Lupus (2017) 26, 1463–1472

journals.sagepub.com/home/lup

REVIEW

Primary prevention of cardiovascular disease in patients with

systemic lupus erythematosus: case series and literature review
S Fasano1, DP Margiotta2, L Navarini2, L Pierro1, I Pantano1, A Riccardi1, A Afeltra2 and G Valentini1
1
Department of Clinical and Experimental Medicine, University of Campania ‘Luigi Vanvitelli’, Naples, Italy; and 2Unit of Allergology,
Immunology and Rheumatology, Campus Bio-Medico University, Rome, Italy

Background: Systemic lupus erythematosus is associated with an increased risk of cardiovas-

cular disease. Low-dose aspirin, hydroxychloroquine and statins have been suggested to play a
prophylactic role of cardiovascular events. This study is devoted to reviewing the literature on
the topic and assessing the effects of these drugs in preventing a first cardiovascular event in a
two-centre Italian series. Methods: A PubMed search on cardiovascular prevention in sys-
temic lupus erythematosus was performed. Moreover, systemic lupus erythematosus patients
admitted to two centres from 2000–2015, who at admission had not experienced any cardio-
vascular event, were investigated. Aspirin, hydroxychloroquine and statin use, and the occur-
rence of any cardiovascular event, were recorded at each visit. Kaplan-Meier and Cox
regression analyses were performed to evaluate the role of traditional, disease-related cardio-
vascular risk factors and of each of the three drugs in the occurrence of new cardiovascular
events. Results: The literature search produced conflicting results. Two hundred and ninety-
one systemic lupus erythematosus patients were included in the study and followed for a
median of eight years. During follow-up, 16 cardiovascular events occurred. At multivariate
analysis, taking aspirin (hazard ratio: 0.24) and hydroxychloroquine for more than five years
(hazard ratio: 0.27) reduced, while antiphospholipid antibody positivity (hazard ratio: 4.32)
increased, the risk of a first cardiovascular event. No effect of statins emerged. Conclusion:
Our study confirms an additive role of aspirin and hydroxychloroquine in the primary prophy-
laxis of cardiovascular events in Italian patients with systemic lupus erythematosus. The lack
of any detected effect in previous reports may depend on the design of studies and their short
follow-up period. Lupus (2017) 26, 1463–1472.

Key words: Systemic lupus erythematosus; hydroxychloroquine; aspirin; statins; cardiovas-

cular risk

Introduction related to active disease have been progressively

decreasing. However, CV morbidity and mortality
Systemic lupus erythematosus (SLE) is a multisys- have shown no such decline and, nowadays,
tem autoimmune disease associated with increased CV disease persists as the main cause of death
mortality as compared with the general popula- in patients with SLE. In particular, CV disease devel-
tion,1,2 with early deaths due to active disease and ops earlier and in younger people with SLE as com-
infections and later deaths mostly related to cardio- pared with the general population.6 It has been
vascular (CV) complications.3 proposed, therefore, that SLE should be considered
Over recent decades, due to advances in treat- as a ‘CV disease equivalent’ such as diabetes mellitus,
ment and better understanding of disease mechan- with more aggressive monitoring and treatment.7
isms, 10-year survival of patients with SLE has Despite the increased CV risk in SLE patients, to
dramatically improved.4,5 In particular, deaths date there is no high-quality evidence on which to
base any preventive strategies. Actually, conflicting
results have been reported on the effectiveness of
Correspondence to: Serena Fasano, Rheumatology Section, certain agents in preventing a first CV event, espe-
Department of Clinical and Experimental Medicine, University of cially aspirin (ASA), hydroxychloroquine (HCQ)
Campania ‘Luigi Vanvitelli’, II Policlinico (Building 3), Via
S. Pansini 5, Naples 80131, Italy.
and statins.
Email: serena.fasano@unicampania.it In previous retrospective one-centre studies,
Received 10 May 2017; accepted 4 July 2017 we first provided evidence on the effectiveness of
! The Author(s), 2017. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav 10.1177/0961203317722847
 Primary prevention of cardiovascular disease in SLE
S Fasano et al.
1464
low-dose ASA in the primary prophylaxis of CV
events in SLE8 and subsequently pointed out an
additive effect of long term HCQ therapy in the
same setting.9
Here, we review all previously reported evidence
to define the state of the art of CV risk prevention
in SLE and assess the role of these drugs on a larger
series from two Italian centres.
Methods
Literature search strategy
We analysed current evidence on the CV primary
prophylaxis in SLE by a review of the literature,
including articles published up to February 2016.
This review was based on a bibliographic search in
the PubMed database, using the following key-
words (square brackets contain search filters):
‘aspirin*’[tiab] OR ‘acetylsalicylic acid*’[tiab] OR
‘salicylate*’[tiab] OR ‘anti-platelet*’[tiab] OR ‘anti-
aggregant*’[tiab] OR ‘statin*’[tiab] OR ‘hydroxy-
chloroquine’[tiab] OR ’antithrombotic*’[tiab] OR
‘atherothromb*’[tiab] OR ‘accident*’[tiab] OR
‘stroke*’[tiab] OR ‘cerebrovascular disease*’[tiab]
OR ‘cerebrovascular disorder*’[tiab] OR ‘cardio-
vascular disease*’[tiab] OR ‘heart disease*’[tiab]
OR ‘myocardial infarction’[tiab] OR ‘heart arrest’[-
tiab] OR ‘ischemi*’[tiab] OR ‘ischaemi*’[tiab] OR
‘coronary artery disease’[tiab] OR ‘heart attack*’[-
tiab] OR’ stroke’[tiab]OR ‘infarction’[tiab]OR
‘angina*’[tiab] OR ‘thrombo*’[tiab] OR ‘prophy-
la*’[tiab] OR ‘prevent*’[tiab] OR ‘cardiovasc*’[-
tiab] OR ‘ischaemi*’[tiab] OR ‘ischaemi*’[tiab]
OR ‘Platelet Aggregation Inhibitors’[Mesh] OR
‘Myocardial Ischemia’[Mesh] OR ‘Brain
Ischemia’[Mesh] OR ‘Arteriosclerosis’[Mesh])
AND (‘Lupus*’[tiab] OR ‘Lupus Erythematosus,
Systemic’[Mesh]) AND ‘Humans’[Mesh].
Furthermore, we also included some rele-
vant studies not present in our PubMed search,
but referenced in other articles. Exclusion criteria
were: (a) juvenile SLE; (b) review articles; (c) case
reports; and (d) lack of any pharmacologic CV pre-
vention. Therefore, we selected randomised
controlled trials (RCTs), case-control and cross-
sectional studies, including adult SLE patients, in
which the effects on thrombosis of ASA, HCQ and
statins were analysed. Decisions regarding inclu-
sion or exclusion of papers were taken by consensus
among the authors. From a total of 4135, only 21
articles were included in the final analysis. The
GRADE system (Grades of Recommendation
Lupus
Assessment, Development and Evaluation) was
used to analyse the quality of evidence.10
Enrolment
Patients prospectively admitted from 1 November
2000 to 31 December 2015 to the Rheumatology
Units of either University of Campania ‘Luigi
Vanvitelli’ (previously named Second University
of Naples) or Campus Bio-Medico in Rome were
considered for the study.
Patients were enrolled if, at admission, 1997
updated American College of Rheumatology
(ACR) criteria for SLE11 and/or the 2012 classifi-
cation criteria of the Systemic Lupus International
Collaborating Clinics group (SLICC)12 were satis-
fied and no CV event had been experienced. The
study was approved by local Ethics Committees
(CE 278). Written informed consent was obtained
by each patient.
Follow-up and outcome
Patients were subsequently assessed every six
months, unless requiring more frequent visits for
their clinical condition. At each visit, any interven-
ing CV event, defined as the occurrence of angina
or myocardial infarction (MI), heart failure, tran-
sient ischaemic attack (TIA), stroke or peripheral
arterial thrombosis,13 was recorded. The duration
of follow-up was defined as the time from the first
visit to the first CV event or to the last observation
in patients without thrombosis.
Deaths and their respective causes were identi-
fied from clinical records, hospital discharge or,
when unavailable, by contacting the patient’s rela-
tives. In December 2016, the vital status of each
patient was ascertained.
Clinical and laboratory data
Each database contains information about each
patient from admission throughout follow-up,
and includes demographics, clinical features, expos-
ure to drugs and serologic investigations carried
out to assess disease activity by the Safety of
Estrogens in Lupus Erythematosus National
Assessment SLE Disease Activity Index
(SELENA-SLEDAI)14 and disease damage by the
SLICC/ACR Damage Index (SDI).15 Antinuclear
and anti-dsDNA antibodies were detected by
immunofluorescence using HEp-2 cells and
Crithidia luciliae as substrate;16 antiphospholipid
antibody (aPL) positivity was defined when
at least one of the following was detected at
medium-high titres on two or more occasions at

least 12 weeks apart: lupus anticoagulant, anticar-
diolipin and anti-b2 glycoprotein I antibodies (IgG
and IgM).
Traditional CV risk factors (hypercholesterol-
aemia, hypertriglyceridaemia, diabetes mellitus,
arterial hypertension, smoking and obesity) were
considered to be present if they were observed at
any time during the follow-up period.17
According to the ACR guidelines,18 each
patient was subclassified as severe if any of the
following conditions had occurred during the
follow-up period: glomerulonephritis, central ner-
vous system involvement, heart and lung paren-
chymal manifestations, haemolytic or aplastic
anaemia.
Finally, the cumulative prednisone equivalent
dose, as well as ASA, HCQ and statin use, was
recorded. We considered the cumulative steroids
dose as high when a patient achieved a cumulative
prednisone equivalent dose  40 g, which was
reported to be associated with atherosclerosis in
SLE.19
Statistical analysis
Continuous variables are presented as the
mean  standard deviation (SD) if normally dis-
tributed or as median and quartiles (interquartile
range (IQR)) if distribution was skewed. Kaplan-
Meier curves and the log-rank test were used to
analyse differences in event-free survival.
Univariate Cox regression analysis was used to
identify factors associated with the occurrence
of a CV event. Variables that reached statistical
significance in univariate analysis were included
in the multivariate model. We also derived a pro-
pensity score to account for potential confound-
ing by indication. Using logistic regression, we
found the predicted probability for the two dif-
ferent treatments (ASA or HCQ) using the
same confounders: disease activity (basal
SELENA-SLEDAI > 6), aPL positivity and
severe SLE. These propensity scores were then
used as covariates in a Cox proportional haz-
ards model to establish the relationship between
ASA use, long-term HCQ therapy and CV
events. A p value < 0.05 was considered signifi-
cant. MedCalc software, version 15.4, was used
for all analyses.
Key results from literature
Table 1 lists the 21 papers considered for the
analysis.
Primary prevention of cardiovascular disease in SLE
S Fasano et al.
1465
Low-dose ASA
Wahl et al.20 carried out a decision analysis suggest-
ing that ASA treatment might potentially prevent
both arterial and venous thrombotic manifestations.
These data were supported by Tektonidou et al.,21
who showed that ASA treatment played a protective
role against thrombosis in aPL-positive SLE patients.
Other studies, however, supported a worsening role
of low-dose ASA on thrombosis,22–25 even if these
results might be ascribed to a confounding for iden-
tification bias, i.e. ASA had been prescribed to
patients with an increased CV risk profile. No data
from RCTs on which to base any firm conclusion
were available; thus the evidence was rated as low.
Antimalarials
The influence of antimalarials on CV disease in
SLE has been examined by a number of studies
with controversial results. Wallace first reported
that HCQ might prevent thrombosis in a retro-
spective study on 92 SLE patients.26 In a most
recent prospective cohort study, Ruiz-Irastorza
et al. reported beneficial effects of HCQ against
thrombosis (hazard ratio (HR): 0.28), after control-
ling for other variables such as history of throm-
bosis, presence of aPL and treatment with ASA.27
Moreover, in a case-control study on 54 SLE
patients and 108 controls, Jung et al. confirmed in
a multivariate analysis (odds ratio (OR): 0.32) that
antimalarials were protective against thrombosis,
after adjusting for disease severity and disease dur-
ation.28 Petri et al.29 pointed out a trend for HCQ
to be protective against CV disease, even if this did
not reach statistical significance.
However, other studies failed to demonstrate any
significant association between the use of antimal-
arials and frequency of thrombotic events. In par-
ticular, studies from multi-ethnic cohorts23,30–32
and a long-term cross-sectional study on the
Spanish SLE registry25 failed to detect any favour-
able effect.
A potential confounder of these studies may be
the variability in the exposure time to HCQ previous
to the event. In the majority of these studies, the
time of exposure of patients considered as ‘ever trea-
ted with antimalarials’ is different, resulting in an
incorrect estimation of the drug effect. Actually,
Tektonidou et al.21 detected a significant reduction
of CV events in a group of SLE patients who had
been treated for a longer time. Moreover, a cumu-
lative dose effect was suggested by de Leeuw et al.,33
but the relatively small number of subjects studied
prevented the statistical significance of the results.
The quality of evidence is rated as moderate.
Lupus
 1466

Lupus
Table 1 List of clinical studies considered for the analysis on the use of hydroxychloroquine (HCQ), aspirin (ASA) and statins to prevent thrombosis in patients with
systemic lupus erythematosus (SLE).
Year of Number
First author Country publication Study design Agent of patients Ethnicity (n) Exposure Follow-up Outcome

26
Wallace USA 1987 Observational HCQ 92 NA Ever NA p < 0.05
cohort
Petri29 USA 1992 Observational HCQ 229 Black (133) White/ Ever 3 years p > 0.05
cohort others (96)
Toloza30 USA 2004 Observational HCQ 446 Texan Hispanics Ever 73.8 months p > 0.05
cohort (107),
Puerto Rican
Hispanics (84),
African Americans
(200),
Caucasians (155)
Mok32 China and 2005 Observational HCQ 625 Chinese (258), Ever Chinese 4.56 years p > 0.05
USA cohort Caucasians (227), Caucasians 5.3 years
African Americans African Americans
(140). 5.15 years
Ho31 USA 2005 Observational HCQ 442 Texan Hispanics (99), Prior to event Mean  SD p > 0.05 (in multi-
cohort Puerto Rican 88.4  23.7 months variate analysis)
Hispanics (36),
African Americans
Primary prevention of cardiovascular disease in SLE
S Fasano et al.

(172),
Caucasians (135)
de Leeuw33 Netherlands 2006 Cross-sectional HCQ 72 NA Ever 52 months (31–112) p > 0.05
Ruiz- Spain 2006 Observational HCQ 232 NA At the time of Mean  SD 10.6  7 HR: 0.28 (0.08–
Irastorza27 cohort event years 0.90)
Goldberg46 Canada 2009 Case-control HCQ 478 (cases: 241; Caucasian/Black/ Prior to event Median 8.1 years p > 0.05
controls: 237) Chinese/other, %
cases: 77/10/6/7 vs
controls: 89/3/5/3
Burgos47 USA 2010 Observational HCQ 643 Hispanic-Texan (129) Ever Mean  SD 4.6  3.5 p > 0.05
cohort Caucasian (182) years
African-American
(240)
Hispanic- Puerto
Rican (102)
Zhang48 Canada 2010 Observational HCQ 437 Caucasian (332) Ever Mean  SD 11.3  8.2 p > 0.05
cohort African-American (46) years
Asian (41)
Others (16)
Jung19 Canada 2010 Case- control HCQ 162 (cases: 54, NA Ever Mean  SD 9.6  7.9 OR ¼ 0.32
controls: 108) years.
Yang49 China 2011 Case- control HCQ 278 (cases:139; Chinese Ever Followed for 1 year p ¼ 0.018
controls:139)
Kao50 USA 2013 Observational HCQ 356 White (292) Black (53) Prior to event Mean  SD 4.7  2 p > 0.05
cohort Others (11) years
(continued)
 Table 1 Continued
Year of Number
First author Country publication Study design Agent of patients Ethnicity (n) Exposure Follow-up Outcome

Tektonidou21 Greece 2009 Case–control HCQ and 288 (aPL-nega- NA Ever Median 104 months Duration of HCQ
ASA tive:144; aPL- for aPL-positive treatment
positive:144) and 112 months for HR:0.99 p ¼ 0.05
aPL-negative for aPL-positive
HR:0.98 p ¼ 0.04
for aPL-
negative
Pons-Estel24 USA 2009 Observational HCQ and 637 Texan Hispanic (118) Ever Mean 6.6 years p > 0.05
cohort ASA Puerto Rican Hispanic
(102)
African Americans
(236)
Caucasian (181)
Bertoli23 USA 2009 Observational HCQ and 1333 Texan Hispanics (139) Ever Median 6.4 years p > 0.05
cohort ASA Puerto Rican
Hispanics (102)
African Americans,
(472)
S Fasano et al.

Caucasians (620)
Gustafsson22 Sweden 2012 Observational HCQ and 208 Caucasian (195) Ever Mean 12.3 years p ¼ 0.04
cohort ASA Others (13)
Fernandez- Spain 2015 Cross-sectional HCQ and 3658 Caucasian (3485) Ever NA p ¼ 0.001
Nebro25 ASA Black Africans (8)
Asians (21)
Other (29)
Wahl20 France 2000 Decision ASA NA NA NA NA Benefit
analysis
Norby34 Norway 2009 RCT Fluvastatin 33 NA 40 mg versus placebo 87 months
Primary prevention of cardiovascular disease in SLE

p > 0.05
Yu35 Taiwan 2015 Case-control Statins 4095 NA High dose 8.4  3.5 years p < 0.05 (HR 0.44)

aPL: antiphospholipid antibody; HR: hazard ratio; NA: not available; RCT: randomised controlled trial; SD: standard deviation.
1467

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 Primary prevention of cardiovascular disease in SLE
S Fasano et al.
1468
Statins
Only two studies measured the association between
statins and clinical CV events in SLE. A post-hoc
analysis of the Assessment of LEscol in Renal
Transplantation (ALERT) trial investigated the
effects of fluvastatin on CV disease after kidney
transplantation in 33 patients with SLE during a
follow-up of 87 months.34 Although there were
fewer major cardiac events in the fluvastatin
group than in the placebo group, this did not
reach statistical significance. However, the study
group was small and composed by SLE patients
at very high risk for thrombotic events.
A retrospective cohort study described the effects
of statins on CV disease in a cohort of 4095 SLE
patients with dyslipidaemia from the Taiwan
National Health Insurance Research Database.35
During the follow-up of 144 months, CV disease
was significantly reduced in the groups treated
with high-dose statins (>365 cumulative daily
dose) compared to controls.
Moreover, three RCTs investigated radiological
findings consistent with atherosclerosis rather than
reductions in CV events in adult SLE patients treated
with statins or a placebo. In the Plazak et al. study of
60 SLE patients randomised to atorvastatin or pla-
cebo for one year, coronary artery calcification was
significantly retarded in the atorvastatin group.36
However, rosuvastatin did not significantly
reduce carotid intima media thickness (CIMT) pro-
gression compared with similar-sized groups of pla-
cebo-treated SLE patients.37
Similarly, no differences in subclinical measures
of atherosclerosis (coronary artery calcification,
CIMT, carotid plaque) or disease activity were
found in the Lupus Atherosclerosis Prevention
Study (LAPS),38 but atorvastatin-treated partici-
pants showed a trend of slower CIMT progression.
On the other hand, we did not include these stu-
dies for the evidence rating, because changes in sur-
rogate CV measures do not accurately predict the
real CV risk profile. The evidence was rated as low
and the benefits of statins in reducing clinical car-
diac events in SLE need to be further investigated.
Results from our cohorts
Baseline data
During the study period, 246 patients were
admitted to the Naples Unit, 119 patients to the
Rome Unit. Out of them, 189 and 102, respectively,
had not experienced any CV event at admission.
Lupus
Table 2 Demographic, serological, clinical and clinimetric
characteristics of systemic lupus erythematosus (SLE) patients
at baseline
Patients 291
Gender (n;%) F (271; 93.1%) M (20; 6.9%)
Age, years (median, IQR) 33 (25–42)
Autoantibody profile, (n;%) Anti-dsDNA (140; 48.1%)
Anti-Sm (37; 12.7%)
aPL (92; 31.6%)
Severe SLE (n;%) 158; 54.2%
Smokers (n;%) 105; 36.0%
Obesity (n;%) 37; 12.7%
Hypertension (n;%) 78; 26.8%
Hypercholesterolaemia (n;%) 39; 13.4%
Hypertriglyceridaemia (n;%) 33; 11.3%
Diabetes (n;%) 14; 4.8%
SELENA-SLEDAI  6, (n;%) 150; 51.5%
SDI, median (range) 0 (0-3)
aPL: antiphospholipid antibody; IQR: interquartile range; SELENA-
SLEDAI: Safety of Estrogens in Lupus Erythematosus National
Assessment SLE Disease Activity Index; SDI: Systemic Lupus
International Collaborating Clinics/American College Of
Rheumatology Damage Index.
Table 2 lists the main epidemiological, sero-
logical and clinical features of the 291 patients.
Out of them, 271 (93.1%) were women, with a
median (IQR) age at study entry of 31 (25–41)
years. One hundred and fifty-eight patients
(54.2%) had severe disease and 92 (31.6%) were
aPL positive. Thirty-seven patients (12.7%) had a
body mass index > 30 and 105 (36%) had smoked
before their entry into the study. Hypertension was
diagnosed in 78 (26.8%) patients, while diabetes
mellitus in 14 (4.8%) patients. High levels of total
serum cholesterol and triglycerides were observed
in 39 (13.4%) and 33 (11.3%) patients, respectively.
Follow-up data
The median duration of follow-up was eight years
(IQR ¼ 4–15). In December 2016, 12 (4.1%)
patients were lost to follow-up. Non-lethal throm-
botic manifestations occurred in 16 patients (stroke
in two patients, TIA in five patients, acute MI in
seven patients and peripheral gangrenes in the
remaining two) with an incidence rate of 6/1000
person-years. This rate of ischaemic events
observed in our SLE cohort was seven-fold higher
than that expected in the Italian population
matched for age and sex. Of the 291patients,
five (1.7%) died during the study period: two
from cancer between 13–14 years of SLE course
(one died of lung cancer at the age of 61 years;
the other of brain cancer at the age of 39 years);
a patient by hepatic cirrhosis at the age of 61 years
after nine years of follow-up; the remaining two

patients died of active SLE after 4 and 15 years of
follow-up, respectively. No patient died as direct
result of CV complications.
Regarding medication, 218 (74.9%) patients
were ever treated with ASA. Two-hundred and
fifty-five (87.6%) patients received HCQ at any
Figure 1 Rate of cardiovascular events over time in systemic
lupus erythematosus patients treated or not with aspirin
(ASA).
Figure 2 Rate of cardiovascular events over time in the group
treated with aspirin (ASA) between hydroxychloroquine
(HCQ) users versus non-users.
Primary prevention of cardiovascular disease in SLE
S Fasano et al.
1469
time during the follow-up. The median time on
antimalarials was seven years (IQR 4–14 years).
The majority of patients (190; 65.2%) received
both treatments with ASA and HCQ, whereas
eight (2.7%) patients received neither ASA nor
HCQ. Sixty-five (22.3%) patients were treated
with HCQ alone and 28 (9.6%) received ASA
alone. Twenty-five (8.5%) patients used statins.
Survival analysis
Kaplan-Meier analysis revealed a greater overall
CV event-free rate in ASA-treated patients
(log-rank test 2 ¼ 7.15; p ¼ 0.007; Figure 1). CV
event-free survival did not differ between the
190 patients treated with both ASA and HCQ
and the 28 patients treated with ASA alone
(p ¼ 0.567; Figure 2). Nevertheless, Kaplan-Meier
Figure 3 Rate of cardiovascular events over time between
patients reaching cumulative hydroxychloroquine (HCQ)
dose > 600g and patients treated with aspirin (ASA) alone or
lower cumulative HCQ dosages.
Lupus
 Primary prevention of cardiovascular disease in SLE
1470
analysis revealed a greater CV event-free rate in the
160 ASA-treated patients who had reached a cumu-
lative HCQ dosage > 600 g (which corresponds to a
standard daily dose for at least five years) than in
the 131 patients treated with either ASA alone or
added to HCQ at a cumulative dosage < 600 g
(2 ¼ 16.24; p ¼ 0.0001) (Figure 3).
Predictors of CV events
At univariate analysis, patients with a first CV
event compared with those without any thrombotic
events were aPL positive (p ¼ 0.017; HR: 2.91) and
had significantly higher blood pressure (p ¼ 0.017;
HR 3.58), hypercholesterolaemia (p ¼ 0.015; HR
3.40) and higher disease damage at last visit
(p ¼ 0.032; HR 1.56). Moreover, ASA treatment
(p ¼ 0.012; HR 0.27) and HCQ use (p ¼ 0.012
HR0.26) for more than five years were negative
predictors while statins, that had been used in a
small percentage of patients, did not show any
association (p ¼ 0.619). All other variables exam-
ined, including smoking, obesity, hypertriglyceri-
daemia, diabetes mellitus, disease activity, severe
SLE, steroids were not associated, either positively
or negatively, with the occurrence of CV events
(Table 3). At multivariate analysis, taking ASA
and HCQ for more than five years were protective
against thrombosis (HR 0.24, 95% confidence
interval (CI) 0.08 – 0.70, and HR 0.27, 95% CI
0.08–0.86, respectively), while aPL positivity (HR
4.32, 95% CI 1.48–12.61) increased the risk of a
first CV event. After adjustment for propensity
Table 3 Factors predicting the occurrence of a first cardio-
vascular event during follow-up in univariate analysis (signifi-
cant values in bold)
Features p value
ASA treatment 0.012
HCQ treatment > 5 years 0.021
Statins 0.619
Hypertension (ever) 0.017
aPL positivity 0.034
Cumulative damage at last visit 0.032
Smoke (ever) 0.963
Obesity (ever) 0.091
Hypercholesterolaemia (ever) 0.015
Hypertriglyceridaemia (ever) 0.506
Diabetes mellitus (ever) 0.818
Severe SLE 0.789
SLEDAI last visit 0.126
aPL: antiphospholipid antibody; ASA: aspirin; CI: confidence interval;
HCQ: hydroxychloroquine; SLE: systemic lupus erythematosus;
SLEDAI: SLE Disease Activity Index.
Lupus
S Fasano et al.
scores, results were very similar: the HR was 0.24
(95% CI: 0.07–0.81; p ¼ 0.021) for long-term HCQ
therapy and 0.24 (95% CI: 0.07–0.75; p ¼ 0.014) for
the use of ASA.
Discussion
Prevention of long-term CV complications in
patients with SLE is still an unsolved issue.
Although the traditional CV risk factors do not
fully explain such an accelerated development of
atherosclerosis, minimising the CV risk requires
strategies directed to identify and treat aggressively
hypertension, dyslipidaemia, diabetes and obesity,
which should be routinely employed in the manage-
ment of all patients with SLE.
The approach to the prevention of CV events in
SLE should, however, include the control of dis-
ease-related risk factors and disease activity as well.
Despite the lack of agreement on strategies to be
performed, observational data from longitudinal
studies suggest that ASA, HCQ and statins might
represent attractive agents for primary CV preven-
tion. Each of the three drugs has a rationale for its
use: ASA has a long-established role in the second-
ary CV prophylaxis in the general population, and is
considered in primary prevention in subjects with
increased risk of CV disease in whom the benefits
of ASA outweigh any harmful effects;39 antimalar-
ials reduce platelet aggregation by inhibiting
thromboxane A2 production and contrasting the
binding of antiphospholipid–b2-glycoprotein I com-
plexes to phospholipid bilayers,40–42 and have been
reported to improve lipid and glucose metabolism;43
statins have pleiotropic properties on vascular and
immune system.44 However, there are no RCTs that
confirm these encouraging results and support evi-
Hazard
ratio 95%CI
dence-based recommendations in SLE patients.
In order to address the topic, we conducted a
0.27 0.10–0.75 systematic review analysing 4135 studies using a
0.26 0.08–0.82 PubMed search. We found moderate evidence
0.59 0.07–4.53
3.58 1.24–10.33
that HCQ prevents CV disease in SLE patients,
2.91 1.08–7.86 while evidence supporting a relevant effect of
1.56 1.03–2.37 ASA and statins in this context is low. Actually,
1.02 0.37–2.76 data supporting the efficacy of HCQ are more
2.66 0.85–8.28 solid due to the higher number of patients treated
3.40 1.26–9.14
1.53 0.43–5.38
and its good safety profile. However, data coming
1.26 0.16–9.60 from single studies suggest additional effects of
0.87 0.32–2.35 ASA in protecting lupus patients against a first
1.11 0.97–1.27 thrombosis.
In addition, we extended our previous studies8,9
by considering patients from another referral unit.
In our first study, we investigated the effectiveness

of ASA for the prevention of a first thrombosis in
SLE and detected a significant reduction in the
occurrence of CV events in ASA-treated patients.8
Our present data confirm the previous evidence of
the beneficial effects of ASA in CV prevention in a
high-risk population such as SLE patients. The dis-
crepancies observed between our results and
those of other cohorts21–25 might depend on the
different levels of CV disease in distinct countries,
as the incidence of CV events is lower in the general
Italian population. Moreover, in these studies
the anti-platelet therapy was almost exclusively
taken by those patients who had a previous high
CV risk. Therefore, we are inclined to believe that
ASA should be prescribed to all SLE patients espe-
cially those with a significant CV risk (positive aPL
antibodies, hypertension, dyslipidaemia), unless
contraindicated.
In that first study,8 we failed to demonstrate any
significant effect of antimalarials on CV prevention.
In the second one,9 we investigated HCQ effects by
subdividing patient according to the length of treat-
ment and the cumulative dosage. We found that
antimalarials, when administered for more than
five years, were protective against thrombosis in
SLE, after controlling for other variables, including
treatment with ASA. The present study further
reinforces that finding.
The discrepancy among the studies on the effect-
iveness of HCQ in CV prevention might depend
on differences in presence/absence of a control
group, aPL and disease status, variable definition
of clinical outcomes and heterogeneity in the ethnic
composition of study populations and, most
importantly, on the different duration of patients’
exposures to HCQ prior to the event. Indeed, a
time-dependent effect of HCQ exposure has been
suggested by two other studies.21,45 Further pro-
spective studies are needed to confirm the efficacy
of HCQ in CV prophylaxis in patients with SLE
and to demonstrate the definite mechanism of its
thrombo-protection.
We failed to detect any effects of statins.
Nevertheless, the number of patients treated with
these drugs was quite low.
Several limitations in our study should be
acknowledged. Actually, both literature review and
personal results derive from observational studies.
Therefore any observed association between treat-
ment and results might be biased by a number of
confounders influencing treatment decisions.
However, data coming from well-designed observa-
tional studies often give a more realistic view than
RCTs, in which there is strict selection of patients.
Primary prevention of cardiovascular disease in SLE
S Fasano et al.
1471
Conclusion and implications
Despite the limitations and the consequent impos-
sibility of making definite recommendations, our
data support the use of HCQ and ASA in all
lupus patients as potential agents for primary CV
prophylaxis in SLE. This treatment could be main-
tained long-term unless contraindicated, whatever
the subsequent course of SLE. Controlled, pro-
spective studies are needed to provide a better def-
inition of the role of antimalarials, ASA and statins
in primary CV prevention in SLE.
Declaration of conflicting interests
The authors declared no potential conflicts of inter-
est with respect to the research, authorship, and/or
publication of this article.
Funding
The authors received no financial support for the
research, authorship, and/or publication of this article.
References
1 Jacobsen S, Petersen J, Ullman S, et al. A multicentre study of 513
Danish patients with systemic lupus erythematosus. II. Disease mor-
tality and clinical factors of prognostic value. Clin Rheumatol 1998;
17: 478–484.
2 Bartels CM, Buhr KA, Goldberg JW, et al. Mortality and
cardiovascular burden of systemic lupus erythematosus in a US
population-based cohort. J Rheumatol 2014; 41: 680–687.
3 Urowitz MB, Bookman AA, Koehler BE, et al. The bimodal mor-
tality pattern of systemic lupus erythematosus. Am J Med 1976; 60:
221–225.
4 Cervera R, Khamashta MA, Font J, et al. Morbidity and mortality
in systemic lupus erythematosus during a 10-year period: A com-
parison of early and late manifestations in a cohort of 1,000
patients. Medicine (Baltimore) 2003; 82: 299–308.
5 Doria A, Iaccarino L, Ghirardello A, et al. Long-term prognosis
and causes of death in systemic lupus erythematosus. Am J Med
2006; 119: 700–706.
6 Manzi S, Meilahn EN, Rairie JE, et al. Age-specific incidence rates
of myocardial infarction and angina in women with systemic lupus
erythematosus: Comparison with the Framingham Study. Am J
Epidemiol 1997; 145: 408–415.
7 Skamra C, Ramsey-Goldman R. Management of cardiovascular
complications in systemic lupus erythematosus. Int J Clin
Rheumatol 2010; 5: 75–100.
8 Iudici M, Fasano S, Gabriele Falcone L, et al. Low-dose aspirin as
primary prophylaxis for cardiovascular events in systemic lupus ery-
thematosus: A long-term retrospective cohort study. Rheumatology
(Oxford) 2016; 55: 1623–1630.
9 Fasano S, Pierro L, Pantano I, et al. Long-term hydroxychloro-
quine therapy and low-dose aspirin may have an additive effective-
ness in the primary prevention of cardiovascular events in patients
with systemic lupus erythematosus. J Rheumatol 2017; 44: 1032–
1038.
Lupus
 Primary prevention of cardiovascular disease in SLE
S Fasano et al.
1472
10 Atkins D, Best D, Briss PA, et al. Grading quality of evidence and
strength of recommendations. BMJ 2004; 328: 1490.
11 Hochberg MC. Updating the American College of Rheumatology
revised criteria for the classification of systemic lupus erythemato-
sus. Arthritis Rheum 1997; 40: 1725.
12 Petri M, Orbai A-M, Alarcón GS, et al. Derivation and validation
of the Systemic Lupus International Collaborating Clinics classifi-
cation criteria for systemic lupus erythematosus. Arthritis Rheum
2012; 64: 2677–2686.
13 Bild DE, Bluemke DA, Burke GL, et al. Multi-ethnic study of
atherosclerosis: Objectives and design. Am J Epidemiol 2002; 156:
871–881.
14 Buyon JP, Petri MA, Kim MY, et al. The effect of combined estro-
gen and progesterone hormone replacement therapy on disease
activity in systemic lupus erythematosus: A randomized trial.
Ann Intern Med 2005; 142: 953–962.
15 Gladman D, Ginzler E, Goldsmith C, et al. The development and
initial validation of the Systemic Lupus International
Collaborating Clinics/American College of Rheumatology
damage index for systemic lupus erythematosus. Arthritis Rheum
1996; 39: 363–369.
16 Palmieri V, Migliaresi P, Orefice M, et al. High prevalence of sub-
clinical cardiovascular abnormalities in patients with systemic
lupus erythematosus in spite of a very low clinical damage index.
Nutr Metab Cardiovasc Dis NMCD 2009; 19: 234–240.
17 The Multi-Ethnic Study of Atherosclerosis. Multi-ethnic study of
atherosclerosis. MESA study events manual of operations. Bethesda,
MD: National Heart, Lung, and Blood Institute, 2004.
18 Hahn BH, McMahon MA, Wilkinson A, et al. American
College of Rheumatology guidelines for screening, treatment,
and management of lupus nephritis. Arthritis Care Res 2012;
64: 797–808.
19 Doria A, Shoenfeld Y, Wu R, et al. Risk factors for subclinical
atherosclerosis in a prospective cohort of patients with systemic
lupus erythematosus. Ann Rheum Dis 2003; 62: 1071–1077.
20 Wahl DG, Bounameaux H, de Moerloose P, et al. Prophylactic
antithrombotic therapy for patients with systemic lupus erythema-
tosus with or without antiphospholipid antibodies: Do the benefits
outweigh the risks? A decision analysis. Arch Intern Med 2000; 160:
2042–2048.
21 Tektonidou MG, Laskari K, Panagiotakos DB, et al. Risk factors
for thrombosis and primary thrombosis prevention in patients with
systemic lupus erythematosus with or without antiphospholipid
antibodies. Arthritis Rheum 2009; 61: 29–36.
22 Gustafsson JT, Simard JF, Gunnarsson I, et al. Risk factors for
cardiovascular mortality in patients with systemic lupus erythema-
tosus, a prospective cohort study. Arthritis Res Ther 2012; 14: R46.
23 Bertoli AM, Vilá LM, Alarcón GS, et al. Factors associated with
arterial vascular events in PROFILE: A multiethnic lupus cohort.
Lupus 2009; 18: 958–965.
24 Pons-Estel GJ, González LA, Zhang J, et al. Predictors of cardio-
vascular damage in patients with systemic lupus erythematosus:
Data from LUMINA (LXVIII), a multiethnic US cohort.
Rheumatology (Oxford) 2009; 48: 817–822.
25 Fernández-Nebro A, Rúa-Figueroa Í, López-Longo FJ, et al.
Cardiovascular events in systemic lupus erythematosus: A nation-
wide study in Spain from the RELESSER registry. Medicine
(Baltimore) 2015; 94: e1183.
26 Wallace DJ. Does hydroxychloroquine sulfate prevent clot forma-
tion in systemic lupus erythematosus? Arthritis Rheum 1987; 30:
1435–1436.
27 Ruiz-Irastorza G, Egurbide MV, Pijoan JI, et al. Effect of antimal-
arials on thrombosis and survival in patients with systemic lupus
erythematosus. Lupus 2006; 15: 577–583.
28 Jung H, Bobba R, Su J, et al. The protective effect of antimalarial
drugs on thrombovascular events in systemic lupus erythematosus.
Arthritis Rheum 2010; 62: 863–868.
29 Petri M, Perez-Gutthann S, Spence D, et al. Risk factors for cor-
onary artery disease in patients with systemic lupus erythematosus.
Am J Med 1992; 93: 513–519.
Lupus
30 Toloza SMA, Uribe AG, McGwin G, et al. Systemic lupus erythe-
matosus in a multiethnic US cohort (LUMINA). XXIII. Baseline
predictors of vascular events. Arthritis Rheum 2004; 50: 3947–3957.
31 Ho KT, Ahn CW, Alarcón GS, et al. Systemic lupus erythematosus
in a multiethnic cohort (LUMINA): XXVIII. Factors predictive of
thrombotic events. Rheumatology (Oxford) 2005; 44: 1303–1307.
32 Mok CC, Tang SSK, To CH, et al. Incidence and risk factors of
thromboembolism in systemic lupus erythematosus: A comparison
of three ethnic groups. Arthritis Rheum 2005; 52: 2774–2782.
33 de Leeuw K, Freire B, Smit AJ, et al. Traditional and non-tradi-
tional risk factors contribute to the development of accelerated
atherosclerosis in patients with systemic lupus erythematosus.
Lupus 2006; 15: 675–682.
34 Norby GE, Holme I, Fellström B, et al. Effect of fluvastatin on
cardiac outcomes in kidney transplant patients with systemic lupus
erythematosus: A randomized placebo-controlled study. Arthritis
Rheum 2009; 60: 1060–1064.
35 Yu H-H, Chen P-C, Yang Y-H, et al. Statin reduces mortality and
morbidity in systemic lupus erythematosus patients with hyperlip-
idaemia: A nationwide population-based cohort study.
Atherosclerosis 2015; 243: 11–18.
36 Plazak W, Gryga K, Dziedzic H, et al. Influence of atorvastatin on
coronary calcifications and myocardial perfusion defects in sys-
temic lupus erythematosus patients: A prospective, randomized,
double-masked, placebo-controlled study. Arthritis Res Ther
2011; 13: R117.
37 Mok CC, Wong CK, To CH, et al. Effects of rosuvastatin on
vascular biomarkers and carotid atherosclerosis in lupus: A rando-
mized, double-blind, placebo-controlled trial. Arthritis Care Res
2011; 63: 875–883.
38 Petri MA, Kiani AN, Post W, et al. Lupus Atherosclerosis
Prevention Study (LAPS). Ann Rheum Dis 2011; 70: 760–765.
39 Ridker PM, Cook NR, Lee I-M, et al. A randomized trial of low-
dose aspirin in the primary prevention of cardiovascular disease in
women. N Engl J Med 2005; 352: 1293–1304.
40 Achuthan S, Ahluwalia J, Shafiq N, et al. Hydroxychloroquine’s
efficacy as an antiplatelet agent study in healthy volunteers:
A proof of concept study. J Cardiovasc Pharmacol Ther 2015; 20:
174–180.
41 Rand JH, Wu X-X, Quinn AS, et al. Hydroxychloroquine directly
reduces the binding of antiphospholipid antibody-beta2-glycopro-
tein I complexes to phospholipid bilayers. Blood 2008; 112:
1687–1695.
42 Virdis A, Tani C, Duranti E, et al. Early treatment with hydroxy-
chloroquine prevents the development of endothelial dysfunction
in a murine model of systemic lupus erythematosus. Arthritis Res
Ther 2015; 17: 277–286.
43 Petri M. Hydroxychloroquine use in the Baltimore lupus cohort:
Effects on lipids, glucose and thrombosis. Lupus 1996; 5: S16–S22.
44 Davignon J. Beneficial cardiovascular pleiotropic effects of statins.
Circulation 2004; 109: III39–43.
45 Ruiz-Irastorza G, Egurbide MV, Pijoan JI, et al. Effect of antimal-
arials on thrombosis and survival in patients with systemic lupus
erythematosus. Lupus 2006; 15: 577–583.
46 Goldberg RJ, Urowitz MB, Ibañez D, et al. Risk factors for devel-
opment of coronary artery disease in women with systemic lupus
erythematosus. J Rheumatol 2009; 36: 2454–2461.
47 Burgos PI, McGwin G, Reveille JD, et al. Factors predictive of
thrombotic events in LUMINA, a multi-ethnic cohort of SLE
patients (LXXII). Rheumatology (Oxford) 2010; 49: 1720–1725.
48 Zhang W, Aghdassi E, Reich HN, et al. Glomerular filtration rate
predicts arterial events in women with systemic lupus erythemato-
sus. Rheumatol Oxf Engl 2011; 50: 799–805.
49 Yang L, Tao J, Tang X, et al. Prevalence and correlation of con-
ventional and lupus-specific risk factors for cardiovascular disease
in Chinese systemic lupus erythematosus patients. J Eur Acad
Dermatol Venereol JEADV 2012; 26: 95–101.
50 Kao AH, Lertratanakul A, Elliott JR, et al. Relation of carotid
intima-media thickness and plaque with incident cardiovascular
events in women with systemic lupus erythematosus. Am J
Cardiol 2013; 112: 1025–1032.
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