Elsevier

Thrombosis Research

Volume 136, Issue 4, October 2015, Pages 763-768
Thrombosis Research

Full Length Article
Peri-procedural management of dabigatran and rivaroxaban: Duration of anticoagulant discontinuation and drug concentrations

https://doi.org/10.1016/j.thromres.2015.08.006Get rights and content

Highlights

  • We measure per-procedural residual concentration of direct oral anticoagulant [DOAC]

  • Duration of DOAC discontinuation is the only factor associated with minimal [DOAC]

  • A 48-hour discontinuation does not guarantee a [DOAC] < 30 ng/mL in all patients

  • Normal PT and aPTT are flawed to predict [DOAC] < 30 ng/mL

  • DOAC should be stopped > 48 hr before procedures requiring normal coagulation

Abstract

Background

Peri-procedural management of direct oral anticoagulants (DOAC) is challenging. The optimal duration of pre-procedural discontinuation that guarantees a minimal DOAC concentration ([DOAC]) at surgery is unknown. The usual 48-hour discontinuation might not be sufficient for all patients.

Objectives

To test the hypothesis that a 48-hour DOAC discontinuation is not sufficient to ensure a minimal per-procedural [DOAC], defined as [DOAC] < 30 ng/mL. To investigate the factors associated with per-procedural [DOAC]. To evaluate the ability of normal PT and aPTT to predict [DOAC] < 30 ng/mL.

Methods

Patients treated with dabigatran or rivaroxaban, and requiring any invasive procedure were included in this multicentre, prospective, observational study. [DOAC], PT and aPTT were measured during invasive procedure.

Results

Sixty-five patients were enrolled. Duration of DOAC discontinuation ranged from 1-168 h. Per-procedural [DOAC] ranged from < 30 to 466 ng/mL. [DOAC] < 30 ng/mL occurred more frequently after 48-hour discontinuation than after a shorter delay. [DOAC] remained ≥ 30 ng/mL in 36% and 14% of measurements performed 24-48 h and 48 h-120 h after discontinuation, respectively. According to ROC curve, a cut-off value of 120 hours for DOAC discontinuation had a better specificity than a cut-off value of 48 hours to predict [DOAC] < 30 ng/mL. Normal PT and aPTT ratios had good specificity and positive predictive value, but limited sensitivity (74%) and negative predictive value (73%) to predict [DOAC] < 30 ng/mL.

Conclusions

A 48-hour discontinuation does not guarantee a [DOAC] < 30 ng/mL in all patients. Normal PT and aPTT are flawed to predict this threshold and could not replace specific assays. Further studies are needed to define the relationship between per-procedural [DOAC] and clinical outcomes.

Introduction

Direct oral anticoagulants (DOAC) are currently licenced for thromboprophylaxis after hip and knee arthroplasty, for long-term prevention of thromboembolic events in non-valvular atrial fibrillation as well as for the treatment and secondary prophylaxis of venous thromboembolism. They include dabigatran, rivaroxaban and apixaban.

Although each year 10% of all patients receiving long-term anticoagulants require surgery or any invasive procedure [1], [2], the optimal peri-procedural management of DOACs remains challenging and based on little reliable evidence, especially regarding high bleeding risk procedures. With short half-lives and rapid offset and onset of action, DOACs could theoretically be stopped shortly before and restarted soon after an invasive procedure. Based on these pharmacokinetic properties, the protocol of the pivotal trial RELY, assessing dabigatran for stroke prevention in atrial fibrillation (SPAF), initially indicated discontinuation of dabigatran 24 hours before an invasive procedure in all patients [2]. Summary of Product Characteristics (SmPC) recommends discontinuing rivaroxaban 24 hours prior to invasive procedures with a moderate or high risk of bleeding. As a result, the European Society of Cardiology recommends discontinuing DOACs 24 hours before procedure with a minor bleeding risk in patients with a normal kidney function, and 48 hours before procedure with a major bleeding risk regardless of the drug [3]. Similarly, the Italian Federation of Thrombosis Centers proposes stopping dabigatran 24 to 48 hours before surgery, depending on renal function [4]. However, none of these proposals based on basic pharmacology has been assessed using either robust clinical or biological endpoints and there are no published studies relating peri-operative DOAC concentrations. Thus, data on the daily care management of DOACs in unselected patients undergoing invasive procedures are urgently needed.

Indeed, an important interindividual pharmacokinetic variability has been shown in patients included in pivotal trials and treated with fixed doses of DOACs. In the RE-LY sub-study, peak plasma levels varied from 2.3 ng/mL to 1000 ng/mL after administration of dabigatran 150 mg twice daily [5]. In patients receiving rivaroxaban 20 mg once daily for treatment of acute DVT, the 5th–95th percentile range for peak concentration was wide (22 to 535 ng/mL) [6]. Moreover, several factors including renal or liver function or drug interactions, may significantly affect the elimination half-life of the drugs [7]. Therefore, the duration of DOAC discontinuation to reach a low concentration before high bleeding risk procedure likely varies among patients and a systematic 48-hour discontinuation as mentioned herein above, may not be suitable for all patients.

We hypothesized that a 48-hour discontinuation of dabigatran or rivaroxaban might not be sufficient for all patients to ensure a minimal DOAC concentration at the time of invasive procedure. We defined the minimal concentration as a DOAC concentration below 30 ng/mL, which corresponds to the expected plasma DOAC concentration reached after 3 half-lives, when most of the drug (87.5% of the Cmax) has been eliminated, assuming the Cmax values are of 215 and 175 ng/mL (SmPC values for SPAF patients) with rivaroxaban and dabigatran respectively [5], [6]. To test this hypothesis, we performed an observational study including patients with a wide range of dabigatran- or rivaroxaban-discontinuation durations and facing an invasive procedure. In these patients, we investigated the factors, and specifically the delay between the last intake and the procedure, influencing the per-interventional residual concentrations. In addition, we evaluated the ability of the combination of a normal prothrombin time (PT) and a normal activated partial thromboplastin time (aPTT) to predict a DOAC concentration below 30 ng/mL.

Section snippets

Patients and Methods

The CORIDA (COncentration of RIvaroxaban and DAbigatran) study was a multicenter, prospective, observational study conducted from June 2013 to April 2014 in 4 centres in France (Hôpital Cochin, Institut Mutualiste Montsouris, Fondation Rothschild, Hôpital du Val de Grâce). Ethical approval for this study was issued by the Institutional Review Board (Comité de Protection des Personnes Ile de France 1, ref. 2013–13272); informed consent was obtained from all study participants before inclusion.

Patients

In each participating centre, physicians in charge of the study prospectively enrolled consecutive patients undergoing an invasive procedure and receiving dabigatran or rivaroxaban for SPAF or treatment of VTE. Invasive procedure was defined as any elective or urgent surgery, endoscopy and cardiac catheterization. Urgent procedure was defined as a procedure required within 48 hours. This observational study had no impact on the procedures and peri-interventional anticoagulation management that

DOAC Concentration and Standard Laboratory Tests

One blood sample was collected for each patient in the operating theater, at the beginning of the procedure. Blood was drawn into citrate tubes and centrifuged within 2 h at 2500 g for 15 min at 15 °C. In centers other than Cochin, aliquotes of plasma were frozen at − 30 °C prior to onward shipment on dry ice to Cochin University Hospital (Paris, France) for central analysis. All measurements were centrally performed in the hematology laboratory of Cochin hospital on a STA-R® analyser (Stago,

Data Collection

The following characteristics of the peri-procedural DOAC management were recorded: DOAC type and indication, duration from discontinuation to invasive procedure, use of heparin bridging and finally results from the blood sample collected in the operating theater.

Data pertaining to invasive procedure consisted of type, date and outcome. Procedures associated with a high bleeding risk in the context of perioperative anticoagulant drug administration included urologic surgery, pacemaker

Statistical Analysis

Descriptive statistics used means ± SD for quantitative variables and numbers (percentages) for qualitative ones. Groups were compared using Mann–Whitney tests for quantitative variables and chi2 or Fisher’s exact tests for qualitative ones. Comparisons of individuals with DOAC concentration < 30 ng/mL and DOAC concentration ≥ 30 ng/mL were performed using the same tests. Among factors associated with the concentrations below 30 ng/mL, quantitative variables tested were age, weight, creatinin

Patient Baseline Characteristics and Pre-procedural DOAC Management

Sixty-five patients were enrolled in the study. Baseline characteristics are summarized in Table 1. Most of them received rivaroxaban (60%), and all except one were treated for SPAF (three with a history of stroke). Types of invasive procedures are summarized in Table 2. Urgent and high bleeding risk procedures represented 30% and 49% respectively of the overall procedures.

The mean time between the last drug intake and the procedure was 58.2 ± 46.7 hours (range: 1 to 168 h). Pre-procedural bridging

Discussion

In this prospective observational study, we showed that a dabigatran or rivaroxaban discontinuation greater than or equal to 48 h was suitable for the majority of patients as their residual concentration was minimal at the time of procedure, i.e. less than 30 ng/mL. We also found, as expected, that duration of pre-procedural DOAC discontinuation was the main predictive factor of a per-procedural DOAC concentration < 30 ng/mL. Nevertheless, a 48-hour discontinuation did not suit all patients as 14%

Conclusion

Peri-procedural management of DOAC-treated patients is challenging. We showed that a 48 h discontinuation of dabigatran or rivaroxaban did not guarantee a minimal DOAC concentration for all patients. Thus, stopping DOACs more than 48 hours before a planned invasive procedure with high haemorragic risk seems to be a safer option to reach minimal DOAC concentrations. Moreover, conventional laboratory assays, PT and aPTT, are flawed to predict minimal DOAC concentrations and could not replace

Funding

None.

Conflicts of Interest

A. Godier has received honoraria for participating in expert meeting from Bayer Healthcare, BMS/Pfizer, Boehringer-Ingelheim.

I. Gouin-Thibault has received honoraria for participating in expert meeting from Bristol-Myers Squibb/Pfizer, Bayer Healthcare and Boehringer-Ingelheim.

C Flaujac has received honoraria for participating in expert meeting from Bayer Healthcare.

No conflicts of interest for remainder authors.

Acknowledgements

We thank Valérie Dias (Université Paris Descartes) for linguistic support.

References (17)

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This work has been presented to the French Society of Anesthesiology and critical care (Paris, 18/09/2014).

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