Anticoagulant drugs or antiplatelet drugs, or both, for reducing the risk of blood clots and stroke in people with antiphospholipid syndrome

Review question

This review aimed to find out which type of treatment works best for preventing stroke and other blood clotting (thrombotic) events in people with antiphospholipid syndrome (APS).

Background

APS is a disease where the immune system produces antibodies against the person's own cells. The presence of such antibodies increases the risk of developing blood clots (thrombosis) in blood vessels (veins or arteries, or both) and can cause pregnancy-related complications such as miscarriage. Blood clots in arteries can cause strokes. Two types of drugs are commonly used to prevent blood clots in people with APS: anticoagulants such as warfarin (which interfere with proteins that form blood clots) and antiplatelet drugs such as aspirin (which prevent cells called platelets from sticking together).

Study characteristics

The evidence is current to 22 November 2019. We looked for studies that randomly allocated people with APS to different treatments, including anticoagulants, antiplatelet drugs, or both. We identified eight studies involving 811 participants, with the average age between 36 and 50 years. Three studies compared rivaroxaban (a new oral anticoagulant) with standard-dose warfarin (a vitamin K antagonist – VKA). Two studies compared two intensities of VKA anticoagulation: high versus standard. One study compared standard-dose VKA plus aspirin versus standard-dose VKA alone. The remaining studies compared different combinations of anticoagulants or antiplatelet drugs (e.g. aspirin). One study compared dual antiplatelet drugs versus single antiplatelet drugs. Interventions lasted from 180 days to a median of 58.4 months.

Key results

In three studies comparing rivaroxaban (NOAC) with standard-dose VKA there were similar proportions of participants with blood clots, bleeding, or death (moderate-certainty evidence), but there were more participants with stroke in the NOAC group than in the VKA group (moderate-certainty evidence). In the two studies comparing high-dose versus a standard-dose VKA, similar proportions of participants had blood clotting and major bleeding problems (low-certainty evidence), but participants in the high-dose group had a greater risk of minor and any bleeding problems (low-certainty evidence). A study comparing standard VKA plus an antiplatelet drug with standard-dose VKA observed more participants with any thromboembolic event with combined treatment (low-certainty evidence) and similar proportions of participants for other outcomes (very low- to low-certainty evidence).

The remaining studies comparing different combinations of antiplatelet drug and/or VKA were inconclusive regarding benefits or harms (low- or very low-certainty evidence).

We identified two ongoing studies and three studies are awaiting classification.

Certainty of the evidence

Most of the results were imprecise and did not clearly indicate benefit or harm.

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).

Read the full 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 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 strategy: 

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.

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