Summary of results and comparison with other studies
In our further analysis of the RIGHT-2 study, we found that 26% of the 1149 cases suspected by paramedics to be a stroke had a non-stroke final diagnosis. Patients with a stroke mimic were younger, had less atrial fibrillation, lower BP, fewer FAST positive signs, and a longer onset-to-randomisation compared to those with a confirmed stroke. The most common stroke mimics were neurological conditions; epileptic seizures, migraines and primary headache disorder, and functional neurological illness accounted for almost half of all the cases. The only significant difference between groups at baseline was a lower SBP in the GTN group. At 90 days, patients with stroke mimics had better mRS scores than those with stroke and this finding was maintained in sensitivity analyses and at 365 days. The lack of difference in the rate of serious adverse events between the two groups supports the safety of the GTN intervention among patients with stroke mimic conditions.
These findings add to prior work on prehospital stroke recognition. The rate of 26% stroke mimics is consistent with pooled results for 6870 patients in physician and paramedic-led EMS systems and larger reviews that included pre and in-hospital settings [6, 17]. Our results corroborated previous reports that stroke mimic patients are younger, less likely to display atrial arrhythmias, have a lower BP, and milder stroke signs at presentation compared to stroke patients [5, 18,19,20,21]. In contrast to earlier findings, we did not observe that mimic patients are more often female, have more vascular risk factors or a history of previous stroke [5, 18,19,20, 22]. The common stroke mimic conditions were similar to those seen in other studies [5, 18,19,20, 22].
The key but unexpected finding was that 90-day and one-year functional outcomes were better with GTN than the sham. This was despite the absence of any significant demographic or clinical differences between the two treatment groups at baseline (other than SBP), or during their in-hospital care. In addition, the 90-day quality of life score was higher in the GTN group. We suggest several possible explanations.
First, although there were no imbalances in measured prognostic factors between the groups at baseline, there may have been imbalances in unmeasured factors. Second, it is possible that cardiovascular and cerebrovascular events were missed, possibly due to atypical presentation, and included among the mimics. The subgroups with the highest odds of a better outcome with GTN were aged over 80, female, AF, hypertension, previous stroke, normal GCS, and high score on FAST. Third, it is possible that bias in the assessment of outcomes favoured GTN. However, this is unlikely due to the trial design which utilised remote assessment of outcomes at follow-up by a blinded assessor. Fourth, the greater number of deaths among mimic cases who received the sham intervention could have influenced the results. However, a comparison of the 90-day mRS scores for surviving cases was still in favour of GTN and anyway if GTN were effective, it might well reduce death as well as dependence.
Fifth, the results could have been caused by chance, particularly given the small sample size and the moderate rate of non-adherence to the study protocol in the mimic group. Stroke mimic cases in both treatment groups included a wide variety of different neurological and non-neurological diagnoses and it is difficult to explain the effect of GTN across these disorders. Further, EQ-5D differed at day 90 (with a tendency at day 365) in favour of the GTN group, and the point estimate of the BI also favoured the GTN group (although not meeting significance).
Last, the results may reflect an actual treatment effect whereby GTN improves outcome in non-stroke mimics. GTN dilates the blood vessels, increases blood supply and lowers BP due to smooth muscle relaxation. This vasodilatory effect of GTN may improve vasospastic migraine which can present as hemiparesis or hemianopia. The improvement in the seizure group could again be attributed to vasodilation by GTN. Brain oedema has been observed in patients scanned shortly after seizure activity and would cause compression of smaller vessels. Further, NO has generic antimicrobial effects (P Bath, review in preparation) and so might have attenuated the infectious causes of mimic.
This study has direct implications for pre-hospital stroke research. In particular, the frequency of stroke mimic conditions may have an unexpected impact in any intention-to-treat analysis. Mobile stroke units (where available) may still not be the solution with high rates of mimics observed among call-outs [23]. Even hospital hyperacute stroke trials are not immune to mimics with 17% of the patients enrolled into the NOR-TEST trial having a final diagnosis of a stroke mimic [24]. For now, prehospital trials will need to be designed with the impact of mimics in mind. Developing point of care diagnostics to improve accuracy in selecting the intended trial population of stroke patients is vital [25].
Strengths and limitations
This study used high-fidelity data and the potential for bias was reduced by the limited inclusion criteria and the use of community recruitment. However, at 297 cases, the sample size was relatively small, and some cases were lost to follow-up. We also noted baseline blood pressure differences between the two study groups. Further, the use of simple randomisation may have contributed to potential undetected baseline imbalance. This approach allowed for rapid randomisation and treatment administration, but future trials could consider using phone or internet-based randomisation in the pre-hospital arena at greater expense.