Elsevier

The Lancet

Volume 385, Issue 9977, 18–24 April 2015, Pages 1519-1526
The Lancet

Articles
The Preventive Antibiotics in Stroke Study (PASS): a pragmatic randomised open-label masked endpoint clinical trial

https://doi.org/10.1016/S0140-6736(14)62456-9Get rights and content

Summary

Background

In adults with acute stroke, infections occur commonly and are associated with an unfavourable functional outcome. In the Preventive Antibiotics in Stroke Study (PASS) we aimed to establish whether or not preventive antimicrobial therapy with a third-generation cephalosporin, ceftriaxone, improves functional outcome in patients with acute stroke.

Methods

In this multicentre, randomised, open-label trial with masked endpoint assessment, patients with acute stroke were randomly assigned to intravenous ceftriaxone at a dose of 2 g, given every 24 h intravenously for 4 days, in addition to stroke unit care, or standard stroke unit care without preventive antimicrobial therapy; assignments were made within 24 h after symptom onset. The primary endpoint was functional outcome at 3 months, defined according to the modified Rankin Scale and analysed by intention to treat. The primary analysis was by ordinal regression of the primary outcome. Secondary outcomes included death, infection rates, antimicrobial use, and length of hospital stay. Participants and caregivers were aware of treatment allocation but assessors of outcome were masked to group assignment. This trial is registered with controlled-trials.com, number ISRCTN66140176.

Findings

Between July 6, 2010, and March 23, 2014, a total of 2550 patients from 30 sites in the Netherlands, including academic and non-academic medical centres, were randomly assigned to the two treatment groups: 1275 patients to ceftriaxone and 1275 patients to standard treatment (control group). 12 patients (seven in the ceftriaxone group and five in the control group) withdrew consent immediately after randomisation, leaving 2538 patients available for the intention-to-treat-analysis (1268 in the ceftriaxone group and 1270 in the control group). 2514 (99%) of 2538 patients (1257 in each group) completed 3-month follow-up. Preventive ceftriaxone did not affect the distribution of functional outcome scores on the modified Rankin Scale at 3 months (adjusted common odds ratio 0·95 [95% CI 0·82–1·09], p=0·46). Preventive ceftriaxone did not result in an increased occurrence of adverse events. Overgrowth infection with Clostridium difficile occurred in two patients (<1%) in the ceftriaxone group and none in the control group.

Interpretation

Preventive ceftriaxone does not improve functional outcome at 3 months in adults with acute stroke. The results of our trial do not support the use of preventive antibiotics in adults with acute stroke.

Funding

Netherlands Organization for Health Research and Development, Netherlands Heart Foundation, and the European Research Council.

Introduction

Infection is a common complication in the acute phase after stroke.1 In a meta-analysis of 87 studies, the pooled infection rate after stroke was 30%,2 most commonly pneumonia and urinary tract infections. About half of pneumonia cases occur within the first 48 h after stroke onset.3 Many studies have shown that the occurrence of infections after stroke is associated with poor functional outcome and mortality,3, 4 although other investigators have reported that infection after stroke is merely a marker of stroke severity without an independent outcome effect when it is treated promptly.5

Five randomised studies have assessed the preventive use of antimicrobials in patients with acute stroke, with conflicting results.6, 7, 8, 9, 10 A Cochrane meta-analysis including 506 patients concluded that although studies differed in populations analysed, type of antimicrobial used, and definition of infection, overall antimicrobial prophylaxis reduced the infection rate from 36% to 22% (relative risk 0·58 [95% CI 0·43–0·79]) without major adverse effects.11 However, whether or not preventive antimicrobials reduce the risk of poor functional outcome after stroke remains uncertain.11 Existing guidelines for management of acute stroke state that preventive use of antibiotics is not indicated because it has not been proven effective.12 We undertook this study to establish whether or not preventive antimicrobial therapy with a third-generation cephalosporin, ceftriaxone, improves functional outcome in patients with acute stroke.

Section snippets

Study design and participants

In this multicentre, prospective, randomised, open-label, masked endpoint trial—the Preventive Antibiotics in Stroke Study (PASS)—we randomly assigned patients from 30 sites, including academic and non-academic medical centres, in the Netherlands in a 1:1 ratio to treatment with ceftriaxone in addition to stroke unit care, or to standard stroke unit care without preventive antimicrobial therapy.

Patients were enrolled by their treating physicians. Patients were eligible for inclusion if they

Results

Between July 6, 2010, and March 23, 2014, 2550 adult patients from 30 Dutch sites were enrolled and randomly assigned in a 1:1 ratio to the two study groups: 1275 patients to receive ceftriaxone and 1275 patients to receive standard stroke unit treatment without ceftriaxone (the control group) (figure 1). 12 patients (seven in the ceftriaxone group and five in the control group) withdrew consent immediately after randomisation, leaving 2538 patients available for the intention-to-treat-analysis

Discussion

Our study did not show improved functional outcome by preventive antimicrobial therapy in patients with acute stroke, nor did it shorten length of hospital stay or reduce in-hospital or follow-up mortality. One possible reason for these findings could be the high-quality care provided at the stroke units participating in the trial. Prophylaxis with ceftriaxone prevented infections and had a favourable safety profile, but was not associated with a shift in the distribution of scores on the mRS.

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