AVERT: a major milestone in stroke research
Authors: Peter M Rothwell
Journal: The Lancet (2015)

Prevention of stroke is, of course, the ideal scenario, but with more than 10 million major strokes every year worldwide, acute treatment and rehabilitation should also be optimised. Organised acute stroke care within dedicated stroke units reduces death and dependency after stroke,1Langhorne P Williams BO Gilchrist W Howie K Do stroke units save lives?.Lancet. 1993; 342: 395-398Summary PubMed Scopus (560) Google Scholar but which elements of such care confer this benefit is uncertain. Systematic prevention of common complications and more expert nursing care undoubtedly contribute, but in the physiologically unstable setting of acute stroke, the benefits and harms of each specific element of care need to be reliably assessed. How soon and how intensively patients with acute stroke should be mobilised is an obviously important question. Early mobilisation after stroke, whether sitting, standing, or walking, is recommended in many guidelines, but, as with most nursing and therapist interventions, the evidence base has been weak. The rationale for early and more intensive mobilisation is that bed rest might increase immobility-related complications and could slow neurological recovery by impairing early brain plasticity and repair. On the other hand, forced sitting and standing might lead to falls and injury and could reduce cerebral perfusion, autoregulation being impaired in acute stroke, and thereby exacerbate ischaemia. Early mobilisation might also worsen any post-stroke hypertension and increase the risk of rebleeding after intracerebral haemorrhage or after thrombolysis for ischaemic stroke. In The Lancet, the AVERT Collaboration group randomly assigned 2104 patients within 24 h of onset of acute stroke to early mobilisation or usual care.2The AVERT Trial Collaboration GroupEfficacy and safety of very early mobilisation within 24 h of stroke onset (AVERT): a randomised controlled trial.Lancet. 2015; (published online April 17.)http://dx.doi.org/10.1016/S0140-6736(15)60690-0Google Scholar The intervention tested was not simply earlier, but was also more frequent and of a higher dose than usual care. Indeed, the difference achieved in frequency and dose was greater than the difference in timing of first mobilisation (median 18 h vs 22 h after stroke onset). The trial was well designed and executed, with only six patients lost to follow-up, and external validity seems likely to be good. Participating sites were located in both metropolitan and regional settings, and ranged in size from 33 to 1200 stroke admissions per year. Although the trial took 8 years to recruit patients from 56 acute stroke units, the proportion of eligible patients recruited was higher than in many acute stroke trials,3Rothwell PM External validity of randomised controlled trials: to whom do the results of this trial apply?.Lancet. 2005; 365: 82-93Summary Full Text Full Text PDF PubMed Scopus (1744) Google Scholar and patient refusals (n=446) were remarkably low. The 3 month mortality rate of only 8% was less than half of that reported in previous acute stroke trials,4Mishra NK Diener HC Lyden PD Bluhmki E Lees KR for the VISTA CollaboratorsInfluence of age on outcome from thrombolysis in acute stroke: a controlled comparison in patients from the Virtual International Stroke Trials Archive (VISTA).Stroke. 2010; 41: 2840-2848Crossref PubMed Scopus (94) Google Scholar perhaps because relatively minor strokes were eligible. The investigators hypothesised that more intensive, early out-of-bed activity would improve functional outcome at 3 months, reduce immobility-related complications, and accelerate walking recovery, with no increase in neurological complications. None of these predictions proved correct. There was no difference in walking recovery between the early mobilisation group and the usual care group, and a good overall functional outcome at 3 months (the primary outcome) was less frequent in the intervention group (adjusted odds ratio [OR] 0·73, 95% CI 0·59–0·90). The unadjusted result for the primary outcome was less convincingly adverse (OR 0·85, 95% CI 0·72–1·00), but the adjustment for age and stroke severity was robust to different analysis methods. The absence of a difference between the groups in immobility-related complications might partly be due to improvements in stroke-unit practice in the past few years and a move away from prolonged bed rest, such that only 7% of patients in the usual care group stayed in bed for more than 48 h after stroke onset. However, the adverse effect of the intervention on the primary outcome seems to have been driven at least partly by a non-significant increase in neurological deterioration in the intervention group as compared with the usual care group. The non-significant increase in mortality in the intervention group was driven mainly by progression or recurrence (42 such deaths in the intervention group vs 26 deaths in the usual care group). The overall increase in mortality in the intervention group was non-significant, and remains so when combined with the few data (15 deaths in 81 patients with early mobilisation vs six deaths in 78 patients with usual care) from three small previous trials (fixed-effects OR 1·35, 95% CI 0·99–1·83).5Lynch E Hillier S Cadilhac D When should physical rehabilitation commence after stroke: a systematic review.Int J Stroke. 2014; 9: 468-478Crossref PubMed Scopus (54) Google Scholar Nevertheless, it seems reasonable to conclude that a beneficial effect on mortality is unlikely. In view of the clinical, causal, and physiological heterogeneity of acute stroke, subgroup–treatment effect interactions might well be expected, and many clinicians had a-priori concern about starting mobilisation early in patients with intracerebral haemorrhage.6Skarin M Bernhardt J Sjöholm A Nilsson M Linden T 'Better wear out sheets than shoes': a survey of 202 stroke professionals' early mobilisation practices and concerns.Int J Stroke. 2011; 6: 10-15Crossref PubMed Scopus (25) Google Scholar Therefore, that both the primary outcome (adjusted OR 0·48, 95% CI 0·25–0·92) and 3 month mortality (0·31, 0·11–0·88) were significantly better in the usual care group than the early mobilisation group in patients with intracerebral haemorrhage is noteworthy. The investigators are cautious in their interpretation of this finding on the basis that they did not stratify for stroke subtype at randomisation and did not prespecify any expected subgroup effects themselves, and because no subgroup–treatment effect interaction was statistically significant. However, significance is a poor measure of the validity of subgroup effects,7Rothwell PM Subgroup analysis in randomised controlled trials: importance, indications and interpretation.Lancet. 2005; 365: 176-186Summary Full Text Full Text PDF PubMed Scopus (682) Google Scholar partly because most trials are substantially underpowered to detect them (AVERT recruited only 258 patients with intracerebral haemorrhage). Further analyses of frequency and dose of intervention received in relation to apparent harms could be informative, but updated clinical guidelines should not overestimate the statistical obstacles to interpretation of what seems to be potentially substantial harm in patients with intracerebral haemorrhage, particularly in view of the a-priori clinical concern and evidence that excessive variability in blood pressure, which might be exacerbated by early and intensive mobilisation, is associated with a poor outcome in acute intracerebral haemorrhage.8Manning L Hirakawa Y Arima H et al.Blood pressure variability and outcome after acute intracerebral haemorrhage: a post-hoc analysis of INTERACT2, a randomised controlled trial.Lancet Neurol. 2014; 13: 364-373Summary Full Text Full Text PDF PubMed Scopus (170) Google Scholar There also seems to be little to lose by a cautious approach to early mobilisation in this group. AVERT is a milestone in stroke research in that it has shown that large, international, high-quality trials of complex interventions in stroke care, led by physiotherapists and nurses, are possible. The trial contributes several other important lessons. First, it reminds us that high-quality randomised controlled trials of acute stroke so often confound expectations—the overall balance of benefits and harms of any intervention are almost impossible to predict reliably from first principles. Second, it shows the effect that simple interventions can have on outcome in this physiologically complex and unstable disorder. Findings from the ongoing HeadPoST trial (ClinicalTrials.gov, NCT02162017), comparing the effectiveness of the lying flat (0°) head position with the sitting up (≥30°) head position in the first 24 h of admission to hospital with acute stroke, are likely to be similarly important in this regard. Finally, the low rate of patients refusing to participate in AVERT shows that patients also see the importance of simple, pragmatic research questions. Ironically, the main barriers to more such research are those put up by agencies intended to represent the public interest: the trial regulators with their unnecessarily complex bureaucratic framework for trial performance, which often results in trial prevention, and the medical research funding agencies that in many countries have little interest in the needs of patients and clinicians for answers to pragmatic questions about making the best use of existing interventions in routine clinical practice.9Rothwell PM Funding for practice-oriented clinical research.Lancet. 2006; 368: 262-266Summary Full Text Full Text PDF PubMed Scopus (36) Google Scholar Thankfully, those agencies in Australia and the UK that funded AVERT took a different view. I declare no competing interests. Efficacy and safety of very early mobilisation within 24 h of stroke onset (AVERT): a randomised controlled trialFirst mobilisation took place within 24 h for most patients in this trial. The higher dose, very early mobilisation protocol was associated with a reduction in the odds of a favourable outcome at 3 months. Early mobilisation after stroke is recommended in many clinical practice guidelines worldwide, and our findings should affect clinical practice by refining present guidelines; however, clinical recommendations should be informed by future analyses of dose–response associations. Full-Text PDF Open Access