Research Talk - Shadi Yaghi - Brown-Rhode Island Hospital

October 27, 2021

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00:00It's.
00:06Yes, OK, perfect. Alright, uh.
00:12So I'm just gonna come.
00:14Present some investigator initiated
00:18studies here were myself and some
00:21of my colleagues are doing so.
00:24The first one I'm going to
00:26present this perfuse icast,
00:29which was submitted last year
00:31and we got some comments and we
00:35are resubmitting in November.
00:37So some background about entrepreneurial
00:39after Austero Sis as everyone knows,
00:42intracranial symptomatic
00:43large vessel after all.
00:45As a strong predictor of earlier
00:48occurrence and current treatment
00:50consists of aggressive medical treatment
00:52with anti thrombotic treatment,
00:54mainly dual antiplatelets
00:56high intensity statin,
00:58risk factor modification and lifestyle
01:02coaching and this was based on the
01:06sample's trial that samples and visit.
01:10They both tested standing and showed
01:13superiority of medical treatment.
01:15But you know.
01:16The question that comes is the best
01:18medical treatment work for everyone,
01:20and this is a nice study or figure here.
01:25Comparing samples to wested and you can see.
01:28So this is the medical arm of samples
01:31and this is what patients and you can see
01:35that the risk is significantly lower.
01:38Occurrence and Sampras,
01:39versus what sets or medical treatment over
01:43the past decade has significantly improved.
01:45But unfortunately the recurrence risk using
01:49real-world data is still relatively high,
01:53and this is a study from Northwestern
01:57University from Chicago showing that
02:01even in patients who were treated.
02:04Using the sample as a treatment regimen,
02:09aggressive medical treatment.
02:1148 patients.
02:12The risk of recurrence at 30 days was 20%,
02:16so that's still significantly high and
02:20there's a lot of work that still needs
02:22to be done, and reducing the risks.
02:24So why those medical treatments fail?
02:26Of course you know medication,
02:28non compliance or risk factor
02:30control is a contributing factor.
02:32Plavix resistance as.
02:34Mentioned, uh earlier today by uh,
02:38you know, Doctor Rodrick had mentioned that,
02:41you know, traffics resistance may
02:43be a component and diagonal,
02:46or maybe a better option.
02:48But you know,
02:48there's not a lot of data on that,
02:50but definitely,
02:52that's one potential contributing factor,
02:56and another one is impaired distal perfusion.
03:00So if the perfusion across
03:03stenosis is impaired,
03:04medic optimal medical treatment.
03:06Is less likely than the improve
03:10acutely the perfusion across stenosis
03:12and reduce the risk of deterioration
03:15or recurrence and the setting.
03:18So what are mechanisms of stroke in
03:21patients with intracranial Atheros sclerosis?
03:24This is from a study that we published
03:27a couple years ago looking at.
03:30The MRI and the perfusion study on
03:34on patients who have symptomatic
03:3670 to 99% stenosis,
03:39so this is a patient here.
03:41As you can see they have borderzone
03:43infarction and they have a perfusion deficit.
03:45So these fires are likely related
03:48to low blood flow.
03:50This one is a core infarct with
03:52no perfusion deficit,
03:54likely related artery and Bill Isation.
03:58This one is another patient who has a.
04:00Borderzone infarct so this is an
04:04internal borderzone cortical borderzone
04:06infarction with some perfusion delay,
04:09and this one is deep and far likely
04:11related to perforated perforated disease
04:14with no significant perfusion delay.
04:17So these are all different
04:20mechanisms of stroke.
04:21In patients with intracranial athero.
04:23So Arthur to artery embolization perforate
04:26are disease and impaired distal blood flow.
04:29So what are we looking at?
04:31Perfusion and perfused icast
04:34where our aims are two main aims.
04:38One to validate perfusion delay
04:40volume and border zone and function
04:43as biomarkers of increased recurrence
04:47in patients with symptomatic
04:4970 to 99 anterior circulation.
04:52I cast and the second one is to determine
04:56the 90 day recurrence rate in patients with.
05:00You know each of the biomarkers
05:02borderzone and fart,
05:03optimal perfusion, delay,
05:05threshold and volume,
05:06and the third one is when both
05:10are combined together.
05:11The outcomes so the primary
05:13outcome is recurrent stroke,
05:14or that at 90 days we
05:16have secondary outcomes.
05:18These patients are going to
05:19be followed for one year,
05:21so the secondary outcome is looking
05:23at the 12 month recurrent stroke
05:25or that and we're looking at also
05:2890 day modified Rankin scale.
05:30There's an outcome adjudication
05:33committee that will be adjudicating all
05:36outcomes in our study inclusion exclusion,
05:39so ischemic stroke in the setting of.
05:4270% or more stenosis of UM,
05:44the M1 segment or the intracranial
05:47ICA less than three days from
05:50last known normal NIH zero to 10.
05:53Three more with MRSA.
05:54Zero to three exclusion.
05:56Other competing mechanisms or unable
05:58to obtain MRI or perfusion imaging.
06:02Patients will be managed medically.
06:05Dual antiplatelets for 90 days, then single.
06:08Agent high intensity statin therapy
06:10were also planning each patient.
06:13With a lifestyle coach using the same
06:16company that was used in the sample's trial,
06:20it's also being used in Captiva
06:22and an increased intervent so you
06:25know the study is going to pay for
06:29a lifestyle coach to try to ensure
06:32that lifestyle modifications are done
06:34risk factor control as well as an
06:38important aspect of medical management.
06:40So this is a biomarker validation study.
06:43That has a go.
06:45No go criteria to move forward for
06:49potential interventional study testing,
06:52potentially angioplasty,
06:53plus or minus standing in the high
06:58risk patients who have impaired distal
07:01perfusion based on the biomarkers.
07:03So this study would move forward an
07:06interventional study if the 90 day
07:09recurrence risk and the validated
07:11biomarkers was more than 15.
07:13Percent,
07:14that is the the 95% confidence
07:17interval lies above 15%.
07:20The sample size calculation was 250
07:24patients that accounted for 15%
07:27loss to follow up and that gives
07:29super adequate power for all aims.
07:32The projected study is over 4 1/2
07:36years with recruitment over 33 months.
07:39So that's the first study we
07:41re submitting in November,
07:43so fingers crossed.
07:46The second study that was proposed Genentech.
07:49It's looking at the safety of
07:52alteplase and patients on direct
07:54oral anticoagulants and this is
07:57called that by myself and Kristaps
08:00threats from here from Brown so
08:03we know that patients with a third
08:06face heightened risk of ischemic
08:08stroke and this risk is reduced by
08:11oral anticoagulation and recent
08:13studies have shown that in patients
08:15with history
08:15of a field.
08:16Or hospitalized for ischemic stroke.
08:19Nearly 40% of them were using
08:21anticoagulation at the time of the event,
08:24and 50% of which war were on
08:26a direct oral anticoagulant.
08:28So these patients are typically
08:31excluded from from alteplase.
08:33And actually we looked at data from two
08:37large comprehensive stroke centers,
08:39where in 130% of the exclusion
08:43of patients excluded from TPA.
08:47Who would be otherwise eligible were
08:50excluded only because they were on a
08:53direct oral anticoagulants within 48 hours,
08:55and another study 194 patients
08:59were excluded only because they
09:01were on a direct oral anticoagulant
09:03over a 2 1/2 year period.
09:06So that's like 7 patients per month
09:09excluded only because they were
09:11on a direct oral anticoagulant.
09:13So you know,
09:14it's all to play safe and these patients.
09:16Why should we? I think that it's safe.
09:18UM, one, you know. There are many reasons.
09:21One doax have improved safety profile
09:24and lower risk of intracranial
09:26hemorrhage than warfarin.
09:29And another important reason is
09:31that dogs have a short half life
09:35and as you see here from some
09:38pharmacokinetic data and this is on 10A.
09:42Anti 10A treatments and you can
09:45see that apixaban within 12 hours.
09:48The level is pretty low rivaroxaban
09:51at 24 hours the level is lower
09:54edoxaban at 12 hours and there's
09:57similar pharmacokinetic data for the
10:00bigger Tran showing that you know
10:03the drug level at about 12 hours.
10:06Is this law as well?
10:07So alteplase may be safe if you're
10:10giving it beyond 12 hours from
10:13the last dose of.
10:14Doac and also several studies
10:17including recent meta analysis,
10:19shows that treatment alteplase treatment
10:22and patients on doac is likely safe.
10:27But these are observation ull
10:29studies with some selection bias,
10:31so it's hard to make a firm conclusion.
10:34So the aim of the study is to
10:36determine the risk of symptomatic
10:38intracranial hemorrhage with
10:40alteplase in patients with acute
10:43ischemic stroke on doac therapy.
10:45With the last doors of 12 to 48
10:48hours or apixaban and Dabigatran
10:51and 24 to 48 hours for over oxygen,
10:55and the hypothesis is that the risk of
10:58symptomatic intracranial hemorrhage
11:00is less than 10% in these patients
11:02we have some secondary aims as well,
11:05which you know I can skip for
11:07the purpose of time,
11:08so the inclusion exclusion criteria,
11:11any ischemic stroke eligible
11:13patient for alteplase.
11:15With the exception of being on Doac,
11:17and as I said,
11:19the last dose should be 12 to 48
11:21hours for apixaban and dabigatran,
11:2424 to 48 for the proxy ban.
11:26There are some exclusion criteria as well.
11:28We did some power calculation and
11:31sample size of 144 patients would
11:34be needed to achieve our goal and
11:37this would be using six centers
11:40and a 33 month enrollment period
11:42with three months of follow up so.
11:46I think this will be a very good
11:48study for our network,
11:50so hoping that after this conference
11:52we can touch base and see if any
11:55of the sites are not within
11:57our network, is is interested.
12:00Finally, just like 2 minutes on this.
12:04So this is another investigator
12:06initiated study that you know we're
12:09very fortunate to have a lot of sites,
12:13including sites from our own RCC contribute.
12:17So this is a large retrospective,
12:20multicenter study comparing doax warfarin for
12:23the treatment of venous sinus thrombosis.
12:27So we know that the recent randomized
12:31trial suggested that the bigger trend
12:33may be as effective as warfarin,
12:35and the treatment of CVD.
12:37Our aim was to compare direct
12:40oral anticoagulants.
12:41Warfarin and a real world
12:43international cohort. So we had.
12:45This is a retrospective.
12:47Study that had sites from EU.
12:49S. Europe New Zealand over six
12:51years and all of these patients.
12:54We included them if they received
12:57oral anticoagulation and had
12:59confirmed cerebral venous thrombosis.
13:01We used inverse probability of treatment.
13:04Weighted Cox regression models.
13:07Outcomes were recurrence cerebral
13:09or systemic, venous thrombosis,
13:11death and we looked at recanalization
13:14rates and major hemorrhage and patients
13:17treated with warfarin versus doac's.
13:20So the results we had 1029 CVD
13:25patients across 27 centers.
13:28847 met our inclusion criteria and
13:30these are the study sites and EU,
13:33S and Europe and we had a site
13:36in New Zealand as well,
13:39so the paper is now under review and stroke
13:42and to be presented at the upcoming ISC.
13:45So stay tuned and I will stop here and
13:48thank you for your attention and I'll.
13:51Take any questions.
14:00Charlie, this is the great presentation
14:04for the DOAX study with Alteplase,
14:07there's going to be an exclusion if they're
14:10also on antiplatelet therapy or not,
14:12I don't think so, but you know
14:16something to consider for sure.
14:19Thank you, thank you. OK, so.