By Sue Hughes

Patients with acute ischemic stroke who have large vessel occlusion (LVO) have shown an impressive benefit from having their head lowered to a flat position until they are able to undergo thrombectomy in a new landmark randomized clinical trial.

The ZODIAC trial was stopped early because of the magnitude of the benefit seen at the first interim analysis.

"We found that the number needed to harm if the head of the bed was elevated to 30 degrees compared with the patient being laid flat was 1.88. That means that for every two patients that you sit up, one will deteriorate significantly compared to the baseline score, which will not happen if they are laid flat. So, this was a very robust finding," said study author Anne W. Alexandrov, PhD.

Alexandrov, a professor of nursing and neurology at the University of Tennessee Health Science Center in Memphis, Tennessee, presented the results from the ZODIAC trial today at the International Stroke Conference 2024 being held in Phoenix, Arizona.

"Our results show a surprisingly large effect size. We were expecting a sizeable effect based on our preliminary work, but we were quite shocked — in a good way — at how large the benefit was in this study from such a simple intervention," she said. "Our findings suggest that gravitational force can play an important role in improving blood flow to the brain temporarily while patients are waiting for thrombectomy and can minimize the risk of neurological deficits and ultimately disability."

Zero-degree head positioning is a safe and effective strategy to optimize blood flow to the brain until the thrombectomy can be performed, she concluded, and it should be considered the standard of care for patients with stroke prior to thrombectomy.

"I believe that this is one of the most important things that we can do first for a patient with a large vessel occlusion stroke, and I think it takes on critical significance in patients who do not arrive initially at a hospital that can do thrombectomy and have to be transferred," she stressed. "As soon as a large vessel occlusion stroke is diagnosed on the initial CT scan then the staff should be putting the patient's head down flat to keep the brain optimally perfused."

Commenting on the ZODIAC results, Louise McCullough, MD, chair of neurology at McGovern Medical School and codirector of UT Health Neurosciences, in Houston, Texas, said these were "very interesting findings."

"Simply laying the bed flat is such a simple and low-cost thing to do and definitely seems to improve early outcomes in this study. The only thing I would worry about would be the risk of aspiration pneumonia but that was not seen in this study," she said.

"Often with thrombectomy, there are delays, even under the best of circumstances when the patients present to a comprehensive stroke center, so this is a nice bridge to increase perfusion to the ischemic brain while waiting for the artery to be opened," McCullough added.

Zero Degrees

In her presentation, Alexandrov explained that hospital beds for patients with stroke are typically elevated at the head, but pilot studies conducted by Alexandrov's team have shown that when the head of the bed is flat at zero degrees, patients with LVO stroke benefit from increased gravitational blood flow through the blocked artery and more open collateral arteries.

The ZODIAC trial was conducted to see whether his would translate into a clinical benefit.

The trial enrolled patients with CT angiography–confirmed LVO stroke viable parenchyma who had a baseline National Institutes of Health Stroke Scale (NIHSS) score measured while lying flat immediately following neuroimaging.

They were then randomly assigned to remaining lying flat (head at zero degrees) or for their head to be raised to 30 degrees. Repeat NIHSS scores were measured every 10 minutes until the patient was moved to the cath lab table for thrombectomy, with the final NIHSS scored by a protocol naive practitioner.

The primary endpoint was early neurologic deterioration (> 2 points on the NIHSS score) prior to thrombectomy.

"We chose to measure our primary endpoint prior to thrombectomy because thrombectomy itself has such a powerful effect at improving outcome, and we wanted to see if they would be more stable or potentially even improve if they were lying flat or with their head raised up," Alexandrov noted.

On November 1, 2023, after a preplanned interim analysis was performed on 92 patients enrolled from 12 comprehensive stroke centers in the United States, the data safety monitoring board stopped enrollment into the trial because of "overwhelming efficacy" of the zero-degree head positioning.

Results showed that the primary endpoint of early neurologic deterioration of 2 points or more on the NIHSS score occurred in just 1 of 45 patients (2.2%) in the group who were laid flat compared with 26 of 47 patients (55.3%) of the group whose heads were raised to 30 degrees (P < .001).

A similar benefit was seen when a larger deterioration (4 or more points on the NIHSS score) was considered. This occurred again in just one patient in the zero degrees group (2.2%) vs 20 patients (42.5%) in the 30 degrees group (P < .001).

The NIHSS score was also measured at 24 hours after thrombectomy and at 7 days/hospital discharge. Results at these time points again showed a greater benefit in the zero degree group than in the 30 degrees group.

Improvements in the NIHSS score at 24 hours occurred in 87% vs 61% of patients (P =.008) and at 7 days or discharge in 87% vs 68% (P = .045).

"That was a bit of a surprise to us," Alexandrov commented. "These were exploratory endpoints. We expected that thrombectomy itself would be the intervention that made the big difference in outcome. However, there was no difference in thrombectomy blood flow status in either group, and we could not find anything else that would account for that improvement at 24 hours or 7 days/discharge so it appears that positioning the head at zero degrees in patients with a large vessel occlusion stroke prior to thrombectomy may be preserving more brain because of increased blood flow," she said.

"Our preliminary work has shown that blood flow is increased by 20% if a patient is placed at zero degrees compared to 30 degrees, and so, it is likely that this is having an important effect in keeping these patients stable until the clot is removed," she added.

By 3 months following surgery, there was no significant difference in outcomes between the two groups, but there was a trend toward benefit in the modified Rankin scale (mRS) scores that appears to favor the zero degrees group, Alexandrov noted. These results show mRS 0-1 scores for 53% of the zero degrees group vs 45% for the 30% group (P = .53) and mRS 0-2 scores in 69% vs 56% (P = .28).

"This was an exploratory endpoint, and the study was not powered to show a difference at this timepoint. We would have probably needed four or five times the sample size to be able to see a difference at 90 days," she said.

McCullough noted that it would not be expected to show a difference in mRS score at 3 months in a study of just 92 patients, especially as thrombectomy itself usually has such a large beneficial effect. But she said the head-lowering intervention is still worth doing for the early benefit seen.

"The mRS score is a crude measure. It does not pick up subtle changes or smaller neurological effects," McCullough added. "But an early benefit on NIHSS scores as shown in this study will probably result in some long-term benefit, and there does not appear to be any downside."

Different to the HEADPOST Trial

A previous study — the HEADPOST trial — reported in 2017, found no difference in disability or safety outcomes in patients with acute stroke from positioning either lying flat or sitting up in the first 24 hours of hospitalization. However, that study enrolled mainly patients with mild stroke, whereas the ZODIAC trial included patients with much larger strokes and LVO.

Alexandrov said the two trials had very different designs and were asking different questions.

"HEADPOST tried to identify if the head of the bed position could be some type of treatment especially in low- or middle-income countries where they may not have direct access to many resources," she explained.

She pointed out that the HEADPOST trial did not use imaging to identify the types of patients with stroke included. "So, their data do not answer the question of head position for large vessel occlusion strokes," she said.

Alexandrov also noted that patients in the HEADPOST trial were randomized later than in ZODIAC, the primary endpoint in HEADPOST was at 3 months, and the NIHSS score was not serially assessed in the hospital. "So, their findings and their methodology are quite different to what we did."

Results Do Not Apply Before Imaging Is Known

Alexandro cautioned that the ZODIAC results do not apply to patients who have not yet been diagnosed with definite LVO, for example, those with suspected stroke on the way to hospital.

"These patients are probably best to have their head raised slightly simply because we don't know at this stage if they may have had a hemorrhagic stroke — if this is the case, there is a chance that lying the head flat could cause increased intracranial pressure," she explained.

"But once the patient goes into the CT scanner, within 30 seconds we should know whether there is blood on the scan or not, and within the next 3 or 4 minutes, we are going to know if they have a large vessel occlusion. The patient is flat in the CT scanner for those few minutes, and we are now saying if a large vessel occlusion is seen on the scan, then they should be kept flat until thrombectomy is performed."

Alexandrov noted that the question on head position has not been answered for patients found to have had an ischemic stroke but who do not have LVO.

"We don't know if keeping a patient flat would make a difference in small vessel stroke. It may not. This is a different situation," she said. "The large vessel occlusion stroke is going to affect a larger territory of brain and when it's very proximal — for example in the internal carotid artery — it could impact the entire hemisphere. Because of that, improved blood flow due to gravitational force is particularly important."