“The results of PRECIOUS do not support preventive use of antiemetic, antipyretic, or antibiotic drugs in older patients with acute stroke,” senior study author Bart van der Worp, MD, professor of acute neurology at University Medical Center, Utrecht, the Netherlands, concluded.
“This trial was all about prevention,” trial co-investigator, Philip Bath, MD, professor of stroke medicine at the University of Nottingham (England), said in an interview.
“It was trying to improve outcomes by preventing infection, fever, and aspiration pneumonia, but the message from these results is that while we should be on the lookout for these complications and treat them early when they occur, we don’t need to give these medications on a prophylactic basis.”
The PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke (PRECIOUS) trial was presented at the annual European Stroke Organisation Conference, held in Munich.
Dr. Van der Worp explained that infections, fever, and aspiration pneumonia frequently occur following stroke, particularly in older patients, and these poststroke complications are associated with an increased risk of death and poor functional outcome.
“We assessed whether a pharmacological strategy to reduce the risk of infections and fever improves outcomes of elderly patients with moderately severe or severe stroke,” he said.
Previous studies looking at this approach have been performed in broad populations of stroke patients who had a relatively low risk of poststroke complications, thereby reducing the potential for benefit from these interventions.
The current PRECIOUS trial was therefore conducted in a more selective elderly population with more severe strokes, a group believed to be at higher risk of infection and fever.
The trial included patients aged 66 years or older with moderately severe to severe ischemic stroke (National Institutes of Health Stroke Scale score ≥ 6) or intracerebral hemorrhage.
They were randomized in a 3 x 2 factorial design to oral, rectal, or intravenous metoclopramide (10 mg three times a day); intravenous ceftriaxone (2,000 mg once daily); oral, rectal, or intravenous paracetamol (1,000 mg four times daily); or usual care.
Medications were started within 24 hours after symptom onset and continued for 4 days or until complete recovery or discharge from hospital, if earlier.
“We assessed these three simple, safe, and inexpensive therapies – paracetamol to prevent fever; the antiemetic, metoclopramide, to prevent aspiration; and ceftriaxone, which is the preferred antibiotic for post-stroke pneumonia in the Netherlands,” Dr. van der Worp said.
The primary outcome was modified Rankin Scale (mRS) score at 90 days.
The trial was aiming to enroll 3,800 patients from 67 European sites but was stopped after 1,493 patients had been included because of lack of funding. After excluding patients who withdrew consent or were lost to follow-up, 1,471 patients were included in the intention-to-treat analysis.
Results showed no effect on the primary outcome of any of the prophylactic treatments.
“None of the medications had any effect on the functional outcome at 90 days. This was a surprise to me,” Dr. Van der Worp commented. “I had expected that at least one of the medications would have been of benefit.”
A secondary outcome was the diagnosis of pneumonia, which again was not reduced by any of the medications.
“Remarkably, neither ceftriaxone nor metoclopramide had any effect on the risk of developing pneumonia. It was all quite disappointing,” van der Worp said.
There was, however, a reduction in the incidence of urinary tract infections in the ceftriaxone group.
Trying to explain why there was a reduction in urinary tract infections but not pneumonia with the antibiotic, Dr. Van der Worp pointed out that poststroke pneumonia is to a large extent caused by a mechanical process (aspiration), and bacteria may only play a minor role in its development.
He said he was therefore surprised that metoclopramide, which should prevent the mechanical process of aspiration, did not reduce the development of pneumonia.
He suggested that some patients may have already experienced aspiration before the metoclopramide was started, noting that many patients with acute stroke already have signs of pneumonia on CT scan in the first few hours after symptom onset.
A previous smaller study (MAPS) had shown a lower rate of pneumonia in stroke patients given metoclopramide, but in this study the drug was given for 3 weeks.
Discussing the PRECIOUS trial at the ESOC meeting, Christine Roffe, MD, professor of stroke medicine at Keele (England) University, and senior investigator of the MAPS study, suggested that a longer period of metoclopramide treatment may be needed than the 4 days given in the PRECIOUS study, as the risk of pneumonia persists for longer than just a few days.
She noted that another trial (MAPS-2) is now underway in the United Kingdom to try and confirm the first MAPS result with longer duration metoclopramide.
Dr. Van der Worp responded: “Certainly, I think that the MAPS-2 study should be continued. It is investigating a much longer duration of treatment, which may be beneficial, especially in patients with more severe strokes.”
On the reason for the disappointing results with paracetamol, Dr. Van der Worp elaborated: “We found that only a very few of these older patients developed a fever – only about 5% in the control group. Paracetamol did reduce the risk of fever, but because the proportion of patients who developed fever was so small, this may have been why it didn’t translate into any effect on the functional outcome.”
Dr. Roffe concluded that PRECIOUS was an important study. “There is also a positive message here. We have all been worried about using too many antibiotics. We need to make sure we use these drugs responsibly. I think this trial has told us there is little point in using antibiotics in a preventative way in these patients.”
She added that although the trial was stopped prematurely, it had produced decisive results.
“Yes, I believe that even if the trial was much larger, we still would not have shown an effect,” Dr. Van der Worp agreed.
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