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Randomized Controlled Trial
. 2022 Jan;17(1):93-100.
doi: 10.1177/17474930211006286. Epub 2021 Apr 7.

Physical Fitness Training in Patients with Subacute Stroke (PHYS-STROKE): Safety analyses of a randomized clinical trial

Torsten Rackoll  1   2   3 , Alexander H Nave  1   4   5   6 , Martin Ebinger  1   7 , Matthias Endres  1   4   5   6   8 , Ulrike Grittner  6   9 , Agnes Flöel  1   10 ; ; for the PHYS-Stroke study group
Affiliations
Randomized Controlled Trial

Physical Fitness Training in Patients with Subacute Stroke (PHYS-STROKE): Safety analyses of a randomized clinical trial

Torsten Rackoll et al. Int J Stroke. 2022 Jan.

Abstract

Background and aim: To report the six-month safety analyses among patients enrolled in the "Physical Fitness Training in Subacute Stroke-PHYS-STROKE" trial and identify underlying risk factors associated with serious adverse events.

Methods: We performed a pre-specified safety analysis of a multicenter, randomized controlled, endpoint-blinded trial comprising 200 patients with moderate to severe subacute stroke (days 5-45 after stroke) that were randomly assigned (1:1) to receive either aerobic, bodyweight supported, treadmill-based training (n = 105), or relaxation sessions (n = 95, control group). Each intervention session lasted for 25 min, five times weekly for four weeks, in addition to standard rehabilitation therapy. Serious adverse events defined as cerebro- and cardiovascular events, readmission to hospital, and death were assessed during six months of follow-up. Incident rate ratios (IRR) were calculated, and Poisson regression analyses were conducted to identify risk factors for serious adverse events and to test the association with aerobic training.

Results: Six months after stroke, 50 serious adverse events occurred in the trial with a higher incidence rate (per 100 patient-months) in the training group compared to the relaxation group (6.31 vs. 3.22; IRR 1.70, 95% CI 0.96 to 3.12). The association of aerobic training with serious adverse events incidence rates were modified by diabetes mellitus (IRR for interaction: 7.10, 95% CI 1.56 to 51.24) and by atrial fibrillation (IRR for interaction: 4.37, 95% CI 0.97 to 31.81).

Conclusions: Safety analysis of the PHYS-STROKE trial found a higher rate of serious adverse events in patients randomized to aerobic training compared to control within six months after stroke. Exploratory analyses found an association between serious adverse events occurrence in the aerobic training group with pre-existing diabetes mellitus and atrial fibrillation which should be further investigated in future trials.

Data access statement: The raw data and analyses scripts are provided by the authors on a secure online repository for reproduction of reported findings.

Keywords: Aerobic treadmill training; safety; serious adverse events; stroke rehabilitation; subacute stroke.

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Conflict of interest statement

Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: All authors declare no financial relationships with any organization that might have an interest in the submitted work. TR reports no disclosure. 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. ME reports no disclosure. MEn reports grant support from Bayer, the German Research Foundation under Germany’s Excellence Strategy—EXC-2049—390688087, 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, Novartis, all outside the submitted work. UG reports financial support of Centogene AG, outside of the submitted work. AF reports grant support from the German Research Foundation, German Federal Ministry of Education and Research, the German Center for Neurodegenerative Diseases, European Union, Else Kröner Fresenius Stiftung, 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.

Figures

Figure 1.
Figure 1.
Flow chart of patient enrollment and follow-up of the PHYS-STROKE trial.
Figure 2.
Figure 2.
Model-based estimates of events in subgroups of SAE for status of DM (a) and AF (b) in both treatment groups per 100 patient-months. Estimated marginal means are calculated from Poisson regression with Treatment, respective comorbidity, β-blocker medication and an interaction term for treatment with respective comorbidity and are adjusted for age, sex and NIHSS. Results are shown with 95% CI.
Figure 3.
Figure 3.
Kaplan–Meier curve of cumulated SAE occurrence stratified by DM (a) and AF (b) status over time. Interactions are shown as treatment with or without comorbidity.
See this image and copyright information in PMC

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