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EURO PEAN
SO CIETY O F
Original scientific paper CARDIOLOGY ®

European Journal of Preventive

Cardiology

Predictors of cardiovascular events 0(00) 1–7

! The European Society of
Cardiology 2014
in patients with systemic lupus Reprints and permissions:
sagepub.co.uk/journalsPermissions.nav
erythematosus (SLE): a systematic DOI: 10.1177/2047487314546826
ejpc.sagepub.com
review and meta-analysis

Flavia Ballocca1, Fabrizio D’Ascenzo1, Claudio Moretti1,

Pierluigi Omedè1, Enrico Cerrato1, Umberto Barbero1,
Antonio Abbate2, Maria Tiziana Bertero3,
Giuseppe Biondi Zoccai4 and Fiorenzo Gaita1

Abstract
Background: Cardiovascular disease represents an important cause of morbidity and mortality in patients with a diag-
nosis of systemic lupus erythematosus (SLE), due to a complex interplay between traditional risk factors and disregulation
of autoimmunity but uncertainty is still present about the most important predictors of cardiovascular events.
Objectives: The aim of our work was to perform a collaborative systematic review on the main predictors of cardio-
vascular events in SLE patients.
Methods: PubMed and Cochrane were systematically searched for eligible studies on SLE and cardiovascular events
between January 2008 and December 2012. Study features, patient characteristics and incidence of stent thrombosis
were abstracted and pooled, when appropriate, with random-effect methods (point estimate – 95% confidence intervals)
and consistency of predictors was formally appraised.
Results: A total of 17,187 patients was included; of those, 93.1% were female and the median age was 39 years. After a
median follow-up period of 8 years, cardiovascular events presented in 25.4%, including acute myocardial infarction
(4.1%) and stroke (7.3%). The most important predictors may be divided into traditional risk factors, such as male gender
(OR 6.2, CI 95% 1.49–25), hyperlipidaemia (OR 3.9, CI 95% 1.57–9.71), familiar history of cardiac disease (OR 3.6, CI
95% 1.15–11.32) and hypertension (OR 3.5, CI 95% 1.65–7.54), and SLE-related features, such as the presence of auto-
antibodies (OR 5.8 and 5.0, CI 95% 3.28–7.78) and neurological disorders (OR 5.2, CI 95% 2.0–13.9). A low correlation
was shown for the importance of organ damage and SLE activity (respectively OR 1.4, CI 95% 1.09–4.44 and OR 1.2, CI
95% 1.2–1.2), as well as for age at diagnosis (OR 1.1, CI 95% 1.07–1.17).
Conclusions: Cardiovascular events in SLE patients are caused by a multifactorial mechanism, including both traditional
and disease-specific risk factors. A global valuation with an individual risk stratification based on both these features is
important to correctly manage these patients in order to reduce negative outcomes.

Keywords
Systemic lupus erythematosus, cardiovascular events, predictors
Received 28 April 2014; accepted 21 July 2014

4
1
Division of Cardiology, Città della Salute e della Scienza, University of Department of Medico-Surgical Sciences and Biotechnologies, Sapienza
Turin, Italy University of Rome, Italy
2
VCU Pauley Heart Center, Virginia Commonwealth University, Corresponding author:
Richmond, VA, USA Flavia Ballocca, Division of Cardiology, Città della Salute e della Scienza,
3
Department of Clinical Immunology, AO Ordine Mauriziano, Torino, University of Turin, Corso Bramante 88-90, 10126 Turin, Italy.
Italy Email: flaviabl@hotmail.it

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2 European Journal of Preventive Cardiology 0(00)

2008 publication of the guidelines of the Eular that

Introduction deeply impacted on clinical practice.21
Systemic lupus erythematosus (SLE) is a chronic auto-
immune disorder with a wide spectrum of clinical mani-
Study selection
festations, ranging from malar rash, arthralgias and
characteristic plasma autoantibodies to life-threatening Retrieved citations were first screened independently by
manifestations such as nephritis or thrombosis. two unblinded reviewers at the title and/or abstract
In the past, renal and central nervous system involve- level, with divergences resolved after consensus.
ment were the main causes of mortality1–2 but with If potentially pertinent, they were then appraised as
improvement in therapy, especially steroid treatment, complete reports according to the following explicit
life expectancy has been extended, with a parallel selection criteria, which were piloted over the first five
increase in cardiovascular mortality and morbidity. cases. Inclusion criteria were (all had to be met for
Traditional risk factors (such as diabetes, hyperten- inclusion): (i) human studies; (ii) investigating patients
sion, hyperlipidaemia and smoking addiction) are with diagnosis of SLE, defined by American College of
common in these young patients, probably as a side Rheumatology criteria,22–23 with a thrombotic event
effect of immunosuppressant therapy;3,4 on the other (iii) published between 2008 and 2012 (iv) reporting
hand, from a pathological and clinical point of view, predictors of cardiovascular events obtained through
they do not completely explain the increased frequency univariable or multivariable analysis. Exclusion criteria
and the early presentation of cardiovascular disease in were (any one alone was enough for exclusion): (i) non-
this population.5–7 It is probable that an increased human setting; (ii) duplicate reporting (in which case
inflammatory response, as well as steroid therapy, the manuscript reporting the largest sample of patients
may play a crucial role in atherogenesis.8–11 Several with SLE and cardiovascular events was selected, or if
studies have been made to investigate this topic and equal, the study with the largest number of overall
to identify some predictors of the thrombosis burden patients).
– a crucial step to prevent undesirable outcomes.12–15
However, the evidence of increased cardiovascular dis-
ease incidence at the current time is fraught with conflict-
Data extraction
ing data on risk and predictors, which remains difficult to The following data were independently abstracted by two
overcome without a systematic approach. Therefore we unblinded reviewers on pre-specified electronic forms,
aimed to perform a meta-analysis focusing on incidence which were piloted over the first five cases, with divergences
and predictors of cardiovascular events in SLE patient. resolved after consensus. In particular, authors, journal,
year of publication, baseline, disease and therapy features,
events and multivariate predictors (estimator, point sum-
Methods mary estimate of risk, 95% confidence intervals).
This work was conducted in keeping with current End-points of interest for the present review were the
guidelines, including the recent Preferred Reporting incidence of cardiovascular events in SLE patients at the
Items for Systematic reviews and Meta-Analyses different time points as well as univariable and multi-
(PRISMA) amendment to the Quality of Reporting of variable predictors of cardiovascular events. Given the
Meta-analyses (QUOROM) statement, as well as rec- exploratory yet comprehensive scope of this collabora-
ommendations from The Cochrane Collaboration tive review, no explicit primary end-point was specified.
and Meta-analysis Of Observational Studies in
Epidemiology (MOOSE).16–19
Internal validity and quality appraisal
The quality of the studies included was independently
Search strategy
appraised by two unblended reviewers on pre-specified
MEDLINE/PubMed was searched for pertinent art- electronic forms, which were piloted over the first five
icles published in English between January 2008 and cases, with divergences resolved after consensus.
December 2012 according to the following strategy, in Modifying the MOOSE item list in order to take into
keeping with established methods20 and incorporating account the specific features of studies included, we
wild cards (identified by *): (systemic lupus erythema- separately abstracted and appraised study design, set-
tosus OR SLE) AND (((coronary OR arterial) AND ting, data source and statistical methods for univariable
(stent* OR ptca OR angioplasty OR cabg OR bypass and multivariable analysis, as well as – in keeping with
AND (graft* OR surgery))) OR (myocardial infarction The Cochrane Collaboration approach – the risk of
OR dissection OR thrombosis OR acute coronary syn- analytical, selection, adjudication, detection and attri-
drome)). We choose the time criteria because of the tion bias (expressed as low, moderate or high risk of

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Ballocca et al. 3

bias, as well as incomplete reporting leading to inability Hypertension was reported in 42.6% of the patients,
to ascertain the underlying risk of bias). dyslipidaemia in 44% and almost 20% were active
smokers (Table 1).
The median length of SLE diagnosis was 9 years,
Data analysis and synthesis
and most of the patients were on therapy with steroids
Continuous variables are reported as mean (standard (69.7%) and/or with other immunosuppressants
deviation) or median (1st; 3rd quartiles). Categorical (50.5%) and 36% with platelet inhibitors. Cardiovas-
variables are expressed as n/N (%). Statistical cular events presented in 25.4%, including acute myo-
pooling for incidence estimates was performed accord- cardial infarction (4.1%) and stroke (7.3%) (Table 2).
ing to a random-effect model with generic inverse-
variance weighting, computing risk estimates with Frequency and consistency of SLE predictors
95% confidence intervals, using RevMan 5 (The
in cardiovascular events
Cochrane Collaboration, The Nordic Cochrane
Centre, Copenhagen, Denmark). Conversely, risk esti- Many candidate risk factors were considered in the
mates were not pooled from individual studies as this studies of our meta-analysis, some of them common
approach would have not been feasible and valid given in the general population, some specific to SLE
the high risk for publication bias). We instead adopted patients. The most frequently and consistently reported
the approach of Ross et al.,24 and appraised the preva- predictors of cardiovascular events in SLE patients
lence of studies in which a given predictor was proven were male gender (OR 6.2, CI 95% 1.49–25), the pres-
significantly and independently associated with the out- ence of plasmatic anticardiolipin antibodies (OR 5.8,
come of interest. Small study bias was appraised by CI 95% 2.22–15.5) and global anti-phospholipid
graphical inspection of funnel plots. Using rates of
event as dependent variables, a meta-regression was
performed to test the effect of clinical features. Table 1. Patients’ baseline features.
Hypothesis testing for superiority was set at the two-
tailed 0.05 level. Hypothesis testing for statistical Studies N ¼ 32
homogeneity was set at the two-tailed 0.10 level and Patients, total 17,187
based on the Cochran Q test, with I2 values of 25%, Patients, median 288 (132; 688)
50% and 75% representing, respectively, mild, moder- Age (years) 39.5 (35.5; 44.5)
ate and extensive statistical inconsistency.
Female gender 93.1 (88.2; 93.1)
Hypertension 42.6 (34.8; 53.3)
Results Dyslipidaemia 43.9 (34.2; 61.2)
Diabetes 6.5 (4.5; 10.6)
Review profile and included studies Smoker
From a total of 2799, 32 studies were included Active 19.5 (16.4; 30)
(Figure 1); the median follow-up was 8 years (1st quar- Previous 33.3 (29.9; 41.7)
tile 6.7 years; 3rd quartile 8.8 years). Reported as median (1st; 3rd quartiles) or n/N
A total of 17,187 patients was included; of those, (with patients or studies as denominators, as
93.1% were female with a median age of 39 years. appropriate).

2799 records identified through

2320 studies excluded because
database searching
before 2008

30 not in human subjects

52 not in English
272 no full text
93 not reporting independent
predictors
32 studies included in the
systematic review

Figure 1. Literature search strategy and review profile.

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4 European Journal of Preventive Cardiology 0(00)

antibodies (OR 5.0, CI 95% 3.28–7.78) and the pres- study effects and reporting bias. These results were con-
ence of neurological disorders (OR 5.2, CI 95% 2.0– firmed at a subsequent meta-regression analysis.
13.9); dyslipidaemia (OR 3.9, CI 95% 1.57–9.71), famil-
ial history of cardiac disease (OR 3.6, CI 95% 1.15 –
Internal validity
11.32), hypertension (OR 3.5, CI 95% 1.65–7.54), as
well as azathioprine and steroid treatment, also The most important features of this study are summar-
appeared to be significant predictors, even though less ized in Table 4. The design was more frequently retro-
consistently (Figure 2, Table 3). spective (56%), with a multicentre setting in 46.8%;
A low correlation was shown with organ damage and most of the studies were conducted in North America
SLE activity (respectively OR 1.4, CI 95% 1.09–4.44 and (40.6%) and Europe (37.5%).
OR 1.2, CI 95% 1.2–1.2), as well as for the age at diag-
nosis (OR 1.1, CI 95% 1.07–1.17). However, it must be
Discussion
emphasized that these are not pooled estimates but esti-
mates from single studies and so at high risk of small Patients with SLE have an increased risk of cardiovas-
cular events, especially a thrombotic event. To the best
of our knowledge, this is the first systematic review
Table 2. Patients’ disease features and outcomes.
focusing on incidence and predictors of cardiovascular
Studies N ¼ 32 events in SLE patients. In a total of 17,187 patients
from 32 studies, the incidence of cardiovascular
Follow-up (years) 8 (6.7; 8.8) events was almost 25% and 4.5% of the patients had
Length of SLE diagnosis (years) 9.1 (4.7; 11.3) an acute myocardial infarction.
Therapy None of the 17 candidate predictors identified
Steroid treatment 69.7 (56; 80) occurred in all the studies included, reflecting the com-
Other immunosuppressants 50.5 (37.9; 79.5) plex pathophysiology of cardiovascular events in SLE
Platelet inhibitors 36.1 (16.5; 43) and the limitations in its classification, and the ensuing
Oral anticoagulants 16.5 (14.7; 27.7) challenges in conducting case-control or cohort studies
Cardiovascular events 25.4 (13.1; 32.4) capable of providing precise, accurate and consistent
Death 19.1 (11.3; 26.8) statistical results. Nevertheless, analysing some candi-
Cardiovascular death 4.1 (2.1; 6) date predictors of cardiovascular events in this popula-
tion, it emerged that they can be divided in two groups:
AMI 4.5 (2.4; 9.6)
traditional risk factors and features of SLE patients.
Stroke 7.3 (4.1; 11.8)
In the first group, male gender was one of the stron-
Reported as median (1st; 3rd quartiles). gest predictors but the weight of this feature should be

Male gender 6.25

a-CL (anticardiolipin) + 5.87
Neurological disorders 5.20
APS antibodies (all) 5.05
Hyperlipidaemia 3.91
Family history 3.62
Hypertension 3.52
LA (lupus anticoagulant) + 3.48
Azathioprine 3.18
Steroids 2.46
Smoking 2.20
Immumomodulator therapy 1.95
Nephritis 1.65
Systemic lupus international collaborating... 1.44
Duration of SLE (per 5 years) 1.27
SLEDAI2K - disease activity 1.20
Age 1.12
0 5 10 15 20 25 30
%

Figure 2. Most powerful predictors of cardiovascular thrombotic events in SLE patients.

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Ballocca et al. 5

carefully considered, remembering that most SLE may be related both to high inflammatory response due
patients are women. An important role is also played to the autoimmune disease and to long-term pharma-
by dyslipidaemia, hypertension, familial history of cor- cological treatment with immunosuppressants, espe-
onary artery disease (CAD) and smoking addiction. cially steroids. The impact of cigarette smoking may
The prevalence of these risk factors in such young be multifactorial: on the one hand, it may contribute
patients is unusual in the global population; the early to cardiovascular risk amplifying the classical athero-
onset of pathologies such as hypertension and diabetes genic process. On the other hand, it may play a role in
some aspects of SLE evolution: smoking has been asso-
ciated with progression of lupus nephritis to end-stage
Table 3. Predictors of cardiovascular events in SLE patients. renal disease, it may reduce the response to immuno-
suppressant therapies, and, by causing a low-grade
Predictor OR (95% CI)
systemic inflammatory response, it may worsen the
Male gender 6.2 (1.49–25) progression of the disease.25,26
Anticardiolipin (a-CL) 5.8 (2.22–15.5) In the second group, the highest correlation with
Neurological disorders 5.2 (2.0–13.9) cardiovascular events was shown by the presence of
Anti-phospholipid (APS) antibodies 5.0 (3.28–7.78) autoantibodies, such as antiphospholipid antibodies,
Hyperlipidaemia 3.9 (1.57–9.71)
anticardiolipin antibodies and lupus anticoagulant,
which are produced in 30–40% of SLE patients.
Family history 3.6 (1.15–11.32)
However, this risk factor does not fully explain the
Hypertension 3.5 (1.65–7.54)
increased thrombosis risk in SLE because literature
Lupus anticoagulant (LA) 3.5 (1.29–9.36) data show that only 10% of ‘positive’ patients experi-
Azathioprine treatment 3.2 (1.33–7.59) ence a thrombotic event and 40% of SLE thrombosis
Steroid treatment 2.4 (1.03–5.88) cases are autoantibodies negative.27,28
Smoking addiction 2.2 (1.40–3.46) The increased risk seen in this population seemed to be
Immunosuppressant therapy 1.9 (1.18–3.21) associated with the therapy used to cure the autoimmune
Nephritis 1.6 (1.04–2.60) disease, both steroid and immune suppressant.29 Part of
Systemic SLE damagea 1.4 (1.09–4.44) the effect of these treatments may be related to their
Duration of SLE (per 5 years) 1.3 (1.12–1.43) impact on hypertension, dyslipidaemia and diabetes –
SLEDAI2K – disease activity 1.2 (1.2–1.2) well-known side effects of steroids – explaining the high
Age 1.1 (1.07–1.17)
prevalence of these comorbidities in this young popula-
tion.30 Furthermore, high dosages of glucocorticoids are
Reported as median (1st; 3rd quartiles). aSystemic Lupus International associated with higher disease activity and therefore they
Collaborating Clinics Damage Index. are probably a proxy variable. Nevertheless, the activity
and severity of the disease, expressed by some multi-
variable scores such as Systemic SLE Damage and
SLEDAI2K, as well as disease duration, seemed con-
Table 4. Key features of included studies. versely to have a smaller impact on cardiovascular risk.
Studies N ¼ 32 This result appears to contradict the hypothesis of
increased atherogenesis due to the inflammatory
Study design response in SLE, underlying the multifactorial mechan-
Prospective cohort, n (%) 14 (43.7) ism of cardiovascular disease in these patients.
Retrospective cohort, n (%) 18 (56.2%) Therefore, cardiovascular events in SLE patients
Year of publication 2010 (2009; 2011) cannot be systematically avoided just by addressing a
Setting, n (%) single or a few risk factors but only through a global
Single centre 17 (53.1) appraisal and management of each individual patient.
Multicentre 15 (46.8) To correctly manage these patients, it becomes funda-
Location, n (%) mental to individually risk-stratify the patient, stressing
Worldwide 1 (3.1)
the importance of acting on modifiable common risk
factors such as hypertension and dyslipidaemia, and
North America 13 (40.6)
accurately searching for SLE-specific features.
Europe 12 (37.5)
Asia 5 (15.6)
Follow-up (years) 8 (6.7; 8.8) Limits of this study
Reported as n/N (with studies as denominator) or median Our systematic meta-analysis has some limitations
(1st; 3rd quartiles). related to the nature of the primary studies.

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6 European Journal of Preventive Cardiology 0(00)

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This research received no specific grant from any funding artery disease in systemic lupus erythematosus: a pro-
agency in the public, commercial or not-for-profit sectors. spective proof-of-concept cohort study. Arthritis Res
Ther. 2011; 13: R156.
Conflicts of interest 16. Moher D, Cook DJ, Eastwood S, et al. Improving the
None declared by authors. quality of reports of meta-analyses of randomized con-
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