Intra - Arterial Thrombolysis for acute stroke Jeanne Teitelbaum md Associate Professor Neurology and Critical Care

Intra - Arterial Thrombolysis Effect on recanalisation Effect on clinical outcome Risks ?? Indications

Why consider IAT IV rt-PA: Limited to < 3H Clear but limited clinical benefit Rate of recanalisation (doppler): Complete: 32% Partial or none 68%: 67% MCA, 25% BA, no ICA (Christou et al 2001)

Why consider IAT Persistent obstruction persistent deficit Increase the therapeutic window Post-operative stroke Reduce hemorrhagic complications

I.A.T. Theoretical Advantages Higher concentrations delivered to the clot Gentle mechanical disruption of the clot Precise imaging of anatomy, pathology and collateral pattern Exact degree and timing of recanalisation

I.A.T. Potential Disadvantages Catheter manipulation Systemic heparinisation Delay in initiation of thrombolysis Skilled facilities

Intra-arterial Thrombolysis The Evidence

Anterior Circulation

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

PROACT II Trial mRS < 2 : 40% VS 25% (+- SIG) Recanalisation at 2h: 66% vs 18% Hemorrhage at 36h: all: 46% vs 16% symptomatic: 10% vs 2% No difference in mortality

I.A.T. Rate of Recanalisation Depends on site and type of occlusion PROACT II :66% overall Urbach et al 2002: Thrombus 53%: 23% carotid T, 74% distal M1 60% M2

I.A.T. Rate of Recanalisation Depends on site and type of occlusion Urbach et al 2002: Embolus 59% overall 1of 6 with cardiac thrombus 15 of 19 (79%) without thrombus

I.A.T. Therapeutic Window PROACT II: 6h Arnold et al stroke 2002: 100 pts Urokinase, MCA, NIH = 14 Average 236 minutes Recanalisation: 76% Outcome: excellent 47%, good 21%, poor 22%, dead 10%, hemorrhage 7%

I.A.T. Therapeutic Window Evidence that TTT influences outcome New studies in progress: 1.5 to 6 h.

MRI data Kidwell et al Ann Neurol 2000 7 patients DWI and PWI pre and post I.A.L. DWI 3 and 9 h post recanalisation delayed re of DWI at 7 days Final volume 86% of original pre - lysis

IV plus IA thrombolysis Stroke Bridging Trial Lewandowski CA et al Stroke 1999 Randomized pilot study. 35 patients tPA IV 0.6 mg/Kg then IA 20 mg Symptomatic hemorrhage: 11% both groups Recanalisation at 2h: All: 55% IV/IA vs 10% IA M1: 100% IV/IA vs 67% (PROACT)

IV plus IA Thrombolysis Ernst et al Stroke 2000 Continuation of the bridging trial 20 patients Anterior circulation CVA, NIHSS > 10, planned tPA within 3H Same dose and method of administration

IV plus IA Thrombolysis Ernst et al Stroke 2000 Results: Initial NIHSS: 11 to 31 (median 21) IV tPA: median 2H (1H12min to 4H 10 min) IA tPA: median 3H 30 min

IV plus IA Thrombolysis Ernst et al Stroke 2000 Recanalisation: 69% Heparin bolus in 11patients, infusion in 7 4 hemorrhages, 1 sympt 10 of 16 patients mRS 0-2. No change in 90d mortality

IV plus IA Thrombolysis Zaidat et al Stroke 2002 207 pts thrombolysed from 1995-2000 IA or IV + IA 101 had angio 18 ipsilateral distal ICA occlusion

IV plus IA Thrombolysis Zaidat et al Stroke 2002 No difference between groups for: Recanalisation (70%) Outcome: mRS 0-2 77% in survivors Sympt hemorrhage (15-20%) Mortality: 50% !!

I.A.T. Post-Operative Period Chalela et al, Stroke 2001 Retrospective, median time to stroke 21h Median TTT: 4.5h (1 to 8h) tPA or UK 36 patients, 3 major bleeds, 2 post craniotomy, all fatal Minor bleed 25%

Posterior Circulation

Vertebrobasilar Thrombosis Life-threatening event: mortality 75-86% No effective therapy Heparin: accepted but unproven Some authors reporting success with IAT: Retrospective Small groups

Vertebrobasilar I.A.T. Time frame: 1 to 48 h after last progression Most patients present 24 - 48 h after onset Only 3 studies with > 10 patients

Vertebrobasilar I.A.T. Cohort mortality is decreased compared to historic controls when successful thrombolysis has been achieved. Benefit even 24 h after presentation.

Vertebrobasilar I.A.T. 4 major series Average time to therapy: up to 24h Mortality: 46%, 54%, 67%, 75% Recanalization: 75%, 71%, 54%, 75% Hemorrhage: 7%, 0%, 9%, 15% Rethrombosis: --- 10%, --- 30% Recanalized mortality: 26% to 30%

Vertebrobasilar I.A.T. Factors affecting outcome Infarction of a critical amount of brainstem tissue Coma and quadriparesis at presentation Lack of recanalization, rethrombosis

Possible Conclusions

I.A.T. Anterior Circulation The lack of recanalization is linked to poor outcome. Better rate of recanalization: 70 vs 34%. Likely better effect on outcome than IV tPA Larger therapeutic window (6h), Can be given post-operatively (except post craniotomy)

I.A.T. Anterior Circulation Combined IV-IA: may be as good or better than IA alone. Can be started faster. Hemorrhage rates 7 – 10% Drawbacks: technique, time to initiation, dose variation.

I.A.T. Vertebrobasilar system No satisfactory studies. Very grim prognosis I.A.T. only life-saving therapy available Beneficial effect on mortality and morbidity with recanalization

I.A.T. Vertebrobasilar system Up to 24h after deterioration, up to 48h after onset. Less benefit if coma, quadriparesis, large area of infarct pre-treatment.

?? Indications

Indications in Anterior Circulation Persistent occlusion post IV tPA < 3h Within 6 h, but time to treatment is correlated with outcome. IV contra-indicated with evidence of viable tissue: post-op, > 3H tPA 9 to 40 mg (med 21) UK 40,000 – 1,500,000 (med 500,000)

Indications in Posterior Circulation Worsening symptomatology despite heparin Visualized occlusion Up to 24h after onset of worsening UK 250,000-500,000 per H x 2 then 250,000u per H x 4. With heparin. tPA: less well studied.