Morbidity and Mortality with Pericardial Effusion Associated with Direct Oral Anticoagulants and P-glycoprotein Inhibitors

Pericardial effusion is a rare but potentially fatal adverse effect reported with apixaban, dabigatran, edoxaban, and rivaroxaban (direct oral anticoagulants). We report three cases of pericardial effusion that occurred at a single institution with two patients requiring urgent pericardiocentesis. All patients took a direct oral anticoagulant with a p-glycoprotein inhibitor or a combined p-glycoprotein and CYP3A4 inhibitor. Our patients had underlying conditions predisposing them to developing pericardial effusion.

Direct Oral Anticoagulants (DOACs) are recommended as first-line drugs for stroke prevention in patients with non-valvular atrial fibrillation [1]. Similarly, the American College of Chest Physicians recommends DOACs over warfarin for patients with venous thromboembolism [2]. Unlike warfarin, DOACs have a lower propensity for drug interactions and offer the convenience of fixed dosing with less frequent laboratory monitoring. Apixaban, dabigatran, edoxaban, and rivaroxaban are the four DOACs marketed in the United States [3-6]. However, the manufacturers of apixaban, dabigatran, edoxaban, and rivaroxaban caution prescribers about the potential risk of increased exposure when taken concurrently with p-glycoprotein inhibitors (with or without strong CYP3A4 inhibitors).

Hemorrhagic pericardial effusion is classified as a major bleeding event and is characterized by blood accumulation in the pericardial space, potentially resulting in cardiac tamponade [7]. Pharmaceutical companies have not included pericardial effusion cases when summarizing major bleeding events in the DOAC package inserts. However, there are published reports of hemorrhagic pericardial effusion associated with the four marketed DOACs [8-24]. In most cases, patients had a predisposing factor such as acute/chronic kidney disease, malignancy, or drug interaction. Also, given the rarity of pericardial effusion associated with DOACs, the incidence of this adverse effect has not been established.

We report here our experience with three patients who were hospitalized with pericardial effusion associated with a DOAC. This report intends to heighten awareness about the occurrence of pericardial effusion in patients taking DOACs in conjunction with interacting drugs.

We initially conducted a single-center retrospective cohort study of patients with or without DOAC therapy who experienced pericardial effusion between February 2018 and March 2024. Demographic, laboratory, clinical characteristics, treatment interventions, and outcomes were retrieved from the medical records. The San Joaquin General Hospital Institutional Review Board Committee approved the study.

Patients 18 years and older with pericardial effusion were eligible for study inclusion. Exclusion criteria included acute or chronic aortic dissection, cardiac valve replacement or coronary artery bypass graft surgery within 30 days, myocardial infarction, or traumatic injury to the chest within 30 days of pericardial effusion.

The DOAC registry at San Joaquin General Hospital showed 2,117 apixaban, 1,073 rivaroxaban, and 220 dabigatran recipients from February 2018 to March 2024. Our review of the echocardiography database revealed 105 pericardial effusion cases. After screening for exclusion criteria, we identified 74 patients with pericardial effusion (10 patients on DOAC and 64 patients not on DOAC). Of the ten patients on DOAC, seven were on apixaban, two on rivaroxaban, and one on dabigatran. Three of the 10 patients died shortly after their diagnosis of pericardial effusion, and two patients (one of the deaths) required urgent pericardiocentesis. Our review identified three cases of pericardial effusion resulting in hospitalizations with two deaths that could have been attributed to DOAC therapy. Table 1 includes details of the three patients’ anticoagulation history, treatment indication, stroke risk for atrial fibrillation (if applicable), bleeding risk, and p-glycoprotein inhibitor drug interactions.

Case 1

A 63-year-old Caucasian male with past medical histories significant for atrial fibrillation, myocardial infarction status post automatic implantable cardioverter-defibrillator (AICD), heart failure with reduced ejection fraction (HFrEF), chronic obstructive pulmonary disease/asthma, hypertension, and hyperlipidemia was brought in by ambulance after being found at home wedged between his bed and wall for more than 4 hours. When found by emergency medical services, the patient lost his pulse and went into cardiac arrest, requiring cardiopulmonary resuscitation (CPR). En route, he had CPR for an unknown duration. He received two doses of intraosseous epinephrine, 1 mg. Upon arrival at the Emergency Department (ED), his Glasgow Coma Score was at 3 requiring intubation, and he was in pulseless electrical activity (PEA). He received four rounds of Advanced Cardiac Life Support (ACLS) with a Return of Spontaneous Circulation (ROSC).

The patient’s vital signs were as follows: heart rate 93 beats per minute, respiratory rate 13 breaths per minute, blood pressure 102/66 mm Hg, SpO2 97% on ventilator. His temperature was at 36 degrees Celsius and his body mass index was at 45.71 kg/m2.

He was on dabigatran for atrial fibrillation and his other home medications included albuterol inhaler, carvedilol, ciclesonide inhaler, digoxin, furosemide, hydralazine, ipratropium inhalation solution, isosorbide mononitrate, lisinopril, montelukast, nicotine transdermal supplements, potassium chloride extended-release, simvastatin, and tiotropium bromide. Laboratory results showed an elevated WBC count of 32.9 x 10^9/L and neutrophilia (91.0%). He was anemic with a hemoglobin of 10.6 g/dL. His chemistry showed acute renal impairment, with a serum creatinine of 2.23 mg/dL, estimated glomerular filtration rate (eGFR) of 26 mL/minute/1.73 m2, and creatine clearance of 37 mL/min. The patient showed evidence of coagulopathy, with an international normalized ratio (INR) of 5.2. BNP was at 173 but troponins were negative.

Computed tomography (CT) of the chest/abdomen/pelvis with contrast revealed a pericardial effusion measuring 1.8 cm in thickness, indicating a potential hemopericardium. The bedside cardiac ultrasound showed a large pericardial effusion, prompting the decision to proceed with a pericardiocentesis. The pericardial fluid analysis revealed a red blood cell count of 4,927,765 and red/turbid fluid. After the removal of about 1,000 mL of sanguineous fluid from the pericardium, the patient was noted to have improved cardiac activity with organized rhythm and palpable pulses. The pericardial drain was left in place. However, he was still hypotensive therefore, norepinephrine was started. The patient’s AICD was interrogated which showed low voltage and end of service. The post-pericardiocentesis echocardiogram showed a mildly dilated left ventricle with a biplane ejection fraction of 37%. A small and loculated pericardial effusion was present.

The patient was admitted to the Medical Intensive Care Unit for status post-cardiac arrest. After a discussion of the goal of care with the patient’s family, the care plan proceeded to focus on providing comfort and symptom management rather than life-prolonging treatment. The patient died six hours later. The patient’s cause of death was considered as cardiopulmonary collapse related to PEA, from cardiac tamponade with hemo-pericardial effusion with underlying acute exacerbation of congestive heart failure. Other contributing causes of death included supratherapeutic INR due to the use of dabigatran for atrial fibrillation, renal failure, and aspiration pneumonia.

Case 2

A 77-year-old Hispanic female with past medical histories significant for lower extremity deep vein thrombosis (DVT), chronic kidney disease, heart failure with preserved ejection fraction (HFpEF), hypertension, hyperlipidemia, hypothyroidism, liver cirrhosis, type 2 diabetes mellitus (DM), and cerebrovascular accident who presented to the geriatric clinic as somnolent, not very responsive, with bilateral wheezing and lower extremity edema. The geriatric clinic sent her to the ED due to concern for abnormal labs and a fluid overload state. The patient presented with mild labored breathing, with exams notable for bilateral crackles and 2+ pitting edema on bilateral lower extremities.

She was on rivaroxaban 2.5 mg daily for the history of DVT and her other home medications included amlodipine, aspirin, atorvastatin, carvedilol, furosemide, levothyroxine, losartan, melatonin, polyethylene glycol, quetiapine, oral semaglutide, and senna. Upon arrival at the ED, her vital signs were as follows: temperature 36.8 degrees Celsius, heart rate 64 beats per minute, respiratory rate 24 breaths per minute, blood pressure 101/62 mm Hg, and oxygen saturation of 94% on room air. Her BMI was at 34.68 kg/m2. Laboratory tests indicated anemia, with hemoglobin of 10.4 g/dL, and thrombocytopenia at 71 x 10^9/L. Her routine chemistry indicated worsening renal function, as shown by her serum creatinine of 3.88 mg/dL (2.37 mg/dL, two months ago) and an eGFR of 11 mL/minute/1.73 m2 (20 mL/minute/1.73 m2, two months ago and creatinine clearance was at 15 milliliters per minute. Her TSH was elevated at 68 uIU/mL.

The chest CT without contrast revealed mild cardiomegaly and moderate pericardial effusion, along with pleural effusions. The patient was admitted to telemetry for an acute exacerbation of heart failure then she was transferred to intermediate care and started furosemide via continuous infusion and dobutamine drip. She resumed home rivaroxaban 2.5 mg daily. During hospitalization, she developed atrial fibrillation. Echocardiography showed a normal-sized left ventricle, ejection fraction of 61.6%, and a small pericardial effusion. The pericardiocentesis was not recommended as pericardial effusion was likely developed from volume overload, uremia, or poorly controlled hypothyroidism and the patient did not have the evidence of tamponade. Furthermore, apixaban 2.5 mg twice daily was recommended to replace rivaroxaban due to the patient’s new onset of atrial fibrillation. On hospital day 5, following a discussion with the patient’s family regarding the prognosis and goals of care, the care was transitioned to comfort measures, and the patient expired.

Case 3

A 70-year-old South Asian male with past medical histories significant for atrial fibrillation, HFpEF, stage IV large B-cell lymphoma with metastasis to the lung, status post five cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), pancytopenia secondary to chemotherapy, depression, type 2 DM, obesity, and obstructive sleep apnea was sent to the ED from the heart failure clinic for CHF exacerbation. He experienced worsening exertional shortness of breath during normal daily activity and weight gain over the past two weeks.

The patient started apixaban 5 mg twice daily approximately 400 days earlier for atrial fibrillation. He began his first cycle of R-CHOP 194 days before presenting to the ED. Throughout his R-CHOP cycles, apixaban was held when the platelet count dropped below 100 x 10^9/L and the fifth cycle of R-CHOP started.

His home medications included allopurinol, atorvastatin, bumetanide, diltiazem, ergocalciferol, glipizide, loratadine, metformin, metolazone, and oral potassium chloride. Upon arrival at the ED, his vital signs were as follows: temperature 36.2 degrees Celsius, heart rate 80 beats per minute, respiratory rate 18 breaths per minute, blood pressure 94/57 mm Hg, and SpO2 97 % on room air.

Laboratory tests showed anemia at Hb 8.1 g/dL and thrombocytopenia of 99 x 10^9/L. The routine chemistry panel indicated acute renal impairment as the patient’s serum creatinine was elevated at 2.22 mg/dL compared to 1.27 mg/dL from two months ago. His eGFR was at 29 mL/minute/1.73 m2.

During hospital days 1 through 4, the patient was treated with IV furosemide, and oral metolazone was added on hospital day 3. On hospital day 4, the patient was transferred to the intensive care unit, as he required a vasopressor for hypotension. His diuretic regimen changed to a continuous infusion of furosemide and dobutamine. On hospital day 5, the patient’s ECG revealed low voltage throughout all leads, a ventricular rate of 109 beats per minute, atrial fibrillation, and ventricular premature complexes. The echocardiogram showed an ejection fraction of 39%, right ventricular systolic pressure of 56 mmHg, a moderate-sized pericardial effusion with tamponade physiology, and a large pleural effusion. Before starting apixaban in the past, echocardiography did not indicate pericardial effusion in the past. Fifteen days after beginning the first cycle of R-CHOP (while on apixaban), trace pericardial effusion was noted in the echocardiogram. Then three days after starting the fifth cycle of R-CHOP (while on apixaban), moderate-sized pericardial effusion and pleural effusion were noted in the echocardiogram. The patient underwent pericardiocentesis and had 900 mL of dark-colored bloody fluid removed. Immediately following the procedure, the patient’s blood pressure significantly improved, and the dobutamine was discontinued. Pericardial fluid analysis showed red blood cell counts of 3,238,148 and red/turbid fluid.

The patient improved over the next two days, requiring fewer doses of furosemide, and kidney function was also improved. On hospital day 8, the pericardial drain was removed, draining an additional 250 mL with a total net output of 1.15 L. The patient was discharged the next day on oral bumetanide, and apixaban was continued to be held.

Spontaneous hemopericardium has been reported for all the DOACs marketed in the United States of America [8-25]. The incidence of this rare adverse effect has not been established - we report the hemopericardium cases, one patient on dabigatran and another on apixaban required urgent pericardiocentesis at our institution. From 2018 to 2024, the incidence of hemopericardium resulting in pericardiocentesis was 0.45% for 220 dabigatran recipients and 0.05% for 2,117 apixaban recipients. One out of 1,073 (0.09%) rivaroxaban recipients developed a small pericardial effusion.

While our case 1 patient’s most likely cause of death was cardiopulmonary collapse related to PEA from cardiac tamponade with underlying acute exacerbation of heart failure, other contributors deserve mention. Dabigatran is a known substrate of the efflux transporter protein p-glycoprotein. Our patient had an eGFR at 26 mL/minute/1.73 m2 and took dabigatran with two p-glycoprotein inhibitors: carvedilol [26,27] and simvastatin [28]. The European Society of Cardiology states that there is limited data on the safety and efficacy of using DOACs for morbidly obese patients requiring stroke prevention for atrial fibrillation [29]. Our patient showed signs of coagulopathy, with an INR of 5.2 on admission. The manufacturer recommends lowering the dose of dabigatran by 50% if a patient has a creatinine clearance of 30 to 50 milliliters per minute and takes dronedarone or ketoconazole [4]. The package insert does not list other potential p-glycoprotein inhibitor drug interactions with dabigatran. Our patient underwent prolonged CPR, which could have contributed to the development of pericardial effusion.

Our rivaroxaban patient (case 2) had multiple underlying conditions that could have caused her to develop pericardial effusion. Severe hypothyroidism, uremia, and volume overload secondary to acute heart failure exacerbation can lead to pericardial effusion [30-32]. However, our patient presented with a creatinine clearance of 15 milliliters per minute and took two p-glycoprotein inhibitors (atorvastatin [33] and carvedilol [26,27]) with rivaroxaban 2.5 mg daily. She received an off-label dose of rivaroxaban to prevent the recurrence of DVT. The manufacturer recommends avoiding rivaroxaban for this indication if patients have a creatinine clearance below 15 milliliters per minute. Furthermore, rivaroxaban undergoes dual elimination – hepatic metabolism through CYP3A4/CYP2J2 and renal excretion through p-glycoprotein-mediated secretion [6]. It is possible that our patient’s poor renal function, combined with the drug interactions, could have increased the effects of rivaroxaban.

Our apixaban patient (case 3) had two comorbidities that increased his risk for developing pericardial effusion: congestive heart failure and B-cell lymphoma status post five cycles of R-CHOP [32,34]. Two drugs in the R-CHOP regimen, cyclophosphamide and doxorubicin, may increase the risk of developing pericardial effusion [34]. Before starting apixaban and fifteen days after starting his first cycle of R-CHOP (while on apixaban), his echocardiogram did not show clinically relevant pericardial effusion. He developed a moderate-sized pericardial effusion 3 days after starting his fifth cycle of R-CHOP (while on apixaban). He took apixaban concomitantly with diltiazem, a p-glycoprotein inhibitor, and a moderate CYP3A4 inhibitor [35]. The manufacturer recommends reducing the dose of apixaban by 50% if a patient takes a combined p-glycoprotein inhibitor and a strong CYP3A4 inhibitor such as itraconazole, ketoconazole, or ritonavir [3]. Our patient’s apixaban therapy was held for 107 days before undergoing urgent pericardiocentesis. However, it is possible that the combined effects of many months of potentially supratherapeutic levels of apixaban, five cycles of R-CHOP, and stage IV B-cell lymphoma could have contributed to developing a hemopericardium. Table 2 summarizes key drug interactions that require dose reduction or avoidance of apixaban, dabigatran, edoxaban, and rivaroxaban.

This report underscores the importance of considering patients’ underlying medical conditions and drug interactions before initiating and during DOAC therapy. Pericardial effusion is a rare occurrence with DOAC therapy, but it can lead to fatal outcomes. The DOAC manufacturers do not include comprehensive lists of drug interactions, making it challenging for clinicians to avoid potentially harmful interactions. An alert triggered in electronic health records, providing a list of p-glycoprotein inhibitor drug interactions before prescribing and dispensing DOACs in hospitals and clinics, would help prevent serious adverse events

Limitations

Our study has limitations as the results are based on only three clinical case series in a single center therefore, it cannot be extrapolated to a wider population.

The incidence of DOAC-associated hemopericardium was less than 0.5% at our institution. Clinicians need to be vigilant about drug interactions with p-glycoprotein inhibitors and underlying conditions predisposing patients to developing pericardial effusion.

Consent

The San Joaquin General Hospital Institutional Review Board approved waiving the patient’s informed consent for this retrospective review.

Ethical declarations

This article was published after the San Joaquin General Hospital Institutional Review Board approved waiving the patients’ informed consent. The patients’ personal information was not mentioned so the case series report was published anonymously.

Disclaimer (Artificial Intelligence)

Author(s) hereby declare that NO generative AI technologies such as Large Language Models (ChatGPT, COPILOT, etc.) and text-to-image generators have been used during the writing or editing of this manuscript.

We would like to express our sincere gratitude to Dr. Syung Min Jung for invaluable support of this research.

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