Introduction
The
number of stroke survivors with impairments is increasing, rendering
effective rehabilitation interventions a major unmet medical need.1 Aerobic training is a recommended treatment modality in stroke rehabilitation to counter cardiorespiratory deterioration.2–4
However, it remains uncertain whether training in the critical early
period of stroke recovery can be carried out safely. Cardiorespiratory
stress applied during early rehabilitation might cause adverse effects.5
The
evidence of safety of aerobic training early after stroke is scarce.
The latest Cochrane Collaboration meta-analysis aggregated estimates of
adverse effects including cerebro- and cardiovascular events in the
stroke population but could not identify a higher risk in aerobic
training compared to control interventions.6 Of note, the evidence derived mainly from small studies with limited reporting of adverse events.
Surprisingly
and in contrast to smaller stroke rehabilitation trials, the results of
the recent “Physical Fitness Training in Subacute Stroke” (PHYS-STROKE)
trial,7
which randomized subacute stroke patients to early aerobic training or
relaxation, identified a higher risk of serious adverse events (SAE)
within three months post stroke in the training group compared to
control.
Aims
In
accordance with the trial protocol, we now report the final safety data
of the six-month trial follow-up and additionally provide exploratory
analyses aimed to identify patient-related risk factors for SAE
associated with aerobic training. The six months’ follow-up was chosen
to unveil longer term effects of an early aerobic training in the
subacute phase after stroke.
Methods
The trial protocol,8 statistical analysis plan (https://doi.org/10.6084/m9.figshare.5375026.v1),
and the primary efficacy endpoints of the multi-center, randomized,
controlled PHYS-STROKE trial (clinicaltrials.gov identifier:
NCT01953549) were published previously.7
The protocol was approved by the local ethics committee of the Charité
Universitätsmedizin Berlin (EA1/138/13). Patients with either ischemic
or hemorrhagic stroke in the subacute phase (5–45 days post onset) were
included into the trial. The inclusion and exclusion criteria of the
trial are listed in the Supplementary Table 1. All patients gave written
informed consent.
Detailed intervention procedures have been previously described.7
In brief, patients were randomly assigned to receive either bodyweight
supported, treadmill-based, aerobic training or relaxation sessions, in
addition to standard rehabilitation therapy over a period of four weeks
with five sessions per week á 25 min each. The target heart rate (THR)
in the training group was calculated by the formula: 180 – “years of
age”, which was hypothesized to approximate 50–60% of each patient’s
maximum heart rate. The THR was reduced by 10 beats per minute in case
of β-blocker medication.9
Pre-defined
safety endpoints included the following SAE: recurrent non-fatal
cardio- or cerebrovascular event, readmission to an acute care hospital,
or death within six months post stroke. Cerebrovascular event included
any stroke or transient ischemic attack confirmed by cerebral imaging
with or without clinical manifestation that led to new ICD-10 diagnosis.
Readmission to an acute care hospital had to be confirmed by discharge
letter.
All SAE occurring during hospitalization at the
rehabilitation clinic were monitored by a study site physician and had
to be reported within 24 h after onset to the coordinating trial center.
SAE that occurred after discharge from hospital were inquired from the
trial participants or their relatives and confirmed by discharge letters
during clinical follow-up visits at three and six months post stroke.
Access to the population registry of Berlin was requested to retrieve
current health status for patients unavailable at the six-month
follow-up. Medical monitoring appointed by the Center for Stroke
Research Berlin checked data fidelity and reporting of SAE at each study
site. An independent data and safety monitoring board (DSMB) overlooked
all SAE on a regular basis.
As part of the accompanying biomarker
study “Biomarkers And Perfusion – Training-Induced Changes After Stroke
” (BAPTISe), cerebral magnetic resonance imaging (MRI) was acquired for
a subsample of patients (n = 110) before and after the study
intervention.10
New ischemic lesions visible on diffusion-weighted imaging with or
without clinical manifestation were reported to the coordinating trial
center. In an exploratory framework, we analyzed relationships of SAE
occurrence with patient characteristics, pre-existing comorbidities,
medication, and pertinent blood biomarkers (details in supplementary
appendix). All comorbidities needed to have a formal diagnosis issued
with the respective ICD code at baseline.
Descriptive summary
statistics are presented as mean and standard deviation (SD) or median
and interquartile range (IQR) where appropriate. The pre-defined safety
endpoints were analyzed using Poisson regression models with individual
observation time until six months of follow-up as time at risk, which
allows for calculating incidence rates (IR) and incidence rate ratios
(IRR) with 95% confidence intervals (CI).11
We calculated mixed Poisson regression models with number of SAE as a
dependent variable, treatment arm as an independent variable, and a
random effect (random intercept) to account for center heterogeneity.
Additionally, we incorporated individual observation times
(log-transformed time of observation as offset). Sensitivity analysis
was performed without recurrent strokes detected on cerebral MRI within
the BAPTISe study.
For our exploratory risk factor analysis, we
fitted multiple Poisson regression models to assess the association of
preexisting comorbidities, treatment group, and SAE. Models were
controlled for age, sex, and stroke severity to test robustness of
associations. Well-established cardiovascular risk factors, i.e.
arterial hypertension, atrial fibrillation, diabetes mellitus, history
of cerebrovascular event, history of cardiac disease, number of
comorbidities, and related medication (antiplatelets, oral
anticoagulants, β-blocker, and statins) were added to the models.
Additionally, two-way interaction terms with respective risk factors and
treatment group were tested. Decision on the final models was based on
Bayesian information criterion (BIC). This was done to achieve
parsimonious models with high exploratory power, to avoid overfitting
and to avoid inclusion of highly correlated variables. Additionally, to
illustrate the direction of interaction effects, we used estimated
marginal means of subgroups from the final model. Kaplan-Meier curves
were used to verify found associations and to illustrate time to first
SAE in relevant risk factor subgroups. All analyses are exploratory with
regard to the original analysis plan and were not corrected for
multiple testing (see Supplements).
Results
The PHYS-STROKE trial randomized 200 patients (training, n = 105 vs. relaxation, n = 95) of which 190 (95%) were followed-up until six months post stroke (Figure 1).
Four patients of the training group (4%) and six patients of the
relaxation group (6%) were lost to follow-up. Eight patients (training,
n = 5 vs. relaxation, n = 3) had to discontinue the intervention due to
SAE. Protocol adherence and baseline characteristics can be found in
Supplementary Tables 2 and 3. Patients had a mean age of 69 years (SD 12
years) and 41% were females. Incident strokes were predominantly
ischemic (90%) with a median acute National Institute of Health Stroke
Scale (NIHSS) score of 8 (5 to 12). Patients randomly allocated to the
training group were more severely affected than patients in the
relaxation group (acute NIHSS: 9 (5–12) vs. 7 (5–11)).
Over
the course of the trial, 50 SAE occurred in 39 patients. Fifteen
recurrent cerebrovascular events and 30 readmissions to an acute care
unit were observed. Five patients died within the observation period
(training, n = 1 vs. relaxation, n = 4). All fatal events took place
after the intervention phase. No cardiovascular event was recorded.
Median time from start of intervention to SAE occurrence was 41 days
(IQR 14–111). Eighteen SAE (36%) appeared during the intervention phase
(training: eight strokes and six readmissions; relaxation: four
readmissions) but none during an intervention session. Nine patients
(training, n = 6 vs. relaxation, n = 3) had more than one SAE.
Individual SAE are listed in the Supplementary Table 4.
Recurrent
cerebrovascular events were due to ischemic stroke (n = 13, 10 in the
training and 3 in the relaxation group) or transient ischemic attacks
(n = 2, one per group). Five ischemic strokes (training, n = 4 vs.
relaxation, n = 1) were asymptomatic incidental findings on baseline
(n = 2) or post-intervention (n = 3) MRI within the BAPTISe study.
Hospital readmissions primarily occurred because of cardiac
complications (27%) and are listed in the Supplementary Table 5. In the
training group, one patient died due to an urosepsis, and in the
relaxation group, two patients died from a recurrent cerebral
infarction, one from an acute aortic dissection, and one cause remained
unknown. All fatal events were judged unrelated to the intervention by
the DSMB. Three recurrent ischemic events in the training group were
judged as “possibly although unlikely related to the intervention”; all
other SAE were judged “unlikely” to be related to the intervention.
Incidence rates for SAE from Poisson regression analyses are presented in Table 1.
Comparing aerobic training with relaxation, within six months of
follow-up, the risk per 100 patient-months was 2.3 events and 0.9 events
for recurrent cerebrovascular events (IRR: 2.43, 95% CI 0.83 to 8.76,
p = 0.13), 4.3 and 2.1 for readmission to an acute hospital (IRR 2.06,
95% CI 0.97 to 4.73, p = 0.07), and 0.11 and 0.93 for fatal events (IRR
of 0.22; 95% CI 0.01 to 1.50, p = 0.18), respectively. Sensitivity
analysis after exclusion of any incidental MRI findings from the
“BAPTISe” substudy (n = 5) demonstrated similar IRR for cerebrovascular
events (IRR 2.06, 95% CI 0.58 to 9.59).
| Table 1. Serious adverse events until six months post-stroke |
|
Table 1. Serious adverse events until six months post-stroke
Distributions
of patient characteristics with SAE occurrence are displayed in the
Supplementary Table 6. Unadjusted Poisson regression models identified a
higher risk of SAE in patients with vs. patients without arterial
hypertension in the training group compared to the relaxation group.
Similarly, this was observed for patients with diabetes mellitus (DM),
atrial fibrillation (AF), higher hs-CRP, and higher serum cortisol.
We
fitted multiple Poisson regression models with respective preexisting
comorbidities and cardiovascular risk constellations and identified
parsimonious models with best explanatory power (identified by BIC)
analyzing the association of DM and AF with SAE with an interaction
between treatment and DM (IRR for interaction 7.10, 95% CI 1.56 to
51.24; Figure 2(a)) and between treatment and AF (IRR for interaction 4.37, 95% CI 0.94 to 31.81; Figure 2(b)),
respectively, after adjusting for age, sex, and NIHSS. Kaplan-Meier
curves illustrate the course of SAE occurrence for DM and AF in Figure 3.
Details of models and model selection can be found in Supplementary
Table 7. Due to the small number of SAE and due to collinearities, it
was not possible to derive one model including the association of DM and
AF with SAE in parallel.
Discussion
The
results of this analysis from a randomized, controlled stroke
rehabilitation trial extends the current knowledge of safety of an early
bodyweight supported, treadmill-based aerobic training after stroke and
provides evidence of potential harms compared to a relaxation program
in the early subacute phase after moderate to severe stroke. We detected
50 SAE within six months after stroke which corresponds to a higher
incidence rate of SAE than has been reported in previous trials.6
Additionally, exploratory analyses identified potential risk factors
for SAE. When randomized to the aerobic training group, patients with
preexisting diabetes mellitus or atrial fibrillation had a seven-fold or
four-fold higher risk of experiencing SAE, respectively. In contrast,
risks for SAE were similar for patients without DM or without AF in both
intervention groups.
So far, aerobic training was deemed safe in the stroke population.6
In our trial, SAE occurred more frequently in the aerobic training
group with a peak during the intervention phase. Particularly, recurrent
cerebrovascular events happened in temporal relation with the training
intervention, whereas patients in the relaxation group had no similar
event.
Case fatality rates were lower in the training group after six months of follow-up compared to the relaxation group.
A
detailed risk assessment of aerobic training is urgently needed, given
that guidance for carers of stroke patients remains contradictory and
does not systematically account for individual patient characteristics.2–4,12,13
So far, adverse events are rarely reported in stroke rehabilitation
trials investigating aerobic training, and associations of adverse
events with comorbidities are not discussed.6
In fact, only 4 out of 17 trials on aerobic, treadmill-based exercise
in the latest Cochrane review reported preexisting comorbidities of
study participants in their publications, and in only seven
publications, SAE assessment was described.6
None of these reports tested for an association of specific patient
characteristics and SAE occurrence. The PHYS-STROKE trial, however,
reported a possible relation of patient characteristics to SAE
occurrence for the first time and aimed to identify subgroups of
patients with higher risk.
Diabetic patients are at higher risk
for recurrent vascular events and poor outcome after stroke compared to
patients without diabetes.14
We found a higher association of DM with aerobic exercise in our study
population. To the best of our knowledge, no literature exists
investigating the risk of aerobic training in stroke patients with DM.
Presence
of AF was associated with a higher risk of SAE occurrence in patients
undergoing aerobic exercise in the present study. In general, patients
with AF demonstrate a high risk of stroke.15
Literature on tolerability of aerobic training in stroke patients with
AF is scarce. So far, exercise is recommended for all patients with AF,
but large exercise intervention studies with assessment on safety are
still missing.16
In a meta-analysis of exercise rehabilitation trials comprising
patients with AF but without stroke, aerobic exercise was considered
safe.17
The American Association of Cardiovascular and Pulmonary Rehabilitation
recommends to slowly progress in exercise intensity in early cardiac
rehabilitation.18
This may be also applicable in early stroke rehabilitation for patients
with concomitant AF, a hypothesis to be explored systematically in
future trials.
The PHYS-STROKE trial entails the largest number of
subacute stroke patients receiving aerobic training within a randomized
clinical trial so far, but several limitations should be considered
when interpreting our findings: First, the PHYS-STROKE trial was not
powered to detect SAE. However, our trial was the first large study to
conduct aerobic training in moderate to severe subacute stroke patients.
Further research with rigorous reporting on adverse events is
necessary. Second, despite randomization, stroke severity was not
balanced between both treatment arms. Patients in the training group had
more severe strokes as indicated by the NIHSS, which might have put
patients at higher risk for SAE. However, NIHSS score was not
substantially associated with SAE occurrence after adjustment for other
covariates. Third, we used a pragmatic approach in our trial to assess
THR of patients which may have over- or under-estimated the THR that
would have been elicited by gradual exercise testing. Therefore,
associations between intensity of aerobic training and rate of adverse
events should be interpreted with caution. Fourth, the exact mechanisms
underlying SAE occurrence following aerobic training cannot be
determined in our study. Tentatively, SAE occurrence might also be
related to preexisting comorbidities (see Supplementary Tables 3 and 4).
However, comorbidities were similarly high in both intervention groups.
Fifth, information on risk factors associated with cardiovascular
events such as level of previous physical activity or diet were not
assessed in the PHYS-STROKE trial. Although data on pre-stroke behavior
might be vital, assessment of such measures are subject to recall bias.
Lastly, our trial incorporated a rigorous training regimen with training
sessions five times per week over a four-week period. A slower
progression of training intensity might be necessary to reduce potential
risks in a vulnerable patient population.
Aerobic fitness
training early after moderate to severe stroke may cause harm compared
to relaxation, and increased risk of SAE was particularly attributed to
patients with preexisting diabetes mellitus or atrial fibrillation in
the PHYS-STROKE trial. Future trials are needed to confirm or refute
these exploratory findings.
Data Availability Policy
The
raw data and analyses scripts are provided by the authors on a secure
online repository for reproduction of reported findings (https://doi.org/10.5281/zenodo.3899830).
