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Meta-Analysis
. 2025 Jun;125(6):563-573.
doi: 10.1055/a-2446-1348. Epub 2024 Nov 21.

Usual On-therapy Ranges of Drug Concentrations in Patients with Atrial Fibrillation Treated with Direct Oral Anticoagulants: A Systematic Review and Meta-analysis

Tim A C de Vries  1   2   3   4 , Imaad U Mallick  5   6 , Vinai C Bhagirath  6   7   8 , John W Eikelboom  6   7   8 , Calvin Gomes  9 , Qilong Yi  10 , Sean McGrath  11 , Jack Hirsh  7 , Noel C Chan  6   7   8
Affiliations
Meta-Analysis

Usual On-therapy Ranges of Drug Concentrations in Patients with Atrial Fibrillation Treated with Direct Oral Anticoagulants: A Systematic Review and Meta-analysis

Tim A C de Vries et al. Thromb Haemost. 2025 Jun.

Abstract

Although most patients with atrial fibrillation (AF) receiving a direct oral anticoagulant (DOAC) do not require drug concentration measurements, there are situations where such information could be useful. Existing guidance documents provide usual on-therapy ranges for drug concentrations, but these have important limitations.This is a systematic review and meta-analysis of studies reporting trough and peak levels of DOAC regimens approved for stroke prevention in AF. We used random effects models and the quantile estimation method to estimate the median and a usual on-therapy range (10th and 90th percentiles).Of 4,822 unique publications, 53 studies met eligibility (29,266 trough and 12,103 peak levels). Usual on-therapy ranges for trough levels were 38 to 155 and 58 to 206 ng/mL for apixaban 2.5 and 5 mg twice daily; 35 to 138 and 33 to 151 ng/mL for dabigatran 110 and 150 mg twice daily; 8 to 54 and 13 to 66 ng/mL for edoxaban 30 and 60 mg daily; and 16 to 74 and 19 to 72 ng/mL for rivaroxaban 15 and 20 mg daily. The corresponding range for peak levels were 96 to 251 and 132 to 343; 65 to 223 and 76 to 285; 57 to 219 and 127 to 407; 131 to 384, and 169 to 313 ng/mL, respectively.This systematic review and meta-analysis provides updated and more representative usual on-therapy ranges of DOAC levels in patients with AF.

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Conflict of interest statement

T.A.C.dV. reports nonfinancial support from Daiichi Sankyo and personal fees from Bristol-Myers-Squibb, both outside the submitted work. He also reports that he is a member of the adjudication committee of the Low International Normalized Ratio to Minimize Bleeding with Mechanical Valves (LIMIT) and Direct Oral Anticoagulation versus Warfarin after Cardiac Surgery (DANCE) trials, which are sponsored by the Population Health Research Institute. V.C.B. reports personal fees from Bayer and Pfizer, outside the submitted work. N.C.C. reports personal fees from Stago, Boehringer Ingelheim, and Novo Nordisk, outside the submitted work. J.W.E. reports grants and personal fees from Anthos, Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, Ionis, Janssen, Merck, and Pfizer, personal fees from USV, during the conduct of the study; grants and personal fees from Anthos, Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, Ionis, Janssen, Merck, and Pfizer, personal fees from USV, outside the submitted work. The other authors have no conflict of interest to disclose.

Figures

Fig. 1.
Fig. 1.
Flow of study selection. This flow diagram illustrates the flow of study selection. * After deduplication, all hits were screened for eligibility by two reviewers (I.U.M. and C.G.). In the instance of disagreement, the final decision was determined by a third reviewer (T.A.C.dV. or N.C.C.); † If there was overlap in study populations among primary studies, we avoided double counting by using the data of interest from the more comprehensive publication.
Fig. 2
Fig. 2
Median (and 10 th –90 th percentiles) of drug levels for apixaban. The squares represent the pooled median values, the solid bold lines the pooled estimates for the 10 th to 90 th percentile range, and the whiskers the interval from the lower bound of the 95% CI of the pooled 10 th percentile (left side) to the upper bound of the 95% CI of the pooled 90 th percentile value (right side). P10 10 th percentile; P90 90 th percentile; CI, confidence interval; DOAC, direct oral anticoagulant; No., number. *Some studies reported on multiple subgroups of patients. Each subgroup was then considered a unique study; † Estimated with random effects models using the (modified) QE method; ‡ The interval from the lower bound of the 95% CI of the pooled 10 th percentile to the upper bound of the 95% CI of the pooled 90 th percentile value; § Level of evidence following the GRADE-framework and determined for each outcome of interest (i.e., median, 10 th percentile, and 90 th percentiles).
Fig. 3
Fig. 3
Median (and 10 th –90 th percentiles) of drug levels for dabigatran. The usual on-therapy ranges of the 75 mg twice daily dose are presented in Supplementary Fig. S2 of Supporting Information File 4 [available in the online version]. The squares represent the pooled median values, the solid bold lines the pooled estimates for the 10 th to 90 th percentile range, and the whiskers the interval from the lower bound of the 95% CI of the pooled 10 th percentile (left side) to the upper bound of the 95% CI of the pooled 90 th percentile value (right side). P10 10 th percentile; P90 90 th percentile; CI confidence interval; DOAC direct oral anticoagulant; No. number. *Some studies reported on multiple subgroups of patients. Each subgroup was then considered a unique study; † Estimated with random effects models using the (modified) QE-method; ‡ The interval from the lower bound of the 95% CI of the pooled 10 th percentile to the upper bound of the 95% CI of the pooled 90 th percentile value; § Level of evidence following the GRADE-framework and determined for each outcome of interest (i.e., median, 10 th percentile, and 90 th percentile).
Fig. 4
Fig. 4
Median (and 10 th –90 th percentiles) of drug levels for edoxaban. The usual on-therapy ranges of the 15 mg once daily dose are presented in Supplementary Fig. S3 of Supporting Information File 4 [available in the online version]. The squares represent the pooled median values, the solid bold lines the pooled estimates for the 10 th to 90 th percentile range, and the whiskers the interval from the lower bound of the 95% CI of the pooled 10 th percentile (left side) to the upper bound of the 95% CI of the pooled 90 th percentile value (right side). P10 10 th percentile; P90 90 th percentile; CI confidence interval; DOAC direct oral anticoagulant; No. number. * Some studies reported on multiple subgroups of patients. Each subgroup was then considered a unique study; † Estimated with random effects models using the (modified) QE-method; ‡ The interval from the lower bound of the 95% CI of the pooled 10 th percentile to the upper bound of the 95% CI of the pooled 90 th percentile value; § Level of evidence following the GRADE-framework and determined for each outcome of interest (i.e., median, 10 th percentile, and 90 th percentile).
Fig. 5.
Fig. 5.
Median (and 10 th – 90 th percentiles) of drug levels for rivaroxaban. The usual on-therapy ranges of the 10 mg once daily dose are presented in Supplementary Fig. S4 of Supporting Information File 4 (available in the online version). The squares represent the pooled median values, the solid bold lines the pooled estimates for the 10 th to 90 th percentile range, and the whiskers the interval from the lower bound of the 95% CI of the pooled 10 th percentile (left side) to the upper bound of the 95% CI of the pooled 90 th percentile value (right side). P10 10 th percentile; P90 90 th percentile; CI confidence interval; DOAC direct oral anticoagulant; No. number. * Some studies reported on multiple subgroups of patients. Each subgroup was then considered a unique study; † Estimated with random effects models using the (modified) QE-method; ‡ The interval from the lower bound of the 95% CI of the pooled 10 th percentile to the upper bound of the 95% CI of the pooled 90 th percentile value; § Level of evidence following the GRADE-framework and determined for each outcome of interest (i.e., median, 10 th percentile, and 90 th percentile).
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