Multiple Sclerosis Tied to Increased Risk for Stroke, CVD, Death

Batya Swift Yasgur, MA, LSW

May 12, 2020

Multiple sclerosis (MS) is associated with an increased risk for acute coronary syndrome (ACS), stroke, and death, a finding that is unexplained by traditional risk factors, new research suggests.

Researchers found that patients with MS had a 28% increased risk for ACS, a 59% increased risk for cerebrovascular disease, and a 32% increased risk for any macrovascular disease compared to matched healthy control persons.

In addition, patients with MS had a 1.5-fold higher risk for cardiovascular disease (CVD) mortality and more than a threefold increased risk for all-cause mortality.

"Vascular risk assessment and management in people with MS is extremely important, given their increased vascular risk and the impact that vascular comorbidities have on MS-specific outcomes," lead investigator Raffaele Palladino, PhD, assistant professor, Department of Public Health, University Frederico II, Naples, Italy, told Medscape Medical News.

The study was published online May 4 in JAMA Neurology.

"Sparse" Evidence

Evidence from population-based studies is sparse, and much of the previous research was conducted in specific settings and so the findings have limited generalizability, said Palladino, who is also a research associate at the Department of Primary Care and Public Health, Imperial College London, United Kingdom.

"We thought this study could offer an important contribution to the current knowledge of the association between MS and increased vascular risk and mortality. Furthermore, evidence on sex-related differences is still limited, while this was one of the focuses of the present study," he added.

The study data came from a large global database of electronic medical records and included 12,251 adult patients diagnosed with MS between 1987 and 2018. The researchers compared these patients to 72,575 healthy control persons who did not have MS or other demyelinating diseases.

Covariates consisted of demographic factors; vascular risk factors, such as smoking status; comorbidities; and medication use during the index year and the year of MS diagnosis.

The mean follow-up time for patients with MS and control persons was 10.3 and 11.5 years, respectively.

The proportion of individuals who used cardiovascular medication was "broadly similar" for the two cohorts, although more patients with MS smoked compared to control persons.

Women at Greater Risk

The incidence of macrovascular disease and mortality per 100,000 person-years during the study period was considerably higher for individuals with MS compared to control persons (see table).

Outcome People With MS vs Control Persons
ACS 204.5 vs 116.8
Cerebrovascular disease 159.6 vs 81.4
Composite macrovascular events 291.8 vs 159.1
Mortality 2223.3 vs 619.5 events


Multivariable analysis revealed that in comparison to control persons, patients with MS had a dramatically higher risk for ACS, cerebrovascular disease, and macrovascular disease (for ACS: hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.09 – 1.51; for cerebrovascular disease: HR, 1.59; 95% CI, 1.32 – 1.92]; for macrovascular disease: HR, 1.32; 95% CI, 1.15 – 1.52).

Women with MS had a 42% increased risk for ACS, a 78% increased risk for cerebrovascular disease, and a 49% increased risk for any macrovascular disease compared to control persons.

Mortality risk was also considerably higher. In adjusted analyses, those with MS had a 3.46-fold increased risk for all-cause mortality and a 1.47-fold increased risk for CVD mortality compared to control persons.

The risk for all-cause mortality in women with MS was more than triple that of female control persons (HR, 3.52; 95% CI, 3.28 – 3.77). Women also showed a 1.3-fold increase in CVD mortality (subhazard ratio [SHR], 1.30; 95% CI, 1.04 – 1.62).

In comparison, men with MS had a 2.7-fold increased risk for all-cause mortality (HR, 2.74; 95% CI, 2.35 – 3.18) and a 1.5-fold increased risk for CVD mortality (SHR, 1.54; 95% CI, 1.06 – 2.23).

"The reasons for sex differences are uncertain but may reflect differences in unmeasured risk factors, such as diet, other comorbidities, or effectiveness of risk factor management," the authors note.

In the study population, almost 3% of participants with and those without MS were taking lipid-lowering medications during the index year (2.7% and 2.9%, respectively). Almost all of these medications were statins.

Those with MS who were not taking lipid-lowering medications had a 3.6-fold increased mortality rate compared to control persons who were not taking lipid-lowering medications. By contrast, the mortality rate for individuals with MS who were taking lipid-lowering medications was increased twofold.

When stratified by sex, these findings remained "broadly similar."

How MS increases vascular risk is unclear. However, Palladino noted that MS enhances vascular inflammation, which is known to play a role in vascular disease and may be a driver of the increased risk. He noted that further research is needed to clarify this association.

Identify Early, Treat Aggressively

Commenting on the study for Medscape Medical News, Scott Newsome, DO, associate professor of neurology, Johns Hopkins Hospital, Baltimore, Maryland, said that the findings add to the mounting evidence that for patients with MS, medical conditions should be identified early and treated aggressively to "prevent bad outcomes, including death."

Newsome, who is also the director of the Neurosciences Consultation and Infusion Center at Green Spring Station, Maryland, recommended a "multidisciplinary approach to treating MS, including partnering with primary care clinicians."

Additionally, "it is important to encourage our patients to focus on healthy lifestyle choices, as this has shown to favorably impact quality of life and outcomes," said Newsome, who was not involved with the study.

Further research is needed to investigate the potential protective effects of lipid-lowering medications "before people with MS are ubiquitously started on these therapies as part of the regular treatment regimen," Newsome added.

The authors agree. "Given the adverse effects of these comorbidities on outcomes in patients with MS, further investigation is needed," they conclude.

The study was supported in part by the NW London National Institute for Health Research Applied Research Collaboration. Palladino reports no relevant financial relationships. The other authors' disclosures are listed on the original article. Newsome reports no relevant financial relationships.

JAMA Neurol. Published online May 4, 2020. Abstract

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