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Patient-Centered Outcomes in a Randomized Trial Investigating a Multimodal Prevention Program After Transient Ischemic Attack or Minor Stroke: The INSPiRE-TMS Trial

Originally publishedhttps://doi.org/10.1161/STROKEAHA.120.037503Stroke. 2022;53:2730–2738

Abstract

Background:

The INSPiRE-TMS trial (Intensified Secondary Prevention Intending a Reduction of Recurrent Events in Transient Ischemic Attack and Minor Stroke Patients) investigated effects of a multicomponent support program in patients with nondisabling stroke or transient ischemic attack. Although secondary prevention targets were achieved more frequently in the intensified care group, no significant differences were seen in rates of recurrent major vascular events. Here, we present the effects on prespecified patient-centered outcomes.

Methods:

In a multicenter trial, we randomized patients with modifiable risk factors either to the intensified or conventional care alone program. Intensified care was provided by stroke specialists and used feedback and motivational interviewing strategies (≥8 outpatient visits over 2 years) aiming to improve adherence to secondary prevention targets. We measured physical fitness, disability, cognitive function and health-related quality of life by stair-climbing test, modified Rankin Scale, Montreal Cognitive Assessment, and European Quality of Life 5 Dimension 3 Level during the first 3 years of follow-up.

Results:

Of 2072 patients (mean age: 67.4years, 34% female) assessed for the primary outcome, patient-centered outcomes were collected in 1,771 patients (877 intensified versus 894 conventional care group). Physical fitness improved more in the intensified care group (mean between-group difference in power (Watt): 24.5 after 1 year (95% CI, 5.5–43.5); 36.1 after 2 years (95% CI, 13.1–59.7) and 29.6 (95% CI, 2.0–57.3 after 3 years). At 1 year, there was a significant shift in ordinal regression analysis of modified Rankin Scale in favor of the intensified care group (common odds ratio, 1.23 [95% CI, 1.03–1.47]) but not after 2 (odds ratio, 1.17 [95% CI, 0.96–1.41]) or 3 years (odds ratio, 1.16 [95% CI, 0.95–1.43]) of follow-up. However, Montreal Cognitive Assessment and European Quality of Life 5 Dimension scores showed no improvement in the intensified intervention arm after 1, 2, or 3 years of follow-up.

Conclusions:

Patients of the intensified care program group had slightly better results for physical fitness and modified Rankin Scale after 1 year, but none of the other patient-centered outcomes was significantly improved.

Registration:

URL: https://www.clinicaltrials.gov; Unique identifier: NCT01586702.

Although first-ever cerebrovascular events are often associated with mild or moderate clinical deficits,1 independence in daily living, and good health-related quality of life, these patients are at high risk of recurrent cardiovascular events,2 cognitive decline,3 loss of independence in daily life,4 socioeconomic,4 and emotional problems.5 Secondary prevention programs are recommended by the American Heart Association.6 Nonetheless, even in trials investigating the implementation of secondary prevention in routine care, medication adherence7,8 and risk factor control8–10 remain suboptimal.

The Inspire-TMS trial (Intensified Secondary Prevention Intending a Reduction of Recurrent Events in Transient Ischemic Attack and Minor Stroke Patients) was a large multicenter randomized trial analyzing the effects of a support program on secondary stroke prevention and evaluated whether intensified care by stroke physicians and prevention nurses improves the outcome after transient ischemic attack or minor stroke.11 Although most secondary prevention targets were met more frequently in the intensified care group, the trial was neutral on the primary outcome: A composite of major vascular events consisting of stroke, acute coronary syndrome, and vascular death.11

Prespecified secondary outcomes of the INSPiRE-TMS trial were the effects of the intensified care program on achieving prevention targets with regard to risk factor control and medication adherence as well as on physical fitness and modified Rankin Scale (mRS). Effects on quality of life were predefined as tertiary outcome measure.12

Patient-centered outcome measures (PCOM) including health-related quality of life, mood, disability scores, and cognition help to better integrate the patients’ perspective into stroke research.13 Although effects of secondary prevention on PCOM are indirect (ie, better functional outcome or cognition by fewer recurrent events or better fitness through more physical activity), these outcomes focus more on patients’ daily life. In contrast to recurrent vascular events that in most trials occur in a relatively small proportion of patients, PCOM can be measured in every patient, and hence, effects on similar important outcomes may be more likely to be detected.14

Methods

Study Design and Participants

The study design, randomization, masking, procedures, and primary outcome results have been published in detail previously.11,12 In brief, the INSPiRE-TMS trial was a 2 arms randomized trial with PROBE design carried out at 7 German and 1 Danish stroke center between 2011 and 2017 aiming to reduce the recurrent vascular event rate. We included patients with transient ischemic attack or amaurosis fugax only if ABCD2 score (stroke risk prediction score after TIA based on age, blood pressure, clinical features and duration of TIA, and a history of diabetes) was at least 3 to ensure to treat patients with a reasonable risk profile.15 Furthermore, we recruited patients with central artery occlusion, intracerebral hemorrhage, or minor stroke. All patients had an mRS score ≤2 and were randomized within 14 days after the event. Eligibility criteria were age of 18 years or older, the proximity of the patients’ residence to a study, and at least 1 of 4 modifiable risk factors (ie, arterial hypertension, diabetes mellitus, atrial fibrillation, or current smoking).

Exclusion criteria were malignant diseases (life expectancy <3 years), relevant cognitive deficits, which were suspected to seriously impede future interventions, any current substance dependency, and strokes or transient ischemic attacks with atypical causes like dissection or vasculitis. Patients were allocated to intensified secondary prevention (on top of conventional care) or a conventional care group. The trial was approved by the Ethics Committee of the Charité Universitätsmedizin Berlin (EA2/084/11). Additional approval was obtained from local ethics committees of all participating centers. All patients provided written informed consent. Data are presented according to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) reporting guideline16 and are available from the corresponding author upon reasonable request.

Randomization and Masking

Patients were randomized after the assessment of baseline parameters by a secure web-based randomization program in a 1:1 ratio to both groups with block randomization (block size=3) and stratification for study centers. The program was provided by the Charité Coordination Center for Clinical Studies (Berlin, Germany). Members of the clinical events committee, who evaluated potential primary events, were blinded to study arm allocation, but patients, study nurses, and physicians were not.

Procedures

Participants of the intensified care group were checked by trained nurses and specialized stroke physicians at 8 appointments in 2 years. Patients were instructed in classical risk factor control, other pharmaceutical preventions (ie, platelet inhibitors, oral anticoagulants), and lifestyle changes (smoking cessation, physical activity, nutrition) according to current guidelines recommendations.17–19 Results of target values for risk factors are summarized in Table 1. The physician actively asked about problems of adherence, mood disturbances, and barriers for physical activities, supported the participants in finding proper solutions for any of these problems and provided information for complementary offerings such as senior citizens’ sports or smoking cessation programs as well as nutritional counseling. To improve adherence, physicians used feedback and motivational interviewing techniques20 and summarized all recommendations in a written report in a patient-comprehensible language. Whenever possible, a close relative of the patient was involved. Structured questionnaires and the interviewing guidelines for physicians are presented in the Supplemental Material. The general practitioner was called by telephone if appropriate, for example, in complex cases, in terms of critical findings or to achieve consent.

Table 1. Secondary Prevention Targets and Compliance

ComplianceTarget value1 y follow-up2 y follow-up3 y follow-up
Intensified careConventional careIntensified careConventional careIntensified careConventional care
Blood pressure<140/85 mm Hg in nondiabetic411/786 (52.3%)*331/805 (41.1%)*339/609 (55.7%)*257/562 (45.7%)*243/477 (50.9%)*197/448 (44.0%)*
<130/80 mm Hg in diabetic
NonsmokersComplete abstinence744/857 (86.8%)*711/871 (81.6%)*614/706 (87.0%)*547/682 (80.2%)*485/572 (84.8%)454/554 (81.9%)
Diabetic controlHbA1c<58.5 mmol/mol730/774 (94.3%)706/766 (92.2%)565/620 (91.1%)511/555 (92.1%)424/467 (90.8%)402/440 (91.4%)
CholesterolLDL<100 mg/dL557/783 (71.1%)*484/773 (62.6%)*433/625 (69.3%)*360/572 (62.9%)*323/468 (69.0%)*272/449 (60.6%)*
Physical activity>30 min sport at least 3 d/wk271/850 (31.9%)*161/848 (19.0%)*203/699 (29.0%)*135/678 (19.9%)*159/579 (27.5%)*103/550 (18.7%)*
Nutrition>4 portions of fruits or vegetables per day333/853 (39.0%)*139/864 (16.1%)*251/699 (35.9%)*114/682 (16.7%)*191/578 (33.0%)*103/554 (18.6%)*
Atrial fibrillationRegular intake of oral anticoagulation174/195 (89.2%)172/202 (85.1%)156/171 (91.2%)*134/160 (83.8%)*129/145 (89.0%)121/139 (87.1%)

HbA1c indicates sugar-linked hemoglobin A1c; and LDL, low-density lipoprotein.

* Follow-up results with significant between-group differences.

† Corresponds to 2.59 mmol/L.

‡ In patients with at least one specified risk factor (ie, symptomatic, hemodynamically relevant intracranial stenosis or extracranial stenosis >50% according to NASCET (ultrasound criteria based on the The North American Symptomatic Carotid Endarterectomy Trial) or unstable plaque in plaque imaging in the corresponding extracranial artery or known coronary artery disease) an LDL value <70 mg/dL was recommended, which is not considered in the current table, as these risk factors were not assessed systematically over the course of the study.

Annual outcome assessments were carried out by trained study nurses in both groups preferably in onsite appointments or otherwise by telephone or postal mail.

Outcomes

Independence in daily life measured by the mRS was predefined as a secondary efficacy outcome and was evaluated by ordinal distribution analysis of the mRS. Patients or close relatives were asked standardized questions by trained nurses to assess mRS scores.

Physical activity was measured by the stair-climbing power test21: Participants were encouraged to ascend as quickly as possible to the first landing of a stairway. The performance (power) was calculated according to the equation: power=body weight×9.8×height of the staircase/mean time of 2 runs. Patients were allowed to use the banisters, if necessary.

Quality of life was assessed through a self-complete version of the Quality of Life (EuroQoL) 5 Dimension 3 Level (EQ5D-3L) questionnaire in the corresponding language. The EQ5D-3L consists of the 5 dimensions mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 levels ranging from 1 (no problems) to 3 (extreme problems). We used the European Quality of Life Visual Analogue Scale–validated syntax provided by the EuroQol Research Foundation for Germany to convert the 5 dimensions of the EQ5D-3L into a single summary index ranging from 0 (no quality of life) to 1 (best quality of life). Dead patients were rated as 0 in the summary index but excluded from the single dimensions. In this study, the EQ-5D was completed without the descriptive system instruction of the German version and without the visual analogue scale.

The cognitive function was assessed using the Montreal Cognitive Assessment (MOCA) test according to instruction.22.A score<26 points was established as cognitive impairment, a cutoff that had been previously validated.23

Statistical Analysis

All outcomes are analyzed in an intention-to-treat approach after 1, 2, and 3 years of follow-up. We present baseline characteristics for all patients with mRS information after first follow-up and provide numbers of missing data if >5% are missing. Descriptive statistics are presented as mean±SD for continuous variables or numbers of patients with percentages for categorical variables. For dichotomized outcomes, we calculated odds ratios (ORs), for normally distributed data mean differences and 95% CI. Furthermore, an ordinal regression analysis was carried out to test for group differences in mRS. Ordinal regression analysis was not adjusted for baseline parameters because of random allocation of patients. To minimize bias due to different survival rates in cognitive testing, we calculated mean differences between baseline MOCA scores and the respective follow-up score. Statistics of best- and worst-case scenarios and multiple imputation analysis are described in the Supplemental Material. The statistical analysis was performed using SPSS Statistics (IBM, version 25.0), and a P<0.05 was considered as statistically significant. We did not correct for multiple testing.

Role of the Funding Sources

The funding sources (German Federal Ministry of Education and Research, Pfizer, and German Stroke Foundation) were not involved in study design, data acquisition, data analysis, data interpretation, or writing of the article. The corresponding author had full access to all data in the study and he had the final responsibility for the decision to submit for publication.

Results

Participants and Baseline Characteristics

Between August 22, 2011, to October 30, 2017, 2098 patients were enrolled and randomized to the intensified (n=1048) or conventional care group (n=1050). For the primary outcome analysis, we used information from follow-up appointments until December 21, 2018, when the target number of 317 patients with major vascular events on December 21, 2018, had been reached.11 For the current analysis of patient-centered outcomes, we added information from appointments until October 30, 2019, with at least 2 years of follow-up in all patients.

From all 2072 patients included in the analysis of the primary outcome (major cardiovascular events) information on mRS score was available in 1771 patients (85.5%) with 877 (85.1%) in the intensified care group and 894 (85.8%) patients in the conventional care group (Figure).

Figure.

Figure. Trial design. EQ5D-3L indicates European Quality of Life 5 Dimension 3 Level; MOCA, Montreal Cognitive Assessment; mRS, modified Rankin Scale; and PCO, patient-centered outcome.

Baseline characteristics of 1771 patients with mRS information at 1 year were evenly matched between both groups and are presented in the Supplemental Material. Patients of the intensified care group attended on average 6.8 of 7.7 possible outpatient appointments (87.6%).

Outcome Analysis

Physical fitness as measured with the modified stair-climbing test improved in both groups over time but was better in the intensified care group in all follow-ups (Table 2). Furthermore, randomization to the intensified care program was associated with a favorable functional outcome in an ordinal shift analysis of the mRS score after 1 year (OR, 1.23 [95% CI, 1.03–1.47]), but there was no significant difference after 2 (OR, 1.17 [95% CI, 0.96–1.40]) and 3 years of follow-up (OR, 1.16 [95% CI, 0.95–1.43]; Table 2).

Table 2. Patient-Centered Outcome Measures After 1, 2, and 3 Years of Follow-Up in the Intensified Care and Conventional Care Group

Patient-centered outcome measure1-y follow-up2-y follow-up3-y follow-up
Intensified careConventional careMean difference/(common) odds ratio (95% CI)Intensified careConventional careMean difference/(common) odds ratio (95% CI)Intensified careConventional careMean difference/(common) odds ratio (95% CI)
No. of patients with stair climbing test resultsn=587n=579n=431n=413n=327n=293
Result in Watt375±180350±14924.5 (5.5 to 43.5)*391±185355±15436.1 (13.1 to 59.1)*399±192369±15829.6 (2.0 to 57.3)*
No. of patients who completed mRSn=877n=894n=747n=731n=628n=612
Median score of mRS1 (0 to 1)1 (0 to 1)1.23 (1.03 to 1.47)*1 (0 to 1)1 (0 to 1)1.17 (0.96 to 1.41)1 (0 to 1)1 (0 to 1)1.16 (0.95 to 1.43)
mRS score of 0 or 1765(87.2%)746 (83.4%)1.36 (1.04 to 1.77)*612 (81.9%)577 (78.9%)1.21 (0.94 to 1.57)493 (78.5%)462 (75.4%)1.19 (0.91 to 1.55)
No. of patients who completed MOCA testn=752n=772n=586n=561n=462n=425
Score <26 points283 (37.6%)307 (39.8%)1.09 (0.89 to 1.34)238 (40.4%)217 (38.7%)0.93 (0.73 to 1.18)175 (37.9%)133 (31.2%)0.74 (0.56 to 0.98)*
No. of patients who completed EQ5D-3Ln=822n=845n=687n=685n=565n=558
 EQ5D-3L summary index (0 to 1)0.824±0.2300.811±0.2420.013 (−0.009 to 0.036)0.793±0.2730.790±0.2700.003 (−0.026 to 0.032)0.773±0.2920.770±0.3080.003 (−0.032 to 0.038)
Mobility (1, 2, 3)1.29±0.451.29±0.461.30±0.461.31±0.471.31±0.471.28±0.46
Self-care (1, 2, 3)1.06±0.251.07±0.271.06±0.261.07±0.271.07±0.271.08±0.28
Usual activities (1, 2, 3)1.20±0.441.23±0.451.21±0.431.21±0.431.22±0.461.22±0.44
Pain and discomfort (1, 2, 3)1.50±0.581.55±0.601.54±0.621.57±0.591.58±0.621.52±0.57
Anxiety and depression (1, 2, 3)1.28±0.501.26±0.501.25±0.491.24±0.461.25±0.461.20±0.42

EQ5D-3L indicates European Quality of Life 5 Dimension 3 Level; EQ-VAS, European Quality of Life Visual Analogue Scale; MOCA, Montreal Cognitive Assessment; and mRS, modified Rankin Scale.

* Significant between-group differences.

† EQ5D-3L summary index as a global health-related quality of life score was calculated by the results of the 5 dimensions with an EQ-VAS-validated syntax.

Patients showed improvement in cognitive function as assessed by the MOCA test with increasing time interval from index events irrespective of treatment group. The proportion of patients with abnormal MOCA values (<26) did not differ in the first 2 years (1 year: 37.6 versus 39.8%, OR, 1.09 [95% CI, 0.89–1.34]; 2 year: 40.4 versus 39.7%, OR, 0.93 [0.73–1.18] but was higher in the intensified care group at 3 years (37.9 versus 31.2%, OR, 0.74 [0.56–0.98]; Table 2). To account for baseline differences and reduce bias due to different mortality rates we analyzed mean differences between baseline and follow-up scores resulting in no significant between-group mean differences (1 year: 0.38 versus 0.55, P=0.23; 2 year: 0.45 versus 0.58, P=0.47; 3 year: 0.45 versus 0.67, P=0.25).

The intervention did not improve patients’ health-related quality of life, and there was no significant group difference at any dimension at any time of follow-up (Table 2).

Between-group differences regarding physical fitness and functional outcome remained significant in a multiple imputation analysis as presented in the Supplemental Material.

Discussion

The INSPiRE-TMS trial evaluated a structured, multifaceted secondary prevention program that improved quality of secondary prevention in stroke patients that did however not translate into a significant reduction of major vascular events. The effects of the intensified care program on patient-centered outcomes were inconsistent. Although increased physical activity in the intensified care group was associated with better fitness and also functional outcome after 1 year, there were no apparent effects on quality of life or cognition. These improvements in physical fitness and functional outcome were only modest in magnitude. As missing data were a major limitation of the current analysis, we performed a sensitivity analysis including multiple imputation analysis, which confirmed that between-group differences regarding physical fitness and mRS were modest but still significant.

Until now, secondary prevention trials with multifaceted support programs struggled to establish improved risk factor control, lifestyle changes and medication adherence8,9,24–26 and most trials have failed to achieve a reduction of the major vascular events.7,11,24 Furthermore, a Cochrane review from 2018 found no significant differences in risk factor control for educational or behavioral interventions.27 The large-scale Austrian Stroke-Card trial showed a significant reduction of major vascular events, better functional state, and quality of life in a structured secondary prevention program while control of classical risk factors (eg, blood pressure control or physical fitness) was not significantly different between groups after one year of follow-up.28 The secondary stroke prevention “Taking Charge after Stroke” trial reported significant improvement in quality of life as primary outcome.29 Nonetheless, results of PCOM in secondary prevention trials were also, if reported at all, inconsistent regarding assessment and outcome.28–32

The INSPiRE-TMS trial as a large secondary stroke prevention trial succeeded in overcoming some of these difficulties by achieving improved medication adherence and risk factor control in poststroke patients. The failure of the trial to detect a protective effect on recurrent vascular events and patient-centered outcomes may be explained by smaller effects on risk factor control than anticipated. Also, risk factor control was less pronounced compared to our own preparative33 which is partially explained by contamination effects11 and a strong temporal trend of improving adherence to secondary prevention guidelines.11,34 Although there was no significant reduction of major vascular events in the intensified care group, we assumed that patient-centered outcomes may capture positive effects of the secondary stroke prevention program in patients’ daily life as they may be more sensitive than the sole assessment of major vascular events because risk factors like high arterial blood pressure are main drivers of other cardiovascular diseases, for example, cerebral small vessel disease which is in turn associated with disability, cognitive decline, depressive symptoms, and a health-related quality of life.35,36 On the other between-group differences in physical fitness might have been too small and the follow-up period might have been too short to find differences in patients’ quality of life or cognitive functioning. A fading effect of the intervention, which was intense in the first but absent in the third year might have further reduced between-group differences after 3 years. Future trials should evaluate programs with longer periods of the intervention. Conversely, loss of power due to more missing data after 2 and 3 years of follow-up could have prevented the detection of between-group differences.

Primary and secondary outcomes might have been more improved in the INSPiRE-TMS trial if secondary prevention targets had been more ambitious. Data of the SPRINT trial (Systolic Blood Pressure Intervention Trial) suggest that in patients with high cardiovascular risks blood pressure target levels <120 mm Hg can reduce morbidity and all-cause mortality,37 but these data became only available at the end of our study and the trial results. They are also not directly applicable to stroke patients because previous stroke was an exclusion criterion in this trial. In our outcome analysis, we did not differentiate between moderate or vigorous physical activities, and a cut point of 3× of at least 30 to 40 minutes per week is generally a minimum level of physical activity recommended by current guidelines.6 But as one-quarter of the participants were ≥75 years at baseline, target levels had to be achievable for the majority of patients and too aggressive target levels might have negative effects on motivation. Results of the stair-climbing test clearly indicate that there was a significant improvement in physical fitness in the intensive care group. We used intake of fruits and vegetables per day as a validated and established indicator of a more healthy diet,38 but encouraged patients of the intensified care group in every appointment to adopt a healthy diet according to current guideline recommendations.6

Despite regular evaluations of depressive symptoms and respective recommendations, if necessary, intensified care did not translate into more consistent treatment of depressive symptoms. Consequently, we did not find a positive effect of the intervention on the rate of depressive symptoms assessed by EQ5D. However, repetitive remembrance of stroke deficits and risks of recurrence may have had a negative influence on anxiety and mood. Further trials should investigate whether more aggressive treatment of psychiatry comorbidities may enhance quality of life.

Cognitive function was impaired at baseline in either group (mean MOCA score of 25.24 and 25.13) and seemed to improve over time irrespective of treatment allocation. After 3 years of follow-up, there was a significant between-group difference in the percentage of patients with MOCA <26 in favor of the control group (OR, 0.74 [95% CI, 0.56–0.98]; P=0.037). Both results could not be verified in a multiple imputation analysis. We suggest that drop-out of patients may have introduced a bias towards better average cognitive function in patients with complete data. This explanation is supported by the disappearance of a significant difference when the analysis was repeated with mean differences between individual baseline and 3-year follow-up test results (0.46 versus 0.72, P=0.174). However, the continuous improvement of MOCA scores in the complete case analysis may be partially explained by practice effects, which are common in neuropsychological assessment.39

Surprisingly, functional improvement as measured by the mRS did not translate into better health-related quality of life results. The mRS and the EQ5D-3L are both validated in stroke patients40,41 and moderately correlated with each other.42 In the current study, patients were instructed orally without handing out the descriptive system instruction of the German version of the EQ5D for patients, and we did assess EQ5D-3L without the visual analogue scale (European Quality of Life Visual Analogue Scale). Ceiling and floor effects of the EQ5D-3L could have prevented the detection of between-group differences.40

There are some limitations of our study: The mRS scores were assessed by trained nurses who were not blinded to group allocation. However, mRS scores were routinely assessed by a standardized questionnaire. Hence, a relevant reporting bias by unblinded rating appears unlikely. Another limitation is the underrepresentation of women in the INSPiRE-TMS trial, who represent only 33% of the cohort irrespective of the study center. Underrepresentation of women in secondary prevention trials is a well-known phenomenon, which potentially reduces the information value of a study. However, a meta-analysis of randomized cardiovascular prevention trials constitutes mean female inclusion rates of 30%,43 which is in the range of the current study. One possible explanation that has been discussed in literature is that cardiovascular diseases establish later in life in women, but the main reasons for female underrepresentation in clinical trials still remain largely unknown.43 The authors are not aware of any systematic difference in the recruitment process in the current study and assume that a real-world secondary prevention program would result in similar participation results. Hence, we do not surmise that the female inclusion rate of the current study hinders its generalizability. We did not correct for multiple testing and therefore, the difference in functional outcome after one year should be interpreted with caution. Furthermore, PCOM information was assessed during onsite appointments resulting in a considerable number of patients with missing information. Missing data were unlikely to be missing completely at random, hence we performed a sensitivity analysis including multiple imputation analysis. This analysis was not predefined and therefore exploratory. Finally, because of the heterogeneity of different interventional programs, there is a lack of comparability between secondary prevention trials.24

Taken together, the INSPiRE-TMS trial showed that a multifaceted support program leads to better achievement of secondary prevention targets poststroke with enhanced physical activity and subsequently improved physical fitness that is associated with favorable functional outcome after one year. No effects were observed for other PCOMs including cognition, mood, and health-related quality of life.

Article Information

Supplemental Material

Sensitivity Analysis

Tables S1–S6

Study Design

Contributors

Nonstandard Abbreviations and Acronyms

EQ5D-3L

European Quality of Life 5 Dimension 3 Level

INSPiRE-TMS trial

Intensified Secondary Prevention Intending a Reduction of Recurrent Events in TIA and Minor Stroke Patients

MOCA test

Montreal Cognitive Assessment test

mRS

modified Rankin Scale

PCOM

patient-centered outcome measures

Disclosures Dr Endres reports grants from Bayer and fees paid to the Charité from Bayer, Boehringer Ingelheim, Bristol Myers Squibb (BMS), Daiichi Sankyo, Amgen, GSK, Sanofi, Covidien, Novartis, Pfizer, all outside the submitted work. Dr Palm reports financial support from Beyer Healthcare and BMS paid to his institution for serving on a scientific advisory board outside the submitted work. Dr von Weitzel-Mudersbach reports speaker fees and consultancy honoraria during the conduct of the study from Pfizer. Dr Audebert reports speaker fees and consultancy honoraria during the conduct of the study from Bayer Vital, Boehringer Ingelheim Pharma, BMS, Novo Nordisk, and Pfizer. The other authors report no conflicts.

Footnotes

This manuscript was sent to Georgios Tsivgoulis, Guest Editor, for review by expert referees, editorial decision, and final disposition.

Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.120.037503.

For Sources of Funding and Disclosures, see page 2737.

Presented in part at the International Stroke Conference, Los Angeles, CA, February 19–21, 2020.

Correspondence to: Thomas Ihl, MD, Klinik und Hochschulambulanz für Neurologie, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany. Email

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