Methods: We recruited independent patients with clinically confirmed lacunar ischaemic stroke without cognitive impairment to a prospective randomised clinical trial, LACunar Intervention-1 (LACI-1). We randomised patients using a central web-based system, 1:1:1:1 with minimisation, to masked ISMN 25 mg bd, cilostazol 100 mg bd, both ISMN and cilostazol started immediately, or both with start delayed. We escalated doses to target over two weeks, sustained for eight weeks. Primary outcome was the proportion achieving target dose. Secondary outcomes included symptoms, safety (haemorrhage, recurrent vascular events), cognition, haematology, vascular function, and neuroimaging. LACI-1 was powered (80%, alpha 0.05) to detect 35% (90% versus 55%) difference between the proportion reaching target dose on one versus both drugs at 55 patients. Registration ISRCTN12580546.
Findings: LACI-1 enrolled 57 participants between March 2016 and August 2017: 18 (32%) females, mean age 66 (SD 11, range 40-85) years, onset-randomisation 203 (range 6-920) days. Most achieved full (64%) or over half (87%) dose, with no difference between cilostazol vs ISMN, single vs dual drugs. Headache and palpitations increased initially then declined similarly with dual versus single drugs. There was no between-group difference in BP, pulse-wave velocity, haemoglobin or platelet function, but pulse rate was higher (mean difference, MD, 6.4, 95%CI 1.2-11.7, p = 0.02), platelet count higher (MD 35.7, 95%CI 2.8, 68.7, p = 0.03) and white matter hyperintensities reduced more (Chi-square p = 0.007) with cilostazol versus no cilostazol.
Interpretation: Cilostazol and ISMN are well tolerated when the dose is escalated, without safety concerns, in patients with lacunar stroke. Larger trials with longer term follow-up are justified.
Funding: Alzheimer's Society (AS-PG-14-033).
MATERIAL AND METHODS: A prospective, quasi-experimental physiological study. Selected healthy subjects were observed electrocardiographically for 60 s continuously in three equal phases of 20 s each - baseline phase, nasoendoscopic phase, and recovery phase (post-nasoendoscopy). Heart rate fluctuations were charted, followed by identification of a positive nasocardiac reflex group of subjects and a negative group. Analyses against multiple variables were done.
RESULTS: A total of 53 subjects were analysed. Heart rate during the baseline phase was 81.0 ± 9.9, nasoendoscopic phase was 72.7 ± 10.1, and recovery phase was 75.2 ± 9.6. Sixteen subjects (30.2%) had a positive nasocardiac reflex, and they remained in sinus rhythm with no occurrences of skipped beats, atrioventricular blocks or asystoles. One subject (1.9%) developed temporary ectopic premature ventricular contractions after nasoendoscopy. No variables were found affecting the incidence of a nasocardiac reflex in our study.
CONCLUSIONS: The pattern of heart rate dynamics was consistent as heart rates drop rapidly upon endoscope insertion and recover in some measure after its withdrawal. Although all our subjects remained asymptomatic, clinicians should not overlook the risks of a severe nasocardiac reflex when performing nasoendoscopy. We recommend that electrical cardiac monitoring be part of the management of vasovagal responses during in-office endonasal procedures.