BP Lowering en Route to Hospital Flops in Acute Stroke

If you were actually to think about this, lowering blood pressure makes no sense for clot strokes. You would be reducing the oxygen supply to the penumbra, increasing the death rate of those neurons. Does anyone in stroke think or have a strategy at all?

BP Lowering en Route to Hospital Flops in Acute Stroke

RIGHT-2 trial shows no benefit, possible harm from nitroglycerin patch

• by Crystal Phend, Senior Associate Editor, MedPage Today February 07, 2019

HONOLULU -- Nitroglycerin given by paramedics to rapidly lower blood pressure for suspected acute stroke patients didn't improve outcomes and showed a strong signal of being dangerous in the RIGHT-2 trial.
"I'm delighted to give you another neutral study," quipped Philip Bath, MD, of the University of Nottingham City Hospital in England, in reporting the late-breaking trial here at the American Heart Association's International Stroke Conference, results of which were simultaneously published in The Lancet.
Functional outcome as measured by the modified Rankin Scale (mRS) at 90 days showed no difference in the overall trial population, with an average of 3 points on the 7-point scale in both those who got the patch and those who got sham dressings and a nonsignificant adjusted common odds ratio (OR) of 1.04 for poor outcome (P=0.69).
Even among those with a final diagnosis of stroke or transient ischemic stroke, both groups averaged the same mRS of 3, although the adjusted common OR for poor outcome strongly trended to higher risk with nitroglycerin at 1.25 (P=0.083).
"We were close to getting a negative trial," Bath said. "It is technically neutral, [but] we were well on our way to being negative."
Among secondary outcomes, the intervention was worse in patients with intracerebral hemorrhage (P=0.057), the most severe strokes (National Institutes of Health Stroke Scale score over 12, P=0.044), and those enrolled within an hour of symptom onset (P=0.014).
There's no reason to go further with nitroglycerin in this setting, but there are lessons for future trials of other agents, commented Jeffrey Saver, MD, of the University of California, Los Angeles, whose FAST-MAG trial of prehospital magnesium also flopped.
"We now know for sure that two neuroprotective agents don't work -- magnesium and nitroglycerin. Those are the only two that have been tested in the realistic time frame," he told MedPage Today. "We clearly have more work to do. There were concerning, unexpected adverse effects with the nitroglycerin. Would you do a vasoactive as opposed to a neuroprotective agent early on? This trial is going to suggest we should be cautious when doing that."
An accompanying editorial agreed that it may be the end of the line for blood pressure lowering in this setting, as transdermal nitroglycerin (or glyceryl trinitrate) is a nitric oxide donor that lowers blood pressure through vasodilation.
"We believe the clinical community now has data from numerous populations suggesting that blood pressure lowering in the acute and hyperacute setting is not beneficial to patients with stroke," wrote Karen Johnston, MD, of the University of Virginia in Charlottesville, and Valerie Durkalski-Mauldin, PhD, of the Medical University of South Carolina in Charleston.
Nitroglycerin did have the expected impact on blood pressure, which was 5.8/2.6 mm Hg lower after initial treatment and 5.3/2.6 mm Hg lower than in the sham group on day 2. "However, these differences between groups in blood pressure might not be considered clinically relevant in this setting," the editorial noted.
Hopes for very early intervention aren't dead, though, Saver said, pointing to hypothermia and a novel group of oxygen diffusion enhancers being investigated for neuroprotection in the prehospital setting.
Other lessons for future hyperacute stroke treatment trials are "to consider the implications of enrolling, yet excluding, stroke mimics in the primary analysis," given the higher than expected rate of such patients in RIGHT-2, the editorialists said.
Whereas the trial was powered with the assumption of 20% stroke mimics, additional patients had to be enrolled after the rate was initially over 30%. In the end, 26% of the 1,149 enrolled had stroke mimics while 52% had ischemic stroke, 13% intracerebral hemorrhage, and 9% transient ischaemic attack.
FAST-MAG had avoided the stroke mimic problem (only 4% in that trial) through use of telemedicine consultation in the ambulance.
RIGHT-2 enrolled patients with presumed stroke, face-arm-speech-time (FAST) score of 2 or 3, and systolic blood pressure above 120 mm Hg who were seen by eight ambulance services in the U.K. They were randomized to a nitroglycerin patch or a sham patch within 4 hours of symptom onset. The first dose was given by paramedics in the ambulance and three others were planned over the subsequent days, although adherence to the following doses in hospital was low.
Results were similar between groups for treatment-related mortality and serious adverse events.

The study was funded by the British Heart Foundation.
Bath disclosed relationships with Platelet Solutions, Moleac, DiaMedica, Phagenesis, Nestle, and ReNeuron.
Saver disclosed being an advisor for the RIGHT-2 trial.

last updated 02.07.2019

• Primary Source

  The Lancet

  Source Reference: Bath PM, et al "Prehospital transdermal glyceryl trinitrate in patients with ultra-acute presumed stroke (RIGHT-2): An ambulance-based, randomised, sham-controlled, blinded, phase 3 trial" Lancet 2019; DOI: 10.1016/S0140-6736(19)30194-1.

• Secondary Source

  The Lancet

  Source Reference: Johnston KC, Durkalski-Mauldin VL "Considering prehospital stroke trials: Did RIGHT-2 get it right?" Lancet 2019; DOI: 10.1016/S0140-6736(19)30276-4.