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British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 2014 Aug 21;78(3):599–609. doi: 10.1111/bcp.12364

A proposal for dose-adjustment of dabigatran etexilate in atrial fibrillation guided by thrombin time

Paul K L Chin 1,✉, Daniel F B Wright 2, David M Patterson 3, Matthew P Doogue 1, Evan J Begg 1
PMCID: PMC4243910  PMID: 24592851

Abstract

Dabigatran is an oral anticoagulant that is increasingly used for atrial fibrillation (AF). Presently, many authorities state that routine laboratory coagulation monitoring is not required. However, data have recently been published demonstrating that higher trough plasma dabigatran concentrations are associated with lower thromboembolic and higher haemorrhagic event rates. Using these data, we simulate a range of AF patients with varying risks for these events and derive a target range of trough plasma dabigatran concentrations (30–130 μg l−1). Finally, we propose that a conventional screening coagulation assay, the thrombin time (TT), can be used to discern whether or not patients are within this range of dabigatran concentrations.

Keywords: atrial fibrillation, blood coagulation, dabigatran, dosing, monitoring

Introduction

Dabigatran is an orally administered direct thrombin inhibitor used for the prevention of thromboembolism. It is a widely used anticoagulant for atrial fibrillation (AF) 1–6. It is often stated that dabigatran therapy does not require laboratory coagulation monitoring because it has a predictable dose–response relationship 7–10. These assertions have been questioned on the grounds that the reported population variability in dabigatran clearance is in the order of 50% (coefficient of variation, CV) even after accounting for differences in renal function between individuals 11. Notably, this CV is greater than that reported for S-warfarin clearance 12,13. In addition, therapeutic anticoagulation requires a balance between the risk of clotting and the risk of bleeding due to the innate variability and sensitivity of the coagulation network. It has therefore been proposed that dose-adjustment according to clotting times in the individual patient should be the standard of care when using any anticoagulant 12.

In this review, we begin with some background on dabigatran pharmacokinetics and pharmacodynamics, and construct a target trough dabigatran plasma concentration range using data from the published literature. We then discuss the use of coagulation assays to monitor dabigatran therapy. Finally, we make a case for using the conventional thrombin time (TT) to guide dabigatran dosing, discuss limitations of the present proposal and outline future work that may be needed.

Dabigatran pharmacokinetic and pharmacodynamic considerations

Dabigatran is a highly polar compound that is administered orally as an inactive prodrug, dabigatran etexilate 14,15. Dabigatran etexilate has a reported oral availability of about 7% 16, a value that is decreased by reduced stomach acidity 17,18 and by increased intestinal P-glycoprotein function (Figure 1) 19. Following absorption, dabigatran etexilate is metabolized by esterases, including carboxylesterase 1 (CES1), via the intermediate metabolites BIBR 951 and BIBR 1087, to the active metabolite, dabigatran 16,20. BIBR 951 is thought to have activity against thrombin, whereas BIBR 1087 is said to be inactive 21. The metabolism from dabigatran etexilate to dabigatran appears to be rapid and virtually complete, with the combined plasma AUC(0,∞) for the prodrug and its intermediate metabolites being less than 0.4% of the plasma dabigatran AUC(0,∞) in healthy volunteers 21,22. Therefore the contribution of BIBR 951 to drug activity can be considered insignificant 16.

Figure 1.

Figure 1

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An abbreviated pharmacokinetic/pharmacodynamic model of dabigatran. DE, dabigatran etexilate; F, oral availability; fe, fraction excreted unchanged in urine; CES, carboxylesterase enzyme; DG, dabigatran glucuronides; Xa:Va, factor Xa:factor Va complex; II, factor II; XF, cross-linked fibrin. Grey boxes indicate reported thrombin inhibitors 68,21,23,69

Dabigatran itself is renally cleared, with a high fraction excreted unchanged in urine (fe) of around 0.8 16. Unlike its prodrug dabigatran etexilate, dabigatran is not known to be a substrate of P-glycoprotein. Plasma dabigatran concentrations are therefore not expected to be affected by P-glycoprotein function at the renal tubules 14. Glucuronidation appears to be responsible for the remainder of dabigatran clearance 16. Data from healthy volunteers suggest that the glucuronides are eliminated renally 16.

The principal measurable metabolite resulting from dabigatran glucuronidation is 1-O-acylglucuronide. The other glucuronides (2-O, 3-O and 4-O-acylglucuronide) were reported to be below the limit of detection in plasma samples taken up to 6 h following either oral dabigatran etexilate or intravenous dabigatran administration 16. The dabigatran glucuronides are all thought to be active against thrombin because substitution of glucuronic acid for the carboxylate functional group of dabigatran, does not interfere with the thrombin binding site 23. Dabigatran 1-O-acylglucuronide increases activated partial thromboplastin time (aPTT) in a dose-dependent manner to the same degree as dabigatran itself, for concentrations up to around 1000 nmol l−1 for either compound 23. To put this into context, the 90th percentile of peak plasma dabigatran concentrations observed in the RE-LY trial from over 9000 patients treated with dabigatran etexilate was around 700 nmol l−1 1,24,25. Therefore, for clinical purposes, dabigatran 1-O-acylglucuronide can be considered to have the same potency and efficacy as dabigatran itself, and the anticoagulant effect will depend on the combined AUC values of these compounds.

The magnitude of anticoagulation in an individual patient treated with dabigatran etexilate is determined by (i) the concentrations of active compounds at the site of action, including BIBR 951, dabigatran and its glucuronides and (ii) the concentrations and innate sensitivity of coagulation network constituents, including factor II and fibrinogen (Figure 1). Therefore, these will influence an individual’s risk of thromboembolic or haemorrhagic events following exposure to dabigatran etexilate.

A target dabigatran concentration range for AF treatment?

In this section, we examine relevant published data from individuals with AF given dabigatran etexilate regarding plasma dabigatran concentrations and thromboembolic and haemorrhagic events. Using these, we generate a proposed target plasma dabigatran concentration range.

Reilly et al. recently examined the relationships between dabigatran concentrations and thromboembolic and haemorrhagic events 25. These data came from the RE-LY trial, which randomized individuals with AF to warfarin, with dosing targeted at an International Normalized Ratio (INR) of 2–3, or to dabigatran etexilate with fixed dosing that was not guided by coagulation monitoring 1. There were two dabigatran etexilate arms to which individuals were randomly assigned, including 110 mg twice daily and 150 mg twice daily, with median follow-up of 2.0 years. After 1 month of maintenance dosing, a trough dabigatran concentration was collected from each individual, 10–16 h after the previous dose of dabigatran etexilate. The 10th to 90th percentiles of trough steady-state dabigatran concentrations for the 110 mg and 150 mg dabigatran etexilate arms were 28–155 and 40–215 μg l−1, respectively. The report by Reilly et al. demonstrated that higher dabigatran trough concentrations at steady-state were associated with lower rates of ischaemic stroke/systemic embolic event (SEE) and higher rates of major bleeding. They generated logistic regression curves to quantify the rates of these adverse events for an index 72-year-old male with non-valvular AF, diabetes mellitus and previous ischaemic stroke over the dabigatran trough concentration range of 10–300 μg l−1 (21–636 nmol l−1). The index 72-year-old male reflects the mean age and thromboembolic risk of the population studied in the RE-LY study 1.

The logistic regression curves, defined by Reilly et al., can be used to define a target trough concentration range that could guide dabigatran etexilate therapy in the setting of AF 12,26,27. We digitized these lines of best fit using Engauge Digitizer (version 4.1, http://sourceforge.net). The resulting data for trough concentrations vs. (i) ischaemic stroke/SEE risk and (ii) major bleeding risk were each fitted to a two phase exponential decay equation, with r2 > 0.999 for both risk equations (GraphPad Prism version 6.03, GraphPad Software, La Jolla, CA, USA, http://www.graphpad.com). Each equation was adjusted by weighting relevant adverse events according to the hazard ratios for death, relative to an ischaemic stroke. We used the event weight values generated by Eikelboom et al., which were based on data from the RE-LY study 28. It should be noted that the subtypes of events contributing to each of (i) ischaemic stroke/SEE and (ii) major bleeding, are not uniformly weighted. For example, both haemorrhagic stroke and extracranial bleeding were counted as major bleeding events, but had weights of 3.23 and 0.63, respectively. Thus, from the literature, we extracted the numbers of subtypes of events contributing to ischaemic stroke/SEE and major bleeding in the RE-LY study 1,29,30. Using these data, we generated the weight-adjusted risk equations for stroke/SEE and major bleeding (see Appendix for the equations).

We then generated a combined weight-adjusted risk equation by adding these equations together (see Appendix). The resulting plot is shown in Figure 2. The trough concentration (∼30 μg l−1) associated with the lowest combined weight-adjusted risk on our plot is relatively low compared with the observed trough concentrations reported for the two dabigatran etexilate dose rates in the RE-LY study. This reflects the finding by Reilly et al. that the thromboembolic risk declined steeply at low concentrations, with little additional advantage from higher concentrations 25.

Figure 2.

Figure 2

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Weight-adjusted event risk curves for 72-year-old male with AF, diabetes mellitus and prior stroke (CHA2DS2-VASc = 4, HAS-BLED = 2). Black line, combined risk; blue line, stroke/systemic embolic event risk; red line, major bleeding risk

A more widely applicable target trough concentration range may be fashioned using standardized methods for assessing the balance of adverse event risks associated with anticoagulation in individuals with non-valvular AF 31–35. Of these, the CHA2DS2-VASc and HAS-BLED scoring systems are the most widely accepted methods for estimating an individual’s ischaemic stroke and major bleeding risk, respectively 36. The 2012 European Society of Cardiology guidelines for AF management state that patients with CHA2DS2-VASc ≥1 should routinely be anticoagulated 37. While Reilly et al. provide some data relating event rates in RE-LY to these two scoring systems, the CHA2DS2-VASc and HAS-BLED data are amalgamated into three (0–1, 2, >2) and two (0–1, >1) risk categories, respectively 25. Greater detail is available from previous studies of anticoagulation for non-valvular AF, including those involving ximelagatran, an earlier oral direct thrombin inhibitor, and warfarin (Table 1) 38,39. We calculate that the index 72-year-old male reported by Reilly et al. would have CHA2DS2-VASc and HAS-BLED scores of 4 and 2, respectively. By anchoring to this 72-year-old male, we proportionally adjusted our weight-adjusted risk equations for a range of individuals with a variety of combinations of CHA2DS2-VASc and HAS-BLED scores to explore the range of trough concentrations associated with the lowest combined weight-adjusted risk. Examples involving ‘extreme’ scores are presented in Figure 3. Figure 3A is consistent with the notion that patients with a high risk of major bleeding may not derive any benefit from dabigatran exposure, despite a moderate risk of stroke/SEE. For patients with non-valvular AF deemed to derive some benefit from dabigatran etexilate, Figures 3B and C suggest that the general target trough range is 30–130 μg l−1. Targeting dosing according to measured trough plasma dabigatran concentrations may therefore be a useful approach.

Table 1.

Stroke and major bleeding risk with anticoagulation therapy, according to risk stratification 38,39

CHA2DS2-VASc total score* Thromboembolic risk (% per year)
1 0.46
2 0.78
3 1.16
4 1.43
5 2.42
6 3.54
7 3.44
8 2.41
9 5.47
HAS-BLED total score† Major bleeding risk (% per year)
0 1.2
1 2.8
2 3.6
3 6.0
4 9.5
5 7.5
6 0.0
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*

CHA2DS2-VASc score (total 0–9 points) based on: 1 point for each of congestive heart failure/left ventricular dysfunction, hypertension, diabetes mellitus, vascular disease, female gender, age 65–74 years; 2 points for each of age ≥75 years, previous stroke/transient ischaemic attack/thromboembolism 32. A total score of 0 is not included as such individuals should not routinely be anticoagulated 37. Few individuals had a total score >6 37.

†

HAS-BLED score (total 0–9 points) based on: 1 point for each of hypertension, renal dysfunction, hepatic dysfunction, previous stroke, bleeding history/predisposition, labile INR, age >65 years, co-administered antiplatelet drug, alcohol excess 34. Few individuals had total score >4, and none had a total score >6 34.

Figure 3.

Figure 3

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Combined weight-adjusted risk curves for: (A) CHA2DS2-VASc = 4, HAS-BLED = 4 (concentration associated with lowest combined risk ≤10 μg l−1); (B) CHA2DS2-VASc = 1, HAS-BLED = 0 (30 μg l−1); (C) CHA2DS2-VASc = 6, HAS-BLED = 2 (130 μg l−1)

Measuring dabigatran concentrations

While brief descriptions of plasma dabigatran assays have been reported in several clinical papers 16,18,19,21,22,40–43, only Delavenne et al. have published a comprehensive dabigatran assay method detailing the development and validation procedures in accordance with FDA guidelines 44. However, the mass spectrometry-based method presented by Delavenne et al. did not include quantification of the dabigatran glucuronides, which, as discussed above, contribute towards the anticoagulation effect. This becomes particularly relevant if the plasma concentrations of the glucuronides are significant relative to the concentration of dabigatran itself.

Reports of the contribution of the dabigatran glucuronides to total active drug-related exposure in plasma from dabigatran etexilate range from 10 to 35% 16,18,21,22,40,41, with no apparent influence of mild to severe renal 22 or moderate hepatic impairment 21. The range is only slightly narrower (15–35%) when the reports are restricted to those involving healthy young individuals who were administered a single dabigatran etexilate dose of 150 mg 18,21,22,41. However, the variability of the contribution of the glucuronides to overall drug exposure has been reported to be low in healthy young individuals, as reflected by a coefficient of variation (CV) of 8–10% 40. Based on this CV, for example, a mean contribution of 35% would have a 95% CI of 28, 42%. These findings suggest there is only modest biological variation in the contribution of the glucuronides to total active drug-related exposure. Instead, the reported variability (10–35%) most likely stems from inaccuracy in the measurement of the glucuronides.

Several sources of inaccuracy in the measurement of the glucuronides are possible. For example, the glucuronides may be unstable during sample storage 16. This is difficult to establish as the glucuronides were not assayed directly in any of the reported studies 16,18,21,22,40,41. Instead, these were inferred from the difference in plasma dabigatran concentrations before and after alkalinization (hydrolyzing the glucuronides to dabigatran) 16,18,21,22,40. In the RE-LY study, the reported dabigatran concentrations came from the measurement of dabigatran in alkalinized samples 24,25. It has been reported that 1-O-acylglucuronide spontaneously degrades in a pH 7.4 aqueous buffer at 37°C with an apparent in vitro half-life of 1 h 23. The stability of dabigatran under alkaline conditions is unclear 45. Beyond brief descriptions within clinical papers, we are not aware of any published method paper for a dabigatran assay that includes quantification of the glucuronides in human plasma.

Coagulation assays and dabigatran

Given the uncertainty surrounding the dabigatran assay, as well as its limited availability, the coagulation assays are attractive alternative biomarkers to guide dabigatran etexilate dosing. Coagulation assays are expected to reflect inter-individual variability in both dabigatran pharmacokinetics and pharmacodynamics, i.e. active drug concentrations and the endogenous coagulation network. A number of studies have examined the relationship between plasma dabigatran concentrations and a range of coagulation assays 40,46–54. These include the conventional screening assays, such as the INR, activated partial thromboplastin time (aPTT) and thrombin time (TT), and the less widely available assays, such as the ecarin clotting time (ECT) and the dilute thrombin time (dTT).

Of the conventional assays, the INR and aPTT are insensitive at lower plasma dabigatran concentrations, whereas the TT has been described as being excessively sensitive 48,49,51,55. Data from our research at Christchurch Hospital, which includes 52 individuals who provided 120 blood samples following at least 10 days of oral dabigatran etexilate at a constant dose rate, reflect these conclusions 56. All our dabigatran-treated individuals had TT values well above our ‘normal’ reference range of 18–28 s, with the lowest value being 82 s (Figure 4). Further, plasma dabigatran concentrations above 90 μg l−1 were consistently associated with TT values above the maximum reported time of 300 s.

Figure 4.

Figure 4

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Correlation between plasma dabigatran concentrations and (A) TT and (B) HTI. For TT, the maximum reported time was 300 s, and TT > 300 s have been set to 300 s (no reported TT value was actually 300 s). Solid lines represent the lines of best fit. Dashed lines represent the reference range at our institution, Christchurch Hospital. r2 values are for the line of best fit, which for the TT data do not include those values with TT > 300 s. Data from 52 individuals on dabigatran etexilate providing 120 blood samples at steady-state [56]

The dTT was developed to compensate for the sensitivity of the TT in the presence of direct thrombin inhibitors 57. The dTT involves dilution of the test plasma sample with normal pooled plasma. At least two published versions of the dTT have been developed specifically for dabigatran 50,52, including a commercial assay (Hemoclot® Thrombin Inhibitor, HTI, Hyphen BioMed, Neuville-sur-Oise, France). r2 values in excess of 0.90 have consistently been reported between HTI times and plasma dabigatran concentrations 47,48,51–53, which is confirmed by our data (Figure 4B). Further, the HTI assay can be used to quantify indirectly ‘total’ dabigatran plasma concentration by using calibrators from the manufacturers of the HTI assay, which consist of plasma samples containing known concentrations of dabigatran.

The dabigatran concentration–clotting time relationships outlined above will vary depending on the clot-activating reagent, and the analyzer instrument used for the coagulation assays 48,51. Nonetheless, at first glance, the HTI assay appears to be suitable for monitoring patients on dabigatran. However, there is a potentially important caveat regarding the HTI assay and the dTT tests in general. As a consequence of the dilution with normal pooled plasma, the impact of inter-individual differences in plasma fibrinogen concentrations on the clotting time is diminished (Figure 1) 51. Therefore, the dTT tests are more correctly considered as tests for quantifying the total amount of thrombin inhibitors resulting from dabigatran etexilate administration (including BIBR 951, dabigatran and the dabigatran glucuronides), rather than as coagulation assays that account for both active drug concentrations and the individual patient’s endogenous coagulation network. The TT, on the other hand, is more representative of the interplay of active drug concentrations and clotting factors, and given its wide availability deserves further consideration as a marker for guiding dabigatran dosing.

The thrombin time for monitoring dabigatran effect and guiding dosing

The potential utility of the TT in comparison with the HTI assay is illustrated in Figure 5, which shows the Christchurch data restricted to dabigatran concentrations < 90 μg l−1. Data for dabigatran concentrations ≥90 μg l−1 were excluded from this plot as the TT values were consistently >300 s (our maximum reported TT). For the two data points indicated with arrows in Figure 5A, it can be postulated that the TT of 254 s represents a greater degree of anticoagulation than the point with a TT of 155 s, even though the dabigatran concentrations are 44 and 45 μg l−1, respectively. The corresponding points on the HTI in Figure 5B have results of 29 and 32 s, respectively. Note that both TT and HTI assays have a CV of <11% at our laboratory 56. Given that the dabigatran glucuronides (amounting to 10–35% of total active drug exposure) were not measured by our dabigatran assay, the total active dabigatran concentrations would be 11–54% higher than the measured dabigatran concentrations, to account for the dabigatran glucuronides. In this case, the ‘total’ dabigatran concentration above which our TT assay consistently returned values >300 s would be ≥100 μg l−1. Thus, it appears that our TT assay gives quantifiable results at dabigatran concentrations ≤100 μg l−1. While this is less than 130 μg l−1, the upper limit of the target dabigatran concentration derived in the section ‘A target dabigatran concentration range for AF treatment?’ above, an inspection of Figure 3C indicates that combined weight-adjusted risk for 100 μg l−1is minimally higher than 130 μg l−1. Using the line of best fit in Figure 5A, the target trough plasma dabigatran concentration of 30–100 μg l−1 corresponds to a TT range of 130–300 s.

Figure 5.

Figure 5

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Correlation between plasma dabigatran concentrations <90 μg l−1 and (A) TT and (B) HTI. For TT graph, TT > 300 s set to 300 s. Solid lines represent the lines of best fit. r2 values are for the line of best fit, which for the TT data do not include those values with TT > 300 s. Arrows indicate a selected pair of blood samples (see text, section ‘The thrombin time for monitoring dabigatran effect and guiding dosing’)

It has been argued that a ‘rapid, widely available, specific and sensitive assay’ is required for monitoring dabigatran 51. We believe the TT goes a long way towards fulfilling the stated requirements. Individuals who might benefit from monitoring the anticoagulation effect include those who are about to undergo invasive procedures, have suffered a thromboembolic or haemorrhagic event or are suspected of non-adherence 7–9,58–60. Further, other individuals may also benefit from laboratory coagulation evaluation, including those for whom dabigatran etexilate treatment is currently contraindicated as a result of pharmacokinetic drug interactions 19, and those for whom the covariates of dabigatran concentrations are relevant (Table 2) 59–62.

Table 2.

Magnitude of effect of covariates on dabigatran plasma concentrations

Covariate Mean exposure ratio (90% CI)*
Stomach acidity
 Pantoprazole [18] 0.80 (0.67, 0.95)
Intestinal P-glycoprotein function
 Verapamil [42]† 1.71 (1.34, 2.15)
 Rifampicin [19]‡ 0.33 (0.27, 0.41)
 rs4148738 [20] 1.12 (1.08, 1.17)
Intestinal/hepatic CES1 function
 rs2244613 [20]†† 0.85 (0.81, 0.90)
Renal impairment [22]
 Mild 1.50 (0.78, 2.90)
 Moderate 3.15 (1.63, 6.08)
 Severe 6.31 (3.54, 11.25)
Patient adherence Not available
Opening the dabigatran etexilate capsule prior to administration [8] 1.75
Prolonged exposure of the capsule to humidity [70] Not available
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*

This represents the mean ratio (90% CI) of the AUC(0,∞) of individuals with the covariate to healthy controls without the covariate, or for polymorphisms, the mean ratio (95% CI) of either peak or trough concentrations of single allele carriers to wildtype.

†

Other P-glycoprotein inhibitors (with reported mean AUC(0,∞) ratio) include: ketoconazole (2.5) 9; dronedarone (2.0) 71; amiodarone (1.6) 9; clarithromycin (1.5) 43; quinidine (1.5) 9; ticagrelor (1.5) [72] loading doses of clopidogrel (1.3) 41.

‡

Other P-glycoprotein inducers include carbamazepine, phenytoin, phenobarbitone (exposure ratios have not been reported) 19.

The other ABCB1 polymorphism (with reported mean ratio of peak concentrations)is rs1045642 (1.08) 65.

††

Other CES1 polymorphisms (with reported mean ratio of trough concentrations) include: rs4122238 (0.86) 20; rs8192935 (0.89) 20.

Limitations of the present target trough TT proposal

There are several important limitations to our proposal. Ideally, a target TT range would be defined directly from events, but there are currently insufficient data in the public domain for such an analysis. The trough TT range of 130–300 s we propose reflects a trough plasma dabigatran range of 30–100 μg l−1. The foundation upon which this range is derived includes the veracity of a) drug concentration measurements, for both the RE-LY study (as discussed above) and the data from our observations and b) the relationship between the drug concentrations and events. A significant limitation of the analysis by Reilly et al. is that dabigatran concentration data largely came from blood samples taken 1 month following enrolment, whereas the majority of thromboembolic and haemorrhagic events occurred at least 12 months following enrolment 1,30. This time lag is likely to have contributed to the wide 95% CI of the lines of best fit of the logistic regression curves 25. Further, whilst biologically plausible, the relationship between events and plasma dabigatran concentrations can be questioned. In considering this, there are the data from the BISTRO II trial relating dabigatran concentrations to thrombotic and haemorrhagic rates in patients post-hip/knee joint replacement 63. Post-operatively, dabigatran etexilate was administered for a duration of 6–10 days and plasma concentrations were measured within the first 5 days. The duration of follow-up was 4–6 weeks. The time lag between blood samples for drug concentrations and events was thus shorter in the BISTRO II trial than in the RE-LY trial. Peak dabigatran concentrations at steady-state for the 1576 individuals administered dabigatran etexilate in BISTRO II were reported to be 48–271 μg l−1. Logistic regression curves correlating peak plasma dabigatran concentration with rates of deep vein thrombosis and bleeding indicate that concentrations around 50–100 μg l−1 were associated with the lowest combined adverse event risk. While these were peak rather than trough concentrations, they are consistent with the notion that the plasma dabigatran concentrations associated with the lowest combined risk of thrombotic and haemorrhagic events are relatively low compared with the total range of concentrations reported in both the RE-LY and BISTRO II trials 25,63.

We derived the range by simulating ‘extreme’ individuals (Figure 3), which is based on several assumptions. We converted the risk data for various CHA2DS2-VASc and HAS-BLED scores from warfarin/ximelagatran trials by anchoring to the index 72-year-old male described by Reilly et al. and applied these to dabigatran (Table 1). This assumes that the relationships between different scores from the warfarin/ximelagatran trials are relevant to dabigatran, e.g. that an individual with HAS-BLED = 4 has 9.5/3.6 times the major bleeding risk of an individual with a score of 2. Further, the ‘universal’ range, 30–100 μg l−1, may not be appropriate for all individuals, and instead an approach using individualized targets may be superior 64. However, a FDA analysis of the RE-LY trial data had findings similar to our own 65. We submit that our proposed target trough dabigatran concentrations and TT should be investigated further, and that our present proposal is merely a step towards finding an approach to dosing dabigatran etexilate that will ultimately improve patient outcomes.

Regarding patient outcomes, there may be little gain in terms of ischaemic stroke/SEE from using a targeted approach, given that well in excess of 90% of individuals in the RE-LY trial achieved trough concentrations over 30 μg l−1 25. Instead, the main anticipated benefit of our proposal is a reduction in major bleeding risk, which is relevant given that there is presently no readily available, rapid and convenient method of reversing the anticoagulant effects resulting from dabigatran etexilate 66.

Our proposed TT target range is specific to the TT assay we used, and its wider applicability is thus hindered by the lack of standardization of TT assays. How might others apply our proposed trough TT target range of 130–300 s, based on a target dabigatran concentration range of 30–100 μg l−1? Given that our reference range is 18–28 s, the range of the TT ratio based on the mid-range of 23 s is around 6–13. How does this conversion from plasma dabigatran concentrations to TT ratios compare with other studies using data from individuals given dabigatran? Using the plots of TT ratio vs. plasma dabigatran concentrations reported by Stangier et al. 40 and Hawes et al. 48, a range of 30–100 μg l−1 converts to TT ratios of 4–9 and 5–15, respectively. Given the widespread uptake of dabigatran etexilate, there may be an argument, ultimately, for standardization of the TT assays.

The problem of the ‘excessive’ sensitivity of the TT limits the amount of information available to the clinician from this test when, such as occurs at our laboratory, a result above the maximum reported time is only reported as the maximum time itself. How much higher is the true result? It has been suggested that, of the conventional screening coagulation assays, the INR and aPTT can be used in addition to the TT to distinguish between various degrees of high dabigatran exposure 48. Given the ready availability and rapid turnaround of these assays, it seems reasonable to use this combination of coagulation assays, especially when a TT above the maximum reported time is reported, or overdose is suspected.

Future work

Data from studies addressing the limitations will be important in progressing this proposal. Further analyses from the RE-LY study of clinical outcomes in relation to clotting times are anticipated 25,67. Coagulation results and plasma dabigatran concentrations from blood samples that are temporally proximate to relevant adverse clinical events may allow more accurate and precise delineation of the dose–response relationship.

If and when the above issues are addressed, and the target TT appropriately revised, dabigatran etexilate dosing guided by TT feedback should be tested in an interventional trial. If instead, outcomes are found to have a stronger correlation with plasma dabigatran concentrations than clotting times, a thorough examination of the assay methods for measuring the glucuronides, by comparing assays with and without sample alkalinization, should be carried out.

Conclusions

Oral anticoagulation using dabigatran etexilate in the setting of AF has achieved widespread global uptake, with impressive ‘real world’ results reflecting those achieved in the pivotal RE-LY trial 4,5,68. This is despite assertions that it is a drug with a narrow therapeutic index 55,58. Nonetheless, as pointed out by Duffull et al., ‘where it is possible to reduce the risk of bleeding or thrombosis … by taking reasonable actions, these actions should be taken’ 58. We believe monitoring the TT in patients treated with dabigatran etexilate, and using this feedback to adjust dosing, is a reasonable and potentially beneficial action.

Appendix

graphic file with name bcp0078-0599-m1.jpg

Equation 1 Ischaemic stroke/systemic embolic event weight-adjusted risk equation.

graphic file with name bcp0078-0599-m2.jpg

Equation 2 Major bleeding weight-adjusted risk equation.

graphic file with name bcp0078-0599-m3.jpg

Equation 3 Combined weight-adjusted risk equation.

D is the trough plasma dabigatran concentration at steady-state. All constants have been rounded to three significant figures for the purpose of presentation here.

Competing Interests

All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work. MPD was a member of the Pharmaceutical Benefits Advisory Committee of Australia (PBAC) that considered an application for the funding of dabigatran and provided advice to the Australian government about funding dabigatran.

Paul K. L. Chin is a recipient of the Health Research Council of New Zealand Clinical Research Training Fellowship (2012–2014).

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