Intra - Arterial Thrombolysisfor acute stroke

Intra - Arterial Thrombolysisfor acute stroke

Jeanne Teitelbaum mdJeanne Teitelbaum md

Associate ProfessorAssociate Professor

Neurology and Critical CareNeurology and Critical Care

Intra - Arterial ThrombolysisIntra - Arterial Thrombolysis

Effect on recanalisationEffect on recanalisation Effect on clinical outcomeEffect on clinical outcome RisksRisks ?? Indications?? Indications

Why consider IATWhy consider IAT

IV rt-PA:IV rt-PA: Limited to < 3HLimited to < 3H Clear but limited clinical benefitClear but limited clinical benefit RRate of recanalisation (doppler):ate of recanalisation (doppler):

Complete: 32%Complete: 32% Partial or none 68%: 67% MCA, 25% BA, Partial or none 68%: 67% MCA, 25% BA,

no ICAno ICA

(Christou et al 2001)(Christou et al 2001)

Why consider IATWhy consider IAT

Persistent obstruction persistent deficitPersistent obstruction persistent deficit Increase the therapeutic windowIncrease the therapeutic window Post-operative strokePost-operative stroke Reduce hemorrhagic complicationsReduce hemorrhagic complications

I.A.T. Theoretical Advantages I.A.T. Theoretical Advantages

Higher concentrations delivered to the clotHigher concentrations delivered to the clot Gentle mechanical disruption of the clotGentle mechanical disruption of the clot Precise imaging of anatomy, pathology and Precise imaging of anatomy, pathology and

collateral patterncollateral pattern Exact degree and timing of recanalisationExact degree and timing of recanalisation

I.A.T. Potential DisadvantagesI.A.T. Potential Disadvantages

Catheter manipulationCatheter manipulation Systemic heparinisationSystemic heparinisation Delay in initiation of thrombolysisDelay in initiation of thrombolysis Skilled facilitiesSkilled facilities

Intra-arterial ThrombolysisIntra-arterial Thrombolysis

The EvidenceThe Evidence

Anterior Circulation

PROACT II TrialPROACT II Trial

First phase III trial of I.A.T.First phase III trial of I.A.T. Pro-UK + heparin vs IV heparin within 6h.Pro-UK + heparin vs IV heparin within 6h. 180 patients, M1 or M2 MCA occlusion.180 patients, M1 or M2 MCA occlusion. Average NIHSS 17.Average NIHSS 17. Median time to I.A.T 5.7 hours.Median time to I.A.T 5.7 hours.

PROACT II TrialPROACT II Trial

mRS < 2 : 40% VS 25% (+- SIG)mRS < 2 : 40% VS 25% (+- SIG) Recanalisation at 2h: 66% vs 18%Recanalisation at 2h: 66% vs 18% Hemorrhage at 36h:Hemorrhage at 36h:

all: 46% vs 16%all: 46% vs 16% symptomatic: 10% vs 2%symptomatic: 10% vs 2%

No difference in mortalityNo difference in mortality

I.A.T. Rate of Recanalisation Depends on site and type of occlusion I.A.T. Rate of Recanalisation Depends on site and type of occlusion

PROACT II :66% overallPROACT II :66% overall Urbach et al 2002:Urbach et al 2002:

Thrombus 53%: 23% carotid T,Thrombus 53%: 23% carotid T,

74% distal M174% distal M1

60% M260% M2

I.A.T. Rate of Recanalisation Depends on site and type of occlusion

I.A.T. Rate of Recanalisation Depends on site and type of occlusion

Urbach et al 2002:Urbach et al 2002:Embolus 59% overallEmbolus 59% overall

1of 6 with cardiac thrombus1of 6 with cardiac thrombus

15 of 19 (79%) without thrombus15 of 19 (79%) without thrombus

I.A.T. Therapeutic WindowI.A.T. Therapeutic Window

PROACT II: PROACT II: 6h6h Arnold et al stroke 2002: 100 ptsArnold et al stroke 2002: 100 pts

Urokinase, MCA, NIH = 14Urokinase, MCA, NIH = 14Average Average 236 minutes236 minutesRecanalisation: Recanalisation: 76%76%Outcome: excellent 47%, good 21%, Outcome: excellent 47%, good 21%,

poor 22%, dead 10%, hemorrhage 7%poor 22%, dead 10%, hemorrhage 7%

I.A.T. Therapeutic WindowI.A.T. Therapeutic Window

Evidence that TTT influences outcomeEvidence that TTT influences outcome New studies in progress: 1.5 to 6 h.New studies in progress: 1.5 to 6 h.

MRI data Kidwell et alMRI data Kidwell et al

Ann Neurol 2000Ann Neurol 2000 7 patients7 patients DWI and PWI pre and post I.A.L.DWI and PWI pre and post I.A.L. DWI 3 and 9 h post recanalisationDWI 3 and 9 h post recanalisation delayed re of DWI at 7 daysdelayed re of DWI at 7 days Final volume 86% of original pre - lysisFinal volume 86% of original pre - lysis

IV plus IA thrombolysisStroke Bridging TrialIV plus IA thrombolysisStroke Bridging Trial

Lewandowski CA et al Stroke 1999Lewandowski CA et al Stroke 1999 Randomized pilot study. 35 patientsRandomized pilot study. 35 patients tPA IV 0.6 mg/tPA IV 0.6 mg/Kg then IA 20 mgKg then IA 20 mg Symptomatic hemorrhage: 11% both groupsSymptomatic hemorrhage: 11% both groups Recanalisation at 2h:Recanalisation at 2h:

All: 55% IV/IA vs 10% IAAll: 55% IV/IA vs 10% IAM1: 100% IV/IA vs 67% (PROACT) M1: 100% IV/IA vs 67% (PROACT)

IV plus IA ThrombolysisErnst et al Stroke 2000IV plus IA ThrombolysisErnst et al Stroke 2000

Continuation of the bridging trialContinuation of the bridging trial 20 patients20 patients Anterior circulation CVA, NIHSS > 10, Anterior circulation CVA, NIHSS > 10,

planned tPA within 3Hplanned tPA within 3H Same dose and method of administrationSame dose and method of administration

IV plus IA ThrombolysisErnst et al Stroke 2000IV plus IA ThrombolysisErnst et al Stroke 2000

Results:Results: Initial NIHSS: 11 to 31 (median 21)Initial NIHSS: 11 to 31 (median 21) IV tPA: median 2H (1H12min to 4H 10 IV tPA: median 2H (1H12min to 4H 10

min)min) IA tPA: median 3H 30 minIA tPA: median 3H 30 min

IV plus IA ThrombolysisErnst et al Stroke 2000IV plus IA ThrombolysisErnst et al Stroke 2000

Recanalisation: 69%Recanalisation: 69% Heparin bolus in 11patients, infusion in 7Heparin bolus in 11patients, infusion in 7 4 hemorrhages, 1 sympt 4 hemorrhages, 1 sympt 10 of 16 patients mRS 0-2.10 of 16 patients mRS 0-2. No change in 90d mortalityNo change in 90d mortality

IV plus IA ThrombolysisZaidat et al Stroke 2002IV plus IA ThrombolysisZaidat et al Stroke 2002

207 pts thrombolysed from 1995-2000207 pts thrombolysed from 1995-2000 IA or IV + IAIA or IV + IA 101 had angio101 had angio 18 ipsilateral distal ICA occlusion18 ipsilateral distal ICA occlusion

IV plus IA ThrombolysisZaidat et al Stroke 2002IV plus IA ThrombolysisZaidat et al Stroke 2002

No difference between groups for:No difference between groups for:Recanalisation (70%)Recanalisation (70%)Outcome: mRS 0-2 77% in survivorsOutcome: mRS 0-2 77% in survivorsSympt hemorrhage (15-20%)Sympt hemorrhage (15-20%)Mortality: 50% !!Mortality: 50% !!

I.A.T. Post-Operative PeriodI.A.T. Post-Operative Period

Chalela et al, Stroke 2001Chalela et al, Stroke 2001 Retrospective, median time to stroke 21hRetrospective, median time to stroke 21h Median TTT: 4.5h (1 to 8h)Median TTT: 4.5h (1 to 8h) tPA or UKtPA or UK 36 patients, 3 major bleeds, 2 post 36 patients, 3 major bleeds, 2 post

craniotomy, all fatal Minor bleed 25%craniotomy, all fatal Minor bleed 25%

Posterior Circulation

Vertebrobasilar ThrombosisVertebrobasilar Thrombosis

Life-threatening event: mortality 75-86%Life-threatening event: mortality 75-86% No effective therapyNo effective therapy Heparin: accepted but unprovenHeparin: accepted but unproven Some authors reporting success with IATSome authors reporting success with IAT::

RetrospectiveRetrospectiveSmall groupsSmall groups

Vertebrobasilar I.A.T.Vertebrobasilar I.A.T.

Time frame: 1 to 48 h after last progressionTime frame: 1 to 48 h after last progression Most patients present 24Most patients present 24 -- 48 h after onset48 h after onset Only 3 studies with > 10 patientsOnly 3 studies with > 10 patients

Vertebrobasilar I.A.T.Vertebrobasilar I.A.T.

Cohort mortality is decreased compared to Cohort mortality is decreased compared to historic controls when successful historic controls when successful thrombolysis has been achieved.thrombolysis has been achieved.

Benefit even 24 h after presentation.Benefit even 24 h after presentation.

Vertebrobasilar I.A.T.4 major seriesVertebrobasilar I.A.T.4 major series

Average time to therapy: up to 24hAverage time to therapy: up to 24h Mortality: 46%, 54%, 67%, Mortality: 46%, 54%, 67%, 75%75% Recanalization: 75%, 71%, 54%, 75%Recanalization: 75%, 71%, 54%, 75% Hemorrhage: 7%, 0%, 9%, 15%Hemorrhage: 7%, 0%, 9%, 15% Rethrombosis: --- 10%, --- Rethrombosis: --- 10%, --- 30%30% Recanalized mortality: 26% to 30%Recanalized mortality: 26% to 30%

Vertebrobasilar I.A.T.Factors affecting outcomeVertebrobasilar I.A.T.Factors affecting outcome

InfaInfarrction of a critical amount of brainstem ction of a critical amount of brainstem tissuetissue

Coma and quadriparesis at presentationComa and quadriparesis at presentation Lack of recanalization, rethrombosisLack of recanalization, rethrombosis

Possible ConclusionsPossible Conclusions

I.A.T. Anterior CirculationI.A.T. Anterior Circulation

The lack of recanalization is linked to poor The lack of recanalization is linked to poor outcome.outcome.

BBetter rate of recanalizationetter rate of recanalization: 70 vs 34%: 70 vs 34%.. Likely better effect on outcome than IV tPALikely better effect on outcome than IV tPA Larger therapeutic windowLarger therapeutic window (6h) (6h), , Can be given post-operatively (except post Can be given post-operatively (except post

craniotomy)craniotomy)

I.A.T. Anterior CirculationI.A.T. Anterior Circulation

Combined IV-IA: may be as good or better Combined IV-IA: may be as good or better than IA alone. Can be started faster.than IA alone. Can be started faster.

Hemorrhage rates 7 – 10%Hemorrhage rates 7 – 10%

Drawbacks: technique, time to initiation, Drawbacks: technique, time to initiation, dose variation.dose variation.

I.A.T. Vertebrobasilar systemI.A.T. Vertebrobasilar system

No satisfactory studies.No satisfactory studies. Very grim prognosisVery grim prognosis I.A.T. only life-saving therapy availableI.A.T. only life-saving therapy available Beneficial effect on mortality and morbidity Beneficial effect on mortality and morbidity

with recanalizationwith recanalization

I.A.T. Vertebrobasilar systemI.A.T. Vertebrobasilar system

Up to 24h after deterioration, up to 48h Up to 24h after deterioration, up to 48h after onset.after onset.

Less benefit if coma, quadriparesis, large Less benefit if coma, quadriparesis, large area of infarct pre-treatment.area of infarct pre-treatment.

?? Indications?? Indications

Indications in Anterior CirculationIndications in Anterior Circulation

Persistent occlusion post IV tPA < 3hPersistent occlusion post IV tPA < 3h Within 6 h, Within 6 h, but but time to treatment is time to treatment is

correlated with outcome.correlated with outcome. IV contra-indicated with evidence of viable IV contra-indicated with evidence of viable

tissue: post-op, > 3Htissue: post-op, > 3H tPA 9 to 40 mg (med 21)tPA 9 to 40 mg (med 21) UK 40,000 – 1,500,000 (med 500,000)UK 40,000 – 1,500,000 (med 500,000)

Indications in Posterior CirculationIndications in Posterior Circulation

Worsening symptomatology despite heparinWorsening symptomatology despite heparin Visualized occlusionVisualized occlusion Up to 24h after onset of worseningUp to 24h after onset of worsening UK 250,000-500,000 per H x 2 then UK 250,000-500,000 per H x 2 then

250,000u per H x 4. With heparin.250,000u per H x 4. With heparin. tPA: less well studied.tPA: less well studied.