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International Stroke Conference: Nitroglycerin Patches Applied En Route to the Hospital Fail to Improve Stroke Outcomes



Article In Brief

Figure

Shown is the distribution of mRS scores at day 90 for the group getting nitroglycerin patches (GTN) versus placebo.

Treatment with the nitroglycerin patches had no effect on treating patients with ischemic strokes in the ambulance en route to the hospital. But the study authors and independent experts agreed that the trial showed the viability of research protocols using paramedics.

HONOLULU—Suspected stroke patients who are treated with nitroglycerin patches on the way to the hospital do not appear to benefit from the early treatment, researchers reported here at the 2019 International Stroke Conference.

While the outcomes did not support earlier studies suggesting that nitroglycerin patches administered within the first six hours of stroke onset reduced death or disability in ischemic stroke and intracerebral hemorrhage, the findings did support the viability of using pre-hospital, paramedic-based studies for interventions, the researchers said in their presentation at the conference and in the paper, which was simultaneously published online on February 6 in The Lancet.

The risk of having a poor outcome, as assessed by the seven-level modified Rankin Scale score at 90 days after randomization, was an odds ratio of 1.25 (p=0.083)—or almost a negative result, said Philip Bath, MBBS, DSc, the Stroke Association Professor of Stroke Medicine at the University of Nottingham, United Kingdom.

In the intention-to-treat population of the so-called RIGHT-2 (Rapid Intervention With Glyceryl Trinitrate in Hypertensive Stroke Trial-2), which included patients with stroke mimics, the risk of a poor outcome was an odds ratio of 1.04 (p=0.69), Dr. Bath reported at the conference.

“This was a neutral trial,” Dr. Bath told Neurology Today. “What we learned from this trial is that glyceryl trinitrate (nitroglycerin in the United States) should not be applied to patients with suspected stroke as they are being transported to the hospital by paramedics except in the setting of a clinical trial.”

Dr. Bath said that it appears that treatment with the nitroglycerin patches had no effect on treating patients with ischemic strokes; it had a worsening effect on people who were having a hemorrhagic stroke. The poorer outcomes seen with hemorrhagic stroke is what drove the overall results toward a borderline negative trial, he said.

Study Design

In the randomized, sham-controlled phase 3 trial, researchers enrolled adult patients who were seen by paramedics after an emergency telephone call for presumed stroke. The patients were eligible for the trial if they presented within four hours of onset of their symptoms to a trial-trained paramedic from a participating ambulance service and could be taken to a participating hospital. The paramedics had to assess the patients as having a face-arm-speech-time (FAST) score of 2 or 3, and systolic blood pressure 120 mmHg or higher to meet eligibility criteria.

The patients had to have at least two abnormalities suggestive of stroke and be conscious to enter the trial. More than 50 percent of the patients consented to be included in the study themselves. Paramedics managed the primary consent process, and patients with capacity gave written informed consent that covered the whole trial. If capacity was absent, proxy consent was obtained from an accompanying relative, caregiver, or friend, if present, or from the paramedic if no accompanying person was present. Confirmatory consent was obtained from the patient, or their relative, caregiver, or friend in the hospital when the patient lacked capacity in the ambulance, Dr. Bath said.

Participants were randomly assigned to receive transdermal glyceryl trinitrate at a dose of 5 mg once daily for four days or a similar sham dressing. The paramedics in the UK trial were responsible for placing the patch on the subjects en route to the hospital. The paramedics were unaware if they were administering the active drug or the placebo, but the participants were told which agent they were receiving. The first treatment was administered by the paramedic immediately after randomization in the ambulance, and further treatments were given to the patient for up to three days while in the hospital. Patches or dressings were placed on the shoulder or back and the site was changed daily.

Between Oct 22, 2015, and May 23, 2018, the 516 paramedics from eight UK ambulance services recruited 1,149 participants. The median time to randomization was 71 minutes. In the final analysis, the study enrolled 597 patients—52 percent of the total—who were diagnosed with ischemic stroke; 13 percent of the patients were diagnosed with intracerebral hemorrhage, 9 percent experienced a transient ischemic attack (TIA), and 26 percent had stroke mimics.

Overall, using the glyceryl trinitrate patches lowered systolic blood pressure 5.8 mmHg compared with the sham group (p<0.0001); diastolic blood pressure declined 2.6 mmHg compared with the sham group (p=0.0026) at hospital admission.

Figure

“What we learned from this trial is that glyceryl trinitrate (nitroglycerin in the United States) should not be applied to patients with suspected stroke as they are being transported to the hospital by paramedics except in the setting of a clinical trial.”—DR. PHILLIP BATH

The researchers planned to enroll 850 patients in the trial, expecting that 12 percent would have so-called stroke mimics – seizures, migraines or functional strokes, Dr. Bath said. But the trial actually enrolled 26 percent of the patients with these mimic events which required enrolling a total of 1,149 individuals. Of the 419 patients with investigator-confirmed stroke or transient ischemic attack (TIA) and who were give the active patch, 71 experienced an intracerebral hemorrhage; 292 were diagnosed with an ischemic stroke, and 56 were diagnosed with a TIA.

One of the other findings in the study, Dr. Bath said, was that when patients with stroke mimics were treated with nitroglycerin they improved across the board (p=0.008)—whether the cause of the mimic was a seizure, a migraine headache, or a functional stroke, often caused by sudden and often distressing life events.

“I am not sure I believe this is a real finding,” he said, “because there is no unifying mechanism of action.”

Expert Commentary

Larry B. Goldstein, MD, FAAN, chairman of neurology and co-director of the Kentucky Neuroscience Institute at the University of Kentucky, who was not involved with the trial, had a similar reaction to the unexpected finding in the stroke mimics. “I am confounded by this as well,” he told Neurology Today.

“There is no indication for using this drug in patients in the early stages of stroke, and there is some concern that it could do harm in some patients,” Dr. Goldstein said.

Still, he acknowledged that the fact that the researchers did show that this type of study could be performed in the ambulance setting “is not a trivial finding. This was a well done and well analyzed trial.”

In an editorial in The Lancet, Karen C. Johnston, MD, MSc, Harrison Distinguished Professor and chair of neurology at the University of Virginia in Charlottesville, and Valerie Durkalski-Mauldin, PhD, professor of public health sciences at the Medical University of South Carolina in Charleston, suggested that design flaws may have prevented the trial from being successful, but probably would not have altered the outcome.

“Regardless of these limitations, RIGHT-2 has provided high-level evidence that glyceryl trinitrate given within 4 hours of onset does not significantly improve outcome in hyperacute patients presenting with possible stroke,” they wrote.

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“There is no indication for using this drug in patients in the early stages of stroke, and there is some concern that it could do harm in some patients.”—DR. LARRY B. GOLDSTEIN

But they said there is a silver lining in the failed trial. “The trial has added to the existing data that show that future hyperacute treatment trials can successfully offer study treatment in the pre-hospital setting. Although the intervention did not improve clinical outcome, pre-hospital treatment with glyceryl trinitrate used 184 ambulance stations in eight ambulances services in England and Wales as the trial sites, and 516 paramedics as the front-line recruiting investigators.”

“This trial is the first in the United Kingdom to our knowledge to show the ability of the emergency medical service teams to successfully enroll in a hyperacute stroke clinical trial in the field. The FAST-MAG [Field Administration of Stroke Therapy-Magnesium] in the USA has previously shown such a model, with the enrollment of 1,700 patients in a phase 3 trial assessing magnesium in acute stroke in the Los Angeles area,” they noted. “Such trials are changing the paradigm of acute stroke research by showing the feasibility of very early treatment initiation within a median of 45 minutes for FAST-MAG and 73 minutes for RIGHT-2.”

Disclosures

Dr. Bath has served as a consultant for and on the advisory board of Platelet Solutions Ltd, Moleac, DiaMedica Therapeutics, Inc, Phagenesis, Nestle, and ReNeuron. Drs. Johnston and Durkalski-Mauldin had no competing interests.

Link Up for More Information


•. Bath PM, Scutt P, Anderson CS, et al; for the RIGHT-2 Investigators. Prehospital transdermal glyceryl trinitrate in patients with ultra-acute presume stroke (RIGHT-2): An ambulance-based, randomized, sham controlled, blinded, phase 3 trial https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30194-1/fulltext. Lancet 2019; Epub 2019 Feb 6.
    •. Johnston KC, Durkalski-Mauldin VL. Comment. Comment: Considering prehospital stroke trials: Did RIGHT-2 get it right https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30276-4/fulltext. Lancet 2019; Epub 2019 Feb 6.