Thrombolysis Followed by Apixaban for Massive Pulmonary Embolism and Free-floating Thrombus in Right Ventricle in a Patient with Breast Cancer.

Free-floating thrombus in the right ventricle, associated with a massive acute pulmonary embolism (PE), is a rare phenomenon. PE is an important clinical entity with considerable mortality despite advances in diagnosis and treatment. The prognosis of PE depends on right ventricular dysfunction, myocardial injury markers, and early treatment. In this report, we present the case of a 71-year-old woman with a history of breast cancer admitted to intensive care unit for PE complicated by syncope. Although our case may seem complex because it is not represented in the guidelines, the result was satisfactory and showed how treatment with new anticoagulants (in this case apixaban) after massive thrombolysis of PE could be considered and included in the new guidelines.

INTRODUCTION

The current ESC guidelines on diagnosis and management of acute pulmonary embolism (PE) emphasize the importance of differentiating among patients who are at high risk of mortality (those with shock and/or hypotension), who may be candidates for thrombolytic therapy or surgery, and those with less severe presentations. Due to pulmonary bed obstruction, PE can result in acute right ventricular (RV) failure, a life-threatening condition. As most patients die within the first hours of presentation, early diagnosis is of the utmost importance. The mortality rate listed in the International Cooperative PE Registry was 58% for patients who were hemodynamically unstable at the time of presentation and 15% for those who were hemodynamically stable.[1] Appropriate therapy is best selected using risk stratification primarily by assessing hemodynamic impact as the strongest marker of short-term prognosis. The patients who have acute RV dysfunction and myocardial injury without overt hemodynamic compromise may be at intermediate risk for an adverse early outcome. These patients (referred to henceforth as patients with intermediate-risk PE) may also be candidates for early reperfusion therapy. In normotensive patients with intermediate-risk PE, in PEITHO trial (PE thrombolysis), the composite primary outcome of early death or hemodynamic decompensation was reduced after treatment with a single intravenous (iv) bolus of tenecteplase.[2]

At the stage of clinical suspicion of PE, hemodynamically unstable patients with shock or hypotension should immediately be identified as high-risk patients. They require an emergency diagnostic, and if PE is confirmed, primary pharmacological (or, alternatively, surgical or interventional) reperfusion therapy was performed.

Although the use of thrombolysis has been investigated in these patients, anticoagulation remains the standard treatment approach. Rivaroxaban and apixaban have shown similar efficacy and, in some cases, reduced major bleeding compared with standard approaches for acute treatment. The direct oral anticoagulants do not require regular coagulation monitoring and have been shown to reduce the risk of recurrent venous thromboembolism (VTE) versus placebo when given for >12 months.[3] This use after thrombolysis, at this time, is off-label and should be performed with caution in well-chosen subjects.

CASE REPORT

We present a case of a patient with massive PE (MPE) referred to our emergency department and successfully treated with systemic thrombolysis (alteplase) followed by iv unfractionated heparin (UFH) and then by oral apixaban. A 71-year-old woman with a history of hypertension and cancer was admitted (at 7.43 a.m) 1 h after onset of sudden syncope associated with hypotension. Evaluation of PE probability was performed with Wells criteria; a score of 6.0 points was obtained that groups patients with a median probability of disease of approximately 28%. Lower extremity venous Doppler examination performed in the emergency area showed no thrombus formation. The possibility of a form of paraneoplastic syndrome was the most plausible cause, given the recent intervention for breast cancer and treatment with aromatase inhibitors (anastrozole).

The patient was cyanotic, hemodynamically unstable, hypotensive (90/60 mmHg), with dyspnea and low oxygen saturation (85%) in oxygen with a Venturi mask (6 L/min) and with primary hypoxemia, hypocapnia, and metabolic acidosis (pH 7.326; PO2 51 mmHg, PCO2 34 mmHg, HCO3 19.5 mmol/L, EB 8 mmol/L).

European guidelines regard the clinical severity rating of an acute PE episode based on the estimated PE-related risk defined by mortality in the hospital or 30 days for which reason the risk was calculated by PE Severity Index. The patient is in a high-risk class (V, 171 points) with a mortality of about 25% to 30 days.

After first aid consisting of iv line placement, oxygen treatment, and fluid infusion, to confirm the diagnosis, it was decided to refer the patient contrast chest computed tomography (CT) [Figure 1a and b] which showed MPE associated with hypotension; thus, the patient was admitted to coronary care unit (CCU). No free thrombus was detected on CT.

Figure 1

(a and b) Computed Tomography Angiography performed on admission, shows arterial occlusion with failure to enhance the entire lumen due to a large filling defect

The echocardiogram performed immediately at entry to the CCU [Figure 2a and b], showed a distended right ventricle (RV) with free wall hypokinesis and free-floating thrombus.[4]

Figure 2

(a and b) Right ventricle enlargement with floating thrombus

According to the guidelines, the patient was at high risk of mortality. Our therapeutic decision was the treatment with thrombolysis. The risk of bleeding was moderate for the following reasons: mastectomy performed 1 year earlier, history of breast cancer without metastasis, and in treatment with aromatase inhibitors (anastrozole). According to the HAS-BLED score for major bleeding risk, the patient obtained two points which is equivalent to a 5% bleeding risk. Anticoagulation can be considered by accepting the risk.

At 9:00 am (within 3 h after symptom onset and 67 min from admission in CCU), after informing the patient and obtaining written consent, thrombolytic treatment was carried out with recombinant tissue plasminogen activator (10 mg bolus, then 90 mg over 2 h) and a subsequent (just after thrombolytic treatment) heparin bolus (5000 IU) with subsequent heparin infusion (1000 U/h), and/or according to partial thromboplastin time for the first 48 h.[5]

The time from symptom onset to thrombolytic therapy is an important determinant of tissue salvage in patients with acute PE. After 48 h, anticoagulation was started with apixaban 10 mg twice daily for 7 days, followed by 5 mg BID),[6] according to the new guidelines ESC on PE although it is not clear after use after thrombolysis, so it can be considered out of the label and should use caution in subjects well chosen.[7]

A rapid improvement in oxygen saturation, an increase in blood pressure, a complete absence of cyanosis, and a reduction in polypnea were observed just after the thrombolytic treatment. Furthermore, the troponin and atrial natriuretic peptide valuse returned to normal at 72 hours after thrombolysis which returned to the normal range 72 h after thrombolysis.

Echocardiogram repeated after 24 h [Figure 3] from thrombolysis showed a clear improvement of the hemodynamics of the RV, a reduction of RV dilatation and of pulmonary pressures, and disappearance of septal motion, and reduction of vena cava diameter. On the 5th day, the patient was completely asymptomatic with normalization of cardiac parameters and was transferred from the intensive care ward cardiology. The patient was discharged on the 8th day with the treatment new oral anticoagulants (NOACs). No bleeding was observed during hospitalization. A control at 30 days showed a good hemodynamic status and normal function of the RV. There were no bleeding complications to report. The patient was continuing NOACs treatment which was prescribed sine die.

Figure 3

Reduction of right ventricle diameter after 24 h from thrombolysis

The consent of the publication of scientific work has been signed by the patient.

DISCUSSION

At present, medical behavior, dictated by the philosophy of “not doing any harm,” has led many doctors not to use life-saving drugs such as thrombolytics in patients with moderate to high-risk PE. One of the ways to identify and choose acceptable risks is to ask yourself questions on th best or worst thing that happen if I do this. So a careful approach can lead to better evaluation of the benefit in patient management with high-risk pulmonary embolism.

Once you make the diagnosis of PE, one must follow a precise algorithm which consists of three steps: What is the patient's clinical status?, is there a RV dysfunction?, and is thrombolysis indicated ?. To obtain these data, echocardiographic examination is very important. In fact, an increased RV–left ventricle diameter ratio, hypokinesia of the free RV wall, increased velocity of the jet of tricuspid regurgitation, and decreased tricuspid annulus plane systolic excursion indicating RV dysfunction have been reported in ≥25% of patients with PE in prognostic stratification and used to risk stratify patients.

Meta-analyses have shown that RV dysfunction detected by echocardiography and increased hs-Tn high sensitivity-troponin (TNI) and BNP levels is associated with an elevated risk of short-term mortality in patients without hemodynamic instability. For this reason, an immediate echocardiographic valuation is recommended to evaluate the reperfusive management.

The innovative and revolutionary attitude, not only by guidelines but also by all doctors involved in emergency, regards the stratification of the patient's first medical contact, which becomes “patient-centered” and “PE-centered,” then not the “burden” thrombotic but the criticality of the clinical picture. The clinical classification of the severity of an episode of acute PE is based on the estimated PE-related early mortality risk defined by in-hospital or 30-day mortality. This stratification, which has important implications both for the diagnostic and therapeutic strategies proposed in the 2014 ESC guidelines on the diagnosis and management of acute PE, is based on the patient's clinical status at presentation, with high-risk PE being suspected or confirmed in the presence of shock or persistent arterial hypotension and not high-risk PE in their absence. Arterial hypotension and shock are rare but important clinical presentations since they indicate central PE and/or a severely reduced hemodynamic reserve. Syncope is infrequent but may occur regardless of the presence of hemodynamic instability.[8] Acute RV failure with resulting low systemic output is the leading cause of death in patients with high-risk PE. Thrombolytic treatment of acute PE restores pulmonary perfusion more rapidly than anticoagulation with UFH alone. The early resolution of pulmonary obstruction leads to a prompt reduction in pulmonary artery pressure and resistance, with a concomitant improvement in RV function. In patients with mobile right heart thrombi, the therapeutic benefits of thrombolysis remain controversial. Good results were reported in some series, but in other reports, short-term mortality exceeded 20% despite thrombolysis. Among the treatment options include the fibrinolysis that is able to dissolve the clot, but this therapy is controversial and many of us do not have very clear which is the best way to manage these patients.

A rational approach to deciding whether fibrinolysis is indicated, will be based on the benefit assessment compared to risk of major bleeding and intracranial hemorrhage. The report the risk / benefit largely depends on the clinical presentation. The benefit of fibrinolysis is clearly a huge topic in cardiac field arrest or haemodynamic instability. The report risk/benefit is largely dependent on the clinical presentation. The benefit of fibrinolysis is clearly a huge subject in cardiac arrest or hemodynamic instability.[9]

Patients who have MPE with systemic hypotension and cardiogenic shock have a high mortality rate when receiving heparin alone. Available evidence strongly suggests the use of thrombolytic treatment in these patients.

The incidence of bleeding complications in patients with PE treated with thrombolytic agents is approximately 20%, but the incidence of fatal bleeding, usually intracranial, is <1%. Oral anticoagulants should be initiated as soon as possible and preferably on the same day as the parenteral anticoagulant. Vitamin K antagonists have been the “gold standard” in oral anticoagulation for more than 50 years, and warfarin and acenocoumarol remain the predominant anticoagulants prescribed for PE. Anticoagulation with UFH, low molecular weight heparin (LMWH), or fondaparinux should be continued for at least 5 days and until the international normalized ratio has been 2.0–3.0 for 2 consecutive days. The main limitation is the contraindication of non-Vitamin K oral antagonist after thrombolysis as stated in the SmPC and in the main studies (especially Apixaban for the Initial Management of PE and Deep-Vein Thrombosis as First-line Therapy [AMPLIFY] study). In addition, in the AMPLIFY study, exclusion criteria included that there was subjects with cancer who will be treated for 6 months or more with LMWH therapy.

It is not our case the patient had a history of cancer without metastasis and was not in heparin treatment.

Non-Vitamin K-dependent NOACs are valid alternative.[10]

The AMPLIFY study compared single oral drug treatment using the direct factor Xa inhibitor apixaban (10 mg twice daily for 7 days, followed by 5 mg BID.) with conventional therapy (enoxaparin/warfarin) in 5395 patients with acute VTE, 1836 of whom presented with PE. The primary efficacy outcome was recurrent symptomatic VTE or death related to VTE. Apixaban was noninferior to conventional therapy for the primary efficacy outcome and major bleeding occurred less frequently under apixaban compared with conventional therapy. Patients receiving thrombolytic treatment at admission were not included in these studies.[1011]

This clinical case may be interesting to bridge the gap on the treatment of new anticoagulants after 48 h after thrombolysis.

The result of this particular and complex case was satisfactory and shows how treatment with new anticoagulants (in this case apixaban) after MPE thrombolysis could be considered.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published, and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.