Authors: Songnan Wen, Tasneem Z. Naqvi
Categories: Echo Innovation, Anticoagulation, Atrial fibrillation, Cardioversion, Malignancy, Transesophageal echocardiogram
Source: CASE : Cardiovascular Imaging Case Reports
Authors: Songnan Wen, Tasneem Z. Naqvi
Per current guidelines, anticoagulation strategy for atrial fibrillation (AF) is determined by the patient's CHA2DS2-VASc score, the benefits and risks of which have been well demonstrated by large-scale clinical trials and registries. In the last decade, non–vitamin K antagonist oral anticoagulants (NOACs) have become the anticoagulants of choice and are prescribed as the default in most patients with AF in place of warfarin. However, the role of NOACs in the presence of malignancy is not well established. Herein we present a patient who had renal cell carcinoma and developed AF.
An 80-year-old woman was incidentally found to be in AF prior to a renal biopsy procedure. Medical history included renal cell carcinoma on immunotherapy, type 2 diabetes, and hypertension. The patient’s CHA2DS2-VASc score was 5, and HASBLED score was 3. The patient’s body mass index was 29.9 kg/m^2^. Serum creatine was 1.17 mg/dL. Estimated glomerular filtration rate was 47 mL/min. After 2 doses of apixaban at 5 mg, the patient was referred for transesophageal echocardiogram– (TEE-) guided electrical cardioversion (ECV). On presentation, blood pressure was 137/84 mm Hg, pulse rate 82 beats/min, temperature 36.4°C, respiratory rate 16 breaths/min, and oxygen saturation 96% on room air. The cardiovascular examination revealed irregular rate and rhythm, no murmurs, and jugular venous distension. The TEE identified thrombus in the left atrial appendage (LAA; Figures 1A and 2A, Video 1), with normal LV function (ejection fraction 55%). Cardioversion was cancelled, and the patient was continued on apixaban 5 mg twice per day for 30 days. Due to persistent AF, the patient was referred again for TEE-guided ECV. The TEE showed no residual thrombus but spontaneous echo contrast (SEC) in the LAA (Figure 1B, Video 2). After administration of an ultrasound-enhancing agent, LAA views showed no definitive residual filling defect in the LAA compared to the prior TEE (Figure 2B, Video 3). There was mild SEC in the enlarged atria, and LAA emptying velocities were markedly reduced at 10 to 20 cm/s. Based on the presence of prior thrombus, residual SEC, active malignancy, low LAA velocities, and our earlier experience of evaluating LAA post ECV with in situ TEE,^1^ the TEE probe was left in situ during planned ECV (34-36 cm from the incisor teeth) and placed parallel to the patient’s left side. The patient was placed in the supine position, and after confirming adequate sedation, ECV was performed with one biphasic shock (200 Joules; anterior/posterior positioned pads), which restored sinus rhythm. Per protocol, no live TEE imaging was performed during ECV (using the freeze button) in an effort to reduce thermal injury to the esophagus. Post-ECV LAA images were obtained immediately (within 5 seconds), after sinus rhythm was achieved. These images showed development of echo-dense material in the LAA lobe (Figure 1C and D), which became more organized (Figure 1D, Video 4) over the next few beats (within 1 minute post-ECV). No mitral inflow A wave (Figure 3A) was present, and there was a complete loss of LAA Doppler velocities (Figure 3B) during sinus rhythm, indicating marked left atrial and LAA stunning. The LAA thrombus persisted during TEE imaging for another 3 minutes. At this point, the TEE probe was withdrawn, the referring provider was informed of the findings, and the patient was admitted under cardiology service. Enoxaparin (80 mg subcutaneously twice a day) along with warfarin were initiated and apixaban was discontinued. Therapeutic international normalized ratio was achieved after 2 days, enoxaparin was discontinued, and the patient was discharged on coumadin. The patient remained in sinus rhythm and had no reported clinical events at 6-month follow-up. The patient was placed back on apixaban 2.5 mg every 12 hours by the primary care provider after 6 months.Figure 1Two-dimensional TEE, mid-upper esophageal LAA long-axis (105°-146°) views obtained serially, demonstrate (A) a thrombus (arrow) at baseline (3 weeks before) and (B) SEC without thrombus (arrow) after 30 days of anticoagulation (apixaban 5 mg twice a day) and immediately before ECV; (C) in situ TEE demonstrates a rapidly formed new thrombus with poorly defined borders (yellow arrow) immediately post-ECV in normal sinus rhythm (white arrow**s; P wave on electrocardiogram) and (D) a well-defined thrombus (yellow arrow) seconds later using color B mode as patient remains in sinus rhythm (white arrow; P wave on electrocardiogram). LA, Left atrium; LAA, left atrial appendage.Figure 2Two-dimensional TEE after administration of an ultrasound-enhancing agent, mid-upper esophageal LAA long-axis (104°) view, demonstrates a filling defect (A, arrow) in the LAA, 1 month before ECV. Biplane (70° and 160°) views (B) show resolution of the filling defect (arrows) at 1-month follow-up after therapeutic anticoagulation with apixaban 5 mg twice a day. LAA, Left atrial appendage.Figure 3Two-dimensional TEE-guided pulsed-wave Doppler of (A) the mitral inflow, midesophageal 4-chamber (0°) view and (B) LAA ostium, mid-upper esophageal long-axis (138°) view, demonstrates absence of A waves (white arrows, A) and absence of systolic Doppler velocity during sinus rhythm (B) immediately post-ECV despite sinus rhythm (yellow arrows; P waves on electrocardiogram) consistent with electromechanical uncoupling and LAA stunning, respectively. LA, Left atrium; LAA, left atrial appendage; LV, left ventricle; RA, right atrium.
In this report, we present an 80-year-old woman with AF and high CHA2DS2-VASc score whose LAA thrombus got resolved with 1 month of NOAC therapy. However, the patient was at elevated risk of a thromboembolic event as suggested by a high CHA2DS2-VASc score and echocardiographic features of marked atrial enlargement, reduced LAA velocities, and residual LAA SEC pre ECV. At the same time, the patient had an active malignancy with possible malignancy-associated hypercoagulability state. Severe SEC with suspected acute thrombus formation was seen during in situ TEE immediately after ECV and was treated with enoxaparin and warfarin without clinical consequence.
Pre-ECV TEE two-dimensional imaging of the LAA in multiple angles did not show a thrombus but did show SEC in the LAA; hence we administered an ultrasound-enhancing agent, using a low mechanical index, left-ventricular cavity opacification contrast acquisition protocol to improve LAA opacification. Although SEC was seen in the LAA, there was no residual LAA thrombus or filling defect seen, and we proceeded with ECV.
Patients with AF who have malignancy carry an even higher risk of thromboembolic event than those with similar CHA2DS2-VASc score because of the prothrombotic state associated with malignancy. Several factors involved in the immune response to neoplasia, such as the development of acute phase reactants, abnormal protein metabolism, necrosis, and hemodynamic rearrangements, can all contribute to the overall activation of blood coagulation in cancer patients. Malignant cells not only produce and release procoagulant and fibrinolytic activities, as well as inflammatory cytokines, but also directly interact with other blood cells, that is, endothelial cells, platelets, and monocytes.^2^ As direct thrombin inhibitor (dabigatran) or factor Xa inhibitors, NOACs may not cover all these mechanisms, and resolution of preformed thrombus does not necessarily imply that a patient’s hypercoagulable status has been changed, as evidenced by the echocardiography findings prior to ECV in this case. However, as a vitamin K antagonist, warfarin is also known to have pleiotropic nonanticoagulation effects, including a preventive and therapeutic role in inflammation,^3^ as well as both immunostimulatory and immunosuppressive effects.^4^^,^^5^ This allows warfarin to exhibit more powerful anticoagulant effects, especially in patient populations with complex comorbidities like cancer in this case. Our patient developed new LAA thrombus immediately after ECV but experienced no thromboembolic event on warfarin. A repeat TEE was not requested after the switch to warfarin during follow-up due to the satisfactory clinical outcome in our patient.
Current guidelines recommend that patients with AF should be anticoagulated for 3 weeks prior to and 4 weeks after ECV (the “3-4 weeks rule”).^6^ Evidence supporting this recommendation was based on the observation that the majority of preformed left atrial or LAA thrombi during AF can be dissolved with 3 weeks of anticoagulant treatment. Observations also showed that the stunned left atrium can regain function within the fourth week. This “3-4 weeks rule” was derived from previous studies using warfarin^7^ and may not apply to patients with AF who have an extremely high risk of thromboembolic events that could have been underestimated by the CHA2DS2-VASc score alone. Traditionally, the presence of SEC on TEE is not a contraindication for ECV in patients who have completed the required anticoagulation therapy. However, in high-risk patients this may represent inadequate anticoagulation and allow for thrombus formation due to atrial stunning post-ECV.
An in situ TEE throughout the ECV procedure in our patient allowed us to detect post-ECV LAA thrombus, which would have been missed with the conventional approach of removing the TEE probe after excluding LAA thrombus pre-ECV. We have demonstrated the utility of this approach in a series of 37 patients in an earlier report.^1^ We have also demonstrated the potential value of an in situ TEE protocol in patients with complex LAA anatomy.^8^ Future studies of larger sample size are warranted to understand the coagulative pathophysiology immediately after ECV and differences between various anticoagulant regimens in very high-risk patients.
Our case highlights the role of in situ TEE to evaluate LAA post-ECV in guiding an anticoagulation strategy in patients with AF who are at high risk of thromboembolism despite adequate duration of therapeutic anticoagulation and irrespective of CHA2DS2-VASc score. These include patients with hypercoagulable state or patients with SEC or adverse appendage anatomy where empirical practice of TEE-guided ECV can miss post-ECV development of a new LAA thrombus.
The authors declare that the work described has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans.
The authors declare that since this was a non-interventional, retrospective, observational study utilizing de-identified data, informed consent was not required from the patient under an IRB exemption status.
The authors declare that this report did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.