Author: Francesco Arba

The “Secondary Prevention” session was an interesting session chaired by Dr. Sheila Cristina Martins from Brazil and Paula Munoz Venturelli from Chile.

 The first speaker was Dr. Philip Nash, London, United Kingdom, who gave a talk about “Increased risk of recurrent stroke in patients with impaired kidney function: a pooled analysis of individual patient data

Dr. Nash presented a pooled analysis of the Microbleeds International Collaborative Network (MICON), an international, multicentre collaboration. A total of 18 sites that provided renal data on more than 20000 patients. The aim of the present study was to investigate the relation between renal impairment and recurrent stroke risk. Between the two groups (renal impairment vs no renal impairment) the group with renal impairment had more vascular risk factors such as hypertension, diabetes, and so on. From an imaging point of view, the renal impairment group had a higher percentage of mixed (cortical and deep) cerebral microbleeds. The study demonstrated that renal impairment increased the rate of stroke recurrence with anaose-response effect, suggesting a direct biological relation. Conversely, renal impairment was not associated with higher intracerebral hemorrhage risk. The biological mechanisms supporting this association may be endothelial dysfunction and an increase of small vessel disease severity, so increasing the risk of stroke recurrency. The conclusion of Dr. Nash was that there was an overall increase of recurrent stroke of 33%, and that renal function should be routinely tested in clinical practice and evaluated in relation to stroke risk. 

 Dr. Jori Ruuskanen, from Turku, Finland, presented “Intensity of statin therapy after ischemic stroke and long term outcomes: a population-based study cohort study

Although statins have been used in clinical practice for a long time, there are still controversies and inconsistencies about statin use in long-term secondary prevention: for example, AHA/ASA guidelines recommend statin use only in atherosclerotic disease, whereas in other guidelines there was no stratification across stroke subtype. This observational population-based study included data from around 45000 patients from 2005-2018, with a median follow-up of around six years. Data were extracted from a national registry; diagnosis of stroke was made with ICD-9 codes. Patients were divided into high-dose statins (e.g. Atorvastatin 80 mg, Rosuvastatin 40 mg, etc.) vs low-dose statins. The primary outcomes were all-cause death, secondary recurrent ischemic stroke, cardiovascular death, occurrence of intracerebral hemorrhage. The study found that a high-intensity statin regimen was associated with a lower risk of death and major cardiovascular outcomes, with a number needed-to-treat of 14.6 for death and 19.1 for recurrent stroke. Dr. Ruuskanen concluded that high-intensity statin use was feasible and has efficacy in the long term. 

However, many limitations should be acknowledged to this study, as pointed out by many questions from the participative audience.

 Dr. Nikolaos Avramiotis, from Basel, Switzerland, presented an updated systematic review and meta-analysis (the previous one was outdated -2010) of the management of secondary prevention therapy for extracranial carotid dissection (“Antithrombotic drugs for carotid artery dissection-update of a Cochrane Systematic Review”). Given that new therapeutic approaches have been established in clinical practice (e.g. Direct Anticoagulants Drugs) a new review appeared to be justified. The review followed the Cochrane methodology for reviews and included both randomized controlled trials and non-randomized studies and compared anticoagulant versus antiplatelet therapy. A total of 44 studies were included, of which 2 were randomized controlled trials, so little evidence came from RCT, whreas the majority of available evidence was from observational studies (i.e. higher risk of bias). Outcomes of interest were: death, death/disability as a composite outcome, recurrent stroke, symptomatic intracerebral hemorrhage. The results showed that death was lower in the anticoagulant group, similar to death/disability (perhaps driven by death), whereas the risk of recurrent stroke gave a neutral result. Conversely, symptomatic intracerebral hemorrhage was lower in the antiplatelets. Dr. Avramiotis acknowledged relevant limits to this study (e.g. many observational data, few RCT, heterogeneity in outcome reporting measurements, and length of follow-up), but suggested that treatment should be individualized. As the audience pointed out during the discussion, there are no data, however, regarding treatment timing, duration, and type of anticoagulants, so the conclusion was that more studies are needed. 

 Dr. Rustam Al-Shahi Salman, from Edinburgh, United Kingdom, presented “Medical Management +/- surgery for symptomatic cerebral cavernous malformation: a randomised pilot trial

This pilot randomized controlled trial was focussed on a frequently overlooked pathology that may cause cerebral hemorrhage and epilepsy. Given the little available evidence about management in such cases, an RCT is warranted. However, before moving into a large clinical trial, feasibility on recruitment rate, feasibility of procedures. Another important objective tested in the study was to address barriers and identify strategies to improve recruitment in the trial. A multidisciplinary team (neurologist, neuroradiologist, neurosurgeons, etc) is needed for the management of cerebral cavernomas, and the speaker stressed the fact that usual care practices so far prevented equipoise in treatment allocation, and logistical issues led to different clinical practice. The study enrolled 60 participants, with baseline characteristics equally distributed in the two groups (medical vs surgery management). Outcomes were similar between the two groups, but the trial was underpowered to investigate meaningful statistical differences. The main conclusive remarks were that around a third of approached patients were randomized, and a larger phase III trial is feasible. However, to reach the planned sample size (between 590 and 1900 participants) a definitive trial will need to involve 36-259 enrolling sites, which could be a major issue for funding agencies. 

 Dr. Bonaventure Ym Ip, from Hong Kong, in his speech “Early stent-assisted angioplasty in symptomatic intracranial stenosis: a randomized trial”, presented the results of a single centre, randomized, open-label, outcome blinded trial on the management of intracranial stenosis in patients with recent non disabling stroke. The experimental arm was angioplasty/stent treatment and the control arm was double antiplatelet therapy (aspirin 80 mg and clopidogrel 75 mg). The trial enrolled 150 patients, almost a third of included patients were randomized within 14 days from the index stroke. The primary endpoint was the composite outcome stroke/death 30 days after randomization, and occurred in 24% in the medical arm vs 16% in the experimental arm, whereas ischemic stroke in the same vascular territory occurred in 20% in the control (medial) arm and in 12% of the experimental arm. Both results, although suggested a different treatment effect, were not statistically significant. The conclusion was that stent did not result in a lower risk of stroke/death, there were no major safety concerns. Some observations were that the trial was likely underpowered, and the medical arm has likely a different aspirin regimen than the one recommended by many guidelines. 

 The two following talks were about the subanalysis of the ELAN trial. 

In the first talk delivered by Dr. Roman Rohner, from Bern, Switzerland, the topic was “Early versus later anticoagulation after ischemic stroke in people with atrial fibrillation and hemorrhagic transformation”. In this study, authors looked more closely to differences in patients who experienced hemorrhagic transformation. Hemorrhagic transformation was classified accorting with the ECASS-II classification and divided into hemorrhagic infarction (HI) type 1, HI type 2, pranchymal hemorrhage (PH) type 1 and PH2. The groups analysed were early vs late introduction of anticoagulation as defined in the ELAN trial. The primary outcomes were: recurrent ischemic stroke, symptomatic intracerebral hemorrhage, major extracranial bleeding, systemic embolism, and vascular death at 30 days after randomization.  The 12% of whole ELAN trial population had HT of any grade. The authors found no major treatment effect heterogeneity or major safety concerns between the two groups, however, in patients with PH (i.e. the most severe grade of HT) there was a 25% of increased risk of poor functional outcome. The output of the study was to provide a possible recommendation for clinicians: in atrial fibrillation patients with HI early DOAC is reasonable, in those with PH1 an individualized benefit-risk assessment should be performed, in PH2 early DOAC is likely to be harmful. This information could be useful and guide clinicians in everyday practice. 

 In the second talk Dr. Masatoshi Koga, from Suita, Osaka, Japan, illustrated results from “Risk of Ischemic and Hemorrhage events with anticoagulation early after stroke -an analysis from ELAN trial”. In this subanalysis of the ELAN trial, the risk of both ischemic and hemorrhagic events in patients treated with DOAC were assessed. The primary outcome were composite recurrent ischemic stroke, symptomatic intracerebral hemorrhage, major extracranial bleeding. Dr. Koga showed us that there was no association of anticoagulation with bleeding events, although baseline NIHSS, history of heart failure, and body weight < 75 Kg had significant associations. The same speaker continued with the last talk, “Early direct oral anticoagulation initiation post intacranial hemorrhage among Japanese patients with atrial fibrillation”. The SAFE-ICH was a multicentre prospective, observational study to determine the incidence of thrombotic and bleeding events in Japanese atrial fibrillation patients after early (<=14 days) DOAC. The primary outcomes were symptomatic intracerebral hemorrhage, stroke, or death within 30 days from DOAC initiation. A total of 240 patients reinitiated DOAC use after-ICH. Spontaneous ICH represented 85% of all cerebral hemorrhages, 79% were spontaneous, 3%  were traumatic, 3% were cerebral amyloid angiopathy, then subdural hematoma. 

In 12 (5%) patients the primary endpoint occurred, no deaths were attributed to DOAC reinitiation in those with spontaneous intracerebral ICH, and all events occurred in patients with subdural heamatoma of traumatic hemorrhage. Dr. Koga concluded that early reinitiation of DOAC in patients with spontaneaous cerebral hemorrhage was overall safe, caution should be adopted when dealing with traumatic or subdural hemorrhage.