Alteplasa tratamiento trombolítico del ictus isquémico en fase aguda (ampliación de indicaciones fft)




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ALTEPLASA

Tratamiento trombolítico del ictus isquémico en fase aguda (ampliación de indicaciones FFT)

Informe para la CFyT del Hospital Universitario Son Dureta

Fecha 07/10/2010








1.- IDENTIFICACIÓN DEL FÁRMACO Y AUTORES DEL INFORME

Fármaco: Alteplasa

Indicación clínica estudiada: Ampliación de indicaciones FFT (Fuera Ficha Técnica):


1-Tratamiento trombolítico en ictus isquémico de < 3 horas y

- edad > 80 años

- presencia de retinopatía diabética (SITS_MOST)

- antecedente de ictus menos de tres meses + diabetes

- tratamiento con anticoagulantes orales previos con INR <1,4

2 - Tratamiento trombolítico en ictus isquémico de 3 a 4,5 h,

3 - Tratamiento trombolítico en ictus isquémico de 4,5 a 6 h

4 - Trombolisis intraarterial

5 - Trombolisis intraaterial de rescate

6 - Tratamiento trombolítico en el ictus del despertar o de inicio incierto


Autores: Francesc Puigventos, Patricia Gonzalez. Servicio de Farmacia HUSD


2.- SOLICITUD

Facultativo que efectuó la solicitud: Dra Inés Legarda

Servicio: Neurologia

Fecha recepción de la solicitud:19-03-1010

Petición a título: x Consenso + Jefe de Servicio


3.- AREA DESCRIPTIVA DEL MEDICAMENTO

Nombre genérico: Alteplasa

Nombre comercial: Actilyse

Laboratorio: Boehringer Inhelheim

Grupo terapéutico. Antitrombóticos Código ATC: B01AD-

Vía de administración: IV

Tipo de dispensación: H

Vía de registro: Por reconocimiento mutuo inicial + Autorización provisional EMEA 2002

Presentaciones y precio

Forma farmacéutica y dosis

Envase de x unidades

Código

Coste por unidad PVP con IVA

Coste por unidad PVL

Vial 1 mg/ml 20 mg 20 ml

1

--

--

184 €

Vial 1 mg/ml 50 mg 50 ml

1

--

--

459 €


4. INDICACIONES CLÍNICAS FORMALMENTE APROBADAS.


Tratamiento fibrinolítico del ictus isquémico agudo:


FDA: Autorización en 1996

EMA: Autorización provisional en 2002

AEMPS: Ficha técnica Dic 2008.


AEMPS Ficha técnica Actilyse Dic 2008.

Las indicaciones aprobadas y las contraindicaciones de uso son las siguientes


Tratamiento fibrinolítico del ictus isquémico agudo.


● El tratamiento debe iniciarse dentro de las 3 horas después de la presentación de los síntomas de ictus y después de la exclusión previa de hemorragia intracraneal mediante técnicas de imagen apropiadas.


Uso en niños, adolescentes y pacientes ancianos


● Actilyse no está indicado en el tratamiento del ictus agudo en pacientes pediátricos menores de 18 años o adultos mayores de 80 años.


Contraindicaciones específicas en el ictus isquémico agudo:


● Síntomas de accidente isquémico que empiezan más de 3 horas antes del inicio de la perfusión o cuando se desconoce la hora del inicio de los síntomas,

● Déficit neurológico leve o síntomas de rápida mejora antes del inicio de la perfusión,

● Ictus grave evaluado clínicamente (p.ej. NIHSS>25) y/o por técnicas de imagen apropiadas,

Convulsiones al inicio del ictus,

● Evidencia de una hemorragia intracraneal en la TC

● Síntomas que sugieran hemorragia subaracnoidea, incluso con TC normal

● Administración de heparina dentro de las 48 horas previas y un tiempo de tromboplastina que exceda el límite superior normal,

● Pacientes con historia previa de ictus y diabetes concomitante,

Ictus previo en los últimos 3 meses,

● Recuento plaquetar inferior a 100.000/mm3,

● Presión sanguínea > 185 / 110 mm Hg, o controles agresivos (farmacoterapia intravenosa) necesarios para reducir la presión sanguínea a estos límites,

● Niveles de glucosa en sangre < 50 ó > 400 mg/dl.


Contraindicaciones generales:


● Trastorno hemorrágico significativo actual o durante los últimos 6 meses

● Diátesis hemorrágica conocida

● Pacientes que reciben anticoagulantes orales.

● Hemorragia grave o peligrosa manifiesta o reciente

● Sospecha o historia conocida de hemorragia intracraneal

● Sospecha de hemorragia subaracnoidea o trastorno después de una hemorragia subaracnoidea por aneurisma

● Cualquier historia de lesión del sistema nervioso central (es decir, neoplasia, aneurisma, cirugía intracraneal o espinal)

● Masaje cardíaco externo traumático reciente (menos de 10 días), parto obstétrico reciente, punción reciente de un vaso sanguíneo no comprimible (p.ej. punción de la vena yugular o subclavia)

● Hipertensión arterial grave no controlada

● Endocarditis bacteriana,

● Pancreatitis aguda

● Enfermedad gastrointestinal ulcerativa documentada durante los últimos 3 meses, varices

esofágicas, aneurismas arteriales, malformaciones venosas/arteriales

● Neoplasia con riesgo de hemorragia aumentado

● Enfermedad hepática grave, incluyendo insuficiencia hepática, cirrosis, hipertensión portal (varices esofágicas) y hepatitis activa

● Cirugía mayor o traumatismo importante en los últimos 3 meses


FDA: Ficha técnica Activase Dic 2005

Las indicaciones aprobadas y las contraindicaciones de uso en USA son las siguientes


Acute Ischemic Stroke:


● Activase® (Alteplase) is indicated for the management of acute ischemic stroke in adults for improving neurological recovery and reducing the incidence of disability. Treatment should only be initiated within 3 hours after the onset of stroke symptoms, and after exclusion of intracranial hemorrhage by a cranial computerized tomography (CT) scan or other diagnostic imaging method sensitive for the presence of hemorrhage


Contraindicated:

● Evidence of intracranial hemorrhage on pretreatment evaluation

● Suspicion of subarachnoid hemorrhage on pretreatment evaluation

● Recent (within 3 months) intracranial or intraspinal surgery, serious head trauma, or previous stroke

● History of intracranial hemorrhage

● Uncontrolled hypertension at time of treatment (e.g., > 185 mm Hg systolic or > 110 mm Hg diastolic)

● Seizure at the onset of stroke

● Active internal bleeding

● Intracranial neoplasm, arteriovenous malformation, or aneurysm

● Known bleeding diathesis including but not limited to:

- Current use of oral anticoagulants (e.g., warfarin sodium) or an International

Normalized Ratio (INR) >1.7 or a prothrombin time (PT) > 15 seconds

- Administration of heparin within 48 hours preceding the onset of stroke and have

an elevated activated partial thromboplastin time (aPTT) at presentation

- Platelet count < 100,000/mm3


Posología en ictus isquémico agudo según ficha técnica.

0,9 mg de alteplasa/kg de peso (hasta un máximo de 90 mg) perfundidos por vía intravenosa durante 60 minutos con un 10 % de la dosis total administrada como bolo intravenoso inicial.




5.- EVALUACIÓN DE LA EFICACIA y SEGURIDAD EN LAS INDICACIONES FFT



Revisión de evidencias para las indicaciones clínicas evaluadas. En el protocolo presentado se describen los principales estudios publicados deforma exhaustiva. Se presenta información complementaria y bibliografía adicional,


1-Tratamiento trombolitico en ictus isquemico de < 3 horas y

- edad > 80 años

- presencia de retinopatia diabetica

- antecedente de ictus menos de tres meses + diabetes

- tratamiento con anticoagulantes orales previos con INR <1,4


EDAD > 80 AÑOS


A. ENSAYOS


No disponibles


B. ESTUDIOS OBSEVACIONALES


Ver bibliografía original del protocolo presentado:


-David Tanne et al. Intravenous Tissue Plasminogen Activator for Acute Ischemic Stroke in Patients Aged 80 Years and Older: The tPA Stroke Survey Experience. Stroke 2000;31;370-375


CONCLUSIONS: Among AIS patients treated with intravenous tPA, age-related differences in characteristics and disposition were identified. No evidence for withholding tPA treatment for AIS in appropriately selected patients aged >/=80 years was identified.


-T Lorenzano et al. Intravenous thrombolysis with rt-PA in acute ischemic stroke patients aged older than 80 years in Italy. Cerebrovasc Dis 2008; 25 (1-2): 129-35


CONCLUSIONS: Acute ischemic stroke patients aged >80 years treated with i.v. rt-PA have a higher mortality than younger patients, but there are no differences for SICH nor for favorable outcome. Our data suggest that thrombolytic therapy should not be a priori denied for appropriately selected >80-year-old patients but randomized controlled clinical trials are necessary before definite recommendations can be given


-ST Engelter et al. Intravenous thrombolysis in stroke patients of > or = 80 versus < 80 years of age : a systematic review across cohort studies. Age Ageing 2006; 35: 572-580


RESULTS: six studies were included[n = 2,244 patients; 477 (21%) aged >/=80 years]. Significant differences inbaseline characteristics to the disadvantage of older patients were present inall studies. Compared with younger patients, older patients had a 3.09-time (95%

CI = 2.37-4.03; P < 0.001) higher 3-month mortality and were less likely toregain a 'favourable outcome' (OR = 0.53; 95% CI = 0.42-0.66; P<0.001). Thelikelihood for 'sICH' (OR = 1.22; 95% CI = 0.77-1.94; P = 0.34) was similar inboth age groups.

CONCLUSION: intravenous rtPA-treated stroke patients of >/=80years of age have a less favourable outcome than younger ones. Imbalances inpredictive baseline variables to the disadvantage of the older patients maycontribute to this finding. Compared with the younger cohort, rtPA-treated strokepatients aged >/=80 years do not seem exceedingly prone to sICH. Thus, there is scope for benefit from thrombolysis for the older age group. Hence, to obtain

reliable evidence on the balance of risk and benefit of intravenous rtPA for stroke patients aged >/=80 years, it is safe and reasonable to include Duch patients in randomised placebo-controlled trials.


-J De Keyser et al. Intravenous alteplase for stroke: beyond the guidelines and in particular clinical situations. Stroke 2007; 38 (9): 2612-8


-Mateen FJ,et al.; CASES Investigators. Outcomes of thrombolysis for acute ischemic stroke in octogenarians versus nonagenarians. Stroke. 2010 Aug;41(8):1833-5. Epub 2010 Jun 24


BACKGROUND AND PURPOSE: Little is reported on the outcomes of nonagenarians who are treated with intravenous tissue plasminogen activator for acute ischemic stroke. It is uncertain whether nonagenarians have higher mortality and worse functional outcomes than octogenarians.

RESULTS: Twenty-eight nonagenarians and 242 octogenarians were treated with intravenous tissue plasminogen activator for acute ischemic stroke over the 2.5-year observation period. Nonagenarians and octogenarians did not differ on any of the baseline clinical or demographic variables. Both groups were predominantly female (77% nonagenarians and 61% octogenarians), hypertensive (54% and 60%), and predominantly had severe strokes (National Institutes of Health Stroke Scale score >15; 58% and 52%). The rate of symptomatic intracerebral hemorrhage (7% nonagenarians versus 4% octogenarians; P=0.359), 90-day mortality (52% versus 33%; P=0.087), and 30-day favorable functional outcomes ([modified Rankin score

CONCLUSIONS: There is no significant difference in 90-day mortality, 30-day functional outcome, or rate of symptomatic intracerebral hemorrhage between nonagenarians and octogenarians treated with intravenous tissue plasminogen activator when comparing populations of similar baseline risk.


-Meretoja A et al Off label thrombolysis is not associated with poor outcome in patients with

stoke. Stroke 2010; 41; 1450-8


Estudio observacional de 985 pacientes en un hospital de Helsinky. 51% de los pacientes eran indicaciones FFT que son: -Edad >80 años, -Ictus leve (score <5 en NIHSS), -uso de antihipertensivos antes del tratamiento, -tiempo síntoma/aguja >3h, -TA> 185/110 mmHg, y -antiacoagulacion oral. La edad > 80 años es la única contraindicacion asociada a mal resultado (OR 2.18 (1,27-3,73) en análisis multivariante (escala de Rankin).


C. GUÍAS CLÍNICAS


European Stroke Organisation guideline update http://www.eso-stroke.org/pdf/ESO%20Guidelines_update_Jan_2009.pdf


It is recommended that intravenous rtPA may also be administered in selected patients under 18 years and over 80 years of age, although this is outside the current European labelling (Class III, Level C)


-Gregory W. Albers et al: Antithrombotic and Thrombolytic Therapy for Ischemic Stroke*

American College of Chest Physicians Evidence- Based Clinical Practice Guidelines (8th Edition) CHEST 2008; 133:630S–669S


Inclusion Criteria: Age _ 18 years, clinical diagnosis of stroke with a clinically meaningful neurologic deficit, clearly defined time of onset of _ 180 min before treatment, and a baseline CT showing no evidence of intracranial hemorrhage.


- PRESENCIA DE RETINOPATÍA DIABÉTICA (SITS_MOST)

- ANTECEDENTE DE ICTUS MENOS DE TRES MESES + DIABETES

- TRATAMIENTO CON ANTICOAGULANTES ORALES PREVIOS CON INR <1,4


- No incluidas como contraindicación por FDA,


- No definidas en Guia AHA 2007


-Marta Rubiera et al. Is it Time to Reassess the SITS-MOST Criteria for Thrombolysis? A Comparison of Patients With and Without SITS-MOST Exclusion Criteria Stroke. 2009;40:2568-2571.)

Requirements included :

(1) documented intracraneal occlusion;

(2) <6 hours stroke with mismatch on multiparametric MRI2;

(3) International Normalized Ratio (INR) <1.8;

(4) Age, clinical stroke severity, or Diabetes Mellitus and previous symptomatic stroke (DM_stroke) were not contraindications;

(5) other tPA-contraindications (<6-hour time window, recent stroke, extent lesion on neuroimaging, severe comorbidity/disability) constituted exclusion from treatment and from the study.


-Nils Wahlgren et al ,Thrombolysis with alteplase for acute ischaemic stroke inthe Safe Implementation of Thrombolysis in Stroke- Monitoring Study (SITS-MOST): an observational study Lancet 2007; 369: 275–82


Methods 6483 patients were recruited from 285 centres (50% with little previous experience in stroke thrombolysis) in 14 countries between 2002 and 2006 for this prospective, open, monitored, observational study.

Interpretation:These data confirm that intravenous alteplase is safe and eff ective in routine clinical use when used within 3 h of stroke onset, even by centres with little previous experience of thrombolytic therapy for acute stroke. The findings should encourage wider use of thrombolytic therapy for suitable patients treated in stroke centres.


2 - TRATAMIENTO TROMBOLITICO EN ICTUS ISQUÉMICO DE 3 A 4,5 H,


A. ENSAYOS


-Hacke W et al Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke. N Engl J Med 2008;359:1317-29. ECASS3

Results

We enrolled a total of 821 patients in the study and randomly assigned 418 to the alteplase group and 403 to the placebo group. The median time for the administration of alteplase was 3 hours 59 minutes.

More patients had a favorable outcome with alteplase than with placebo (52.4% vs. 45.2%; odds ratio, 1.34; 95% confidence interval [CI], 1.02 to 1.76; P = 0.04). In the global analysis, the outcome was also improved with alteplase as compared with placebo (odds ratio, 1.28; 95% CI, 1.00 to 1.65; P<0.05).

The incidence of intracranial hemorrhage was higher with alteplase than with placebo for any intracranial hemorrhage, 27.0% vs. 17.6%; P = 0.001; for symptomatic intracranial hemorrhage, 2.4% vs. 0.2%; P = 0.008).

Mortality did not differ significantly between the alteplase and placebo groups (7.7% and 8.4%, respectively; P = 0.68). There was no significant difference in the rate of other serious adverse events.

Conclusions

As compared with placebo, intravenous alteplase administered between 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcomes in patients with acute ischemic stroke; alteplase was more frequently associated with symptomatic intracranial hemorrhage.


-Ahmed N et al. Implementation and outcome of thrombolysis with alteplase 3—4·5 h after an acute stroke: an updated analysis from SITS-ISTR. The Lancet Neurology, Volume 9, Issue 9, Pages 866 - 874, September 2010

Background


In September, 2008, the European Acute Stroke Study III (ECASS III) randomised trial and the Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Registry (SITS-ISTR) observational study reported the efficacy and safety of the extension of the time window for intravenous alteplase treatment from within 3 h to within 4·5 h after stroke onset. We aimed to assess the implementation of the wider time window, its effect on the admission-to-treatment time, and safety and functional outcome in patients recorded in SITS-ISTR.

Methods


Patients treated according to the criteria of the European Summary of Product Characteristics, except for the time window, were included. Patients were grouped according to whether they were registered into SITS-ISTR before or after October, 2008. We measured admission-to-treatment time and rates of symptomatic intracerebral haemorrhage, mortality, and functional independence at 3 months.

Findings


23 942 patients were included in SITS-ISTR between December, 2002, and February, 2010, of whom 2376 were treated 3—4·5 h after symptom onset. The proportion of patients treated within 3—4·5 h by the end of 2009 was three times higher than in the first three quarters of 2008 (282 of 1293 [22%] vs 67 of 1023 [7%]).

The median admission-to-treatment time was 65 min both for patients registered before and after October, 2008 (p=0·94).

352 (2%) of 21 204 patients treated within 3 h and 52 (2%) of 2317 treated within 3—4·5 h of stroke had symptomatic intracerebral haemorrhage at 3 months (adjusted odds ratio [OR] 1·44, 95% CI 1·05—1·97; p=0·02).

2287 (12%) of 18 583 patients who were treated within 3 h and 218 (12%) of 1817 who were treated within 3—4·5 h had died by the 3-month follow-up (adjusted OR 1·26, 95% CI 1·07—1·49; p=0·005);

10 531 (57%) of 18 317 patients treated within 3 h of stroke and 1075 (60%) of 1784 who were treated within 3—4·5 h were functionally independent at 3 months (adjusted OR 0·84, 95% CI 0·75—0·95; p=0·005).

Interpretation


Since October, 2008, thrombolysis within 3—4·5 h after stroke has been implemented rapidly, with a simultaneous increase in the number of patients treated within 3 h; admission-to-treatment time has not increased. Safety and functional outcomes are less favourable after 3 h, but the wider time window now offers an opportunity for treatment of those patients who cannot be treated earlier. Thrombolysis should be initiated within 4·5 h after onset of ischaemic stroke, although every effort should be made to treat patients as early as possible after symptom onset.

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