Impact of P-glycoprotein and CYP3A4-interacting drugs on clinical outcomes in patients with atrial fibrillation using non-vitamin K antagonist oral anticoagulants : a nationwide cohort study
© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology..
AIMS: The clinical relevance of common pharmacokinetic interactions with non-vitamin K antagonist oral anticoagulants (NOACs) often remains unclear. Therefore, the impact of P-glycoprotein (P-gp) and CYP3A4 inhibitors and inducers on clinical outcomes in NOAC-treated patients with atrial fibrillation (AF) was investigated.
METHODS AND RESULTS: AF patients were included between 2013 and 2019 using Belgian nationwide data. Concomitant use of P-gp/CYP3A4-interacting drugs at the time of NOAC initiation was identified. Among 193 072 NOAC-treated AF patients, 46 194 (23.9%) and 2903 (1.5%) subjects concomitantly used a P-gp/CYP3A4 inhibitor or inducer, respectively. After multivariable adjustment, concomitant use of P-gp/CYP3A4 inhibitors was associated with significantly higher major bleeding [adjusted hazard ratio (aHR) 1.24, 95% confidence interval (CI) (1.18-1.30)] and all-cause mortality risks [aHR 1.07, 95% CI (1.02-1.11)], but not with thromboembolism in NOAC-treated AF patients. A significantly increased risk of major bleeding was observed with amiodarone [aHR 1.27, 95% CI (1.21-1.34)], diltiazem [aHR 1.28, 95% CI (1.13-1.46)], verapamil [aHR 1.36, 95% CI (1.03-1.80)], ticagrelor [aHR 1.50, 95% CI (1.20-1.87)], and clarithromycin [aHR 1.55, 95% CI (1.14-2.11)]; and in edoxaban [aHR 1.24, 95% CI (1.06-1.45)], rivaroxaban [aHR 1.25, 95% CI (1.16-1.34)], and apixaban users [aHR 1.27, 95% CI (1.16-1.39)], but not in dabigatran users [aHR 1.07, 95% CI (0.94-1.23)]. Concomitant use of P-gp/CYP3A4 inducers (e.g. antiepileptic drugs like levetiracetam) was associated with a significantly higher stroke risk [aHR 1.31, 95% CI (1.03-1.68)], but not with bleeding or all-cause mortality.
CONCLUSION: Concomitant use of P-gp/CYP3A4 inhibitors was associated with higher bleeding and all-cause mortality risks in NOAC users, whereas the use of P-gp/CYP3A4 inducers was associated with higher stroke risks.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:9 |
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| Enthalten in: |
European heart journal. Cardiovascular pharmacotherapy - 9(2023), 8 vom: 14. Dez., Seite 722-730 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Grymonprez, Maxim [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 20.12.2023 Date Revised 20.12.2023 published: Print Citation Status MEDLINE |
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| doi: |
10.1093/ehjcvp/pvad070 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM362851670 |
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| 100 | 1 | |a Grymonprez, Maxim |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Impact of P-glycoprotein and CYP3A4-interacting drugs on clinical outcomes in patients with atrial fibrillation using non-vitamin K antagonist oral anticoagulants |b a nationwide cohort study |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Completed 20.12.2023 | ||
| 500 | |a Date Revised 20.12.2023 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. | ||
| 520 | |a AIMS: The clinical relevance of common pharmacokinetic interactions with non-vitamin K antagonist oral anticoagulants (NOACs) often remains unclear. Therefore, the impact of P-glycoprotein (P-gp) and CYP3A4 inhibitors and inducers on clinical outcomes in NOAC-treated patients with atrial fibrillation (AF) was investigated | ||
| 520 | |a METHODS AND RESULTS: AF patients were included between 2013 and 2019 using Belgian nationwide data. Concomitant use of P-gp/CYP3A4-interacting drugs at the time of NOAC initiation was identified. Among 193 072 NOAC-treated AF patients, 46 194 (23.9%) and 2903 (1.5%) subjects concomitantly used a P-gp/CYP3A4 inhibitor or inducer, respectively. After multivariable adjustment, concomitant use of P-gp/CYP3A4 inhibitors was associated with significantly higher major bleeding [adjusted hazard ratio (aHR) 1.24, 95% confidence interval (CI) (1.18-1.30)] and all-cause mortality risks [aHR 1.07, 95% CI (1.02-1.11)], but not with thromboembolism in NOAC-treated AF patients. A significantly increased risk of major bleeding was observed with amiodarone [aHR 1.27, 95% CI (1.21-1.34)], diltiazem [aHR 1.28, 95% CI (1.13-1.46)], verapamil [aHR 1.36, 95% CI (1.03-1.80)], ticagrelor [aHR 1.50, 95% CI (1.20-1.87)], and clarithromycin [aHR 1.55, 95% CI (1.14-2.11)]; and in edoxaban [aHR 1.24, 95% CI (1.06-1.45)], rivaroxaban [aHR 1.25, 95% CI (1.16-1.34)], and apixaban users [aHR 1.27, 95% CI (1.16-1.39)], but not in dabigatran users [aHR 1.07, 95% CI (0.94-1.23)]. Concomitant use of P-gp/CYP3A4 inducers (e.g. antiepileptic drugs like levetiracetam) was associated with a significantly higher stroke risk [aHR 1.31, 95% CI (1.03-1.68)], but not with bleeding or all-cause mortality | ||
| 520 | |a CONCLUSION: Concomitant use of P-gp/CYP3A4 inhibitors was associated with higher bleeding and all-cause mortality risks in NOAC users, whereas the use of P-gp/CYP3A4 inducers was associated with higher stroke risks | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Atrial fibrillation | |
| 650 | 4 | |a Bleeding | |
| 650 | 4 | |a Drug interaction | |
| 650 | 4 | |a Mortality | |
| 650 | 4 | |a NOAC | |
| 650 | 4 | |a Thromboembolism | |
| 650 | 7 | |a Anticoagulants |2 NLM | |
| 650 | 7 | |a ATP Binding Cassette Transporter, Subfamily B, Member 1 |2 NLM | |
| 650 | 7 | |a CYP3A4 protein, human |2 NLM | |
| 650 | 7 | |a EC 1.14.14.55 |2 NLM | |
| 650 | 7 | |a Cytochrome P-450 CYP3A |2 NLM | |
| 650 | 7 | |a EC 1.14.14.1 |2 NLM | |
| 650 | 7 | |a Cytochrome P-450 CYP3A Inducers |2 NLM | |
| 650 | 7 | |a Cytochrome P-450 CYP3A Inhibitors |2 NLM | |
| 700 | 1 | |a Carnoy, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Capiau, Andreas |e verfasserin |4 aut | |
| 700 | 1 | |a Boussery, Koen |e verfasserin |4 aut | |
| 700 | 1 | |a Mehuys, Els |e verfasserin |4 aut | |
| 700 | 1 | |a De Backer, Tine L |e verfasserin |4 aut | |
| 700 | 1 | |a Steurbaut, Stephane |e verfasserin |4 aut | |
| 700 | 1 | |a Lahousse, Lies |e verfasserin |4 aut | |
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