International Stroke Conference
February 6–8, 2019
Robert W. Regenhardt, MD, PhD
@rwregen
Moderators: Jean Claude Baron, Andrew Demchuk
The first talk, by Nerses Sanossian, was titled
“Neuro-protection in
the Pre-hospital Setting.” Sanossian began by introducing the ischemic
cascade in which there are rapid changes over minutes to hours (O2
depletion, energy failure, terminal depolarization, ion homeostasis
failure), secondary changes over minutes to days (excitotoxicity,
SD-like depolarizations, disturbance of ion homeostasis), and delayed
changes over days to weeks (inflammation, apoptosis). While no
neuro-protective agent has proven successful in phase 3 clinical trials,
he asserts that these agents still hold promise. Reconsideration of
mechanistic targets is important as there has been a shift in treatment
paradigm with thrombectomy now the priority for LVO strokes. As these
patients are collected from locations of symptom onset, transported to
thrombectomy capable hospitals, and admitted for acute care, when is the
best time to offer a neuro-protective agent? Future trials must balance
the timing against the cost. An agent could be administered
pre-hospital, post-arrival/pre-imaging, post-tPA, pre/during transfer if
needed, pre-thrombectomy, or post-thrombectomy. There are unique
considerations for each timepoint. In the pre-hospital setting, consent
can be difficult, there is no imaging available, agents should be safe
in ICH, have no interaction with tPA, easily stored in ambulances,
administration should be easy (avoid pumps and compounding), agents
should be effective despite fewer patients recanalizing, and have robust
experimental data at early time points. In-hospital initiation allows
standard consent, imaging is available (could tailor agent to stroke
subtype), pharmacies can store and dispense agents, agents can be
combined with recanalization (improved delivery to target tissue and
opportunity for targeting reperfusion injury and hemorrhagic
transformation), and patients can be more carefully selected after
imaging for those most likely to benefit.
Indeed, a long criticism of many animal models was that they utilized
ischemia followed by reperfusion; in the thrombectomy era, now 80% of
LVO patients may achieve reperfusion making the prior model more
translatable. Several pre-hospital trials have paved the way for future
work, including FAST-MAG testing magnesium (completed 2015), RIGHT 2
testing glyceryl trinitrate (completed 2019), FRONTIER testing NA1
(recruiting until 2020), and PHAST-TSC testing trans-sodium crocetinate
(approved to start 2019). FAST-MAG had an average symptom onset to agent
administration time of 45 min. The agent to tPA time was 92 min and the
agent to thrombectomy time was 230 min, illustrating how much faster
these pre-hospital agents can be administered. One of the latest agents,
trans-sodium crocetinate (PHAST-TSC), is intended to work by enhancing
diffusion of oxygen to hypoxic tissues by altering the structure of
water molecules in plasma. Preclinical data suggests there may be a
benefit for both ischemic and hemorrhagic stroke, making this an
exciting pre-hospital target.
Michael Hill gave the second talk, titled
“Expanding the Time Window
for Thrombectomy: Neuro-protection in the Era of Endovascular
Treatment.” Hill began by reminding us that despite thrombectomy’s
enormous efficacy for LVO strokes, 37% of those treated are still
disabled and 10% still die. The problem is not solved. One approach may
be expanding the time window by administering an agent, perhaps
pre-hospital, that can prevent infarct expansion and allow more patients
to be candidates for thrombectomy. While time is a convenient
“surrogate for physiology,” there is significant variation between
individual patients and it is only one variable in the equation for
infarct progression. Indeed, imaging characteristics may be more
important than time as shown in the DAWN and DEFUSE 3 trials for
thrombectomy and the WAKEUP and EXTEND trials for tPA.
Hill asked, “Can we help patients on the way to thrombectomy?” He
believes we can as about 1/3 have infarct progression while being
transferred for thrombectomy. He favors the approach of in-field
delivery of an agent to “suspend” strokes. “Freezing ischemic penumbra
evolution” has been shown in a rodent model using NA1. Hill also argued
that in the era or thrombectomy our human patients are now better
modeled by preclinical rodent monofilament ischemia and reperfusion
experiments since humans are now achieving reperfusion. Much of the
preclinical work with this model is now more translatable. Hill stated
that the ESCAPE- NA1 trial is testing the efficacy of NA1 specifically
in patients undergoing thrombectomy (recruiting until 2020). It is
recruiting at 50 sites and has over 800 already enrolled. He told the
audience to look for the results next year.
“Preventing Reperfusion Injury: Neuro-protection after Acute Stroke
Treatment” by Lauren Sansing was the third talk. Sansing outlined
reasons for the renewed interest in neuro-protection. Like the previous
speaker, she made the point that while thrombectomy is highly effective,
there is still room for improvement as only 10% of those treated
achieve full recovery with mRS 0. Previous trials of neuro-protective
agents may have failed as there were low rates of recanalization. In the
thrombectomy era, drug is more likely to be delivered to target tissue
after recanalization. In the past, there was less regulation on
preclinical design. More recently, both the NIH and most journals have
increased the level of rigor expected. There has also been increased
interactions between basic scientists and clinicians through efforts of
NINDS, Stroke Net, and academic groups.
Sansing believes that inflammation plays a key central role in many
underlying mechanisms of ischemic injury. She described that the
inflammatory response after stroke can be described as a balance of
injurious effects and reparative effects. The injurious effects involve
IL-1β, TNF, IL-6, endothelial cell activation, platelet aggregation,
recruitment of pro-inflammatory neutrophils, monocytes, T cells, and
inflammatory microglia. These processes lead to infarct growth, neuronal
loss, and astrogliosis. In contrast, the reparative effects involve
TGFβ, IL-10, IL-4, BDNF, alternatively activated microglia and
macrophages, and regulatory T and B cells. These processes lead to
clearance of debris, resolution of inflammation, angiogenesis, and
neurogenesis.
Sansing further discussed thrombo-inflammation and the no-reflow
phenomenon, in which there is infarct growth into the penumbra, failure
of collateral flow, and tissue infarction despite recanalization of the
parent vessel. She described that inflammation may be the underling
mechanism, including NFΚB, MMP-9, PAI-1, PAR4, leukocyte margination,
and neutrophil-platelet aggregates. Inflammation is also involved in
several biologic comorbidities, such as aging, diabetes, and
hyperglycemia.
Sansing then outlined several promising immunomodulatory targets in
the translational pipeline. IL-6 receptor antagonism is one example; a
meta-analysis of 24 studies showed elevated IL-6 is associated with poor
outcomes. Tocilizumab (anti-IL-6R) is FDA approved for RA and GCA and
has shown promising results in preliminary studies. Another is PAR1
functional selectivity with 3K3A-APC. Multiple preclinical studies in
aged mice of both sexes with comorbidities such as hypertension have
demonstrated effects. The RHAPSODY trial, a phase 2A dose escalation of
3K3A-APC in conjunction with tPA and/or thrombectomy, showed possibly
lower rates of hemorrhagic transformation. Sphingosine 1 phosphate
signaling with the use of fingolimod, which is FDA approved for MS, is
another target. It modulates several cell types but is best known for
inhibiting egress of memory T cells from lymph nodes. A meta-analysis of
many preclinical models and early preclinical trials are promising. The
FAMTAIS trial is ongoing. Lastly, IL-1 receptor antagonism has been
explored in over 25 papers and 76 experiments. The phase 2 trial,
SCIL-STROKE, enrolled 80 patients to examine Anakinra. While there was
no effect on 90-day outcomes, a mediation analysis with baseline IL-6
showed promise and raised new questions.
Angel Chamorro gave the final talk, titled
“Vasculo-protection for
Stroke.” He opened by stating “Failure is not the opposite of success.
It is part of success.” He summarized major lessons learned in the
field, including the importance of studying the whole neurovascular unit
and not just neurons. He stated the “ischemic cascade is a mess,”
underscoring its complicated, inter-related, and multidirectional
mechanisms. Chamorro argued that perhaps the best target is reducing
oxidative stress. Recanalization is important and full reperfusion is
better than partial reperfusion.
Chamorro believes that the vessels themselves are the next exciting
target for vasculo-protection. Endothelial cells produce free radicals,
which can lead to tight junction opening with blood brain barrier (BBB)
degradation and pericyte contraction with no reflow. This may underlie
mechanisms of futile recanalization. Indeed, it appears that
neuro-protective agents can act directly on the vessels as agents to
suppress ROS are still effective in reducing infarct size even when
unable to cross the BBB.
Chamorro then discussed uric acid, the end product of nucleotide
metabolism, in depth. By reducing nitrosylation of proteins, it is one
of the strongest antioxidants, according to Chamorro. In preclinical
models, uric acid has met all the STAIR criteria. Furthermore, it has
been studied in both sexes, in hypertensive rats, in hyperglycemic mice,
and there is tPA synergism. In human stroke patients, Chamorro has
shown that uric acid levels are associated with good functional outcomes
at hospital discharge. The URICO-ICTUS phase 2b/3 trial showed a trend
for improvement given soon after tPA. Uric acid appears to have the most
pronounced effects in patients with hyperglycemia, perhaps by blunting
toxic effects of glucose. Chamorro believes this may be particularly
important as we now know intensive glucose control is not enough to
influence outcomes (SHINE). He showed data that glucose is a treatment
modifier of thrombectomy utilizing HERMES data. He concluded by stating
that uric acid is ready for definitive validation in a large phase 3
trial, but funding is lacking.
The ensuing discussion involved several interesting questions, but
one of the most widely debated was, How should we decide which agent to
test next in humans? The NINDS recently launched a model to test up to 6
neuroprotectants in parallel. Perhaps combinations of agents will be
more effective. Agents should only be considered if all STAIR criteria
are met. Others questioned if we should re-test agents that previously
failed in the pre-thrombectomy era given that the human condition of LVO
and thrombectomy now includes reperfusion. Drug companies may lack
incentive to re-test agents that are past their patents. Furthermore, it
may be that patient selection is key. I believe that for any agent, we
should learn lessons from the thrombectomy trials; we should select
patients that are most likely to benefit from a given agent as to not
dilute their effects. Time and target are critical. Considerations of
stroke subtypes and white matter vs gray matter injury mechanisms will
also likely be important. I agree with the speakers and appreciate their
optimism. Neuro-protective strategies have a role in the future, and
funding their study is essential.
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