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Meta-Analysis
. 2017 Oct 2;10(10):CD012169.
doi: 10.1002/14651858.CD012169.pub2.

Antiplatelet and anticoagulant agents for secondary prevention of stroke and other thromboembolic events in people with antiphospholipid syndrome

Malgorzata M Bala  1 , Magdalena Celinska-Lowenhoff, Wojciech Szot, Agnieszka Padjas, Mateusz Kaczmarczyk, Mateusz J Swierz, Anetta Undas
Affiliations
Meta-Analysis

Antiplatelet and anticoagulant agents for secondary prevention of stroke and other thromboembolic events in people with antiphospholipid syndrome

Malgorzata M Bala et al. Cochrane Database Syst Rev. .

Update in

Abstract

Background: Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by arterial or venous thrombosis (or both) and/or pregnancy morbidity in association with the presence of antiphospholipid antibodies. The prevalence is estimated at 40 to 50 cases per 100,000 people. The most common sites of thrombosis are cerebral arteries and deep veins of the lower limbs. People with a definite APS diagnosis have an increased lifetime risk of recurrent thrombotic events.

Objectives: To assess the effects of antiplatelet or anticoagulant agents, or both, for the secondary prevention of recurrent thrombosis, particularly ischemic stroke, in people with antiphospholipid syndrome.

Search methods: We searched the Cochrane Stroke Group Trials Register (February 2017), CENTRAL (last search February 2017), MEDLINE (from 1948 to February 2017), Embase (from 1980 to February 2017), and several ongoing trials registers. We also checked the reference lists of included studies, systematic reviews, and practice guidelines, and we contacted experts in the field.

Selection criteria: We included randomized controlled trials (RCTs) that evaluated any anticoagulant or antiplatelet agent, or both, in the secondary prevention of thrombosis in people diagnosed with APS according to the criteria valid when the study took place. We did not include studies specifically addressing women with obstetrical APS.

Data collection and analysis: Pairs of review authors independently selected studies for inclusion, extracted data, and assessed the risk of bias for the included studies. We resolved any discrepancies through discussion or by consulting a third review author and, in addition, one review author checked all the extracted data.

Main results: We included five studies involving 419 randomized participants with APS. Only one study was at low risk of bias in all domains. One study was at low risk of bias in all domains for objective outcomes but not for quality of life (measured using the EQ-5D-5L questionnaire). We judged the other three studies to be at unclear or high risk of bias in three or more domains.The duration of intervention ranged from 180 days to a mean of 3.9 years. One study compared rivaroxaban (a novel oral anticoagulant: NOAC) with standard warfarin treatment and reported no thrombotic or major bleeding events, but it was not powered to detect such differences (low-quality evidence). Investigators reported similar rates of clinically relevant non-major bleeding (risk ratio (RR) 1.45, 95% confidence interval (CI) 0.25 to 8.33; moderate-quality evidence) and minor bleeding (RR 1.21, 95% CI 0.51 to 2.83) for participants receiving rivaroxaban and the standard vitamin K antagonists (VKA). This study also reported some small benefit with rivaroxaban over the standard VKA treatment in terms of quality of life health state measured at 180 days with the EQ-5D-5L 100 mm visual analogue scale (mean difference (MD) 7 mm, 95% CI 2.01 to 11.99; low-quality evidence) but not measured as health utility (MD 0.04, 95% CI -0.02 to 0.10 [on a scale from 0 to 1]).Two studies compared high dose VKA (warfarin) with moderate/standard intensity VKA and found no differences in the rates of any thrombotic events (RR 2.22, 95% CI 0.79 to 6.23) or major bleeding (RR 0.74, 95% CI 0.24 to 2.25) between the groups (low-quality evidence). Minor bleeding analyzed using the RR and any bleeding using the hazard ratio (HR) were more frequent in participants receiving high-intensity warfarin treatment compared to the standard-intensity therapy (RR 2.55, 95% CI 1.07 to 6.07; and HR 2.03, 95% CI 1.12 to 3.68; low-quality evidence).In one study, it was not possible to estimate the RR for stroke with a combination of VKA plus antiplatelet agent compared to a single antiplatelet agent, while for major bleeding, a single event occurred in the single antiplatelet agent group. In one study, comparing combined VKA plus antiplatelet agent with dual antiplatelet therapy, the RR of the risk of stroke over three years of observation was 5.00 (95% CI 0.26 to 98.0). In a single small study, the RR for stroke during one year of observation with a dual antiplatelet therapy compared to single antiplatelet drug was 0.14 (95% CI 0.01 to 2.60).

Authors' conclusions: There is not enough evidence for or against NOACs or for high-intensity VKA compared to the standard VKA therapy in the secondary prevention of thrombosis in people with APS. There is some evidence of harm for high-intensity VKA regarding minor and any bleeding. The evidence was also not sufficient to show benefit or harm for VKA plus antiplatelet agent or dual antiplatelet therapy compared to a single antiplatelet drug. Future studies should be adequately powered, with proper adherence to treatment, in order to evaluate the effects of anticoagulants, antiplatelets, or both, for secondary thrombosis prevention in APS. We have identified five ongoing trials mainly using NOACs in APS, so increasing experimental efforts are likely to yield additional evidence of clinical relevance in the near future.

PubMed Disclaimer

Conflict of interest statement

Malgorzata M Bala: receives honoraria as a freelancer from a company doing health technology assessments and systematic reviews for various clients; she is not aware of any direct conflict of interest. This activity did not conflict with the conduct of the review. Magdalena Celinska‐Lowenhoff: none known. Wojciech Szot: participates in clinical trials not related to the topic of this review. Agnieszka Padjas: none known. Mateusz Kaczmarczyk: none known. Mateusz Swierz: none known. Anetta Undas: lecture honoraria from Boehringer Ingelheim, Bayer Pharma AG, Sanofi‐Aventis, Pfizer/Bristol‐Meyers‐Squibb within the previous three years. Personal fees from the publisher Medycyna Praktyczna.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1
Comparison 1 Anticoagulant drugs (NOAC) or high‐dose VKA vs standard VKA therapy, Outcome 1 Any thromboembolic event at the longest follow‐up.
1.2
1.2
Comparison 1 Anticoagulant drugs (NOAC) or high‐dose VKA vs standard VKA therapy, Outcome 2 Any thromboembolic event at the longest follow‐up.
1.3
1.3
Comparison 1 Anticoagulant drugs (NOAC) or high‐dose VKA vs standard VKA therapy, Outcome 3 Major bleeding at the longest follow‐up.
1.4
1.4
Comparison 1 Anticoagulant drugs (NOAC) or high‐dose VKA vs standard VKA therapy, Outcome 4 Major bleeding at the longest follow‐up.
1.5
1.5
Comparison 1 Anticoagulant drugs (NOAC) or high‐dose VKA vs standard VKA therapy, Outcome 5 Mortality (any cause) at the longest follow‐up.
1.6
1.6
Comparison 1 Anticoagulant drugs (NOAC) or high‐dose VKA vs standard VKA therapy, Outcome 6 Stroke at the longest follow‐up.
1.7
1.7
Comparison 1 Anticoagulant drugs (NOAC) or high‐dose VKA vs standard VKA therapy, Outcome 7 TIA at the longest follow‐up.
1.8
1.8
Comparison 1 Anticoagulant drugs (NOAC) or high‐dose VKA vs standard VKA therapy, Outcome 8 VTE at the longest follow‐up.
1.9
1.9
Comparison 1 Anticoagulant drugs (NOAC) or high‐dose VKA vs standard VKA therapy, Outcome 9 Myocardial infarction at the longest follow‐up.
1.10
1.10
Comparison 1 Anticoagulant drugs (NOAC) or high‐dose VKA vs standard VKA therapy, Outcome 10 Other thrombotic events at the longest follow‐up.
1.11
1.11
Comparison 1 Anticoagulant drugs (NOAC) or high‐dose VKA vs standard VKA therapy, Outcome 11 Quality of life at day 180.
1.12
1.12
Comparison 1 Anticoagulant drugs (NOAC) or high‐dose VKA vs standard VKA therapy, Outcome 12 Clinically relevant non‐major bleeding at 210 days.
1.13
1.13
Comparison 1 Anticoagulant drugs (NOAC) or high‐dose VKA vs standard VKA therapy, Outcome 13 Minor bleeding at the longest follow‐up.
1.14
1.14
Comparison 1 Anticoagulant drugs (NOAC) or high‐dose VKA vs standard VKA therapy, Outcome 14 Any bleeding at the longest follow‐up.
1.15
1.15
Comparison 1 Anticoagulant drugs (NOAC) or high‐dose VKA vs standard VKA therapy, Outcome 15 Any bleeding at the longest follow‐up.
2.1
2.1
Comparison 2 VKA plus antiplatelet agent vs single antiplatelet agent, Outcome 1 Stroke at 1‐year follow‐up.
2.2
2.2
Comparison 2 VKA plus antiplatelet agent vs single antiplatelet agent, Outcome 2 Bleeding outcomes at a mean of 3.9 years.
3.1
3.1
Comparison 3 VKA plus antiplatelet agent vs dual antiplatelet therapy, Outcome 1 Stroke at 3 years.
4.1
4.1
Comparison 4 Dual antiplatelet therapy vs single antiplatelet agent, Outcome 1 Stroke at 1 year.
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