January-February 2020, Volume 17, Issue 1
How To Treat the Patient With Antiphospholipid Antibody Syndrome Who Needs Anticoagulation?
Published on: January 09, 2020
When asked to reflect on the publications of the past year that I will remember most, I have to admit that I first thought of Dr. Keith Stewart’s 2019 editorial in ASH Clinical News titled “The Biggest Losers.”1 While not about clotting (unless one considers the venous thromboembolism risks of long-distance air travel), this was a hilarious and thought-provoking read, and one that I recommend colleagues check out.
Dr. Stewart’s publication has, of course, no bearings on my clinical patient management. What have, however, impacted my clinical practice are three publications on antiphospholipid syndrome (APS) from the past 15 months,2,5,6 and these are the articles I will discuss.
The TRAPS study2 (Table; online only) was reviewed in detail in the March/April 2018 and November/December 2018 issues of The Hematologist. This randomized trial compared rivaroxaban with the vitamin K antagonist (VKA) warfarin in patients with APS who were “triple positive” for antiphospholipid antibodies (APLAs) and had had a thrombotic event (venous, arterial, or microthrombosis). After enrollment of 120 patients, the study was prematurely terminated because of an excess of events — a composite of thromboembolism, major bleeding, and vascular death — in the rivaroxaban arm. Eleven events (19%) were reported in the rivaroxaban arm, and two events (3%) in the warfarin arm (HR, 6.7; 95% CI, 1.5-30.5; p=0.01). Most importantly, thromboembolic events occurred in seven patients (12%) randomized to rivaroxaban, with no event in the warfarin group; all thrombotic events were arterial. Major bleeding occurred in four patients (7%) in the rivaroxaban group and in two patients (3%) in the warfarin group. The authors of the study concluded that in high-risk patients with APS, the use of rivaroxaban was associated with an increased risk of events (thrombotic or bleeding) and thus, showed no benefit over VKA, but instead demonstrated excess risks.
Of note, this study may have had significant bias toward VKA performing better than rivaroxaban as it may have preferentially enrolled patients who were expected to do well on VKA. Unfortunately, the authors did not report in their baseline characteristics table what anticoagulant the patients had been on before study enrollment and how long they had been on prior anticoagulation. VKAs are known to have a substantial failure rate, with recurrent thrombosis occurring in up to 11.1 percent of patients.3,4 In clinical practice, such patients are often switched to another anticoagulant and would likely not have been approached for enrollment onto the TRAPS study given their history of VKA failure. Therefore, this study likely enrolled patients who, by their history of having tolerated a VKA well, were expected to continue to do well on a VKA. On the other hand, numerous patients randomized to the rivaroxaban arm were likely rivaroxaban-naïve and thus never had a chance to show rivaroxaban failure. This may have led to a bias of the observed lower thrombosis rate in VKA compared to the rivaroxaban group. The same limitation applies to the study by Dr. Josep Ordi-Ros and colleagues.5
Therefore, the only scientifically accurate clinical conclusion that can be drawn from the TRAPS study as well as the study by Dr. Ordi-Ros and colleagues is that patients with APS and a history of thrombosis who have done well on a VKA are best continued on a VKA as they have a low VKA failure rate, but may have a higher thrombosis rate if switched to rivaroxaban. However, in patients with newly diagnosed APLA positivity or newly diagnosed bona fide APS (i.e., repeatedly positive APLA tests at least 3 months apart), it is currently unknown whether a VKA or a direct oral anticoagulant (DOAC) is a better choice; either one can lead to anticoagulant failure.
The randomized rivaroxaban versus VKA study5 (Table) was similar in design to the TRAPS study, but it included patients with any type of APS (i.e., single-, double-, or triple-positive APLA tests; at least 60.5% of the enrolled patients were “triple positive”). The primary efficacy endpoint was the proportion of patients with new thrombotic events: 11.6 percent in the rivaroxaban-treated group (10 arterial and 2 venous events) versus in 6.3 percent in the VKA group (3 arterial and 3 venous events). The primary safety outcome was major bleeding, which occurred in 6.3 percent in the rivaroxaban group versus 7.4 percent in the VKA group. The authors concluded that rivaroxaban showed a non–statistically significant near doubling of the risk for recurrent thrombosis. Noteworthy again is the fact that the thrombotic events in the rivaroxaban group were predominately arterial, mostly strokes.
The caveats regarding this study are the same as those discussed for the TRAPS trial; due to the study design, patients were enrolled who had tolerated a VKA well prior to randomization, whereas patients randomized to rivaroxaban were rivaroxaban-naïve. Thus, this study may also have been unintentionally biased toward enrolling patients preselected for a low risk of VKA failure. The results, therefore, are potentially biased toward suggesting that patients with APS with VKA do better on a VKA than on rivaroxaban. My conclusion from this study is the same as the one from the TRAPS study: Patients with APS and a history of thrombosis who have done well on a VKA are best continued on a VKA because they have a low VKA failure rate, but a higher rate if switched to rivaroxaban. It is important to highlight that the strong statement in the “Summary for Patients,”5 that “rivaroxaban should not be used to prevent blood clots in patients with APS,” is scientifically not accurate or justifiable, given the study limitations discussed here. I am concerned about this strong statement, from a patient management as well as medical-legal point of view.
The retrospective Japanese study6 compared the outcomes of anti-Xa DOACs (edoxaban, n=12; rivaroxaban, n = 5; apixaban, n=1) and warfarin in a “real world utilization” setting (Table). Of the 206 identified patients with APS, 18 had been treated with an anti-Xa DOAC; 36 controls were treated with a VKA were matched by age, gender, coexistence of systemic lupus erythematosus, and the presence of antiplatelet therapy from the pool of the available 206 patients with APS. The primary endpoint was event-free survival (EFS) for five years; events were defined as recurrence of arterial or venous thrombosis and severe bleeding. “Triple positivity” was present in 33.3 percent of the DOAC-treated patients, and 38.9 percent of the warfarin-treated patients. Two analyses were done; as 14 of 18 DOAC-treated patients had been switched from warfarin to a DOAC (because they “wished to avoid restrictions around food containing a lot of vitamin K”), an analysis was possible that compared EFS while on warfarin with EFS while on a DOAC in the same patient. EFS was significantly shorter during DOAC treatment than during warfarin therapy (HR, 12.1; 95% CI, 1.7-248.0). Additionally, a comparison between patients treated with Xa-inhibitors and those on warfarin also showed a significantly shorter EFS in the DOAC-treated group (HR, 11.9; 95% CI, 2.9-56.0). The authors concluded that “factor Xa inhibitors may not be recommended for APS.”
Caveat: This was a retrospective and small study (only 18 DOAC patients enrolled) with the usual limitations of a retrospective and small study. The results have wide confidence intervals. A fair conclusion from this study is that anticoagulation failure may occur on anti-Xa DOACs as well as on warfarin.
In terms of noteworthy ongoing research, the ASTRO-APS study, which randomized APS patients with thrombosis to apixaban or warfarin, is ongoing but no longer recruiting due to a loss of funding.7,8 The follow up of the 49 enrolled patients ends in April 2020, and results will hopefully be presented at the International Society on Thrombosis and Haemostasis meeting in Milan, Italy, in July 2020. I expect additional useful information from this study that will help us discuss the most suitable anticoagulant for patients with APS. Of note, the study design needed modifications while enrollment was ongoing because of a possibly higher than expected rate of stroke among patients with a history of stroke who were randomized to apixaban, raising concern that a higher rate of arterial thrombosis may be seen with apixaban than with warfarin. However, results need to be awaited before any solid conclusion can be drawn. Unfortunately, this study is small, which will limit the strength of its findings.
My Clinical Management Conclusions
In conclusion, given the heterogeneity of APS patients, in respect to their thrombotic events (arterial or venous) as well as the number of positive test assays and type and titer of their APLA tests, one has to be careful to not take a “one-management-fits-all” approach. Individual antithrombotic decision-making in APS patients is needed. The sidebar below summarizes my current approach.
My Approach to Antithrombotic Therapy in Patients With APS
- I discuss with the patient the three published studies: TRAPS, Ordi-Ros et al, and Sato et al.
- I acknowledge that the TRAPS and Ordi-Ros studies have design limitations and that the Sato study is small and retrospective, that limited data exist on best management, and that many of the treatment decisions are nonevidence-based.
- I heavily include the patient’s opinion and treatment preference into the decision-making.
- I recommend regular clinic follow-up for re-evaluation of best management strategy based on a repeat risk-benefit assessment and new clinical-scientific publications.
Acknowledging the nonevidence based for a number of my treatment approaches, given the sparsity of data, this is my general approach:
- The patient with newly diagnosed venous thromboembolism (VTE), provoked or unprovoked, not tested at this point for APLA:
I do not routinely obtain APLA tests upon the diagnosis of acute VTE, because (a) APLA can be transiently positive at the time of an acute thrombotic event without reflecting true APS, (b) lupus anticoagulant can be false-positive while on an anticoagulant, (c) APLA positivity that will lead to an eventual diagnosis of APS is uncommon, and (d) detecting APLA in the patient with an acute VTE does not influence my management. I would discuss a DOAC versus warfarin as I would in any other patient. The patient with a one-time positive APLA cannot yet be classified as having APS and the data from TRAPS and the Ordi-Ros study do not apply to such a patient. It is unknown which anticoagulant is better in de-novo diagnosed APS patients, whether warfarin or one of the DOACs. Both warfarin and DOACs (at least rivaroxaban and possibly edoxaban and apixaban) have a significant failure rate.
- The patient with VTE and APS:
My general preference is to use warfarin, not a DOAC, if an anticoagulant is indicated. Whether long-term or short-term anticoagulation is indicated depends on the various predictors of thrombosis recurrence: (a) what the provoking risk factors for VTE or arterial thrombosis were or what underlying arteriosclerosis risk factors the patient has, (b) which APLA test(s) is/are positive,8 and what the APLA titers are.
- The patient with APS (no matter whether single, double, or triple positive) who is doing well on warfarin:
I recommend not to change therapy, but rather to continue warfarin, because the TRAPS and Ordi-Ros studies showed that patients who are doing well on warfarin have a risk of not doing well (mostly risk of arterial thrombotic events) when switched to rivaroxaban.
- The patient with APS who needs to be on anticoagulation, but has a high “warfarin hate factor”9:
I consider empiric dabigatran in the patient with a high warfarin “hate factor” (fluctuating INRs, etc.) rather than rivaroxaban or another anti-Xa DOAC, as the TRAPS and Ordi-Ros studies showed a high failure rate of rivaroxaban. Additionally, there have been signals from the ongoing ASTRO-APS study that Apixaban may also have a higher failure rate (arterial events).10 Additionally, the Sato study suggested that anti-Xa agents might have a high failure rate. For that reason, I am also not keen on using fondaparinux, another anti-Xa anticoagulant, in the patient with a high “warfarin hate factor.” I acknowledge that dabigatran has not been studied in APS (i.e. has not been shown to be inferior to warfarin); however, as a thrombin inhibitor it has a different mode of action to the anti-Xa DOACs and may, therefore, be a viable non-anti-Xa treatment option.
- The patient with APS who has been on an anti-Xa DOAC and has done well for up to two to 2.5 years:
My preference is to switch this patient to warfarin. In the TRAPS study several of the arterial thrombotic events occurred several months after the patient had initially done well on rivaroxaban: four of seven arterial events (57 %) occurred eight to 23 months after randomization to rivaroxaban. Similarly, in the Ordi-Ros study arterial events in the rivaroxaban group occurred up to 31 months after randomization. This argues that one may want to change to warfarin not only a “triple-positive” APS patient, but any APS patient who is currently on rivaroxaban and has done well for up to two to 2.5 years. This is typically a difficult call to make.
- The patient with APS (no matter whether single, double, or triple positive) who has been on an anti-Xa DOAC and has done well for more than two to 2.5 years:
I tell that patient that one could either continue the DOAC or switch to warfarin. For this scenario, no data exist that one treatment is better (i.e. more effective) than the other, as length of follow-up in the TRAPS and Ordi-Ros study was limited.
- The patient with a history of an arterial thrombotic event and APS:
I tend to consider combined anticoagulant plus aspirin therapy, unless the bleeding risk is high. Unfortunately, the majority of studies investigating the management of patients with APS, including the three studies discussed in this article, have enrolled patients with both venous or arterial thrombosis.2-6 Data are lacking whether an anticoagulant is a more effective choice than an anti-platelet agent and opinions on best management vary. I wonder whether a combination of an anticoagulant plus an anti-platelet agent might be the most effective treatment to prevent recurrent thrombotic events, given the risk for a potentially devastating arterial thrombosis (stroke, heart attack) when anticoagulant failure occurs. Additionally, as patients with APS are often of younger age, the bleeding risk with combined therapy may not be very high. I typically re-evaluate the patient on combination therapy a few months after the start of such treatment, to ensure therapy is well tolerated.
- General comment:
With any of these treatment decisions, detailed discussion and shared decision-making with the patient is key, given the limited data available on best APS treatment. Decision-making in APS patients is case-by-case. Clinic follow-up should take place.
Key Data From the Three Published APS DOAC Versus VKA Studies
| ||TRAPS Study2||Ordi-Ros et al Study5||Sato et al Study6|
|Patient population||Triple positive APS||APS (single, double or triple positive)||APS (single, double or triple positive)|
|Study design||Prospective, randomized, open-labeled; warfarin vs. rivaroxaban||Prospective, randomized, open-labeled; warfarin vs. rivaroxaban||Retrospective|
|N; total in study||120||190||54|
| N; on VKA||61||95||36|
| N; on Rivaroxaban||59||95||5|
| N; on Apixaban||none||none||1|
| N; on Edoxaban||none||none||12|
| N; on Dabigatran||none||none||0|
|Findings|| || || |
| Recurrent thrombosis|
DOAC vs. VKA
|12% vs. 0%|
|11.6% vs. 6.3% |
[95% CI, 0.71-4.76]
|21.4% vs. 5.5% per person-years|
| Major bleeding|
DOAC vs. VKA
|7% vs. 3%|
[95% CI, 0.4-12.5]
|6.3% vs. 7.4%|
[95% CI, 0.30-2.46]
|3.6% vs. 1.3% per person-years|
|Conclusion||Increased rate of events (thrombotic + bleeding) on rivaroxaban compared to warfarin||Rivaroxaban showed a non-statistically significant near doubling of the risk for recurrent thrombosis||EFS (thrombosis + bleeding) in patients on DOAC was significantly shorter compared to warfarin-treated patients|
|Main caveats||Lack of information provided on pre-randomization treatment||Lack of information provided on pre-randomization treatment||Retrospective analysis; small size of study|
Abbreviations: APS, antiphospholipid syndrome; DOAC, direct oral anticoagulant; VKA, vitamin K antagonist.
Stewart K. The biggest losers. ASH Clinical News. 2019;5:8.
Pengo V, Denas G, Zoppellaro G, et al. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018;132:1365-1371.
Crowther MA, Ginsberg JS, Julian J, et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med. 2003;349:1133-1138.
Finazzi G, Marchioli R, Brancaccio V, et al. A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). J Thromb Haemost. 2005;3:848-853.
Ordi-Ros J, Sáez-Comet L, Pérez-Conesa M, et al. Rivaroxaban versus vitamin K antagonist in antiphospholipid syndrome: A randomized noninferiority trial. Ann Intern Med. 2019; doi: 10.7326/M19-0291. [Epub ahead of print].
Sato T, Nakamura H, Fujieda Y, et al. Factor Xa inhibitors for preventing recurrent thrombosis in patients with antiphospholipid syndrome: a longitudinal cohort study. Lupus. 2019;28:1577-1582.
Woller SC, Stevens SM, Kaplan DA, et al. Apixaban for the Secondary Prevention of Thrombosis Among Patients With Antiphospholipid Syndrome: Study Rationale and Design (ASTRO-APS). Clin Appl Thromb Hemost. 2016;22:239-247.
Woller SC, Stevens SM, Kaplan DA, et al. Protocol modification of apixaban for the secondary prevention of thrombosis among patients with antiphospholipid syndrome study. Clin Appl Thromb Hemost. 2018;24:192.
Garcia D, Akl EA, Carr R, et al. Antiphospholipid antibodies and the risk of recurrence after a first episode of venous thromboembolism: a systematic review. Blood. 2013;122:817-824.
Moll S. New insights into treatment of venous thromboembolism. Hematology Am Soc Hematol Educ Program. 2014;2014:297-305.
Conflict of Interests
Dr. Moll indicated no relevant conflicts of interest.
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