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Patients with multiple sclerosis (MS) are at increased risk for all-cause mortality, mortality related to cardiovascular issues, and macrovascular events. Experts discuss the need to carefully monitor MS patients for cardiovascular risk.

People with multiple sclerosis (MS) are at a greater risk of macrovascular events, all-cause mortality, and mortality related to cardiovascular issues, according to a large population study recently published in JAMA Neurology.

Derived from more than 12,000 people with MS matched with about six controls each, the findings offer a rigorous portrait of the cardiovascular risks that MS patients face, and the researchers say, point to the need for careful assessment of these risks to pave the way for the best outcomes. The findings also underscored the heightened risks of women with MS, who fared worse on most of the outcomes that investigators explored.

We thought this study could offer an important contribution to the current knowledge on the association between MS and increased vascular risk and mortality, said Raffaele Palladino, PhD, a research associate in primary care and public health at the Imperial College of London and assistant professor of public health at the University of Naples.

Evidence from previous population-based studies is sparse and many of the previously published studies were conducted in specific settings with limited generalizability to the general population. Furthermore, evidence on sex-related differences is still limited, while this was a focus of the present study.

The data came from the UK Clinical Practice Research Datalink, one of the world's largest electronic medical records databases, covering 7 percent of the UK population and representative of the populace in age, sex and race, and ethnicity. Researchers reviewed MS cases from 1987 to 2018, with an average follow-up of about 11 years. Subjects were considered to have MS only if they had 3 documented MS events.

Researchers found that those with MS had a 32 percent increased risk of any macrovascular diseasewhich included acute coronary syndrome, cerebrovascular disease or peripheral artery diseasecompared with those without MS (HR=1.32; 95% CI: 1.15-1.52). Women with MS had a 49 percent increased risk of any macrovascular disease (HR=1.49; 95% CI: 1.26-1.77).

There were no differences seen in men for macrovascular outcomes when all years were considered, but researchers did find a difference when considering only MS cases from 2002 to 2018the period during which MRI criteria had become standard for diagnosing MS. In that period, men had a 67 percent increased risk of any macrovascular disease (HR=1.67; 95% CI: 1.15-2.43).

People with MS had a 3.5-fold increased risk of all-cause mortality compared with those without the disease (HR=3.46; 95% CI: 3.28-3.65) and 47 percent increased risk of cardiovascular disease mortality (subdistribution HR=1.47; 95% CI: 1.27-1.71). There was a 3.5-fold increased risk for women with MS (HR = 3.52; 95% CI: 3.28-3.77) in all-cause mortality and a 30 percent increased risk for women with MS for cardiovascular mortality (HR=1.30; 95% CI: 1.04-1.62), compared with those who did not have MS.

Men with MS had a 2.7-fold increased risk of all-cause mortality compared with those without MS (HR=2.74; 95% CI: 2.35-3.18), and they had a 54 percent increased risk of cardiovascular disease mortality (subdistribution HR=1.54; 95% CI: 1.06-2.23).

We would recommend aggressive vascular risk monitoring and possibly treatment especially in women with MS, Dr. Palladino said.

This appeared to be the first population-level study to look at the effect of lipid-lowering medications of people with MS on all-cause mortality, researchers said. About 3 percent of the study population was taking a lipid-lowering drug in the index year, the year of the first MS event2.7 percent in those with MS, 95 percent of which were statins, and 2.9 percent in controls, 94 percent of which were statins.

Compared with the controls who were not taking lipid-lowering medications, those with MS who were not taking these drugs had a 3.6-fold increased all-cause mortality (HR=3.62; 95% CI, 3.43-3.83). But compared to controls taking lipid-lowering drugs, those with MS taking these drugs had just a two-fold increased all-cause mortality (HR=1.95; 95% CI: 1.58-2.42).

Lipid-lowering medications seemed to have a protective association with all-cause mortality in people with MS, Dr. Palladino sad. Therefore, a thorough vascular risk assessment should be performed in people with MS at time of diagnosis and follow-up visits to identify those who might benefit the most from intensive vascular risk reduction strategies, which might include lipid-lowering treatment.

Overall, he said, the findings point to the need for careful management of MS patients when it comes to their cardiovascular risk.

Vascular risk and vascular comorbidities assessment should become integrated into the care of people with MS, given the adverse impacts of vascular comorbidities on the MS disease trajectory and cardiovascular outcomes in people with MS, he said. This will require a collaborative approach with primary care.

Shiv Saidha, MD, associate professor of neurology at Johns Hopkins, said the study is highly informative, confirming prior findingsthat those with MS have a heightened risk of macrovascular diseasewhile also containing some findings that are new.

The study findings are in alignment with prior studies, and not unsurprisingly this study also found that people with MS have a higher all-cause, as well as cardiovascular disease-related mortality, he said. This being said, the finding that people with MS treated with lipid lowering agents such as statins may have a lower mortality rate is both novel and instructive.

He said that clinical care of people with MS has included increased attention to smoking cessation and tight control and management of vascular comorbidities, in light of mounting data that worse outcomes are linked with these habits and comorbidities.

Dr. Saidha said the findings should serve as a reminder for clinicians to counsel patients on factors that could promote vascular health. But he said the field needs to learn more about the causality involved here.

Mechanistically, it is important to elucidate the basis for why people with MS may be more susceptible to macrovascular disease/complications, he said. This could have an impact on how best to manage vascular risk specifically among people with MS, as well as potentially lead to the identification of novel targets/strategies to aid the management of MS. Moreover, while the current study did account for some traditional vascular risk factors, it did not account for the effect of MS disability/activity levels, diet, BMI, or other lifestyle factors, which in various combinations, may have major roles in the pathogenic risk for underlying vascular dysfunction. Alternatively, there may be other directly MS-related pathobiological underpinnings.

Sharon G. Lynch, MD, FAAN, professor of neurology and neuroimmunology division chief at the University of Kansas School of Medicine, said the findings of a modest correlation with MS and cerebrovascular disease dovetail with findings at her center a few years ago showing a similar correlation between MS and stroke.

Several things come to mind that could help to explain this, including reduced exercise in the MS populations, diet, and other lifestyle issues, Dr. Lynch said.

She said she has not noticed that there is a major, increased risk of vascular problems among her MS patients. But she said the findings suggest that awareness of the risk among primary care providers would be helpful.

For the most past, I recommend exercise and a healthy diet and, of course, smoking cessation in all of my patients, regardless of vascular risk. I don't manage other risk factors such as diabetes, hyperlipidemia, or hypertension personally, but instead, encourage them to work with their primary care provider for management of these risk factors, she said. I don't know that clinical care should change in specific way (in light of the study), but we do need to encourage our patients to take care of their health in general, rather than focusing solely on MS.

Drs. Palladino and Gutierrez had no relevant disclosures. Dr. Saidha has received consulting fees from Medical Logix for the development of CME programs in neurology and has served on scientific advisory boards for Biogen, Genentech Corporation, EMD Serono, and Celgene. He is the principal of investigator-initiated studies funded by Genentech Corporation and Biogen Idec and received support from the Race to Erase MS Foundation. He has received equity compensation for consulting from JuneBrain LLC, a retinal imaging device developer. He is also the site investigator of a trial sponsored by MedDay Pharmaceuticals.

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