The initiation of early neuroprotection for acute ischemic stroke remains a tantalizing goal for vascular neurologists given the limiting window for IV tPA and the time delay to endovascular therapy. Preclinical studies showed that nitric oxide donors might improve outcomes after stroke by reducing infarct size and increasing cerebral blood flow. In the ENOS study, transdermal nitroglycerin (GTN) given to patients with stroke within 48 hours, GTN was found to be safe but did not lead to improved outcomes. In a subset of these patients, however, in a group of 273 patients where GTN was given within 6 hours from randomization, improved outcomes on modified Rankin scale was seen.

Here, the authors performed a more thorough analysis of that specific subset of patients who received GTN early. Unlike the patients who were randomized later than 6 hours from ictus, this group of patients was more likely to have an ICH, more severe stroke, a cardioembolic cause for ischemic stroke, and to receive thrombolysis. In addition, the group randomized to GTN had less severe strokes and lower rates of cortical stroke syndromes. Blood pressure was lowered an average of 9.4/3.3 mmHg in the treatment group. There was a statistically significant shift to a lower/better mRS at 90 days in the group randomized to GTN, with a number need to treat (NNT) of 5.2 to shift mRS. In addition, there were improvements in the 90-day measures of Barthel Index, quality of life, cognition, and mood.

As the authors point out, however, positive subgroup analyses within large trials are often spurious and due to chance. Perhaps more pertinently, significant confounders exist in this subgroup analysis, where improved outcomes could potentially be explained by the lower stroke severity and lower rates of cortical stroke syndromes in the treatment group. The results here are promising, but should be interpreted with caution. The RIGHT-2 trial will further assess safety and efficacy of GTN delivered in the hyper-acute setting by paramedics in a larger population, and may give us some more answers.