Direct oral anticoagulants (DOACs) have become the cornerstone for prevention and treatment of venous and arterial thrombosis. The convenience of standardized dosing without a constant need for monitoring has led to their becoming mainstream, even in high-risk scenarios. However, their use remains controversial in patients with thrombotic antiphospholipid antibody syndrome (tAPS). In the past decade, a few randomized controlled trials have been conducted comparing different DOACS to vitamin K antagonists (VKAs) for treatment of patients with tAPS. Unfortunately, these studies were small or not sufficiently powered to assess individual thrombotic outcomes or to analyze these subgroups; thus the choice of DOACs versus VKAs remains uncertain.
The authors published a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing the safety and efficacy of DOACS versus VKAs for prevention of subsequent venous and arterial thrombosis in patients with tAPS. The main efficacy outcomes were a composite of arterial thrombotic events (ATEs) and venous thromboembolic events (VTEs). The main safety outcome was major bleeding and clinically relevant nonmajor bleeding as defined by the International Society of Thrombosis and Hemostasis. They also did a subgroup analysis for triple-positive tAPS versus dual- or single-positive tAPS, men versus women, and history of arterial thrombotic event versus no history.
The meta-analysis included 474 patients who were enrolled in four open-label RCTs from multiple sites across the globe. There were 234 individuals in the DOAC arm and 240 in the VKA arm, with an average age of 48 years; 68% were female, and 56.5% had triple-positive tAPS. The mean person time in therapeutic range of patients on VKA was 60 percent, and the mean follow-up was 19 months.
Overall, use of DOACs compared to VKAs was associated with increased odds of subsequent arterial events (10.3% vs. 1.3%, odds ratio [OR], 5.43; 95% CI, 1.87-15.75), most significantly for stroke (8.6% vs. 0%, OR, 10.74; 95% CI, 2.29-50.38). The risk of myocardial infarction and acute limb ischemia was not statistically different (1.3% vs. 0%; OR, 2.15; 95% CI, 0.35-13.11; p = 0.41; I2 = 0%) and (0.4% vs. 1.3%; OR, 0.58; 95% CI, 0.12-2.92; p = 0.51; I2 = 0%) respectively.
The odds of VTE risk were not significantly different between patients assigned to DOACs (1.7% vs. 1.3%; OR, 1.20; 95% CI, 0.31-4.55; p = 0.79; I2 = 0%). On a more granular level, the odds of pulmonary embolism (0.4% vs. 0%; OR, 1.49; 95% CI, 0.23-9.53; p = 0.68; I2 = 0%) and deep vein thrombosis (1.3% vs. 1.3%; OR, 1.03; 95% CI, 0.23-4.57; p = 0.97; I2 = 0%) were not significantly different between patients assigned to DOACs versus VKAs.
Overall, the odds of major bleeding were not significantly different between patients randomized to DOACs versus VKAs (4.3% vs. 4.2%; OR, 1.02; 95% CI, 0.42-2.47; p = 0.97; I2 = 0%). The odds of clinically relevant nonmajor bleeding were also not significantly different between patients on DOACs versus VKAs (6.0% vs. 2.9%; OR, 1.90; 95% CI, 0.78-4.66; p = 0.16; I2 = 0%).
Lastly, all-cause mortality was not significantly different between patients randomized to DOACs versus VKAs (2.6% vs. 1.7%; OR, 1.43; 95% CI, 0.44-4.62; p = 0.55; I2 = 0%).
On subgroup analysis, when comparing triple versus double versus single tAPS positivity, all had higher arterial thrombotic rates with no major difference in VTE or major bleeding. Similarly, neither sex nor history of previous arterial event had an impact on the effect of DOACs in comparison to VKAs in terms of outcomes.
The authors concluded that among patients with tAPS, when compared with VKAs, treatment with DOACs is associated with an increase in the odds of arterial thrombotic events, whereas the odds of VTE and major bleeding are not significantly different between the two groups (Figure). The results also suggest an increased likelihood of subsequent arterial thrombotic events, especially stroke, in patients taking DOACs versus VKAs, regardless of the type of tAPS (triple-positive vs. others), sex, and history of priorate vs VTE.
This study provides high-grade evidence from four well-designed open-label RCTs. There is strength in numbers, and this meta-analysis pools the highest quality available data to provide robust evidence for the management of tAPS.
A few salient points to highlight from this publication: 1) significantly high rates of ATEs in the DOAC group in comparison to the VKA group with the highest rates of stroke; 2) no significant difference in rates of myocardial infarction, ALI, VTE, bleeding, and all-cause mortality; 3) increased risk of ATE in the follow-up time even if the enrollment in the trial might have been triggered by VTE events; and 4) triple versus double/single antibody positivity continued to show an effect on stroke but not on other arterial thrombotic/VTEs.
The reason DOACs are less effective than VKAs in preventing arterial thrombosis, particularly stroke, in patients with thrombotic APS remains unclear. A hypothesis that has been repeatedly brought forward by many experts is a consideration that VKAs prove to be more effective because they suppress multiple pathways leading into thrombosis as compared with DOACs. Another potential reason could be related to the shorter half-life of DOACs compared with VKAs, or the short periods of nonadherence that may increase the risk of a thrombotic event.
Current data would suggest that DOACs are less efficacious than VKAs in tAPS, but the decision for agent of choice for an individual patient is grounded in shared decision-making. Further research with larger patient cohorts is needed to answer the questions posed here.
Dr. Shah indicated no relevant conflicts of interest.