Management of cardiovascular risk in systemic lupus erythematosus: a systematic review

Abstract

Systemic lupus erythematosus is associated with accelerated atherosclerosis and increased risk of cardiovascular complications. The aim of this study was to review the effectiveness of interventions for primary and secondary prevention of cardiovascular events and mortality and to review the effectiveness of interventions for cardiovascular risk factor reduction in systemic lupus erythematosus patients. A systematic review was conducted. Electronic databases Medline and Embase (1961–2015) were searched. Nineteen articles met the inclusion criteria and were selected. Low-calorie and/or low glycaemic index calories may be a useful option for secondary prevention in obese patients with systemic lupus erythematosus, and exercise would be useful in improving the endothelial function measured by flow-mediated dilation in this group of patients. The use of lipid-lowering drugs may improve the lipid profile in patients with systemic lupus erythematosus and hyperlipidaemia, but the effect of this treatment on overall cardiovascular mortality remains unknown. Antiplatelets, anticoagulants, antimalarials and lipid-lowering drugs may be effective in the primary and secondary prevention of major cardiovascular events, such as acute myocardial infarction or stroke. Similarly, lipid-lowering drugs and antimalarial drugs appear to reduce the serum levels of total cholesterol, low-density lipoprotein, glucose, diastolic blood pressure and calcium deposition at the coronary arteries. They may also improve insulin resistance and the level of high-density lipoproteins. It appears that treatment with antihypertensive drugs reduces blood pressure in patients with systemic lupus erythematosus, but the available studies are of low quality.

Keywords

Systemic lupus erythematosus cardiovascular risk factors cardiovascular events

Introduction

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease of variable clinical course that primarily affects women. The prevalence of SLE is 91 per 100,000 people in Spain,¹ with an estimated incidence in Europe of 3.3 to 4.8 cases per 100,000 inhabitants/year.² The survival rate of SLE at 10 years has significantly improved over the last 50 years in Europe and now is at around 90%.³ However, the long-term survival seems to have remained stationary between 44 and 84% since the 1980s.⁴ The most common cause of late mortality in patients with SLE is cardiovascular disease; an underlying chronic inflammatory state being key to the development of early atherosclerosis.⁵ Van Leuven et al.⁶ suggested that the pathophysiological pathway that promotes atherosclerosis begins years before the diagnosis of SLE, when the inflammatory process begins, so that SLE itself should be considered as an independent cardiovascular risk factor (CVRF).⁷ In addition, accelerated atherosclerosis in SLE appears to result from the interaction of multiple traditional CVRFs and factors related to SLE itself.⁸

Although it is well established that various preventive measures effectively reduce the impact of CVRFs in the general population, their effectiveness has not been recognized in patients with SLE. Given the high morbidity and mortality of cardiovascular disease in these patients, it is necessary to approach CVRFs from a multidisciplinary perspective in SLE; an approach that can both inhibit the inflammation cascade and reduce cardiovascular risk.⁹

The aim of this study was to (1) to review the effectiveness of interventions for primary and secondary preventions of cardiovascular events and mortality and (2) to review the effectiveness of interventions for CVRF reduction in SLE patients.

Methods

A systematic review of studies that could answer the research questions was undertaken.

Identification and selection of studies

A comprehensive literature search was conducted on Medline and Embase from 1961 to December 2015, restricting the search to articles in English, French and Spanish in humans. The search strategy included MeSH terms and free text of synonymous and related terms of ‘lupus,’ ‘cardiovascular risk’ and its treatment (see Supplementary Table 1). The search strategies were supervised by an expert librarian and two authors who independently reviewed the titles and abstracts of articles and applied the selection criteria.

By types of studies, meta-analysis, systematic reviews, randomized controlled trials, phase II, III and IV, non-randomized and uncontrolled clinical trials, and observational studies (cross-sectional, cohort and case-control) were eligible. By types of participants, studies were eligible if they included adult patients with SLE or patients with secondary antiphospholipid syndrome (APS) to SLE. By types of interventions, the selection was of studies evaluating the effectiveness of interventions for health promotion (i.e. healthy diet, reducing obesity and those overweight, smoking cessation and increased physical activity), treatment of classic CVRFs (hyperlipidaemia, hypertension, diabetes, treatments that improve vascular endothelial function or flow, antiplatelets and anticoagulants) or treatment of CVRFs directly related to SLE (antimalarials, glucocorticoids, immunosuppressants).

The main outcome measures studied were fatal and nonfatal cardiovascular events, i.e. myocardial infarction (MI), unstable angina, coronary bypass or percutaneous coronary angioplasty, stroke and peripheral artery disease. As secondary endpoints, mortality and changes in major CVRF factors, such as systolic/diastolic blood pressure (SBP/DBP), body mass index (BMI), waist circumference, coronary calcium, glucose levels, insulin resistance (HOMA-IR), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, flow-mediated dilation (FMD) and smoking cessation were included.

Data extraction and bias assessment

The articles whose titles or abstracts matched the inclusion criteria were read in full. Failure of a single eligibility criterion was enough to exclude a study (see Supplementary Table 2). Any disagreements were resolved by consensus between the two reviewers and with the help of a third reviewer. Two reviewers extracted data from papers independently in report form.

The quality of evidence was analyzed by a critical reading of the selected full-text articles following the Scottish Intercollegiate Guidelines Network (SIGN) guidelines. The information collected included population, description of the study design, comparison group, outcome measures and results.

Results

The search produced a total of 1111 records, of which only 19 studies met the selection criteria established and constituted this systematic review (see Figure 1), covering the publication period from 1984 to 2015. The studies included were: one cross-sectional study, three cohort studies, three case-control studies, four non-randomized clinical trials, five randomized clinical trials (RCT), one systematic review of the literature and two meta-analyses (see Table 1). Most of the studies were randomized clinical trials with a level of scientific evidence and grade of recommendation SIGN 1+ B. Excluded studies and reasons for exclusion are mentioned in Supplementary Table 2.

Table 1

Evidence table

Reference	Design and duration	Population	Exposure/ intervention	Comparison	Results	Authors’ conclusions	Quality of evidence
Dos Reis-Neto et al.¹²	Non-randomized clinical trial 16 weeks	38 patients with SLE	18 patients performed aerobic exercise programmes (10 minutes warm-up, 40 minutes walking and 10 minutes stretching)	20 patients who did not do exercise	After 16 weeks, FMD increased in the exercise group but showed no change in the control group. FMD increased from a baseline of 6.3% to 14.1% at 16 weeks in the exercise group (p = 0.006), with only a slight increase from 8.4% to 9.4% in the control group (p = 0.598).	Exercise improves endothelial function in patients with SLE.	EL 1-RG not useful
Tarr et al.²¹	Prospective cohort study five years	272 patients with SLE	Treatment with antiplatelet (ASA and clopidogrel) and anticoagulants (coumarinic)	Control group	During follow-up, three patients with aPL+ had a stroke (one patient was receiving antiplatelet therapy and two were untreated). In the APS group, there were two patients with MI (both patients received anticoagulant treatment) and five patients with stroke (four patients with acetyl salicylic acid + anticoagulant; one patient with acetyl salicylic acid).	Oral anticoagulants and antiplatelet agents reduce the incidence of arterial events in patients with SLE (with aPL+ and APS)	EL 2+ RG C
Arnaud et al.¹⁸	Meta-analysis	192 patients with SLE and CVRFs	109 patients were treated with low doses of antiplatelet (ASA)	83 patients with SLE without ASA treatment (30%)	Lower incidence of arterial thrombotic events in patients treated with ASA compared with patients without this treatment (OR 0.43, 95% CI 0.20–0.94).	Lower risk of thrombotic events (primary prevention) in SLE patients treated with low-dose ASA	EL 1++ RG B
Davies et al.¹⁰	RCT, open six weeks	23 patients with SLE	11 patients conducted a low-glycaemic diet	12 patients conducted a low-caloric diet	There was significant weight loss in both groups (mean ± SD: low glycaemic index diet 3.9 ± 0.9 kg; calorie restricted diet 2.4 ± 2.2 kg, p < 0.01 from baseline in each group). The difference in weight loss between the groups was, however, not significant. There were significant reductions in waist and hip girth measurements in each group.	Diets of low caloric and/or low glycaemic index positively contribute in improving CVRFs in patients with SLE	EL 1 + RG B
Arnaud et al.¹⁹	Meta-analysis	440 patients with SLE and CVRFs	261 patients with treatment with antiplatelet (low doses of ASA)	179 patients with SLE without ASA treatment	Arterial thrombotic events are analyzed in a subgroup of patients with SLE and APS. ASA produced a protective effect of arterial thrombotic events (OR 0.55, 95% CI: 0.31–0.98).	Lower risk of thrombotic events (primary prevention) in SLE patients treated with low-dose ASA	EL 1++ RG B
Cuadrado et al.²⁰	RCT, open five years	232 patients with SLE	166 patients with antiplatelet (ASA) and anticoagulant (warfarin) treatment	66 patients with SLE without ASA treatment	There is a double incidence of thrombotic events (stroke, MI) in patients without treatment compared with patients with ASA (4.9 events/100 person-years at risk vs 1.8 events/100 person-years at risk, respectively)	Primary prophylaxis with ASA reduces the risk of thrombotic events in patients with SLE	EL 1-RG not useful
Yu et al.¹⁴	Case-control study. 12 years	4095 patients with SLE and hyperlipidaemia	Lipid-lowering therapy (statins or other lipid-lowering drugs)	Cohort adjustment for sex, age and comorbidities (hypertension, diabetes, chronic kidney disease) untreated	Lower mortality and number of cardiovascular events in patients with high doses of statins compared with untreated patients.	Statins reduce mortality and morbidity, including MI and stroke, in patients with SLE	EL 2+ GRC
Ferreira et al.¹⁵	Non-randomized clinical trial, open eight weeks	88 patients with SLE	64 patients with lipid-lowering therapy (atorvastatin). Thirty-one patients without CVRFs and 33 with CVRFs (hypertension, dyslipidaemia and obesity)	24 patients with SLE untreated.	FMD increased in patients treated with atorvastatin (3.8% and 6.9% baseline and eight weeks, p < 0.001). No significant changes of FMD in controls (4.7 baseline vs 4.1, p = 0.426). Secondary outcomes: HDL cholesterol levels were significantly lower (47 ± 12 mg/dL vs 41 ± 8 mg/dL, p = 0.049) and mean DBP was significantly higher (74 (70–80) mmHg vs 80 (78–83) mmHg, p = 0.01) in the control group compared to the intervention group.	Endothelial function (vasodilatation) improved with atorvastatin treatment, independent of the presence of conventional risk factors for atherosclerotic disease. Additionally, the intervention group showed higher levels of HDL compared with the control group (p = 0.049) and lower values of DBP compared with the control group (p = 0.01).	EL 1-RG not useful
Ruiz-Irastorza et al.²⁴	SR 1982–2007	Eight studies (2129 patients with SLE and CVRFs)	Treatment with HCQ	Control group	Most studies found that treatment with HCQ reduces thrombotic events (OR <1, CI 95%)	HCQ has a protective effect on thrombotic events in patients with SLE	EL 1+ RG B
Kaiser et al.²⁵	Nested case-control	1534 patients with SLE and CVRFs and/or previous cardiovascular events	Treatment with HCQ	Patients with SLE untreated	Treatment with HCQ is a protective factor of thrombosis, with an OR of 0.62 and a p value of 4.9 × (10⁻⁴)	HCQ is a protective factor of thrombosis in patients with CVRF and/or previous cardiovascular events	EL 2+ RG C
Petri et al.¹⁶	RCT, double blind two years	200 patients with SLE without CVRFs	Lipid-lowering therapy (atorvastatin)	Patients with SLE and placebo	Helical CT scan and Doppler ultrasound of the carotid arteries to determine the coronary and carotid calcium. At baseline, 43% of patients had coronary artery calcium. At two years, there was no significant difference between the groups in the progression of coronary artery calcium, carotid intima media thickness or carotid plaque. There was no significant difference between the groups in disease activity, measures of inflammation or endothelial cell activation.	There is no evidence that atorvastatin reduces atherosclerosis	EL 1+ RG B
Jung et al.²⁶	Case-control with logistic regression two years	162 patients with SLE and thrombotic events	54 were treated with HCQ	108 patients with SLE without thrombotic events	The use of antimalarial drugs was associated with a lower risk of thrombotic events, with an OR = 0.31, 95% CI. Separate analyses were done for arterial and venous thrombotic events, which yielded similar results.	Antimalarial drugs protect against thrombus formation and produce a 68% reduction of thrombotic events.	EL 2+ RG C
Plazak et al.¹⁷	RCT, double blind one year	60 patients with SLE	28 patients treated with lipid-lowering agents (atorvastatin)	32 patients with SLE and placebo	CT scans were performed to determine the level of coronary calcium one year after treatment. Coronary calcium deposits significantly increased in the placebo group, with no significant changes in the atorvastatin group. Secondary outcomes: lower low-density lipoprotein, triglycerides and overall cholesterol levels in patients with intervention (21%, 25%, and 13%, respectively) in the atorvastatin group.	No progression of atherosclerosis measured by coronary CT scan in patients with SLE treated daily with atorvastatin for a year.	EL 1+ RG B
Wright et al.¹¹	RCT double blind and parallel groups 24 weeks	60 patients with SLE	30 SLE patients received diet with supplements of polyunsaturated omega-3 fatty acids	30 patients with SLE and placebo	Dilation of the brachial artery (FMD) was measured in the group that received a diet with supplements of polyunsaturated omega-3 fatty acids and in the placebo group at baseline and at 12 and 24 weeks. FMD was significantly increased from baseline at week 12 and week 24 in the intervention group, median (range), baseline FMD 3.0% (20.5 to 8.2) vs week 12 FMD 5.7% (21.0 to 10.8), p = 0.002 and vs week 24 FMD 8.9% (1.3 to 16.9), p = 0.001. There was no significant change in FMD at 12 or 24 weeks in the placebo group.	Supplementing the diet with omega 3 fatty acids improves endothelial function in patients with SLE	EL 1+ RG B
Ruiz- Irastorza et al.²⁷	Cohort	232 patients with SLE	Treatment with antimalarial drugs	SLE patients who have never taken antimalarials	Protective effect of treatment with antimalarial drugs in SLE patients against the development of thrombosis (HR 0.82%, CI 0.08–0.09)	The results of the study support the continued use of antimalarial drugs in the treatment of SLE without contraindications	EL 2+ RG C
Penn et al.²⁸	Cross-sectional study 16 years	149 patients with SLE non-diabetic	71 patients treated with HCQ	78 patients with SLE non-diabetic untreated with HCQ	Patients treated with HCQ showed lower levels of fasting glucose (87.1 mg/dL vs 91.5 mg/dL in control group), p = 0.009, insulin resistance [assessed by the homeostasis model assessment (HOMA-IR) calculation of 2.51 (1.73, 3.55) 194 in the treatment group vs 2.87 (1.97, 4.28) 179 in the control group without treatment), p = 0.046, and LDL levels (102 ± 32 mg/dL) in the treatment group vs (118 ± 34 mg/dL) in the control group), p = 0.004.	HCQ seems to have a beneficial effect on cardiovascular risk in SLE	EL 2-RG not useful
O’Neill et al.¹³	Cohort three years	308 patients with SLE and CVRFs	Strategies for smoking cessation		Almost half of smoking patients in the study stopped smoking with the anti-smoking strategy (47%)	Strategies for smoking cessation are effective for reducing or stopping smoking in SLE patients.	EL 2+ RG C
Bursztyn et al.²²	Non-randomized clinical trial six months	Eight patients with SLE	Nifedipine treatment	Eight patients with SLE after treatment with nifedipine	Reduction in BP from 151.9 ± 10/103.7 ± 8.6 mmHg to 130 ± 14.1/87.5 ± 5 mmHg after six months treatment with nifedipine.	Nifedipine may reduce blood pressure in SLE patients.	EL 1 + RG B
Herlitz et al.²³	Non-randomized clinical trial >six months	14 patients with SLE	Treatment with captopril	14 patients with SLE after treatment with captopril	Decrease in BP from 178 ± 7/110 ± 4 to 145 ± 5/92 ± 3 mmHg, after six months treatment with captopril.	Captopril as a concomitant treatment may contribute to improving the blood pressure in lupus nephritis patients.	EL 1+ RG B

Abbreviations: ACO: oral anticoagulant; MI: myocardial infarction; aPL: antiphospholipid antibodies; APS: antiphospholipid syndrome; ASA: acetylsalicylic acid; BP: blood pressure; CI: confidence interval; CT: computed tomography; CVRFs: cardiovascular risk factors; DBP: diastolic blood pressure; EL: evidence level; FMD: flow-mediated dilation; GI: glycaemic index; HCQ: hydroxychloroquine; HDL: high-density lipoprotein; HR: hazard ratio; LDL: low-density lipoprotein; OR: odds ratio; RG: recommendation grade; SLE: systemic lupus erythematous; SR: systematic review; TG: triglycerides; SD: standard deviation.

The total number of patients with SLE included in this review was 10,236. A very important variability in sample size of the studies was observed, ranging from eight to 4095 patients. The duration of the follow-up in longitudinal studies ranged from six weeks to 16 years. The most common interventions were antiplatelets and lipid-lowering drugs, and the outcome measure most frequently reported was the occurrence of thromboembolic events. The characteristics of the included studies are shown in the evidence table (Table 1).

Interventions for health promotion

Interventions aimed at promoting health were mainly diet, exercise and smoking cessation.

Diet. The effect of diet in patients with SLE was studied in two RCTs. In the study by Davies et al.,¹⁰ 23 women with SLE and BMI > 25 kg/m² treated with prednisone followed a low-glycaemic diet (n = 11) or a low-calorie index diet (n = 12) for six weeks. Both diets produced an effective, equivalent and statistically significant reduction of weight (decrease of the initial weight of 3.9 ± 0.9 kg and 2.4 ± 2.2 kg with low glycaemic index and low caloric index, respectively, p < 0.01). Both diets improved waist and hip circumferences. Wright et al.¹¹ determined the effectiveness of omega-3-polyunsaturated fatty acid supplements on endothelial function in SLE patients without CVRFs and not treated with glucocorticoids. Primary outcome was the endothelial function measured by FMD at the brachial artery as of baseline and at 12 and 24 weeks. There was a statistically significantly increase in FMD in the intervention group (FMD 3%, 5.7% and 8.9% at baseline, 12 and 24 weeks, respectively, p = 0.001), but not in the placebo group. Low-calorie diets, low-glycaemic index diets and supplements of polyunsaturated omega-3 fatty acids are interventions with a level of evidence and grade of recommendation of SIGN 1 + B.

Exercise. Reis-Neto et al. analyzed the effectiveness of a 16-week exercise programme in patients with SLE (n = 38) without CVRFs on endothelial function measured by brachial artery FMD.¹² The exercise group showed an increase in the primary endpoint from 6.3 to 14.1% (p = 0.006), while no statistically significant changes were observed in the control group (p = 0.598). Although it seems that physical exercise could improve FMD in SLE patients without CVRFs, as results were obtained from an observational study, they might not be free of bias and should be taken as a recommendation in clinical practice cautiously (level of scientific evidence 1−).

Smoking cessation. The primary objective of the cohort study by O’Neill et al.¹³ on smoking cessation was to analyze whether stratification tables used in the general population were useful to calculate cardiovascular risk in patients with SLE. The study included 308 patients with SLE, and the risk of cardiovascular events was calculated using the Framingham–Wilson tables and the Systematic Coronary Risk Evaluation (SCORE). A lipid-lowering therapy and a strategy for reducing smoking were prescribed in subjects with a SCORE >7.5%. Calculating a baseline risk did not modify subsequent management in 96.5% of cases, since patients with cardiovascular risk were already receiving appropriate treatment. A secondary endpoint of this study was to estimate the smoking cessation rate in a period of approximately three years: 47% of the patients stopped smoking or reduced consumption after the introduction of a proper strategy. The level of evidence and grade of recommendation was SIGN 2+ C.

Pharmacological interventions

Lipid-lowering therapy. The effect of lipid lowering on cardiovascular risk of patients with SLE has been studied in three clinical trials and one case-control study controlled by the effect of age, sex and comorbidities (hypertension, diabetes and chronic kidney disease). Yu et al.¹⁴ conducted a case-control study of 8.4 ± 3.5 years on a population of 4095 patients with SLE and hyperlipidaemia nested in the Taiwan National Health Insurance Research Database. Mortality rate was lower in patients with high doses of statins (hazard ratio (HR) = 0.44) as well as low doses of statins plus hydroxychloroquine (HR = 0.38). In addition, high doses of statins significantly reduced the incidence of acute myocardial infarction (HR = 0.20, 95% confidence interval (CI): 0.13–0.31) and stroke (HR = 0.14; CI 95%: 0.08–0.25). In the clinical trial by Ferreira et al., 20 mg/day of atorvastatin produced a beneficial effect in 64 SLE patients, 33 of whom had hypertension, dyslipidaemia and obesity and 31 had no CVRFs, who were compared to a control group without atorvastatin.¹⁵ The main outcome, FMD at eight weeks, increased significantly from 4% to 7% in the atorvastatin group and did not increase in the untreated group. The intervention group showed changes in other secondary outcomes, with significantly higher levels of HDL cholesterol and lower DBP values than the control group (HDL of 47 mg/dL and 41 mg/dL in the intervention and control groups; p = 0.049; DBP of 74 mmHg and 80 mmHg in the intervention and control groups, respectively). Nevertheless, this was a non-randomized clinical trial, and thus with a potential selection bias.

Other studies have failed to find any significant changes in other surrogate markers of atherosclerosis, such as a two-year RCT conducted by Petri et al.¹⁶ in which 200 patients with SLE without previous cardiovascular events were treated with atorvastatin 40 mg/day (n = 99) or placebo (n = 101). The main outcome was the extent of coronary calcium, determined by computed tomography (CT) scan. There were no statistically significant differences between the groups with respect to changes in coronary artery calcium score after two years (atorvastatin, 1.24 vs placebo, 1.35; p = 0.62).

Secondary outcomes were LDL and triglycerides levels, showing a reduction in both parameters in the intervention group compared with the control group (LDL cholesterol, 2.9 mg/dL vs 2.3 mg/dL; p < 0.05; triglycerides, 1.6 mg/dL vs 1.2 mg/dL; p < 0.05).

By contrast, in the RCT conducted by Plazak et al.,¹⁷ lower coronary calcium deposits measured by CT scan were observed in 28 SLE patients without CVRFs after one year of treatment with 40 mg atorvastatin compared to 32 SLE patients receiving placebo (intervention group, 54.5 mm at baseline and 51.0 mm after one year of treatment with atorvastatin, non-significant). With regard to secondary outcomes, patients treated with atorvastatin showed a decrease in LDL cholesterol (21%), triglycerides (25%) and total cholesterol (13%) after a year of treatment. In summary, the data about effect of lipid lowering treatment on coronary calcium are contradictory and large prospective clinical trials are needed. Although there is an effect in improving the lipid profile, the effect of this treatment on overall cardiovascular mortality is yet unknown (level of scientific evidence and grade of recommendation SIGN 1+ B.)

Antiplatelet and anticoagulant treatment. Four reports (two meta-analyses, one RCT and one prospective cohort study) studied the effect of antithrombotic drugs (antiplatelet agents and anticoagulants) on cardiovascular risk in SLE patients. The main outcome in both meta-analyses^18,19 was the efficacy of acetylsalicylic acid (ASA) for the primary prevention of thrombotic events in patients with SLE and CVRFs. The first meta-analysis obtained data from five cohort studies summing 497 participants with positive antiphospholipid antibodies, of whom 192 were patients with SLE.¹⁸ The second meta-analysis included 11 studies (10 cohorts and one RCT), with a total of 440 patients with SLE.¹⁹ An analysis of the efficacy of ASA was conducted according to the occurrence of thrombotic events in SLE patients treated with low dose ASA compared to untreated patients (excluding patients receiving clopidogrel or oral anticoagulants). Results of both meta-analyses indicated that ASA is effective for the primary prevention of thrombosis, with an odds ratio (OR) of 0.43 [95% CI: 0.20–0.94] and 0.55 [95% CI: 0.31–0.98], respectively. Cuadrado et al. conducted an open RCT in 232 SLE patients without previous cardiovascular events, of whom 166 patients received treatment (82 with ASA and 84 with ASA + warfarin) and 66 were untreated.²⁰ The primary outcome was the occurrence of thrombotic events (primary prevention) during five years of follow-up in three groups, as follows: patients treated with ASA alone, ASA plus warfarin, and without antithrombotic treatment. No differences were found in the rate of thrombotic events between patients with ASA or with ASA plus warfarin; however, the rate of thrombotic events in the untreated group was twice the rate in the intervention group (4.9 events/100 person-years versus 1.8 events/100 person-years, respectively [HR = 2.43, 95% CI: 0.87–6.79)]. As it is an open trial, the likelihood of bias is large and the quality of the evidence limited. The cohort study conducted by Tarr et al. analyzed the effectiveness of primary and secondary prevention of antithrombotic therapy in patients with SLE (n = 272).²¹ MI and stroke were the main outcomes. Three different groups were analyzed: patients with SLE and positive antiphospholipid antibody (n = 81), patients with SLE and APS (n = 84), and patients with SLE and negative antiphospholipid antibody (n = 107). Fifty-two of the 81 patients in the group with positive antiphospholipid antibodies received primary prophylaxis, of whom 50 were treated with ASA, one with coumarin and one with clopidogrel; 79 of 84 patients in the group with APS received prophylaxis with anticoagulants and/or antiplatelets: 37 ASA, 23 coumarin, two clopidogrel, and 17 ASA plus coumarin. After five years, a patient with positive antiphospholipid antibodies treated with ASA had a stroke and two patients with positive antibody without prophylaxis had strokes. In the group with SLE and APS, there were two MI and five strokes (one with ASA and four with ASA + coumarin). In summary, the use of antiplatelet agents and/or anticoagulants appears to be useful in the primary prevention of thrombotic events in patients with SLE, with a level of scientific evidence and grade of recommendation SIGN 1++ B. It also appears that the secondary prevention of thrombotic events (MI and stroke) may be beneficial in these patients (level of evidence and grade of recommendation SIGN 2+C).

Antihypertensive. Two small, non-randomized, uncontrolled open clinical trials analyzed the effect of antihypertensive treatment in patients with SLE. In the case series of Bursztyn et al., eight SLE patients received 40 mg/day nifedipine, and blood pressure (BP) was reduced from 151.9 ± 10/103.7 ± 8.6 mmHg to 130 ± 14.1/87.5 ± 5 mmHg in six months.²² In the study by Herlitz et al., 14 patients received captopril and reduced BP from 178 ± 7/110 ± 4 to 145 ± 5/92 ± 3 mmHg.²³ In conclusion, it appears that treatment with antihypertensive drugs effectively reduces BP in patients with SLE, although the studies analyzed did not include a control group, and so the level of evidence and grade of recommendation were SIGN 3 D.

Specific treatment of SLE

Antimalarials. Five studies have analyzed the effectiveness of antimalarials on cardiovascular risk in SLE: one meta-analysis, one cohort study, two case-control studies and one cross-sectional study. Ruiz-Irastorza et al.²⁴ demonstrated the effect of hydroxychloroquine in the primary prevention of thrombotic events in patients with SLE and CVRFs in a meta-analysis. Individual studies also showed a lower risk of thrombotic events with antimalarials.^25–27 Penn at al. reviewed the clinical records of 149 non-diabetic patients with SLE, half of whom had been treated with antimalarials.²⁸ Endpoints were glucose levels (mg/dL), insulin resistance (HOMA-IR) and LDL over an average period of 16 years. The group exposed to antimalarials showed lower glucose fasting levels (87.1 mg/dL versus 91.5 mg/dL) and insulin resistance (HOMA-IR = 194 versus 179) than the control group. Similarly, LDL levels were lower compared to the untreated group (LDL of 102 mg/dL and 118 mg/dL in the groups with and without treatment, respectively). In summary, it appears that the use of hydroxychloroquine in patients with SLE and CVRFs is useful for the primary prevention of thrombotic events, with a level of scientific evidence and grade of recommendation SIGN 1+ B. Also, the use of hydroxychloroquine seems to have a positive effect on glucose levels, insulin resistance and LDL levels, with a level of scientific evidence 1−, but it is not possible to establish the degree of recommendation SIGN.

Discussion

Although SLE is associated with a higher risk of cardiovascular complications, studies that have examined the efficacy of interventions on CVRFs in SLE patients are scarce.

SLE patients exhibit obesity in a large proportion.⁵ Consequently, it is necessary to prevent and treat weight gain in these patients. One of the studies of this review analyzed the effect of diets with low-calorie and/or low glycaemic index on weight in overweight patients with SLE, showing that both diets are a useful measure in secondary prevention of obesity in these patients (SIGN 1+ B).¹⁰ To prevent the development of a factor as important as obesity in cardiovascular risk, new studies in patients who have not yet gained excess weight (primary prevention) are needed. We have also found a beneficial effect of diet with polyunsaturated omega-3 fatty acids on the FMD in SLE patients without CVRFs, but new studies on the effects on patients with SLE and CVRFs or previous cardiovascular events are warranted.

Studies examining the effect of exercise in SLE are scarce and the only ones found suggest that exercise improves FMD in patients without CVRFs. Consequently, it appears that exercise would be useful in improving vasodilatation in this group of patients; however, the study that analyzes this effect lacks external validity and it is not possible to extrapolate the results to clinical practice. It would also be necessary to examine whether exercise can improve FMD in patients with SLE and CVRFs.

Smoking seems less frequent in patients with SLE,¹³ although the RELESSER study has found an increased risk of cardiovascular events in active smokers and ex-smokers (37%; OR = 1.48, 95% CI: 1.06–2.07).⁸ Very few studies focussed on the effect of smoking cessation in CVRFs in patients with SLE. One such study suggests that smoking cessation strategies (counselling) can help reduce consumption, but it does not analyze the impact of this measure on cardiovascular endpoints (level of scientific evidence and grade of recommendation SIGN 2+ C).

The frequency of diabetes is also high in SLE patients.⁵ Lupus patients with diabetes exhibited an increased risk of cardiovascular events in the RELESSER study (OR = 2.22, CI 95%: 1.32–3.74).⁸ However, only one study, of a cross-sectional nature, has studied the association between blood glucose levels or insulin resistance with hydroxychloroquine,²⁸ and thus the strength of a recommendation is limited.

The use of lipid-lowering drugs is widespread in the general population because of the many benefits of primary and secondary prevention of cardiovascular events. It seems that the effect is identical in patients with SLE. Yu et al.¹⁴ reported that the use of high doses of statins decreased mortality and cardiovascular events in patients with SLE and hyperlipidaemia without previous events. Unfortunately, the level of evidence is insufficient, as this was a case-control study, making it necessary to undertake studies of higher quality.

In addition, RCTs^16,17 showed the efficacy of atorvastatin to reduce total cholesterol, LDL and triglycerides levels in SLE patients without previous CVRFs. Although the outcomes analyzed are secondary, the level of evidence and the grade of recommendation SIGN of these clinical trials (level of evidence 1+, grade of recommendation B) suggest that SLE patients without CVRFs should be treated with atorvastatin; nevertheless, new studies are needed focussed on other outcomes such as the occurrence of major cardiovascular events (MI, stroke). Both RCTs examined surrogate endpoints of atherosclerosis with mixed results.

A non-randomized clinical trial examined the effect of atorvastatin on FMD, HDL cholesterol levels and DBP values in SLE patients without CVRFs.¹⁵ Despite the improvement of these three parameters, it is not possible to draw firm conclusions given the evidence level of the study.

SLE patients have a higher risk of ischemic heart disease, stroke and other thrombotic events.⁵ All studies have indicated that the use of antiplatelet therapy (ASA and/or clopidogrel) may be useful for primary prevention of thrombotic events in patients with SLE. The use of ASA appears effective in primary prevention of thrombotic events in patients with SLE and CVRFs with high level of evidence. The only study that analyzed the effect of antiplatelet agents and/or anticoagulants as secondary prevention of thrombotic events was an observational cohort study,²¹ so new studies with higher levels of evidence may be needed.

Regarding specific treatment of SLE, most reports analyzed the effect of antimalarial drugs (hydroxychloroquine) on cardiovascular risk in SLE, noting that this drug may be useful in the primary prevention of thrombotic events in patients with SLE and CVRFs, with a level of scientific evidence and grade of recommendation SIGN 1+ B. The presence of thrombosis was analyzed in patients with SLE, CVRFs and prior treatment with hydroxychloroquine in a nested case-control. The risk of thrombotic events was lower in patients treated with hydroxychloroquine, and this drug also appears to be useful for the secondary prevention of thrombotic events; however, it was an observational case-control study and studies with higher levels of evidence are needed to verify these findings.

Hypertension is also a frequent CVRF in lupus patients.⁵ The two studies found in this search were not controlled clinical trials;^22,23 therefore, it is necessary to conduct clinical trials including a control group to establish stronger inferences. Although the small sample size of the studies reduces the usefulness of the results, and they should not have been included in a review, we finally decided to include them because there are no other studies on this outcome and we did not settle any exclusion criterion based on sample size.

No studies have been found on the potential effect of glucocorticoids and immunosuppressants on CVRFs, although it is well known that glucocorticoids increase cardiovascular risk in the general population.

The implications of this review for clinical practice are based primarily on the usefulness of dietary measures with low-caloric and/or low glycaemic index diets in patients with SLE who are overweight. It would also be advisable to use diets with polyunsaturated omega-3 fatty acids, as they improve the FMD. The effects of physical activity on CVRFs in patients with SLE have been inaccurate and further studies are needed. It is recommended that cessation of smoking is advised for these patients. Further studies analyzing the effect of smoking cessation on CVRFs in patients with SLE are also needed. It is essential to conduct additional studies to examine the intervention on blood glucose levels in order to reduce diabetes in these patients, since existing studies are scarce and do not enable a causal relationship to be determined.

Existing evidence indicates that the use of statin may reduce overall mortality in patients with SLE and hyperlipidaemia, but more studies are necessary. However, the use of atorvastatin in SLE patients without CVRFs should be appropriate as this drug increases FMD independently of its cholesterol lowering action. However, studies analysing more specific outcomes, such as the occurrence of cardiovascular events, should be carried out.

The use of ASA and hydroxychloroquine is recommended in patients with SLE and CVRFs in order to prevent the occurrence of first thrombotic events. There are many studies exploring the use of antiplatelet therapies and/or anticoagulants in the general population, but specific studies about these effects are required in patients with SLE.²⁵ The use of antihypertensive drugs in patients with SLE and HTA is advised;^22,23 however, given the absence of a control group in the trials found in this review, it is important to conduct new studies involving untreated patients.

In conclusion, the results of this review suggest that interventions aiming at controlling CVRFs may be effective in patients with SLE. Rheumatologists should be aware of the importance of cardiovascular risk assessment and proceed accordingly. We suggest some recommendations to be implemented in clinical practice.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest 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.

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