Anticoagulation therapy for secondary stroke prevention in a patient with active malignancy and non-valvular atrial fibrillation

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Alexandra Maria Chitroceanu1, Raluca Ileana Nistor2,3, Alina Nicula3,4, Andrea Olivia Ciobanu1,3


1 Department of Cardiology, Emergency University Hospital, Bucharest, Romania
2 Department of Neurology, Emergency University Hospital, Bucharest, Romania
3 “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
4 Department of Radiology and Medical Imaging, Emergency University Hospital, Bucharest, Romania


Abstract: Introduction – The choice of anticoagulation in cancer patients with atrial fibrillation (AF) and stroke remains challenging. Data on direct oral anticoagulant (DOAC) treatment for this group of patients is scarce. Case report – A 73-year old woman with a history of malignancy, AF and ischemic stroke was admitted for dysarthria. She had stopped an-ticoagulation for one year because of haematuria due to bladder cancer relapse. Brain imaging techniques confi rmed acute ischemic lesions in multiple vascular territories, and no haemorrhage. Transoesophageal echocardiography showed a mobile thrombus in left atrial appendage. We decided to restart oral anticoagulation and opted for apixaban. Discussions – There are no clear guidelines for anticoagulant therapy in patients with cancer and stroke. Several characteristics support DOACs as a choice for long-term treatment: shorter half-life compared to VKAs, lower risk of intracranial bleeding, less food or drug interactions, easier administration and no need for INR control. An exploratory analysis in the ARISTOTLE trial of AF patients and active or a history of cancer showed the superior safety and efficacy with apixaban versus warfarin among patients with and without cancer. Conclusion – The underlying malignancy is associated with a higher risk both for bleeding and prothrombotic state and DOACs may be a reasonable choice in this category of patients. Keywords: Atrial fibrillation, stroke, cancer, direct oral anticoagulant.

INTRODUCTION
Oral anticoagulation therapy in patients with active malignancy and atrial fibrillation (AF) is challenging. The rate of stroke in patients with cancer seems to be higher compared to general population1, and both can-cer and AF are independent risk factors for ischemic stroke. Thus, anticoagulation therapy must be consi-dered in these patients. However, higher bleeding risk associated with cancer leads to an underuse of oral anticoagulation in patients with malignancies2. Moreo-ver, data on direct oral anticoagulant (DOAC) treat-ment for this group of patients is scarce. Our aim was to address the issue of DOAC therapy for secondary stroke prevention in a patient with active malignancy and non-valvular AF.

CASE PRESENTATION
A 73-year old hypertensive, diabetic woman presen-ted in the emergency department with new onset dysarthria. Her medical history started sixteen years ago, when she was diagnosed with endometrial can-cer, surgically treated. Two years later, urinary bla-dder cancer was diagnosed, followed by surgery and chemotherapy. The patient was symptom free up to one year ago, when she suffered an acute ischemic stroke and was found in atrial fibrillation. Anticoagula-tion therapy with dabigatran 150 mg BID was initiated. The patient presented haematuria while on DOAC treatment. Bladder cancer relapse was diagnosed, and dabigatran was stopped. She presented with dysart-hria in the emergency department, one year after ha-ving stopped treatment with dabigatran.
Resting 12-lead electrocardiogram showed AF with normal ventricular rate. Laboratory tests reve-aled mild microcytic hypochromic anaemia (Hb=9.7 g/dL, Ht=27%, MCV=72 fL, MCH=22 pg), confirmed
by blood smear with a low ferritin level (100 pg/mL), and no other signifi cant changes. Brain computed tomography in the emergency room showed multi-ple chronic sequelae, with no recent lesions and no haemorrhage (Figure 1). However, diffusion magne-tic resonance imaging (MRI) revealed three acute is-chemic lesions in multiple vascular territories (Figure 2). Carotid ultrasound showed non-significant stable atherosclerotic plaques. However, frequent bilateral microembolic signals were detected using transcranial Doppler (Figure 3). These findings did not support an atherothrombotic mechanism for stroke, but sugges-ted cardioembolism as a cause for this event. The pati-ent was referred for transoesophageal echocardiogra-phy (TEE), as part of the diagnostic work-up, showing a mobile thrombus in the left atrial appendage (Figure 4).
In summary, our patient had a history of recurrent cardioembolic ischemic strokes, some symptomatic, some asymptomatic, in multiple vascular territories, with a CHA2DS2-VASc score of 8 and a HAS-BLED risk of 3. We decided to restart oral anticoagulation and opted for apixaban 5 mg BID, taking into consideration normal renal function, no recent bleed, patient functional impairment (Karnofsky Performance Scale Index 60%) and preference. The patient was dischar-ged with no further complications and remained stable at one year follow up.

DISCUSSION
Atrial fibrillation and cancer often coexist, especially in older patients. Moreover, the incidence and prevalen-ce of AF is higher in patients with malignancy compa-red to general population, either at the time of cancer diagnosis or during the course of the disease3. This may be a result of comorbid conditions (such as hypertension), direct tumour effect (systemic inflammation, dehydration), as a complication of cancer therapy, or due to increased survival in cancer patients3. Both age and malignancy increase the risk of thromboembolic events as well as the risk of bleeding4. Hence, anticoa-gulation therapy in cancer patients is challenging.
In our case, the patient was diagnosed with recur-rent ischemic cardioembolic stroke in the context of atrial fi brillation and left atrial appendage thrombus, requiring long term anticoagulation. There are cur-rently no clear guidelines for anticoagulant therapy in patients with cancer and stroke. The most recent recommendations emphasize the importance of inter-disciplinary teamwork to estimate individual patient risk and choose the most appropriate therapy, also considering patient preference3. Low molecular wei-ght heparin (LMWH) is contraindicated in secondary prevention in the setting of acute stroke, but may be an option for long-term treatment3. Vitamin K an-tagonists (VKAs) were traditionally preferred over DOACs in cancer patients, based on greater clinical experience with these drugs3. However, diffi culti-es in achieving a good anticoagulation control, most frequently with supratherapeutic levels of INR, incre-ase the general concern of bleeding risk5. Localized bleeding diathesis as a result of local injury by tumour invasion, tissue damage from radiation, mucosal blee-ding from visceral malignancies or thrombocytopenia from myelosuppressive chemotherapy can also incre-ase the risk of bleeding5.
Additionally, our patient presented with mild ane-mia, but refused any further invasive diagnostic tests. However, this condition proved to be chronic and the-re were no recent signs of active bleeding. Moreover, the small cerebral lesions diagnosed by diffusion MRI are associated with a low risk of haemorrhagic trans-formation, and allow for anticoagulation treatment ini-tiation three days from the acute stroke onset.
Several characteristics may support the use of DOACs as a reasonable choice in cancer patients with AF for long-term treatment: shorter half-life compa-red to VKAs (which may be an important issue for in-terruptions in case of invasive procedures), lower in-tracranial bleeding risk, less food or drug interactions, easier administration and no need for INR control.
Active malignancy was an exclusion criteria in most DOAC AF trials3. An exploratory analysis in the ARIS-TOTLE trial of AF patients and active or a history of cancer showed the superior safety and efficacy with apixaban versus warfarin among patients with and without cancer6. Apixaban was associated with a greater benefit for the composite of stroke/systemic embo-lism, myocardial infarction and death in active cancer (HR 0.30, 95% CI 0.11-0.83) versus without cancer (HR 0.86, 95% CI 0.78- 0.95)6.

Figure 1. Brain computed tomography image showing multiple chronic sequelae (green arrows), with no recent lesions and no haemorrhage.

Figure 2. Diffusion magnetic resonance imaging revealing three acute ischemic lesions (red arrows) in multiple vascular territories and chronic lesions (green arrows).

Figure 3. Transcranial Doppler image showing frequent bilateral microembolic signals.

Figure 4. Transoesophageal echocardiography image showing left atrial appendage thrombosis.

CONCLUSION
The choice of anticoagulation therapy in cancer pati-ents with atrial fibrillation and stroke remains challen-ging. The underlying malignancy is associated with a higher risk both for bleeding and prothrombotic state. DOACs may be a reasonable choice in this category of patients, however further randomised controlled trials need to address the multiple treatment choices we have.
Conflict of interest: none declared.

References:
1. Fitzpatrick T, Carrier M, Gal G Le. Cancer, atrial fibrillation, and stroke. Thromb Res Elsevier; 2017;155: 101–5.
2. Boriani G, Proietti M, Laroche C, Fauchier L, Marin F, Nabauer M, Potpara T, Dan G-A, Kalarus Z, Diemberger I, Tavazzi L, Maggioni AP, Lip GYH. Contemporary stroke prevention strategies in 11 096 European patients with atrial fibrillation: a report from the EUROb-servational Research Programme on Atrial Fibrillation (EORP-AF) Long-Term General Registry. EP Eur 2018;20: 747–57.
3. Steffel J, Verhamme P, Potpara TS, Albaladejo P, Antz M, Desteghe L, Haeusler KG, Oldgren J, Reinecke H, Roldan-Schilling V, Rowell N, Sinnaeve P, Collins R, Camm AJ, Heidbüchel H. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 2018;39: 1330–93.
4. Asnani A, Manning A, Mansour M, Ruskin J, Hochberg EP, Ptaszek LM. Management of atrial fibrillation in patients taking targeted can-cer therapies. Cardio-Oncology 2017; 3:2.
5. Kamphuisen PW, Beyer-Westendorf J. Bleeding complications dur-ing anticoagulant treatment in patients with cancer. Thromb Res El-sevier; 2014;133: S49–55.
6. Melloni C, Dunning A, Granger CB, Thomas L, Khouri MG, Garcia DA, Hylek EM, Hanna M, Wallentin L, Gersh BJ, Douglas PS, Alexan-der JH, Lopes RD. Efficacy and safety of Apixaban versus Warfarin in patients with atrial fibrillation and a history of cancer: insights from the ARISTOTLE Trial. Am J Med Elsevier; 2017;130: 1440–8.e1.

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