Professor Eric E. Smith and Professor Hugh Markus
Prof. Eric E. Smith and Prof. Hugh Markus

A conversation with Professor Eric E. Smith, MD, Ph.D., Professor of Neurology, Cumming School of Medicine, University of Calgary, Canada, and Professor Hugh Markus, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Interviewed by Shashank Shekhar, MD, MS, Assistant Professor, Division of Vascular Neurology, University of Mississippi Medical Center, USA; @ArtofStroke.

They will be discussing the article “New Treatment Approaches to Modify the Course of Cerebral Small Vessel Diseases,” published in the January 2020 issue of Stroke. The article is part of a Focused Updates in Cerebrovascular Disease series of articles on topics related to cerebral small vessel diseases.

Dr. Shekhar: I would like to thank Prof. Smith and Prof. Markus for agreeing to do this interview. In this interesting review paper, you have discussed in detail the new treatment approaches to modify the course of small vessel disease. Could you tell the readers why you decided to write about this topic?

Prof. Smith: Cerebral small vessel disease is a common condition of aging. We now know that it can cause cognitive decline and stroke. When I chaired a writing group for the American Heart Association that produced a scientific statement on stroke prevention in persons with silent cerebrovascular disease (Smith et al, Stroke 2017; 48:e44-e71), one of the interesting things we found is that there were few clinical trials that focused on small vessel disease. There are no medications specifically indicated for cerebral small vessel disease. The time seemed ripe to review progress in this area, and indeed we found emerging evidence for new treatment strategies in early phase trials.

Prof. Markus: Cerebral small vessel disease is an enormous health problem — it causes a quarter of all strokes and is the most common cause of vascular dementia. Despite this, there are few, if any, treatments for established disease, and it remains one of the great therapeutic challenges in stroke. We wanted to summarize where we were and describe a pathway forwards.

Dr. Shekhar: You have mentioned that pathophysiology of chronic small vessel disease (cSVD) is complex and involves multiple pathways. Some genetic studies also point to the possibility that antiplatelet and anticoagulation therapy may have less effect on cSVD. Could you explain some of the pathophysiologies of cSVD and background studies?

Prof. Smith: The pathophysiology of cSVD is different from other causes of stroke, so the treatments might differ as well. There are two main vascular pathologies of cSVD: hypertensive arteriopathy and cerebral amyloid angiopathy. In addition to thrombotic occlusion of arteries, the effects of cSVD on the brain may also be mediated by other factors such as bleeding, increased blood vessel permeability, and inflammation. This raises the possibility that a cocktail of treatments, not only antithrombotics, might be most effective in preventing its progression.

Prof. Markus: Recent studies have suggested that genes which contribute to increased thrombosis or coagulation increase the risk of cardioembolic and large artery stroke, but do not increase the risk of small vessel stroke. This suggests that antithrombotic therapies may be less effective in small vessel disease, although this hypothesis needs testing in clinical trials.

Dr. Shekhar: Could you briefly discuss the five different intervention categories that could help prevent the progression of cSVD?

Prof. Smith: We found a variety of new therapies in development, including some non-drug related treatments. They could be grouped into these broad categories: lifestyle and behavioral (predominantly testing forms of physical exercise), new targets for conventional treatments (such as lower blood pressure goals), remote ischemic conditioning, new drugs (such as cilostazol), and drugs for reducing vascular beta-amyloid build up.

Dr. Shekhar: Could you name a few drug trials for cSVD? Any potential agent with good preclinical data that you believe might be clinically successful?

Profs. Smith and Markus: The field of cSVD trials is still young, with lots of interesting ideas but without enough information yet to pick a clear set of winners. Over the last year, exciting data from the SPRINT trial has shown that intensive, compared with standard, blood pressure lowering reduced the risk of MRI assessed SVD and may also reduce associated dementia. We found many other trials in early phase, testing new drugs and other strategies for feasibility and safety prior to planning larger definitive studies. The larger of these studies are testing different kinds of antihypertensives on brain blood flow and stroke. My own team is interested in the effects of remote ischemic conditioning, a treatment that uses a blood pressure cuff to temporarily cut off blood flow to the arm, which conditions the brain to protect itself from the low blood flow that can occur with cSVD. We are testing the tolerability of daily treatment in a small early phase trial (NCT04109963).

Dr. Shekhar: You have nicely described the way to optimize the trial design for cSVD. Could you mention some of the important ones?

Prof. Smith: The key area for optimization is to classify patients properly using neuroimaging. This is necessary to detect and classify cSVD, including which type, and also to measure progression, which can be detected on brain imaging before clinical events occur. The modern cSVD trials reflect this knowledge. The Standards for Reporting Vascular Changes on Neuroimaging (STRIVE) provide radiological definitions for cSVD which are widely used in the field.

Dr. Shekhar: We know that many studies are investigating the best ways to prevent cSVD. What is your current clinical practice for patients with cSVD?

Prof. Smith: The current management of patients with cSVD should vary depending on the type of cSVD and the clinical symptoms. cSVD has two common causes (hypertension and cerebral amyloid angiopathy), in addition to rarer causes such as the genetic disease CADASIL, and can present in many different ways, including ischemic stroke, hemorrhagic stroke, cognitive decline, or as an incidentally discovered finding on brain imaging done for another reason. For patients with stroke, relevant guidelines from the American Heart Association should be followed. For patients without stroke, there is less clear guidance, hence the need for clinical trials. One important aspect of management that seems to be relevant for all of these types and manifestations of cSVD is good control of blood pressure.

Prof. Markus: I’d agree that treating blood pressure intensively, down to a systolic of 125-130mmHg, is key and I’d prioritize this.

Dr. Shekhar: What recommendations do you have for the new breed of clinicians or non-clinical researchers in improving the overall care in patients with cSVD?

Prof. Smith: Increasingly, we will be able to individualize treatment to specific forms of cSVD and specific pathways using a precision medicine approach. This field is ripe for young researchers because I anticipate that in the coming years, we will see new discoveries of the biology of the neurovascular unit. A better understanding of the molecular processes that cause vessel wall thickening, leakiness, and altered reactivity in the setting of hypertension or cerebral amyloid angiopathy will likely yield new therapeutic targets.