Physical Fitness Training in Patients with Subacute Stroke (PHYS-STROKE): multicentre, randomised controlled, endpoint blinded trial

OBJECTIVE: To determine the safety and efficacy of aerobic exercise on activities of daily living in the subacute phase after stroke. DESIGN: Multicentre, randomised controlled, endpoint blinded trial. SETTING: Seven inpatient rehabilitation sites in Germany (2013-17). PARTICIPANTS: 200 adults with subacute stroke (days 5-45 after stroke) with a median National Institutes of Health stroke scale (NIHSS, range 0-42 points, higher values indicating more severe strokes) score of 8 (interquartile range 5-12) were randomly assigned (1:1) to aerobic physical fitness training (n=105) or relaxation sessions (n=95, control group) in addition to standard care. INTERVENTION: Participants received either aerobic, bodyweight supported, treadmill based physical fitness training or relaxation sessions, each for 25 minutes, five times weekly for four weeks, in addition to standard rehabilitation therapy. Investigators and endpoint assessors were masked to treatment assignment. MAIN OUTCOME MEASURES: The primary outcomes were change in maximal walking speed (m/s) in the 10 m walking test and change in Barthel index scores (range 0-100 points, higher scores indicating less disability) three months after stroke compared with baseline. Safety outcomes were recurrent cardiovascular events, including stroke, hospital readmissions, and death within three months after stroke. Efficacy was tested with analysis of covariance for each primary outcome in the full analysis set. Multiple imputation was used to account for missing values. RESULTS: Compared with relaxation, aerobic physical fitness training did not result in a significantly higher mean change in maximal walking speed (adjusted treatment effect 0.1 m/s (95% confidence interval 0.0 to 0.2 m/s), P=0.23) or mean change in Barthel index score (0 (-5 to 5), P=0.99) at three months after stroke. A higher rate of serious adverse events was observed in the aerobic group compared with relaxation group (incidence rate ratio 1.81, 95% confidence interval 0.97 to 3.36). CONCLUSIONS: Among moderately to severely affected adults with subacute stroke, aerobic bodyweight supported, treadmill based physical fitness training was not superior to relaxation sessions for maximal walking speed and Barthel index score but did suggest higher rates of adverse events. These results do not appear to support the use of aerobic bodyweight supported fitness training in people with subacute stroke to improve activities of daily living or maximal walking speed and should be considered in future guidelines. TRIAL REGISTRATION: ClinicalTrials.gov NCT01953549

Current smoking does not modify the treatment effect of intravenous thrombolysis in acute ischemic stroke patients—a post-hoc analysis of the WAKE-UP trial

Background: The “smoking paradox” indicates that patients with acute ischemic stroke (AIS) who smoke at the time of their stroke may have a better prognosis after intravenous thrombolysis than non-smokers. However, findings are inconsistent and data analyzing the effect of smoking on treatment efficacy of intravenous thrombolysis are scarce. Methods: We performed a pre-specified post-hoc subgroup analysis of the Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial that randomized AIS patients with unknown time of symptom onset who had diffusion-weighted imaging-fluid attenuation inversion recovery (DWI-FLAIR) mismatch to either alteplase or placebo. Patients were categorized as current smokers or non-smokers (including former smokers and never-smokers). Baseline demographic and clinical characteristics, as well as clinical and imaging follow-up data were analyzed according to smoking status. Results: Four hundred and eighty six patients were included in the analysis. Current smokers (133, 27.4%) were younger (60.1 ± 13.0 vs. 67.2 ± 10.3 years; p < 0.001) and less often had arterial hypertension (45.0% vs. 56.8%; p = 0.02) or atrial fibrillation (3.8% vs. 15.3%; p < 0.001). The acute stroke presentation was more often due to large vessel occlusion among current smokers (27.1 vs. 16.2%; p = 0.01), and smokers had a trend towards more severe strokes (National Institutes of Health Stroke Scale score>10 in 27.1% vs. 19.5%; p = 0.08). The treatment effect of alteplase, quantified as odds ratio for a favorable outcome (modified Rankin Scale [mRS] score at 90 days of 0 or 1), did not differ between current smokers and non-smokers (p-value for interaction: 0.59). After adjustment for age and stroke severity, neither the proportion of patients with favorable outcome, nor the median mRS score at 90 days differed between current smokers and non-smokers. When additional potential confounders were included in the model, the median mRS score was higher in current smokers than in non-smokers (cOR of better outcome for current smokers vs. non-smokers: 0.664 [0.451–0.978], p = 0.04). Conclusions: In patients with mild to moderate MRI-proven AIS and unknown time of symptom onset with DWI-FLAIR mismatch, current smokers had worse functional outcome as compared to non-smokers. Current smoking did not modify the treatment effect of alteplase. Clinical Trial registration: Main trial (WAKE-UP): ClinicalTrials.gov, NCT01525290; and EudraCT, 2011-005906-32. Registered 02 February 2012

A Mechanistic Link to Peripheral Endothelial Dysfunction

Background: Sleep‐disordered breathing (SDB) after acute ischemic stroke is frequent and may be linked to stroke‐induced autonomic imbalance. In the present study, the interaction between SDB and peripheral endothelial dysfunction (ED) was investigated in patients with acute ischemic stroke and at 1‐year follow‐up. Methods and Results: SDB was assessed by transthoracic impedance records in 101 patients with acute ischemic stroke (mean age, 69 years; 61% men; median National Institutes of Health Stroke Scale, 4) while being on the stroke unit. SDB was defined by apnea‐hypopnea index ≥5 episodes per hour. Peripheral endothelial function was assessed using peripheral arterial tonometry (EndoPAT‐2000). ED was defined by reactive hyperemia index ≤1.8. Forty‐one stroke patients underwent 1‐year follow‐up (390±24 days) after stroke. SDB was observed in 57% patients with acute ischemic stroke. Compared with patients without SDB, ED was more prevalent in patients with SDB (32% versus 64%; P<0.01). After adjustment for multiple confounders, presence of SDB remained independently associated with ED (odds ratio, 3.1; [95% confidence interval, 1.2–7.9]; P<0.05). After 1 year, the prevalence of SDB decreased from 59% to 15% (P<0.001). Interestingly, peripheral endothelial function improved in stroke patients with normalized SDB, compared with patients with persisting SDB (P<0.05). Conclusions: SDB was present in more than half of all patients with acute ischemic stroke and was independently associated with peripheral ED. Normalized ED in patients with normalized breathing pattern 1 year after stroke suggests a mechanistic link between SDB and ED

Untersuchungen zu neuartigen Markern der Risikostratifizierung und aerobem Fitnesstraining nach ischämischem Schlaganfall

Die Erfassung neuer Risikofaktoren und Erforschung neuer Behandlungskonzepte ist ein grundlegender Teil gegenwärtiger Schlaganfallforschung. In dieser Habilitationsschrift werden Forschungsarbeiten vorgestellt, die sich mit neuen diagnostischen Markern sowie aerobem Fitnesstraining als non-pharmakologische Therapie bei akuten und subakuten Schlaganfallpatienten beschäftigten. Das serologisch gemessene Lipoprotein (a) [Lp(a)] wurde als unabhängiger Risikofaktor für den ischämischen Schlaganfall identifiziert. Durch eine durchgeführte systematische Literaturrecherche und Meta-Analyse von prospektiven und retrospektiven Studien konnten wir nachweisen, dass ein erhöhter Lp(a)-Serumspiegel das relative Risiko für einen Schlaganfall um 30-40% erhöht. Im Rahmen einer prospektiven Beobachtungsstudie mit Patienten mit erstmaligem ischämischen Schlaganfall konnten wir ferner feststellen, dass ein Lp(a)-Spiegel >30 mg/dl das Risiko für ein erneutes vaskuläres Ereignis nach einem Jahr signifikant erhöhen kann. Es ist somit anzunehmen, dass das Lp(a) zumindest für spezielle Patientenpopulationen ein relevanter Faktor für das vaskuläre Residualrisiko nach Schlaganfall darstellt. Bildgebend konnte in der Akutphase bei Schlaganfallpatienten mit einem proximalen Gefäßverschluss mittels MRT nachgewiesen werden, dass das Ausmaß von hyperintensen Gefäßzeichen in der FLAIR-MRT mit einem verbesserten Funktionsniveau nach drei Monaten assoziiert ist. Ferner wurde in dieser Patientenpopulation ein klarer Zusammenhang zwischen hyperintensen Gefäßzeichen in der FLAIR-MRT und dem Grad der zerebralen Kollateralisierung gefunden und damit ein MRT-basierter, kontrastmittelfreier Surrogatparameter für die zerebrale Kollateralisierung bei akuten Schlaganfallpatienten bestimmt. Die Verwendung der post-KM-MRA Sequenz als neue Methode zur MRT-basierten Darstellung der Thrombuslänge bei Patienten mit akutem ischämischen Schlaganfall wurde in einer weiteren MRT-Studie vorgestellt. Damit konnte ein weiterer bildgebender Biomarker zur frühen Abschätzung des späteren Funktionsniveaus bei Patienten mit akutem ischämischen Schlaganfall erfasst werden. Im Vergleich zur Akutbehandlung des Schlaganfalls, ist die Qualität der wissenschaftlichen Evidenz für Therapien in der Subakutphase des Schlaganfalls als niedrig einzuschätzen. In einer multizentrischen, randomisierten, kontrollierten Studie haben wir ein aerobes, Laufband-basiertes Fitnesstraining mit einer Kontrollintervention bestehend aus Entspannungsübungen direkt miteinander verglichen, um die Wirksamkeit und Sicherheit eines Laufbandtrainings für Patienten im subakuten Stadium nach Schlaganfall zu untersuchen. Die Ergebnisse unserer Studie zeigten hierbei, dass ein aerobes, Laufband-basiertes Fitnesstraining den Entspannungsübungen mit Bezug auf Ganggeschwindigkeit und Alltagskompetenz nach drei Monaten nicht überlegen war, jedoch mit einem erhöhten Risiko für schwerwiegende, unerwünschte Ereignisse assoziiert war. Durch die vorgestellten Arbeiten konnten wir bei akuten Schlaganfallpatienten mit dem Lp(a) einen laborchemischen Biomarker und mit dem FLAIR-MRT-basierten hyperintensem Gefäßzeichen sowie der mittels post-KM MRA gemessenen Thrombuslänge zwei bildgebende Biomarker identifizieren, die eine verbesserte Risikostratifizierung und Abschätzung des Langzeitverlaufs von Schlaganfallpatienten zulassen. Die Ergebnisse der randomisierten, kontrollierten PHYS-STROKE Studie erlaubten uns einen wichtigen, leitlinienrelevanten Beitrag zum Einsatz eines frühen Fitnesstrainings in der Neurorehabilitation zu liefern. Die gewonnenen Erkenntnisse aus den vorgestellten Arbeiten offenbaren im Hinblick auf Risikoabschätzung und Therapie eine hohe klinische Relevanz und dienen ferner als Grundlage für zukünftige wissenschaftliche Untersuchungen der klinischen Schlaganfallforschung

Is lipoprotein(a) a risk factor for ischemic stroke and venous thromboembolism?

The structural similarity with plasminogen as well as thrombogenic and atherogenic in vitro functions raise the question if lipoprotein(a) (Lp(a)) is a risk factor for venous thromboembolism (VTE) and ischemic stroke. Numerous case-control and prospective studies using different cut-off values to define high Lp(a) generated conflicting evidence for both VTE and ischemic stroke. Several meta-analyses demonstrated independent associations of elevated Lp(a) with a history of VTE or ischemic stroke. However, the evidence of prospective studies for associations of Lp(a) with incident stroke or recurrent VTE remains inconclusive. For ischemic stroke, data suggest that Lp(a) increases the risk of large-artery atherosclerosis stroke, but not cardioembolic or lacunar stroke. Lp(a) may increase the risk of VTE in the presence of additional thrombophilic risk factors. Larger cohort studies are needed to elaborate the importance of higher Lp(a) cut-offs and interactions with other risk factors and subgroups of stroke or VTE. The value of Lp(a) to estimate residual vascular risk after the first thromboembolic event remains to be adequately explored

Elevated Serum Inflammatory Markers in Subacute Stroke Are Associated With Clinical Outcome but Not Modified by Aerobic Fitness Training: Results of the Randomized Controlled PHYS-STROKE Trial

Background: Inflammatory markers, such as C-reactive Protein (CRP), Interleukin-6 (IL-6), tumor necrosis factor (TNF)-alpha and fibrinogen, are upregulated following acute stroke. Studies have shown associations of these biomarkers with increased mortality, recurrent vascular risk, and poor functional outcome. It is suggested that physical fitness training may play a role in decreasing long-term inflammatory activity and supports tissue recovery. Aim: We investigated the dynamics of selected inflammatory markers in the subacute phase following stroke and determined if fluctuations are associated with functional recovery up to 6 months. Further, we examined whether exposure to aerobic physical fitness training in the subacute phase influenced serum inflammatory markers over time. Methods: This is an exploratory analysis of patients enrolled in the multicenter randomized-controlled PHYS-STROKE trial. Patients within 45 days of stroke onset were randomized to receive either four weeks of aerobic physical fitness training or relaxation sessions. Generalized estimating equation models were used to investigate the dynamics of inflammatory markers and the associations of exposure to fitness training with serum inflammatory markers over time. Multiple logistic regression models were used to explore associations between inflammatory marker levels at baseline and three months after stroke and outcome at 3- or 6-months. Results: Irrespective of the intervention group, high sensitive CRP (hs-CRP), IL-6, and fibrinogen (but not TNF-alpha) were significantly lower at follow-up visits when compared to baseline (p all ≤ 0.01). In our cohort, exposure to aerobic physical fitness training did not influence levels of inflammatory markers over time. In multivariate logistic regression analyses, increased baseline IL-6 and fibrinogen levels were inversely associated with worse outcome at 3 and 6 months. Increased levels of hs-CRP at 3 months after stroke were associated with impaired outcome at 6 months. We found no independent associations of TNF-alpha levels with investigated outcome parameters. Conclusion: Serum markers of inflammation were elevated after stroke and decreased within 6 months. In our cohort, exposure to aerobic physical fitness training did not modify the dynamics of inflammatory markers over time. Elevated IL-6 and fibrinogen levels in early subacute stroke were associated with worse outcome up to 6-months after stroke. Clinical Trial Registration: ClinicalTrials.gov, NCT01953549

Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer

International audienc