Bioprosthetic Valve Thrombosis while on a Novel Oral Anticoagulant for Atrial Fibrillation

Open AccessPublished:March 07, 2018DOI:https://doi.org/10.1016/j.case.2017.11.002

      Highlights

      • BPVT occurred while on a DOAC for treatment of AF.
      • Echocardiographic and pathologic images of BPVT are shown.
      • The definition of NVAF is not uniform in clinical trials or guidelines.
      • The optimal anticoagulation strategy for BPV and AF is unclear.
      • Caution is advised in using DOACs for AF in patients with BPVs.

      Graphical abstract

      Keywords

      Introduction

      Valvular heart disease (VHD) affects >100 million people worldwide.
      • Iung B.
      • Vahanian A.
      Epidemiology of valvular heart disease in the adult.
      Surgical valve replacement is currently offered for many patients with VHD,
      • Nishimura R.A.
      • Otto C.M.
      • Bonow R.O.
      • Carabello B.A.
      • Erwin J.P.
      • Guyton R.A.
      • et al.
      2014 AHA/ACC guideline for the management of patients with valvular heart disease. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      and 80% of devices are bioprosthetic valves (BPVs).
      • Brown J.M.
      • O’Brien S.M.
      • Wu C.
      • Sikora J.A.H.
      • Griffith B.P.
      • Gammie J.S.
      Isolated aortic valve replacement in North America comprising 108,687 patients in 10 years: changes in risks, valve types, and outcomes in the Society of Thoracic Surgeons National Database.
      Thromboembolism is a major life-threatening complication in patients with prosthetic heart valves. Anticoagulation with vitamin K antagonists (VKAs) is considered reasonable 3 to 6 months postoperatively to prevent BPV thrombosis (BPVT).
      • Nishimura R.A.
      • Otto C.M.
      • Bonow R.O.
      • Carabello B.A.
      • Erwin J.P.
      • Fleisher L.A.
      • et al.
      2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease. A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      However, the appropriate antithrombotic therapy for preventing BPVT in the setting of comorbid atrial fibrillation (AF) is not well defined. The increasing availability and widespread use of direct oral anticoagulants (DOACs) raises questions of safety in patients with BPVs and AF.
      There are currently no randomized controlled trials using DOACs in patients with BPVs and AF. We present the case of a patient with mitral and aortic BPVs with comorbid AF who was treated with a DOAC and ultimately developed thrombosis of both valves.

      Case Description

      A 63-year-old Caucasian man presented with a 1-month history of progressive New York Heart Association class IV dyspnea, pedal edema, productive cough, and night sweats. His history included aortic valve replacement for a bicuspid aortic valve and mitral valve replacement for mitral regurgitation with 25- and 27-mm Carpentier Edwards Perimount BPVs (Edwards Lifesciences, Irvine, CA), respectively, 4 years prior. He also had paroxysmal AF, coronary artery disease with prior stent placement, hypertension, hyperlipidemia, and a 45-pack-year smoking history. Medications included apixaban 5 mg twice a day, metoprolol tartrate 150 mg twice a day, furosemide 40 mg/d, and a multivitamin.
      He was treated for sepsis from presumed mitral valve endocarditis between two outside hospitals 5 months before the current presentation. He completed a 6-week course of intravenous (IV) ceftriaxone and vancomycin. Transesophageal echocardiography (TEE) after completion of IV antibiotics reported a concern for “old endocarditis” on the mitral valve leaflet, with mild mitral regurgitation.
      On admission to our hospital, physical examination revealed a body temperature of 36.4°C, oxygen saturation of 98% on room air, a respiratory rate of 18 breaths/min, a heart rate of 108 beats/min, and blood pressure of 114/85 mm Hg. The patient had reduced air entry to the lung bases with inspiratory crackles in the lower two thirds bilaterally. Cardiovascular examination showed an irregularly irregular pulse, raised jugular venous pressure with a grade I diastolic murmur at the apex, grade II systolic murmur at the left upper sternal border, prominent P2, and 1+ pedal edema to the mid shin bilaterally.
      Laboratory analysis revealed a white blood cell count of 7,600/L (normal range, 4,200–10,200/L) and a pro-calcitonin level of 0.08 ng/mL (normal range, ≤0.5 ng/mL). Brain natriuretic peptide was elevated at 8,216 pg/mL (normal range, ≤83 pg/mL). Blood cultures were drawn in the emergency department. Chest radiography showed small bilateral pleural effusions, mild interstitial pulmonary edema, and mild cardiomegaly. A clinical diagnosis of cardiogenic pulmonary edema was made, and the patient was treated with IV diuretics.
      Initial transthoracic echocardiography was performed and showed a mobile mass on the mitral valve prosthesis with severe mitral valve stenosis (Figure 1) and thickening of the aortic valve prosthetic leaflets (Figure 2). Given these findings, TEE was pursued. TEE showed a large (4.5 × 1.5 cm) highly mobile homogeneous mass attached to the atrial aspect of the medial leaflet of the prosthetic mitral valve with marked prolapse from the ventricle to the atrium (Figure 3, Video 1, Video 2, Video 3). This was associated with severe stenosis (mean diastolic Doppler gradient, 18–27 mm Hg at a heart rate of 76–83 beats/min) and mild regurgitation. TEE also showed an echodense immobile mass attached to the aortic side of the aortic prosthetic valve annulus (1.0 × 0.9 cm) along the prosthetic right and noncoronary cusps, consistent with thrombus (Figure 4, Video 4). Severe left atrial and moderate right atrial enlargement was noted, with severe right ventricular enlargement and a moderate decrease in right ventricular systolic function. Left ventricular chamber size was normal, and ejection fraction was 55% to 60%.
      Figure thumbnail gr1
      Figure 1Transthoracic echocardiogram demonstrating mobile thrombus (arrows) on the mitral valve in the short-axis view (A) and four-chamber view (B).
      Figure thumbnail gr2
      Figure 2Short-axis view of the aortic valve demonstrating thickening of the bioprosthetic aortic valve leaflets, particularly in the noncoronary cusp (arrow). Restricted motion of the noncoronary cusp is also noted.
      Figure thumbnail gr3
      Figure 3Transesophageal echocardiogram demonstrating mobile thrombus (arrows) on the mitral valve with marked prolapse into the left atrium in two-dimensional (A) and three-dimensional views from the left atrium (B,C).
      Figure thumbnail gr4
      Figure 4Echocardiogram demonstrating thickening (arrows) involving the right and the noncoronary cusp of the aortic valve concerning for thrombus. Transthoracic echocardiogram (A), two-dimensional image from the transesophageal echocardiogram (B), and three-dimensional image from the transesophageal echocardiogram (C) are shown.
      The patient was treated with IV unfractionated heparin for BPVT. Other medications during his hospitalization included oral aspirin 81 mg/d, oral metoprolol 150 mg twice daily, and IV furosemide 40 mg/d. Blood cultures remained negative at 72 hours. A thrombophilia workup was negative, and brain magnetic resonance imaging was negative for embolic phenomena. Repeat TEE at 72 hours showed no improvement in valvular function or thrombus size, and thus the patient underwent surgical redo mitral and aortic tissue valve replacement with a 31-mm Medtronic Mosaic porcine heart valve (Medtronic, Minneapolis, MN) in the mitral position and a 23-mm Edwards pericardial tissue heart valve in the aortic position. Pathology showed noninfective bland thrombus associated with minimal organizing pannus and focal calcifications. The left atrial appendage was surgically excluded. Surgical specimens showed a large thrombus on the mitral valve that was mostly occlusive and a subvalvular thrombus on the aortic valve with a thin laminar thrombus on the noncoronary cusp (Figure 5).
      Figure thumbnail gr5
      Figure 5Surgical pathology specimen demonstrating a large occlusive thrombus of the bioprosthetic mitral valve (A) and a thin, laminar thrombus (arrow) between the right and noncoronary cusp of the bioprosthetic aortic valve (B).
      Postoperative transthoracic echocardiography showed well-seated and functional aortic and mitral prostheses. The aortic valve prosthesis systolic mean Doppler gradient was 8 mm Hg, and the mitral valve prosthesis diastolic mean Doppler gradient was 8 mm Hg (heart rate 80 beats/min). Our patient was discharged to a rehabilitation center on postoperative day 7 on warfarin therapy with a target international normalized ratio of 2.0 to 3.0. There was no valve thrombosis on repeat transthoracic echocardiography at 3-month follow-up.

      Discussion

      Surgical repair of VHD with either a mechanical prosthesis or a BPV is performed in appropriately selected patients, with growing popularity of BPVs, which now account for nearly 80% of all surgical aortic valve replacements in the United States.
      • Brown J.M.
      • O’Brien S.M.
      • Wu C.
      • Sikora J.A.H.
      • Griffith B.P.
      • Gammie J.S.
      Isolated aortic valve replacement in North America comprising 108,687 patients in 10 years: changes in risks, valve types, and outcomes in the Society of Thoracic Surgeons National Database.
      Anticoagulation strategies, although well established for mechanical valve prostheses, are not well defined for BPVs despite their increasing popularity. Particular considerations for anticoagulation with BPV are (1) prevention of early BPVT, (2) treatment of established BPVT, and (3) selection of anticoagulation in patients with BPVs and AF. The role of DOACs in these scenarios is unknown because of a lack of randomized controlled trials.
      Although the risk for thrombosis in BPVs is significantly less than with mechanical valve prostheses, it is not negligible. Recent data suggest that the risk for BPVT could be as high as 10% to 12%, and it is most likely to occur in the first 1 to 2 years after valve implantation.
      • Egbe A.C.
      • Pislaru S.V.
      • Pellikka P.A.
      • Poterucha J.T.
      • Schaff H.V.
      • Maleszewski J.J.
      • et al.
      Bioprosthetic valve thrombosis versus structural failure: clinical and echocardiographic predictors.
      The 2017 American Heart Association (AHA) and American College of Cardiology (ACC) guidelines on VHD recommend the use of a VKA with a target international normalized ratio of 2.5 after either aortic or mitral bioprosthetic implantation for 3 to 6 months after surgery in patients at low risk for bleeding.
      • Nishimura R.A.
      • Otto C.M.
      • Bonow R.O.
      • Carabello B.A.
      • Erwin J.P.
      • Fleisher L.A.
      • et al.
      2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease. A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      Following this initial high-risk period, VKAs are the recommended choice for anticoagulation to treat BPVT.
      • Nishimura R.A.
      • Otto C.M.
      • Bonow R.O.
      • Carabello B.A.
      • Erwin J.P.
      • Fleisher L.A.
      • et al.
      2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease. A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      Although the safety of DOACs in this setting is not established, there are several studies exploring their possible role in prevention or treatment of thrombosis. A study by Chakravarty et al.
      • Chakravarty T.
      • Søndergaard L.
      • Friedman J.
      • De Backer O.
      • Berman D.
      • Kofoed K.F.
      • et al.
      Subclinical leaflet thrombosis in surgical and transcatheter bioprosthetic aortic valves: an observational study.
      in 2017 suggested that both DOACs and VKAs were effective in the prevention and treatment of subclinical BPVT, and both were superior to dual antiplatelet therapy. However, there was no significant reduction in stroke rates with DOACs, and the study did not address bleeding risk. Of the patients with BPVT, 16% had AF, and 8% of patients were on anticoagulation at the time of BPVT diagnosis; 5% were taking VKAs and 3% DOACs. The study did not differentiate if patients with AF received VKAs, DOACs, or antiplatelet therapy for the treatment of subclinical BPVT. Two randomized clinical trials, GALILEO (ClinicalTrials.gov identifier NCT02556203) and ATLANTIS (ClinicalTrials.gov identifier NCT02664649), are ongoing to evaluate the use of rivaroxaban and apixaban, respectively, in preventing BPVT in patients with transcatheter aortic valve replacements. The ATLANTIS trial will also include a subgroup of patients with coexisting AF.
      AF is the most common cardiac arrhythmia and is implicated in 15% of all strokes in the United States.
      • You J.J.
      • Singer D.E.
      • Howard P.A.
      • Lane D.A.
      • Eckman M.H.
      • Fang M.C.
      • et al.
      Antithrombotic therapy for atrial fibrillation: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines.
      The introduction of DOACs has expanded the therapeutic options for primary and secondary stroke prevention in patients with nonvalvular AF (NVAF).
      • Di Biase L.
      Use of direct oral anticoagulants in patients with atrial fibrillation and valvular heart lesions.
      Selection of anticoagulation in AF depends first on whether AF is valvular or not; however, society guidelines and landmark trials adopt different definitions of NVAF. The presence of a BPV is not formally categorized as valvular or NVAF in the most recent ACC/AHA updated VHD guidelines, and they do not explicitly address preferred anticoagulation in these patients.
      • Nishimura R.A.
      • Otto C.M.
      • Bonow R.O.
      • Carabello B.A.
      • Erwin J.P.
      • Fleisher L.A.
      • et al.
      2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease. A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      In this document, VKAs are recommended in patients with rheumatic mitral stenosis and mechanical prosthetic valves only, and DOACs are permitted in patients with native VHD. This is a change from the ACC/AHA/Heart Rhythm Society 2014 guidelines on the management of AF, which include the presence of a BPV in the definition of valvular AF.
      • January C.T.
      • Wann L.S.
      • Alpert J.S.
      • Calkins H.
      • Cigarroa J.E.
      • Cleveland Jr., J.C.
      • et al.
      2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society.
      In contrast, the European Society of Cardiology's 2016 guidelines move away from distinguishing valvular AF from NVAF and rather discuss anticoagulation in the setting of various underlying conditions. Notably, BPVs are not specifically addressed in these guidelines.
      • Kirchhof P.
      • Benussi S.
      • Kotecha D.
      • Ahlsson A.
      • Atar D.
      • Casadei B.
      • et al.
      2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS.
      Although the safety of DOACs for stroke prevention in NVAF is well established, few studies have addressed the use of DOACs in patients with AF and BPVs. The most recent 2017 ACA/AHA updated guideline on VHD
      • Nishimura R.A.
      • Otto C.M.
      • Bonow R.O.
      • Carabello B.A.
      • Erwin J.P.
      • Fleisher L.A.
      • et al.
      2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease. A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      states that patients with BPVs and AF are at higher risk for embolic events and should undergo anticoagulation irrespective of CHA2DS2-VASc score; however, they do not specify preferred choice of anticoagulation. These updated guidelines acknowledge that the landmark trials evaluating DOACs for use in AF had variable definitions of NVAF, and some included BPV as NVAF, while others did not,
      • Renda G.
      • Ricci F.
      • Giugliano R.P.
      • De Caterina R.
      Non–vitamin K antagonist oral anticoagulants in patients with atrial fibrillation and valvular heart disease.
      and thus the data are not currently robust enough to make a specific recommendation on choice of anticoagulant in the setting of a BPV, neither differentiating by the valve position (aortic vs mitral). These recommendations differ from the 2014 ACC/AHA guidelines for VHD, which state that a VKA is the preferred anticoagulant in these patients.
      A number of retrospective single-center studies have already shown promising results for the role of DOACs in AF and BPVs. One study, in which 73 patients were prescribed a DOAC and aspirin, showed efficacy and safety in the reduction of thromboembolic events, at the expense of increased bleeding.
      • Yadlapati A.
      • Groh C.
      • Malaisrie S.C.
      • Gajjar M.
      • Kruse J.
      • Meyers S.
      • et al.
      Efficacy and safety of novel oral anticoagulants in patients with bioprosthetic valves.
      Another study looked at 27 patients with AF and BPV and randomized them to receive dabigatran or warfarin, with a primary end point of new intracardiac thrombus on TEE at 90 days. Unfortunately, the study was terminated early because of low enrollment, but the preliminary results showed that one patient in the warfarin group (8.3%) versus no patients in the dabigatran group developed an intracardiac thrombus.
      • Durães A.R.
      • de Souza Roriz P.
      • de Almeida Nunes B.
      • Albuquerque F.P.
      • de Bulhões F.V.
      • de Souza Fernandes A.M.
      • et al.
      Dabigatran versus warfarin after bioprosthesis valve replacement for the management of atrial fibrillation postoperatively: DAWA pilot study.
      Furthermore, recent post hoc subgroup analyses of landmark trials comparing DOACs with warfarin, including BPVs, have suggested that certain DOACs are noninferior to warfarin. The ENGAGE AF–TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48)
      • De Caterina R.
      • Renda G.
      • Carnicelli A.P.
      • Nordio F.
      • Trevisan M.
      • Mercuri M.F.
      • et al.
      Valvular heart disease patients on edoxaban or warfarin in the ENGAGE AF-TIMI 48 trial.
      and the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation)
      • Pokorney S.D.
      • Rao M.P.
      • Wojdyla D.M.
      • Gersh B.J.
      • Lopes R.D.
      • Lewis B.S.
      • et al.
      Abstract 17277: apixaban use in patients with atrial fibrillation with bioprosthetic valves: insights from ARISTOTLE.
      trials have already published results, while the RIVER (Rivaroxaban for Valvular Heart Disease and Atrial Fibrillation) (ClinicalTrials.gov identifier NCT02303795) will be completed in 2018.
      The ENGAGE AF–TIMI 48 trial included 191 patients with BPVs and found that several efficacy and safety outcomes, including death, cardiovascular death, myocardial infarction, and major bleeding, were more prevalent in patients with VHD in general. Nonetheless, safety and efficacy of edoxaban compared with warfarin were similar in participants with VHD. In addition, a variety of bleeding end points were significantly less frequent with edoxaban, regardless of the presence of VHD. Thus, patients with AF and VHD, including those with BPVs, in the ENGAGE AF–TIMI 48 trial appear to derive at least the same benefit from being treated with edoxaban instead of warfarin.
      • De Caterina R.
      • Renda G.
      • Carnicelli A.P.
      • Nordio F.
      • Trevisan M.
      • Mercuri M.F.
      • et al.
      Valvular heart disease patients on edoxaban or warfarin in the ENGAGE AF-TIMI 48 trial.
      Rivaroxaban is also being actively investigated in patients with VHD in the RIVER trial, a phase 2 study examining rivaroxaban versus warfarin in patients with AF with bioprosthetic mitral valves.
      The ARISTOTLE trial included 82 patients with BPVs and showed that there were similarly few events in both the apixaban and the warfarin groups. There were two stroke events, and there were no statistically significant differences between the apixaban and warfarin groups for major bleeding, stroke or systemic embolism, all-cause death, and cardiovascular death. Of note, 41% had concomitant aspirin use.
      • Pokorney S.D.
      • Rao M.P.
      • Wojdyla D.M.
      • Gersh B.J.
      • Lopes R.D.
      • Lewis B.S.
      • et al.
      Abstract 17277: apixaban use in patients with atrial fibrillation with bioprosthetic valves: insights from ARISTOTLE.
      Furthermore, a recent meta-analysis by Siontis et al.,
      • Siontis K.C.
      • Yao X.
      • Gersh B.J.
      • Noseworthy P.A.
      Direct oral anticoagulants in patients with atrial fibrillation and valvular heart disease other than significant mitral stenosis and mechanical valves: a meta-analysis.
      which included BPVs, showed that DOACs were as effective as warfarin in stroke reduction in patients with VHD, excluding hemodynamically significant mitral stenosis and mechanical valves.

      Conclusions

      With the rapid increase in clinician comfort using DOACs, their use in patients with AF and BPVs is also more frequent; however, it is not currently evidence-based practice. The lack of randomized controlled trials in patients with BPVs and AF leads to great variability in clinical practice when selecting anticoagulants for these patients.
      Our case demonstrates a common clinical scenario of a patient with aortic and mitral BPVs and concomitant AF who qualifies for long-term anticoagulation. He was treated with a DOAC and presented with BPVT of both his mitral and aortic prostheses.
      • Egbe A.C.
      • Pislaru S.V.
      • Pellikka P.A.
      • Poterucha J.T.
      • Schaff H.V.
      • Maleszewski J.J.
      • et al.
      Bioprosthetic valve thrombosis versus structural failure: clinical and echocardiographic predictors.
      Although the use of DOACs in patients with BPVs and AF does appear to be promising on the basis of post hoc analysis and small studies, our case serves as a cautionary tale that there is a lack of data to routinely support the use of DOACs in these patients.

      Supplementary Data

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