Introduction
Direct oral anticoagulants (DOACs) are now preferred over warfarin for indications such as non-valvular atrial fibrillation (NVAF), venous thromboembolism (VTE), coronary artery disease (CAD) and peripheral artery disease (PAD). DOACs approved by the United States Food and Drug administration (FDA) include dabigatran (VTE treatment and prophylaxis, NVAF for stroke prevention),¹ rivaroxaban (VTE treatment and prophylaxis, NVAF for stroke prevention, prevention of major adverse cardiovascular events in CAD and PAD),² apixaban (VTE treatment and prophylaxis, NVAF for stroke prevention),³ edoxaban (VTE treatment, NVAF for stroke prevention)⁴ and betrixaban (VTE prevention).⁵ DOAC use leads to a reduction in thrombotic events at the expense of increased risk of major and minor bleeding events. Hemopericardium is one such serious adverse effect.

Incidence of Hemopericardium with DOACs
Among randomized controlled trials, only five trials have reported pericardial hemorrhage with DOACs (incidence of up to 0.05%).^6-10 Since the introduction of DOACs, post marketing experience with DOACs has noted case studies of this rare but life-threatening condition. In a systematic review, Asad et al. identified a total of 26 tamponade cases (5 with apixaban, 9 with dabigatran and 12 with rivaroxaban) and reiterated that pericardial bleeding is a life-threatening, but fortunately, rare clinical event.¹¹ In another meta-analysis by Caldeira et al. the incidence of pericardial bleeding was found to be similar with usage of vitamin K antagonists.¹² Recently, another case was of pericardial bleeding was reported with the use of rivaroxaban for NVAF in a patient on dialysis.¹³ The factors associated with elevated risk of pericardial bleeding included older age, male gender, renal dysfunction, and coagulation abnormalities. The timing of bleeding has ranged from 2 days to 6 months of initiating rivaroxaban.¹¹ Based on the Naranjo Causality Scale, the case studies have reported a "probable" association between rivaroxaban and hemorrhagic pericarditis.^14,15

Potential Mechanisms
The renal clearance of DOACs is variable, for example, 80% elimination of dabigatran,¹ 44-64% of rivaroxaban,² 27% of apixaban,³ and 50% of edoxaban.⁴ In patients with renal insufficiency, especially end-stage renal disease (ESRD), there are limited data from clinical trials evaluating the safety of DOACs. In patients with severe renal dysfunction, DOACs can accumulate, increasing the likelihood of bleeding complications.¹³ Dysfunctional platelets due to uremia pose an additional bleeding risk.

In addition, drug-drug interactions also pose an increased bleeding risk with DOACs. For example, amiodarone, diltiazem and saw palmetto (CYP3A4 and/or P-glycoprotein inhibitors) inhibit the metabolism of rivaroxaban, and apixaban and increase their serum levels.^2,3 Other combinations which have shown to enhance bleeding risk include the concomitant use of apixaban and selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors.¹⁶ Antiplatelets such as aspirin, clopidogrel, and ticagrelor when used with DOACs increase the bleeding risk due to an enhanced antithrombotic effect. Similarly, concomitant use of DOACs with NSAIDs such as ibuprofen, the first-line therapy to treat acute pericarditis, can increase the risk of bleeding into the already inflamed pericardial space.¹⁷

Management
In patients who have risk factors for increased bleeding with DOACs including demographic, co-morbidities and co-administration of medications as described above, serum DOAC level monitoring might aid in clinical decision making. Serum assays for DOAC monitoring are available but not routinely used to monitor the anticoagulant effects of DOACs. However, to manage the balance of thrombosis and bleeding, especially in high-risk patients, anti-Factor Xa (FXa) assays and direct thrombin inhibitor (DTI) assays can be utilized.¹⁸ These approaches might be useful in the off-label use of DOACs.

Pericardial bleeding must be suspected when a patient presents with a combination of symptoms including dyspnea, tachypnea, chest pain, chest discomfort relieved by sitting and leaning forward, syncope, dizziness, and weakness. These symptoms are usually accompanied by pulsus paradoxus, hypotension, elevated jugular venous pressure, and muffled heart sounds. Once pericardial bleeding is suspected, diagnostic bedside echocardiography needs to be urgently performed to confirm the diagnosis and determine the extent of hemodynamic compromise caused by pericardial hemorrhage. In patients who do not have cardiac tamponade on initial assessment, but in whom the suspicion is high, repeat echocardiography during clinical follow-up may be appropriate to detect early signs of developing cardiac tamponade in the presence of large or rapidly accumulating effusions. The decision to drain a pericardial effusion must account for the clinical assessment, echocardiographic findings, and the risk of the procedure. Cardiac tamponade with overt hemodynamic compromise requires emergent removal of pericardial fluid. Catheter pericardiocentesis is the treatment of choice in most patients where an indwelling catheter is generally left in the pericardial space until fluid return is <25 mL/day.

Early case reports of DOAC associated pericardial hemorrhage were published before availability of specific DOAC reversal agents. The place of reversal agents in the management of these patients remains unexplored. Reversal agent idarucizumab was reported to be used in a case of dabigatran associated hemopericardium.¹⁹ No cases have been reported where andexanet alfa was used. The reversal agents might have a role in the management of pericardial hemorrhage after pericardiocentesis if there is persistently high bloody output from the indwelling catheter.

Future Directions
Pericardial hemorrhage is a rare but serious adverse effect associated with DOACs. In patients at high-risk of bleeding, careful use of DOACs is recommended especially among patients with severe renal dysfunction. In the high-risk group, the use of available laboratory assays to personalize antithrombotic therapy needs to be further explored. Among patients who develop pericardial hemorrhage, the role of DOAC reversal agents needs to be further investigated.

References

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Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Cardiac Surgery, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Pericardial Disease, Pulmonary Hypertension and Venous Thromboembolism, Atherosclerotic Disease (CAD/PAD), Anticoagulation Management and Atrial Fibrillation, Anticoagulation Management and Venothromboembolism, Atrial Fibrillation/Supraventricular Arrhythmias, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Statins, Interventions and Coronary Artery Disease, Interventions and Imaging, Interventions and Vascular Medicine, Echocardiography/Ultrasound

Keywords: Fibrinolytic Agents, Warfarin, Antithrombins, Pericardial Effusion, Purinergic P2Y Receptor Antagonists, Ibuprofen, Diltiazem, Serotonin Uptake Inhibitors, Serotonin, Cytochrome P-450 CYP3A, Atrial Fibrillation, Atrial Fibrillation, Antithrombin Proteins, Aspirin, Pericardiocentesis, Cardiac Tamponade, Amiodarone, Anti-Inflammatory Agents, Non-Steroidal, Peripheral Arterial Disease, Coronary Artery Disease, Catheters, Indwelling, Catheters, Indwelling, United States Food and Drug Administration, Dizziness, Venous Thromboembolism, Heart Sounds, Norepinephrine, Dialysis, Vitamins, Blood Platelets, Follow-Up Studies, Hemorrhage, Thrombosis, Pericarditis, Uremia, Renal Insufficiency, Hypotension, Kidney Failure, Chronic, Risk Factors, Syncope, Echocardiography, Drug Interactions, Stroke, Dyspnea, Tachypnea, Kidney Diseases, Venous Pressure, Chest Pain, Vitamin K

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