Physical Fitness Training in Patients with Subacute Stroke (PHYS-STROKE): multicentre, randomised controlled, endpoint blinded trial

Abstract

Objective: To determine the safety and efficacy of aerobic exercise on activities of daily living in the subacute phase after stroke.

Design: Multicentre, randomised controlled, endpoint blinded trial.

Setting: Seven inpatient rehabilitation sites in Germany (2013-17).

Participants: 200 adults with subacute stroke (days 5-45 after stroke) with a median National Institutes of Health stroke scale (NIHSS, range 0-42 points, higher values indicating more severe strokes) score of 8 (interquartile range 5-12) were randomly assigned (1:1) to aerobic physical fitness training (n=105) or relaxation sessions (n=95, control group) in addition to standard care.

Intervention: Participants received either aerobic, bodyweight supported, treadmill based physical fitness training or relaxation sessions, each for 25 minutes, five times weekly for four weeks, in addition to standard rehabilitation therapy. Investigators and endpoint assessors were masked to treatment assignment.

Main outcome measures: The primary outcomes were change in maximal walking speed (m/s) in the 10 m walking test and change in Barthel index scores (range 0-100 points, higher scores indicating less disability) three months after stroke compared with baseline. Safety outcomes were recurrent cardiovascular events, including stroke, hospital readmissions, and death within three months after stroke. Efficacy was tested with analysis of covariance for each primary outcome in the full analysis set. Multiple imputation was used to account for missing values.

Results: Compared with relaxation, aerobic physical fitness training did not result in a significantly higher mean change in maximal walking speed (adjusted treatment effect 0.1 m/s (95% confidence interval 0.0 to 0.2 m/s), P=0.23) or mean change in Barthel index score (0 (-5 to 5), P=0.99) at three months after stroke. A higher rate of serious adverse events was observed in the aerobic group compared with relaxation group (incidence rate ratio 1.81, 95% confidence interval 0.97 to 3.36).

Conclusions: Among moderately to severely affected adults with subacute stroke, aerobic bodyweight supported, treadmill based physical fitness training was not superior to relaxation sessions for maximal walking speed and Barthel index score but did suggest higher rates of adverse events. These results do not appear to support the use of aerobic bodyweight supported fitness training in people with subacute stroke to improve activities of daily living or maximal walking speed and should be considered in future guidelines.

Trial registration: ClinicalTrials.gov NCT01953549.

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: German Ministry for Health and Education (01EO0801) through Center for Stroke Research Berlin grant G.2.15; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. AHN is participant in the Berlin Institute of Health BIH-Charité clinical scientist programme and reports grants from BIH during the conduct of the study. AM reports funding from Neurocure (German Research Foundation EXC257). MEn reports grant support from Bayer, the German Research Foundation, the German Federal Ministry of Education and Research, the German Center for Neurodegenerative Diseases, the German Centre for Cardiovascular Research, the European Union, Corona Foundation, and Fondation Leducq; fees paid to the Charité from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Amgen, GlaxoSmithKline, Sanofi, Covidien, Ever, Novartis, all outside the submitted work. AF reports grant support from the German Research Foundation, German Federal Ministry of Education and Research, European Union, Else Kröner Fresenius Stiftun, and Hannelore Kohl Stiftung; consultant fees from Novartis and Bayer, and honoriums for presentations in scientific symposia by Novartis and Bayer, all outside the submitted work. UMW reports honorariums for presentations in scientific symposia by Novartis and Bayer.

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Figures

Fig 1

Flowchart of enrolment and randomisation. Multiple imputation was performed for intention-to-treat analyses of full analysis dataset

Fig 2

Progression of training modalities during intervention period. (A) Distance (m) achieved (only available for participants who used treadmill). (B) Walking speed (km/h) reached on treadmill. (C) Change in incline (%) on treadmill (only available for participants who used treadmill). (D) Proportion of participants with different levels of bodyweight support over time. (E) Mean change in heart rate by group measured before and after intervention sessions during intervention period. (F) Proportion of participants who achieved their target heart rate during training. Participants are grouped by baseline functional ambulation category (FAC) score of 0-2 and 3-5 (higher scores indicate less dependency)

Fig 3

Boxplot showing medians (interquartile ranges) for maximal walking speed assessed by 10 m walk test (top panel), and Barthel index score (bottom panel) for each study visit and intervention group. Data are based on measurements without multiple imputation. Number of participants at each scheduled study visit was: baseline (n=105 in aerobic physical fitness training group, n=95 in relaxation group:), post-intervention (n=87, n=85), three months post-stroke (n=89, n=77), and six months post-stroke (n=80, n=65). Dots represent outliers

Fig 4

Prespecified subgroup analyses. Forest plots display maximal walking speed and Barthel index scores. Results are based on multiple imputation. No data were available for time from stroke to intervention for four participants who were excluded at screening. National Institutes of Health Stroke scale (NIHSS) score was missing for one participant owing to missing hospital chart. FAC=functional ambulation category. *P value for primary outcome measure. †P values for age×group interaction

Fig 5

Subgroup analyses of continuous variables using splines. Differences in maximal walking speed and Barthel index scores (follow-up three months after stroke-baseline) as a function of age and National Institutes of Health stroke scale (NIHSS) score at days 3-5 after stroke