Recombinant Tissue-type Plasminogen Activator Therapy Research Articles

Impact of Off-Hour Admission on In-Hospital Outcomes for Patients With Stroke Receiving Reperfusion Therapy in China.

The structure and staffing of hospitals greatly impact patient outcomes, with frequent changes occurring during nights and weekends. This retrospective cohort study assessed the impact of admission timing on in-hospital management and outcomes for patients with stroke receiving reperfusion therapy in China using data from a nationwide registry. Data from patients receiving reperfusion therapy were extracted from the Chinese Stroke Center Alliance. Hospital admission time was categorized according to day/evening versus night and weekday versus weekend. Primary outcomes were in-hospital death or discharge against medical advice, hemorrhage transformation, early neurological deterioration, and major adverse cardiovascular events. Logistic regression was performed to compare in-hospital management performance and outcomes based on admission time categories. Overall, 42 381 patients received recombinant tissue-type plasminogen activator (r-tPA) therapy, and 5224 underwent endovascular treatment (EVT). Patients admitted during nighttime had a higher probability of receiving r-tPA therapy within 4.5 hours from onset or undergoing EVT within 6 hours from onset compared with those admitted during day/evening hours (adjusted odds ratio, 1.04 [95% CI, 1.01-1.08]; P=0.021; adjusted odds ratio, 1.72 [95% CI, 1.59-1.86]; P<0.001, respectively). However, no significant difference was observed between weekend and weekday admissions for either treatment. No notable differences were noted between weekends and weekdays or nighttime and daytime periods in door-to-needle time for r-tPA or door-to-puncture time for EVT initiation. Furthermore, weekend or nighttime admission did not have a significant effect on the primary outcomes of r-tPA therapy or EVT. Nevertheless, in patients undergoing EVT, a higher incidence of pneumonia was observed among those admitted at night compared with those admitted during day/evening hours (adjusted odds ratio, 1.22 [95% CI, 1.05-1.42]; P=0.011). Patients admitted at nighttime were more likely to receive r-tPA therapy or EVT within the time window recommended in the guidelines. However, patients receiving EVT admitted at night had an increased risk of pneumonia.

Increased microvascular permeability and low level of low-density lipoprotein cholesterol predict symptomatic intracerebral hemorrhage in acute ischemic stroke.

Symptomatic intracerebral hemorrhage is a serious potential complication of recombinant tissue-type plasminogen activator thrombolysis in acute ischemic stroke. We investigated the optimal imaging and clinical parameters to predict symptomatic intracerebral hemorrhage in acute ischemic stroke patients after recombinant tissue-type plasminogen activator therapy. We retrospectively reviewed 151 acute ischemic stroke patients with thrombolytic therapy, who were dichotomized into symptomatic intracerebral hemorrhage group and non-symptomatic intracerebral hemorrhage group. They underwent multimodal computed tomography, including the measurement of permeability surface. We compared the clinical and radiological characteristics between symptomatic intracerebral hemorrhage group and non-symptomatic intracerebral hemorrhage group, using univariate analysis. Receiver operating characteristic analysis and multivariate logistic regression analyses were then used to determine symptomatic intracerebral hemorrhage predictors. Of 151 patients, 14 patients (9.27%) developed symptomatic intracerebral hemorrhage on follow-up imaging. Relative permeability surface (infarct permeability surface/contralateral normal permeability surface) (p < 0.05) and baseline low-density lipoprotein cholesterol level (p < 0.05) were both predictors of symptomatic intracerebral hemorrhage. Receiver operating characteristic analysis of relative permeability surface revealed an optimal relative permeability surface threshold of 2.239, with an area under the curve of 0.87 (95% confidence interval, 0.732-1.0). The relative permeability surface was 2.239, the sensitivity for symptomatic intracerebral hemorrhage was 85.7%, the specificity was 94.9%, the positive predictive value was 70.6%, and the negative predictive value was 95.5%. For low-density lipoprotein cholesterol, the optimal threshold was 2.45, with an area under the curve of 0.726 (95% confidence interval, 0.586-0.867), the sensitivity for symptomatic intracerebral hemorrhage was 73.0%, the specificity was 64.3%, the positive predictive value was 67.16%, and the negative predictive value was 79.09%. Our study demonstrated that increased infarct permeability surface and low level of low-density lipoprotein cholesterol can be two predictors of symptomatic intracerebral hemorrhage. Detection of relative permeability surface and low-density lipoprotein cholesterol may help clinicians to identify acute ischemic stroke patients with the higher risk of symptomatic intracerebral hemorrhage; intravenous thrombolytic therapy should be carefully performed for patients with high relative permeability surface and low low-density lipoprotein cholesterol. We may take relative permeability surface and low-density lipoprotein cholesterol into account to refine therapeutic decision-making in acute ischemic stroke.

Influence of Thrombolysis on the Safety and Efficacy of Blocking Platelet Adhesion or Secretory Activity in Acute Ischemic Stroke in Mice.

In acute ischemic stroke (AIS), there is an alarming discrepancy between recanalization rates of up to 70% by combined recombinant tissue-type plasminogen activator (rt-PA) therapy and mechanical thrombectomy, and no clinical benefit in at least every second stroke patient. This is partly due to ischemia/reperfusion (I/R) injury. In a translational approach, we used mice lacking dense- (Unc13d-/-) or α-granules (Nbeal2-/-) and mice after blocking of platelet glycoprotein receptor (GP) Ib conferring protection from I/R injury. These mice underwent transient middle cerebral artery occlusion (tMCAO) and, as in the clinic, were treated with rt-PA. Our data show that rt-PA treatment is still safe in conjunction with selected anti-platelet therapies and pave the way for eagerly awaited additive treatment options in acute human stroke.

Releasing the Brakes on the Fibrinolytic System in Pulmonary Emboli

Background: In patients with hemodynamically significant pulmonary embolism, physiological fibrinolysis fails to dissolve thrombi acutely and r-tPA (recombinant tissue-type plasminogen activator) therapy may be required, despite its bleeding risk. To examine potential mechanisms, we analyzed the expression of key fibrinolytic molecules in experimental pulmonary emboli, assessed the contribution of α2-antiplasmin to fibrinolytic failure, and compared the effects of plasminogen activation and α2-antiplasmin inactivation on experimental thrombus dissolution and bleeding. Methods: Pulmonary embolism was induced by jugular vein infusion of 125 I-fibrin or fluorescein isothiocyanate-fibrin labeled emboli in anesthetized mice. Thrombus site expression of key fibrinolytic molecules was determined by immunofluorescence staining. The effects of r-tPA and α2-antiplasmin inactivation on fibrinolysis and bleeding were examined in a humanized model of pulmonary embolism. Results: The plasminogen activation and plasmin inhibition system assembled at the site of acute pulmonary emboli in vivo. Thrombus dissolution was markedly accelerated in mice with normal α2-antiplasmin levels treated with an α2-antiplasmin–inactivating antibody ( P &lt;0.0001). Dissolution of pulmonary emboli by α2-antiplasmin inactivation alone was comparable to 3 mg/kg r-tPA. Low-dose r-tPA alone did not dissolve emboli, but was synergistic with α2-antiplasmin inactivation, causing more embolus dissolution than clinical-dose r-tPA alone ( P &lt;0.001) or α2-antiplasmin inactivation alone ( P &lt;0.001). Despite greater thrombus dissolution, α2-antiplasmin inactivation alone, or in combination with low-dose r-tPA, did not lead to fibrinogen degradation, did not cause bleeding (versus controls), and caused less bleeding than clinical-dose r-tPA ( P &lt;0.001). Conclusions: Although the fibrinolytic system assembles at the site of pulmonary emboli, thrombus dissolution is halted by α2-antiplasmin. Inactivation of α2-antiplasmin was comparable to pharmacological r-tPA for dissolving thrombi. However, α2-antiplasmin inactivation showed a unique pattern of thrombus specificity, because unlike r-tPA, it did not degrade fibrinogen or enhance experimental bleeding. This suggests that modifying the activity of a key regulator of the fibrinolytic system, like α2-antiplasmin, may have unique therapeutic value in pulmonary embolism.

Needed dialog: regionalization of stroke systems of care along the trauma model.

The burden of stroke is indisputable. Stroke is the fourth leading cause of death and the leading cause of major disability in the United States, and affects ≈800 000 people every year.1 Of these events, ≈87% are acute ischemic strokes, or ≈700 000 per year. Furthermore, stroke accounts for ≈200 000 deaths and results in an estimated $73 billion cost to the United States healthcare system annually,2 the single highest Medicare reimbursement entity for long-term adult care. Interventions that positively impact the outcome of ischemic stroke would be of tremendous value to both patients and society at large. Although improvements have been made with increased public awareness, enhanced prehospital triage systems, and hospital stroke certification programs, recent studies suggest that acute ischemic stroke reperfusion interventions (both intravenous and intra-arterial) remain significantly underused.3 In most community settings, only 5% of patients with acute stroke actually receive intravenous recombinant tissue-type plasminogen activator (r-tPA) therapy.3,4 Furthermore, advanced stroke care goes beyond acute reperfusion with intravenous or intra-arterial techniques: for patients who develop significant infarcts, subsequent care, such as dedicated neurointensive management, intracranial pressure monitoring and control, decompressive surgery, or hemorrhage evacuation are all potentially critical aspects of managing ischemic or hemorrhagic strokes that can significantly affect patient outcome. These resources are often found only at comprehensive stroke centers (CSCs). Intra-arterial therapies, such as intra-arterial (IA) thrombolysis or mechanical thrombectomy, have emerged as a means of restoring perfusion after large vessel occlusion and have exhibited excellent recanalization and outcome measures in recent prospective trials.5–13 Although 3 randomized trials published in 2013 demonstrated no added benefit to IA intervention compared with intravenous tPA alone,14–16 the randomized controlled trials the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands …

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&lt;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&lt;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&lt;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.

Analysis of blood pressure, heart rate, NIHSS score, GCS score of cerebral infarction patients with cerebral hemorrhage after recombinant human tissue-type plasminogen activator (rt-PA) therapy

Objective To analyze the blood pressure,heart rate,the US national institutes of health stroke scale(NIHSS) score,Glasgow coma scale(GCS) score for cerebral infarction patients with cerebral hemorrhage after recombinant human tissue-type plasminogen activator (rt-PA) therapy.Methods From April 2011 to April 2013,48 cases with cerebral infarction after intravenous rt-PA thrombolysis were collected.These cases were divided into two groups:the first group (32 cases):without cerebral hemorrhage after thrombolysis; the second group (16 cases):with cerebral hemorrhage after thrombolysis.The systolic blood pressure,diastolic blood pressure,heart rote,NIHSS score and GCS score were compared between the two groups before and after thrombolysis.Results After thrombolysis,the systolic and diastolic blood pressure were significantly increased in cerebral hemorrhage cases compared with before thrombolysis and patients without cerebral hemorrhage.After thrombolysis,the NIHSS score was significantly reduced in the cases without cerebral hemorrhage compared with that before thrombolysis,while the NIHSS score was significantly higher in the cases with cerebral hemorrhage compared with that before thrombolysis.After thrombolysis,the heart rate and GCS score showed no significant difference between the patients with and without cerebral hemorrhage.Conclusions The rising of systolic blood pressure,diastolic blood pressure and NIHSS score helps us determine the early cerebral hemorrhage after thrombolysis in cerebral infarction patients. Key words: rt-PA; Cerebral infarction; Cerebral hemorrhage; Blood pressure; NIHSS score

Factors Associated with Early Recanalization Failure following Intravenous rt-PA Therapy for Ischemic Stroke

Background: Although intravenous recombinant tissue-type plasminogen activator (rt-PA) therapy can be effective for ischemic stroke, a considerable percentage of patients do not receive any benefit as a result of early recanalization failure. We aimed to investigate the factors associated with early recanalization failure following intravenous rt-PA therapy. Methods: Patients with acute ischemic stroke and internal carotid artery (ICA) or middle cerebral artery occlusion on initial magnetic resonance angiography (MRA) who received intravenous rt-PA therapy within 3 h of stroke onset and underwent follow-up MRA within 8 h after treatment were enrolled. Baseline characteristics, stroke features, onset to treatment time, initial National Institutes of Health Stroke Scale (NIHSS) score, initial Alberta Stroke Programme Early CT Score on diffusion-weighted imaging-ASPECTS (Alberta Stroke Program Early Computed Tomography Score), the presence of ICA or M1 origin (the residual length <5 mm) (ICA/M1 origin occlusion), initial vital signs, and laboratory findings were recorded. Early recanalization on the follow-up MRA within 8 h was evaluated by modified Mori grade: grade 0, no reperfusion; grade 1, movement of thrombus; grade 2, partial recanalization, and grade 3, complete recanalization. Results: Seventy subjects (35 women, 77 ± 12 years) were enrolled. The median (interquartile range: IQR) NIHSS score was 18 (12.5-24), and the mean onset to treatment time was 141 ± 54 min. ICA was occluded in 29%, M1 origin in 17%, M1 middle in 13%, M1 distal in 26% and M2 in 15%. The median (IQR) pretreatment diffusion weighted imaging-ASPECTS was 8 (6-9), and follow-up time of MRA was 65 min (59-70) after rt-PA therapy. Thirty-two subjects (46%) showed modified Mori grade 0; 10 (14%), grade 1; 9 (13%), grade 2, and 19 (27%), grade 3. Multivariate analyses revealed ICA/M1 origin occlusion (OR 3.71, 95% CI 1.03-14.87, p = 0.044), and C-reactive protein (per 0.1-mg/dl increment, OR 1.19, 95% CI 1.03-1.44, p = 0.013) were independently associated with subjects with no recanalization (grade 0-1), whereas age (per years old, OR 0.93, 95% CI 0.86-0.99, p = 0.014) and high-density lipoprotein cholesterol (per 1-mg/dl increment, OR 0.94, 95% CI 0.89-0.98, p = 0.004) were inversely associated with those. Conclusion: ICA/M1 origin occlusion and C-reactive protein were positively and high-density lipoprotein cholesterol was negatively associated with early recanalization failure.

Prospective, Randomized, Open-Label Phase II Trial on Concomitant Intraventricular Fibrinolysis and Low-Frequency Rotation After Severe Subarachnoid Hemorrhage

The goal of this randomized, open-label phase II study was to investigate the effect of concomitant low-frequency head-motion therapy and intraventricular fibrinolysis in patients after surgical or endovascular treatment for aneurysmal subarachnoid hemorrhage. Sixty patients experiencing subarachnoid hemorrhage were randomized into treatment with intraventricular application of recombinant tissue-type plasminogen activator and lateral rotational therapy (experimental) or treatment as usual (control). The primary end point was defined as functional outcome, measured by Glasgow Outcome Scale at discharge and at 3-month follow-up. Clot clearance rate, radiographic features of delayed cerebral ischemia, and posthemorrhagic hydrocephalus were defined as secondary end points. The majority of patients (78.3%) experienced severe subarachnoid hemorrhage. Although there was a higher incidence of subgaleal hematomas in the experimental group, there was no difference in the incidence of adverse or severe adverse events between the 2 groups. Despite significantly higher clot clearance rates, there was no beneficial effect on the incidence of delayed cerebral ischemia and poor functional outcome, as well as posthemorrhagic hydrocephalus after experimental treatment. Despite the ineffectiveness on reduction of delayed cerebral ischemia or poor functional outcome, intraventricular fibrinolysis and kinetic therapy seems to be a safe and effective concept for therapeutic reduction of subarachnoid clot in a patient collective experiencing predominantly severe subarachnoid hemorrhage. Therefore, future studies should investigate this treatment in a larger patient collective with a lower degree of primary brain injury and until full clot clearance on serial imaging. http://www.controlled-trials.com. Unique identifier: ICRCTN13230264.

Early Ischemic Change on CT Versus Diffusion-Weighted Imaging for Patients With Stroke Receiving Intravenous Recombinant Tissue-Type Plasminogen Activator Therapy

Alberta Stroke Programme Early CT Score (ASPECTS) is a quantitative topographical score to evaluate early ischemic change in the middle cerebral arterial territory on CT as well as on diffusion-weighted imaging (DWI). The aim of the present study was to elucidate the relationship between CT-ASPECTS and DWI-ASPECTS for patients with hyperacute stroke and their associations with outcomes after recombinant tissue-type plasminogen activator therapy based on a multicenter registry. ASPECTS was assessed on both CT and DWI before intravenous 0.6 mg/kg alteplase in 360 patients with stroke (119 women, 71 ± 11 years old). The outcomes were symptomatic intracerebral hemorrhage within 36 hours and independence at 3 months defined by a modified Rankin Scale score of 0 to 2. DWI-ASPECTS was positively correlated with CT-ASPECTS (ρ=0.511, P<0.001) and was lower than CT-ASPECTS (median 8 [interquartile range, 6 to 9] versus 9 [8 to 10], P<0.001). Higher baseline National Institutes of Health Stroke Scale score (standardized partial regression coefficient [β] 0.061, P<0.001) and cardioembolic stroke (β 0.35, P<0.001) were related to this discrepancy. The area under the receiver operating characteristic curve for predicting sICH (12 patients) using ASPECTS was 0.673 (95% CI, 0.503 to 0.807) by CT and 0.764 (95% CI, 0.635 to 0.858) by DWI (P=0.275). The area for predicting independence at 3 months (192 patients) was 0.621 (0.564 to 0.674) by CT and 0.639 (0.580 to 0.694) by DWI (P=0.535). For patients with hyperacute stroke, DWI-ASPECTS scored approximately 1 point lower than CT-ASPECTS. Both CT-ASPECTS and DWI-ASPECTS were useful predictors of symptomatic intracerebral hemorrhage and independence at 3 months after recombinant tissue-type plasminogen activator.

Cerebral β‐amyloid detected by Pittsburgh compound B positron emission topography predisposes to recombinant tissue plasminogen activator‐related hemorrhage

Cerebral amyloid angiopathy (CAA) may be an important predisposing factor for the hemorrhagic complications of recombinant tissue-type plasminogen activator (rt-PA) therapy. We studied patients treated within 3 hours of onset of ischemic stroke with rt-PA using positron emission tomography to compare Pittsburgh compound B (PiB) (a cerebral β-amyloid ligand) retention in those with and without parenchymal hemorrhage (PH) and normal controls. Neocortical PiB retention was higher among patients with PH compared with patients without PH and normal controls, suggesting underlying CAA as a predisposing factor for rt-PA-related hemorrhage. This finding may provide an impetus for the development of a more practical rapid pretreatment screening technique.

Pretreatment ASPECTS on DWI predicts 3-month outcome following rt-PA

To evaluate whether the pretreatment Alberta Stroke Programme Early CT Score (ASPECTS) assessed using diffusion-weighted imaging (DWI) predicts stroke outcomes at 3 months following IV recombinant tissue-type plasminogen activator (rt-PA) therapy. Stroke patients treated with rt-PA (0.6 mg/kg alteplase) in 10 stroke centers in Japan were retrospectively studied. ASPECTS was assessed on DWI just prior to rt-PA injection. The primary outcome was a modified Rankin Scale (mRS) score of 0-2 at 3 months. Secondary outcomes included death at 3 months and symptomatic intracerebral hemorrhage (sICH) within 36 hours. For the 477 patients (316 men, 71 +/- 11 years old) enrolled, the median NIH Stroke Scale score was 13 (interquartile range 7-18.5), the median ASPECTS on DWI was 8 (7-10), and sICH was identified in 15 patients (3.1%). At 3 months, 245 (51.4%) had an mRS score of 0-2, and 29 (6.1%) had died. Patients with an mRS score of 0-2 had higher median ASPECTS (9; interquartile range 8-10) than other patients (8; 6-9, p < 0.001). Using receiver operating characteristic curves, the optimal cutoff ASPECTS to predict an mRS score of 0-2 was > or =7. On multivariate regression analysis, ASPECTS > or =7 was related to an mRS score of 0-2 (odds ratio 1.85; 95% confidence interval 1.07-3.24), ASPECTS < or =4 was related to death (3.61; 1.23-9.91), and ASPECTS < or =5 was related to sICH (4.74; 1.54-13.64). ASPECTS on DWI was independently predictive of functional and vital outcomes at 3 months, as well as sICH within 36 hours, following rt-PA therapy for stroke patients.

Recombinant tissue-type plasminogen activator therapy of thrombosis in 16 neonates.

We report 16 cases of neonatal vascular thrombosis treated with the same protocol for recombinant tissue-type plasminogen activator infusion. Flow restoration was complete in seven patients, partial in seven, and absent in two. Safety was satisfactory provided contraindications were respected.

Frequency of “optimal anticoagulation” for acute myocardial infarction after thrombolysis with front-loaded recombinant tissue-type plasminogen activator and conjunctive therapy with recombinant hirudin (HBW O23)

This retrospective analysis reviewed 183 patients with acute myocardial infarction who were given front-loaded recombinant tissue-type plasminogen activator (rt-PA) and r-hirudin (HBW 023) in 1 of 4 dose groups (bolus dose of 0.07, 0.1, 0.2, or 0.4 mg/kg, followed by an infusion of 0.05, 0.06, 0.1, or 0.15 ma/kg/hour over 48 hours). Activated partial thromboplastin time (aPTT) levels were determined at baseline and at 4, 8, 12, 16, 20, 24, 32, 40, and 48 hours. Of the 178 patients with r-hirudin treatment for ≥12 hours, anti-coagulation was optimal in 55.1% (all aPTTs >2 × baseline), suboptimal in 33.7% (lowest aPTT >1.5 but <2 × baseline), and inadequate in 11.2% (≥1 aPTT but < 1.5 × baseline). Optimal anticoagulation was observed more frequently in the higher dose groups (dose 1, 15%; dose 2, 44.4%; dose 3, 63.4%; dose 4, 73.4%; p for trend <0.0001). Patency (according to Thrombolysis in Myocardial Infarction trial grade 2 or 3) of the infarct artery after 36 to 48 hours was higher in the group with optimal anticoagulation compared with those with suboptimal or inadequate anticoagulation: 97.9%, 88.4%, and 85%, respectively (p = 0.03 optimal vs suboptimal or inadequate anticoagulation). In conclusion, r-hirudin in a dose of 0.1 or 0.15 mg/kg/hour achieves an optimal anticoagulation in about 63% or 74% of patients, which is associated with an enhanced patency 24 to 48 hours after rt-PA. A subsequent study revealed that this effective anticoagulation may be accompanied by an increased risk of severe bleeding complications after thrombolysis.

Clinical features and pathogenesis of intracerebral hemorrhage after rt-PA and heparin therapy for acute myocardial infarction

Parenchymatous intracerebral hemorrhage (ICH) is a serious, infrequent complication of thrombolytic therapy for acute myocardial infarction. We studied the clinical and radiologic features, manner of presentation, associated factors, and temporal course in 23 patients with ICH associated with 150 mg or 100 mg recombinant tissue-type plasminogen activator (rt-PA) and heparin therapy for acute myocardial infarction in the Thrombolysis in Myocardial Infarction (TIMI) II Pilot and Randomized Clinical Trial. In TIMI II, 13 of the 23 ICH patients developed or maintained systolic blood pressure > or = 160 mm Hg or diastolic blood pressure > or = 90 mm Hg during the rt-PA infusion and before the onset of neurologic symptoms. Six patients (26%) had life-threatening ventricular arrhythmias, five before onset of neurologic symptoms. A decreased level of consciousness was the earliest neurologic abnormality in 15 (65%) and the most common initial physical finding (in 19, or 82%). Onset was usually gradual (70%), but time to maximal deficit was frequently (61%) within 6 hours of onset. The locations of the primary ICH sites were lobar in 16 (70%), thalamic in four (17%), and brainstem-cerebellum in three (13%), but the putamen was never the primary site. Multiple lobar hemorrhages occurred in six cases (26%). The timing and size of ICH was similar among patients treated with 150 mg rt-PA and 100 mg rt-PA. Brain CT demonstrated an arteriovenous malformation in one case. Four patients had hypofibrinogenemia, which was profound in three patients. Pathologic findings were available for five patients. Of these, three patients had cerebral amyloid angiopathy, and one had hemorrhagic transformation of an ischemic cerebral infarction found at autopsy. We conclude that ICH following rt-PA and heparin therapy for acute myocardial infarction presents as a distinctive clinical syndrome. Intracerebral bleeding after combined thrombolytic and antithrombotic therapy may be associated with cerebral amyloid angiopathy and other vascular lesions. Acute or persistent hypertension before or during rt-PA infusion, life-threatening ventricular arrhythmias, and hypofibrinogenemia, either alone or in combination, may play roles in some cases. Care should be exercised when considering thrombolytic therapy for patients with risk factors for ICH.

Recombinant tissue-type plasminogen activator therapy in prosthetic mitral valve thrombosis: assessment by transthoracic and transesophageal echocardiography

Prosthetic cardiac thrombosis is a life-threatening complication that needs prompt diagnosis and therapy. We used recombinant tissue-type plasminogen activator (rT-PA), followed by heparin, in three patients with mitral prosthetic thrombosis, which was evident in two and suspect in one. Transthoracic and transesophageal echocardiography were employed in the diagnosis of both thrombosis and its resolution. No complications occurred. Immediately after the end of treatment with rT-PA, clinical status and echocardiographic data improved in all cases: transthoracic echocardiography showed the normalization of prosthetic function and transesophageal echocardiography showed resolution of thrombosis. One patient needed reoperation for rethrombosis due to the presence of prosthetic fibrous clot. rT-PA, followed by heparin, led to a good clinical result without bleeding and embolic complications in selected patients with mitral prosthetic thrombosis. Transthoracic and transesophageal echocardiography are complementary diagnostic tools in the diagnosis and management of patients with prosthetic thrombosis.

Comparison of front-loaded recombinant tissue-type plasminogen activator, anistreplase and combination thrombolytic therapy for acute myocardial infarction: Results of the thrombolysis in myocardial infarction (TIMI) 4 trial

Objectives. The aim of our study was to determine a superior tbrombolytic regimen from three: anistreplase (APSAC), frontloaded recombinant tissue-type plasminogen activator (rt-PA) or combination thrombolytic therapy.Background. Although thrombolytic therapy has been shown to reduce mortality and morbidity after acute myocardial infarction, it has not been clear whether more aggressive thrombolyticantithrombotic regimens could improve the outcome achieved with standard regimens.Methods. To address this issue, 382 patients with acute myocardial infection were randomized to receive in a double-blind fashion (along with intravenous heparin and aspirin) APSAC, front-loaded rt-PA or a combination of both agents. The primary end point “unsatisfactory outcome” was a composite clinical end point assessed through hospital discharge.Results. Patency of the infarct-related artery (Thrombolysis in Myocardial Infarction [TIMI] grade 2 or 3 flow) at 60 min after the start of thrombolysis was significantly higher in rt-PA-treated patients (77.8% vs. 59.5% for APSAC-treated patients and 59.3% for combination-treated patients [rt-PA vs. APSAC, p = 0.02; rt-PA vs. combination, p = 0.03]). At 90 min, the incidence of both infarct-related artery patency and TIMI grade 3 flow was significantly higher in rt-PA-treated patients (60.2% had TIMI grade 3 flow vs. 42.9% and 44.8% of APSAC- and combination-treated patients, respectively [rt-PA vs. APSAC, p < 0.01; rt-PA vs. combination, p = 0.02]). The incidence of unsatisfactory outcome was 41.3% for rt-PA compared with 49% for APSAC and 53.6% for the combination (rt-PA vs. APSAC, p = 0.19; rt-PA vs. combination, p = 0.06). The mortality rate at 6 weeks was lowest in the rt-PA-treated patients (2.2% vs. 8.8% for APSAC and 7.2% for combination thrombolytic therapy [rt-PA vs. APSAC, p = 0.02; rt-PA vs. combination, p = 0.06]).Conclusions. Front-loaded rt-PA achieved significantly higher rates of early reperfusion and was associated with trends toward better overall clinical benefit and survival than those achieved with a standard thrombolytic agent or combination thrombolytic therapy. These findings support the concept that more rapid reperfusion of the infarct-related artery is associated with improved clinical outcome.

Effects of thrombolytic therapy administered 6 to 24 hours after myocardial infarction on the signal-averaged ECG. Results of a multicenter randomized trial. LATE Ancillary Study Investigators. Late Assessment of Thrombolytic Efficacy.

Thrombolytic therapy reduces mortality after acute myocardial infarction, even when treatment is initiated relatively late after onset of symptoms. The mechanism underlying this survival benefit is incompletely understood. In a prospectively designed ancillary study of a randomized, placebo-controlled trial of late thrombolytic therapy (LATE), the signal-averaged (SA) ECG was recorded before hospital discharge in an effort to assess the effect of thrombolytic therapy on arrhythmia substrate. Three hundred ten patients were enrolled at 23 participating sites; 160 patients received placebo, and 150 patients received recombinant tissue-type plasminogen activator (rTPA) therapy 6 to 24 hours after onset of symptoms. Compared with placebo, rTPA tended to reduce the frequency of SAECG abnormality (filtered QRS duration > 120 milliseconds) by 37% (95% CI, -64%, +6%; P = .087) and the filtered QRS duration (105.7 +/- 13.8 versus 108.8 +/- 14.6 milliseconds, P = .05). In the prespecified subgroup of 185 patients with ST elevation on the qualifying ECG, rTPA resulted in a 52% reduction (95% CI, 4% to 77%, P = .011) of SAECG abnormality and a shorter filtered QRS duration (105.7 +/- 10.9 versus 110.7 +/- 15.9 milliseconds, P = .01). No benefit was seen in patients without ST elevation on ECG. Late thrombolytic therapy produced a more stable electrical substrate, which probably represents an important mechanism of mortality benefit.

Clinical importance of thrombocytopenia occurring in the hospital phase after administration of thrombolytic therapy for acute myocardial infarction

Objectives. The purpose of this study was to examine the incidence and clinical implications of thrombocytopenia that occurs in hospital after administration of thrombolytic therapy for acute myocardial infarction.Background. The use of thrombolytic therapy in patients with acute myocardial infarction has improved mortality rates, but hemorrhage remains a major complication. Because thrombocytopenia may be associated with hemorrhage after thrombolytic therapy, we examined the incidence and clinical implications of thrombocytopenia after administration of thrombolytic therapy for acute myocardial infarction.Methods. The patient population comprised 1,001 patients enrolled in Phases 2,3 and 5 of the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) trial and the urokinase trial. Patients received recombinant tissue-type plasminogen activator, urokinase or combination therapy in various dosing schemes. All patients received heparin, aspirin and a calcium-channel blocking agent. Thrombocytopenia occurring anytime after thrombolytic therapy was defined as a nadir platelet count either <100,000/μl or < 1/2 baseline. Blood loss was quantified by a bleeding index. Multiple logistic regression was used to evaluate the independent contribution of thrombocytopenia in a model predicting inhospital mortality.Results. Thrombocytopenia occurred in 16.4% of patients, with no difference among the thrombolytic regimens. Patients with thrombocytopenia had a lower median acute ejection fraction and a higher likelihood of three-vessel coronary artery disease than patients without thrombocytopenia. Patients with thrombocytopenia had more hemorrhage, a higher in-hospital mortality rate and a more complicated hospital course than patients without thrombocytopenia, even after consideration of other important variables, including age, acute ejection fraction, number of diseased vessels, bypass surgery and use of intraaortic balloon counterpulsation.Conclusions. Thrombocytopenia after thrombolytic therapy is a common event and is associated with excess hemorrhage and mortality. Platelet counts should be monitored daily after administration of thrombolytic therapy because the appearance of thrombocytopenia identifies a subset of patients at increased risk for hemorrhage and death.

Disappearance of a syndrome: Dressler's syndrome in the era of thrombolysis.

The incidence of the post-myocardial infarction syndrome (Dressler's syndrome) among thrombolized patients has not been established yet. To clarify this issue we prospectively studied 201 consecutive patients with acute myocardial infarction who had undergone recombinant tissue-type plasminogen activator therapy followed by 5 days of heparin administration. All patients were followed for at least 3 months for clinical signs of Dressler's syndrome. None of the 148 patients (76%) who showed clinical signs of early reperfusion had Dressler's syndrome. The sole patient in the group who manifested the syndrome developed it 3 weeks following extensive anterior myocardial infarction with no evidence of reperfusion. Although 4 patients manifested signs of early pericarditis, none developed the syndrome. We conclude that Dressler's syndrome has in fact been rendered a rare phenomenon among patients who benefit from thrombolytic therapy.