Endovascular Neurointervention in Cerebral Beyond Thrombolytics

Curtis A. Given II, MD Co-Director, Neurointerventional Services Baptist Physician Lexington

72 y/o female with a recent diagnosis of paroxysmal atrial fibrillation developed right hemiparesis and global aphasia while at interstate “rest stop”. Patient was taken to regional medical facility (Corbin Baptist Regional) within 1 ½ hours of onset of symptoms.

NIHSS was 16 and head CT was normal. IV-tPA was administered by the Emergency room physician and the patient was transferred to UK.

Upon arrival to UK, the patient was hemiplegic with global aphasia and NIHSS was 22. Repeat head CT was normal. Patient was immediately taken to the Angiography suite First pass with Merci retriever was performed at approximately 6 hours after the onset of symptoms Two passes of the Merci retriever resultant in complete recanalization of the left middle cerebral artery The patient began to have purposeful movement of her right arm and leg Immediately after the procedure. MRI of the head on the following day revealed only a few small infarcts. She was discharged home, independent and without the need for rehabilitation, and an NIHSS of 0. • Impact – Every 45 seconds someone in the U.S. has a stroke – Stroke is #3 cause of death – Stroke is #1 cause of adult disability – Approximately 87% ischemic • Limited treatment options – Intravenous lytic • Limitation: must be administered within 3 hours of stroke onset • Estimated <5% of stroke patients receive IV lytic – Mechanical revascularization with Merci® and Penumbra ® Retrieval Systems • Option beyond 3 hour window, and for patients who are ineligible for or who fail IV t-PA therapy Time Window for Potential Stroke Treatments

Time Window 0-4.5 hrs 0-6 hrs >6 hrs ‡

Options • IV tPA • Merci • Merci • Merci* • Penumbra • Penumbra • Penumbra* •Solitaire •Solitaire •Solitaire • IA Lytic†

* 0-3 hours in patients who are contraindicated for IV tPA or who fail IV tPA therapy. † Not FDA approved. ‡ The MERCI and Multi MERCI trials evaluated patients up to 8 hours Patient Selection for Intra-arterial Therapy

. Generally patients with symptoms of large vessel occlusion (NIHSS > 8)

. No changes of large infarct (less than 1/3 of vascular territory) on CT or DWI

. No hemorrhage on CT

. < 8 hours since “last seen normal” OR significant tissue “at-risk/penumbra” on imaging

. Any patient with basilar occlusion

. Large vessel occlusion on CTA/MRA

Contraindications to IA Thrombolysis

• CT-documented hemorrhage or significant mass effect • Fibrinogen < 120 mg* • Platelet count < 80,000* • Active internal bleeding or recent surgery (<10 days)* • Prior allergic reaction to r-tPA* • BP > 200 systolic or >120 diastolic despite medical therapy • No clot on angiography

* Not contraindication to mechanical thrombectomy What about patients presenting after 8 hours or “wake up” ?

• Significant problem, particularly in patients with an unknown time to onset (“wake up” strokes). • Traditionally, these patients offered only supportive measures • 50% of patients may have a persistent ischemic penumbra at 24 hrs. Slide borrowed from Dr. Lev’s ASNR presentation 2008

TTP > 6 sec rCBF 60% rCBV 110% Trials of Intra-arterial Thrombolytic Agents PROACT II Furlan A. et al. JAMA 282:2003, 1999

• Randomized open-label trial of prourokinase (r-pro-UK) 9 mg with heparin vs systemic heparin in patients with middle cerebral artery occlusions within 6 hours of onset. • Pro-urokinase delivered over 2 hours by microcatheter into the middle cerebral artery at the face of the clot. • Mechanical clot disruption was not permitted. • Final angiogram at 2 hours in both groups. Pre Interim Post – 20 mg IA r-tPA Endovascular Thrombectomy of Cerebral Vessels

• Merci Retriever • First surgical device cleared by the FDA for acute ischemic stroke patients • Restores blood flow to the brain by physically removing thrombus from the occluded precerebral or cerebral vessel Candidates for Merci Therapy

Only used for patients with ischemic stroke, not hemorrhagic stroke

• Patients who are ineligible for treatment with intravenous tPA : – outside 3-4.5 hour window – other clinical factors, eg. recent surgery, long-term current use of anticoagulants for atrial fibrillation, allergy to t-PA • Patients who have failed (or not responding to) prior intravenous t-PA therapy Specialized Devices

• Merci® Retriever • Merci® Microcatheter • Merci® Balloon Guide Catheter

Endovascular thrombectomy devices were cleared by the FDA in August 2004

Merci Registry Background

The Merci Registry is a Post-Market study designed to capture “real-world” interventional treatment of acute stroke with the Merci Retriever system, unconstrained from the “trial” environment Merci Registry

The Largest, Prospective Multi-Center Study of Mechanical Embolectomy for AIS

• Prospective, multi-center study (36 centers) • 1,000 patients enrolled in 3 years – Interim results presented at ISC 2010 analyzed 625 patients • Inclusion criteria: procedure must have included a Merci Retriever and patient informed consent • No exclusion criteria • Interim results validated MERCI and Multi MERCI results in a much larger unconstrained cohort Revasc Rates by Final TICI Score Merci Registry – Interim Analysis Good Outcomes by Final TICI Score Merci Registry – Interim Analysis

Good Outcomes defined as mRS=0-2 at 90 days Penumbra Thrombectomy System

The Penumbra System is designed to revascularize large vessel occlusions in the intracranial circulation. The Penumbra System uses a unique microcatheter and SeparatorTM based thrombus debulking approach to intracranial vessel revascularization.

The Penumbra advantages are:

•Proximal working position

•Continuous Aspiration

•Variable sizing for variable

So What’s Next?

• “Stent-trievers” • Solitaire® and Trevo® • Allow for faster and higher recanalization rates, with fewer device deployments (‘passes’), and improved

clinical outcomes relative to Trevo™ Merci

Retrieve with Confidence

Merci Retriever ® Clinical History

The Solitaire™ FR device Retrospective data demonstrates higher angiographic and neurological outcomes when compared to these Merci® registries.

**TICI 2a-3 classification was used Merci® Competitive Messages:

1. 2.5x improvement in Recanalization 2. 1.7x improvement in neurological outcomes 3. 55% reduction in mortality Solitaire™ FR revascularization device vs. The Concentric ® Merci® Retriever1 (SWIFT Study)

(Core Lab) 79 yo WM awoke and walked to bathroom at 9am, wife heard loud noise and went to find husband lying in the floor of bathroom, aphasic and right sided hemiplegic. Transferred to CBH and received full-dose tPA at 12pm (approx. 3hrs after symptom onset). Initial NIHSS was 24 upon arrival to CBH. CT Perfusion scan shows large area of ischemia in left MCA territory consistent with large vessel occlusion, sent for possible thrombectomy.

Partial flow restoration with Solitaire at 130pm (4.5 hrs after sx onset) Two passes with 4x20mm Solitaire

The next day, the patient had regained anti-gravity strength in the right upper and lower extremities and significant improvement in speech (mild-moderate residual expressive aphasia). 24 hr NIHSS had improved to 6 (initial was 24). TTD rCBV 24 hr CT TREVO 2 Thrombectomy REvascularization of large Vessel Occlusions in acute ischemic stroke

. Randomized, prospectively controlled, multi-center, non- inferiority IDE study of arterial revascularization in acute ischemic stroke patients

. Up to 25 sites (at least 20 sites in North America) – 1st and only site in Kentucky

. 178 patients, with a planned interim analysis at 120

. Randomized 1:1, with test arm using the Trevo device, the control arm using the Merci device

27 yo male with history of eosinophilic myocarditis and dilated cardiomyopathy, presented with acute onset of left facial droop, left hemiplegia, dysarthria and gaze defect. Initial NIHSS=16. He was antiocoagulated for his cardiomyopathy and prior stroke (prior full recovery) with a PT/INR or 26.7/2.3 (therapeutic anticoagulation).

Given anticoagulation, he was not a candidate for thrombolytic therapy (tPA). Was evaluated and treated my partner Christian Ramsey.

rCBV rCBV rCBV TTD TTD TTD “relative cerebral “relative cerebral “relative cerebral “time-to-drain” “time-to-drain” “time-to-drain” blood volume” blood volume” blood volume” rCBV rCBV rCBV TTD TTD TTD “relative cerebral “relative cerebral “relative cerebral “time-to-drain” “time-to-drain” “time-to-drain” blood volume” blood volume” blood volume” 4x20mm Solitaire

The next day, the patient had regained full strength in the left upper and lower extremities and with only minimal residual facial droop. 24 hr NIHSS had improved to 1 (initial was 16).

TTD “time-to-drain”

57 yo BF with “wake up” stroke manifesting as slurred speech and right arm/leg paralysis, resulting in fall to floor upon getting out of bed. PMH significant for non-ischemic cardiomyopathy with pacemaker (EF 30-35%), type II DM, and dyslipidemia (not on statin therapy). Initial NIHSS was 8 in the ED, and was NIHSS of 11 prior to procedure. rCBV “relative cerebral blood volume”

4 passes with the Solitaire and 6mg of IA tPA into the left MCA TTD TTD Initial CT Perfusion F/u CT Perfusion 3 days later

At the time of transfer to rehab, she regained full strength in her right lower extremity and her speech had significantly improved. Unfortunately she was still plegic in the right upper extremity.

. 334 patients received “endovascular” therapy . “Endovascular” Treatment after IV t-PA administration (11 patients did . 181 patients, 163 patients completed (18 not receive angiogram, 89 patients excluded – lack of occlusion, clinical endovascular therapy was not administered). improvement, etc.)  142 patients received “standard” therapy consisting of additional IA t-PA  42.5% . Median time to treat 3.75 hrs of patients in the “endovascular” arm . 109 patients (67%) received intra-arterial t-PA received intra-arterial t-PA as MONO as MONO THERAPY (0.9mg/kg given over 1hr, THERAPY. median dose 40mg)  22 patients - EKOS cath and t-PA . ONLY 56 patients (33%) received adjunctive  95 patients – Merci (57 got additional IA t- mechanical thrombectomy PA)  23 stent-treivers ------ ONLY 14 % of  54 patients – Penumbra (38 got additional the “endovascular” arm received current IA t-PA) treatment  5 patients – Solitaire (2 got additional IA t-  18 Solitaire PA) ONLY 1.5% of patients in the  5 Trevo “endovascular” received most current  5 Merci treatment.  9 Penumbra  16 patients – “other” (9 got additional IA t- PA)  not specified as to what “other” is . Remainder of devices not specified in the article.

. In the 2 “landmark” trials assessing “endovascular” stroke therapy recently published  Only 28 patients (5.4%) of the endovascular arm were treated with “current” technology (i.e. stent-trievers)  63% of patients receiving “endovascular” therapy received only IA tPA therapy (no mechanical thrombectomy of any method, i.e. no Merci, no Penumbra, no stent-triever) . In my opinion, these trials were largely a revisit of the PROACT trials circa 1998.

. CBH is one of 20-25 sites that are conducting a prospective randomized trial comparing IV tPA versus IV tPA and Solitaire in the treatment of large vessel occlusions and acute stroke.

• 62 yo WF with history of CHF (20-25% EF), Cardiomyopathy, COPD, and recent ablation • Normal state of health until 11pm, when she sustained a witnessed fall, with acute onset of aphasia and right sided hemiplegia

4/26/11

• Presented to CBH ED and received IV tPA (bolus at 1:30 am, 2.5 hrs after sx onset) • Initial NIHSS was 17 Left CCA Right CCA

Only mild clinical improvement (NIHSS 15), brought to cath lab, initial angios at 2:30am Left CCA

Right CCA

Left ICA with occluded left MCA

Left VA s/p aspiration thrombectomy with 9F Concentric Balloon catheter Carotid Wallstent, effectively (luckily) trapped residual clot against ECA origin, protecting the CCA/ICA Opening flow to ICA, allowed for tPA to reach intracranial circulation, and natural lysis of clot. No further intervention done. 4/27/11

She regained full strength in the right side of her body and had only expressive aphasia on 4/27/11. She began to recover speech on 4/28/11, and was left with only a mild aphasia Be Proactive You do not have to wait for the stroke

2002 2006 Conclusion

. Evolving field with new technologies allowing us to extend the therapeutic window well beyond 3 hours . Perfusion imaging will likely triage patient care in future . Future (? current) standard of care likely to involve a combination of IV and Endovascular therapies