ExStroke Pilot Trial of the effect of repeated instructions to improve physical activity after ischaemic stroke: a multinational randomised controlled clinical trial

Trial participants

Patients with ischaemic stroke aged ≥40 years from six stroke units in Denmark and from one neurological department each in Chengdu, China, Warsaw, Poland, and Tartu, Estonia, were eligible if they were able to walk unassisted. Canes and walkers were allowed. Participants were enrolled within 90 days of onset of stroke symptoms. Verbal and written informed consent were obtained prior to enrollment. Exclusion criteria were inability to understand the meaning of the trial, unwillingness to participate, medical contraindications to exercise, or a modified Rankin scale of 4 or 5 before the qualifying event. The modified Rankin scale for activities of daily living ranges from 0 to 5, where 0 means no limitations and 5 means confinement to bed and requiring constant help.22 23 Stroke severity was assessed at baseline with the Scandinavian stroke scale (SSS), which ranges from 0 to 58, the latter meaning no deficits in the measured items.24

Patient enrolment started in August 2003 and was completed in October 2005. In the Danish department that included most participants only about 15% of stroke patients were recruited into the trial.21 About 15% expressed unwillingness to participate because of reluctance to engage in physical training. Other reasons for non-eligibility were fatal stroke, severe neurological deficits, dysphasia or cognitive impairment, discharge to nursing homes, transfer to other departments due to comorbidity, enrolment in other trials, or age below 40 years.

Interventions

The experimental intervention consisted of repeated encouragement and verbal instruction on being physically active given by a physiotherapist, except for the Chinese centre, where a neurologist provided the instruction. The control group received information on the possible benefits of physical activity but no specific instruction. Both groups received standard treatment with antithrombotic drugs, antihypertensive treatment, and statins as needed after individual assessment. Physiotherapists and physicians examined patients during their hospital stay, and rehabilitation was carried out according to the customs of the department.

Patients randomised to the intervention group met up with a trial physiotherapist (or neurologist in China) for instruction in a detailed training programme to start after discharge from the hospital. At the first session the instructor spent about 30-60 minutes getting acquainted with the participant and evaluating the consequences of the stroke. Considerable effort was taken to motivate the participant. The aim was to make the participant choose the most suitable types of physical activity for him or her. The programme was individualised according to each patient’s resources, former activities, and preferences. Patients were encouraged to use facilities for physical activity in their local community. They were encouraged to use fitness centres, to walk several kilometres a day (possibly as Nordic walking with sticks to improve balance), to go to public swimming pools, and to exercise in their local senior centre. Bicycling (with a cycle helmet) was also encouraged for those who cycled. At each visit the instructor and participant would fill in a standard agreement form with various choices of physical activity (see extra material on bmj.com), with one copy of the completed form for the participant to take home and another to be kept in the participant’s file.

At the follow-up visits—every three months during the first year, and thereafter every six months until the end of the trial—the instructor spent about 20-30 minutes with the participant on repeated instructions and readjustment of the physical activity plan. Between visits a telephone call was made to remind each participant in the intervention group about the physical activity agreement. Participants were asked in detail about their activities and encouraged to increase efforts and to exercise more, and were told that to become sweaty and short of breath was desirable.

No telephone calls were made in the control group. Participants in the control group received standard treatment without detailed information on physical activity. They were seen for clinical visits with the same frequency as the intervention group.

Assessment of physical activity

At their entry to the study, we ascertained participants’ level of physical activity during the week before their stroke, and at each follow-up visit we ascertained their level of physical activity in the week preceding the visit. The physical activity scale for the elderly (PASE)19 20 has 12 questions about different activities (walking outside the home, light sport, moderate sport, strenuous sport, exercises to increase muscle strength and endurance, light housework, heavy housework, home repairs, lawn work or yard care, caring for another person, work for pay, and work as a volunteer), and each question has subsidiary questions as to the frequency per week and the time per day spent on the activity. The PASE score can range from 0 to over 400, with a higher score meaning a higher level of physical activity. The validity and reliability of the PASE questionnaire has been tested in several studies,19 20 25 26 27 28 29 and it is reliable for interview, mail, and telephone administration27 28 and valid in a variety of population groups, including those with disability. The PASE score was positively and significantly correlated (r = 0.68 (95% confidence interval 0.35 to 0.86)) with the doubly labelled water method, which is considered the gold standard for measuring energy expenditure.25 In a random sample of 49 participants in the ExStroke Pilot Trial we tested if their PASE score reflected their physical capacity.29 We found a significant correlation between PASE score and their score on the senior fitness test,30 which reflects the capacity to perform everyday activities during functional examination of strength, aerobic capacity, and balance.

Study objectives

Our objective was to assess if repeated verbal encouragement and instruction in being physically active would result in a long term improvement in the level of physical activity, and, further, to explore the effect of the intervention on mortality and new cerebrovascular and cardiovascular events, on falls and fractures, and on the modified Rankin scale.22 23

Outcome measures

The primary outcome was the difference in PASE score between the two groups. Secondary outcomes included the time from randomisation to recurrent stroke, myocardial infarction, or death (from any cause). Other outcomes were time to vascular death, frequency of recurrent stroke, modified Rankin scale, and falls and fractures.

Stroke was defined as the sudden onset of a neurological deficit with symptoms continuing for more than 24 hours or leading to death with no apparent cause other than vascular. In all such patients the results of computed tomography or magnetic resonance imaging were compatible with a stroke diagnosis. Diagnosis of myocardial infarction followed international guidelines. Vascular death was defined as death from stroke, myocardial infarction, or other vascular causes or sudden unexpected death. Falls were defined as sudden unintentional contact with the floor or ground. All events were adjudicated by an independent adjudication committee, which was blinded to the intervention group of the patient.

Sample size

The sample size calculation assumed a minimal relevant mean difference of 20 PASE points between the intervention and the control groups and a standard deviation of 50 PASE points. Based on the sample size calculation (α = 0.05, β = 0.20), 99 patients would be needed in each group.21 A total of 300 patients were planned to be included to allow for dropouts. A difference of 20 PASE points corresponds to an increase of physical activity (such as walking outside the home for two hours three times a week) that was considered a realistic goal and which is associated with an odds ratio of 0.72 (95% confidence interval 0.59 to 0.89) of first stroke.28

Randomisation

The ExStroke Pilot Trial is a randomised, multicentre, multinational clinical trial with masked outcome assessment in patients with ischaemic stroke. The participants were centrally randomised to intervention group or control group. Generation of allocation sequences was computer based. Allocation concealment was achieved through centralised randomisation by telephone or email. The randomisation was stratified with regard to sex, age, stroke severity, and centre. Stratification was conducted into two groups for age (40-70 years, ≥70 years), two groups for stroke severity (Scandinavian stroke scale 20-39 points, 40-58 points), and two groups for centre (Danish, or non-Danish) in blocks of 10, randomising patients 1:1 to experimental and control intervention. Block size was unknown to investigators.

Randomisation implementation

The investigator, who was informed from the Copenhagen Trial Unit via telephone or email whether a patient was randomised to intervention or control group, told the patient the result of the randomisation. For those in the intervention group the investigator arranged an appointment with the physiotherapist or provided the intervention herself.

Masking and blinding

In each centre an interviewer masked to the randomisation of the patient obtained the PASE score at the follow-up visits. These interviewers were physicians, medical students, or secretaries who were otherwise uninvolved in the conduct of the trial. They were instructed in how to use the PASE questionnaire and were told not to ask the patients about the group assignment. These investigators also obtained information about recurrent stroke, myocardial infarction, and falls—events that were adjudicated by a blinded adjudication committee.

Statistical methods

The data were analysed on the basis of intention to treat and of per protocol. A mixed model analysis (proc mixed SAS 9.1) including the repeated measures option was used to assess the time course of PASE. It proved necessary to code the data by using a square root transformation of the PASE scale (the variability of the PASE score increased with increasing score, and the square root scale eliminated this variability and improved normality). To obtain an estimate of the effect of the intervention from the mixed model program, the mean square root PASE in each group was calculated. By squaring the two mean values and calculating their difference, we obtained the difference between the two groups in the original scale. The standard error of the difference in mean PASE score was then calculated by using the fact that the standard error of the difference between the two mean values comprises (almost exactly) the same percentage of this difference whether the original scale or the square root scale is used.

The per protocol analysis included the patients who attended all six follow-up visits. To compensate for differences in pre-stroke PASE score between the two groups, we included the square root transformed pre-stroke PASE score as a covariate.

The difference in modified Rankin scale between the two groups at 3, 6, 12, and 24 months after randomisation was assessed with a non-parametric test (Mann-Whitney). Cox analyses were used to assess the effect of the intervention on time to a clinical event.

Registration of the trial

The protocol was approved by local ethics committees in Denmark (KF11006/04) and in the countries of the participating centres. The trial was registered with the Danish Data Protection Agency (J No 2003-41-3564) and at www.ClinicalTrials.gov (NCT00132483) .

Independent safety and monitoring board

The Independent Safety and Monitoring Board conducted one interim analysis. There was no safety concern as to continuing the trial.