Keywords direct oral anticoagulant - blood coagulation tests - drug monitoring - biological variation - population - factor Xa inhibitors - anticoagulants - hemorrhage
Introduction
Anticoagulant therapy has been revolutionized by the replacement of drugs requiring dose adjustments based on results of coagulation assays (heparin and vitamin K antagonists), with anticoagulants that do not require laboratory monitoring.[1 ] The shift, which began in the 1990s with the introduction of low molecular weight heparin, improved the convenience of anticoagulant therapy, and reduced cost by minimizing the need for in-hospital treatment.[1 ] The introduction of direct oral anticoagulants (DOACs) has further simplified anticoagulation therapy. All four available DOACs (i.e., apixaban, dabigatran, edoxaban, and rivaroxaban), when used in fixed doses without laboratory monitoring of anticoagulant activity, are at least as effective and safe as warfarin for the prevention of ischemic strokes in patients with nonvalvular atrial fibrillation (AF).[1 ]
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[4 ] As a result, DOACs are used in fixed doses, either in a high dose or low dose depending on the patient's characteristics.[1 ]
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Although most patients treated with fixed doses of DOACs do not need laboratory monitoring, there are clinical circumstances in which measurements of drug level might be desirable.[1 ]
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[6 ] In the absence of therapeutic ranges, less reliable metrics such as usual on-therapy ranges (10th to 90th or 5th to 95th percentile ranges) of trough and peak drug concentrations have been proposed to guide physicians if they consider it necessary to measure drug levels.[3 ]
[5 ] The previously published usual on-therapy ranges were derived from few studies of limited applicability to patients with AF (e.g., derived from healthy subjects, patients with other indications for treatment with a DOAC, or reduced validity due to reliance on pharmacokinetic modelling.[3 ]
[5 ] Since the initial publication of the guidance documents and product monographs, over 50 clinical studies have been published examining drug levels in patients taking DOACs for stroke prevention in AF.[6 ]
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In this systematic review and meta-analysis, we provide updated estimates for the 10th to 90th percentile ranges (i.e., middle 80% of drug levels) for trough and peak concentrations of the four approved DOACs when used in patients with AF using assays commonly used in clinical practice. This update provides clinicians with more representative estimates of the usual on-therapy ranges of DOACs than previously reported, to help guide their decision-making.
Methods
Protocol
This report adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations (PRISMA checklist provided in [Supplementary Table S1 ] of [Supporting Information File 1 ], available in online version only).[59 ] Our protocol is provided in [Supporting Information File 2 ] (available in online version only).
Data Sources and Searches
We electronically searched MEDLINE via Ovid for articles reporting on plasma concentrations of DOACs in patients with AF treated with DOACs to prevent ischemic strokes published between the inception of the database and January 2023. The full search strategy is presented in [Supplementary Table S2 of Supporting Information File 1 ] (available in online version only). This search was supplemented by manual review of the reference list of articles identified from the initial search.
Study Selection
Studies were eligible for inclusion if they reported either or both trough and peak drug levels in ng/mL (or in units that allowed for direct conversion to ng/mL) for DOACs (apixaban, dabigatran, edoxaban, rivaroxaban) approved for stroke prevention in AF. 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.
Eligible studies included randomized controlled trials and observational studies that collected blood samples and reported cross-sectional data on drug levels. We excluded case reports and case series, pharmacokinetic simulations, studies that did not separately report DOAC drug levels of patients with AF from those who were treated for other indications (e.g., treatment or prevention of venous thromboembolism), as well as reports that did not differentiate levels by DOAC type and administered dose. We further excluded studies written in a non-English language and those with total sample size of <10 patients. 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.).
Data Extraction and Estimation of Nonreported Percentiles of Drug Concentrations
Two reviewers (I.U.M. and C.G.) independently extracted data using a standardized case report form that included the following variables: the number of patients, the DOAC dose and frequency, measures of distribution (mean, median, standard deviation, percentiles, interquartile range) of trough and peak DOAC drug concentrations for each DOAC regimen, and the laboratory method used to determine levels. The percentiles of interest were the 50th , 10th , and 90th percentiles. If not reported in the individual studies, these percentiles were calculated directly from the original dataset if the study was published by the authors of the current review,[6 ]
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[42 ] or in most situations, these were estimated using simulations based on the published measures of central tendency and dispersion. More details regarding these simulation strategies are described in [Supporting Information File 2 ] (available in online version only).
Outcome Measures
The outcomes of interest were the 50th (median), 10th , and 90th percentile drug concentration for each DOAC regimen at trough and at peak. We defined the usual on-therapy range as the range spanning between the pooled 10th and 90th percentiles of drug level. We also report the lower bound of the 95% confidence interval (CI) of the pooled 10th percentile value and the upper bound of the 95% CI of the pooled 90th percentile value to provide a more conservative estimate of the usual on-therapy range.
Statistical Analyses
We estimated the pooled median, 10th and 90th percentile of DOAC drug concentration in ng/mL for each respective dose using the quantile estimation (QE) method.[60 ]
[61 ] This method estimates the variance of the study-specific medians from the reported summary statistics and then performs an inverse–variance weighted meta-analysis of medians.[60 ]
[61 ] We applied the same estimation strategy to estimate the pooled 10th and the pooled 90th percentile of trough and peak levels for each DOAC dosing regimen.
In all models, we prioritized summary statistics reported in the primary studies over simulated ones. Because the distributions of DOAC drug levels are right-skewed, we did not use the reported mean and standard deviation of some studies because the QE method would assume that data were normally distributed. Instead, for these studies, we used the simulated median, 25th and 75th percentile values. Given the method of data collection and the likely heterogeneity between studies due to differences in populations and methods of measurement, we used the random effects model (REM) in all analyses.[62 ] More details on the performed statistical analyses are provided in [Supporting Information File 2 ] (available in online version only).
Sensitivity Analyses
To assess the robustness of our findings on 10th and 90th percentile values, we performed two sets of prespecified sensitivity analyses for DOAC dosing regimen and one post hoc defined analysis. As defined in our protocol, we only considered these analyses whenever at least 10 studies provided data on the percentile of interest ([Supporting Information File 2 ], available in online version only).[63 ]
In these analyses we redetermined the on-therapy ranges (i.e., 10th and 90th percentiles) selecting only the studies (1) at low risk of bias and low concern of inapplicability to our review question, (2) for which the 10th and 90th percentile values were provided in the report, and (3) that determined levels with liquid chromatography–mass spectrometry/mass spectrometry.
We used mixed-effects models to assess for significant differences between the subsets of studies using the dichotomized variable as a potential modifier (i.e., low risk of bias and low concern of inapplicability vs. other studies, reported vs. simulated percentile of interest, or liquid chromatography–mass spectrometry/mass spectrometry vs. chromogenic assays). We kept Tau constant if there were five or fewer studies in either subset[63 ] and defined a significant difference between the subsets as a Wald test producing a two-tailed p -value < 0.05.
Quality Assessments
Assessing the quality of evidence of systematic reviews reporting on usual on-therapy ranges is less well established. We adopted the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to rate the quality of evidence for each outcome (i.e., median, 10th percentile, 90th percentile) of each DOAC dosing regimen.[64 ] To rate each study on their risk of bias and our concern of indirectness, we answered several prespecified signaling questions. These signaling questions sought to assess the risk of bias due to patient selection (domain 1 of QUADAS-2 tool) and due to method of drug concentration measurement (domain 2 through 4 of QUADAS-2 tool), as well as our concern of indirectness due to patient selection ([Supplementary Tables S1 ]–[S4 ] in [Supporting Information File 3 ], available in online version only).[65 ] The considerations and criteria for performing the quality assessments and rating of each domain (i.e., risk of bias, indirectness, inconsistency, and precision), including our rationale to not perform a formal publication bias assessment, are presented in [Supplementary Table S5 ] of [Supporting Information File 3 ] (available in online version only). The interpretation of the level of evidence ratings are described in [Supplementary Table S6 ] of [Supporting Information File 3 ] (available in online version only).
Results
Study Selection
We identified 4,833 publications of which 11 were duplicates. We screened the title and abstract of the 4,822 unique hits, of which 4,460 were excluded because they were irrelevant to our review question. After reading the full text, we excluded another 309 from the remaining 362 hits and were left with a total of 53 studies ([Fig. 1 ]).[6 ]
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[58 ] These included studies collectively reported on a total of 29,266 trough levels and 12,103 of peak levels. The characteristics of the included studies are presented in [Supplementary Table S1 ] of [Supporting Information File 4 ] (available in online version only).
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.
Usual On-Therapy Ranges
In this section we present the usual on-therapy ranges of trough and peak levels of DOAC doses approved in most regulatory regions. A more detailed description of the results of each meta-analytic model is provided in [Supporting Information File 4 ] (available in online version only), which includes the number of studies and patients available, measures of heterogeneity, as well as the ranges of the less commonly used dosing regimens.
Apixaban: [Fig. 2 ] illustrates the usual on-therapy ranges of both trough and peak concentrations for the two approved dosing regimens of apixaban.
Fig. 2 Median (and 10th –90th percentiles) of drug levels for apixaban. The squares represent the pooled median values, the solid bold lines the pooled estimates for the 10th to 90th percentile range, and the whiskers the interval from the lower bound of the 95% CI of the pooled 10th percentile (left side) to the upper bound of the 95% CI of the pooled 90th percentile value (right side). P10 10th percentile; P90 90th 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;[60 ]
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‡ the interval from the lower bound of the 95% CI of the pooled 10th percentile to the upper bound of the 95% CI of the pooled 90th percentile value; § Level of evidence following the GRADE-framework and determined for each outcome of interest (i.e., median, 10th percentile, and 90th percentiles).[64 ]
For the 2.5 mg twice daily dose of apixaban, the pooled estimate for the usual on-therapy range (10th to 90th percentile range) of trough levels is 38 to 155 ng/mL, with lower and upper bounds of the 95% CIs for 10th and 90th percentiles of 31 and 181 ng/mL, respectively. The corresponding range for peak levels is 96 to 251 ng/mL with lower and upper bounds of the 95% CIs for 10th and 90th percentiles of 84 and 271 ng/mL, respectively.
For the 5 mg twice daily dose of apixaban, the pooled estimate for the usual on-therapy range (10th to 90th percentile range) of trough levels is 58 to 206 ng/mL, with lower and upper bounds of the 95% CI for 10th and 90th percentiles, respectively, of 46 and 236 ng/mL. The corresponding range for peak levels is 132 to 343 ng/mL, with lower and upper bounds of the 95% CIs for 10th and 90th percentiles, respectively, of 109 and 371 ng/mL.
Dabigatran: [Fig. 3 ] illustrates the usual on-therapy ranges of both trough and peak concentrations for the two commonly approved dosing regimens of dabigatran (i.e., 110 mg twice daily and 150 mg twice daily). The usual on-therapy ranges of all three available dabigatran dosing regimens, which includes the 75 mg twice daily dose, are presented in [Fig S2 ] of [Supporting Information File 4 ] (available in online version only).
Fig. 3 Median (and 10th –90th 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 online version only]. The squares represent the pooled median values, the solid bold lines the pooled estimates for the 10th to 90th percentile range, and the whiskers the interval from the lower bound of the 95% CI of the pooled 10th percentile (left side) to the upper bound of the 95% CI of the pooled 90th percentile value (right side). P10 10th percentile; P90 90th 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;[60 ]
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‡ the interval from the lower bound of the 95% CI of the pooled 10th percentile to the upper bound of the 95% CI of the pooled 90th percentile value; § Level of evidence following the GRADE-framework and determined for each outcome of interest (i.e., median, 10th percentile, and 90th percentile).[64 ]
For the 110 mg twice daily dose of dabigatran, the pooled estimate for the usual on-therapy range (10th to 90th percentile range) of trough levels is 35 to 138 ng/mL, with lower and upper bounds of the 95% CIs for 10th and 90th percentiles, respectively, of 29 and 157 ng/mL. The corresponding range for peak levels is 65 to 223 ng/mL, with lower and upper bounds of the 95% CIs for 10th and 90th percentiles, respectively, of 51 and 265 ng/mL.
For the 150 mg twice daily dose of dabigatran, the pooled estimate for the usual on-therapy range (10th to 90th percentile range) of trough levels is 33 to 151 ng/mL, with lower and upper bounds of the 95% CIs for 10th and 90th percentiles, respectively, of 27 and 172 ng/mL. The corresponding range for peak levels is 76 to 285 ng/mL with lower and upper bounds of the 95% CIs for 10th and 90th percentiles, respectively, of 64 and 327 ng/mL.
Edoxaban: [Fig. 4 ] illustrates the usual on-therapy ranges of both trough and peak concentrations for the two commonly approved dosing regimens of edoxaban (i.e., 30 mg once daily and 60 mg once daily). The usual on-therapy ranges of all three available edoxaban dosing regimens, which includes the 15 mg once daily dose, are presented in [Fig S3 ] of [Supporting Information File 4 ] (available in online version only).
Fig. 4 Median (and 10th –90th 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 online version only]. The squares represent the pooled median values, the solid bold lines the pooled estimates for the 10th to 90th percentile range, and the whiskers the interval from the lower bound of the 95% CI of the pooled 10th percentile (left side) to the upper bound of the 95% CI of the pooled 90th percentile value (right side). P10 10th percentile; P90 90th 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;[60 ]
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‡ the interval from the lower bound of the 95% CI of the pooled 10th percentile to the upper bound of the 95% CI of the pooled 90th percentile value; § Level of evidence following the GRADE-framework and determined for each outcome of interest (i.e., median, 10th percentile, and 90th percentile).[64 ]
For the 30 mg once daily dose of edoxaban, the pooled estimate for the usual on-therapy range (10th to 90th percentile range) of trough levels is 8 to 54 ng/mL with lower and upper bounds of the 95% CIs for 10th and 90th percentiles, respectively, of 6 and 82 ng/mL. The corresponding range for peak levels is 57 to 219 ng/mL, with lower and upper bounds of the 95% CIs for 10th and 90th percentiles, respectively, of 15 and 349 ng/mL.
For the 60 mg once daily dose of edoxaban, the pooled estimate for the usual on-therapy range (10th to 90th percentile range) of trough levels is 13 to 66 ng/mL, with lower and upper bounds of the 95% CIs for 10th and 90th percentiles, respectively, of 11 and 110 ng/mL. The corresponding range for peak levels is 127 to 407 ng/mL, with lower and upper bounds of the 95% CIs for 10th and 90th percentiles, respectively, of 39 and 519 ng/mL.
Rivaroxaban: [Fig. 5 ] illustrates the usual on-therapy ranges of both trough and peak concentrations for the two commonly approved dosing regimens of rivaroxaban (i.e., 15 mg once daily and 20 mg once daily). The usual on-therapy ranges of all three available rivaroxaban dosing regimens, which includes the 10 mg once daily dose, are presented in [Fig. S4 ] of [Supporting Information File 4 ] (available in online version only).
Fig. 5. Median (and 10th – 90th 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 ]. The squares represent the pooled median values, the solid bold lines the pooled estimates for the 10th to 90th percentile range, and the whiskers the interval from the lower bound of the 95% CI of the pooled 10th percentile (left side) to the upper bound of the 95% CI of the pooled 90th percentile value (right side). P10 10th percentile; P90 90th 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;[60 ]
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‡ the interval from the lower bound of the 95% CI of the pooled 10th percentile to the upper bound of the 95% CI of the pooled 90th percentile value; § Level of evidence following the GRADE-framework and determined for each outcome of interest (i.e., median, 10th percentile, and 90th percentile).[64 ]
For the 15 mg once daily dose of rivaroxaban, the pooled estimate for the usual on-therapy range (10th to 90th percentile range) of trough levels is 16 to 74 ng/mL with lower and upper bounds of the 95% CIs for 10th and 90th percentiles, respectively, of 13 and 90 ng/mL. The corresponding range for peak levels is 131 to 384 ng/mL, with lower and upper bounds of the 95% CIs for 10th and 90th percentiles, respectively, of 98 and 433 ng/mL.
For the 20 mg once daily dose of rivaroxaban, the pooled estimate for the usual on-therapy range (10th to 90th percentile range) of trough levels is 19 to 72 ng/mL with lower and upper bounds of the 95% CIs for 10th and 90th percentiles, respectively, of 15 and 81 ng/mL. The corresponding range for peak levels is 169 to 313 ng/mL with lower and upper bounds of the 95% CIs for 10th and 90th percentiles, respectively, of 146 and 391 ng/mL.
The level of evidence for all outcomes (i.e., median, 10th percentile, 90th percentile) of each DOAC dosing regimen ranged from high to very low as reported in [Supplementary Table S12 of Supporting Information File 3 ] (available in online version only). The level of evidence was based on our assessments of the risk of bias, indirectness, inconsistency, and imprecision assessments (summarized in [Supplementary Tables S7 ]–[S11 ] of [Supporting Information File 3 ], available in online version only).
Sensitivity Analyses
Performing the sensitivity analysis was impossible (because only a single study was available or all studies fell into the same category) or noninformative because fewer than 10 studies were available in 30 (68%) of analyses on risk of bias and concern of inapplicability, 22 (50%) on method of data extraction, and 22 (50%) on the laboratory methods used to determine levels.
For the DOAC regimens for which these analyses were feasible, rather than including all eligible studies, selecting only the studies at low risk of bias and concern of inapplicability studies ([Supplementary Table S1 ] [available in online version only] and [Supplementary Figs. S1 ]–[S4 ] of [Supporting Information File 5 ] [available in online version only]), those studies that provided the 10th and 90th percentile values in their report ([Supplementary Table S2 ] and [Figs. S5–S8 ] of [Supporting Information File 5 ] [available in online version only]), or studies that used liquid chromatography–mass spectrometry/mass spectrometry to determine levels ([Supplementary Table S3 ] and [Supplementary Figs. S9–S12 ] of [Supporting Information File 5 ] [available in online version only]) did not result in consistently higher or lower 10th or 90th percentile values.
Discussion
In this systematic review and meta-analysis, we provide clinicians with the best-available information on the usual on-therapy range of drug levels in patients taking DOACs for stroke prevention in nonvalvular AF. We pooled data from 53 studies reporting on a total of 29,266 trough levels and 12,103 peak levels to generate estimates of the usual on-therapy range for trough or peak levels for approved dosing regimens of four DOACs.[6 ]
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[58 ] Our estimates overlap those reported in guidelines and monographs[3 ]
[5 ] but are more representative because these were derived from a more comprehensive dataset that included only patients with AF and excluded pharmacokinetic modelling studies. Despite the methodological limitations of our study and of those of the included studies, our usual on-therapy ranges are an improvement on those currently reported. Our estimates better reflect trough and peak levels of all approved dosing regimens in AF, because we took indication and timing of sample collection into consideration.
These usual on-therapy ranges for trough and peak levels of DOACs can help clinicians who decide to measure levels to manage their patients who experience unexpected bleeding as well as those who were ineligible for inclusion or were underrepresented in the randomized trials. About 25% of patients treated in clinics who are prescribed the lower dose of a DOAC do not meet the recommended dose reduction criteria (i.e., off-label dose reduction).[66 ]
[67 ] Clinicians who use off-label dosing mainly select the lower dose and use this dose in patients who they suspect are at high risk of bleeding or drug overexposure. For example, patients with severe comorbidities (e.g., advanced kidney or liver disease), those with extreme clinical characteristics (e.g., extremes of body weight or age), and patients who are taking drugs that are known to interact with a DOAC.[3 ]
[5 ] In such patients, the risk of underdosing could be mitigated if the dose reduction is limited to patients with consistently high drug levels.[6 ]
[42 ] Although the use of off-label dose adjustment in selected patients is debated,[3 ]
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[68 ] there is evidence that drug levels are associated with thromboembolic and bleeding events,[10 ]
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[71 ] and that use of the dosages currently approved for patients with AF is likely to result in unacceptably high bleeding risks in selected patients.[72 ]
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Strengths and Limitations
The main strengths are the comprehensive search with inclusion of more than 50 studies of patients with AF from across the globe. As a result, our estimates of the usual on-therapy ranges are more comprehensive and representative than those currently reported in guidelines and product monographs.
Limitations of the study include (1) the relative paucity of data for some dosing regimens, (2) the fact that usual on-therapy ranges do not represent therapeutic ranges, (3) the variation in the outcomes among studies (heterogeneity). In addition, despite attempts to perform sensitivity analyses, these analyses were mostly inconclusive, and we were unable to definitively explore the impact of risk of bias, concern of inapplicability, and differences in laboratory methods on the ranges of drug levels. It is possible that heterogeneity is in part contributed to by differences in the studied populations and methods of measurement. Consequently, it is important for diagnostic laboratories to assess measurement of uncertainty for their assays to guide the interpretation of drug levels.[74 ]
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[76 ] If usual on-therapy ranges are used to help in making decisions, it is recommended that laboratories use validated assays that have been calibrated according to current standards.[5 ]
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[76 ] When providing test results, laboratories may consider taking uncertainty about our usual on-therapy ranges into consideration, for instance, by reporting whether levels fall within the usual on-therapy range, within its 95% CIs, or outside either range.[74 ] Finally, if the dose is modified because the test falls outside the usual range, we suggest that the assay should be repeated to determine that the dose response is appropriate.
Conclusion
In this systematic review and meta-analysis, we pooled data from 53 studies that collectively included over 30,000 patients to provide updated estimates for the 10th to 90th percentile ranges (i.e., middle 80% of drug levels) for trough and peak concentrations of the four approved DOACs when used in patients with AF using methods commonly used in clinical practice. This update provides clinicians with more representative estimates of the usual on-therapy ranges of DOACs than previously reported, to help guide their decision-making.
What is known about this topic?
DOACs do not require routine monitoring of drug levels, but measurement of levels might be desirable in some situations.
In the absence of therapeutic ranges, usual on-therapy ranges (10th to 90th ) of drug concentrations are used to interpret measurements.
Existing guidance documents provide usual on-therapy ranges for drug concentrations, but these have important limitations.
What does this paper add?
