Diffuse Alveolar Hemorrhage Secondary to Direct Oral Anticoagulants: A Systematic Review of Reported Cases

Introduction:

Direct oral anticoagulants (DOACs), also known as non-vitamin K oral anticoagulants, include rivaroxaban, dabigatran, apixiban, edoxaban, and betrixaban. Guidelines have recently identified DOACs as the first line treatment in venous thromboembolism and nonvalvular atrial fibrillation. As the use of these anticoagulants has gradually increased in last few years, the reports of bleeding-related adverse drug events with these agents has increased. There are very few data related to diffuse alveolar hemorrhage (DAH) with DOACs, a dreaded complication of any anticoagulant.

Objective:

To perform a systematic review of all reported cases of DAH secondary to DOAC use.

Methods:

Using several search terms, we reviewed all cases of DAH associated with DOACs which were published and indexed in English language in PubMed and EMBASE in the last 10 years. The bibliography of each relevant article was searched for additional related reports. Statistical analysis was performed using Statistical Packages for the Social Science (SPSS).

Results:

A total of 34 cases were included in the study. Mean age was 69±15 years; 68% were male, 32% were female. Rivaroxaban, dabigatran, apixaban, and edoxaban were used in 41%, 35%, 21%, 3% of patients respectively. Atrial fibrillation was the commonest indication for DOAC use, 68%. Hemoptysis was the commonest presenting symptom, 74%. DAH was diagnosed with Computed Tomography (CT), Bronchoalveolar Lavage (BAL), and both in 68%, 56%, and 35% respectively. A total of 18 (53%) cases required mechanical ventilation. There was a total of 7 (21%) deaths, while 20 (59%) survived.

Conclusion:

Despite reports of lower risk of major bleeding compared to other anticoagulants, DAH is still a possibility with DOAC use. DOACs' absorption and elimination relies largely on P-glycoprotein (P-gp) efflux transporters, coadministration of P-gp inhibitors such as Amiodarone, a common antiarrhythmic used in atrial fibrillation in conjunction with anticoagulation, may result in disturbance of DOAC's concentrations in the blood, increasing the risk of potential side effects. Autoimmune diseases can lead to DAH independently. Owing to the diseased lung tissue in patients with autoimmune disease, the use of DOAC's may enhance the already present risk of DAH. Renal function plays a role in excretion of DOAC's, AKI may cause accumulation of DOAC's in the body leading to major side effects. Newer cases reported the use of idracuzimab; a newly FDA-approved drug for dabigatran reversal. In conclusion; caution should be taken with the increasing use of DOAC's in management of complex care patients requiring anticoagulation, prompt diagnosis and management is key for survival and prevention of complications, and new reversal agents may play a future role in the management of such complications.

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