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Impact of P-glycoprotein and/or CYP3A4-interacting drugs on effectiveness and safety of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation : a meta-analysis

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Abstract
Aims P-glycoprotein (P-gp) and CYP3A4-interacting drugs influence plasma levels of non-vitamin K antagonist oral anticoagulants (NOACs). However, the clinical relevance is questioned. Therefore, the impact of pharmacokinetically-interacting drugs on the effectiveness and safety of NOACs in patients with atrial fibrillation (AF) was investigated. Methods A meta-analysis was performed based on randomized controlled trials and observational studies retrieved from Pubmed and Embase that investigated the impact of concomitantly used P-gp/CYP3A4-interacting drugs on the risk-benefit profile of NOACs in AF patients. Results Fifteen studies were included, investigating 21 711 and 306 421 NOAC-treated AF patients with and without P-gp/CYP3A4 inhibitor use respectively, while only 1 study included P-gp/CYP3A4 inducers. In NOAC-treated AF patients, concomitant use of P-gp/CYP3A4 inhibitors was associated with significantly higher major bleeding (relative risk [RR] 1.10, 95% confidence interval [CI; 1.01-1.19]) and all-cause mortality risks (RR 1.14, 95%CI [1.05-1.23]) compared to not using P-gp/CYP3A4 inhibitors, while the risks of stroke/systemic embolism (RR 0.88, 95%CI [0.77-1.01]), intracranial bleeding (RR 0.89, 95%CI [0.68-1.15]) and gastrointestinal bleeding (RR 1.09, 95%CI [0.91-1.30]) were not significantly different. Concomitant use of amiodarone with NOACs was associated with lower thromboembolic (RR 0.75, 95%CI [0.61-0.92]), similar major bleeding (RR 0.92, 95%CI [0.80-1.07]) but higher mortality risks (RR 1.21, 95%CI [1.05-1.39]). Coadministration of verapamil or diltiazem was associated with higher major bleeding risks (RR 1.64, 95%CI [1.31-2.06]), but comparable thromboembolic (RR 1.10, 95%CI [0.75-1.61]) and mortality risks (RR 1.01, 95%CI [0.77-1.33]). Conclusion Given the higher bleeding and mortality risks in NOAC-treated AF patients concomitantly using P-gp/CYP3A4 inhibitors, close monitoring is warranted.
Keywords
CARDIOVASCULAR OUTCOMES, CONCISE GUIDE, RIVAROXABAN, WARFARIN, PHARMACOKINETICS, AMIODARONE, PREVENTION, DABIGATRAN, APIXABAN, STROKE, amiodarone, atrial fibrillation, calcium channel blocker, drug, interaction, meta-analysis, NOAC, P-glycoprotein

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MLA
Grymonprez, Maxim, et al. “Impact of P-Glycoprotein and/or CYP3A4-Interacting Drugs on Effectiveness and Safety of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation : A Meta-Analysis.” BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, vol. 88, no. 7, 2022, pp. 3039–51, doi:10.1111/bcp.15265.
APA
Grymonprez, M., Vanspranghe, K., Capiau, A., Boussery, K., Steurbaut, S., & Lahousse, L. (2022). Impact of P-glycoprotein and/or CYP3A4-interacting drugs on effectiveness and safety of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation : a meta-analysis. BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 88(7), 3039–3051. https://doi.org/10.1111/bcp.15265
Chicago author-date
Grymonprez, Maxim, Kevin Vanspranghe, Andreas Capiau, Koen Boussery, Stephane Steurbaut, and Lies Lahousse. 2022. “Impact of P-Glycoprotein and/or CYP3A4-Interacting Drugs on Effectiveness and Safety of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation : A Meta-Analysis.” BRITISH JOURNAL OF CLINICAL PHARMACOLOGY 88 (7): 3039–51. https://doi.org/10.1111/bcp.15265.
Chicago author-date (all authors)
Grymonprez, Maxim, Kevin Vanspranghe, Andreas Capiau, Koen Boussery, Stephane Steurbaut, and Lies Lahousse. 2022. “Impact of P-Glycoprotein and/or CYP3A4-Interacting Drugs on Effectiveness and Safety of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation : A Meta-Analysis.” BRITISH JOURNAL OF CLINICAL PHARMACOLOGY 88 (7): 3039–3051. doi:10.1111/bcp.15265.
Vancouver
1.
Grymonprez M, Vanspranghe K, Capiau A, Boussery K, Steurbaut S, Lahousse L. Impact of P-glycoprotein and/or CYP3A4-interacting drugs on effectiveness and safety of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation : a meta-analysis. BRITISH JOURNAL OF CLINICAL PHARMACOLOGY. 2022;88(7):3039–51.
IEEE
[1]
M. Grymonprez, K. Vanspranghe, A. Capiau, K. Boussery, S. Steurbaut, and L. Lahousse, “Impact of P-glycoprotein and/or CYP3A4-interacting drugs on effectiveness and safety of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation : a meta-analysis,” BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, vol. 88, no. 7, pp. 3039–3051, 2022.
@article{8767489,
  abstract     = {{Aims P-glycoprotein (P-gp) and CYP3A4-interacting drugs influence plasma levels of non-vitamin K antagonist oral anticoagulants (NOACs). However, the clinical relevance is questioned. Therefore, the impact of pharmacokinetically-interacting drugs on the effectiveness and safety of NOACs in patients with atrial fibrillation (AF) was investigated. Methods A meta-analysis was performed based on randomized controlled trials and observational studies retrieved from Pubmed and Embase that investigated the impact of concomitantly used P-gp/CYP3A4-interacting drugs on the risk-benefit profile of NOACs in AF patients. Results Fifteen studies were included, investigating 21 711 and 306 421 NOAC-treated AF patients with and without P-gp/CYP3A4 inhibitor use respectively, while only 1 study included P-gp/CYP3A4 inducers. In NOAC-treated AF patients, concomitant use of P-gp/CYP3A4 inhibitors was associated with significantly higher major bleeding (relative risk [RR] 1.10, 95% confidence interval [CI; 1.01-1.19]) and all-cause mortality risks (RR 1.14, 95%CI [1.05-1.23]) compared to not using P-gp/CYP3A4 inhibitors, while the risks of stroke/systemic embolism (RR 0.88, 95%CI [0.77-1.01]), intracranial bleeding (RR 0.89, 95%CI [0.68-1.15]) and gastrointestinal bleeding (RR 1.09, 95%CI [0.91-1.30]) were not significantly different. Concomitant use of amiodarone with NOACs was associated with lower thromboembolic (RR 0.75, 95%CI [0.61-0.92]), similar major bleeding (RR 0.92, 95%CI [0.80-1.07]) but higher mortality risks (RR 1.21, 95%CI [1.05-1.39]). Coadministration of verapamil or diltiazem was associated with higher major bleeding risks (RR 1.64, 95%CI [1.31-2.06]), but comparable thromboembolic (RR 1.10, 95%CI [0.75-1.61]) and mortality risks (RR 1.01, 95%CI [0.77-1.33]). Conclusion Given the higher bleeding and mortality risks in NOAC-treated AF patients concomitantly using P-gp/CYP3A4 inhibitors, close monitoring is warranted.}},
  author       = {{Grymonprez, Maxim and Vanspranghe, Kevin and Capiau, Andreas and Boussery, Koen and Steurbaut, Stephane and Lahousse, Lies}},
  issn         = {{0306-5251}},
  journal      = {{BRITISH JOURNAL OF CLINICAL PHARMACOLOGY}},
  keywords     = {{CARDIOVASCULAR OUTCOMES,CONCISE GUIDE,RIVAROXABAN,WARFARIN,PHARMACOKINETICS,AMIODARONE,PREVENTION,DABIGATRAN,APIXABAN,STROKE,amiodarone,atrial fibrillation,calcium channel blocker,drug,interaction,meta-analysis,NOAC,P-glycoprotein}},
  language     = {{eng}},
  number       = {{7}},
  pages        = {{3039--3051}},
  title        = {{Impact of P-glycoprotein and/or CYP3A4-interacting drugs on effectiveness and safety of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation : a meta-analysis}},
  url          = {{http://dx.doi.org/10.1111/bcp.15265}},
  volume       = {{88}},
  year         = {{2022}},
}

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