The Randomized Controlled STRAWINSKI Trial: Procalcitonin-Guided Antibiotic Therapy after Stroke

Clinical Trial published: 24 April 2017 doi: 10.3389/fneur.2017.00153 The randomized Controlled STraWinSKi Trial: ProcalcitoninGuided antibiotic Therapy after Stroke Lena Ulm 1,2,3, Sarah Hoffmann 1,3, Darius Nabavi4, Marcella Hermans 4, Bruno-Marcel Mackert 5, Frank Hamilton5, Ingo Schmehl 6, Gerhard-Jan Jungehuelsing3,7, Joan Montaner 8, Alejandro Bustamante8, Mira Katan9, Andreas Hartmann 10, Stefan Ebmeyer11, Christiane Dinter 11, Jan C. Wiemer11, Sabine Hertel11, Christian Meisel 12, Stefan D. Anker 13,14 and Andreas Meisel 1,3* Edited by: Guillaume Turc, Centre hospitalier Sainte-Anne, France Reviewed by: David J. Seiffge, University of Basel, Switzerland Konstantinos Tziomalos, Aristotle University of Thessaloniki, Greece *Correspondence: Andreas Meisel Specialty section: This article was submitted to Stroke, a section of the journal Frontiers in Neurology Received: 08 March 2017 Accepted: 03 April 2017 Published: 24 April 2017 Citation: Ulm L, Hoffmann S, Nabavi D, Hermans M, Mackert B-M, Hamilton F, Schmehl I, Jungehuelsing G-J, Montaner J, Bustamante A, Katan M, Hartmann A, Ebmeyer S, Dinter C, Wiemer JC, Hertel S, Meisel C, Anker SD and Meisel A (2017) The Randomized Controlled STRAWINSKI Trial: Procalcitonin-Guided Antibiotic Therapy after Stroke. Front. Neurol. 8:153. doi: 10.3389/fneur.2017.00153 Frontiers in Neurology | www.frontiersin.org 1 NeuroCure Clinical Research Center, Charité – Universitaetsmedizin Berlin, Berlin, Germany, 2 Centre for Clinical Research, The University of Queensland, Brisbane, QLD, Australia, 3Department of Neurology and Center for Stroke Research Berlin, Charité – Universitaetsmedizin Berlin, Berlin, Germany, 4 Department of Neurology, Vivantes Klinikum Neukoelln, Berlin, Germany, 5 Department of Neurology, Vivantes Auguste-Viktoria-Klinikum, Berlin, Germany, 6 Department of Neurology, Unfallkrankenhaus Berlin, Berlin, Germany, 7 Department of Neurology, Juedisches Krankenhaus Berlin, Berlin, Germany, 8 Neurovascular Research Laboratory, Institut de Recerca, Hospital Universitari Vall d’Hebrón, Universitat Autònoma de Barcelona, Barcelona, Spain, 9Department of Neurology, Universitaetsspital Zuerich, Zurich, Switzerland, 10 Department of Neurology, Klinikum Frankfurt Oder, Frankfurt Oder, Germany, 11 Thermo Fisher Scientific BRAHMS GmbH, Hennigsdorf, Germany, 12 Department of Immunology, Charité – Universitaetsmedizin Berlin, Berlin, Germany, 13 Division of Innovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Centre Goettingen, Goettingen, Germany, 14 Centre for Clinical and Basic Research, IRCCS, Rome, Italy Background: Pneumonia is among the most common acute complications after stroke and is associated with poor long-term outcome. Biomarkers may help identifying stroke patients at high risk for developing stroke-associated pneumonia (SAP) and to guide early treatment. aims: This trial investigated whether procalcitonin (PCT) ultrasensitive (PCTus)-guided antibiotic treatment of SAP can improve functional outcome after stroke. Methods: In this international, multicenter, randomized, controlled clinical trial with blinded assessment of outcomes, patients with severe ischemic stroke in the middle cerebral artery territory were randomly assigned within 40 h after symptom onset to PCTus-based antibiotic therapy guidance in addition to stroke unit care or standard stroke unit care alone. The primary endpoint was functional outcome at 3 months, defined according to the modified Rankin Scale (mRS) and dichotomized as acceptable (≤4) or unacceptable (≥5). Secondary endpoints included usage of antibiotics, infection rates, days of fever, and mortality. The trial was registered with http://ClinicalTrials.gov (Identifier NCT01264549). results: In the intention-to-treat-analysis based on 227 patients (112 in PCT and 115 in control group), 197 patients completed the 3-month follow-up. Adherence to PCT guidance was 65%. PCT-guided therapy did not improve functional outcome as measured by mRS (odds ratio 0.79; 95% confidence interval 0.45–1.35, p = 0.47). Pneumonia rate and mortality were similar in both groups. Days with fever tended to be lower (p = 0.055), whereas total number of days treated with antibiotics were higher 1 April 2017 | Volume 8 | Article 153 Ulm et al. PCT-Guided Antibiotic Therapy in Stroke (p = 0.004) in PCT compared to control group. A post hoc analysis including all PCT values in the intention-to-treat population demonstrated a significant increase on the first day of infection in patients with pneumonia and sepsis compared to patients with urinary tract infections or without infections (p < 0.0001). Conclusion: PCTus-guided antibiotic therapy did not improve functional outcome at 3 months after severe ischemic stroke. PCT is a promising biomarker for early detection of pneumonia and sepsis in acute stroke patients. Keywords: stroke, pneumonia, antibiotic prophylaxis, procalcitonin, outcome, infections, biomarker-guided treatment INTRODUCTION protocol and changed it to <40 h after symptom onset. Exclusion criteria included CT/MRI evidence of intracerebral hemorrhage or lacunar infarction, use of antibiotics within the last 10 days, suspected life expectancy of <3 months (irrespective of the underlying cause), modified Rankin Scale (mRS) before stroke onset ≥4, participation in other interventional trials (pharmaceuticals or medical devices), and pregnancy/lactation. Infections are among the most common acute complications after stroke and associated with poor outcome (1, 2). Prophylactic antimicrobial treatment effectively reduced infection rates in experimental models of stroke (3) and clinical proof-of-concept studies [for a meta-analysis, see the study by Westendorp et al. (4)]. However, the impact of preventive antibiotic treatment on longterm functional outcome remained unclear, as previous clinical trials were not sufficiently powered to address this issue. Recently, two large randomized controlled phase III clinical trials demonstrated that antibiotics commonly used to treat stroke-associated pneumonia (SAP) neither reduce the frequency of pneumonia nor improve the outcome after stroke when administered in a prophylactic manner (5–7). Current European and US stroke guidelines strictly recommend early antibiotic treatment of poststroke infections but advise against their prophylactic use (8). Biomarkers might help to identify patients in the early subclinical course of SAP or even at high risk for developing SAP, thereby tailoring antibiotic treatment to patients with the highest probability to benefit while reducing the risk of antibiotic resistances (9). Procalcitonin (PCT), an early marker of severe bacterial infections (10), has been useful in diagnosing SAP in previous observational clinical studies (11, 12). In addition, PCT guidance has been shown to reduce the duration of antibiotic treatment in critically ill patients, without compromising patients’ saf (...truncated)