Effect of an exercise intervention on global cognition after transient ischemic attack or minor stroke: the MoveIT randomized controlled trial

The MoveIT trial was a single-centre, observer-blinded, randomized controlled trial. Patients were randomized in permuted blocks, using sealed opaque envelopes to conceal treatment allocation. The envelopes were prepared and secured by an independent physician. The outcome measures were recorded on standardized forms by trained observers blinded to the treatment allocation. The control group received usual care for patients after TIA or minor ischemic stroke, consisting of two or three visits to the outpatient clinic. The follow-up period was 2 years after the initial TIA or stroke, and the last patient was assessed in October 2016. All methods in the MoveIT trial were carried out in accordance to the Declaration of Helsinki. Study procedures were approved by local university and hospital research ethics committees, location VU Medical Centre, NL38008.029.11. Written informed consent was obtained from all patients. The study protocol was published in December 2014 in BMJ Open [16]. The trial has been registered in the Netherlands Trial Register with the registration number NL3721 and was first registered at 06-03-2013. Our reporting follows the CONSORT statement for reporting parallel-group randomized trials (http://​www.​consort-statement.​org/​consort-statement/​flowdiagram).

Patients were invited to take part in the study by clinicians at the stroke unit, emergency department and outpatient clinic of our secondary care teaching hospital. They were screened for eligibility and consented between April 2012 and June 2014. Patients were eligible if they 1) were at least 18 years old, 2) presented with a TIA or minor ischemic stroke as defined by a National Institutes of Health Stroke Scale (NIHSS) score ≤ 3, 3) had had the onset of signs and symptoms less than 1 month ago, 4) were able to walk independently, 5) had been discharged from hospital without need for further rehabilitation, [17] 6) had a Mini-Mental State Examination (MMSE) score ≥ 24, 7) had no aphasia and were able to speak Dutch, 8) had no cardiopulmonary contraindications for physical exercise and exercise testing as outlined by the American College of Sports Medicine, [18] and 9) had no chronic disease with an expected survival of less than 2 years.

Cardiopulmonary examination was conducted to ensure the exercise intervention was safe in this group of patients. Before randomization, all potential participants were screened for cardiac contraindications using a checklist that included history of cardiac disease, symptoms of current cardiac and pulmonary disease and the results of an electrocardiogram (ECG). Potential participants with a positive checklist were examined by a cardiologist and/or pulmonologist; the randomization was done after their approval. At baseline, all maximum exercise capacity tests (see below) were checked by the cardiologist and pulmonologist, and in case of abnormalities, additional examinations were done. Patients in the experimental group whose tests showed abnormalities started the exercise intervention after completing the additional examination, upon approval by the cardiologist and/or pulmonologist.

The primary outcome measure was global cognitive functioning, assessed with the Montreal Cognitive Assessment (MoCA) [19] at 1 year post stroke, while the MoCA score at 2 years was a secondary outcome measure. In addition, a standardised neuropsychological examination was conducted at baseline, 1 and 2 year post stroke, which consisted of attention, verbal and visual memory, and executive functioning tests. Cardiorespiratory fitness was measured as maximal exercise capacity or maximal oxygen consumption (V̇O_2max), measured by performing a ramp exercise test on a cycle ergometer (Jaeger) under continuous blood pressure measurement, ECG, and breath-by-breath gas analysis (Oxycon Pro). The amount of self-reported physical activity was measured using the Physical Activity Scale for the Elderly (PASE) questionnaire [20, 21]. In accordance with international literature concerning the attainment of primary goals in secondary stroke prevention, we used a composite score for optimal therapy, defined as the combination of prescribed antithrombotic therapy (antiplatelet agents or oral anticoagulants) and meeting targets for both blood pressure (< 140/90 mmHg) and low density lipoprotein (LDL) cholesterol (< 100 mg/dl) [22]. Self-reported smoking, alcohol consumption, Body Mass Index (BMI) and waist circumference were also assessed. Mental health was assessed using the Hospital Anxiety and Depression Scale (HADS) [23]. The severity of fatigue was measured using the Fatigue Severity Scale (FSS), a 9-item scale of which the average score was used [24]. All secondary outcomes wre measured at baseline and at 12 and 24 months. 

All patients in this trial received standard post-stroke care according to the Dutch multidisciplinary guideline, [25] consisting of a total of two visits to the outpatient clinic during the first 3 months after the TIA or minor stroke. The patients in the experimental group started the exercise intervention with an intake session in which their current exercise behaviour and motivation were assessed and exercise goals were established. The exercise intervention started with a 12-week exercise program which was performed in groups of 10 patients. The patients received two one-hour sessions of exercise training per week, supervised by two specialized physiotherapists. The exercise program consisted of both aerobic and strength training. The aerobic exercise was performed using a cycle ergometer, treadmill, or rowing machine. The Karvonen formula was used to calculate the target heart rate (THR), as follows: resting heart rate + (% desired intensity x [maximum heart rate derived from the maximum exercise test – resting heart rate]). Aerobic exercise started at 40%, and was then gradually increased to 80% THR [18]. During each aerobic exercise training session, heart rate was measured twice to ensure that the patients exercised at the target level. We also used a rating of perceived exertion of 11 to 16 (“light” to “hard”) on the Borg 6–20 Scale [26]. The strength training part of the program, performed on weight machines, started with 3 sets of 10–12 repetitions at 30% of the repetition maximum, and patients gradually progressed to 60–70%. Patients were instructed and guided to perform home-based exercise sessions three times a week, with the aim of achieving independence in exercising and to develop and maintain an active lifestyle that meets recommended physical activity and exercise guidelines. In order to gain insight in the amount and frequency of physical training, patients used an exercise diary, which recorded how much they exercised and what the facilitators and barriers were for an active lifestyle. In this diary the patients kept track of how much they exercised per day and what were motivators and barriers to exercise. After the completion of the 12-weeks group exercise program, follow-up consisted of three visits to the physiotherapist over a 9-month period. During these follow-up visits, the patients received counselling by the physiotherapists, based on motivational interviewing. Patients were motivated to maintain an active lifestyle and to continue exercising, the exercise diary was used as an evaluation method for the patient. The description of our intervention followed an internationally developed template on exercise reporting [27].

Global cognition, assessed with the MoCA test, was selected as the outcome variable to calculate sample size [19, 28]. Using estimates obtained from the literature [29, 30] and our previously performed pilot study, [15] a sample size of 52 patients in each group was needed to reach a power of 80% in detecting a difference in mean MoCA score of 1.5 points, assuming a standard deviation of 2.7 and using a two-sample t test with a 0.05 two-sided significance level. We increased the sample size to 60 patients in each group to anticipate potential dropouts.

Baseline demographic and clinical characteristics of the patients in the experimental and control groups were compared using independent two-sample t-tests (for continuous data) and χ2 analysis (for nominal data). Visual inspection of the distribution was used to assess normality. Primary analyses were unadjusted, following the intention-to-treat principle. The between-group differences in change scores from baseline to 12 months and from baseline to 24 months were investigated using independent t-tests for continuous outcomes. Mann-Whitney non-parametric statistics were used in those cases where assumptions of normality were violated. Mixed-effects regression models were used with a random intercept for longitudinal repeated measures. Each hypothesis was tested with a two-tailed analysis with 0.05 as the level of significance. All analyses were carried out in SPSS, version 22.

The results of the study were shared with all participants with a written summary containing the main outcomes of the study. Patients were not involved in the development, design, recruitment or conduct of the MoveIT study. The burden of the intervention was not assessed by patients themselves.

No between-group differences were found on global cognitive functioning (MD, − 0.7 out of 30, 95% CI, − 1.6 to 0.2) as measured with the MoCA at 12 months (Table 2). The results of the standardised neuropsychological examination on the cognitive domains attention, verbal and visual memory and executive functioning will be published separately.

There were no significant differences between the experimental and control groups in global cognitive functioning as measured with the MoCA at 24 months (Table 2). At baseline, patients in the experimental group had a mean maximal exercise capacity of 23.0 ml/kg/min, compared to 22.0 ml/kg/min in the control group, which is in the 5th percentile of age- and sex-related normative values [18]. The level of fitness was very poor (below the 20th percentile of age- and sex-related normative values) for 86% of the female patients and 61% of the male patients [18]. There were no significant differences between the experimental and control groups in cardiorespiratory fitness at 12 and 24 months (Table 2). We found no between-group difference in the level of self-reported physical activity as measured by the PASE.

No significant difference in the composite score for attainment of optimal secondary prevention targets was found between the study groups. At 12 months, 73% of the patients in the experimental group and 78% in the control group had attained the endpoint of optimal medical therapy, while at 24 months, 60% of the patients in both the experimental and control groups had attained this endpoint. Adherence to antithrombotic medication was 100% in both groups at both 12 and 24 months. We found no between-group differences in systolic blood pressure, diastolic blood pressure, total cholesterol, LDL-cholesterol, weight, waist circumference, or active smoking after 12 and 24 months. The mixed-effects regression model did not found another outcome than the primary analysis (Table 3).

There were no significant between-group differences in the total HADS, HADS Anxiety and HADS Depression scores after 12 and 24 months. The experimental and control groups both had a mean HADS anxiety score at baseline of 4.4 ± 3.2 respectively 5.6 ± 3.7 and mean HADS depression score at baseline of 3.9 ± 3.1 respectively 4.7 ± 3.6. A score of > 8 indicating a possible anxiety disorder or depression applies per subscale [23]. The only significant between-group difference was found for fatigue, in favour of the experimental group at 12 months (Mean Difference (MD), − 0.6 out of 63, 95% CI, 0.1 to 1.1). This mean difference had become non-significant at 24 months (MD, 0.5 out of 63, 95% CI, 0.0 to 1.0).

We found no significant between-group differences in the number of deaths, recurrent TIAs or strokes at 12 and 24 months post stroke. At 24 months, new vascular events had occurred in 7 patients in the experimental group and 15 in the control group (p = 0.10). Two patients in the experimental group and 6 in the control group had a recurrent TIA or ischemic stroke (p = 0.27).

Of the 60 patients in the experimental group, 43 completed the exercise intervention. One patient withdrew from the trial before the intervention started, 8 patients completed the group exercise program of 12 weeks but did not attend the 3 counselling visits thereafter and 8 patients neither completed the group exercise program nor the counselling. Reasons for not completing the exercise intervention were: severe osteoarthritis (n = 2), financial problems (n = 1), lack of time (n = 2), no reason (n = 12).