Direct Oral Anticoagulants and Interstitial Lung Disease: Emerging Clues from Pharmacovigilance

Raschi, Emanuel; Fusaroli, Michele; Diemberger, Igor; Poluzzi, Elisabetta

doi:10.1007/s40264-020-00990-9

Cited by 10 publications

(21 citation statements)

References 9 publications

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“… 8 Reports from a non-Japanese population confirmed that apixaban and edoxaban were associated with a higher risk of ILD, whereas dabigatran and rivaroxaban were not associated with a higher risk. 8 …”

Section: Discussionmentioning

confidence: 94%

“…A total of 962 reports of ILD from 24 720 patients who received NOACs were identified, with 60% of patients being from Asia, 34% in female patients, and 87% in patients older than 65 years. 8 Apixaban, edoxaban, and rivaroxaban consistently emerged with higher-than-expected reporting of ILD, whereas dabigatran did not. 8 Reports from a non-Japanese population confirmed that apixaban and edoxaban were associated with a higher risk of ILD, whereas dabigatran and rivaroxaban were not associated with a higher risk.…”

Section: Discussionmentioning

confidence: 94%

“…Raschi et al 8 summarized a hypothesis-generating study that found an association between ILD and NOACs, especially FXa inhibitors, with disproportionality signals between specific oral anticoagulants. The authors used the US Food and Drug Administration Adverse Event Reporting System to investigate the reporting of ILD associated with NOACs from 2004 to 2019.…”

Section: Discussionmentioning

confidence: 99%

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Development of Interstitial Lung Disease Among Patients With Atrial Fibrillation Receiving Oral Anticoagulants in Taiwan

et al. 2022

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ImportanceThere are emerging concerns from case reports and pharmacovigilance analyses of a possible risk of interstitial lung disease (ILD) associated with the use of factor Xa (FXa) inhibitors.ObjectiveTo evaluate the risk of incident ILD associated with the use of oral anticoagulants (OACs) in patients with nonvalvular atrial fibrillation (NVAF).Design, Setting, and ParticipantsThis nationwide retrospective cohort study used data from the Taiwan National Health Insurance Research Database. Patients with NVAF without preexisting lung disease who received OACs from June 1, 2012, to December 31, 2017, were included. Propensity score stabilized weighting (PSSW) was used to balance covariates across the medication groups (FXa inhibitors, dabigatran, and warfarin, with warfarin as the reference). Patients were followed up from the drug index date until the onset of ILD, death, or end of the study (December 31, 2019), whichever occurred first. Data were analyzed from September 11, 2021, to August 3, 2022.ExposuresPatients with NVAF were treated with FXa inhibitors, dabigatran, or warfarin.Main Outcomes and MeasuresNew-onset idiopathic ILD.ResultsAmong the 106 044 patients (mean [SD] age, 73.4 [11.9] years; 59 995 men [56.6%]) included in the study, 64 555 (60.9%) received FXa inhibitors (apixban [n = 15 386], edoxaban [n = 12 413], and rivaroxaban [n = 36 756]), 22 501 (21.2%) received dabigatran, and 18 988 (17.9%) received warfarin at baseline. The FXa inhibitors were associated with a higher risk of incident ILD (0.29 vs 0.17 per 100 patient-years; hazard ratio, 1.54 [95% CI, 1.22-1.94]; P &lt; .001), whereas dabigatran was associated with a nonsignificant difference in risk of incident ILD compared with warfarin (reference) after PSSW. The higher risk of incident ILD for FXa inhibitors vs warfarin was consistent with several high-risk subgroups.Conclusions and RelevanceResults of this study suggest that FXa inhibitors were associated with lung injury among patients with NVAF who were treated with OACs. Physicians should be vigilant in monitoring for any potential adverse lung outcomes associated with the use of these drugs.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

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Development of Interstitial Lung Disease Among Patients With Atrial Fibrillation Receiving Oral Anticoagulants in Taiwan

et al. 2022

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“…Finally, it should be noted that the correction for multiple comparisons ( Fadini et al, 2018 ), is not commonly adopted in signal detection because it is too conservative and therefore not adequate in a context where a more speculative detection of adverse events using early post-marketing data is required. Therefore, we cannot rule out that associations thus rejected as false alarms could instead be considered of interest in targeted studies, which may evaluate them using other tools to support the existence of causation, such as the Bradford-Hill criteria ( Raschi et al, 2020b ). One example is the association of hydroxychloroquine with psychiatric conditions such as suicidal and self-injurious behaviors and hallucinations with hydroxychloroquine.…”

Section: Discussionmentioning

confidence: 99%

Development of a Network-Based Signal Detection Tool: The COVID-19 Adversome in the FDA Adverse Event Reporting System

et al. 2021

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Introduction: The analysis of pharmacovigilance databases is crucial for the safety profiling of new and repurposed drugs, especially in the COVID-19 era. Traditional pharmacovigilance analyses–based on disproportionality approaches–cannot usually account for the complexity of spontaneous reports often with multiple concomitant drugs and events. We propose a network-based approach on co-reported events to help assessing disproportionalities and to effectively and timely identify disease-, comorbidity- and drug-related syndromes, especially in a rapidly changing low-resources environment such as that of COVID-19.Materials and Methods: Reports on medications administered for COVID-19 were extracted from the FDA Adverse Event Reporting System quarterly data (January–September 2020) and queried for disproportionalities (Reporting Odds Ratio corrected for multiple comparisons). A network (the Adversome) was estimated considering events as nodes and conditional co-reporting as links. Communities of significantly co-reported events were identified. All data and scripts employed are available in a public repository.Results: Among the 7,082 COVID-19 reports extracted, the seven most frequently suspected drugs (remdesivir, hydroxychloroquine, azithromycin, tocilizumab, lopinavir/ritonavir, sarilumab, and ethanol) have shown disproportionalities with 54 events. Of interest, myasthenia gravis with hydroxychloroquine, and cerebrovascular vein thrombosis with azithromycin. Automatic clustering identified 13 communities, including a methanol-related neurotoxicity associated with alcohol-based hand-sanitizers and a long QT/hepatotoxicity cluster associated with azithromycin, hydroxychloroquine and lopinavir-ritonavir interactions.Conclusion: Findings from the Adversome detect plausible new signals and iatrogenic syndromes. Our network approach complements traditional pharmacovigilance analyses, and may represent a more effective signal detection technique to guide clinical recommendations by regulators and specific follow-up confirmatory studies.

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“…We represent the leadership of the largest randomized clinical trials and ongoing registries with edoxaban and wish to comment on the research letter by Raschi et al [ 1 ] that summarized a hypothesis-generating study linking direct oral anticoagulants (DOACs) to interstitial lung disease (ILD), especially with factor-Xa inhibitors, with disproportionality signals between specific anticoagulants.…”

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confidence: 99%

Comment on: “Direct Oral Anticoagulants and Interstitial Lung Disease: Emerging Clues from Pharmacovigilance”

2021

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Direct Oral Anticoagulants and Interstitial Lung Disease: Emerging Clues from Pharmacovigilance

Cited by 10 publications

References 9 publications

Development of Interstitial Lung Disease Among Patients With Atrial Fibrillation Receiving Oral Anticoagulants in Taiwan

Development of Interstitial Lung Disease Among Patients With Atrial Fibrillation Receiving Oral Anticoagulants in Taiwan

Development of a Network-Based Signal Detection Tool: The COVID-19 Adversome in the FDA Adverse Event Reporting System

Comment on: “Direct Oral Anticoagulants and Interstitial Lung Disease: Emerging Clues from Pharmacovigilance”

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