Investigating, developing and implementing a collateral therapeutic is a major objective
in stroke research. The aim is to increase the amount of potentially salvageable
penumbral tissue and expand the tissue time window, thus increasing the efficacy of
reperfusion therapies and improving clinical outcomes.
Head down tilt 15° (HDT15) is a positional therapy consisting of tilting the patient with
the head 15 degrees below the rest of the body. Experimental studies from an
Italian-French group (Dr. Simone Beretta, Fondazione IRCCS San Gerardo dei Tintori and
Prof. Tae-Hee Cho, Hospices Civils de Lyon) showed that HDT15 increased cerebral blood
flow and improved functional outcome and infarct volume in randomised rats with middle
cerebral artery (MCA) occlusion followed by reperfusion. Subsequent perfusion MRI
experiments using the same stroke model by our group confirmed that HDT15 application for
60 minutes significantly increases collateral flow in the ischemic area.
There is no consensus in current clinical practice regarding the most appropriate head
position for acute ischemic stroke (AIS) patients. The sitting position at +30° is the
most common. An international cluster-randomised trial, HeadPoST, randomised over 11000
patients with acute stroke (85% ischemic) to either a lying-flat position or a sitting-up
position (head elevated to at least 30°), maintained for 24 hours. No difference in the
primary efficacy outcome (disability at 90 days measured with the modified Rankin Scale
(mRS)), mortality, or rates of other serious adverse events, including pneumonia, were
observed. However, the HeadPoST trial primarily targeted patients with mild symptoms
without a large vessel occlusion (LVO), who were randomised beyond the usual time window
of reperfusion therapies.
One retrospective study (pre-thrombectomy era) compared two cohorts of AIS patients with
a LVO: patients with a standard position (0 to 30°; N=119), versus those with a HDT15
position (0 to -15°; N=90). The results suggested that HDT15 promotes neurological
improvement compared to the standard position. No difference in serious adverse events
was observed between the two cohorts.
A recent randomized, pilot clinical trial showed promising results of -20° head down
positioning on long-term disability and an excellent safety profile.
Thus, the available clinical evidence raised no safety concern for HDT15 in AIS patients,
but data on its efficacy, notably among AIS patients treated by MT, remains insufficient.
HDT15, for its simplicity, low cost and feasibility, might be an optimal collateral
therapeutic candidate to prolong the survival of the ischemic penumbra and improve the
clinical benefit from reperfusion therapies with disability reduction. HDT15 is readily
feasible by Emergency Services in the prehospital phase of AIS, before reperfusion
therapies.
The DOWN-SUITE study will be the first multicenter, randomised, controlled, open-label
clinical trial with blinded outcome assessment comparing collateral status in patients
with AIS treated with an in-hospital application of HDT15 versus usual positioning before
MT. The duration of HDT15 application (approximately 60-90 minutes) is expected to be
long enough to detect significant changes in cerebral hemodynamics. Building from
preclinical experiments on rodent and non-human primate stroke models carried out by our
French-Italian group, it will provide for the first time the translation of HDT15
efficacy on cerebral hemodynamics and clinical outcome from animal models to AIS
patients.
No therapeutic intervention is currently available to enhance collaterals in AIS.
The DOWN-SUITE trial will provide robust, high-quality evidence on the safety,
feasibility and efficacy of HDT15 as a low-cost collateral therapeutic for AIS.
The investigators hypothesise that HDT15 (-10° to -15°), applied in AIS patients with an
LVO, will improve collateral circulation, prolong the survival of the ischemic penumbra
and improve the clinical benefit from MT compared with standard of care (usual
positioning: 0° to +30°).
The investigators aim to perform a prospective, multicenter, proof of concept,
randomised, controlled, open-label study. As a double-blind is not possible, a blinded
central imaging core lab, whose members will be unaware of the procedure assignments,
will assess all imaging outcomes, including the primary efficacy outcome.
This study will involve adult patients who are eligible for MT and who have AIS due to
left or right MCA occlusion (M1 segment).
Benefit/risk ratio The investigators hypothesise that HDT15 would improve cerebral
collaterals in patients randomised in the intervention group, which could subsequently
reduce the ischemic injury and improve the clinical outcome.
No harm from participating in DOWN-SUITE is expected for patients in the intervention or
control groups. Previous clinical data on HDT15 raised no safety concerns. No difference
in post-stroke complications, including cerebral oedema or haemorrhage, pneumonia or
mortality, was observed in a retrospective observational study. HDT15 is not expected to
interfere with standard care, including the procedural steps of MT. Mild discomfort
related to the tilted position may occur in some patients. The treating physician will
continuously monitor all patients during the entire duration of the HDT15 application. No
additional risk is expected in patients in the control group, as they will receive
standard care.
Overall, this study's benefit/risk ratio is considered very favourable.
This study could potentially establish HDT15 as the first evidence-based collateral
therapeutic for AIS. No therapeutic intervention is currently available to enhance
collaterals in the acute phase of ischemic stroke. Such a collateral-enhancing therapy is
necessary to expand the time window and increase the probability of successful
reperfusion with IVT and MT, resulting in better clinical outcomes.
The results of the DOWN-SUITE trial may pave the way for larger randomised controlled
trials of HDT15 in a wider stroke patient population, such as patients transferred from
spoke hospitals to hub stroke centers to receive thrombectomy and unselected patients
with suspected AIS in the prehospital setting.