Direct Oral Anticoagulants and Interstitial Lung Disease: Emerging Clues from Pharmacovigilance
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RESEARCH LETTER
Direct Oral Anticoagulants and Interstitial Lung Disease: Emerging Clues from Pharmacovigilance Emanuel Raschi1 · Michele Fusaroli1 · Igor Diemberger2 · Elisabetta Poluzzi1
© Springer Nature Switzerland AG 2020
Dear Editor, Evidence has started to accrue on the post-marketing occurrence of rare and unpredictable non-bleeding events with direct oral anticoagulants (DOACs), including liver injury and skin reactions, which has also raised debate on whether or not DOACs can be considered a homogeneous pharmacological class, especially from a safety perspective [1]. Cases of interstitial lung disease (ILD) have also been recently described, especially in Japanese subjects [2, 3], although no observational studies have comprehensively investigated post-marketing evidence of pulmonary toxicity with DOACs. Therefore, we performed a disproportionality analysis in the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) to investigate the reporting of ILD with DOACs over the period 2004–2019. The analyses were implemented on a de-duplicated dataset, by calculating the reporting odds ratio (ROR), deemed significant by the lower limit of the 95% confidence interval (CI) > 1 with at least three cases. ILD was defined by the relevant preferred term in the Medical Dictionary for Regulatory Activity (MedDRA®) terminology. Amiodarone, known to be associated with ILD, was used as a positive control, and warfarin was also analyzed as a reference. The main analysis was performed without pre-specified restriction criteria, i.e., considering all reports and comparing DOACs versus other drugs recorded in FAERS.
* Emanuel Raschi [email protected] 1
Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum - University of Bologna, Via Irnerio 48, 40126 Bologna, Italy
Cardiology Unit, Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum - University of Bologna, Bologna, Italy
2
Sensitivity analyses were planned a priori to test the robustness of findings and assess the impact of potential confounders. Thus, we excluded reports recording (1) bleeding (apart from reports with co-reporting of ILD) using the Standardized MedDRA Query (SMQ) “Haemorrhage”, since the expected high reporting of bleeding with DOACs can mask ILD (the so-called event-related competition bias); (2) amiodarone, expected to be frequently co‐prescribed with DOACs in patients with atrial fibrillation (the so-called co-prescription bias); (3) drugs known to be strongly associated with ILD [4], which may act as a confounding factor and also mask identification of ILD with DOACs (the socalled drug-related competition bias), including anticancer and anti-rheumatic drugs; (4) antineoplastic and immunomodulating drugs (based on the Anatomical Therapeutic Chemical Classification System [ATC] code L), potentially acting as confounders since oncology patients receiving DOACs may develop ILD due to anticancer therapy or as neoplasia-related sequela (e.g., radiotherap
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