,448) were aged 18-40. Among these patients, 12.5% received rt-PA versus 8.8% of those aged >40 (p<0.001). Of patients arriving within 3.5 hours of symptom onset without contraindications, 68.7% of younger patients received IV rt-PA versus 63.3% of older patients (adjusted OR [aOR] 1.30, 95% CI 1.21 to 1.40), without evidence that age-related differences varied by sex (interaction p-value 0.25). Odds ratios of achieving target door-to-CT times and door-to-needle (DTN) times, and outcomes of rtPA-treated patients, are shown in the Table. Conclusions: Young acute ischemic stroke patients did not receive rt-PA treatment at lower rates than older patients. Outcomes were better and the rate of symptomatic intracranial hemorrhage was lower in the young patients. However, younger patients had significantly longer door-to-CT and DTN times, providing an opportunity to improve the care of these patients.

Abstract WMP12: Thrombectomy Saves Lives AND Saves Money: A Call for Action

Background: Six recent multi-centered prospective randomized control trials (MPRCT)showed mechanical thrombectomy significantly improves outcomes of patients with ischemic stroke due to large vessel occlusion. These results were anticipated to have significant impacts on the healthcare costs associated with ischemic stroke. We performed an analysis to determine the cost and utility of combined intravenous (IV) tissue-type plasminogen activator (tPA) and mechanical thrombectomy compared to IV tPA alone for acute large-vessel ischemic stroke. Methods: A meta-analysis of the six most recent MPRCTs was conducted and data was extracted to calculate the number needed to treat (NNT) and number needed to harm (NNH) based on the pooled results. The average costs of hospitalization for various complications associated with ischemic stroke were separately analyzed. There were two groups: "A" were independent (mRS 0-2) after treatment; "B" were disabled (mRS >2). The costs for hospitalization and post-hospitalization were estimated and a comparison was done between the two groups and compared with IV tPA alone versus tPA plus intervention. Results: A total of 1,386 patients were included in this analysis from six recent MPRCTs. Of those 698 received IV tPA alone and 688 were treated with thrombectomy and IV tPA. The thrombectomy arm had 46% (n=316) in group A, while the IV tPA alone arm had 27% (n=188) in group A (p=.001). The NNT was 5.1 for patients receiving thrombectomy (p=.001). That translated to 271 more patients becoming independent. The estimated average in-hospital and post-hospital cost for patients in group A was $20,396 and $55,494 for group B. A cost-savings of $14,613,790 would have been achieved, if all patients underwent thrombectomy along with IV tPA. Conclusions: The addition of thrombectomy to IV tPA translates to substantial cost benefits. If these figures are extrapolated to all stroke patients, the benefits would substantially lessen the economic burden of the entire healthcare system. Thrombectomy after IV tPA makes sense financially as well as clinically. A strong and urgent consideration for amending Healthcare policy and clinical guidelines should be given.

Quality adjusted life year gains associated with administration of recombinant tissue-type plasminogen activator for treatment of acute ischemic stroke: 1998-2011.

Intravenous recombinant tissue-type plasminogen activator (r-tPA) is an approved treatment for select patients with acute ischemic stroke (AIS). Data indicate r-tPA improves functional outcome three months after AIS compared with placebo. This study models the increase in quality adjusted life years (QALYs) associated with r-tPA compared with similar patients not treated with r-tPA. Hospital discharge data for AIS and r-tPA were obtained from the Nationwide Inpatient Sample from 1998 to 2011. Discharge location (home, rehabilitation, long-term care, death) was mapped to modified Rankin Scale (mRS) scores based on National Institute of Neurological Disorders and Stroke (NINDS) Study Group Part 1 and 2 clinical studies. The mRS scores were mapped to relative risk of death and QALYs obtained from the literature. The model estimated expected survival and QALYs by age, gender and mRS for patients receiving r-tPA. Life expectancy and QALYs for patients not receiving r-tPA were estimated based on discharge location and mRS for placebo patients in the NINDS study. AIS discharges declined from over 635,000 in 1998 to over 593,000 in 2011. A total of 183,235 patients received r-tPA. Utilization of r-tPA increased from 1% of AIS patients in 1998 to over 4% in 2011. Estimated projections for QALYs gained from utilization of r-tPA to QALYS without r-tPA were just under 240,000 for the 13 years and with no discounting, and just over 165,000 assuming 3% annual discounting. In the most conservative scenario, assuming no difference in proportional discharge status (i.e. patients not treated with r-tPA are discharged in the same manner as r-tPA patients), the estimated life years gained are approximately 35,000 and QALYS gained are approximately 90,000. r-tPA for AIS has resulted in estimated gains in quality-adjusted life years due to reduction in disability and improvement in functioning since its introduction in 1998.

Neuro-interventions in review for cardiologists

In acute stroke, rapid administration of intravenous recombinant tissue-type plasminogen activator (r-tPA) to stroke patients is the mainstay of treatment. Intravenous r-tPA improves functional outcomes when given within 4.5 h of ischemic stroke onset. Patients eligible for intravenous r-tPA should receive intravenous r-tPA even if endovascular treatments are being considered. Patients should receive endovascular therapy with a stent retriever if they meet appropriate criteria as per the American Heart Association guidelines. With the publication of results of the carotid revascularization endarterectomy versus stenting trial (CREST), there is evidence of no difference in the rate of late ipsilateral stroke after endarterectomy or stenting at 4 and 10 years. CREST provides the physician more options for the treatment of carotid stenosis and has shown that both carotid endarterectomy and carotid artery stenting are effective and safe when performed by experienced operators, and when patients are chosen appropriately.

Changing contraindications for t-PA in acute stroke: review of 20 years since NINDS.

When intravenous (IV) tissue-type plasminogen activator (t-PA) was originally approved by the Food and Drug Administration (FDA) for acute ischemic stroke (AIS) in 1996, there was a lengthy list of contraindications. In the 19 years since the approval of t-PA for AIS, it has been used off label and in patients with those contraindications. In February 2015, the list of contraindications for IV t-PA in AIS was revised and several of the previous contraindications were removed. As only 4 % of patients with ischemic stroke receive treatment with IV t-PA, these changes increase the number of patients eligible for treatment. Anytime there is a significant change in the indications and treatment paradigm with a medication, there can be some resistance to the adaptation of the change into physician's treating habits. We seek to review what the changes to t-PA contraindications are, how they came about, as well as the literature on the previously off-label and currently off-label use of IV t-PA for patients with AIS.

Abstract T P32: Infarct Volume as a Potential Prognostic Biomarker for Acute Ischemic Stroke after Intravenous Recombinant Tissue-Type Plasminogen Activator Therapy

Background: Pretreatment infarct volume has been known as a predictor of outcome in patients with acute ischemic stroke after intravenous recombinant tissue-type plasminogen activator (IV rt-PA) therapy. To confirm the importance of infarct volume in patients with undergoing IV rt-PA therapy, we sought to characterize the relationship between final infarct volume and long-term outcome. Method: We retrospectively reviewed outcomes of acute ischemic stroke patients who had treated with IV rt-PA. Patients underwent magnetic resonance imaging at baseline and 7 days after IV rt-PA. Baseline characteristics, stroke features, time from onset to treatment, initial National Institutes of Health Stroke Scale (NIHSS) score, the presence of major artery occlusion, and laboratory findings were recorded. Outcomes included complete independence (mRS of 0 to 1), unfavorable outcome (mRS of 4 to 6) at 90-day, and mortality within 90-day. Multivariate regression analysis was used to identify predictors of the outcomes. Results: Of 116 patients, 47 (41%) patients achieved complete independence. At univariate analysis, they were younger (median age, 71 versus 77, p=0.008), had a lower prevalence of diabetes mellitus (23% versus 43%, p=0.040), had a lower initial NIHSS score (median, 8 versus 16, p<0.001), had a lower prevalence of internal carotid artery occlusion (9 versus 29%, p=0.010), had no occlusion (36 versus 10%, p=0.001), had a lower prevalence of parenchymal hemorrhage (2 versus 20%, p=0.004), had smaller diffusion-weighted imaging lesion volume at baseline (median, 2.6 versus 8.0ml, p=0.008) and final infarct volume at 7-day (median, 3.8 versus 42.2ml, p<0.001). Age (Odds ratio [OR], 0.943, 95% confidence interval [CI], 0.896 to 0.992; p=0.024) and final infarct volume (OR, 0.952; 95%CI, 0.992 to 0.982; p=0.002) were identified as independent predictors of complete independence. They also predicted unfavorable outcome (p=0.036 and p<0.001) and mortality (p=0.036 and p=0.035). Conclusion: Among patients with acute stroke patients who undergo IV rt-PA therapy, final infarct volume is a critical determinant of 90-day functional outcome and mortality.

Abstract 99: Time to Treatment with Intravenous Tissue Plasminogen Activator and Outcome from Acute Ischemic Stroke in the National US GWTG-Stroke Population

Background: Randomized clinical trials have shown that the benefit of intravenous (IV) tissue-type plasminogen activator (tPA) in acute ischemic stroke is time dependent. However, the generalizability of clinical trial findings to routine practice is uncertain; and modest sample sizes have limited characterization by trial data of the degree to which onset to treatment (OTT) time influences outcome from thrombolytic stroke therapy. Methods: We analyzed data from 58,353 acute ischemic stroke patients treated with tPA within 4.5 hours of symptom onset in 1395 hospitals participating in the Get With the Guidelines-Stroke Program from April 2003, to March 2012. Main outcome measures were 1) independent ambulation at discharge, 2) discharge to home, 3) in hospital mortality, and 4) symptomatic intracerebral hemorrhage. Univariate and multivariate stepwise logistic regression modeling was employed to evaluate the independent impact of OTT time on outcome. Results: Among the 58,353 tPA-treated patients, median age was 72, 50.3% were female, median OTT was 144 minutes (IQR=115-170), and 9.3% (5404) had OTT 0- 90 minutes, 77.2% (45,029) had OTT 91-180 minutes, and 13.6% (7920) had OTT 181-270 minutes. Pretreatment NIHSS, documented in 87.7% of patients, was median 11 (IQR 6-17). Multivariate analysis of NIHSS documented cases, showed shorter OTT time was associated with increased odds of independent ambulation at discharge and discharge to home, and reduced odds of in-hospital mortality and symptomatic intracerebral hemorrhage (Table 1). Conclusions: In national US clinical practice, earlier ischemic stroke treatment with IV tPA is associated with more frequent independent ambulation at discharge and discharge to home, and reduced SICH and mortality. These findings support intensive efforts to accelerate patient presentation and treatment initiation, such as Target Stroke, to maximize benefit of thrombolytic therapy.

Stroke Outcomes of Japanese Patients With Major Cerebral Artery Occlusion in the Post-Alteplase, Pre-MERCI Era

This study examined outcomes of patients with acute ischemic stroke (AIS) with major cerebral artery occlusion after the approval of intravenous recombinant tissue-type plasminogen activator (IV rt-PA) but before approval of the MERCI retriever. We retrospectively enrolled 1170 consecutive patients with AIS and major cerebral artery occlusion (496 women; mean age, 73.9 ± 12.3 years) who were admitted within 24 hours after the onset of symptoms to 12 Japanese stroke centers between October 2005 and June 2009. Cardioembolism was a leading cause of AIS in this group (68.2%). The occlusion sites of the major cerebral arteries included the common carotid artery and internal carotid artery (ICA; 29.6%), middle cerebral artery (52.2%), and basilar artery (7.6%). Recanalization therapy (RT) was performed in 32.0% of patients (IV rt-PA, 20.0%; neuroendovascular therapy, 9.4%; combined, 2.5%). Symptomatic intracerebral hemorrhage within 36 hours with a ≥ 1-point increase in the National Institutes of Health Stroke Scale score occurred in 5.3% of the patients. At 3 months (or at hospital discharge), 29.3% of the patients had a favorable outcome (based on a modified Rankin scale score of 0-2), 23.8% were bedridden, and 15.6% died. After multivariate adjustment, RT was positively associated with a favorable outcome and negatively associated with death, whereas age, baseline National Institutes of Health Stroke Scale score, and ICA occlusion were negatively associated with a favorable outcome and positively associated with death. One-third of the patients with AIS and major cerebral artery occlusion were treated with RT, which was independently associated with favorable outcomes and death. However, 40% of the patients became bedridden or died during the post-alteplase, pre-MERCI era in Japan.

Early thrombolytic treatment reduces analgesic requirement in patients with myocardial infarction

The duration and amount of analgesics required were investigated in 67 patients with myocardial infarction treated with intravenous recombinant tissue-type plasminogen activator (rtPA) or placebo in a randomized double-blind trial. Infusion of rtPA (100 mg)/placebo was started within 5 h after the onset of symptoms, and the requirement for analgesics during the following 48 h was recorded. Sixty-seven per cent of the 30 rtPA-treated patients required analgesic treatment for less than 6 h, compared to 38% of the 37 patients in the placebo group (P = 0.04). During the study period, patients in the rtPA group used the equivalent of 5.3 mg (median value) intravenous morphine, which was significantly less than the 11.2 mg used in the placebo group (P = 0.04). In conclusion, the present study suggests that early thrombolysis with intravenous rtPA reduces the amount and duration of analgesic treatment required by patients with myocardial infarction.

Tissue plasminogen activator and acute pulmonary embolism.

We assessed the efficacy and safety of peripheral intravenous recombinant human tissue-type plasminogen activator (rt-PA) in 47 patients with angiographically documented pulmonary embolism (PE). We administered 50 mg/2 h and, if necessary, an additional 40 mg/4 h. By 6 hours, 94% of the patients had angiographic evidence of clot lysis that was slight in 5, moderate in 12, and marked in 27 patients. Among the 34 patients with pulmonary hypertension prior to treatment, average pulmonary artery pressure decreased from 43/17 (27) to 31/13 (19) mm Hg (P less than 0.0001). The average lung scan perfusion defect decreased from 37% before therapy to 16% (P less than 0.01) after therapy among the 19 patients who had pre- and post-treatment lung scans. Of 7 patients with pre- and post-treatment imaging and Doppler echocardiograms, hypokinetic right ventricular wall movement (mild in 1, moderate in 2, and severe in 4) normalized in 5 and improved to mild hypokinesis in 2. Right ventricular diameter decreased from 3.9 +/- 1.0 to 2.0 +/- 0.5 cm (P less than 0.005). Fibrinogen decreased 33% from baseline at 2 h and 42% from baseline at 6 h. However, patients with the greatest degree of angiographic clot lysis at 2 h had a preponderance of fibrinogenolysis over fibrinolysis, demonstrated by a lower ratio of cross-linked fibrin degradation products to fibrin(ogen) degradation products (0.14 +/- 0.09 vs. 0.54 +/- 0.82) (P less than 0.04). Among selected patients, peripheral intravenous rt-PA is associated with rapid lysis of PE, improved pulmonary perfusion, and improved right ventricular function.