Role of Tissue Plasminogen Activator in Acute Ischemic Stroke

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  • 364 n The Annals of Pharmacotherapy n 2011 March, Volume 45 theannals.com

    ARTICLES

    Stroke is the third leading cause ofdeath in the US behind cardiovascu-lar disease and cancer. Approximately2.7% of men and 2.5% of women olderthan 18 years have had a stroke and thereare nearly 800,000 stroke occurrenceseach year with a mortality rate approach-ing 150,000.1

    Ischemic stroke commonly presentsas an acute onset of focal neurologicdeficit lasting greater than 24 hours.2 Mostpatients present with weakness on one sideof the body, visual impairment, and inabil-ity to speak. Diagnosis is confirmed withcomputed tomography (CT) scanning andmagnetic resonance imaging. Patients athighest risk of developing an ischemicstroke are those with hypertension, dia-betes, dyslipidemia, atrial fibrillation,cigarette smoking, and obesity.2,3

    The immediate goal of therapy in acutestroke is to reduce neurologic injury andlong-term disability. Once the patient isthrough the hyperacute period, the goal oftherapy is to prevent recurrence and ulti-mately decrease mortality.2,3

    The treatment for acute ischemicstroke has a narrow therapeutic window,making timely evaluation and diagnosis

    Role of Tissue Plasminogen Activator in Acute Ischemic Stroke

    Molly A Hatcher and Jessica A Starr

    Cardiology

    Author information provided at end of text.

    OBJECTIVE: To evaluate the literature regarding the use of intravenous tissueplasminogen activator (tPA) in the treatment of acute ischemic stroke, focusingon the appropriate usage criteria and administration time window.

    DATA SOURCES: A PubMed and MEDLINE search was performed (1990-November 2010) using the key words alteplase, tissue plasminogen activator,thrombolytic, ischemic stroke, and cerebrovascular accident.

    STUDY SELECTION AND DATA EXTRACTION: Clinical trials published in English wereevaluated and relevant primary literature evaluating the use of tPA in acuteischemic stroke was included.

    DATA SYNTHESIS: The NINDS (National Institute of Neurological Disorders andStroke) trial revealed clinical efficacy of tPA in the treatment of acute ischemic strokewhen administered within 3 hours of stroke symptom onset and served as thefoundation for the American Heart Association/American Stroke Association(AHA/ASA) acute ischemic stroke guideline recommendations. The ECASS(European Cooperative Acute Stroke Study) I, ECASS II, and ATLANTIS (AlteplaseThrombolysis for Acute Noninterventional Therapy in Ischemic Stroke), part A andB, trials each assessed the efficacy of tPA when administered beyond 3 hours ofischemic stroke onset, but the results of each trial did not support its use beyond 3hours. The ECASS III trial showed clinical efficacy of tPA when administered up to4.5 hours. The SITS-MOST (Safe Implementation of Thrombolysis in Stroke-Monitoring Study) and SITS-ISTR (Safe Implementation of Thrombolysis in StrokeInternational Stroke Thrombolysis Register) registries evaluated the safety andefficacy of tPA at both 3 and 4.5 hours and showed promising results. In 2009, theAHA/ASA stroke guidelines were updated to support the use of tPA in selectpatients up to 4.5 hours after symptom onset.

    CONCLUSIONS: tPA is effective when administered up to 4.5 hours after ischemicstroke symptom onset in select patients. However, timely administration remainsparamount to achievement of optimal therapeutic outcomes.

    KEY WORDS: alteplase, cerebrovascular accident, ischemic stroke, thrombolytic,tissue plasminogen activator.

    Ann Pharmacother 2011;45:364-71.

    Published Online, 8 Mar 2011, theannals.com, DOI 10.1345/aph.1P525

    at TEXAS SOUTHERN UNIVERSITY on December 10, 2014aop.sagepub.comDownloaded from

    http://aop.sagepub.com/

  • essential. Currently, only 2 pharmacologic agents have re-ceived a Class I, Level of Evidence A recommendationfrom the American Heart Association/American StrokeAssociation (AHA/ASA) for use in treatment of acute is-chemic stroke. These agents are intravenous tissue plas-minogen activator (tPA) and aspirin.4,5 tPA is the only fibri-nolytic agent used in the treatment of acute ischemicstroke. It is recommended due to its ability to achieve earlyreperfusion and improve neurologic outcomes; however,its use is limited by its narrow therapeutic index and strictcriteria for use.4 tPA induces its therapeutic effects by initi-ating fibrinolysis through conversion of the inactive en-zyme, plasminogen, into its active form, plasmin.6 Plasminworks by digesting the fibrin molecules that serve as thestructural framework of blood clots, thereby dissolving theoccluding thrombus responsible for an ischemic stroke.While tPA has been shown to be effective in the treatmentof ischemic stroke, it also has the potential to cause life-threatening bleeding.4-6 The risk of such adverse effects hasled to extensive research concerning the appropriate crite-ria for use of tPA in acute ischemic stroke. Currently, theAHA/ASA consensus recommendations regarding the useof tPA in acute ischemic stroke indicate that eligible pa-tients (Table 1) should receive tPA within 3 hours of is-chemic stroke symptom onset.4 This recommendationcame largely from the results of the NINDS (National In-stitute of Neurological Disorders and Stroke) trial.7 Four

    other clinical studies attempted to discern the appropriateuse of tPA in acute ischemic stroke; however, none of thesetrials had results comparable to those of the NINDSstudy.8-11 The ECASS (European Cooperative Acute StrokeStudy) III trial investigated the use of tPA beyond 3 hoursafter stroke symptom onset.12 The results of this trialprompted an update in 2009 to the AHA/ASA consensusrecommendations to include the option of using tPA treat-ment up to 4.5 hours poststroke onset in patients who meeteligibility criteria (Table 2).13 In the treatment of acute is-chemic stroke, tPA is administered intravenously at a doseof 0.9 mg/kg (maximum 90 mg), with 10% of the totaldose given as a bolus over 1 minute and the remaining90% given as a continuous infusion over 1 hour.4-6

    The objective of this paper is to review the literature re-garding the use of tPA in the treatment of acute ischemicstroke, focusing on the appropriate usage criteria and ad-ministration time window.

    Data Sources and Selection

    A search of PubMed and MEDLINE (1990-November2010) was undertaken to select literature relating to the useof tPA in acute ischemic stroke treatment. Key words in-cluded alteplase, tissue plasminogen activator, thrombolyt-ic, ischemic stroke, and cerebrovascular accident. Datasearch restrictions included articles published in English.

    Establishment of the 3-Hour TreatmentWindow

    The NINDS study group assessed the safetyand efficacy of tPA when administered within3 hours of symptom onset in the treatment ofacute ischemic stroke (Table 3).7 A total of 624patients were randomized to receive treatmentwith either tPA 0.9 mg/kg or placebo. Thestudy was carried out in 2 parts. The primaryendpoint of part 1 was clinical efficacy at 24hours after stroke onset. Clinical efficacy wasdefined as either complete resolution of neuro-logic deficit or improvement from baseline by4 or more points on the National Institutes ofHealth Stroke Scale (NIHSS). The primaryendpoint of part 2 was clinical benefit of tPA 3months after stroke onset. Four outcome mea-sures were used in part 2 to assess the func-tionality and recovery of patients: Barthel In-dex (BI), Modified Rankin Scale (mRS), Glas-gow Outcome Scale, and the NIHSS. Thebaseline demographics of the patients weresimilar among groups, with a median NIHSSscore of 14 in both groups in part 1 and a me-dian score of 14 in the tPA group and 15 in the

    The Annals of Pharmacotherapy n 2011 March, Volume 45 n 365theannals.com

    Table 1. Criteria for tPA Administration4

    Diagnosis of ischemic stroke causing measurable neurologic deficit

    Neurologic signs do not diminish spontaneously

    Neurologic signs are not minor or isolated

    Major deficits should be treated with caution

    Stroke symptoms do not suggest presence of subarachnoid hemorrhage

    Symptom onset no more than 3 hours prior to treatment

    No head trauma, prior stroke, or myocardial infarction in the previous 3 months

    No gastrointestinal or urinary tract hemorrhage in previous 21 days

    No major surgery in the previous 14 days

    No arterial puncture at a noncompressible site in the previous 7 days

    No history of previous intracranial hemorrhage

    Nonelevated blood pressure (systolic

  • placebo group in part 2. Results of part 1 revealed agreater, but nonsignificant, improvement in clinical effica-cy 24 hours after stroke onset in the tPA group. Results ofpart 2 revealed significant improvements 3 months afterstroke onset in the tPA group compared to the placebogroup in all 4 outcome measures. The occurrence of in-tracranial hemorrhage was higher in the tPA group than inthe placebo group. The NINDS trial defined symptomaticintracranial hemorrhage as a hemorrhage that was not de-tected by earlier CT scans and had led to signs of hemor-rhage or a decrease in neurologic status. No significant dif-ferences were found in 90-day mortality among the tPAand placebo groups. The investigators concluded thatgreater improvements were seen in patients with ischemicstroke who were treated within 3 hours of stroke symptomonset with tPA, despite higher percentages of hemorrhagein the tPA group.

    Clinical trials conducted following the publication of theNINDS trial focused on finding the appropriate time to ini-tiate treatment with tPA following stroke symptom onset.A summary of each clinical trial is presented in Table 3.

    PROPOSED TREATMENT WITHIN 6 HOURS

    The ECASS I, ECASS II, and ATLANTIS (AlteplaseThrombolysis for Acute Noninterventional Therapy in Is-chemic Stroke), part A trials all investigated extending theuse of tPA to within 6 hours of stroke symptom onset.8-10

    The ECASS I trial assessed the safety and efficacy oftPA when administered up to 6 hours after symptom onsetin the treatment of acute ischemic stroke.8 A total of 620patients were randomized to receive treatment with eithertPA 1.1 mg/kg or placebo. The primary endpoint was pa-tient independence at 90 days determined by the BI and theabsence of symptoms at 90 days determined by the mRS.The baseline demographics were similar between thegroups, with a median NIHSS score of 12 in the tPA groupand 13 in the placebo group. No statistically significant dif-ferences were found at the end of 90 days for either of theprimary endpoints. Intracranial hemorrhagic events weresignificantly higher in the tPA group than in the placebogroup. The ECASS I trial defined an intracranial hemor-

    rhagic event to be 1 of the following: a small petechiaealong the margins of the infarct, confluent petechiae withinthe infarcted area without space-occupying effect, a bloodclot not exceeding 30% of the infarcted area with mildspace-occupying effect, or a dense blood clot exceeding30% percent of the infarct volume with significant space-occupying effect. Mortality rates were higher in the tPAgroup at the end of 90 days than in the placebo group. Dueto the lack of efficacy and the higher mortality and in-tracranial hemorrhage rates found in the tPA group, theECASS I investigators concluded that tPA at a dose of 1.1mg/kg cannot be recommended for use up to 6 hours afterstroke symptom onset in patients with acute ischemicstroke.8

    The ECASS II trial assessed the safety and efficacy oftPA when administered up to 6 hours after symptom onsetin the treatment of acute ischemic stroke.9 A total of 800patients were randomized to receive treatment with eithertPA 0.9 mg/kg or placebo. Less than 20% of all patientswere randomized within 3 hours of symptom onset. Theprimary endpoint was the absence of symptoms and dis-ability at 90 days determined by the mRS. The baseline de-mographics of the patients were similar between groups,with a median NIHSS score of 11 in both groups, whichwas lower than seen in the NINDS and ECASS I trials.There was a trend toward improvement in the tPA groupwith respect to the primary endpoint; however, the resultswere not significant. The overall frequency of intracranialhemorrhage was higher in the tPA group than in the place-bo group, and patients in the tPA group were 2.5 timesmore likely to develop a symptomatic intracranial hemor-rhage than were those in the placebo group. The ECASS IItrial had a broad definition of intracranial hemorrhage in-cluding hemorrhagic infarction, parenchymal infarction,and symptomatic hemorrhage. Symptomatic intracranialhemorrhage was defined as a CT scan showing blood onany site of the brain, documentation of clinical deteriora-tion, adverse events suggesting clinical worsening, or a de-crease in the NIHSS score of 4 or more points. There wereno differences in 30- or 90-day mortality between the 2treatment arms. The ECASS II trial investigators conclud-ed that the use of tPA in acute ischemic stroke did not in-crease morbidity or mortality. Further, they concluded thattPA should continue to be part of routine management inthe treatment of acute ischemic stroke within 3 hours ofsymptom onset.9

    The ATLANTIS part A trial assessed the safety and effi-cacy of tPA when administered up to 6 hours after symp-tom onset in the treatment of acute ischemic stroke.10 A to-tal of 142 patients were randomized to receive either tPA0.9 mg/kg or placebo. Less than 20% of all patients wererandomized within 3 hours of symptom onset. The primaryendpoint was clinical improvement measured by a de-crease of 4 points or more on the NIHSS or complete reso-

    366 n The Annals of Pharmacotherapy n 2011 March, Volume 45 theannals.com

    MA Hatcher and JA Starr

    Table 2. Additional tPA Eligibility Criteria for Treatment Within 4.5 Hours13

    Patients must be

  • Role of Tissue Plasminogen Activator in Acute Ischemic Stroke

    The Annals of Pharmacotherapy n 2011 March, Volume 45 n 367theannals.com

    Tabl

    e3.

    Sum

    mar

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    Dat

    aS

    ynth

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    40-

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    51%

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    cebo

    46%

    Sym

    ptom

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    intr

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    orrh

    age:

    tPA

    6%,p

    lace

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    )(1

    995)

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    tPA

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    .8to

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    t2,n

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    8)91

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    0-18

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    NIH

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    033

    EC

    AS

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    days

    OR

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    (95%

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    .98

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    35)

    Intr

    acra

    nial

    hem

    orrh

    age:

    tPA

    42.8

    %,p

    lace

    bo36

    .8%

    (p

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