Elsevier

The Lancet

Volume 386, Issue 10006, 7–13 November 2015, Pages 1835-1844
The Lancet

Articles
Prophylactic antibiotics after acute stroke for reducing pneumonia in patients with dysphagia (STROKE-INF): a prospective, cluster-randomised, open-label, masked endpoint, controlled clinical trial

https://doi.org/10.1016/S0140-6736(15)00126-9Get rights and content

Summary

Background

Post-stroke pneumonia is associated with increased mortality and poor functional outcomes. This study assessed the effectiveness of antibiotic prophylaxis for reducing pneumonia in patients with dysphagia after acute stroke.

Methods

We did a prospective, multicentre, cluster-randomised, open-label controlled trial with masked endpoint assessment of patients older than 18 years with dysphagia after new stroke recruited from 48 stroke units in the UK, accredited and included in the UK National Stroke Audit. We excluded patients with contraindications to antibiotics, pre-existing dysphagia, or known infections, or who were not expected to survive beyond 14 days. We randomly assigned the units (1:1) by computer to give either prophylactic antibiotics for 7 days plus standard stroke unit care or standard stroke unit care only to patients clustered in the units within 48 h of stroke onset. We did the randomisation with minimisation to stratify for number of admissions and access to specialist care. Patient and staff who did the assessments and analyses were masked to stroke unit allocation. The primary outcome was post-stroke pneumonia in the first 14 days, assessed with both a criteria-based, hierarchical algorithm and by physician diagnosis in the intention-to-treat population. Safety was also analysed by intention to treat. This trial is closed to new participants and is registered with isrctn.com, number ISRCTN37118456.

Findings

Between April 21, 2008, and May 17, 2014, we randomly assigned 48 stroke units (and 1224 patients clustered within the units) to the two treatment groups: 24 to antibiotics and 24 to standard care alone (control). 11 units and seven patients withdrew after randomisation before 14 days, leaving 1217 patients in 37 units for the intention-to-treat analysis (615 patients in the antibiotics group, 602 in control). Prophylactic antibiotics did not affect the incidence of algorithm-defined post-stroke pneumonia (71 [13%] of 564 patients in antibiotics group vs 52 [10%] of 524 in control group; marginal adjusted odds ratio [OR] 1·21 [95% CI 0·71–2·08], p=0·489, intraclass correlation coefficient [ICC] 0·06 [95% CI 0·02–0·17]. Algorithm-defined post-stroke pneumonia could not be established in 129 (10%) patients because of missing data. Additionally, we noted no differences in physician-diagnosed post-stroke pneumonia between groups (101 [16%] of 615 patients vs 91 [15%] of 602, adjusted OR 1·01 [95% CI 0·61–1·68], p=0·957, ICC 0·08 [95% CI 0·03–0·21]). The most common adverse events were infections unrelated to post-stroke pneumonia (mainly urinary tract infections), which were less frequent in the antibiotics group (22 [4%] of 615 vs 45 [7%] of 602; OR 0·55 [0·32–0·92], p=0·02). Diarrhoea positive for Clostridium difficile occurred in two patients (<1%) in the antibiotics group and four (<1%) in the control group, and meticillin-resistant Staphylococcus aureus colonisation occurred in 11 patients (2%) in the antibiotics group and 14 (2%) in the control group.

Interpretation

Antibiotic prophylaxis cannot be recommended for prevention of post-stroke pneumonia in patients with dysphagia after stroke managed in stroke units.

Funding

UK National Institute for Health Research.

Introduction

Post-stroke pneumonia occurs in 10% of patients after an acute stroke, and is associated with a trebled increase in mortality.1, 2, 3 Dysphagia, which occurs in 50–55% of patients after a stroke, is an important risk factor for post-stroke pneumonia; the prevalence of post-stroke pneumonia in patients with dysphagia is 16–19%, compared with 2–8% prevalence in those without dysphagia.4 Prophylactic antibiotics might decrease the risk of post-stroke penumonia,5 mortality, and disability in such patients but could also increase antibiotic-related infections.6

Pooled data from 506 stroke patients5 showed a 14% reduction in all infections with prophylactic antibiotics but their effectiveness in reducing post-stroke pneumonia, mortality, and disability was equivocal. Findings from the Preventive Antibiotics in Stroke Study (PASS)7 showed a significant reduction in infections with ceftriaxone but no effect on functional outcome scores. These studies were heterogeneous in size; some included patients with mild strokes and low risk of post-stroke pneumonia, some were not controlled for quality of stroke care (which is known to reduce post-stroke pneumonia8), and only PASS has assessed the incidence of Clostridium difficile toxin (CDT)-positive diarrhoea. Existing guidelines do not lend support to the use of prophylactic antibiotics in patients who have had a stroke.9 Therefore, the aim of our study was to assess the effectiveness of prophylactic antibiotics for reducing incidence of post-stroke pneumonia, mortality, and admissions to hospital, and improving functional outcome in patients after acute stroke with dysphagia.

Research in context

Evidence before this study

We searched PubMed, Embase, ClinicalTrials.gov, and ISRCTN.org for trials of any design of prophylactic or preventive antibiotics in patients with acute stroke (any setting). We identified one observational study, and two completed randomised clinical trials and three in progress, which showed that first, post-stroke pneumonia was common and associated with high mortality, and second, effectiveness of prophylactic antibiotics was equivocal. Our updated search of the scientific literature in October, 2014, showed five completed trials pooled in a Cochrane meta-analysis (published in 2012), which showed that preventive antibiotics reduced infections (relative risk [RR] 0·58, 95% CI 0·43–0·79) but had little effect on mortality (0·85, 0·47–1·51) and dependence (0·67, 0·32–1·43). Since the review, the Preventive Antibiotics in Stroke Study (PASS) in 2538 patients showed that intravenous ceftriaxone given for 4 days reduced infections but did not improve functional outcomes at 3 months (published in 2015). In addition to the study reported in this paper, a trial is in progress (STRAWINSKI [NCT01264549]), comparing procalcitonin-guided antibiotic treatment with standard care in 230 patients. This study has completed recruitment but the findings have not yet been reported.

Added value of this study

Published studies include 30–40% of patients with mild strokes and no dysphagia, for whom the risk of aspiration and the benefit of prevention are low. Many studies did not control either for the quality of stroke unit care (known to reduce post-stroke pneumonia) or allow for the variations in local antibiotic policies (which determine choice of agent in clinical settings). Only PASS assessed the incidence of Clostridium difficile diarrhoea, an important issue in antibiotic stewardship. Detection bias in previous studies was minimised by masked adjudication to reduced false-positive diagnoses of post-stroke pneumonia. This method does not adjust for false-negative disease missed on initial assessment. Finally, the confounding effect of higher mortality on length-of-stay comparisons was not adjusted in previous studies. This study included only patients at high risk of aspiration managed on specialist stroke units. It allowed for local antibiotic policies to be followed rather than prescribe a specific antimicrobial. A criteria-driven algorithm for diagnosis of post-stroke pneumonia applied to the whole dataset masked to allocation, thus minimising both false-positive and false-negative diagnoses. Comparisons of admissions to hospital were undertaken with death as a competing risk. The study showed that prophylactic antibiotics do not reduce post-stroke pneumonia, mortality, or dependence but might increase the length of hospital stay and poor outcomes in patients after acute stroke with dysphagia who are managed on specialist stroke units.

Implications of all the available evidence

Evidence is against the routine use of antibiotics for prophylaxis against post-stroke pneumonia and suggests judicious use in stroke patients managed on stroke units, even if at high aspiration risk.

Section snippets

Study design and participants

In this prospective, multicentre, cluster-randomised, open-label controlled trial with masked endpoint assessment (STROKE-INF), we randomly assigned 48 UK stroke units (1:1) to give patients either prophylactic antibiotics for 7 days plus standard stroke unit care or standard stroke unit care only. We invited stroke units to complete the Expression of Interest forms through the National Institute for Health Research (NIHR) Stroke Research Network (SRN) trials office. Patients in selected units

Results

Between April 21, 2008, and May 17, 2014, we randomly assigned 48 stroke units (and 1224 patients clustered within the units) to the two treatment groups: 24 to antibiotics and 24 to standard care alone (control; figure 1). 11 units and seven patients withdrew after randomisation before 14 days (withdrawn patients did not receive any treatment), leaving 1217 patients in 37 units for the intention-to-treat analysis (615 in the antibiotics group and 602 in the control group). No patients were

Discussion

We have shown that antibiotic prophylaxis did not reduce post-stroke pneumonia or mortality in patients after acute stroke with dysphagia managed in stroke units. Additionally, prophylactic antibiotics might increase the length of hospital stay and poor outcomes in these patients.

Post-stroke pneumonia in this study was measured in two different ways: first, by the masked application of predefined criteria applied to the whole patient group giving a frequency of 11% at 14 days, and second, by

References (26)

  • National Sentinel Audit for Stroke

    (2008)
  • S Evans et al.

    Minim: allocation by minimisation in clinical trials

  • Pneumonia: Diagnosis and management of community- and hospital-acquired pneumonia in adults

  • Cited by (196)

    View all citing articles on Scopus

    Listed at end of report

    View full text