Update on Thrombolysis and Thrombectomy. Seniorprofessur Neurologie UniversitätsKlinikum und Universität Heidelberg

Transcription

1 Update on Thrombolysis and Thrombectomy

2 Relevant Disclosures I received financial compensation from Boehringer - Ingelheim for my time and efforts as Chairman of the SC of ECASS 1-3 and from Paion for DIAS and DIAS II I have received honoraria for lectures and advisory boards from BI and Paion I have received an unrestricted scientific grant by BI to organize the ECASS 4, an IIT sponsored by the University of Heidelberg I am a member of the SC of SWIFT-PRIME and TASTE

3 Content Introduction: The preconditions for recanalization therapies Part I: Thrombolysis Penumbra and vessel occlusion The Dark Ages- Intra-arterial thrombolysis case series I.V.-Thrombolysis- past and present The groundbreaking studies New lytics and Penumbral selection rtpa in clinical routine Part II: Mechanical recanalization The early cohorts and early RCTs The new Thrombectomy trials Summary

4 Preconditions for Recanalization Treatment Successful recanalization therapies need a perfectly orchestrated stroke management system Recanalization must be offered to all people qualifying, not only to a handful of those, who live near private hospital The management system includes Recognition (FAST) EMS and ER A network of stroke ready hospitals with Stroke Units connected by teleneurology Imaging and interventions Rehabilitation and prevention

5 Preconditions for Recanalization Treatment Stroke ready hospitals offer Imaging (CT, CTA), Stroke Units and co-operation with stroke centers They can perform thrombolysis Stroke centers offer MRI, interventions, neuro-icu facilities and neurosurgery They will receive transferrals from the smaller hospitals for elective therapies Regional organization of stroke services is key

6 How Many Patients Qualify for Recanalization? The incidence of acute ischemic stroke in Germany is /100,000/year, a total of 200,000 new strokes every year In Germany (Population 82 Mio), we have a network of 280 Stroke units, among them comprehensive stroke centers For Argentina (Population 41 Mio), we can expect about 70,000 to 80,000 new strokes per year according to the few epidemiological data available I believe that both incidence and prevalence numbers are much higher

7 How Many Patients Qualify for Recanalization Under optimal circumstances, about 30% of all stroke patients can qualify for i.v. Thrombolysis Of them, about 20-30% may also qualify for thrombectomy Transferral to stroke centers leads to relatively higher numbers of thrombectomy, because the patients come from a larger catchment area In Heidelberg, a city with a catchment area (Lysis) of Inhabitants, we do 300 i.v.rtpa cases per year The thrombectomy number for the first half of 2016 are already over 800, most of them with rtpa co-treatment The Buenos Aires metro area (13 Mio) is comparable BW (10.5 Mio) with 15% rtpa (4,500 rtpa cases per year)

8 Part I: Thrombolysis

9 The Rationale of Recanalization Ischemic stroke is caused by vessel occlusion Successful thrombolysis requires both, salvageable tissue and remaining vessel occlusion This is reflected in the penumbra + mismatch concepts already irreversibly damaged infarct core hypoperfused but still viable tissue at risk to undergo definite infarction Recanalization is time-critical because tissue damage may progress unless reperfusion occurs

10 The Early Thrombolysis Cohorts The original 1979 film It all started with pilot cases of intraarterial thrombolytic therapy in cases with acute basilar artery occlusion, and otherwise deadly condition Published in German, because leading journals would not accept The authors received really encouraging reviews: it for ethical concerns Everybody knows that thrombolysis is dangerous and should be avoided in stroke... The technique described in this paper is unethical and should not be studied further... Zeumer, Hacke, Kolmann and Poeck DMW 107 (1981) Zeumer, Hacke and Ringelstein AJNR 4(1983)

11 The Groundbreaking Trials ECASS (JAMA 1995) The NINDS Study leading to 3 h approval (NEJM 1995) ECASS II (Lancet 1998) The Pooled Analysis of ATLANTIS, ECASS and NINDS indicating benefit up to 4.5 h (Lancet 2004) ECASS 3 confirming the 4.5h time window (NEJM 2008) The second Pooled Analysis (Lancet 2009) IST 3 showing that treatment works outside the labelling and does not cause harm (Lancet 2012) The STTC*-Analysis (Lancet 2012) *Stroke Thrombolysis Trialists Collaborative Group, Lancet 2012

12 The Groundbreaking Studies: NINDS 1996 The NINDS Study consisted of Part 1 and 2 Plain CT selection with emphasis on early treatment A 3 h time window, but one half of the patients had to be treated within 90 mins Part 1 (300) was negative, Part 2 (300) with a different (global) endpoint was positiv and so was the combined analysis

13 NINDS-study 1996: Thrombolysis within 3h increases excellent functional outcome mrs Death Placebo (n = 312) 26% 25% 27% 21% Actilyse (n = 312) 26% +13% 21% 23% 17% 13% more rt-pa treated patients in favourable outcome (mrs 0-1) NINDS Investigators. N Engl J Med 1995; 333 (24):

14 The Groundbreaking Studies: NINDS 1996 Based on the NINDS study rtpa was approved in the US for treatment of AIS in the 3 h time window Because of the relatively small trial and the fact that only a 300 patient substudy was positive, there was a lot of resistance (ER-physicians) in the US to use rtpa The lysis rates were in the order of 2-3% for many years

15 The Groundbreaking Studies: ECASS 3 Trial designed upon request of EMA 3-4.5h time window, 821 patients randomized to rtpa or placebo We didn t believe that it would have a chance to be positive, although we increased the number of patients from 600 to 800 It took some time to finalize the trial, recruitment was difficult, but we succeeded

16 ECASS 3 We were deeply surprised This time the choice of endpoint didn t matter Positive in primary endpoint mrs 0,1, positive in global outcome and in shift An undisputed positive and guideline changing trial mrs score Alteplase (n=418) Placebo (n=403) Intent-to-treat population p=0.024*

17 The Groundbreaking Studies: ECASS 3 The 2008 medical paper of the year Editors choice - The Lancet

18 Stroke Thrombolysis Trialists Cooperation* Single patient date prospective pooled analysis >6.700 Patienten Confirms time dependent treatment effect Indicates increased risk of mortality, mostly over 4.5h and in severe old patients Benefit/risk Ratio remains positive despite increased sich risk Stable effect for age, severity in the under 4.5h group Emberson, Lees, Lyden.Sandercock, Hacke Lancet 2014

19 Stroke Thrombolysis Trialists Cooperation* Emberson, Lees, Lyden.Sandercock, Hacke: STTC ISC 2014, Lancet 2014

20 Stroke Thrombolysis Trialists Cooperation* Emberson, Lees, Lyden.Sandercock, Hacke: 2014

21 Latest News: ENCHANTED-Trial Rationale Testing the hypothesis that low dose (0.6mg/kg) rtpa is equally effective as regular dose (0.9mg/kg) in a (mostly Asian) population Design 2x2 factorial design of 3,310 patients eligible for rtpa within 4h (additionally, patients with elevated BP randomly assigned to early intense or standard BP lowering) 935 patients eligible for that trial included

22 ENCHANTED-Trial: Low vs High Dose rtpa Mdn age 67, asians 70% Results Primary outcome mrs 2-6 Low dose 53.2%, regular dose 51.1% OR 1.09 (95%CI ) The upper boundary exceeded the non-inferiority margin (p for non-inferiority.51) Ordinal mrs Common odds 1.0 (95%CI ), p non-inferiority.04 sich Low dose 1% standard dose 2,,1% p=.01

23 rtpa in the Field Results of RCTs and pooled analyses can be repeated in the field SITS-MOST Data from > thrombolysis patients from a German state (thromectomy excluded) 15% Lysis rate (25% plus in stroke centers) Results comparable with pooled data Gumbinger et al, BMJ 2014

24 rtpa in the Field Gumbinger et al, BMJ 2014

25 Part II: Intra-arterial Thrombectomy (IAT)

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27 Intraarterial Lysis And Mechanical Revascularisation Selection of patients and preparation of the mechanical intervention may be associated with a longer door to needle time than IV-rtPA Lack of collaterals in proximal occlusion may even shorten the window of opportunity On the other hand, once the device is in situ, recanalization may occur faster than with IV rtpa Nevertheless- time is brain is important here too Recanalization 8 or 10h after onset may not be beneficial and in patients with high stroke severity even harmfull

28 History of Transvascular Stroke Trials 2012: Three RCTs are presented (Honululu ISC 2012) and published IMS III (Broderick et al NEJM 2012) MR-RESCUE (Kidwell et al NEJM 2012) SYNTHESIS (Ciccione et al NEJM 2012) All studies missed efficacy endpoints Broderick et al NEJM 2013 Kidwell eta l NEJM 2013 Ciccone eta NEJM 2013

29 History of Transvascular Stroke Trials Reasons include: long time window use of old devices underestimation of rtpa response in distal occlusion, slow recruitment due to treatment outside the trial treatment with no proof of vessel occlusion (Furlan and Hacke IJS 2012) A subgroup analysis of SWIFT PRIME showed signal of efficacy in early reperfusion and severe stroke (Khatri et al Lancet Neurology 2012)

30 Consequences For The New Thrombectomy Trials New Devices Early treatment Severe stroke with proven Carotid T or M1 occlusions On top of rtpa

31 Time and Outcome Grotta and Hacke Stroke 2015 Hacke IJS 2015 Hacke and Diener Nervenarzt 2015

32 The Thrombectomy Trials

33 Treatment Effects mrs 0-2% Good Outcome (mrs 0-2) Compared % % % % % ctl act ctl act ctl act ctl act ctl act MR CLEAN ESCAPE EXTEND IA SWIFT PRIME REVASCAT Range of Differences: 14-31% Berkhemer et al NEJM 2015, Goyank et al NEJM 2015, Campbell et al NEJM 2015, Saver et al NEJM 2015, Jovin et al NEJM 2015,

34 How Can the Differences in Magnitude of Effects be explained? All studies show the same pattern Thrombectomy always significantly superior to standard treatment But: Major differences in the rates of good outcome in both tx and control arms between trials *Berkhemer et al NEJM 2015, Goyank et al NEJM 2015, Campbell et al NEJM 2015, Saver et al NEJM 2015, Jovin et al NEJM 2015,

35 What does this mean for stroke management structures? How many patients are candidates? A center with 1000 Strokes per year possibly 250 rtpa (25%) There of 100 endovascular (20%), probably more with referrals Are there enough endovascular specialists? How do we train more? Also Neurologists?

36 For which patients do the results apply? Severe AIS with average NIH-SS 17 CT-selection (the better, the better the outcome) No age limit CTA proven Carotid-T or M1 occlusions Co-Treatment with rtpa Early treatment with reperfusion or first thrombuspass below 6h Use of Stentriever (Solitaire) Devices Treatment in large volume endovascular centers and drip and ship strategies

37 For which patients do the results not apply? Mild stroke M2 Occlusions Basilar artery occlusion rtpa uneligable patients Recanalization not possible within 6 hours CT: Major infarct, ASPECTS 5 or below, no collaterals

38 What kind of imaging is necessary? All trials were CT and CTA based There were different qualities of CT-assessment required, but superiority of IAT was also achieved with plain CT, even without major infarct assessment ASPECTS 6 or more RAPID assessment in 141 patients The more detailed the assessment was, the better the outcome in both the IAT group and the control

39 Is rtpa necessary for the success? In all trials the far majority of patients received rtpa in a 4.5h time window The lowest rtpa rate was in ESCAPE (76%) which also allowed rtpa ineligable and wake-up patients ECTEND IA and SWIFT PRIME had almost 100% rtpa use The number of non-rtpa patients in the individual trials was to small to draw conclusions Joint analyses of the trials may give more insight into that question

40 How many patients are candidates for IAT? In one trial, which had the most restrictive inclusion criteria, 1000 patients were treated with rtpa and only 70 patients were randomized In general, it appears that about 10% of all ischemic stroke patients present with a severe stroke (NIHSS over 12), not all in a time window suitable for IAT About 20-30% of patients who are treated with rtpa may be candidates for IAT This may be more at large referral centers

41 What does this mean for stroke management structures? Question? How many endovascular centers do we need? The Netherlands (16 Mio inhabitants, 18 centers) 1 center/million inhabitants Berlin (4 Mio): 3 comprehensive stroke Units BW 10.5 Mio): 7 comprehensive SUs How can we offer the treatment economically and with sufficient quality? Large centers, minimum treatment numbers, high personal expertise

42 What kind of results can we expect in everyday routine? If in clinical practice CT criteria are handled not strictly, the time window is not strictly observed and the IAT is performed with devices other than stentrievers, the results may be worse In clinical routine, it appears unlikely that the results of SWIFT PRIME or EXTEND IA can be repeated Results achieved in daily practice may be closer to those of MR CLEAN

43 How many interventional centers do we need? A city with inhabitants and 5 interventional centers, each doing 20 or less IAT per year, mostly on workdays, is not well served This scenario is not economically sound, lacks quality and experise, and bound to widen the indication for IAT for financial reasons beyond the evidence It also allows not for good training conditions if there is a patient only once in 2 weeks

44 Overall Excellent News, and a lot of work in front of us