Reversibility of valve regurgitation due to cancer-related non-bacterial thrombotic endocarditis after switching direct oral anticoagulation for heparin

Abstract

Non-bacterial thrombotic endocarditis (NBTE) is a rare condition related to a state of hypercoagulability in advanced neoplastic disease. Most of the time, arterial thromboembolic event precedes the diagnosis of NBTE. We report here a case of NBTE responsible for multiple ischaemic strokes, which leads to the diagnosis of metastatic pancreatic adenocarcinoma. Aortic and mitral valvular regurgitations secondary to NBTE appeared within 6 weeks despite therapeutic anticoagulation with direct oral anticoagulant (DOAC) in stroke prevention of paroxysmal atrial fibrillation. Bivalvular regurgitations resolved 8 weeks after therapeutic switch to low-molecular-weight heparin (LMWH) and chemotherapy. DOACs are a possible alternative to LMWH for the prevention of venous thromboembolism in patients with active neoplasia. There is a lack of evidence for a clinical efficiency for the prevention of arterial thromboembolism in NBTE. We propose here a short review of the efficacy of anticoagulant therapy for the prevention of arterial thromboembolism in NBTE.

Background

Arterial thromboembolism could reveal a non-bacterial thrombotic endocarditis (NBTE) and be the first clinical signs of neoplastic disease. Images of valve vegetation may be evanescent and appear within weeks, becoming responsible for loss of valve function. NBTE severely worsens the prognosis and quality of life of these patients and should be actively researched in the case of valvular dysfunction or arterial thromboembolic event. Valve dysfunction due to NBTE causes heart failure that could be rapidly reversible on treatment with surgery. In this case report, we show that anticoagulant therapy with LMWH could be effective in non-urgent situations.

Case presentation

A man in his 60s was admitted for dysphasia and apraxia. Cerebral MRI demonstrated multiple ischaemic strokes in the context of paroxysmal atrial fibrillation. Transthoracic echocardiography (TTE) and transoesophageal echocardiography (TEE) did not show any relevant structural or functional abnormality, especially no valvular dysfunction (figure 1, first evaluation). Treatment with apixaban 5 mg two times a day, sotalol 40 mg two times a day, amlodipin 5 mg once a day and atorvastatin 20 mg once a day was initiated. Six weeks later, the patient was readmitted with rapidly increasing dyspnoea reaching New York Heart Association functional evaluation (NYHA) grade III. He had no fever and reported no recent weight loss. Clinical examination revealed a diastolic aortic murmur 2/6, a systolic mitral murmur 3/6, a bilateral hypoventilation and lower extremities pitting oedema. SARS-CoV-2 screening was negative.

Figure 1.

Echocardiographic evolution of non-bacterial thrombotic endocarditis treated with direct oral anticoagulant and after switch to low-molecular-weight heparin: dramatic evolution within 6 weeks to the formation of significant vegetations and aortic and mitral valve regurgitation. 1, normal mitral valve; 2, thickened mitral valve with vegetations on the anterior and posterior leaflets; 3, normal aortic valve; 4, vegetation on the aortic valve non-coronary cusp; 5, vegetation on the mitral valve resolved; 6, vegetation on the aortic valve resolved. TEE, transoesophageal echocardiography; TTE, transthoracic echocardiography.

Investigations

The TTE showed vegetations on both aortic and mitral valves with severe mitral regurgitation and moderate aortic regurgitation. The TEE (figure 1, second evaluation) showed mitral regurgitation evaluated at 56 mL with a regurgitating orifice of 37 mm²; largest vegetation reached 1 cm and on the aortic valve 1.4 cm. Blood analysis showed regenerative normocytic anaemia with haemoglobin at 9.5 (normal value (n.v) 10–15 g/dL) and signs of disseminated intravascular coagulation (DIC) with prolonged International Normalized Ratio (INR) at 1.6, lowered fibrinogen to 109 (n.v. 200–400 mg/dL), thrombocytopenia at 54 000 (n.v. 150 000–450 000/mm³). Haptoglobin was below detection level due to mechanical haemolysis. Neutrophil count was 7666 (n.v. 1500–7000/mm³) and C reactive protein (CRP) remained within the limits of the norm, lipases 120 (n.v. <60 U/L) and LDH 670 (n.v. 125–243 U/L). Serologies for culture negative endocarditis and antiphospholipid syndrome remained negative. Blood cultures remained negative. Thoracoabdominal CT scan performed because of biological abnormalities revealed a pancreas tumour with multiple liver metastases, CA 19.9 was >120 000 (n.v. <36.9 kU/L). Needle aspiration under echo endoscopic control of the pancreatic tumour confirmed a poorly differentiated adenocarcinoma.

Differential diagnosis

Rapidly appearing aortic and mitral vegetation could evoke an infectious endocarditis, but the absence of fever and normal CRP was contraintuitive. In the context of a suspected pancreatic cancer and DIC, the diagnosis of NBTE was proposed.

Treatment

A depletive treatment with intravenous loop diuretic was initiated. Empirical antibiotic therapy started on arrival was discontinued. Apixaban was replaced by LMWH. Chemotherapy with gemcitabine was initiated. In view of the very severe short-term prognosis of the oncological disease and the non-destructive process of the NBTE, we decided not to perform heart valve surgery and preferred comfort-based medical treatment.

Outcome and follow-up

At 3 months, there was no recurrence of ischaemic event; DIC was resolved; and the TTE showed a resolution of the aortic and mitral regurgitations. All symptoms of cardiac failure resolved and the patient’s quality of life improved. The patient died due to cancer progression 5 months after the initial diagnosis, without signs of relapse of cardiac failure.

Discussion

Sixty-five per cent of the cases of NBTE concern the mitral valve and 25% the aortic valve but is rarely associated with a bivalvular regurgitation. The incidence of NBTE in postmortem autopsy series ranges from 0.9% to 1.6% and is associated with pancreas, lung or prostate adenocarcinoma in 80% of the cases.¹

NBTE results from the formation of sterile thrombi consisting of platelets and fibrin on healthy cardiac valves. Inflammatory microenvironment in cancer leads to the release of prothrombotic tumour cells and molecules as tissue factor responsible for an hypercoagulable state and DIC.^{1 2} In comparison with infective endocarditis, in NBTE, vegetation is sterile and induces few tissues damage and fibrotic repair.^1–3 By the way, vegetation is easily dislodged in systemic blood flow, inducing arterial thromboembolic events as stroke, acute coronary syndrome, spleen or kidney infarction most of the time at the origin of the diagnosis of NBTE. In NBTE, regurgitation is associated with a deficient leaflet coadaptation due to vegetation rather than valvular destruction.³

Treatment consists in a tripod: treating the underlying condition, initiating a long-term anticoagulation and restoring valve continence. Treating the underlying cancer appears to be the key point. Even if not curative, cancer treatments could offer a prolonged survival to most patients with cancer. Thus, improving quality of live by treating all other conditions is a priority.

DOACs have been showed to be as effective and safe as Anti Vitamin K (AVK) and heparin therapy to reduce the risk of venous thromboembolism in patients with cancer.^4–7

Although there is a lack of data, DOACs have been empirically proposed for the prevention of arterial thromboembolism in NBTE treatment. Our case report and others (table 1) support that DOACs are insufficient to prevent arterial thromboembolism in NBTE. Moreover, the three cases that reported regression of valvular regurgitation and vegetations were treated with heparin, suggesting a curative effect.^8–10 This difference could be due to pleiotropic effects of heparin beyond inactivation of factor Xa and thrombin as reduction of platelet aggregation.¹¹

Table 1.

Evolving valvular damage associated with NBTE under anticoagulation

Reference	Sex, age (years)	Cancer origin/staging	NBTE	Valve dysfunction	Embolic events	Anticoagulant treatment	Indication of treatment
12	Woman, 62	Lung stage IV	Aortic	Moderate	–	Rivaroxaban 15 mg 1 /day for 13 days	VTED
13	Woman, 64	Lung stage IV	Aortic	Severe	Stroke	Apixaban 5 mg 2/day for 1 week	VTED
8	Man, 69	Gastric stage IIIb	Mitral	Mild	Stroke	Apixaban for 2 months	VTED
14	Man, 63	Lung stage IIIb	Aortic and mitral	Moderate aortic	Stroke	LMWH for 5 days	VTED
15	Woman, 67	Lung	Aortic	Moderate to severe	–	Rivaroxaban for 2 weeks	VTED
16	Woman, 65 Man, 63	Lung stage IIIa Lung stage IV	Mitral Aortic and mitral	Moderate Moderate	Stroke Stroke	LMWH for 10 days LMWH	VTED VTED
9	Woman, 65	Pancreas Stage IV	Aortic and mitral	Severe	–	Rivaroxaban 20 mg 1/day for 3 months	VTED
10	Woman, 63	Ovary Stage IIc	Aortic and mitral	–	–	Rivaroxaban for 3 weeks	VTED
17	Woman, 63	Biliary Stage IV	Aortic and mitral	–	Stroke	Rivaroxaban then apixaban for 4 months	VTED
18	Man, 65	Bladder Advanced stage	Mitral	–	Stroke	Rivaroxaban 30 mg/day for 17 days	VTED
19	Woman, 43	Ovary Stage I	Aortic	–	Myocardial infarct	Rivaroxaban for 28 weeks	VTED
20	Man, 59	Lung	Aortic	–	Stroke	Rivaroxaban for 2 weeks	VTED
21	Man, 54 Man, 61	Pancreas Stage IV Pancreas Stage IV	Mitral Mitral	– –	/ /	Warfarin for 1 month Warfarin for 3 weeks shifted to LMWH for 1 week	Stroke VTED
22	Woman, 59	Pancreas Stage IV	Mitral	/	/	LMWH for 2 weeks	VTED

A short review of anticoagulant therapy in NBTE. Sixteen articles reported progressing valvular damage associated with NBTE despite anticoagulation. Nine of them concerned a DOAC, five LMWH therapy and two AVK. Most patients died rapidly and could not receive oncological treatment. Soga et al is the only one to report curative valvular surgery and complete oncological treatment without thromboembolic relapse or valvular progression in a period of 18 months of observation.⁸ Mantovani et al reported the only case of resolution of severe bivalvular regurgitation after switching rivaroxaban 20 mg prescribed for 3 months to UFH.⁹ Valvular vegetation disappeared after 5 days of treatment with UFH. We found one other case (Orfanelli et al) of resolution of monovalvular vegetations after switching DOAC to heparin therapy.¹⁰ Valvular progression was rapid, within weeks, in the cases that report ultrasonographic follow-up.

DOAC, direct oral anticoagulant; LMWH, low -molecular- weight heparin; NBTE, non-bacterial thrombotic endocarditis; UFH, unfractionated heparin; VTED, venous thromboembolic disease.

In NBTE, surgical indications have not been studied. However, our case highlights the potentially reversible nature of vegetations after adequate anticoagulation and aetiological treatment. Cardiac surgery should finally be restricted to patients with severe congestive heart failure due to valvular dysfunction responsible for life-threatening heart failure or patients with recurrent embolism despite well-conducted anticoagulation.

Strategy for long-term anticoagulation in NBTE should remain based on heparin as neither DOAC nor vitamin K antagonists have demonstrated superiority in preventing arterial thromboembolism.

Learning points.

• Clinical set-up of arterial thromboembolism should include repeated echocardiography.

• Non-bacterial thrombotic endocarditis (NBTE) in patients with cancer is associated with venous thromboembolism that could be prevented with direct oral anticoagulant (DOAC). There is no evidence of prevention of arterial thromboembolism with DOAC in NBTE and, thus, should be treated with heparins.

• NBTE treatment with heparin could improve clinical signs of valvular dysfunction and patients’ quality of life.

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