Giving transdermal nitroglycerin to stroke patients in the ambulance within 3 hours of symptom onset was not shown to be of any benefit in the MR ASAP trial.
The trial involved both patients with ischemic stroke and those with hemorrhagic stroke. In contrast to a previous randomized trial, RIGHT-2, there was no sign of harm with nitroglycerin at 90 days among patients with intracerebral hemorrhage (ICH) in MR ASAP despite a trend toward higher mortality duirng the first 7 days in this group.
The trial was presented on September 1 at the virtual European Stroke Organisation Conference (ESOC) 2021 by Simone Uniken Venema, a PhD candidate at Utrecht University, Utrecht, the Netherlands.
Summing up the clinical implications of the results at an ESOC press conference, senior study investigator Bart van der Worp, Utrecht University Medical Center, said: “I think nitroglycerin in the very early hours after stroke onset in the prehospital setting is now dead because of these results and those from the RIGHT-2 results where there was a trend towards harm in patients with ICH.
“I do think, however, that nitroglycerin could be tested at a later point in time, and I think a trial on this is being planned,” van de Worp added.
The chair of the session at which the results were presented, Joanna Wardlaw, MD, who is also chair of the ESOC Planning Group, said the MR ASAP trial was “a really important study that adds to the body of evidence on early nitroglycerin in stroke and potentially could be interpreted as the impact of blood pressure in stroke.”
As background, Uniken Venema explained that high blood pressure in patients with acute ischemic stroke or ICH is associated with poor outcomes. Nitroglycerin is a nitric oxide donor that reduces blood pressure without having a negative effect on cerebral blood flow.
A previous pooled analysis of five small randomized controlled trials that included a total of 312 patients strongly suggested that nitroglycerin was beneficial when given within 6 h of symptom onset for patients with prehospital stroke. But the larger RIGHT-2 trial, which included 1149 patients, showed no benefit of prehospital nitroglycerin given within 4 h of symptom onset, and there was a potential harm for patients with ICH, Uniken Venema reported.
MR ASAP was a phase 3 randomized trial that evaluated nitroglycerin given within 3 h of symptom onset in a prehospital setting for patients with acute ischemic stroke or ICH. The primary endpoint was functional outcome at 90 days.
Patients with presumed stroke were randomly assigned by ambulance personnel to receive transdermal nitroglycerin 5 mg/d for 24 hours or standard care alone. Patients were then brought to the hospital, where deferred consent was requested. Final follow-up was ascertained at 90 days through a telephone interview.
The trial aimed to enroll 1400 patients with suspected stroke with a Face-Arm-Speech Test (FAST) score of 2 or 3 and systolic blood pressure >140 mm Hg.
But the trial has had a “bumpy ride,” Uniken Venema said.
Enrollment began in April 2018 but was temporarily halted in February 2019 to evaluate safety after the RIGHT-2 results were published. The trial was restarted but was temporarily stopped again in March 2020 because of the COVID pandemic. In February 2021, the data safety monitoring board (DSMB) identified a possible safety problem, and recruitment was stopped again. In June 2021, the trial steering committee decided to terminate the study because of futility.
A total of 380 patients had been enrolled at that time, but 54 of those patients did not provide deferred consent. As a result, the study included 326 patients, 171 in the nitroglycerin arm and 149 in the control arm.
Results showed that in the intention-to-treat population, the primary outcome, functional outcome on the Modified Rankin Scale at 90 days, was neutral with an adjusted common odds ratio for a shift toward a good functional outcome of 0.94 (95% CI, 0.63 – 1.41).
Systolic blood pressure was slightly but not significantly lower in the nitroglycerin group (163 mm Hg vs 170 mm Hg at hospital admission and 139 mm Hg vs 146 mm Hg at 24 h). All other secondary outcomes did not differ between the two groups.
In the safety analyses, there was a trend toward a higher risk for death at 7 days in the nitroglycerin group (9% vs 3%), but this difference was no longer apparent at 90 days (14% vs 13%). The risk for other adverse events was similar in the two groups.
The increased risk for death at 7 days was mainly driven by patients with ICH. This finding was in line with the RIGHT-2 results and led to the DSMB’s decision to stop recruiting these patients.
However, results at 90 days showed that the rate of death among patients with ICH tended to be lower in those who received nitroglycerin. Functional outcome at 90 days also tended to be better in the nitroglycerin group.
A subgroup analysis of the primary outcome showed a significant interaction for diagnosis in which ICH patients tended to benefit from nitroglycerin, whereas for patients with ischemic stroke, outcomes tended to be worse with nitroglycerin. Patients with a prehospital systolic blood pressure <176 mm Hg also had worse results with nitroglycerin.
Questions on Role of Blood Pressure in ICH
Commenting on the study for Medscape Medical News, Tolga Dittrich, MD, University Hospital Basel, Basel, Switzerland, said it was not possible to make definitive statements on the safety of nitroglycerin for patients with ICH, given the different results of RIGHT-2 and MR ASAP and in view of the fact that in MR ASAP, there were only 56 patients with ICH.
Dittrich pointed out that for patients with ICH, the relationship between blood pressure reduction and functional outcome remains a highly topical issue.
“At first glance, it seems pathophysiologically plausible that blood pressure reduction counteracts hematoma expansion and edema formation, so in clinical practice, a large proportion of clinicians would probably not tolerate very high blood pressures in this patient group,” Dittrich added. “However, there are still controversies about the optimal blood pressure target, how quickly it should be achieved, and, most importantly, which drug regimens should be used to achieve it.”
Deferred Consent Lacking
There was also a problem with deferred consent in the MR ASAP study. Deferred consent was supposed to be acquired on arrival at the hospital, but this did not always happen.
“We found that a deferred consent procedure is not practical in an ambulance trial, illustrated by the fact that 14% of our randomized patients did not provide deferred consent. We would advise against using this method in future ambulance trials,” Uniken Venema said.
But Wardlaw questioned this recommendation. “Other studies in the prehospital setting have adopted deferred consent and not seen such a high dropout, and ultimately, if we are going to reduce time to treatment for a range of different types of stroke, then we do need to move increasingly towards ambulance-initiated therapies,” she pointed out.
Uniken Venema elaborated that one of the problems was the involvement of a large number of small hospitals with staff that were not used to conducting research. “If using deferred consent, we would advise using hospitals that have experience in this procedure,” she suggested.
Van der Worp added: “In principle, I am in favor of a deferred consent procedure, but the issue here is that patients were randomized in the ambulance and then dropped at various local hospitals. It would be easier to ask for deferred consent if the treating physician is in the same hospital as the trial investigator.”
The MR ASAP trial was funded by the CONTRAST consortium, which is supported by the Netherlands Cardiovascular Research Initiative. Uniken Venema and van der Worp have disclosed no relevant financial relationships.
European Stroke Organisation Conference (ESOC) 2021: Presented September 1, 2021.