Would you use novel oral anticoagulants (NOACs) for thromboprophylaxis in patients with an underlying hypercoagulable state? A literature review through a case report

Abstract

Antiphospholipid syndrome (APLS) is an autoimmune condition that predisposes to venous and arterial thrombosis. Warfarin is the agent of choice for anticoagulation. However, a need for routine international normalised ratio (INR) checks and multiple drug interactions are some of the difficulties with warfarin. Currently, there is mixed evidence for and against the use of novel oral anticoagulants (NOACs) for thromboprophylaxis. We present a case report of a patient with APLS on a NOAC for secondary thromboprophylaxis who developed a stroke and discuss current evidence regarding the use of NOACs in patients with APLS. The patient was switched to warfarin for secondary thromboprophylaxis with an INR goal of 2–3. Literature review revealed mixed case reports for and against NOACs for secondary prevention of thrombotic events in patients with APLS. There needs to be further randomised controlled trials to evaluate the efficacy of NOACs for thromboprophylaxis in patients with APLS.

Background

Antiphospholipid syndrome (APLS) is an autoimmune condition leading to a hypercoagulable state and predisposing to venous and arterial thrombosis. Warfarin is the recommended anticoagulant in patients with APLS for thromboprophylaxis.¹ However, warfarin requires frequent international normalised ratio (INR) monitoring, has a prolonged onset of action and has numerous drug interactions.^{2 3} Currently, there is mixed evidence for and against the use of novel oral anticoagulants (NOACs) for thromboprophylaxis in APLS, and it remains a controversial topic. The purpose of this article is to present a case of a patient with APLS on a NOAC for secondary thromboprophylaxis who developed a subsequent stroke and to discuss the current evidence regarding the use of NOACs in patients with hypercoagulable state.

Case presentation

A 48-year-old woman with a history of hypertension, hyperlipidaemia, B2 glycoprotein-positive APLS and pulmonary embolism (PE) on apixaban presented with vision difficulty on awakening. She had prior episode of transient blurry vision in the past month lasting 3 days, which had self-resolved. Neurological examination on presentation was significant for a left homonymous hemianopsia, but otherwise it was normal. She did not have any dyspnoea, orthopnoea, or lower extremity oedema concerning systemic occlusion. She also did not have any skin rash.

She was diagnosed with APLS after unprovoked PE about a year prior to this presentation and was started on warfarin. However, after 4 months of initiation of warfarin, she was switched to apixaban by her outpatient provider due to patient preference to avoid frequent INR checks. She remained adherent to apixaban and was without any thrombovascular events for about 6 months prior to this hospital admission.

Investigations

Initially, CT of the head showed subacute right occipital lobe non-haemorrhagic infarct which was redemonstrated on brain MRI (figure 1). CT angiography of the head and neck showed right posterior cerebral artery, P3, thrombus without evidence of vasculopathy.

Figure 1.

Right occipital subacute non-haemorrhagic infarct on brain MRI from hospital day 1 with (A) hypointensity on diffusion-weighted imaging, (B) isointensity on apparent diffusion coefficient, (C) hyperintensity signal on gradient echo and (D) hyperintensity on fluid-attenuated inversion recovery.

In the workup of other aetiology of stroke, transthoracic echocardiogram (TTE) revealed non-bacterial thrombotic endocarditis (NBTE) without evidence of cardiac thrombus or shunt with normal left ventricular ejection fraction (LVEF; figure 2). Erythrocyte sedimentation rate (74 mm/hour, ref. 0–15 mm/hour) and C reactive protein (3.63 mg/dL, ref. <0.5 mg/dL) were elevated. Infectious endocarditis was ruled out, although of low clinical suspicion, with three sets of blood cultures that were negative. She did not have other vascular risk factors; she had low-density lipoprotein of 98 mg/dL and haemoglobin A1c of 4.6%.

Figure 2.

Transthoracic echocardiogram shows anterior leaflet mitral valve (MV) small echogenicity (on the atrial aspect) and moderate MV thickening.

The patient did not have other risk factors, such as history of malignancy, obesity, trauma or immobilisation, for hypercoagulability. She had reported adherence with medications. Bilateral lower extremity duplex scans were negative for deep vein thrombosis to suggest other occlusions. She was found to have iron deficiency anaemia with a haemoglobin of 108 g/L and a haematocrit of 33.4%, and platelets were normal.

Further autoimmune work for systemic lupus and other autoimmune conditions was negative, including anti-Sjogren’s syndrome A, anti-Sjogren’s syndrome B, rheumatoid factor and antinuclear antibody with reflex screen. Prothrombin time (12.8 s, ref. 9.5–12.4 s) and activated partial thromboplastin time (PTT; 42.1 s, ref. 26.7–35 s) were mildly elevated with normal INR (1.2, ref. 0.8–1.2). She had elevated anticardiolipin IgG (100 GPL U/mL, ref. <15) and B2 glycoprotein IgG (86 GPI IgG units, ref. 0–20) and prolonged PTT lupus anticoagulant (115.7 s, ref. 0–51.9 s).

Differential diagnosis

Differential diagnosis for aetiology of her stroke included endocarditis, other autoimmune conditions such as rheumatoid arthritis and paradoxical embolism. However, workup for other aetiology was negative except for NBTE, and given lack of evidence on use of NOAC in patients with APLS, stroke in this patient was attributed to NBTE with failure of NOAC.

Treatment

The suspected aetiology of the stroke was NBTE associated with APLS, and given that the patient had a history of PE and was stable on warfarin initially and experienced an ischaemic stroke while on apixaban, anticoagulation therapy was switched to warfarin with an INR goal of 2–3 with heparin drip bridge.

Outcome and follow-up

The patient presented with an episode of transient left eye vision difficulty a month later following her stroke admission. Her neurological examination at the time was stable for left homonymous hemianopsia, and brain MRI showed stable left occipital non-haemorrhagic infarct. The patient was doing well on warfarin without any new symptoms or arterial events at 1-year follow-up. NBTE was followed with serial echo by her outpatient provider. Her most recent TTE, 2 years later, showed LVEF of 65%, atrial septal aneurysm and no vegetation.

Discussion

APLS has a high risk of thromboembolic complications in the setting of positive antibodies (anticardiolipin, anti-B2 glycoprotein and antiphospholipid antibodies).⁴ Secondary prevention of thromboembolic events in such patients becomes important with an appropriate anticoagulation agent. However, there is mixed evidence about agent of choice between NOACs and vitamin K antagonist (VKA). A recent Cochrane review reports that for secondary prevention of thrombosis in patients with APLS, there is not enough evidence regarding NOACs, and moderate-intensity VKA (INR of 2.5) is preferred compared with high-intensity VKA (INR of 3–4).⁵ However, venous thromboembolism recurrence is more prevalent with INR of <3, which mainly included venous and non-arterial embolism.^{2 5} Other studies recommend warfarin with a target INR of 2–3 versus INR of 3–4, given it did not show fewer thromboembolic events. Signorelli et al described a series of eight cases with APLS and antibody positivity, five of which developed arterial events during the treatment with rivaroxaban, suggesting that a high-risk group such as that with previous arterial thrombosis or triple antibody positivity is less protected with NOAC.⁶ A recently published European guidelines recommend against the use of rivaroxaban or direct oral anticoagulants with triple-positive APLS and arterial event given the high risk of reoccurrence.⁷ In the case we described, the patient was switched to warfarin (with goal INR of 2–3) from apixaban given thromboembolic event while on it.

On the contrary, NOACs have few drug and food interactions for which laboratory monitoring is not required.³ Agents such as rivaroxaban and dabigatran are approved for stroke prevention in atrial fibrillation.³ However, there is a lack of trials for stroke prophylaxis in APLS. The patient with APLS with poor anticoagulation control with VKAs on rivaroxaban showed good safety and efficacy with no recurrence of thrombosis over 10 months on rivaroxaban.⁸ Rivaroxaban in Antiphospholipid Syndrome (RAPS) trial, a randomised trial of warfarin versus rivaroxaban in patients with APLS with previous venous thromboembolism, showed that endogenous thrombin potential was higher in rivaroxaban and had lower peak thrombin generation compared with warfarin.⁹ Although endogenous thrombin potential was increased, there was no increase in thrombotic risk given lower peak thrombin, and hence it is proposed that rivaroxaban is an effective and safe alternative for thromboprophylaxis in those with APLS.⁹ However, further studies are needed in patients with APLS and stroke or other arterial thrombosis given RAPS included a subset of population with recurrent venous thromboembolism.⁹

Furthermore, if a patient with known APLS has a thromboembolic event, anticoagulation is recommended. However, routine screening for APLS is not currently recommended in patients with ischaemic strokes.¹⁰ The Antiphospholipid Antibodies and Stroke Study brings forth that APLS with positive anticardiolipin antibody or lupus anticoagulant in patients who had a stroke does not increase subsequent vascular events.¹⁰

Future studies and retrospective reviews might provide more data for use of NOACs in patients with APLS. However, currently there are mixed case reports for and against NOACs for secondary prevention of thrombotic events in patients with APLS.

Learning points.

• Antiphospholipid syndrome (APLS) with triple positivity has a high risk of recurrent thrombotic events even on a novel oral anticoagulant (NOAC) as seen in our case.

• The standard of care remains to be warfarin.

• There is mixed evidence for and against NOACs for thromboprophylaxis in APLS as seen in our case report, and further randomised controlled trials are warranted.