Efficacy of Dual Antiplatelet Therapy for Preventing Recurrence of Arterial Thrombosis in Patients With Antiphospholipid Syndrome

Naoki Ohnishi; Yuichiro Fujieda; Ryo Hisada; Hiroyuki Nakamura; Masaru Kato; Kenji Oku; Toshiyuki Bohgaki; Olga Amengual; Shinsuke Yasuda; Tatsuya Atsumi

Disclosures

Rheumatology. 2019;58(6):969-974.

Abstract and Introduction

Abstract

Objective: Warfarin is regarded as the standard treatment for preventing thrombotic events in APS, but the recurrence rate is still high. Dual antiplatelet therapy (DAPT) has been shown to be effective for the prevention of acute coronary syndrome or stroke. The objective of this study was to evaluate the efficacy of DAPT for the prevention of thrombosis recurrence in APS patients with history of arterial thrombosis.

Methods: This retrospective cohort study of APS patients was conducted at Hokkaido University Hospital between 1990 and 2016. The secondary prophylactic effects and safety of warfarin monotherapy (Wf), antiplatelet monotherapy (AP), warfarin and antiplatelet combination therapy (Wf + AP) and DAPT were evaluated. The primary endpoints were set as thrombosis-free and adverse events-free survival period. Adverse events were defined as severe bleeding and death.

Results: A total of 90 APS patients were enrolled. Thrombotic recurrence was found in 40 patients (35 arterial and 5 venous thromboses) and serious adverse events in 20 patients (9 severe bleeding events and 14 deaths). Kaplan–Meier analysis demonstrated a 10-year recurrence-free survival rate of 62%. The recurrence rate per 100 patient-years was as follows: Wf: 11.6, AP: 5.5, Wf: + AP: 3.7, DAPT: 1.8. We demonstrated that DAPT significantly reduced the rate of recurrence compared with Wf (log-rank P = 0.001). There were no significant differences in the rate of serious adverse events among the groups.

Conclusion: DAPT might be considered as an effective and safe option for the prophylaxis of recurrent arterial thrombosis in APS.

Introduction

APS is an autoimmune disease characterized by thrombotic events and pregnancy complications with persistently positive aPL.^[1] APS patients suffer from thrombosis in both arteries and veins, while protein C deficiency, Factor V Leiden, and other thrombophilia mostly affect the venous circulation.

According to the guidelines for the management of patients with APS, anticoagulation using warfarin is recommended for secondary prophylaxis of arterial/venous thrombosis by targeting the PT-International normalized ratio (PT-INR) between 2.0 and 3.0.^[2] On the other hand, the APS Workshop guidelines recommend that APS patients with an arterial thrombotic event should be treated with warfarin at PT-INR >3.0 or with antiplatelet plus warfarin combination therapy at PT-INR between 2.0 and 3.0.^[3] The difference between these recommendations may be due to the discrepancy in their main objectives of avoiding treatment-related bleeding events^[4] or preventing severe recurrent thrombosis.^[5] However, a major limitation in both recommendations is that there is no definitive evidence of prevention of recurrent arterial events.

Dual antiplatelet therapy (DAPT) is commonly used in clinical practice for the secondary prevention of arterial thrombotic events in patients at high recurrence risk. Defined as the combination of aspirin and a P2Y₁₂-receptor inhibitor, DAPT has demonstrated superior efficacy over anticoagulant therapy in coronary artery disease. Although there have been no reports of retrospective/prospective studies that compare the effectiveness and safety of DAPT in APS patients,^[6] the benefit of antiplatelet therapy is highly suggestive as most arterial thromboses recur as arterial thrombosis.^[7,8] Although arterial thrombosis in APS is reported most frequently in Japan compared with other countries, still the low prevalence of disease makes prospective trials very difficult.^[5,8] Therefore, our longitudinal APS cohort was used to evaluate the benefit of DAPT in patients with a history of arterial thrombosis.

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Table 1. Baseline clinical and demographic characteristics of the patients
Characteristic	Total	Wf	AP	Wf + AP	DAPT	P
Characteristic	(n = 90)	(n = 13)	(n = 41)	(n = 21)	(n = 15)	P
Female, n (%)	73 (81.1)	10 (76.9)	37 (90.2)	14 (66.7)	12 (80.0)	0.156
Age at disease onset, median (IQR), years	45 (31–53)	34 (26–51)	46 (34–56)	46 (29–53)	44 (36–51.5)	0.594
Follow-up period, median (IQR), years	8 (5–13)	6 (2–10)	7 (4–12)	9 (6–17)	11 (7.5–14)	0.072
Primary APS, n (%)	37 (41.1)	4 (30.8)	20 (48.8)	9 (42.9)	4 (26.7)	0.397
Secondary APS (SLE) on steroids, n (%)	53 (58.9)	9 (69.2)	21 (51.2)	12 (57.1)	11 (73.3)	0.397
Smoker, n (%)	31 (37.8)	5 (38.5)	15 (36.6)	6 (28.6)	5 (33.3)	0.916
Hypertension, n (%)	51 (56.7)	9 (69.2)	25 (61.0)	9 (42.9)	7 (46.7)	0.341
Dyslipidaemia, n (%)	40 (44.4)	9 (69.2)	18 (43.9)	9 (42.9)	4 (26.7)	0.151
Diabetes mellitus, n (%)	16 (17.8)	2 (15.4)	5 (12.2)	5 (23.8)	4 (26.7)	0.527
aPL-S, median (IQR)	31 (14–50.5)	33 (13.0–71.0)	26 (13.0–42.0)	35 (15.0–54.5)	33 (20.0–41.0)	0.434
Arterial thrombosis, n (%)
Cerebral infarction	81 (90.0)	11 (84.6)	39 (95.1)	20 (95.2)	11 (73.3)	0.115
Coronary heart disease	8 (8.9)	2 (15.3)	2 (4.9)	0	4 (26.7)	0.025*
Arterial ischaemia in legs	3 (3.3)	0	1 (2.4)	2 (9.5)	0	0.296
Mesenteric artery occlusion	3 (3.3)	1 (7.7)	1 (2.4)	1 (4.8)	0	0.612
Central retinal artery occlusion	2 (2.2)	0	1 (2.4)	1 (4.8)	0	0.737
Renal infarction	1 (1.1)	0	0	1 (4.8)	0	0.400
Past history of venous thrombosis, n (%)	18 (20.0)	8 (61.5)	2 (4.9)	6 (28.6)	2 (13.3)	0.002*
Deep vein thrombosis	14 (15.6)	5 (38.5)	2 (4.9)	5 (23.8)	2 (13.3)	0.022*
Pulmonary embolism	7 (7.8)	4 (30.8)	0	2 (9.5)	1 (6.7)	0.004*
Superficial thrombophlebitis	2 (2.2)	0	0	0	2 (13.3)	0.017*

*P < 0.05. P-values are multiple comparison between four groups and were estimated using Kruskal–Wallis test. AP: antiplatelet monotherapy; aPL-S: aPL score; DAPT: dual antiplatelet therapy; IQR: interquartile range; n: number of patients; Wf: warfarin monotherapy; Wf + AP: warfarin and antiplatelet combination therapy.

Table S1. Antiplatelet agents
Antiplatelet agents	Total (N=90)	Wf (N=13)	AP (N=41)	Wf + AP (N=21)	DAPT (N=15)
Aspirin (maximum dose 100mg/day )	64 (71.1%)	-	34 (83.9%)	18 (85.7%)	12 (80.0%)
Ticlopidin (200 - 300mg/day) or Clopidogrel (50 - 75mg/day)	12 (13.3%)	-	2 (4.9%)	0 (0%))	10 (66.7%)
Cilostazol (100 - 200mg/day)	10 (11.1%)	-	4 (9.8%)	1 (4.8%)	5 (33.3%)
Other antiplatelet agents*	6 (6.7%)	-	1 (2.4%)	2 (9.5%)	3 (20.0%)

*Other antiplatelet agents included dipyridamole (maximum dose 400mg/day), beraprost sodium (maximum dose 120μg/day), sarpogrelate hydrochloride (maximum dose 300mg/day) or dilazep dihydrochloride (maximum dose 150mg/day). Results are presented as number of patients and percentage in each group. N: number of patients, Wf: warfarin monotherapy, AP: antiplatelet monotherapy, Wf + AP: warfarin and antiplatelet combination therapy, DAPT: dual antiplatelet therapy.

Table S2. Antiphospholipid score and antiphospholipid antibody profiles
		Total (N=90)	Wf (N=13)	AP (N=41)	Wf + AP (N=21)	DAPT (N=15)	P-value
aPL-S		31 [14-50.5]	33 [13.0–71.0]	26 [13.0–42.0]	35 [15.0–54.5]	33 [20.0–41.0]	0.434
aPL-S ≥ 30		47 (54.4%)	8 (61.5%)	18 (43.9%)	13 (61.9%)	8 (53.3%)	0.493
Lupus anticoagulant		74 (82.2%)	9 (69.2%)	32 (78.1%)	19 (90.5%)	14 (93.3%)	0.214
	PTT-LA	62 (68.9%)	5 (38.5%)	27 (65.9%)	17 (81.0%)	13 (86.7%)	0.024*
	KCT	63 (70.0%)	7 (53.9%)	23 (56.1%)	19 (90.5%)	14 (93.3%)	0.002*
	dRVVT	48 (53.3%)	7 (53.9%)	23 (56.1%)	12 (57.1%)	6 (40.0%)	0.724
aCL (IgG or IgM)		43 (47.8%)	8 (61.5%)	18 (43.9%)	12 (57.1%)	5 (33.3%)	0.353
	IgG	24 (26.7%)	5 (38.5%)	9 (22.0%)	7 (33.3%)	3 (20.0%)	0.540
	IgM	6 (6.7%)	1 (7.7%)	2 (4.9%)	2 (9.5%)	1 (6.7%)	0.920
	IgG and IgM	13 (14.4%)	2 (15.4%)	7 (17.1%)	3 (14.3%)	1 (6.7%)	0.773
antiβ2GPI (IgG or IgM)		49 (54.4%)	11 (84.6%)	21 (51.2%)	8 (38.1%)	9 (60%)	0.047*
	IgG	35 (38.9%)	8 (61.5%)	12 (29.3%)	7 (33.3%)	8 (53.3%)	0.115
	IgM	7 (7.8%)	1 (7.7%)	5 (12.2%)	0	1 (6.7%)	0.222
	IgG and IgM	7 (7.8%)	2 (15.4%)	4 (9.8%)	1 (4.8%)	0	0.287
aPS/PT (IgG or IgM)		62 (68.9%)	8 (61.5%)	30 (73.2%)	13 (61.9%)	11 (73.3%)	0.734
	IgG	38 (42.2%)	5 (38.5%)	18 (43.9%)	7 (33.3%)	8 (53.3%)	0.667
	IgM	7 (7.8%)	0	4 (9.8%)	3 (14.3%)	0	0.124
	IgG and IgM	17 (18.9%)	3 (23.1%)	8 (19.5%)	3 (14.3%)	3 (20.0%)	0.924

Results of antibody test are presented as number of antibody positive patients and percentage in each group.*P-values <0.05. P-values are multiple comparison between 4 groups and were estimated using Kruskal-Wallis test. aPL-S: Antiphospholipid score aPL-S are presented as the median (IQR: Interquartile range 25th-75th). aPL: antiphospholipid antibodies, PTT-LA: Activated Partial Thromboplastin Time, KCT: Kaolin Clotting Time, dRVVT: Diluted Russell Viper Venom time, aCL: anticardiolipin antibodies, antiβ2GPI: anti-β2Glycoprotein I antibodies, aPS/PT: Phosphatidylserine-dependent antiprothrombin antibody, N: number of patients, Wf: warfarin monotherapy, AP: antiplatelet monotherapy, Wf + AP: warfarin and antiplatelet combination therapy, DAPT: dual antiplatelet therapy.

Table S3. Recurrent thrombosis, severe bleeding and death
		Total (N=90)	Wf (N=13)	AP (N=41)	Wf + AP (N=21)	DAPT (N=15)	P-value
Arterial thrombosis
	Cerebral infarction	29 (32.2%)	9 (69.2%)	13 (31.7%)	6 (28.6%)	1 (6.7%)	0.004*
	Coronary heart disease	3 (3.3%)	0	3 (7.3%)	0	0	0.184
	Arterial ischemia in legs	1 (1.1%)	1 (7.7%)	0	0	0	0.268
	Central retinal artery occlusion	2 (2.2%)	0	0	1 (4.8%)	1 (6.7%)	0.285
Venous thrombosis
	Deep vein thrombosis	3 (3.3%)	1 (7.7%)	2 (4.9%)	0	0	0.352
	Branch retinal vein occlusion	1 (1.1%)	0	0	0	1 (6.7%)	0.303
	Superficial thrombophlebitis	1 (1.1%)	0	0	1 (4.8%)	0	0.345
Severe bleeding		9 (10.0%)	0	5 (12.2%)	2 (9.5%)	2 (13.3%)	0.373
	Cerebral haemorrhage	4 (4.4%)	0	2 (4.9%)	1 (4.8%)	1 (6.7%)
	Cardiovascular system haemorrhage	2 (2.2%)	0	1 (2.4%)	0	1 (6.7%)
	Alveolar haemorrhage	1 (1.1%)	0	0	1 (4.8%)	0
	Gastrointestinal haemorrhage	1 (1.1%)	0	1 (2.4%)	0	0
	Multiple subcutaneous haemorrhage	1 (1.1%)	0	1 (2.4%)	0	0
Mortality		14 (15.6%)	1 (7.7%)	5 (12.2%)	4 (19.1%)	4 (26.7%)	0.476
	Related to bleeding	3 (3.3%)	0	1 (2.4%)	1 (4.8%)	1 (6.7%)
	Related to thrombosis recurrence	2 (2.2%)	1 (7.7%)	0	1 (4.8%)	0

*P-values <0.05. P-values are multiple comparison between 4 groups and were estimated using Kruskal-Wallis test. Severe bleeding event was defined as the events that required hospitalization and/or blood transfusion. N: number of patients, Wf: warfarin monotherapy, AP: antiplatelet monotherapy, Wf + AP: warfarin and antiplatelet combination therapy, DAPT: dual antiplatelet therapy

Table S4. Risk factors for recurrent thrombosis
	Univariate analysis			Multivariate analysis
	Unadjusted Hazard Ratio	(95% CI)	P value	Adjusted Hazard Ratio	(95% CI)	P value
Warfarin monotherapy	2.93	( 1.394 - 5.731)	0.007*	4.23	( 1.686 – 10.378)	0.003*
Male	1.50	( 0.672 - 3.046 )	0.302	1.05	( 0.442 - 2.296 )	0.909
Age > 50	1.16	( 0.618 - 2.218 )	0.654	1.46	( 0.727 – 3.077 )	0.295
Steroid	1.09	( 0.554 - 2.253 )	0.813	1.01	( 0.492 - 2.175 )	0.984
Smoking	1.43	( 0.722 - 2.714 )	0.295	1.63	( 0.782 - 3.271 )	0.188
Hypertension	1.34	( 0.715 - 2.608 )	0.364	1.18	( 0.602 - 2.382 )	0.637
Dyslipidemia	1.06	( 0.559 - 1.980 )	0.859	1.49	( 0.692 – 3.317 )	0.314
Diabetes Mellitus	1.41	( 0.565 - 3.045 )	0.436	1.76	( 0.683 – 4.036 )	0.225
aPL-S ≥ 30	1.04	( 0.559 - 1.985 )	0.895	1.01	( 0.484 - 2.063 )	0.990