AVERT: Very Early Exercise Safe Following Acute Stroke

Caroline Cassels

May 23, 2008

May 23, 2008 — Getting stroke patients out of bed and engaging in early intensive exercise therapy within 24 hours of symptom onset is a safe method of rehabilitation — even among individuals who have been treated with tissue plasminogen activator (tPA).

New 3-month safety results from a large, multicenter, single-blind, phase 3 study show that, at 5.8%, death rates are low and adverse-event rates acceptable in the trial's first 170 acute ischemic-stroke patients participating in A Very Early Rehabilitation Trial (AVERT).

These most recent findings build on early phase 1 results in 71 patients presented at the American Stroke Association International Conference on Stroke 2007 and reported by Medscape Neurology & Neurosurgery at that time, which showed very early mobilization (VEM) was feasible and appeared safe.

"These latest results are very encouraging. They further confirm our earlier findings and support the hypothesis that early rehabilitation is safe even in patients with severe ischemic stroke," principal investigator Julie Bernhardt, PhD, from the University of Melbourne, in Australia, told Medscape Neurology & Neurosurgery.

Largest Stroke Rehab Trial

With a target recruitment of 2104 patients from 30 centers in Australia, the United Kingdom, Canada, New Zealand, and possibly Singapore, AVERT is the largest stroke-rehabilitation trial to date.

The study's hypothesis is that compared with usual stroke care, VEM will lead to fewer deaths, less disability 3 months poststroke, fewer and less severe complications, and better quality of life at 1 year and be more cost effective.

The inclusion criteria for the ongoing study are deliberately broad and include patients age 18 years or older with confirmed stroke admitted to the hospital within 24 hours of symptom onset. In addition, patients who receive clot-busting therapy with tPA are also allowed to participate if they received approval from the treating physician.

"About 10% of our study sample are patients who have been treated with tPA, so it appears physicians are not concerned about getting this group of patients up, which is good, because the tPA protocol of keeping people on bed rest for 24 hours after treatment is not evidence based," said Dr. Bernhardt.

Patients excluded from the study are those with transient ischemic attack or moderate to severe premorbid disability or who are too ill to participate.

Individuals randomized to VEM received their first intervention, which was delivered by a nurse and physical therapist team, within 24 hours of symptom onset. The intervention continued for 14 days or until discharge, whichever was shorter.

Unblinded Data

The results are still blinded, and therefore it is not yet possible to compare outcomes of those in the VEM group with patients receiving usual stroke care. Dr. Bernhardt said the investigators made the decision to allow the unblinded data to be viewed by the study's independent data monitoring committee.

"It is important to allow for this [unblinded monitoring] because there are concerns among the medical community, including neurologists, that getting people out of bed at an early stage could be detrimental.

"Our data are blinded and will be until the end of the study period. At this point, we're looking at results from the study as a whole and not from the individual arms, and what we're seeing are very low death rates and very acceptable rates of adverse events in this acute population. However, our data monitoring committee has met 3 times now to view the unblinded results and has no concerns about any of the safety aspects of the study," she said.

At 3 months, there were 10 deaths (5.9%) in the study group. All deaths occurred in patients over age 65 years, and the majority of them had severestroke. Of the total number of deaths 4 occurred in the subgroup of 19 patients who received tPA.

According to Dr. Bernhardt there were 41 serious adverse events (excluding death) — with 13.4% of patients experiencing at least 1 adverse event and 4.2% of study subjects having more than one serious adverse event.

The most common adverse event was stroke progression, followed by stroke recurrence, pulmonary embolism, pneumonia, and myocardial infarction. Two patients experienced falls, but these both occurred outside of the intervention period. The bottom line, said Dr. Bernhardt, is that 82.4% of subjects had no adverse events.

Still Recruiting

Scheduled to conclude in 2010, the study is lagging behind in its target recruitment and, as a result, is actively seeking additional centers. A large part of the reason for the slow patient recruitment, said Dr. Bernhardt, is the large number of potential study subjects who do not make it to hospital within the 24-hour timeframe.

"Forty-five percent, so almost half of our potential study subjects, are excluded from participating in the study because they don't get to the hospital fast enough. The other recruitment issue relates to resources. An additional 25% of potential subjects are excluded because the people who are driving this trial — nurses and physiotherapists — can only recruit during 'office hours' when they are working. So patients who arrive at the emergency department after 5 pm or on weekends are excluded by default," she said.

In addition to efficacy end points, the investigators will also be conducting an economic analysis, comparing cost effectiveness of VEM with usual stroke care.

Dr. Bernhardt said her team may also examine regional variations in the time it takes for symptomatic patients to get to the hospital, an analysis that could help inform public health strategies.

Clinicians interested in participating in the AVERT study can contact Dr. Bernhardt at avert@nsri.org.au.

The study is funded by the National Health & Medical Research Council and Australia National Heart Foundation.

17th European Stroke Conference. Presented May 15, 2008.

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