1. IA Thrombolysis for Ischemic Stroke: Part 1--Setting the Stage
Joshua A. Hirsch, MD FSIR
Vice Chief: Interventional Care
Director : Interventional Neuroradiology/Endovascular Neurosurgery
Chief: Minimally Invasive Spine Surgery
Massachusetts General Hospital
Associate Prof: Harvard Medical School

2. Joshua A. Hirsch, MD DISCLOSURES Consulting Fees
Intratech Medical LTD., Medtronic CardioVascular, Inc.

3. Disclosures: stroke Consultant/shareholder Intratech
Steering Committee: MERCI Registry--all honoraria donated to charity (NERF)
Co-investigator on all IA stroke studies at MGH
Some slides provided by industry
Discussion will include off label use of product

4. Stroke=Brain Attack 700,000 cases/yr in the USA
3rd leading cause of death
Estimated that >95% do not get thrombolytic therapy
1/3 MCA strokes die within 1-6 months
survivors left with major disability
N.B. Time is brain

5. IV tPA is the only FDA approved drug for acute stroke*…
Current Status
Mechanism of Action
Comments
Time Window
FDA-approved in 1996 based on NINDS trial
Standard of care for acute treatment
Dissolves clot to reperfuse ischemic cells
Salvage the ischemic penumbra via systemic administration of lytic agent
NINDS trial results 30% relative reduction in long-term disability at 3 months compared to placebo
Systemic treatment, only a small proportion of the agent delivered actually reaches the clot
High incidence of symptomatic hemorrhage (6.4% versus 0.6% placebo) causes reluctance in administration, yet mortality rates at 3 months are the same
<3 hours
Merci retriever and Penumbra catheter now approved
Source: NINDS tPA Stroke Study Group; S.J. Connolly, Am Heart J March 2003; 145 (3):

6. …But very few patients receive IV t-PA therapy.
Patients Receiving IV tPA
18%
45%
Percent of Total Stroke Patients Receiving IV tPA = ~3%
Source: Guidelines for the Early Management of Patients with Ischemic Stroke, AHA 2003
J A Hirsch, A J Yoo, R G Nogueira, L A Verduzco, L H Schwamm, J C Pryor, J D Rabinov, R G Gonzalez. Case Volumes of intra-arterial and intravenous treatment of ischemic stroke in the USA. J NeuroInterv Surg. 2009;1(1):27-31.

7. IV Thrombolysis
rt-PA only FDA-approved lytic for Ischemic Stroke (NINDS trial)
The indication is for IV, systemic admistration only
3 hour time window
Few (<1%) “eligible” patients treated
Longer list of exclusions than for AMI
That having been said, it is relatively easy and rapid to initiate, and does not require specialized equipment or highly technical expertise.

8. IV Thrombolysis
Pooled analysis of 6 major randomized placebo-controlled IV rt-PA stroke trials, including 2775 pts treated with IV rt-PA or placebo within 360 min of stroke onset, suggested a potential benefit beyond 3 h, even though the chances of a favorable 3-month outcome decreases as the interval from stroke onset to start treatment increases.
We began participating a trial about 1.5 years ago to look at the hour group.
ATLANTIS I & II, ECASS I & II, and NINDS I & II

9. Case: Imaging in Acute Stroke
69 y/o female with h/o HTN and AFib
R HP/ aphasia/ L gaze deviation;
Tx’d to NeuroICU – Phenylephrine Rx

10. ACA INFARCT
CTA
DWI
ADC
CBF
CBV
MTT

11. MCA INFARCT
CTA
CTA
FLAIR
DWI
ADC

12. CT PERFUSION MISMATCH
CBV
MTT
CBF

13. CTA demonstration-PCOMM THROMBUS

14. Thrombolysis-Cochrane Database
18 trials (16 double-blind)
5727 pts treated IV urokinase, streptokinase, rt-PA or recombinant IA pro-urokinase up to 6 h after stroke
Significant reduction of pts who were dead or dependent (mRs 3-6) at 3 to 6 months (OR 0.84, 95% CI ) despite a increase in the odds of death within the first 10 days (OR 1.81, 95% CI 1.46 to 2.24), mostly related to symptomatic ICH (OR 3.37, 95% CI 2.68 to 4.22).
Wardlaw, J. M., G. Zoppo, et al. (2003). "Thrombolysis for acute ischaemic stroke." Cochrane Database Syst Rev(3): CD

15. IA Thrombolysis Trials
  Majority of the early work in IAT has been reported in non-randomized case series.
Reports of successful IAT go back to the late 1950’s, when Sussmann and Fitch described the recanalization of an acutely occluded ICA with IA injection of plasmin.
Sussman BJ et al. Thrombolysis with fibrinolysin in cerebral arterial occlusion. JAMA 167: ;1958

16. IA Thrombolysis Trials
A metanalysis of IAT including 27 studies (>10 pts) with a total of 852 IAT pts and 100 controls
More favorable outcomes (41.5 vs. 23% - OR 2.4) and a lower mortality rate (27.2 vs. 40%) with IAT than controls despite a higher frequency of symptomatic ICH (9.5 vs. 3%).
In addition, trend towards better outcomes with combined IV t-PA and IAT than with IAT alone.
(Lisboa R.C. et al, Analysis of the safety and efficacy of intra-arterial thrombolytic therapy in ischemic stroke. Stroke, (12): p )

17. Data, data, data…
Nogueira RG, Yoo AJ, Buonanno FS, Hirsch JA. Endovascular Approaches to Acute Stroke, Part 2: A Comprehensive Review of Studies and Trials. AJNR Am J Neuroradiol

18. IA Thrombolysis Trials – PROACT I
26 pts (NIHSS 17) were treated with r-pro-UK (6 mg/ 2 h) and 14 pts (NIHSS 19) with placebo, at a median of 5.5 hrs from symptom onset.
All pts received high (100 IU/kg bolus f/ by 1K IU/h for 4 h) or low dose (2K IU bolus f/ by a 500 IU/h for 4 h) IV heparin.
Mechanical disruption of the clot was not allowed.
Both the re-canalization rates (TIMI 2/ 3: 57.7 vs. 14.3%) and the incidence of symptomatic ICH (15.4 vs. 7.1%) were higher in the r-pro-UK group.

19. IA Thrombolysis Trials – PROACT I
All pts in the r-pro-UK group with early CT changes >33% of the MCA territory suffered ICH.
In the r-pro-UK group, both re-canalization (At 2hs, 81.8 vs. 40%) and symptomatic ICH (27.3% vs. 6.7%) rates were dependent on dose of heparin.
The overall 90-day cumulative mortality was 26.9% in the r-pro-UK group and 42.9% in the placebo group.

20. IA Thrombolysis Trials – PROACT II (2/96-8/98)
180 pts in a 2:1 randomization to receive in 54 centers in N America
9mg IA r-pro UK plus 4 h low dose IV heparin or low dose IV heparin alone.
Primary clinical outcome: proportion of pts with mRS < 2 at 90 days - 40% of the 121 r-pro-UK pts vs. 25% of the 59 control pts (abs. benefit 15%, rel. benefit 58%, NNT = 7; p =.04).
TIMI 2/3: 66% for the r-pro-UK group vs. 18% for the control group (P< .001).
JAMA December 1999

21. PROACT II Study
PROACT II is the first study of thrombolysis in ischemic stroke to show treatment benefit up to 6 hours (180 patients enrolled)
Patients treated with rPro-UK are 60% more likely to have slight or no neurological disability at 90 days (Rankin < 2)
Patients treated with rPro-UK showed a 15% absolute benefit versus control (40% vs. 25%)
67% of rPro-UK-treated subjects had middle cerebral artery recanalization
There was an 8.4% increased risk of symptomatic intracranial bleeding (10.2% vs. 1.8%) 5

22. PROACT II Study The conclusion of the article
“Despite an increased frequency of early symptomatic intracranial hemorrhage, treatment with IA r-proUK within 6 hours of the onset of acute ischemic stroke caused by MCA occlusion significantly improved clinical outcome at 90 days.”
N.B. Benefit despite prohibition of mechanical clot manipulation! 5

23. MELT trial MELT=MCA Embolism Local Fibrinolytic Intervention Trial
Japanese trial designed the safety and clinical efficacy of IA UK in stroke pts. Up to 6 hours
Aborted prematurely after approval of IV-TPA in Japan

24. MELT trial-good data nonetheless
114 pts. 57 in each group
Baseline NIHSS 14
Primary endpoint of mRS </= 2 was better in UK group (49.1% vs. 38.6%) but not stat signif
Two pre-planned 2ndry endpoints reached stat signif and were better for UK group
Excellent clinical outcome (42.1% vs. 22.8%)
Partial or comp recan 42/57 pts. In IA UK group

25. Combined IV/IA Thrombolysis-strategy at MGH
Four studies have evaluated the feasibility, safety and efficacy of combined IV rt-PA at a dose of 0.6mg/Kg and IAT in patients presenting with acute strokes within 3 hours of symptoms onset. This approach has the potential of combining the advantages of IV rt-PA (fast and easy to use) with the advantages of IAT (titrated dosing, mechanical aids to re-canalization, and higher rates of re-canalization), thus improving the speed and frequency of re-canalization.

26. IMS 1 and 2 Interventional Management of Stroke Study IMS 2
IMS 1--Multicenter, open labeled, single-arm pilot study with the aim of investigating the feasibility and safety of a combined IV/IA
IMS 2
Objective--to cont investigating the feasibility of combined IV/IA approach to restore CBF in acute stroke patients
N.B Main diff between IMS 1 and IMS 2 is that 2 allowed EKOS MicroLys US infusion cath (remember Part 1)

27. IMS 1 and 2: Results
IMS 1
90 day mortality (16%) of IAT was lower (but not stat signif’ly so) than the mortality of placebo (24%) or IV-tPA patient in NINDS
Rate of sympt ICH similar (6.3%) to IV-tPA patient in NINDS (6.6%)--higher than placebo
Significantly better outcome at 90 days for all measures than NINDS placebo-treated subjects
IMS 2
46% of patients achieved a mRS </= two 2 at 90 d
39% IV tPA and 28% of placebo in NINDS
90 day mortality (16%) was lower than either arm of NINDS
21% IV tPA and 24% of placebo in NINDS

28. MERCI Ushered in modern era of mechanical thrombectomy
MERCI Retriever-first stroke device approved by FDA (August 2004)
indication: “to restore blood flow in the neurovasculature by removing thrombus in pts. experiencing acute stroke.”

29. MERCI trial
Prospective single-arm multicenter trial designed to test the safety and efficacy of the MERCI clot retrieval device to restore the patency of intracranial arteries in the first 8 hrs of an acute stroke
All patients ineligible for IV tPA and generally tended to higher burden disease.
If the target vessel could not be opened to at least TIMI 2 flow with 6 passes it was considered a Rx failure of the device.
IA thrombolytics were allowed in cases of device failure of for distal emboli not accessible to the device
Heparin at discretion of investigator

30. MERCI trial Primary outcomes--recan and safety
Secondary outcomes--neurologic outcomes at 90 days in recan vs. non-recan patients
May 2001-Dec pts were screened and 151 pts put in
Mean age 67.0+/-15.5 yrs; Mean NIHSS 20.1+/-6.6; 54/46% M/F
Occlusion sites ICA T 14%, M1 or M2 57%, VB 10%
TIMI 2 and 3 recan was achieved in 69/151 (46%) in the intention to Rx analysis and in 68/141 (48%) in whom the device was deployed
Historical control 18% from control arm of PROACT 2
With adj therapy, rate of recan increased to 60.3%
Clinically signif proc comp occurred in 10/141 (7.1%)

31. MERCI trial
Secondary outcomes--neurologic outcomes at 90 days in recan vs. non-recan patients
Overall
Good outcome mRS</=2 was 27.7%
Mortality was 43.5%
Comp: Recan vs. non recan
Good outcome 46% vs. 10%
Mortality 32% vs. 54%
In a multivariate logistic regression analysis, successful revasc and baseline NIHSS were the strongest predictors of good outcome at 90 days.

32. Multi MERCI trial
International multicenter single-arm trial with 3 objectives, to…
Gain greater experience with the 1st gen Retrievers (X5 and X6) in pts. Ineligible for IVT
Explore Bridging
Collect safety and technical efficacy data on second gen retriever (L5)

33. Multi MERCI trial
Jan 2004-July pts were screened and 177 were enrolled in the study.
Device deployed in 164 pts.--cohort studied
Mean age 68.1+/- 16 yrs. Median baseline NIHSS 19
Occlusion at ICA/ICA T is 32%, M1 or M2 60%, VB in 8%
48pts (29.3%) received IV tPA before intervention and 57 pts. Received IA lytics
Recan rates:
Retriever alone TIMI 2/3 in 55% Rx’ed vessels
With adjuvant therapy 68%
Overall rates of good outcome and mortality were substantially improved compared to MERCI trial AND LIKE IN MERCI successful recan compared favorably to unsuccessful (Good outcome 49 vs. 9.6% and mortality 35 vs. 52%).

34. Penumbra Recent Clinical Trials
Pivotal Trial (complete)
Prospective, single-arm, multi-center
125 patients
Assessed the safety and efficacy of the Penumbra System®
POST Study (complete)
Retrospective, single-arm, multi-center prospective clinical outcome data
157 consecutively treated patients
Real world performance, many with adjunctive lytic therapy 34

35. Penumbra System® Product Family35

36. (distal branch filling)
TIMI Scores
Pivotal (n=125)
POST (n=157)
TIMI
Baseline
Post Procedure
96%
10%
92% 8% I 4% 9% 5% II
(distal branch filling) 0%
54%
III
(complete perfusion)
27%
33%
II + III
81.6%
87%

37. POST Clinical Outcomes (n=157)%
≥ 10 Point Improvement in NIHSS or NIHSS 0-1 at Discharge (n=110)
37%
All Cause Mortality at 90 Days
20%
mRS ≤ 2 at 90 Days (n=122)
41%

38. Safety and Effectiveness
Endpoint
Pivotal (n=125)
POST (n=157)
Revascularization
82%
87%
Procedural SAE’s 3%
5.8%
Symptomatic ICH
11%
6.4%
All Cause Mortality at 90 Days
33%
20%*
mRS ≤ 2 at 90 Days
25%
41%*
* p < 0.05 vs Pivotal. Fisher 2-sided Exact Test

39. POST: Effects of Revascularization on Patient Outcome (n=157)
TIMI 0 - I
(n=20)
TIMI II - III
(n=137)
p-value*
NIHSS = 0-1 at Discharge or improved by > 10 points
10%
40%
0.087
90 Day All Cause Mortality
50%
16%
0.001
90 Day mRS ≤ 2
13%
45%
0.014
* Fisher 2-sided Exact Test

40. Conclusion The effectiveness of IV Rx is real but limited
N.B. it is reaching a small number of patients
The data supporting IAT continues to get stronger
Bridging therapy may play an increasingly important role in the future.
More studies are under way and planned