Current perspectives on the use of intravenous recombinant tissue plasminogen activator (tPA) for treatment of acute ischemic stroke

Figures & data

Table 1 Early prospective randomized clinical trials of intravenous tPA in acute ischemic stroke

Study (publication year)	Treatment group	Time window (median hours)	Primary analysis results*	Safety results**
NINDS tPA study – Part 1 (1995)^Citation1	tPA 0.9 mg/kg	3 hours (1.5)	No difference in early clinical improvement (>4 point decrease in NIHSS or complete resolution) (tPA 47% versus placebo 39%; RR 1.2 [CI 0.9–1.6; P=0.21])	Combined analysis of parts 1 and 2: Increased sICH at 36 hours in tPA group (tPA 6.4% versus placebo 0.6%; P<0.001) No change in overall mortality at 90 days (tPA 17% versus placebo 21%; P=0.30)
NINDS tPA study – Part 2 (1995)^Citation1	tPA 0.9 mg/kg	3 hours (1.5)	Greater favorable outcome in tPA group on global test statistic at 90 days^‡ OR 1.7 (CI 1.2–2.6; P=0.008)
ECASS I (1995)^Citation20	tPA 1.1 mg/kg	6 hours (4.3)	No difference in BI (P=0.99) and mRS (P=0.41) at 90 days	Increase in large parenchymal ICH (tPA 20% versus placebo 7%; (P<0.001) No difference in 30-day mortality (tPA 18% versus placebo 13%; P=0.08)
ECASS II (1998)^Citation29	tPA 0.9 mg/kg	6 hours (NR – 80% between 3 and 6 hours)	No difference in favorable outcome (mRS) at 90 days (tPA 40.3% versus placebo 36.3%; OR 1.2 [CI 0.9–1.6]; P=0.28)	Increased sICH up to 7 days (tPA 8.8% versus placebo 3.4%)
ATLANTIS-A (2000)^Citation19	tPA 0.9 mg/kg	6 hours (4.6)	Increased early clinical improvement in tPA group (>4 increase in NIHSS) (tPA 40% versus placebo 21%; P=0.02) Decreased clinical improvement at 30 days for tPA group (tPA 60% versus placebo 75%; P=0.05)	Increased sICH up to 10 days (tPA 11% versus placebo 0%; P<0.01) Increase mortality at 90 days (tPA 23% versus placebo 7%; P<0.01)
ATLANTIS-B (1999)^Citation49	tPA 0.9 mg/kg	3–5 hours (4.6)	No difference in excellent neurologic recovery (NIHSS ≤1) (tPA 34.5% versus placebo 34%; P=0.89)	Increased sICH up to 10 days (tPA 7% versus placebo 1.1%; P<0.001) No difference in mortality (tPA 11% versus placebo 6.9%; P=0.09)
ECASS III (2009)^Citation33	tPA 0.9 mg/kg	3.0–4.5 hours (4.0)	Greater favorable outcome (mRS) in tPA group at 90 days (OR 1.34 [CI 1.0–1.8; P=0.04])	Increased sICH (tPA 2.4% versus placebo 0.2%; P=0.008) No difference in mortality (tPA 7.7% versus placebo 8.4%; P=0.68)

Notes:

* All outcomes reflect intention-to-treat analyses unless stipulated; **definitions for sICH varied between studies; ^‡global test statistic simultaneously tested for effect in all four outcome measures: BI, mRS, Glasgow outcome scale, and NIHSS.

Abbreviations: ATLANTIS, Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke; BI, Barthel index; CI, confidence interval; ECASS, European Cooperative Acute Stroke Study; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale score; NINDS, National Institute of Neurological Disorders and Stroke; NR, not reported; OR, odds ratio; sICH, symptomatic intracerebral hemorrhage; tPA, tissue plasminogen activator; RR, relative risk; ICH, intracerebral hemorrhage.

Figure 1 (A) Death or dependency defined as mRS 2–6. (B) Risk of symptomatic intracerebral hemorrhage.

Notes: A and B demonstrate point estimates for ORs and 95% CIs between the tPA and control groups for each of the trials. *References for the listed trials: NINDS,¹ ECASS,²⁰ ECASS II,²⁹ ATLANTIS-A,^19,28 ATLANTIS-B,⁴⁹ and ECASS III.³³

Abbreviations: ATLANTIS, Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke; CI, confidence interval; ECASS, European Cooperative Acute Stroke Study; mRS, modified Rankin Scale; NINDS, National Institute of Neurological Disorders and Stroke; OR, odds ratio; rt-PA, recombinant tissue plasminogen activator; tPA, tissue plasminogen activator.

Table 2 tPA-related hemorrhage as defined by different stroke studies

Study name	Hemorrhage type	Radiographic and clinical definition	Rate of hemorrhage
NINDS^Citation1,Citation48	HI and PH	• HI: punctate hyperdensities with indistinct borders in infarct bed with no mass effect. • PH: homogenous hematoma in infarct bed, withsharply defined borders and associated mass effect. • Any neurological deterioration within 36 hours of tPA.	Symptomatic intracranial hemorrhage: 6.4%. Asymptomatic intracranial hemorrhagee: 30%.
ECASS I and II^Citation20,Citation29	HI 1 and 2	• HI 1: small punctate hemorrhage (along margins of infarct) in stroke bed, no mass effect. • HI 2: confluent petechiae (within infarcted tissue) in stroke bed, no mass effect. • >4 point increase in baseline NIHSS within 7 days.	ECASS II HI 1 19.6%, HI 2 15.2%.
	PH 1 and 2	• PH 1: hematoma occupying ≤30% of infarcted area with mild mass effect. • PH 2: hematoma occupying >30% of infarcted area with significant mass effect. • >4 point increase in baseline NIHSS within 7 days.	ECASS II: PH 1 3.7%, PH 2 8.1%.
SITS-MOST^Citation33,Citation52	PH	• Local or remote PH with associated decline in NIHSS. • ICH type PH 2. • ≥4 point increase in baseline NIHSS within 24 hours.	Symptomatic intracranial hemorrhage 1.7% at 24 hours.
ECASS III^Citation33	PH	• Apparent intra or extraparenchymal blood associated with ≥4 point increase in baseline NIHSS that led to death or neurological deterioration.	Symptomatic intracranial hemorrhage 2.4%.

Abbreviations: ECASS, European Cooperative Acute Stroke Study; HI, hemorrhagic infarct; PH, parenchymal hematoma; NIHSS, National Institutes of Health Stroke Scale; NINDS, National Institute of Neurological Disorders and Stroke; SITS-MOST, Safe Implementation of Thrombolysis in Stroke-Monitoring Study; tPA, tissue plasminogen activator; ICH, intracerebral hemorrhage.

Table 3 Risk factor profiles associated with negative outcomes after use of tPA in acute ischemic stroke

	ICH^Citation50,Citation52,Citation56,Citation59		Poor functional outcomes^Citation52,Citation57	Mortality^Citation52,Citation58
Risks factors	Diabetes	Systolic BP	Age	Pre-stroke mRS
	CHF	Early CT changes	Stroke severity	Diastolic BP
	Atrial fibrillation	Serum glucose	Diabetes	Antiplatelet use other than aspirin
	Stroke severity	Platelet count	Blood pressure	CHF
	Age	Weight	Early CT findings	Centers’ previous stroke experience
	Time-to-treatment	Tobacco use	Male
	Antiplatelet use			Male
				Age
				Atrial fibrillation

Abbreviations: BP, blood pressure; CHF, congestive heart failure; CT, computed tomography; mRS, modified Rankin Scale; tPA, tissue plasminogen activator; ICH, intracerebral hemorrhage.

Table 4 Risk and prognostic stratification scales

Risk score	Variables	Assessment
Cucchiara et al^Citation115	Age, NIHSS, admission glucose, and platelet count on admission	ICH
HAT^Citation116	Admission glucose on, NIHSS, hypodensity of CT scan, and DM	ICH
SITS-SICH^Citation59	Age, NIHSS, glucose on admission, SBP, bodyweight, OTT, ASA monotherapy, ASA + clopidogrel, and `history of HTN	ICH
GRASPS^Citation117	Age, NIHSS, admission glucose, SBP, ethnicity, and sex	ICH
SEDAN^Citation118	Age, NIHSS, HDMCA sign on CT, early infarct signs on CT, and admission glucose	ICH
DRAGON^Citation119	HDMCA or early infarct signs on CT, prestroke mRS score, age, admission glucose, OTT, and NIHSS	Functional outcome
SPAN-100 index^Citation120	Age and NIHSS	Functional outcome
iSCORE^Citation121	Age, sex, CNS, stroke subtype, AF, CHF, cancer, renal failure on dialysis, preadmission disability, and admission glucose	Functional outcome
Stroke-TPI^Citation122	NIHSS score, history of stroke, SBP, OTT, age, sex, and DM	Functional outcome
ASTRAL^Citation123	Age, NIHSS, time-of-onset to admission, LOC, range of visual fields, and admission glucose	Functional outcome

Abbreviations: AF, atrial fibrillation; ASA, aspirin; ASTRAL, Acute Stroke Registry and Analysis of Lausanne; CHF, congestive heart failure; CNS, Canadian neurological Scale; CT, computed tomography; DM, diabetes mellitus; GRASPS, Guidance on Risk Assessment and Stroke Prevention Score; HAT, hemorrhage after thrombolysis; HDMCA, hyperdense middle cerebral artery; HTN, hypertension; iSCORE, ischemic stroke predictive risk score; LOC, level of consciousness; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale score; OTT, onset-to-treatment time; SBP, systolic blood pressure; SITS-SICH, Safe Implementation of Treatments in Stroke – Symptomatic Intracerebral Hemorrhage; SPAN, Stroke Prognostication using Age and NIH Stroke Scale; TPI, thrombolytic predictive instrument; ICH, intracerebral hemorrhage; SEDAN, Sugar, Early infarct signs, (hyper)Dense cerebral artery sign on admission CT scan, Age, and NIHSS on admission; DRAGON, (hyper)Dense cerebal artery sign/early infarct signs on admission CT scan, prestroke modified Rankin scale, Age, Glucose level at baseline, Onset-to-treatment time and baseline NIHSS.

Table 5 Common stroke mimics

Seizure

Migraine

Conversion disorder

Demyelinating disease

Encephalitis/meningitis

Toxic/metabolic encephalopathy (hypoglycemia, electrolyte disarray, etc)

Multiple sclerosis

Brain tumor/mass

Stroke reactivation (anamnestic syndrome)

Table 6 Community-based studies on the experience of tPA utilization for acute ischemic stroke

Study (year)	Type	Number of hospitals	Number of patients (percentage treated with tPA)	sICH (24–36 hours)	Protocol violations*
Houston (1998)^Citation124	Prospective	3	30 (2.9%)	7.0%	10.0%
Cologne, Germany (1998)^Citation125	Prospective	1	100 (22.0%)	5.0%	3.0%
Cleveland (2000)^Citation126	Prospective	29	70 (1.8%)	15.7%	50.0%
OSF Stroke Network (2000)^Citation127	Prospective	14	57 (6.3%)	5.3%	8.7%
STARS study (2000)^Citation128	Prospective	57 (US)	389 (NR)	3.3%	32.6%
Indianapolis (2001)^Citation129	Retrospective	10	50 (NR)	8.0%	16.0%
Houston (2001)^Citation130	Prospective	4	269 (15.0%)	4.5%	13.0%
Berlin, Germany (2001)^Citation131	Prospective	1	75 (9.4%)	2.7%	20.0%
Connecticut (2002)^Citation132	Retrospective	16	63 (0.6%)	6.0%	97.0%
Cleveland update (2003)^Citation133	Retrospective	9	47 (2.7%)	6.4%	19.1%
CASES study (2005)^Citation109	Prospective	60	1,135 (1.4%)	4.6%	13.6%
SITS-MOST (2008)^Citation52	Prospective	285	6,483 (NR)	1.7%	NR

Note:

* Includes minor and major protocol violations.

Abbreviations: CASES, Canadian Activase for Stroke Effectiveness Study; NR, not reported; OSF, Order of St Francis; sICH, symptomatic intracerebral hemorrhage; SITS-MOST, Safe Implementation of Thrombolysis in Stroke-Monitoring Study; STARS, Standard Treatment with Alteplase to Reverse Stroke; tPA, tissue plasminogen activator.

Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study GroupN Engl J Med1995333158115877477192

 PubMed Web of Science ®Google Scholar

HackeWKasteMFieschiCIntravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS)JAMA1995274101710257563451

 PubMed Web of Science ®Google Scholar

HackeWKasteMFieschiCRandomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study InvestigatorsLancet1998352124512519788453

 PubMed Web of Science ®Google Scholar

ClarkWMAlbersGWMaddenKPHamiltonSThe rtPA (alteplase) 0- to 6-hour acute stroke trial, part A (A0276g): results of a double-blind, placebo-controlled, multicenter study. Thromblytic therapy in acute ischemic stroke study investigatorsStroke20003181181610753980

 PubMed Web of Science ®Google Scholar

ClarkWMWissmanSAlbersGWJhamandasJHMaddenKPHamiltonSRecombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic StrokeJAMA19992822019202610591384

 PubMed Web of Science ®Google Scholar

HackeWKasteMBluhmkiEThrombolysis with alteplase 3 to 4.5 hours after acute ischemic strokeN Engl J Med20083591317132918815396

 PubMed Web of Science ®Google Scholar

WardlawJMMurrayVBergeEDel ZoppoGJThrombolysis for acute ischaemic strokeCochrane Database Syst Rev20094CD00021319821269

 PubMed Web of Science ®Google Scholar

DerexLNighoghossianNIntracerebral haemorrhage after thrombolysis for acute ischaemic stroke: an updateJ Neurol Neurosurg Psychiatry2008791093109918223014

 PubMed Web of Science ®Google Scholar

WahlgrenNAhmedNErikssonNMultivariable analysis of outcome predictors and adjustment of main outcome results to baseline data profile in randomized controlled trials: Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy (SITS-MOST)Stroke2008393316332218927461

 PubMed Web of Science ®Google Scholar

LarrueVvon KummerRRMullerABluhmkiERisk factors for severe hemorrhagic transformation in ischemic stroke patients treated with recombinant tissue plasminogen activator: a secondary analysis of the European-Australasian Acute Stroke Study (ECASS II)Stroke20013243844111157179

 PubMed Web of Science ®Google Scholar

TanneDKasnerSEDemchukAMMarkers of increased risk of intracerebral hemorrhage after intravenous recombinant tissue plasminogen activator therapy for acute ischemic stroke in clinical practice: the Multicenter rt-PA Stroke SurveyCirculation20021051679168511940547

 PubMed Web of Science ®Google Scholar

MazyaMEgidoJAFordGAPredicting the risk of symptomatic intracerebral hemorrhage in ischemic stroke treated with intravenous alteplase: safe implementation of treatments in stroke (SITS) symptomatic intracerebral hemorrhage risk scoreStroke2012431524153122442178

 PubMed Web of Science ®Google Scholar

SaposnikGDi LeggeSWebsterFHachinskiVPredictors of major neurologic improvement after thrombolysis in acute strokeNeurology2005651169117416247041

 PubMed Web of Science ®Google Scholar

BatemanBTSchumacherHCBoden-AlbalaBFactors associated with in-hospital mortality after administration of thrombolysis in acute ischemic stroke patients: an analysis of the nationwide inpatient sample 1999 to 2002Stroke20063744044616397164

 PubMed Web of Science ®Google Scholar

CucchiaraBTanneDLevineSRDemchukAMKasnerSA risk score to predict intracranial hemorrhage after recombinant tissue plasminogen activator for acute ischemic strokeJ Stroke Cerebrovasc Dis20081733133318984422

 PubMedGoogle Scholar

LouMSafdarAMehdirattaMThe HAT score: a simple grading scale for predicting hemorrhage after thrombolysisNeurology2008711417142318955684

 PubMed Web of Science ®Google Scholar

MenonBKSaverJLPrabhakaranSRisk score for intracranial hemorrhage in patients with acute ischemic stroke treated with intravenous tissue-type plasminogen activatorStroke2012432293229922811458

 PubMed Web of Science ®Google Scholar

StrbianDEngelterSMichelPSymptomatic intracranial hemorrhage after stroke thrombolysis: the SEDAN scoreAnn Neurol20127163464122522478

 PubMed Web of Science ®Google Scholar

StrbianDMeretojaAAhlhelmFJPredicting outcome of IV thrombolysis-treated ischemic stroke patients: the DRAGON scoreNeurology20127842743222311929

 PubMed Web of Science ®Google Scholar

SaposnikGGuzikAKReevesMOvbiageleBJohnstonSCStroke prognostication using age and NIH Stroke Scale: SPAN-100Neurology201380212823175723

 PubMed Web of Science ®Google Scholar

SaposnikGFangJKapralMKThe iScore predicts effectiveness of thrombolytic therapy for acute ischemic strokeStroke2012431315132222308252

 PubMed Web of Science ®Google Scholar

KentDMSelkerHPRuthazerRBluhmkiEHackeWThe stroke-thrombolytic predictive instrument: a predictive instrument for intravenous thrombolysis in acute ischemic strokeStroke2006372957296217068305

 PubMed Web of Science ®Google Scholar

NtaiosGFaouziMFerrariJLangWVemmosKMichelPAn integer-based score to predict functional outcome in acute ischemic stroke: the ASTRAL scoreNeurology2012781916192222649218

 PubMed Web of Science ®Google Scholar

ChiuDKriegerDVillar-CordovaCIntravenous tissue plasminogen activator for acute ischemic stroke: feasibility, safety, and efficacy in the first year of clinical practiceStroke19982918229445322

 PubMed Web of Science ®Google Scholar

GrondMStenzelCSchmullingSEarly intravenous thrombolysis for acute ischemic stroke in a community-based approachStroke199829154415499707190

 PubMed Web of Science ®Google Scholar

KatzanILFurlanAJLloydLEUse of tissue-type plasminogen activator for acute ischemic stroke: the Cleveland area experienceJAMA20002831151115810703777

 PubMed Web of Science ®Google Scholar

WangSLPanWHLeeMCChengSPChangMCPredictors of survival among elders suffering strokes in Taiwan: observation from a nationally representative sampleStroke2000312354236011022063

 PubMed Web of Science ®Google Scholar

AlbersGWBatesVEClarkWMBellRVerroPHamiltonSAIntravenous tissue-type plasminogen activator for treatment of acute stroke: the Standard Treatment with Alteplase to Reverse Stroke (STARS) studyJAMA20002831145115010703776

 PubMed Web of Science ®Google Scholar

Lopez-YunezAMBrunoAWilliamsLSYilmazEZurruCBillerJProtocol violations in community-based rTPA stroke treatment are associated with symptomatic intracerebral hemorrhageStroke200132121611136907

 PubMed Web of Science ®Google Scholar

GrottaJCBurginWSEl-MitwalliAIntravenous tissue-type plasminogen activator therapy for ischemic stroke: Houston experience 1996 to 2000Arch Neurol2001582009201311735774

 PubMed Web of Science ®Google Scholar

KoenneckeHCNohrRLeistnerSMarxPIntravenous tPA for ischemic stroke team performance over time, safety, and efficacy in a single-center, 2-year experienceStroke2001321074107811340212

 PubMed Web of Science ®Google Scholar

BravataDMKimNConcatoJKrumholzHMBrassLMThrombolysis for acute stroke in routine clinical practiceArch Intern Med20021621994200112230423

 PubMed Web of Science ®Google Scholar

KatzanILHammerMDFurlanAJHixsonEDNadzamDMQuality improvement and tissue-type plasminogen activator for acute ischemic stroke: a Cleveland updateStroke20033479980012624312

 PubMed Web of Science ®Google Scholar

HillMDBuchanAMThrombolysis for acute ischemic stroke: results of the Canadian Alteplase for Stroke Effectiveness StudyCMAJ20051721307131215883405

 PubMed Web of Science ®Google Scholar