What is the clinical evidence from this study?

Study design: Case-Control. Population: Atrial fibrillation and venous thromboembolism (n=89284). Intervention: P-gp/CYP3A4 inhibitors vs. No use of interacting drugs. Primary outcome: Serious bleeding events (OR 1.32, 95% CI 1.07-1.62, p=0.008).

What does this research mean for the field?

Concomitant prescription of direct oral anticoagulants with P-gp/CYP3A4 inhibitors is associated with an increased risk of serious bleeding, while concurrent use with certain antiepileptic drugs increases the risk of stroke or systemic embolism. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

July 19, 2021Open Access

Association Between Use of Pharmacokinetic‐Interacting Drugs and Effectiveness and Safety of Direct Acting Oral Anticoagulants: Nested Case‐Control Study

Resultado clave

Concomitant prescription of direct oral anticoagulants with P-gp/CYP3A4 inhibitors was associated with an increased risk of serious bleeding (adjusted OR 1.32).

Diseño del estudio

Tipo

Case-Control (n=89,284)

PICO estructurado

Does concomitant use of P-gp/CYP3A4 interacting drugs increase the risk of bleeding or stroke/systemic emboli in patients taking direct oral anticoagulants for atrial fibrillation or venous thromboembolism?

Población

89,284 adult patients (>18 years) with atrial fibrillation (n=79,302) or recent deep vein thrombosis/pulmonary embolism (n=9,982) who were new users of a direct oral anticoagulant (apixaban, rivaroxaban, or dabigatran). 52.0% women. Based in Israel (Clalit Health Services).

Intervención

Concomitant use of P-gp/CYP3A4 inhibitors (e.g., verapamil, amiodarone) or P-gp/CYP3A4 inducers (e.g., phenytoin, carbamazepine, valproic acid, levetiracetam) dispensed up to 3 months before the index date.

Comparador

No use of interacting drugs, or use of active comparators (drugs used for similar purposes without P-gp/CYP3A4 inhibition or induction effects, such as beta-blockers, propafenone, azithromycin, tetracycline, lamotrigine, clonazepam, gabapentin).

Resultado

Incident cases of (i) serious bleeding event, (ii) stroke/systemic emboli (SE) in patients with AF, or (iii) recurrent DVT/PE, analyzed separately.hard clinical

Concomitant use of DOACs with P-gp/CYP3A4 inhibitors (verapamil, amiodarone) increases bleeding risk, while use with inducers (phenytoin, carbamazepine, valproic acid, levetiracetam) increases the risk of stroke or systemic embolism.

Resultado numérico

Estimación del efecto: OR 1.32 (95% CI 1.07-1.62)

valor p: p=0.008

Limitaciones

Residual confounding might exist due to the retrospective nature of the study
Lack of genetic data for pharmacogenetics evaluation (e.g., SNPs in ABCB1, ABCG2, CES1, and CYP3A5 genes)
Higher proportion of apixaban users relative to dabigatran and rivaroxaban might not reflect patterns of use in other countries
Outcome events and use of potentially interacting drugs were not frequent, limiting power for some associations

Resumen

Concomitant use of direct oral anticoagulants (DOACs) and medications with inhibition/induction effect on P‐gp/CYP3A might increase risk of bleeding/treatment failure, respectively. We designed a nested case‐control study within a Clalit cohort of patients with atrial fibrillation (AF) and a cohort of patients with venous thromboembolism, new users of a DOAC (January 1, 2010 to August 24, 2020). Propensity scores were constructed from demographic/clinical characteristics, and medications at cohort entry. Each case of: (i) serious bleeding event; (ii) stroke/systemic emboli (SE) in patients with AF; (iii) recurrent thromboembolism in patients with thromboembolism, was matched by age, sex, length of follow‐up, year of cohort entry, DOAC type, and DOAC indication, to up to 20 controls. Within 89,284 patients with AF and venous thromboembolism and 126,302 patient‐years of follow‐up, there were 1,587 serious bleeding events. Risk of serious bleeding increased in association with concurrent prescription of P‐gp/CYP3A4 inhibitors. Specifically, higher bleeding risk was associated with dabigatran‐verapamil, rivaroxaban‐verapamil, and rivaroxaban‐amiodarone concurrent prescriptions: adjusted odds ratios (ORs) 2.29 (1.13–4.60), 2.18 (1.07–4.40), and 1.68 (1.14–2.49), respectively. There were 1,116 events of stroke/SE, in 79,302 DOAC‐treated patients with AF and 118,124 patient‐years of follow‐up. Concomitant use of phenytoin, carbamazepine, valproic acid, or levetiracetam was associated with risk for stroke/SE: adjusted OR 2.18 (1.55–3.10). Risk of recurrent venous thromboembolism could not be assessed due to the low number of cases. Concurrent prescriptions of dabigatran or rivaroxaban with verapamil, and of rivaroxaban with amiodarone, are associated with increased risk for serious bleeding. Higher risk for stroke/SE in patients with AF is associated with concurrent prescriptions of DOACs with phenytoin, carbamazepine, valproic acid, or levetiracetam.

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