Markers of cardiovascular risk in patients with antiphospholipid syndrome: A meta-analysis of literature studies

Figures & data

Table I. Characteristics of included studies.

Author		Pop (n)	M/F (n)	Age (y)	HT (%)	Smoking (%)	DM (%)	BMI (kg/m^2)	TC (mg/dL)	LDLc (mg/dL)	HDLc (mg/dL)	TGs (mg/dL)
Medina, 2003 (36)^a	pAPS	28	12/16	40.0 ± 8.5	36	11	0	NA	NA	NA	NA	NA
	Controls	28	12/16	41.7 ± 6.3	0	14	0	NA	NA	NA	NA	NA
Vlachoyiannopoulus, 2003 (22)	pAPS/sAPS	33	0/33	33.9 ± 7.4	6	NA	0	26.0 ± 5.0	194 ± 34	120 ± 27	51 ± 14	89 ± 15
	Controls	33	0/33	33.3 ± 7.9	9	NA	3.0	24.0 ± 5.0	193 ± 37	117 ± 34	57 ± 12	47 ± 8
Roch, 2004 (30)	pAPS	20	4/16	44.0 ± 16.0	NA	NA	NA	NA	NA	NA	NA	NA
	sAPS	14	1/13	43.0 ± 16.0	NA	NA	NA	NA	NA	NA	NA	NA
	Controls	24	3/21	43.0 ± 9.0	NA	NA	NA	NA	NA	NA	NA	NA
Ames, 2005 (18)^b	pAPS	20	13/7	35.0 ± 12.0	5	30	0	< 30.0	NA	NA	NA	NA
	Controls	20	13/7	34.0 ± 12.0	5	20	0	< 30.0	NA	NA	NA	NA
Ames, 2005 (39)	pAPS	18	5/13	42.0 ± 9.0	17	NA	NA	NA	NA	NA	NA	NA
	Controls	16	4/12	41.0 ± 8.0	0	NA	NA	NA	NA	NA	NA	NA
Barón, 2005 (28)^c	pAPS	43	6/37	40.2 ± 7.9	35	23	NA	NA	NA	NA	NA	NA
	Controls	49	7/42	41.0 ± 11.7	6	27	NA	NA	NA	NA	NA	NA
Jimenez, 2005 (32)	pAPS	25	0/25	38.6 ± 11.4	4	36	0	24.2 ± 3.6	203 ± 36	121 ± 27	66 ± 14	91 ± 49
	sAPS	16	0/16	39.9 ± 10.3	NA	NA	NA	NA	NA	NA	NA	NA
	Controls	40	0/40	42.2 ± 11.2	10	37	5	24.9 ± 4.6	190 ± 50	109 ± 42	58 ± 26	78 ± 35
Chrsistodoulou, 2006 (19)	pAPS/sAPS	30	0/30	NA	NA	NA	NA	NA	NA	NA	NA	NA
	Controls	30	0/30	NA	NA	NA	NA	NA	NA	NA	NA	NA
Stalc, 2006 (20)^d	pAPS	25	15/10	47.0 ± 13.0	20	4	4	NA	NA	NA	NA	NA
	Controls	25	15/10	47.0 ± 13.0	12	4	4	NA	NA	NA	NA	NA
Der, 2007 (37)	pAPS	44	NA	52.0 ± 15.0	NA	NA	NA	NA	NA	NA	NA	NA
	Controls	36	NA	50.0 ± 11.0	NA	NA	NA	NA	NA	NA	NA	NA
Margarita, 2007 (29)	pAPS > 40 y	16	NA	> 40	NA	NA	NA	NA	NA	NA	NA	NA
	Controls	14	NA	> 40	NA	NA	NA	NA	NA	NA	NA	NA
	pAPS 30–40 y	17	NA	30–40	NA	NA	NA	NA	NA	NA	NA	NA
	Controls	11	NA	30–40	NA	NA	NA	NA	NA	NA	NA	NA
Belizna, 2008 (5)^e	pAPS/sAPS	58	22/36	29.1 (21–45)	NA	48	0	NA	175 ± 19	101 ± 23	54 ± 3	137 ± 35
	Controls	58	16/42	28.1 (20–45)	NA	62	0	NA	174 ± 21	103 ± 12	56 ± 2	134 ± 27
Soltesz, 2008 (33)	pAPS	28	12/16	NA	NA	NA	NA	NA	NA	NA	NA	NA
	Controls	38	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA
Ames, 2009 (34)^f	pAPS	49	18/31	37.0 ± 11.0	NA	37	0	25.3 ± 3.2	178 ± 35	97 ± 31	37 ± 11	106 ± 55
	Controls	49	18/31	37.0 ± 11.0	NA	24	0	23.4 ± 2.4	182 ± 29	110 ± 29	57 ± 14	83 ± 29
Bilora, 2009 (35)	pAPS	16	10/6	52.6 ± 3.1	31	NA	NA	25.5 ± 4.6	NA	NA	NA	NA
	Controls	16	10/6	52.9 ± 4.1	31	NA	NA	25.1 ± 4.4	NA	NA	NA	NA
Charakida, 2009 (21)^g	pAPS abort	23	0/23	44.6 ± 9.2	26	43	0	26.1 ± 5.8	193 ± 44	132 ± 33	50 ± 17	76 (57–119)
	pAPS VTE	38	0/38	49.4 ± 10.8	32	16	3	25.2 ± 4.5	199 ± 45	126 ± 38	57 ± 13	78 (59–118)
	Controls	77	0/77	47.5 ± 10.4	25	22	2	24.5 ± 4.8	196 ± 39	129 ± 32	56 ± 11	73 (53–113)
Gresele, 2009 (40)^h	pAPS	20	9/11	41.9 ± 4.0	NA	0	0	24.2 ± 0.9	NA	NA	NA	NA
	Controls	39	17/22	41.3 ± 2.9	NA	0	0	23.6 ± 0.7	NA	NA	NA	NA
Caraba, 2010 (38)	pAPS	10	2/8	41.4 ± 4.2	0	30	0	NA	211 ± 20	NA	NA	NA
	Controls	10	2/8	42.0 ± 4.0	0	40	0	NA	196 ± 29	NA	NA	NA
Cugno, 2010 (41)^i	pAPS	40	7/33	38.0 ± 9.0	NA	17.5	NA	22.8 ± 3.4	188 ± 32	119 ± 26	58 ± 14	NA
	Controls	40	7/33	41.0 ± 12.0	NA	20	NA	23.7 ± 4.1	197 ± 32	115 ± 31	62 ± 13	NA
Conti, 2014 (31)^j	pAPS	18	4/14	39.9 ± 11.5	NA	11	5	25.5 ± 3.3	191 ± 24	122 ± 19	49 ± 15	102 ± 59
	sAPS	19	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA
	Controls	25	4/21	42.5 ± 12.0	NA	32	0	22.2 ± 3.1	203 ± 46	126 ± 43	58 ± 10	91 ± 47

abort = recurrent abortions; BMI = body mass index; DM = diabetes mellitus; HDLc = HDL-cholesterol; HT = hypertension; LDLc = LDL-cholesterol; M/F = male/female; NA = not assessed; pAPS = primary antiphospholipid syndrome; Pop = study population; sAPS = secondary antiphospholipid syndrome; TC = total cholesterol; TGs = triglycerides; VTE = venous thromboembolism.

^a54% of patients and 39% of controls were obese; 29% of patients and 29% of controls had hypercholesterolemia; 25% of patients and 29% of controls had hypertriglyceridemia.

^b5% of patients and 5% of controls had hypercholesterolemia; 15% of patients had hypertriglyceridemia.

^c33% of patients and 6% of controls had BMI > 28; 26% of patients and 6% of controls had hypercholesterolemia.

^d8% of patients and 8% of controls had BMI > 27; 28% of patients and 24% of controls had hyperlipidemia.

^eAge is expressed as mean (range). Systolic blood pressure (mmHg, mean± SD) was 110 ± 2.45 in cases and 109 ± 3.20 in controls; diastolic blood pressure (mmHg, mean± SD) was 69 ± 1.68 in cases and 66.4 ± 1.59 in controls.

^fSystolic blood pressure (mmHg, mean± SD) was 125 ± 17.7 in cases and 123 ± 15.1 in controls; diastolic blood pressure (mmHg, mean± SD) was 80 ± 9.6 in cases and 77 ± 7.9 in controls.

^gValues of TGs are expressed as median (interquartile range).

^hSystolic blood pressure (mmHg, mean± SD) was 129 ± 4 in cases and 125 ± 3 in controls; diastolic blood pressure (mmHg, mean± SD) was 77 ± 2 in cases and 74 ± 2 in controls; patients with dyslipidemia were excluded from the study.

ⁱSystolic blood pressure (mmHg, mean± SD) was 120 ± 15 in cases and 133 ± 24 in controls; diastolic blood pressure (mmHg, mean± SD) was 78 ± 10 in cases and 88 ± 11 in controls; glycemia (mg/dL, mean± SD) was 81 ± 10 in cases and 87 ± 10 in controls.

^jSystolic blood pressure (mmHg, mean± SD) was 127 ± 15 in cases and 115 ± 16 in controls; diastolic blood pressure (mmHg, mean± SD) was 79 ± 11 in cases and 73 ± 9 in controls.

Figure 1. Intima-media thickness in antiphospholipid syndrome (APS) patients and controls. A: Common carotid artery intima-media thickness (CCA-IMT). B: Internal carotid artery IMT (ICA-IMT). C: Carotid bifurcation IMT (BIF-IMT). D: Prevalence of carotid plaques. (Abort = recurrent abortions; pAPS = primary antiphospholipid syndrome; sAPS = secondary antiphospholipid syndrome; VTE = venous thromboembolism; y = years of age).

Figure 2. Flow-mediated dilation and nitrate-mediated dilation in antiphospholipid syndrome (APS) patients and controls. A: Flow-mediated dilation (FMD). B: Nitrate-mediated dilation (NMD). (Abort = recurrent abortions; pAPS = primary antiphospholipid syndrome; sAPS = secondary antiphospholipid syndrome; VTE = venous thromboembolism).

Figure 3. Prevalence of pathological ankle-brachial index in antiphospholipid syndrome (APS) patients and controls.

Table II. Sensitivity analysis including ‘high-quality’ studies (i.e. Newcastle–Ottawa Scale ≥ 6).

	Studies (n)	Patients (n)	Effect size MD or OR [95% CI]
CCA-IMT	12 (16 data sets)	430 patients 569 controls	MD: 0.11 [0.06, 0.15]; P < 0.00001 I^2 = 88%; P < 0.00001
ICA-IMT	5 (6 data sets)	136 patients 126 controls	MD: 0.08 [0.05, 0.11]; P < 0.00001 I^2 = 0%; P = 0.53
BIF-IMT	5 (6 data sets)	136 patients 126 controls	MD: 0.09 [0.06, 0.12]; P < 0.00001 I^2 = 0%; P = 0.64
Carotid plaques	4 (6 data sets)	142 patients 239 controls	OR: 3.87 [1.61, 9.31]; P = 0.0003 I^2 = 35%; P = 0.17
FMD	5 (6 data sets)	155 patients 274 controls	MD: − 3.66 [− 5.78, − 1.55]; P = 0.0007 I^2 = 93%; P < 0.00001
NMD	2 (3 data sets)	101 patients 194 controls	MD: − 0.75 [–3.43, 1.92]; P = 0.58 I^2 = 70%; P = 0.04
ABI < 1	No studies	–	–

95% CI = 95% confidence intervals; ABI = ankle-brachial index; BIF-IMT = carotid bifurcation intima-media thickness; CCA-IMT = common carotid artery intima-media thickness; FMD = flow-mediated dilation; ICA-IMT = internal carotid artery intima-media thickness; MD = mean difference; NMD = nitrate-mediated dilation; OR = odds ratio.

Table III. Sensitivity analysis: exclusion of studies potentially evaluating the same population as other included studies.

	Studies (n)	Patients (n)	Effect size MD or OR [95% CI]
CCA-IMT	11 (15 data sets)	411 patients 562 controls	MD: 0.11 [0.07, 0.16]; P < 0.00001 I^2 = 92%; P < 0.00001
ICA-IMT	2 (2 data sets)	65 patients 65 controls	MD: 0.07 [0.02, 0.12]; P = 0.009 I^2 = 9%; P = 0.29
BIF-IMT	2 (2 data sets)	65 patients 65 controls	MD: 0.08 [0.02, 0.13]; P = 0.005 I^2 = 0%; P = 0.53
Carotid plaques	4 (6 data sets)	142 patients 239 controls	OR: 3.87 [1.61, 9.31]; P = 0.0003 I^2 = 35%; P = 0.17
FMD	7 (9 data sets)	243 patients 360 controls	MD: − 4.46 [− 6.28, − 2.63]; P < 0.00001 I^2 = 92%; P < 0.00001
NMD	3 (4 data sets)	126 patients 219 controls	MD: − 1.66 [− 4.35, 1.03]; P = 0.23 I^2 = 74%; P = 0.01
ABI	1	43 patients 49 controls	OR: 5.37 [1.07, 26.87]; P = 0.04 I^2 = NA; P = NA

95% CI = 95% confidence intervals; ABI = ankle-brachial index; BIF-IMT = carotid bifurcation intima-media thickness; CCA-IMT = common carotid artery intima-media thickness; FMD = flow-mediated dilation; ICA-IMT = internal carotid artery intima-media thickness; MD = mean difference; NMD = nitrate-mediated dilation; OR = odds ratio.

Table IV. Subgroup analysis: studies on primary antiphospholipid syndrome.

	Studies (n)	Patients (n)	Effect size MD or OR [95% CI]
CCA-IMT	12 (14 data sets)	352 patients 465 controls	MD: 0.13 [0.08, 0.18]; P < 0.00001 I^2 = 90%; P < 0.00001
ICA-IMT	5 (6 data sets)	136 patients 126 controls	MD: 0.08 [0.05, 0.11]; P < 0.00001 I^2 = 0%; P = 0.53
BIF-IMT	5 (6 data sets)	136 patients 126 controls	MD: 0.09 [0.06, 0.12]; P < 0.00001 I^2 = 0%; P = 0.64
Carotid plaques	3 (3 data sets)	63 patients 108 controls	OR: 3.14 [0.46, 21.32]; P = 0.24 I^2 = 71%; P = 0.03
FMD	8 (10 data sets)	252 patients 373 controls	MD: − 4.22 [− 5.95, − 2.49]; P < 0.00001 I^2 = 92%; P < 0.00001
NMD	4 (5 data sets)	154 patients 257 controls	MD: − 1.80 [− 4.01, 0.42]; P = 0.42 I^2 = 66%; P = 0.02
ABI	1	43 patients 49 controls	OR: 5.37 [1.07, 26.87]; P = 0.04 I^2 = NA; P = NA

95% CI = 95% confidence intervals; ABI = ankle-brachial index; BIF-IMT = carotid bifurcation intima-media thickness; CCA-IMT = common carotid artery intima-media thickness; FMD = flow-mediated dilation; ICA-IMT = internal carotid artery intima-media thickness; MD = mean difference; NMD = nitrate-mediated dilation; OR = odds ratio.

Medina G, Casaos D, Jara LJ, Vera-Lastra O, Fuentes M, Barile L, et al. Increased carotid artery intima-media thickness may be associated with stroke in primary antiphospholipid syndrome. Ann Rheum Dis. 2003;62:607–10.

 PubMed Web of Science ®Google Scholar

Vlachoyiannopoulos PG, Kanellopoulos PG, Ioannidis JP, Tektonidou MG, Mastorakou I, Moutsopoulos HM. Atherosclerosis in premenopausal women with antiphospholipid syndrome and systemic lupus erythematosus: a controlled study. Rheumatology (Oxford). 2003; 42:645–51.

 PubMed Web of Science ®Google Scholar

Roch B, Kopprasch S, Pietzsch J, Schröder HE. Oxidatively modified lipoproteins and their antibodies in patients with antiphospholipid syndrome and systemic lupus erythematosus. Z Rheumatol. 2004; 63:331–7.

 Google Scholar

Ames PRJ, Margarita A, Sokoll KB, Weston M, Brancaccio V. Premature atherosclerosis in primary antiphospholipid syndrome: preliminary data. Ann Rheum Dis. 2005;64:315–17.

 PubMed Web of Science ®Google Scholar

Ames PR, Tommasino C, Fossati G, Matsuura E, Margarita A, Saulino A, et al. Lymphocyte subpopulations and intima media thickness in primary antiphospholipd syndrome. Lupus. 2005;14:809–13.

 Google Scholar

Barón MA, Khamashta MA, Hughes GR, D’Cruz DP. Prevalence of an abnormal ankle-brachial index in patients with primary antiphospholipid syndrome: preliminary data. Ann Rheum Dis. 2005;64:144–6.

 PubMedGoogle Scholar

Jiménez S, García-Criado MA, Tàssies D, Reverter JC, Cervera R, Gilabert MR, et al. Preclinical vascular disease in systemic lupus erythematosus and primary antiphospholipid syndrome. Rheumatology (Oxford). 2005;44:756–61.

 PubMedGoogle Scholar

Christodoulou C, Zain M, Bertolaccini ML, Sangle S, Khamashta MA, Hughes GRV, et al. Prevalence of an abnormal ankle-brachial index in patients with antiphospholipid syndrome with pregnancy loss but without thrombosis: a controlled study. Ann Rheum Dis. 2006; 65:683–4.

 PubMedGoogle Scholar

Stalc M, Poredos P, Peternel P, Tomsic M, Sebestjen M, Kveder T. Endothelial function is impaired in patients with primary antiphospholipid syndrome. Thromb Res. 2006;118:455–61.

 PubMed Web of Science ®Google Scholar

Der H, Kerekes G, Veres K, Szodoray P, Toth J, Lakos G, et al. Impaired endothelial function and increased carotid intima-media thickness in association with elevated von Willebrand antigen level in primary antiphospholipid syndrome. Lupus. 2007;16:497–503.

 PubMed Web of Science ®Google Scholar

Margarita A, Batuca J, Scenna G, Alves JD, Lopez L, Iannaccone L, et al. Subclinical atherosclerosis in primary antiphospholipid syndrome. Ann N Y Acad Sci. 2007;1108:475–80.

 PubMedGoogle Scholar

Belizna CC, Richard V, Primard E, Kerleau JM, Cailleux N, Louvel JP, et al. Early atheroma in primary and secondary antiphospholipid syndrome: an intrinsic finding. Semin Arthritis Rheum. 2008;37:373–80.

 Google Scholar

Soltesz P, Der H, Veres K, Laczik R, Sipka S, Szegedi G, et al. Immunological features of primary anti-phospholipid syndrome in connection with endothelial dysfunction. Rheumatology (Oxford). 2008;47: 1628–34.

 Google Scholar

Ames PR, Antinolfi I, Scenna G, Gaeta G, Margaglione M, Margarita A. Atherosclerosis in thrombotic primary antiphospholipid syndrome. J Thromb Haemost. 2009;7:537–42.

 Google Scholar

Bilora F, Sartori MT, Zanon E, Campagnolo E, Arzenton M, Rossato A. Flow-mediated arterial dilation in primary antiphospholipid syndrome. Angiology. 2009;60:104–7.

 Google Scholar

Charakida M, Besler C, Batuca JR, Sangle S, Marques S, Sousa M, et al. Vascular abnormalities, paraoxonase activity, and dysfunctional HDL in primary antiphospholipid syndrome. JAMA. 2009;302:1210–17.

 PubMed Web of Science ®Google Scholar

Gresele P, Migliacci R, Vedovati MC, Ruffatti A, Becattini C, Facco M, et al. Patients with primary antiphospholipid antibody syndrome and without associated vascular risk factors present a normal endothelial function. Thromb Res. 2009;123:444–51.

 PubMed Web of Science ®Google Scholar

Caraba A, Şerban C, Mihǎescu R, Romoşan I. Subclinical atherosclerosis in primary antiphospholipid syndrome. Annals of the Romanian Society for Cell Biology. 2010;15:293–8.

 Google Scholar

Cugno M, Borghi MO, Lonati LM, Ghiadoni L, Gerosa M, Grossi C, et al. Patients with antiphospholipid syndrome display endothelial perturbation. J Autoimmun. 2010;34:105–10.

 PubMedGoogle Scholar

Conti F, Spinelli FR, Alessandri C, Pacelli M, Ceccarelli F, Marocchi E, et al. Subclinical atherosclerosis in systemic lupus erythematosus and antiphospholipid syndrome: focus on β2GPI-specific T cell response. Arterioscler Thromb Vasc Biol. 2014;34:661–8.

 Google Scholar