Session Chairs: Peter Kelly, Ireland and Alison Halliday, United Kingdom

Report by Marialuisa Zedde, Italy

 

Novel Drug Treatments for Large Artery Disease

Prof. Peter Kelly summarizes the strategies to reduce stroke risk for survivors of acute stroke including optimizing the lifestyle, implementing better the current evidence (e.g. lipid lowering treatment targets), increasing intensity of known risk factors treatment (PCSK9 inhibitors and statins/ezetimibe) and finally addressing new modifiable risk factors (Inflammation). The first two points were treated in detail.

Lipid lowering therapy began with presenting the results of SPARCL trial as a prototypic trial about secondary prevention after noncardioembolic stroke and TIA without previous history of coronary artery disease. The trial enrolled about 5,000 patients and randomly allocated them to high intensity atorvastatin treatment arm vs placebo. 2% of patients had a hemorrhagic stroke during the study period.  The median follow-up of SPAECL was almost five years. For the primary endpoint there was a reduction of all strokes with a RRR of 16%. The absolute increase of hemorrhagic stroke risk is 0.9% and it corresponds to a RRI of 1.66. Overall reduction of major cardiovascular events was about 20%. In a post-hoc analysis of effect of high dose atorvastatin in patients with carotid stenosis, the SPARCL investigators showed a two-fold increase in benefit in comparison to the overall benefit. The question of how low to go was recently addressed in the TST trial. The primary endpoint was a composite endpoint of major cardiovascular events and it was obtained in the intention to treat analysis favouring the low target group (LDL cholesterol < 70 mg/dl) with a RRR 42%. A subgroup analysis focusing on carotid IMT measurement found regression in CAA MT in both arms but greater in low-target group. The question of how low to go was addressed also in FOURIER trial with a PCSK9 inhibitor (evolocumab) and the benefit in patients with previous stroke was consistent with the overall benefit obtained in all participants without increased risk of ICH. The second part of the talk focuses on inflammation as a new target for treatment in atherosclerosis. The data provided by CANTOS trial (canakinumab, monoclonal antibody versus IL1beta) on a large population (10,061 patients with stable CAD) revealed a stable CRP reduction with a concurrent significant reduction in major cardiovascular events (MI, stroke and vascular death) without change in LDL levels.

The trial was not specifically designed to evaluate stroke as isolated primary endpoint but the proof of concept is that anti-inflammatory therapy prevents cardiovascular events and it raised interest about a safe inexpensive drug with a similar action, i.e. colchicine. We have data from CAD randomized trials about stroke reduction in patients treated with colchicine with an overall stroke reduction of 63% in the treated arm. The CONVINCE trial is an ongoing multicentre randomized trial using colchicine in patients with noncardioembolic stroke.

Experimental Therapies for Atherosclerosis: What Is in The Pipeline?

The second talk by Carlos Silvestre-Roig focuses on experimental therapies for atherosclerosis with a translational approach. He described the molecular mechanisms in born and progression of atherosclerosis and again inflammation with the related cytokine cascade has the main role in this process and it confirms to be an interesting and promising target for new treatment not only by drugs but also by adaptive immunity mechanisms. Moreover it may be modulated by lifestyle interventions and physical exercise. He focused mainly on role of neutrophils and NETs on plaque destabilization with an overview of NETs as a biomarker of CVD and as a target for treatment. He concluded that neutrophils and NETs are important drivers of atherosclerotic plaque instability, myocardial infarction and stroke, NET-derived products are promising biomarkers of CVD for risk stratification and tailor treatments but they could represent also a promising therapeutic target to be validated and translated into clinical practice through large and rigorous studies.

Novel Antithrombotic Approaches for People with Large Artery Disease

Meanwhile, Prof. Mike Sharma from Canada talked about novel antithrombotic approaches for people with large artery disease, starting with a useful reminder about the high risk provided by large vessels atherotrombosis among all stroke causes. Atherotrombosis is a progressive and dynamic process and the effects of antithrombotic treatment is limited with a strong biological rationale that supports the use of a dual pathways approach in the choice of antithrombotic treatment with the addition of FXa inhibition to the antiplatelet agent to increase vascular protection. For rivaroxaban, the process of defining the right dosage went through some trials, starting with the ATLAS and ending with the COMPASS study, in which a significant subgroup still had MR evidence of cerebrovascular disease, even of a microvascular type, although it was not a study drawn on the patient with stroke. Considering the endpont stroke, it is highlighted in the COMPASS that the net benefit of the ASA-Rivaroxaban 2.5 mg BID vs ASA association is not offset by a significant increase in ICH. Furthermore, in the subgroup of patients with previous carotid revascularization or asymptomatic carotid stenosis, the risk of stroke was overall higher but the combined treatment maintained its efficacy and safety. Summarizing the key messages of the talk we can say that in patients with CAD or PAD rivaroxaban+ASA vs ASA reduces CV death, stroke or MI by about 25%, reduces stroke by 40% (58% in those with previous stroke) and reduces mortality by about 20%; the greater benefit is evident in patients wth polivasvular disease and in patients with multiple risk factors. From the safety point of view, increasing bleeding is mostly gastrointestinal and frequently unmasks underlying cancer. FXIa is the new target for ongoing trials.

Carotid Artery Stenosis – Treatment Approaches

Prof. Peter Ringleb and Prof. Alison Halliday closed the session talking about the treatment approaches of symptomatic and asymptomatic carotid stenosis respectively.  The talk of Prof. Ringleb was mainly focused on patients with high surgical risk with a clear definition of them as anatomical and clinical factors that have the potential to increase complications following CEA, ranging from death, stroke through to cranial nerve injury. He presented the results of SAPPHIRE trial comparing protected CAS t CEA in this subgroup of patients with a clear non-inferiority of CAS. The metanalysis of Carotid Artery Stenting Trials Collaborations shown a higher risk of periprocedural stroke and death with CAS vs CEA with a strict effect of the age for increasing CAS-related risk. One interesting point is the differentiation between true restenosis after CEA and residual atherosclerosis or recurrent atherosclerosis. He also provided evidence about the relative value of previous irradiation and contralateral occlusion as issues to prefer CAS over CEA.

Each decision must therefore be made on an individual basis and after having carefully and critically examined the criteria of the trials with respect to the individual patient, also taking into account the experience of the local team of CAS-practitioners.

Prof. Halliday discussed the available evidence about asymptomatic carotid stenosis treatment, starting from the ESVS 2018 clinical practice guidelines. In 40 years of carotid trials, more experience has been provided for CEA vs CAS for both symptomatic and asymptomatic patients. She examined the main trials comparing symptomatic and asymptomatic carotid stenosis treatment, following the technical evolution and summarising these data in the following conclusions:

  • CEA is effective for symptomatic tight carotid stenosis (70-95%)
  • For asymptomatic younger patients (< 75 yrs) with tight stenosis, CEA prevents future stroke for at least 10 years
  • CAS may be as effective and safe as CEA in the 2020’s (the results of ongoing trials are waited)
  • All patients should receive good contemporary medical therapy.