Ischemic Stroke Clinical Trial
Official title:
Remote Ischaemic Conditioning in Endovascular Recanalization for Proximal Anterior Circulation Occlusion (RICE PAC) Study
Ischaemic stroke causes significant morbidity and mortality and is a leading cause of
disability within an ageing United Kingdom (UK) population. Proximal anterior circulation
occlusion is associated with a particularly poor prognosis, but its management has undergone
a paradigm shift following clinical introduction of endovascular recanalization,
establishing rapid reperfusion of the ischaemic penumbra.
Remote ischaemic conditioning (RIC) is highly effective at attenuating cerebral infarction
in basic research studies and has the potential to further improve patient outcome if used
as an adjunct to invasive revascularisation strategies. We aim to trial remote ischaemic
conditioning at the time of revascularisation, and then daily for the duration of the
seven-day in-patient stay, compared to a sham conditioning procedure. This pilot,
single-centre study will determine efficacy/ tolerability of RIC to reduce cerebral
infarction (primary endpoint: determined by brain magnetic resonance imaging [MRI]) and
improve functional status (secondary end-points: National Institutes of Health Stroke
Severity (NIHSS); European Quality of Life questionnaire EurQoL), with the data providing
the necessary parameters for power calculations and leveraging charitable funding for a
subsequent multi-centre study.
The aims of our study are to:
1. Demonstrate safety of remote ischaemic conditioning (RIC) in stroke patients;
2. Demonstrate practicality of the intervention (RIC);
3. Demonstrate the practicality of the study protocol and imaging modalities;
4. Determining appropriate and measurable end-points: e.g. cerebral infarct reduction
(MRI), reduction of cerebral oedema, functional assessment and quality of life survey;
5. Provide preliminary data on likely effect size of the RIC intervention versus the sham
procedure.
Background and Rationale:
Acute ischaemic stroke represents a significant cause of morbidity and mortality in the UK.
It is estimated that 110,000 strokes occur in England each year, with an incidence of
between 1-36/1000/year. Patients presenting with a proximal vessel occlusion in the anterior
circulation have a particularly poor prognosis, with approximately 20% 90-day mortality and
significant morbidity despite thrombolysis. Recently, endovascular recanalization with
mechanical thrombectomy trials have brought about a paradigm shift in the optimal management
of this high-risk group of patients; the interventional extraction of the occluding thrombus
demonstrating significant benefits in MR-CLEAN(3), ESCAPE, EXTEND-IA (intra-arterial), SWIFT
PRIME and REVASCAT (revascularisation) studies. Echoing primary percutaneous intervention in
the management of ST-elevation myocardial infarction, endovascular recanalization represents
rapid restoration of blood flow to the ischaemic cerebrum - with the promise of improved
neurological salvage and functional outcome.
Reperfusion Injury:
Reperfusion is not, however, a benign process. Demonstrable in many organ systems including
the brain (but studied most extensively in the heart), reperfusion leads to rapid
restoration of intracellular pH, mitochondrial calcium overload and generation of reactive
oxygen species - conditions that are prime for the opening of the mitochondrial permeability
transition pore (mPTP). The mPTP, a large capacitance pore that forms on the inner
mitochondrial membrane, leads to mitochondrial disruption and the release of proteins that
trigger cell death. Therefore modifying conditions of reperfusion/ triggering cellular
protection pathways are the key targets for optimising tissue salvage associated with
reperfusion following any acute revascularisation intervention.
Remote ischaemic conditioning:
The brain has been demonstrated to share many of the cytoprotective signalling pathways
found in other organs such as the heart, and like the heart, can be protected by ischaemic
conditioning(6). Ischaemic conditioning can be either applied either directly to the organ,
or more conveniently to a remote tissue (such as an arm, through inflation of a blood
pressure cuff), either prior to, during or immediately following the restoration of blood
flow to the ischaemic tissue (pre-, peri- and post-conditioning respectively). The remote
conditioning stimulus leads to the activation of cellular survival kinases (termed the
reperfusion injury salvage kinase (RISK) cascade) that in turn leads to inhibition of mPTP
opening, and thus cell survival.
Ischaemic conditioning and neuro-protection:
While the phenomenon of ischaemic conditioning was first described and best characterised in
the heart, it is well recognised that the ischaemic conditioning can result in
cytoprotection across many mammalian organs, including the brain. Indeed, contemporaneous
with the seminal myocardial preconditioning paper by Reimer, Murray and Jennings in the dog,
Schurr et al demonstrated ischaemic preconditioning could also protect adult rat hippocampal
slices against injurious anoxia/re-oxygenation. Ischaemic conditioning of neuronal tissue
has subsequently been demonstrated to be triggered and mediated by similar receptor and
downstream signalling pathways (e.g. G-protein coupled receptors, RISK pathway activation
and suppression of cell death pathways), and that remote ischaemic conditioning is also
effective at significantly attenuating the volume of cerebral necrosis in rat experimental
models of acute right middle cerebral artery occlusion stroke (typically reducing infarct
size by 40-60%). Similar results are observed in mouse (middle cerebral embolization,
followed by thrombolysis with tissue-plasminogen activator) and in piglet, where the
injurious effects of hypothermic circulatory arrest were attenuated, improving both
functional and histological outcomes.
With building evidence of efficacy against cerebral ischaemia/reperfusion injury in the
pre-clinical basic science studies, there is enthusiasm to translate these encouraging data
into an effective clinical strategy for the management of acute stroke in man. A recent
prospective, open-label, blinded outcome proof-of-concept study in Danish patients undertook
ischaemic per-conditioning in patients presenting with an acute stroke syndrome. With the
conditioning stimulus performed in the ambulance, the ischaemic stroke diagnosis was
made/confirmed later in hospital. In patients with confirmed ischaemic stroke, they found
patients in the intervention arm had a better functional status by National Institutes of
Health Stroke Scale score on admission and an overall smaller infarct, but the study was
overall neutral on the pre-specified primary endpoint (penumbral salvage, defined as the
volume of the perfusion-diffusion mismatch not progressing to infarction after 1 month).
There are useful lessons and observations to be made regarding the design of this trial that
influences the design of the trial proposed within this application. First, thrombolysis
does not guarantee re-canalisation of the culprit artery, and where restoration of blood
flow does occur, the time of onset of reperfusion may be unpredictable. Thus, restoration of
blood flow may either not have occurred, or when it had, may have occurred outside the
protective time-frame of the remote ischaemic conditioning stimulus (classical conditioning
has a protective "window" of typically just 2-3 hours).
Therefore, we are seeking to combine ischaemic conditioning with an effective endovascular
re-canalisation procedure where the success and time of reperfusion are known. Second, in
the Danish study, there would have been significant heterogeneity in aetiology of the
presenting stroke symptoms that will include both anterior and posterior circulation
occlusion and also small vessel disease. The pre-clinical efficacy of remote ischaemic
conditioning is predominantly with models of anterior circulation occlusion and therefore,
we have made this cohort of patients the focus of our study. And finally, there is emerging
evidence that in order to ensure persistent infarct size reduction, it is critical to
combine both initial ischaemic per-conditioning and subsequent post-conditioning to tackle
both the acute reperfusion injury (the first 15 minutes of reperfusion) and the subsequent
second phase of reperfusion injury (that occurs in the following hours and days). Thus our
study is designed to combine both ischaemic per-conditioning and repeated post-conditioning
over the following seven days to harvest the benefit of both conditioning strategies.
Interestingly, a Chinese study (RIC to both arms daily for 300 days after the initial
stroke) was shown to be safe and effective. While this study had a different outcome to ours
(attenuating the rate of stroke recurrence following the initial presentation), the efficacy
of the RIC intervention nonetheless provides further encouragement that RIC may be an
effective intervention in this group of patients.
In summary therefore, we are seeking to combine ischaemic conditioning with an effective
endovascular re-canalisation procedure where the success and time of reperfusion are known,
in a vascular territory that is known to benefit from RIC and are looking to combine both
ischaemic per-conditioning and repeated post-conditioning over the following seven days to
harvest the benefit of both conditioning strategies upon acute and inflammatory phases of
reperfusion injury - encompassing the period over which peak cerebral oedema is typically
observed.
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