Cardiovascular Outcomes in Systemic Lupus Erythematosus

Quick Takes

  • This large nationwide retrospective case-control study from Denmark followed 3,411 systemic lupus erythematosus (SLE) patients and 13,644 matched controls over a median of 8.5 years.
  • Patients with SLE had a nearly twofold greater risk of developing heart failure (HFpEF or HFrEF) compared to their matched controls. In addition, they had greater risk of developing VTE, AF/AFl, ischemic stroke, and a composite of ICD placement/cardiac arrest/ventricular arrhythmias.
  • Among patients who developed heart failure, the mortality of those with SLE was greater than those without SLE.

Study Questions:

For patients with systemic lupus erythematosus (SLE), what is the long-term risk of developing heart failure (HF) and other cardiovascular comorbidities?

Methods:

This was a retrospective case-control study, which used several national (Danish) registries to identify all Danish residents with a first-time SLE diagnosis between 1996-2018. Exclusion criteria included any history of heart disease (ischemic, heart failure), arrhythmias (atrial fibrillation/flutter [AF/AFl], ventricular), stroke, venous thromboembolism (VTE), endocarditis, presence of pacemaker or implantable cardioverter-defibrillator (ICD). Index was defined as the date of diagnosis. Patients were matched with four control subjects by age (up to 1-year difference), sex, year of index date, and comorbidities prior to inclusion. Primary outcome was the incidence of HF (either HF with preserved ejection fraction [HFpEF] or HF with reduced EF [HFrEF]), while secondary outcomes were incidence of AF/AFl, ischemic stroke, myocardial infarction, VTE, ICD or pacemaker implantation, ventricular arrhythmias, cardiac arrest, and death (i.e., all-cause mortality). A secondary analysis was performed in which SLE patients who developed HF were separately matched to non-SLE subjects with HF by age, sex, and year of HF diagnosis. The primary outcome of this secondary analysis was all-cause mortality.

Results:

A total of 3,462 patients with SLE were included, with 13,644 matched controls. Median age was 44.6 years (interquartile range [IQR], 31.9-57.0 years), and 86% were female. Median follow-up from index until HF diagnosis, death, or end of the study was 8.5 years (IQR, 4.0-14.4 years) for the SLE group and 9.4 years (IQR, 4.6-15.3 years) for matched controls. The absolute 10-year risk of incident HF was 3.71% (95% confidence interval [CI], 3.02-4.51%) for SLE patients vs. 1.94% (95% CI, 1.68-2.24%) for controls. Incidence of HF per 1,000 person-years was highest in the first 365 days: 7.26 in SLE patients compared to 1.33 in controls (adjusted hazard ratio [HR], 6.88; 95% CI, 3.53-13.41). Numerous secondary outcomes also occurred more frequently in the SLE group than matched controls, including AF/AFl (5.5 vs. 3.4%), ischemic stroke (4.3 vs. 2.4%), VTE (6.5 vs. 1.9%), and the composite of ICD placement/ventricular arrhythmias/cardiac arrest (0.9% vs. 0.3%). In the secondary analysis, SLE patients who developed HF had higher mortality compared to matched non-SLE patients who developed HF (adjusted HR, 1.50; 95% CI, 1.08-2.08).

Conclusions:

First, SLE patients had an approximately twofold higher long-term risk of incident HF compared to matched control subjects. Although the rate was highest within the first year after an SLE diagnosis, it remained elevated throughout the study period. Second, SLE patients had a higher incidence of multiple other adverse cardiovascular outcomes compared to the matched control subjects, including AF/AFl, VTE, ischemic stroke, and a threefold higher rate of ICD placement/ventricular arrhythmias/cardiac arrest. Last, in a separate analysis, SLE patients who developed HF had higher all-cause mortality compared to matched controls with HF alone.

Perspective:

This was a large case-control study of SLE patients, assessing their long-term risk of HF and numerous other adverse cardiovascular outcomes. Among the strengths of the study were its size, control-to-case ratio (4:1), lengthy follow-up period (median of 8.5 years), and fairly robust findings, which strongly suggest associations between SLE and a wide range of cardiac and cerebrovascular events. At the same time, the impact is limited by the study design, which prevents any conclusions regarding causation, limits calculation to adjusted HRs rather than relative risk, and introduces the possibility of bias. In particular, some important covariates are missing in the initial matching of SLE to non-SLE patients, including body mass index and smoking status. Likewise, the matching of SLE patients with HF to non-SLE patients with HF fails to take into account the type (e.g., HFrEF vs. HFpEF) or severity (e.g., New York Heart Association class or EF) of HF. Finally, there are concerns about the generalizability of the results, given the homogeneity of the Danish population, to patients in other countries. Further research will be needed to validate the results and understand their implications for surveillance, prognostication, and treatment of patients with SLE and cardiovascular complications.

Keywords: Arrhythmias, Cardiac, Atrial Fibrillation, Brain Ischemia, Defibrillators, Implantable, Heart Arrest, Heart Failure, Lupus Erythematosus, Systemic, Myocardial Infarction, Pacemaker, Artificial, Risk, Secondary Prevention, Stroke, Stroke Volume, Venous Thromboembolism, Vascular Diseases


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