RIGHT-2: Prehospital Nitroglycerin Patch Fails to Boost Stroke Outcomes

Patrice Wendling

February 07, 2019

HONOLULU — A sham-controlled trial shows that transdermal glyceryl trinitrate (GTN) does not improve overall outcomes when given in the ambulance in the ultra-acute phase of stroke.

In the target population of patients with ischemic stroke or transient ischemic attack (TIA), the primary outcome — modified Rankin Scale (mRS) score at 90 days — was exactly the same with a GTN or sham patch (3 for both; adjusted common odds ratio for poor outcome with GTN, 1.25; 95% CI, 0.97 - 1.60; P = .083).

"We were close to getting a negative trial; it's technically neutral but we were well on the way to being negative," remarked lead investigator Philip Bath, MB BS, DSc, University of Nottingham, United Kingdom.

The phase 3 Rapid Intervention With Glyceryl Trinitrate in Hypertensive Stroke Trial (RIGHT)-2 trial offers two other intriguing findings: a suggestion of harm with very early GTN in patients with intracerebral hemorrhage, very early stroke (less than 1 hour), and severe stroke; and a positive effect in stroke mimics.

"We cannot recommend GTN in the ambulance," Bath concluded.

The results of RIGHT-2 were presented here at the International Stroke Conference (ISC) 2019 and were published online February 6 in the Lancet.

"It's disappointing the trial is neutral, but one of the important lessons from this trial may be that we should not strive to lower blood pressure very, very acutely in the hemorrhages because, actually, we can make things worse," Bath told theheart.org | Medscape Cardiology.

Philip Gorelick, MD, MPH, Northwestern University, Chicago, who was not involved in the trial, suggested that patients with intracerebral hemorrhage may suffer a "double hit" when treated very early on with GTN, a nitric oxide donor.

"The bottom line here is that when you have a hemorrhage in the brain, it may be a very dangerous proposition to use this drug because it may vasodilate, increasing the hemorrhage in the brain, and if there is truly any antiplatelet effect, you're going to end up preventing the thrombus or clot plug from forming to stop the bleeding," he told theheart.org | Medscape Cardiology.

Gorelick noted that GTN is far less popular in the United States than it is in the United Kingdom, but "this makes us think twice about using a vasodilator type of drug, which we've already known from our experience with sodium nitroprusside."

Early Evidence

Hypertension is common in acute stroke and a predictor of poor outcomes; however, its management in acute stroke remains unclear. Previous studies have shown that lowering blood pressure in the first 24 hours of ischemic stroke and the first 6 hours in intracerebral hemorrhage does not improve outcomes.

Data from the single-center, phase 2 RIGHT trial and a prespecified subgroup analysis of patients treated in the hospital within 6 hours of onset in the ENOS trial, however, suggest that GTN reduces death and disability and is effective in both ischemic stroke and intracerebral hemorrhage, Bath explained.

RIGHT-2 was designed to assess the safety and efficacy of prehospital GTN in patients with presumed stroke, as well as the feasibility of performing a large multicenter, paramedic-delivered trial in this population in the United Kingdom. In the United States, this was demonstrated in the FAST-MAG trial, which successfully recruited 1700 patients and showed no effect on mRS in those given IV magnesium in the ambulance.

For the current trial, 516 paramedics from eight ambulance services in the United Kingdom recruited 850 patients with a face/arm/speech/time (FAST) score of 2 or 3 and a systolic blood pressure of at least 120 mm Hg and randomly assigned them to a GTN patch (5 mg as Transderm-Nitro 5) or a sham patch containing DuoDERM hydrocolloid dressing.

Because the nonstroke diagnosis rate exceeded 30% during the trial, the team decided to expand the sample size to 1050 patients and to perform a hierarchical analysis, comprising a sequential analysis based on the final in-hospital diagnosis in the target population and in all patients (intent-to-treat [ITT] population), Bath said.

Between October 2015 and May 2018, 1149 patients were enrolled, with 568 assigned to the GTN group and 581 to the sham group. The median time to randomization was 71 minutes. At the final diagnosis, 52% of the patients had ischemic stroke, 13% had intracerebral hemorrhage, 10% had TIA, and 26% had a nonstroke mimic. The GTN and sham groups had mean systolic BPs of 162 mm Hg and 163 mm Hg, respectively, and 60% of patients had a FAST score of 3 out of 3.

In patients with stroke or TIA, systolic BP dropped by 5.7 mm Hg at hospital admission and diastolic BP dropped by 2.6 mm Hg in the GTN group, compared with the sham group. At day 2, the respective declines were 5.3 mm Hg and 2.1 mm Hg, Bath reported. There was no difference in blood pressure at days 3 and 4, with similar findings seen in all patients.

GTN Worse When Given Very Early

When the researchers looked at mRS in patients with stroke or TIA, there was no interaction with any of the 11 subgroups, including age, sex, previous stroke, and diagnosis.

"But if you looked at time to randomization, the trial is frankly negative in people treated within 1 hour, it's neutral but with a negative tendency between 1 and 2 hours, and neutral with a positive tendency at more than 2 hours," Bath said. "So something is going on in that first hour."

The difference in mRS by time of randomization was statistically significant (P = .014). There was no difference in death rates at 90 days between the GTN and sham groups (23% vs 19%; adjusted hazard ratio, 1.24; P = .17).

In the ITT population, the adjusted common odds ratio (acOR) for the primary outcome was 1.04 (95% CI, 0.84 - 1.29; P = .69). Death rates were similar between groups.

In the subgroup of patients with a stroke mimic, GTN was safe and appeared to be associated with an improved mRS, a finding that was not localized to any particular type of mimic in a post hoc analysis.

"GTN in mimics was positive, so we have a new treatment for stroke mimics," Bath said to a round of laughter. "And please don't ask me to explain that because I haven't a clue."

Why Different Results?

As for why the results of RIGHT-2 differ from earlier data, Bath noted that the 6-hour population in ENOS was treated at 264 minutes vs 71 minutes in RIGHT-2.

"If you want me to speculate, the problem largely lies with intracerebral hemorrhage, and in that very early first hour we are, of course, breaking the law we learned from medical school, which is that the first part of hemostasis is spasm and we gave an antispasmodic, a vasodilator," he said.

RIGHT-2 demonstrates that large ambulance trials are feasible in the United Kingdom, and it had several strengths, including very early treatment, blinded outcomes and adjudication, good compliance with the first treatment, and the novel hierarchical analysis, which might be useful for future trials, Bath said. Limitations are that it is a single-blind UK-only trial, the protocol was changed, and there was a smaller-than-expected difference in BP, poor adherence on days 2 to 4, and a higher-than-expected mimic rate.

"Clearly nitroglycerin is not a drug to go forward with after RIGHT-2, except for this intriguing finding that stroke mimic benefits did better with nitroglycerin, which is probably just play of chance, although it's fun to think about in what ways nitroglycerin may be helping patients who are having stroke-like symptoms," FAST-MAG investigator, Jeffrey Saver, MD, director, stroke unit, Geffen School of Medicine University of California Los Angeles, told theheart.org | Medscape Cardiology.

The tendency for harm in patients with hemorrhage, he said, "might be related to the specific mechanism of action of nitroglycerin and not to its blood-pressure-lowering, but this is a caution about bringing blood-pressure-lowering drugs ahead for ischemic events in the very first hours after onset."

Upcoming trials that might provide insights include the phase 3 Canadian FRONTIER trial and a phase 3 Scandinavian trial looking at ischemic preconditioning in the ambulance. IN addition, the FAST-MAG group has just announced the phase 2 FAST-TFC trial of a novel oxygen diffusion-enhancing molecule.

In an accompanying editorial, Karen C. Johnston, MD, University of Virginia, Charlottesville, and Valerie L. Durkalski-Mauldin, MD, Medical University of South Carolina, Charleston, suggest that telemedicine techniques that bring the stroke provider into direct contact with the patient and paramedics in the ambulance might be useful in future trials, with early data suggesting reliability and accurate stroke diagnosis.

Nonetheless, they add, "the absence of imaging in most ambulances will continue to limit field personnel from definitively determining ischemic stroke from intracerebral hemorrhage, which will limit hyperacute trials to interventions presumed safe in both populations."

The study was funded by the British Heart Foundation. Bath reported ownership interest in Platelet Solutions and consultant/advisory board participation for Moleac, DiaMedica, Phagenesis, Nestle, and ReNeuron.

Saver reported serving as an unpaid external advisor to RIGHT-2. The editorialists declared no competing interests.

Lancet. Published online February 6, 2019. Full text, Editorial

International Stroke Conference (ISC) 2019: Abstract LB2. Presented February 6, 2019.

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