PMID- 33045766 OWN - NLM STAT- MEDLINE DCOM- 20201113 LR - 20220919 IS - 1469-493X (Electronic) IS - 1361-6137 (Linking) VI - 10 IP - 10 DP - 2020 Oct 12 TI - Antiplatelet and anticoagulant agents for secondary prevention of stroke and other thromboembolic events in people with antiphospholipid syndrome. PG - CD012169 LID - 10.1002/14651858.CD012169.pub3 [doi] LID - CD012169 AB - 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 of APS 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 (AP) or anticoagulant agents, or both, for the secondary prevention of recurrent thrombosis, particularly ischemic stroke, in people with APS. SEARCH METHODS: We last searched the MEDLINE, Embase, CENTRAL, Cochrane Stroke Group Trials Register, and ongoing trials registers on 22 November 2019. We checked reference lists of included studies, systematic reviews, and practice guidelines. We also contacted experts in the field. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that evaluated any anticoagulant or AP agent, or both, in the secondary prevention of thrombosis in people 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 worked on each step of the review, following Cochrane methods. We summarized the evidence using the GRADE approach. MAIN RESULTS: We identified eight studies including 811 participants that compared different AP or anticoagulant agents. NOAC (non-VKA oral anticoagulant: rivaroxaban 15 or 20 mg/d) versus standard-dose VKA (vitamin K antagonist: warfarin at moderate International Normalized Ratio [INR] - 2.5) or adjusted [INR 2.0-3.0] dose): In three studies there were no differences in any thromboembolic event (including death) and major bleeding (moderate-certainty evidence), but an increased risk of stroke (risk ratio [RR] 14.13, 95% confidence interval [CI] 1.87 to 106.8; moderate-certainty evidence). One of the studies reported a small benefit of rivaroxaban in terms of quality of life at 180 days measured as health state on Visual Analogue Scale (mean difference [MD] 7 mm, 95% CI 2.01 to 11.99; low-certainty evidence), but not measured as health utility on a scale from 0 to 1 (MD 0.04, 95% CI -0.02 to 0.10; low-certainty evidence). High-dose VKA (warfarin with a target INR of 3.1 to 4.0 [mean 3.3] or 3.5 [mean 3.2]) versus standard-dose VKA (warfarin with a target INR of 2.0 to 3.0 [mean 2.3] or 2.5 [mean 2.5]): In two studies there were no differences in the rates of thrombotic events and major bleeding (RR 2.22, 95% CI 0.79 to 6.23, low-certainty evidence), but an increased risk of minor bleeding in one study during a mean of 3.4 years (standard deviation [SD] 1.2) of follow-up (RR 2.55, 95% CI 1.07 to 6.07). In both trials there was evidence of a higher risk of any bleeding (hazard ratio [HR] 2.03 95% CI 1.12 to 3.68; low-certainty evidence) in the high-dose VKA group, and for this outcome (any bleeding) the incidence is not different, only the time to event is showing an effect. Standard-dose VKA plus a single AP agent (warfarin at a target INR of 2.0 to 3.0 plus aspirin 100 mg/d) versus standard-dose VKA (warfarin at a target INR of 2.0 to 3.0): One high-risk-of-bias study showed an increased risk of any thromboembolic event with combined treatment (RR 2.14, 95% CI 1.04 to 4.43; low-certainty evidence) and reported on major bleeding with five cases in the combined treatment group and one case in the standard-dose VKA treatment group, resulting in RR 7.42 (95% CI 0.91 to 60.7; low-certainty evidence) and no differences for secondary outcomes (very low- to low-certainty evidence). Single/dual AP agent and standard-dose VKA (pooled results): Two high-risk-of-bias studies compared a combination of AP and VKA (aspirin 100 mg/d plus warfarin or unspecified VKA at a target INR of 2.0 to 3.0 or 2.0 to 2.5) with a single AP agent (aspirin 100 mg/d), but did not provide any conclusive evidence regarding the effects of those drugs in people with APS (very low-certainty evidence). One of the above-mentioned studies was a three-armed study that compared a combination of AP and VKA (aspirin 100 mg/d plus warfarin at a target INR of 2.0 to 2.5) with dual AP therapy (aspirin 100 mg/d plus cilostazol 200 mg/d) and dual AP therapy (aspirin 100 mg/d plus cilostazol 200 mg/d) versus a single AP treatment (aspirin 100 mg/d). This study reported on stroke (very low-certainty evidence) but did not report on any thromboembolic events, major bleeding, or any secondary outcomes. We identified two ongoing studies and three studies are awaiting classification. AUTHORS' CONCLUSIONS: The evidence identified indicates that NOACs compared with standard-dose VKAs may increase the risk of stroke and do not appear to alter the risk of other outcomes (moderate-certainty evidence). Using high-dose VKA versus standard-dose VKA did not alter the risk of any thromboembolic event or major bleeding but may increase the risk of any form of bleeding (low-certainty evidence). Standard-dose VKA combined with an AP agent compared with standard-dose VKA alone may increase the risk of any thromboembolic event and does not appear to alter the risk of major bleeding or other outcomes (low-certainty evidence). The evidence is very uncertain about the benefit or harm of using standard-dose VKA plus AP agents versus single or dual AP therapy, or dual versus single AP therapy, for the secondary prevention of recurrent thrombosis in people with APS (very low-certainty evidence). CI - Copyright (c) 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. FAU - Bala, Malgorzata M AU - Bala MM AD - Chair of Epidemiology and Preventive Medicine, Department of Hygiene and Dietetics, Jagiellonian University Medical College, Krakow, Poland. AD - Systematic Reviews Unit, Jagiellonian University Medical College, Krakow, Poland. FAU - Celinska-Lowenhoff, Magdalena AU - Celinska-Lowenhoff M AD - 2nd Department of Internal Medicine, Department of Allergy and Immunology, Jagiellonian University Medical College, Krakow, Poland. FAU - Szot, Wojciech AU - Szot W AD - Chair of Epidemiology and Preventive Medicine, Department of Hygiene and Dietetics, Jagiellonian University Medical College, Krakow, Poland. FAU - Padjas, Agnieszka AU - Padjas A AD - 2nd Department of Internal Medicine, Department of Allergy and Immunology, Jagiellonian University Medical College, Krakow, Poland. FAU - Kaczmarczyk, Mateusz AU - Kaczmarczyk M AD - Systematic Reviews Unit - Polish Cochrane Branch, Jagiellonian University Medical College, Krakow, Poland. FAU - Swierz, Mateusz J AU - Swierz MJ AD - Chair of Epidemiology and Preventive Medicine, Department of Hygiene and Dietetics, Jagiellonian University Medical College, Krakow, Poland. AD - Systematic Reviews Unit, Jagiellonian University Medical College, Krakow, Poland. FAU - Undas, Anetta AU - Undas A AD - Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland. LA - eng GR - ETM/417/CSO_/Chief Scientist Office/United Kingdom PT - Journal Article PT - Meta-Analysis PT - Research Support, Non-U.S. Gov't PT - Systematic Review DEP - 20201012 PL - England TA - Cochrane Database Syst Rev JT - The Cochrane database of systematic reviews JID - 100909747 RN - 0 (Anticoagulants) RN - 0 (Factor Xa Inhibitors) RN - 0 (Platelet Aggregation Inhibitors) RN - 5Q7ZVV76EI (Warfarin) RN - 9NDF7JZ4M3 (Rivaroxaban) SB - IM UOF - Cochrane Database Syst Rev. 2017 Oct 02;10:CD012169. PMID: 28968483 MH - Anticoagulants/adverse effects/*therapeutic use MH - Antiphospholipid Syndrome/*complications MH - Cause of Death MH - Factor Xa Inhibitors/therapeutic use MH - Hemorrhage/chemically induced MH - Humans MH - Platelet Aggregation Inhibitors/adverse effects/*therapeutic use MH - Randomized Controlled Trials as Topic MH - Rivaroxaban/therapeutic use MH - *Secondary Prevention MH - Stroke/mortality/*prevention & control MH - Thromboembolism/mortality/*prevention & control MH - Warfarin/therapeutic use PMC - PMC8094585 COIS- Malgorzata M Bala: received honoraria as a freelancer from a company doing health technology assessments and systematic reviews for various clients; she has not been involved in any work funded by companies who are manufacturers or marketers of the interventions of interest or potential comparators; she is not aware of any direct conflict of interest.
Magdalena Celinska-Lowenhoff: participates in clinical trials not related to the topic of this review.
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, and Pfizer/Bristol-Meyers-Squibb within the previous three years. Personal fees from the publisher Medycyna Praktyczna. EDAT- 2020/10/13 06:00 MHDA- 2020/11/18 06:00 PMCR- 2021/10/12 CRDT- 2020/10/12 20:16 PHST- 2020/10/12 20:16 [entrez] PHST- 2020/10/13 06:00 [pubmed] PHST- 2020/11/18 06:00 [medline] PHST- 2021/10/12 00:00 [pmc-release] AID - CD012169.pub3 [pii] AID - 10.1002/14651858.CD012169.pub3 [doi] PST - epublish SO - Cochrane Database Syst Rev. 2020 Oct 12;10(10):CD012169. doi: 10.1002/14651858.CD012169.pub3.