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Abstract

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Lancet Neurol. 2009 May;8(5):434-40. doi: 10.1016/S1474-4422(09)70051-1. Epub 2009 Mar 16.

The Paracetamol (Acetaminophen) In Stroke (PAIS) trial: a


multicentre, randomised, placebo-controlled, phase III trial.
den Hertog HM1, van der Worp HB, van Gemert HM, Algra A, Kappelle LJ, van Gijn J, Koudstaal
PJ, Dippel DW; PAIS Investigators.

Collaborators (50)
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Abstract
BACKGROUND:
High body temperature in the first 12-24 h after stroke onset is associated with poor
functional outcome. The Paracetamol (Acetaminophen) In Stroke (PAIS) trial aimed to
assess whether early treatment with paracetamol improves functional outcome in patients
with acute stroke by reducing body temperature and preventing fever.
METHODS:
In a multicentre, randomised, double-blind, placebo-controlled trial, patients with ischaemic
stroke or intracerebral haemorrhage and body temperature between 36 degrees C and 39
degrees C were randomly assigned treatment with paracetamol (6 g daily) or placebo within
12 h from symptom onset. Treatment allocation was based on a computer-generated list of
random numbers with varying block size. The primary outcome was improvement beyond
expectation on the modified Rankin scale at 3 months, according to the sliding dichotomy
approach. This trial is registered, number ISRCTN74418480.
FINDINGS:
Between March, 2003, and May, 2008, 1400 patients were randomly allocated treatment.
260 (37%) of 697 patients receiving paracetamol and 232 (33%) of 703 receiving placebo
improved beyond expectation (adjusted odds ratio [OR] 1.20, 95% CI 0.96-1.50). In a posthoc analysis of patients with baseline body temperature 37-39 degrees C, treatment with
paracetamol was associated with improved outcome (1.43, 1.02-1.97). There were 55
serious adverse events in the paracetamol group (8%) and 70 in the placebo group (10%).
INTERPRETATION:
These results do not support routine use of high-dose paracetamol in patients with acute
stroke. Paracetamol might have a beneficial effect on functional outcome in patients
admitted with a body temperature 37-39 degrees C, but this post-hoc finding needs further
study.
FUNDING:

Netherlands Heart Foundation.

Comment in

Paracetamol for stroke: easy in practice, but not in trials. [Lancet Neurol. 2009]
PMID:
19297248
[PubMed - indexed for MEDLINE]

Abstract
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Int J Stroke. 2015 Apr;10(3):457-62. doi: 10.1111/ijs.12053. Epub 2013 May 22.

Paracetamol (Acetaminophen) in stroke 2 (PAIS 2): Protocol for a


randomized, placebo-controlled, double-blind clinical trial to assess
the effect of high-dose paracetamol on functional outcome in patients
with acute stroke and a body temperature of 365C or above.
de Ridder IR1, de Jong FJ, den Hertog HM, Lingsma HF, van Gemert HM, Schreuder AH, Ruitenberg
A, Maasland EL, Saxena R, Oomes P, van Tuijl J,Koudstaal PJ, Kappelle LJ, Algra A, van der Worp
HB, Dippel DW.

Author information
Abstract
RATIONALE:
In the first hours after stroke onset, subfebrile temperatures and fever have been associated
with poor functional outcome. In the first Paracetamol (Acetaminophen) in Stroke trial, a
randomized clinical trial of 1400 patients with acute stroke, patients who were treated with
high-dose paracetamol showed more improvement on the modified Rankin Scale at threemonths than patients treated with placebo, but this difference was not statistically
significant. In the 661 patients with a baseline body temperature of 370C or above,
treatment with paracetamol increased the odds of functional improvement (odds ratio 143;
95% confidence interval: 102-197). This relation was also found in the patients with a body
temperature of 365C or higher (odds ratio 131; 95% confidence interval 101-168). These
findings need confirmation.
AIM:
The study aims to assess the effect of high-dose paracetamol in patients with acute stroke
and a body temperature of 365C or above on functional outcome.

DESIGN:
The Paracetamol (Acetaminophen) In Stroke 2 trial is a multicenter, randomized, doubleblind, placebo-controlled clinical trial. We use a power of 85% to detect a significant
difference in the scores on the modified Rankin Scale of the paracetamol group compared
with the placebo group at a level of significance of 005 and assume a treatment effect of
7%. Fifteen-hundred patients with acute ischemic stroke or intracerebral hemorrhage and a
body temperature of 365C or above will be included within 12 h of symptom onset.
Patients will be treated with paracetamol in a daily dose of six-grams or matching placebo
for three consecutive days. The Paracetamol (Acetaminophen) In Stroke 2 trial has been
registered as NTR2365 in The Netherlands Trial Register.
STUDY OUTCOMES:
The primary outcome will be improvement on the modified Rankin Scale at three-months as
analyzed by ordinal logistic regression.
DISCUSSION:
If high-dose paracetamol will be proven effective, a simple, safe, and extremely cheap
therapy will be available for many patients with acute stroke worldwide.
2013 The Authors. International Journal of Stroke 2013 World Stroke Organization.
KEYWORDS:
body temperature; functional outcome; inflammation; paracetamol; stroke