Occurrence of intraocular hemorrhages under monotherapy or combination therapy of antiplatelets and anticoagulants using the Japanese Adverse Drug Event Report database

Journal of Pharmacy & Pharmaceutical Sciences · 6 authors, 2 centres

AI SUMMARY

FIDELITY 100%

POPULATIONPatients in the JADER database (688,467 patients after data cleaning) who received oral antiplatelets or anticoagulants between April 2004 and March 2022

INTERVENTIONMonotherapy or combination therapy with antiplatelets (aspirin, clopidogrel, ticagrelor, ticlopidine, prasugrel) and anticoagulants (warfarin, apixaban, dabigatran, edoxaban, rivaroxaban)

COMPARISONAll other drugs in the JADER database (for signal detection); for factor analysis, presence vs. absence of hypertension, diabetes mellitus, and use of intravitreal injections/posterior sub-Tenon triamcinolone acetonide injections

This summary was generated by AI from a single paper. It has not been reviewed by a clinician and is not clinical advice. Verify against the source before acting on it.

AGENT 01 · STRUCTURED SUMMARY

TRACE TO SOURCE

“

TL;DR

This pharmacovigilance study using the JADER database found that monotherapy with aspirin, clopidogrel, warfarin, apixaban, and rivaroxaban, as well as combination therapies such as dual antiplatelet therapy, are associated with increased signals for intraocular hemorrhages. The risk was particularly notable in younger patients on aspirin and elderly patients on warfarin, with most hemorrhages occurring within the first 90 days of treatment. These findings highlight the need for careful monitoring of intraocular bleeding risk when prescribing antiplatelets and anticoagulants.

Full summary

4,234 CHARS

**Background:** Antiplatelets (APs) and anticoagulants (ACs) are widely used to prevent thrombotic events, but they increase bleeding risk. Intraocular hemorrhages (IOHs), though rare, can cause visual impairment and reduce quality of life. Previous meta-analyses have reported conflicting results regarding IOH risk with different anticoagulants, and few studies have distinguished between monotherapy and combination therapy. This study aimed to investigate IOH signals using the Japanese Adverse Drug Event Report (JADER) database, a large pharmacovigilance resource.

**Methods:** Data from April 2004 to March 2022 were obtained from the JADER database, which includes spontaneous adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan. After excluding patients with missing or duplicated data, 688,467 patients were included. IOHs were defined using 17 preferred terms from the Medical Dictionary for Regulatory Activities (MedDRA 25.0 J) under the high level term 'Ocular haemorrhagic disorders'. Ten oral APs and ACs approved in Japan were analyzed: aspirin, clopidogrel, ticagrelor, ticlopidine, prasugrel, warfarin, apixaban, dabigatran, edoxaban, and rivaroxaban. Signal detection was performed using reporting odds ratios (ROR) and information components (IC) with 95% confidence intervals (CIs). A positive signal was defined when the lower limit of the 95% CI of ROR exceeded 1 and that of IC exceeded 0. Multivariable logistic regression was used to assess factors affecting IOH occurrence, including hypertension, diabetes mellitus, and use of intravitreal injections (IVI) or posterior sub-Tenon triamcinolone acetonide injections (PSTAI). Time-to-onset analysis was performed for drugs with more than 10 IOH reports.

**Key Results:** Under monotherapy, IOH signals were detected for aspirin (ROR 1.40, 95% CI 1.08–1.80; IC 0.45, 95% CI 0.08–0.83), clopidogrel (ROR 3.20, 95% CI 2.32–4.43; IC 1.57, 95% CI 1.10–2.04), warfarin (ROR 1.60, 95% CI 1.17–2.19; IC 0.64, 95% CI 0.19–1.10), apixaban (ROR 4.79, 95% CI 3.73–6.16; IC 2.12, 95% CI 1.76–2.49), and rivaroxaban (ROR 8.84, 95% CI 7.21–10.85; IC 2.94, 95% CI 2.64–3.24). Under combination therapy, aspirin showed IOH signals with P2Y12 inhibitors (ROR 3.55, 95% CI 2.74–4.60; IC 1.72, 95% CI 1.34–2.10), warfarin (ROR 3.12, 95% CI 2.10–4.63; IC 1.51, 95% CI 0.93–2.08), and DOACs (ROR 3.64, 95% CI 2.15–6.18; IC 1.61, 95% CI 0.86–2.37). P2Y12 inhibitors showed IOH signals with warfarin (ROR 3.96, 95% CI 2.24–7.00; IC 1.67, 95% CI 0.87–2.48) but not with DOACs. Triple therapy with DAPT and warfarin showed a signal (ROR 6.16, 95% CI 3.29–11.52; IC 2.05, 95% CI 1.17–2.93), but not with DOACs. Age subgroup analysis revealed that aspirin showed a signal in younger patients (ROR 2.14, 95% CI 1.47–3.10; IC 1.01, 95% CI 0.47–1.55) but not in elderly, while warfarin showed a signal only in elderly (ROR 1.52, 95% CI 1.04–2.22; IC 0.56, 95% CI 0.01–1.11). In combination therapy, signals were predominantly observed in elderly patients. Multivariable analysis showed that hypertension and diabetes mellitus were not significant factors for IOH in most drugs, except prasugrel where diabetes mellitus increased risk (OR 6.37, 95% CI 1.71–23.70, p=0.006). IVI and PSTAI significantly increased IOH frequency in several drugs (e.g., aspirin: OR 36.7, 95% CI 19.40–69.40, p<0.001). Time-to-onset analysis showed median onset times of 72.5 days for aspirin, 79.5 days for clopidogrel, 29.0 days for warfarin, 174.0 days for apixaban, and 90.0 days for rivaroxaban, with most cases occurring within the first year.

**Clinical Implications:** This study provides evidence that both monotherapy and combination therapy with certain APs and ACs are associated with increased signals for IOHs. Clinicians should be aware of the potential for IOH, especially in younger patients on aspirin, elderly patients on warfarin, and during the first 90 days of therapy. The findings underscore the importance of monitoring for ocular bleeding in patients receiving these medications, regardless of hypertension or diabetes status. The results may help internists, ophthalmologists, and pharmacists in risk assessment and management of IOH.

PICO

PPOPULATION

Patients in the JADER database (688,467 patients after data cleaning) who received oral antiplatelets or anticoagulants between April 2004 and March 2022

IINTERVENTION

Monotherapy or combination therapy with antiplatelets (aspirin, clopidogrel, ticagrelor, ticlopidine, prasugrel) and anticoagulants (warfarin, apixaban, dabigatran, edoxaban, rivaroxaban)

OOUTCOME

Intraocular hemorrhages (defined by 17 MedDRA preferred terms under the high level term 'Ocular haemorrhagic disorders')

STUDY TYPE

other

SPECIALTY

ophthalmology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

100% · A

ORIGINAL PAPER

PMC10130193

Occurrence of intraocular hemorrhages under monotherapy or combination therapy of antiplatelets and anticoagulants using the Japanese Adverse Drug Event Report database

Journal of Pharmacy & Pharmaceutical Sciences

READ THE FULL PAPER

JUMP TO SECTION

ABSTRACT

Abstract Purpose: An intraocular hemorrhage is an adverse event that can lead to visual acuity impairment. Antithrombotic therapy with antiplatelet agents and anticoagulants may increase intraocular hemorrhage. However, since their frequency is low, studies on the risk of intraocular hemorrhage with these drugs, especially under combination therapy, are limited. This study aimed to investigate the occurrence of intraocular hemorrhages under monotherapy and combination therapy with antiplatelets and anticoagulants by analyzing a large pharmacovigilance database. Methods: Intraocular hemorrhage signals with oral antiplatelets and anticoagulants were evaluated by calculating reporting odds ratios and information components using the Japan Adverse Drug Reactions Report database from April 2004 to March 2022. In addition, differences in signals between younger and elderly patients, affecting factors, and time-to-onset from initial antiplatelet and anticoagulant treatments were analyzed. Results: Aspirin, clopidogrel, warfarin, apixaban, and rivaroxaban, but not ticagrelor, ticlopidine, prasugrel, dabigatran, and edoxaban showed intraocular hemorrhage signals under monotherapy. In combination therapy, dual therapy (aspirin + P2Y 12 inhibitors, warfarin, direct oral anticoagulants, and P2Y 12 inhibitors + warfarin) and triple therapy (aspirin + P2Y 12 inhibitors + warfarin) resulted in intraocular hemorrhage signals. Intraocular hemorrhage signals were observed in younger patients receiving monotherapy with aspirin and in elderly patients receiving monotherapy and combination therapy with warfarin. Affecting factors were diabetes mellitus in patients with prasugrel, use of medications for intravitreal injections, and posterior sub-Tenon injections with some antiplatelets and anticoagulants. The median period of intraocular hemorrhage occurrence after starting monotherapy with aspirin, clopidogrel, warfarin, or rivaroxaban was within 90 days. Conclusion: In addition to monotherapy with several antiplatelets and anticoagulants, combination therapy using aspirin, P2Y 12 inhibitors, and warfarin has the potential risk of intraocular hemorrhage. Particular attention should be paid to the occurrence of intraocular hemorrhages in younger patients taking aspirin, in elderly patients taking warfarin, and within the first 90 days of antiplatelet and anticoagulant use. Keywords: intraocular hemorrhages, antiplatelets, anticoagulants, monotherapy, combination therapy

CITATION EXPORT

Junko Tanaka, Takenao Koseki, Kohsuke Sekido et al.. Occurrence of intraocular hemorrhages under monotherapy or combination therapy of antiplatelets and anticoagulants using the Japanese Adverse Drug Event Report database. Journal of Pharmacy & Pharmaceutical Sciences. (2023). https://doi.org/10.3389/jpps.2023.11263

AUTHORS

6 · 2 CENTRES

Junko Tanaka, Takenao Koseki, Kohsuke Sekido, Masashi Kimata, Yasuki Ito, Shigeki Yamada

1 Department of Pharmacotherapeutics and Informatics, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
2 Department of Ophthalmology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan