Apixaban concentration variability and relation to clinical outcomes in real-life patients with atrial fibrillation

Mavri, Alenka; Vene, Nina; Mijovski, Mojca Božič; Miklič, Marko; Söderblom, Lisbeth; Pohanka, Anton; Malmström, Rickard E.; Antović, Jovan P.

doi:10.1038/s41598-021-93372-9

Cited by 18 publications

(18 citation statements)

References 25 publications

(40 reference statements)

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“…A previous study reported that the median values of C trough and C peak were approximately 25–30% lower in the reduced-dose group than in the standard-dose group [ 7 ]. Similar to the previous real-life studies, the results showed a 25–35% difference in C trough and C peak between the standard- and reduced-dose groups [ 9 , 12 , 20 ]. The results for the reduced-dose group presented a pharmacokinetic alteration, but the clinical outcomes were consistent in terms of efficacy and safety [ 21 ].…”

Section: Discussionsupporting

confidence: 88%

“…A history of stroke events and age ≥ 75 years were major risk factors for stroke events in AF patients [ 31 ]. As mentioned above, it may be that the apixaban plasma levels cannot be used to predict stroke outcomes, as suggested by the previous report [ 12 ]. In addition, a cohort study previously reported that thrombotic complications occurred in AF patients who had depleted apixaban plasma levels (22–145 µ/L) and high CHA 2 DS 2 VASc scores [ 32 ].…”

Section: Discussionmentioning

confidence: 98%

“…Moreover, the therapeutic range of apixaban plasma levels is defined by the expected drug levels in clinical trials [ 7 , 11 ]. Subsequently, several studies have reported intra- and inter-individual variabilities in apixaban peak and trough concentrations, and that the apixaban concentrations were not associated with the clinical outcomes [ 12 , 13 ]. However, the real-world evidence of the related clinical outcomes of apixaban plasma levels in Caucasian and Asian populations is limited.…”

Section: Introductionmentioning

confidence: 99%

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Do Apixaban Plasma Levels Relate to Bleeding? The Clinical Outcomes and Predictive Factors for Bleeding in Patients with Non-Valvular Atrial Fibrillation

et al. 2022

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Apixaban can significantly prevent stroke events in patients with non-valvular atrial fibrillation (NVAF), as can be observed from the large, randomized, controlled trial conducted in the present study. However, the real-world evidence of bleeding events related to the apixaban plasma levels in Asian populations is limited. This study aimed to investigate the apixaban plasma levels and clinical outcomes among NVAF patients receiving apixaban, including determining the risk factors associated with bleeding during routine care. Seventy-one patients were included in the study. The median values were 112.79 (5–95th percentiles: 68.69–207.8) μg/L and 185.62 (5–95th percentiles: 124.06–384.34) μg/L for the apixaban trough (Ctrough) and apixaban peak plasma levels (Cpeak), respectively. Stroke and bleeding were found in 8 (11.27%) and 14 patients (19.72%), respectively. There was no statistical significance for Ctrough and Cpeak in the stroke and non-stroke groups, respectively. The median of Ctrough (139.15 μg/L) in patients with bleeding was higher than that in the non-bleeding group (108.14 μg/L), but there was no statistical significance. However, multivariate analyses showed that bleeding history (odds ratio (OR): 17.62; 95% confidence interval (CI): 3.54–176.64; and p-value = 0.002) and Ctrough (OR: 1.01; 95%: CI 1.00–1.03; and p-value = 0.038) were related to bleeding events. Almost all of the patients presented apixaban plasma levels within the expected range. Interestingly, bleeding events were associated with the troughs of the apixaban plasma levels and bleeding history.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Do Apixaban Plasma Levels Relate to Bleeding? The Clinical Outcomes and Predictive Factors for Bleeding in Patients with Non-Valvular Atrial Fibrillation

et al. 2022

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“…The variation of apixaban or rivaroxaban plasma levels in real-world populations has been studied before in patients with nonvalvular atrial fibrillation (NVAF) [ 23 , 24 , 25 , 26 ] or in populations receiving these DOACs for different indications, including management of VTE [ 27 , 28 , 29 ]. Consistent with our results in VTE patients, Testa et al [ 23 ] found an inter-patient CV of up to 42% at peak and up to 68% at trough levels of apixaban 5 or 2.5 mg BD and of up to 49% at peak and 103% at trough levels of rivaroxaban 20 mg OD in patients with NVAF.…”

Section: Discussionmentioning

confidence: 99%

Variation in Plasma Levels of Apixaban and Rivaroxaban in Clinical Routine Treatment of Venous Thromboembolism

Reda

Rudde

Müller

et al. 2022

Life

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Direct oral anticoagulants (DOACs) apixaban and rivaroxaban are broadly used in the management of venous thromboembolism (VTE). Although not routinely required, measurement of their plasma concentration is advised for an increasing number of indications. Due to the lack of therapeutic ranges, current guidelines recommend reporting DOAC plasma levels together with expected levels from previous pivotal studies. The aim of this study was to assess DOAC level variation in a large VTE patient population. Drug concentrations determined by measurement of the anti-Xa-activity using drug-specific calibrators in citrated plasma samples from patients on rivaroxaban (n = 1471) or apixaban (n = 725) were analyzed. Observed 5th–95th percentile ranges of apixaban peak/trough levels (63–299/13–114 ng/mL for 5 mg, 37–161/7–68 ng/mL for 2.5 mg twice daily) were similar to previously reported mass-spectrometry-based reference data, and 10th–90th percentile ranges of rivaroxaban peak/trough levels (98–367/8–55 ng/mL for 20 mg, 51–211/5–27 ng/mL for 10 mg once daily) were even narrower. Age and drug levels correlated weakly (r ≤ 0.330). Drug levels measured repeatedly in subgroups of patients showed a strong correlation (r ≥ 0.773). In conclusion, anti-Xa-activity-based measurement of apixaban and rivaroxaban yields reliable results. However, the paucity of levels off-range underlines the need for evidence-based thresholds to better assist clinical decision making.

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“…For patients taking apixaban 5 mg twice daily, peak plasma concentrations range between 128–488 ng/ml [ 26 , 27 ]. The low plasma concentrations measured in our study, even in animals taking 15 mg twice daily, suggest that oral absorption is limited or that pigs metabolize apixaban rapidly.…”

Section: Discussionmentioning

confidence: 99%

Apixaban in a porcine model of mechanical valve thrombosis in pulmonary position—a pilot study

Hoof

Truyers

Hauwermeiren

et al. 2022

Interactive CardioVascular and Thoracic Surgery

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OBJECTIVES The newest mechanical valves have low thrombogenicity, making them candidates for anticoagulation with a direct oral anticoagulant. While these drugs hold great promise to replace warfarin, clinical trials have been disappointing so far. We aimed to evaluate apixaban in a porcine model of mechanical valve thrombosis with On-X® (CryoLife) aortic valves implanted in pulmonary position. METHODS On-X® valves were implanted in pulmonary valve position in 9 Yucatan pigs. Animals received prophylactic enoxaparin 40 mg for 1 week. Pigs in the low-dose group received 5 mg apixaban twice daily for 10 weeks. The intermediary-dose group received 5 mg twice daily for 6 weeks and then 10 mg twice daily afterwards. The high-dose group received 15 mg twice daily for 10 weeks. After sacrifice, valves were macroscopically evaluated and thrombus weight was documented. RESULTS The median weight of the 9 animals was 64.3 kg, range 52.5–70.9. In the low-dose group (2 animals), both valves showed manifest, chronic thrombosis with blocked hinges. In the intermediary-dose group, a normal functioning valve without thrombosis was seen in 2/4 animals. In the high-dose group (3 pigs), there was no valve thrombosis. No bleeding events occurred. In all animals, apixaban plasma levels were low compared to clinical target levels. CONCLUSIONS The pulmonary position seems to be an aggressive model for mechanical valve thrombosis in pigs. Apixaban has the potential to prevent valve thrombosis, even in these thrombogenic conditions. Detailed pharmacokinetic studies are needed to determine the ideal apixaban dosage for future experiments and to enable extrapolation to the clinical situation.

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Apixaban concentration variability and relation to clinical outcomes in real-life patients with atrial fibrillation

Cited by 18 publications

References 25 publications

Do Apixaban Plasma Levels Relate to Bleeding? The Clinical Outcomes and Predictive Factors for Bleeding in Patients with Non-Valvular Atrial Fibrillation

Do Apixaban Plasma Levels Relate to Bleeding? The Clinical Outcomes and Predictive Factors for Bleeding in Patients with Non-Valvular Atrial Fibrillation

Variation in Plasma Levels of Apixaban and Rivaroxaban in Clinical Routine Treatment of Venous Thromboembolism

Apixaban in a porcine model of mechanical valve thrombosis in pulmonary position—a pilot study

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