Treatment

How would you treat this patient acutely?

a
Aspirin
See next slide.
b
Warfarin (coumadin)
c
Aspirin and warfarin (coumadin)
d
Double antiplatelet therapy

2019 recommendations on management of patients with acute ischemic stroke (not specific to those with antiphospholipid antibody syndrome) from the American Heart Association/American Stroke Association:

  • Anti-platelet agents:
    • Administration of aspirin is recommended in patients with acute ischemic stroke (AIS) within 24 to 48 hours after onset (or whom intracranial hemorrhage).
    • For those treated with IV alteplase, aspirin administration is generally delayed until 24 hours later but might be considered in the presence of concomitant conditions for which such treatment given in the absence of IV alteplase is known to provide substantial benefit or withholding such treatment is known to cause substantial risk.
    • In patients presenting with minor non-cardioembolic ischemic stroke (NIHSS score ≤3) who did not receive IV alteplase, treatment with dual antiplatelet therapy (aspirin and clopidogrel) started within 24 hours after symptom onset and continued for 21 days is effective in reducing recurrent ischemic stroke for a period of up to 90 days from symptom onset.
  • Anticoagulation:
    • Urgent anticoagulation, with the goal of preventing early recurrent stroke, halting neurological worsening, or improving outcomes after AIS, is not recommended for treatment of patients with AIS.
    • Anticoagulants may be considered for secondary prevention of stroke in some patients (such as if atrial fibrillation or arterial dissection).
    • At present, the usefulness of argatroban, dabigatran, or other thrombin inhibitors for the treatment of patients with AIS is not well established.

Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the
Early Management of Acute Ischemic Stroke A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association

In keeping with the above guidelines, the patient was started on aspirin at time of admission. She was not treated acutely with anticoagulants.

How would you treat this patient chronically?

a
Aspirin
b
Warfarin
See next slide.
c
Aspirin and warfarin
Some hematologists would recommend dual therapy based on her triple positivity.
d
Dual antiplatelet therapy

Let’s look guideline 2021 recommendations on secondary stroke prevention in patients with antiphospholipid syndrome from the American Heart Association/American Stroke Association:

  • In patients with ischemic stroke or transient ischemic attack (TIA) who have an isolated antiphospholipid antibody but do not fulfill the criteria for antiphospholipid syndrome, antiplatelet therapy alone is recommended to reduce the risk of recurrent stroke.
  • In patients with ischemic stroke or TIA who meet the criteria for the antiphospholipid syndrome, it is reasonable to anticoagulate with warfarin to reduce the risk of recurrent stroke or TIA:
    • Although no trials of antithrombotic intervention have been performed exclusively in stroke patients, the available evidence favors anticoagulation with VKA compared with aspirin to reduce recurrent arterial thromboses).
    • Although no trials of antithrombotic intervention have been performed exclusively in stroke patients, the available evidence favors anticoagulation with VKA compared with aspirin to reduce recurrent arterial thromboses. An INR with a target range of 2 to 3 is preferable over an INR with a range 3 because higher-intensity anticoagulation is not superior in preventing thrombotic events and is associated with a higher risk of hemorrhagic complications.
  • In patients with ischemic stroke or TIA, antiphospholipid syndrome with history of thrombosis and triple-positive antiphospholipid antibodies (i.e., lupus anticoagulant, anticardiolipin, and anti– β2 glycoprotein-I), rivaroxaban is not recommended because it is associated with excess thrombotic events compared with warfarin.
  • There are limited data to establish whether the addition of antiplatelet agents to anticoagulation is effective in reducing the risk of recurrent stroke in this population. The clinical consensus favors using only anticoagulation (i.e., no aspirin), however we do not recommend the use of DOACs in general and, specifically, rivaroxaban for antiphospholipid syndrome.

2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association/American Stroke Association

Let’s look at the question of secondary stroke prevention in patients with antiphospholipid antibody syndrome (APS) from the standpoint of an APS-specific guideline:

  • In patients with definite APS and first arterial thrombosis:
    • Treatment with vitamin K antagonist (VKA) is recommended over treatment with low-dose aspirin only.
    • Treatment with VKA with INR 2–3 or INR 3–4 is recommended, considering the individual’s risk of bleeding and recurrent thrombosis.
    • Treatment with VKA with INR 2–3 plus low-dose aspirin may also be considered.
    • Rivaroxaban should not be used in patients with triple aPL positivity and arterial events. Based on the current evidence, we do not recommend use of DOACs in patients with definite APS and arterial events due to the high risk of recurrent thrombosis.
    • In patients with recurrent arterial thrombosis despite adequate treatment with VKA, after evaluating for other potential causes, an increase of INR target to 3–4, addition of low-dose aspirin or switch to low-molecular-weight heparin (LMWH) can be considered.

The European League Against Rheumatism (EULAR), Ann Rheum Dis 2019;78:1296–1304

Patients with antiphospholipid antibody syndrome have an increased risk for thrombosis in:

a
Veins
b
Arteries
c
Small vessels

What is the most common site for arterial thrombosis in patients with antiphospholipid antibody syndrome?

a
Heart
b
Brain
Stroke and transient ischemic attack are the most common arterial events in patients with the antiphospholipid syndrome.
c
Kidney
d
Femoral artery

What is the most common site for venous thrombosis in patients with antiphospholipid antibody syndrome?

a
Deep veins of leg
Patients with venous thromboembolism most commonly present with lower-extremity deep-vein thrombosis, pulmonary embolism, or both.
b
Renal vein
c
Cerebral vein
d
Portal vein

True or false: Patients with antiphospholipid antibody syndrome (APS) with arterial thrombosis have a higher risk of recurrence compared with those with venous thrombosis, and a tendency for recurrences in the same vascular (arterial) bed.

a
True
b
False

If this patient had presented with a deep venous thrombosis instead of a stroke, how would management have differed?

a
Heparin acutely with bridge to warfarin
b
Aspirin alone
c
Warfarin alone
d
Heparin acutely with bridge to DOAC
As we will discuss below, DOACs are generally not recommended in patients with antiphospholipid syndrome.

How long would you continue warfarin for in a patient with antiphospholipid antibody syndrome and unprovoked first venous thrombosis?

a
Three months
b
6 months
c
12 months
d
Indefinitely
Use of long-term anticoagulation in patients with APS is supported by two small direct comparison studies (one RCT, one retrospective cohort) that showed a lower risk of recurrent venous thrombosis among patients with APS on long-term. vs 3–6 months of oral anticoagulation.

According to European League Against Rheumatism (EULAR), in patients with provoked first venous thrombosis, therapy should be continued for a duration recommended for patients without antiphospholipid antibody syndrome (APS) according to international guidelines. Longer anticoagulation could be considered in patients with high-risk antiphospholipid antibody (aPL) profile in repeated measurements or other risk factors for recurrence:

  • The panel recommended a duration of anticoagulation according to international guidelines for patients without APS because the benefit of long-term anticoagulation in this population is unclear.
  • In patients with repeatedly high-risk aPL profile or those with additional risk factors for thrombosis recurrence, longer anticoagulation may be considered.

Ann Rheum Dis 2019;78:1296–1304

The following are considerations regarding the treatment of thrombotic antiphospholipid antibody syndrome (APS):

  • Primary thrombosis prevention:
    • the absolute risk of a first thrombosis in antiphospholipid-antibody–positive patients who do not have other risk factors is probably less than 1% per year.
    • The annual risk of a first thrombosis in patients with persistently moderate-to-high-risk antiphospholipid-antibody profiles and a systemic autoimmune disease or additional thrombotic risk factors may be as high as 5%.
    • The use of low-dose aspirin for primary thrombosis prevention is controversial.
  • Secondary venous thrombosis prevention:
    • Initial therapy with unfractionated or low-molecular-weight heparin, followed by long-term anticoagulant therapy with a vitamin K antagonist such as warfarin (target international normalized ratio [INR], 2 to 3), is recommended. No additional benefit of a target INR of 3–4 vs INR of 2–3.
    • For most patients with persistent antiphospholipid antibodies and otherwise unprovoked venous thromboembolism, discontinuation of anticoagulant therapy would be associated with an unacceptably high risk of recurrent thrombosis.
    • The benefit of prolonged anticoagulation is less certain in patients who are positive for antiphospholipid antibodies and in whom thrombosis was provoked — for example, by a surgical procedure — and in patients with laboratory tests for antiphospholipid antibodies that become negative over time.
  • Secondary arterial thrombosis prevention:
    • For patients with stroke and moderate-to-high-risk antiphospholipid-antibody profiles, treatment with warfarin (target INR, 2 to 3), with or without low-dose aspirin is often recommended.
    • Although there is a biologic rationale for adding aspirin to anticoagulant therapy, dual antithrombotic therapy — because it increases the risk of major hemorrhage — is often reserved for patients with clinically significant risk factors for cardiovascular disease and patients in whom a single antithrombotic agent has failed to prevent recurrence.

N Engl J Med. 2018;378:2010-2021

What about DOACs? Can they be used instead of warfarin for secondary prevention of venous or arterial thrombosis?

a
Yes
b
No
As a general rule, DOAC are not recommended in this patient population. See next slide.

What are the positions of regulatory authorities and scientific societies on the use of DOACs in patients with antiphospholipid antibody syndrome (APS)?

  • EMA recommendation against the use of DOACs for APS, especially in triple-positive patients.
  • The European Society of Cardiology and a consortium of French scientific societies (pulmonology, vascular medicine, cardiology, hematology) recommend against the use of any DOAC in any APS patient.
  • German societies recommend avoidance of DOACs in triple-positive patients only.
  • EULAR recommendations advise avoidance of rivaroxaban only in patients with triple-positivity or arterial events and state that DOACs “could be considered in other patients not able to achieve a target INR despite good adherence to vitamin K antagonist (VKA) or those with contraindications to VKA (eg allergy or intolerance to VKA).”

Recommendations from the International Society on Thrombosis and Haemostasis:

  • VKA should be used instead of DOACs for treatment of thrombotic APS among patients with any of the following:
    • Triple positivity
    • Arterial thrombosis
    • Small vessel thrombosis or organ involvement
    • Heart valve disease according to Sydney criteria
  • DOACs should not be used in APS patients with recurrent thrombosis while on therapeutic intensity VKA.
  • DOACs should not be used in APS patients who are non-adherent to VKA.
  • In single or double positive non-“high risk” APS patients who have been on DOACs with good adherence for several months for a first episode of VTE, we recommend a discussion with the patient of options including perceived risks and uncertainties, in the spirit of shared decision-making and review of whether continued treatment with a DOAC is appropriate.
  • In single- or double-positive non-“high-risk” APS patients with a single prior VTE requiring standard-intensity VKA, with allergy or intolerance to VKA or erratic INRs despite patient adherence, we suggest that alternative VKAs, if available, should be considered prior to consideration of a DOAC.

 Thromb Haemost. 2020;18:2828-2839

According to 2019 European League Against Rheumatism guidelines:

  • Rivaroxaban should not be used in patients with triple aPL positivity due to the high risk of recurrent events.*
  • Direct oral anticoagulants (DOACs) could be considered in patients:
    • Not able to achieve a target INR despite good adherence to VKA.
    • Those with contraindications to VKA (eg, allergy or intolerance to VKA).

*A recent randomized control trial of rivaroxaban versus warfarin in patients with APS with triple aPL positivity was prematurely terminated due to an excess of thromboembolic events (mostly arterial) in the rivaroxaban arm.

Ann Rheum Dis 2019;78:1296–1304

Let’s review treatment principles in patients with antiphospholipid antibodies (aPL):

With whatFor how longINR goal
Primary prophylaxis in patient with aPLNo treatmentNo treatmentN/A
Secondary prevention in patient with aPL and unprovoked venous thrombosisHeparin with bridge to warfarinIndefinitely2-3
Secondary prevention in patient with aPL and provoked venous thrombosisHeparin with bridge to warfarinPer guidelines for patients without APS2-3
Secondary prevention in patient with aPL and arterial thrombosisWarfarin with or without aspirinIndefinitely2-3
aPL, antiphospholipid antibodies; N/A, not applicable