PSP- Classic

Tissue Plasminogen Activator Reduces Risk Of Stroke Disability

CHICAGO, IL -- June 17, 1999 -- In the National Institute of Neurological Disorders and Stroke (NINDS) Recombinant Tissue Plasminogen Activator Stroke Study, individuals treated with the clot-buster t-PA within three hours after the onset of symptoms of acute ischemic stroke were at least 30 percent more likely to have minimal or no disability at 12 months than were the placebo-treated patients.

This report extends the findings of the original study that was reported in 1995 and examined the outcomes of these patients over a three-month period. The study results were published last week in the New England Journal of Medicine.

"This study clearly demonstrates the advantages of receiving early treatment of stroke with t-PA during the three hour window after stroke symptoms begin," said Gregory Albers, M.D. and director of the Stanford Stroke Center in Palo Alto, CA. "The fact that the studies' results are consistent during three and 12 month periods shows that the beneficial effect of t-PA is sustained over time.

"Another important finding of the NINDS trial is that the stroke recurrence rate was similar in the t-PA and placebo group."

However, according to Albers, t-PA treatment is not without risk. Albers added that the rate of symptomatic intracerebral haemorrhage (bleeding in the brain) was higher in t-PA treated patients at both three and 12 month periods. However, the same trend toward a slightly lower death rate in the t-PA treated patients that was seen at three months was still present at one year.

"The major drawbacks to t-PA continue to be the increased risk of haemorrhage and the very short treatment window," Albers said.

Evidence-Based Cardiology

Evaluation of a Weight-Adjusted Single-Bolus Plasminogen Activator in Patients With Myocardial Infarction -- A Double-Blind, Randomized Angiographic Trial of Lanoteplase versus Alteplase

Abstracted by : Carlos S. Ince, MD, The Johns Hopkins Hospital, Baltimore, Md.

Background

Data from thrombolytic trials confirm the mortality benefit of this therapy in the timely treatment of acute mycoardial infarction. The time to complete reperfusion, as evidenced by TIMI grade 3 flow on angiography, is perhaps the most important predictive factor for beneficial outcomes. Current treatment mainstays include accelerated alteplase or double-bolus reteplase. Simpler effective regimens that utilize a single-bolus injection may offer additional benefits through earlier achievement of reperfusion and by reducing the risk of dosing errors.

Lanoteplase is a rationally designed variant of wild-type tissue plasminogen activator (tPA) developed to achieve greater fibrinolytic potency and prolonged half-life. Modifications of the chemical structure allow for enhanced fibrin specificity and allow delivery of effective thrombolytic therapy as a single 2- to 4-minute injection. The current study is a multicenter, double-blind, and randomized dose-ranging study comparing four doses of lanoteplase with alteplase. The primary objective was to determine whether a single-bolus dose of lanoteplase could restore complete coronary blood flow in a dose-related fashion at 60 minutes after injection in patients presenting within 6 hours of an acute myocardial infarction

Methods

Patients presenting within 6 hours of the onset of chest pain, using previously described eligibility criteria, were screened for enrollment. Patients were randomized to receive one of four doses of lanoteplase and alteplase placebo or accelerated alteplase and the lanoteplase placebo in a 1:1:1:1 ratio. All patients received only one active thrombolytic. Lanoteplase was administered in weight-adjusted doses of 15, 30, 60, or 120 kU/kg (not to exceed 12,000 kU). All patients received aspirin and heparin (adjusted for a goal aPTT of 60 to 85 seconds). Conventional anti-anginal therapy, including nitrates and beta-blockers, were used. The primary endpoints included angiographic evaluations of TIMI grade flow at 60 and 90 minutes postinjection. Another angiogram was performed between days 3 and 5. A composite clinical outcome included death, reinfarction, major bleeding, or heart failure within 30 days. Adverse events included bleeding and stroke.

Results

Data were analyzed from 602 of the 613 patients enrolled in the study. There was a statistically significant increase in the proportion of subjects with TIMI grade 3 flow at 60 minutes with increasing doses of lanoteplase doses (P < 0.001). Table 1 depicts TIMI grade flow for each study arm at 60 minutes after treatment initiation.

The proportion of subjects with TIMI grade 3 flow at 60 minutes increased from 23.6% in the 15-kU/kg group to 47.1% in the 120-kU/kg group. A smaller proportion of patients receiving alteplase achieved TIMI 3 flow at 60 minutes, but this was not significantly different from the lanoteplase 120-kU/kg group. Similarly, the angiographic results at 90 minutes demonstrated a statistically significant increase in the proportion of subjects with TIMI 3 flow with increasing lanoteplase dose (26.1% after the 15-kU/kg dose to 57.1% after the 120-kU/kg dose). The corresponding figures for the alteplase group at 90 minutes was 46.4%, which was not statistically different from the 120-kU/kg-lanoteplase group. When TIMI 2 or 3 flow was defined as successful reperfusion, 83.0% of patients receiving 120-kU/kg-lanoteplase were revascularized at 90 minutes compared to 71.4% of those receiving alteplase (difference 11.6%, 95% CI, 0.7% to 22.5%).

The proportions of subjects with unfavorable composite clinical outcomes ranged from 6.5% in the 30-kU/kg-lanoteplase group to 21.8% in the alteplase group. There was no dose-response relationship in the lanoteplase groups. There were 40.7% bleeding events in those receiving any dose of lanoteplase as compared 54.0% of subjects receiving alteplase. Major bleeding, defined as hemorrhagic stroke or bleeding associated with hemodynamic compromise, occurred in 1.5% of those in the lanoteplase groups versus 5.6% of the alteplase group. At 30 days, there were 15 deaths (3.1%) in the lanoteplase groups versus 8 deaths (6.5%) in the alteplase group

Conclusion

Single-bolus, weight-adjusted lanoteplase establishes complete reperfusion in a dose-related fashion up to 120 kU/kg in patients with suspected acute myocardial infarction. Lanoteplase at 120 kU/kg was as effective as alteplase in establishing TIMI 2 or 3 flow at 60 minutes and superior to restoring TIMI grades 2 or 3 flow at 90 minutes. The 30-day composite endpoint suggests that lanoteplase was at least as effective as alteplase in reducing major morbidity and mortality post-myocardial infarction. Thus the lanoteplase data is promising; however, larger trials powered to detect clinical superiority over established thrombolytic agents are warranted. The InTime II investigation will compare lanoteplase (120 kU/kg) with accelerated alteplase.

Table 1.

Tissue Plasminogen Activator for Acute Ischemic Stroke

Antonio Claudio do Amaral Baruzzi, Elias Knobel, Claudio Cirenza, Eduardo Noda Kihara, Valéria Carvalho Souza, Airton Massaro, Pedro Paulo Porto Jr, Paulo Hélio Monzillo, Alberto Alain Gabbai

Hospital Israelita Albert Einstein - São Paulo, SP

Arq Bras Cardiol 68(5):, 347-351, 1997

Purpose - To evaluate thrombolytic therapy with r-tPA for acute stroke within 6h of symptom onset, and assessment of neurologic outcome.

Methods - We studied 6 patients, four women, mean age 63±18 years, with severe neurologic deficit within 6h of stroke onset, and with no spontaneous improvement. The stroke was embolic in 3, and thrombotic in the others. All patients were submitted to a head CT scan followed by either a cerebral angiography in 3 patients, or a transcranial Doppler, in the other 3 for assessment of arterial obstruction, and patency after thrombolytic therapy. We used 0.9mg/kg of r-tPA, IV, over 60min in 5 patients, and 0.5mg/kg by intra-arterial infusion, over 60min, in one. At the beginning a bolus of 10% of the total dose was delivered during 1 to 2min. Head scan was repeated 24h and 7 days after treatment to detect ischemic areas and hemorrhagic complications.

Results - Middle cerebral artery occlusion was observed in 5 patients and posterior cerebral artery occlusion in one. The obstruction was cleared in 4 patients with persistence of the patency after 24h. A complete neurologic recovery was found in one patient, and a partial recovery in three. In two patients there was failure of arterial recanalization with no neurologic recovery. Only one patient had hemorrhagic transformation of ischemic tissue, without neurologic worsening. Death occurred in one patient due to pulmonary infection.