A very early and more intensive rehabilitation program was associated with a reduced likelihood of achieving a favorable outcome at 3 months vs usual care in the first large-scale randomized trial of rehabilitation therapy in patients with acute stroke.

The AVERT study results were presented by Professor Julie Bernhardt, PhD, Florey Institute of Neuroscience and Mental Health, Heidelberg, Victoria, Australia, at the inaugural European Stroke Organisation (ESO) Conference 2015. They were also simultaneously published online in The Lancet.

“Our data show that an early, lower-dose out-of-bed activity regimen is preferable to very early, frequent, higher-dose intervention,” Professor Bernhardt concluded.

“This was an unexpected and intriguing result,” she added. “But it tells us something very important. Earlier intensive rehabilitation was significantly worse than usual care. We have to listen to that.”
Professor Julie Bernhardt
She said that preclinical work and previous smaller studies have suggested that more intensive earlier rehabilitation would be beneficial. “But our results suggest we need to do more work to look at what is the right time for the brain to be challenged with this ‘out of bed’ intervention.”

To Medscape Medical News she commented that the study had only just finished and it was too premature to issue strong recommendations.
“It is very early days,” she said. “We will be coming up with clear recommendations for clinical practice, but for now we can say that earlier high-dose rehabilitation is not better than usual care, which in this study was still early but not quite as early or intensive as the more aggressive arm.”

“However, the challenge is not as simple as just recommending usual care, because usual care is complex and this study was also delivered early and varied from center to center, and we had 56 centers in 5 countries. We have to unpack this so we can give clinicians guidance about their practice and this will be the next step.”

She added: “We do know from previous studies that patients in stroke units who receive earlier rehabilitation than patients on general medical wards have better outcomes. So our message is not that patients should stay in bed for days.”

Groundbreaking Trial

Even though the trial had a negative result, it is regarded as groundbreaking and was very well received by stroke physicians at the ESO conference, with Professor Bernhardt given a standing ovation after her presentation.

ESO president Professor Kennedy Lees, MD, University of Glasgow, described the trial as “a huge achievement.”

Keith Muir, MD, also from the University of Glasgow, said: “AVERT is a fantastic trial. It is hugely relevant for how we organize services.”

“Unfortunately they got a negative result but it shows that large rehabilitation trials comparing two different strategies are feasible so we know now that more trials like this can be done in the future,” Valeria Caso, MD, University of Perugia, Italy, and ESO president-elect, commented to Medscape Medical News. “Until now we haven’t had a scientific approach like this for evaluating rehabilitation.”

Dr Caso suggested that the worse outcome with very early more intensive rehabilitation was probably due to the patients still being hemodynamically unstable. “I think it shows that patients should not be moved too early — that passive mobilization is better in the first 24 hours.”

Asked why she thought this was the case, she replied, “Maybe the circulation needs some time to accept the new situation of brain trauma.”

Professor Bernhardt added: “In stroke, we don’t really understand the cascade that happens in the acute phase of stroke. It appears that the higher-dose, very early intervention may be interfering with the recovery process in some way.”

For the study, 2104 patients were randomly assigned to receive very early mobilization or usual care. Median time to randomization was 18 hours after stroke; 45% of patients had a moderate to severe stroke; 26% were older than 80 years; and 24% of patients had received tissue plasminogen activator.

The very early mobilization intervention included three crucial elements: (1) beginning within 24 hours of stroke onset; (2) focusing on sitting, standing, and walking (ie, out-of-bed) activity; and (3) resulting in at least three additional out-of-bed sessions to usual care.

Patients in the very early intensive group began mobilizing at a median of 18.5 hours after stroke compared with 22.4 hours in the usual care group, and they had a median of 6.5 sessions compared with 3 sessions in the usual care group. Patients in the very early intensive group received a median of 31 minutes of therapy per day vs 10 minutes in the usual care group; they received a total of 201 minutes of therapy compared with 700 minutes in the usual care group.

The primary outcome was functional independence, defined as a modified Rankin Scale (mRS) score of 0 to 2 at 3 months. This showed a significantly worse result in the very early intensive group.

Table. AVERT: Primary Endpoint

Eight percent of patients in the very early intensive group died compared with 7% of patients in the usual care group, and nonfatal serious adverse events occurred in 19% and 20% of patients, respectively. These differences were not significant.

Immobility-related complications also did not significantly differ between the two groups.

Subgroup analysis suggested that the higher-intensity earlier rehabilitation may have been more harmful in patients with intracerebral hemorrhage and more severe ischemic strokes. “But this was not statistically significant and we need look at this in more detail,” Professor Bernhardt said.

In the Lancet paper, the authors note, “Components of our intervention are already part of routine clinical care; therefore, understanding which components might affect outcome is a priority.”

They add: “By further exploration of this rich dataset, our trial provides the best opportunity yet to develop evidence-based guidelines for patients with stroke about the timing, frequency, and amount of out-of-bed activity to improve outcome (or prevent harm). Consequently, as outlined in our published statistical analysis plan, our next priority will be to undertake a dose–response analysis to establish the effect of dose of rehabilitation (rather than group) on efficacy and safety outcomes.”

Professor Bernhardt noted that it has been “notoriously difficult” to do rehabilitation trials, with previous studies having an average sample size of just 52 patients. “There are some trials of several hundred patients but we managed to recruit more than 2000.”

The trial did take 8 years to complete, however, which Professor Bernhardt attributed partly to starting the intervention so early.

“We wanted to randomize patients within 24 hours of stroke onset and the vast majority of patients don’t come into hospital in this time,” she said. “This is very problematic on many levels from a public health point of view, and also for conducting this trial. Future trials will probably look at slightly later timeframes and so should be quicker to recruit.”