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. 2020 Jul 1;77(7):820-828.
doi: 10.1001/jamaneurol.2020.0664.

Evaluating the Risk of Macrovascular Events and Mortality Among People With Multiple Sclerosis in England

Raffaele Palladino  1   2 , Ruth Ann Marrie  3   4 , Azeem Majeed  1 , Jeremy Chataway  5   6
Affiliations

Evaluating the Risk of Macrovascular Events and Mortality Among People With Multiple Sclerosis in England

Raffaele Palladino et al. JAMA Neurol. .

Abstract

Importance: People with multiple sclerosis (MS) are associated with an increased risk of cardiovascular disease and mortality; however, evidence from population-based studies is sparse.

Objective: To assess whether the risk of macrovascular events and mortality differs among people with MS compared with a matched population without MS in England.

Design, setting, and participants: A population-based retrospective matched cohort study was conducted in general practices registered with the Clinical Practice Research Datalink in England between January 1, 1987, and September 30, 2018, with a mean (SD) follow-up of 11.3 (6.5) years. A total of 12 251 patients with MS were matched with up to 6 people without MS (n = 72 572) by age, sex, and general practice. People with 3 or more diagnoses of MS recorded during the study period were included. The first MS diagnosis was considered as index date.

Exposures: Multiple sclerosis status. Analyses were also stratified by sex.

Main outcomes and measures: Main outcomes were acute coronary syndrome, cerebrovascular disease, any macrovascular disease (including peripheral arterial disease), and mortality (all-cause mortality and cardiovascular disease-specific mortality). Cox proportional hazards regression and Fine and Gray proportional subhazard regression models were used to assess differences in rates.

Results: A total of 12 251 people with MS (66.9% women; mean [SD] age, 44.9 [13.3] years) were matched with 72 572 people without MS (69.8% women; mean [SD] age, 44.9 [13.3] years). As compared with people without MS, people with MS were associated with a 28% increased hazard of acute coronary syndrome (hazard ratio [HR], 1.28; 95% CI, 1.09-1.51), 59% increased hazard of cerebrovascular disease (HR, 1.59; 95% CI, 1.32-1.92), 32% increased hazard of any macrovascular disease (HR, 1.32; 95% CI, 1.15-1.52), 3.5-fold increased hazard of all-cause mortality (HR, 3.46; 95% CI, 3.28-3.65), and 1.5-fold increased hazard in cardiovascular disease mortality (HR, 1.47; 95% CI, 1.27-1.71). Differences in macrovascular events were more pronounced among women than men. Mortality risk was also higher for women than men. Treatment with lipid-lowering medications (mainly statins) was associated with lower mortality rates among people with MS.

Conclusions and relevance: This study suggests that MS is associated with an increased risk of cardiovascular and cerebrovascular disease that is not completely accounted for by traditional vascular risk factors. Given the adverse effects of these comorbidities on outcomes in patients with MS, further investigation is needed.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Marrie reported receiving research funding from Canadian Institutes of Health Research, the National Multiple Sclerosis Society, MS Society of Canada, Consortium of Multiple Sclerosis Centers, Crohn’s and Colitis Canada, and the Waugh Family Chair in Multiple Sclerosis. Dr Chataway reported receiving support from the Efficacy and Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership and the Health Technology Assessment (HTA) Programme (NIHR), UK Multiple Sclerosis Society, National Multiple Sclerosis Society and the Rosetrees Trust, National Institute for Health Research University College London Hospitals Biomedical Research Centre, and University College London; serving as a local principal investigator for a trial in multiple sclerosis funded by the Canadian MS Society, and a local principal investigator for commercial trials funded by Actelion, Biogen, Novartis, and Roche; receiving an investigator grant from Novartis; and serving on advisory boards or as a consultant for Azadyne, Biogen, Celgene, MedDay, Merck, and Roche. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Cumulative Hazards of Macrovascular Events for Patients With Multiple Sclerosis (MS) and Matched Controls
For the definition of any macrovascular disease, the following conditions were included: acute coronary syndrome, cerebrovascular disease, and peripheral arterial disease.
Figure 2.
Figure 2.. Cumulative Hazards of All-Cause Mortality for People With Multiple Sclerosis (MS) and Matched Controls in England
Figure 3.
Figure 3.. Association Between Multiple Sclerosis (MS) and Risk of Macrovascular Disease and Mortality Between January 1987 and September 2018 in England
Analyses of mortality outcomes included all individuals with a diagnosis of MS after January 1, 1987, who met case definition criteria for MS and matched controls (see Methods). For analyses of macrovascular diseases, people with a history of the condition at baseline were excluded from the analysis. Date of MS diagnosis was considered as the index date, and a matched index date was assigned to matched controls. Multivariable Cox proportional hazards regression models were used to model the association between MS status and incident rates of acute coronary syndrome, cerebrovascular disease, any macrovascular disease (including acute coronary syndrome, cerebrovascular disease, and peripheral arterial disease), and all-cause mortality. To model differences in rates of cardiovascular disease mortality, competing-risk regressions based on the Fine and Gray proportional subhazard model was used that considered noncardiovascular disease mortality as a competing event, and cumulative incidence functions were computed for subgroups of interest. Regression analyses were adjusted for the following baseline covariates: age; sex; race/ethnicity; index of multideprivation; smoking status; diagnosis of diabetes or depression; use of lipid-lowering, oral antidiabetic, antihypertensive, antiplatelet, and anticoagulation medications; and number of primary care visits in the year before the diagnosis of MS and for the year of diagnosis of MS. For the sensitivity analysis, only patients with MS (and matched controls) who received a diagnosis during the period from 2002 to 2018 were included. HR indicates hazard ratio.
Figure 4.
Figure 4.. Association Between Multiple Sclerosis (MS), Treatment With Lipid-Lowering Medications, and Risk of Macrovascular Disease and Mortality Between January 1987 and September 2018 in England
See this image and copyright information in PMC

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