1. Bleeding Risks with Pradaxa, a New Oral Anticoagulant, and Its Implications in Regional Anesthesiav
Abbas Jamshidi, SRNA, Shawn Collins, DNP, PhD, Ian Hewer, MSN, MA
Western Carolina University, College of Health and Human Sciences, School of Nursing, MS(N) Nurse Anesthesia Program
CLINICAL TRIALS, RESEARCHES and CASE REPORTS
RECOMMENDATIONS
INTRODUCTION
Reversal
Randomized Evaluation of Long-Term anticoagulation Therapy (RE-LY) trial
Dabigatran versus Warfarin in Patients with Atrial Fibrillation
Since its first approval in 1954 by the FDA, Coumadin has been a major oral anticoagulant on the market. A new rival to Coumadin, Pradaxa (Dabigatran), an oral anticoagulant medicine, was approved by the FDA in 2010 to prevent stroke and blood clots in patients with atrial fibrillation[6]. Unlike Coumadin, Pradaxa does not require any monitoring test to assess the extent of anticoagulation [6,8]. However, there have been reports of various bleeding events with patients using Pradaxa [2,4,5,12], and lawsuit cases are forming against Pradaxa [9].
Pradaxa is an irreversible competitive direct acting thrombin inhibitor [8]. In addition, Pradaxa has a short half-life of about hours with predictable pharmacodynamics and pharmacokinetics [7,11]. Clinical trials on patients with atrial fibrillation and acute venous thromboembolism have found Pradaxa to be at least as effective as Coumadin [5,10]. In another study, Pradaxa at a dose of 150 mg was associated with lower rates of stroke and systemic embolism, but the rate for major systemic hemorrhage was found to be comparable to Coumadin [3]. A similar study has found that patients on Pradaxa were able to have their surgeries done within 48 hours of withholding Pradaxa, which is relatively shorter than those on Coumadin [7]. In order to reduce the risk of epidural hematoma after neuraxial anesthesia, it is imperative to follow the published recommendations. The use of new anticoagulant drugs should consider the pharmacological profile of the drug, i.e. the time to reach peak plasma level and its half-life, for a safe regional anesthesia application. Due to the fact that Pradaxa is a new oral anticoagulant drug many anesthesia providers might not be familiar with Pradaxa and its risks for bleeding. This extensive literature review consolidates pharmacokinetics, pharmacodynamics, available clinical trials, and case reports to provide anesthesia practitioners with foundational knowledge about risks of bleeding with Pradaxa and its implications in regional anesthesia.
1) Can be dialyzed with 60% removal within 2-3 hrs (limited supporting data).
2) Activated prothrombin complex concentrates (aPCCs, e.g., FEIBA), or recombinant Factor VIIa, or factors II, IX or X may be considered but their use has not been evaluated in clinical trials.
3) Protamine sulfate and vitamin K are not effective.
4) Administration of platelet concentrates in cases where thrombocytopenia is present [8].
Dabigatran and warfarin were associated with similar rates of periprocedural bleeding (4,591pts, 7,637 surgeries), including patients having urgent surgery. Dabigatran facilitated a shorter interruption of oral dose (49 vs. 114 hrs). [7]
N= 18,113 patients with Atrial fibrilation. Randomized trial, blinded to Pradaxa dose
Outcome
Pradaxa
110 mg BID
P-value
150 mg BID
Warfarin
Major Bleeding/ yr
2.71%
0.003
3.11%
0.31
3.63%
Hemorrhagic Stroke/yr
0.12%
<0.001
0.1%
0.38%
Mortality /yr
3.75%
0.13
3.64%
0.051
4.13%
Perioperative Bleeding Events
Pradaxa 110 mg BID
N= 1,487
Pradaxa 150 mg BID
N=1,546
Warfarin
INR 2-3
N=1,558
P110 vs
P-value
P150 vs
Minor
8.1%
9.0%
7.8%
0.81
0.24
Major
3.8%
5.1%
4.6%
0.28
0.58
Fatal Bleeding
0.2%
0.1%
0.2
0.32
Requiring RBC Transfusion
3.3%
3.5%
4.0%
0.27
0.42
Perioperative Guidelines for Management of Pradaxa in the
RE-LY Trial for Patients Having Surgery [7]
Renal Function
CrCL ml/min
Estimated half-life hour [range]
High bleeding risk surgeries (cardiac, abd, neuro, spinal)
Standard bleeding risk surgeries
Mild
>=50 to 80
15 [12-18]
Hold 2-3 days before
Hold 24 hrs before (2 doses)
Moderate
>=30 to <50
18 [18-24]
Hold 4 days before
Hold at least 2 days before
Severe *
<30
27 [>24]
Hold >5 days
Hold 2-4 days before
Pradaxa 110 mg BID was associated with lower major bleeding than Warfarin, Pradxa 150 mg BID has similar major bleeding rate with Warfarin. [3]
Bleeding
Yrs old
Pradaxa 110 mg BID
Pradaxa 150mg BID
Warfarin
INR 2-3
P110 vs
Warfarin RR/ p-value
P 150 vs Warfarin RR/ p-value
P 110 vs P 150 RR/p-value
Major
<75
>= 75
1.89%
4.43%
2.12%
5.10%
3.04%
4.37%
0.62
1.01/<0.001
0.70
1.18/<0.001
1.12
1.17/0.8
Intracranial
0.14%
0.37%
0.26%
0.41%
0.61%
1.00%
0.22
0.37/0.28
0.43
0.42/0.91
1.92
1.13/0.29 GI
0.84%
2.19%
1.22%
2.88%
1.03%
1.59%
0.82
1.39/0.02
1.19
1.79/0.061
1.46
1.29/0.54
Acute Venous Thromboembolism (DVT, PE) Treatment
* University of Utah Healthcare recommends hematology consult with sever renal function impairment [13]
The American Society of Regional Anesthesia Guidelines on neuraxial procedures and anti-coagulation indicates that medication should be held as follows: Pradaxa (Dabigatran) 2 – 4 days prior (Depends on CrCl) [1]
In a randomized, double-blind, noninferiority trial, a total of 30 of the 1274 patients (Av. Age 55 yrs, Cr.Cl >50 ml/min) randomly assigned to receive Pradaxa 150 mg BID (2.4%), as compared with 27 of the 1265 patients randomly assigned to warfarin [INR 2,3](2.1%), had recurrent venous thromboembolism; the difference in risk was 0.4 percentage points. For the treatment of acute venous thromboembolism, a fixed dose of dabigatran is as effective as warfarin, has a safety profile that is similar to that of warfarin, and does not require laboratory monitoring. [10]
Compared to Warfarin, both doses of Pradaxa have lower risks of intracranial and extracranial bleeding in patients aged <75 years. In patients >= 75 years, intracranial bleeding risk is lower but extracranial bleeding risk is similar or higher with both doses of Pradaxa. RR= Relative risk; Patients <75 yrs (n=10,855) and >75yrs (n=7,258);
P110= Pradaxa 110mg; P150= Pradaxa 150mg. Warfarin dose adjusted to INR of 2-3. [5]
REFERENCES
Pharmacokinetics and Pharmacodynamics
1. ASRA Anticoag Guidelines for Neuraxial Procedureson. Indiana Pain Pain Society website. Accessed December 26, 2012.
2.Béné J, Saïd W, Rannou M, Deheul S, Coupe P, Gautier S. Rectal Bleeding and Hemostatic Disorders Induced by Dabigatran Etexilate in 2 Elderly Patients. The Annals of Pharmacotherapy. 2012; 46.
3. Connolly SJ, Ezekowitz MD, Yusuf S, etal. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med. 2009;361:
4. Dabigatran (Pradaxa): risk of bleeding relating to use. Australian Government Department of Health and Ageing Web Site. November 3, Accessed October 20, 2012.
5. Eikelboom JW, Wallentin L, Connolly SJ, et al. Risk of Bleeding With 2 Doses of Dabigatran Compared With Warfarin in Older and Younger Patients With Atrial Fibrillation. Circulation. 2011;123:
6. FDA approves Pradaxa to prevent stroke in people with atrial fibrillation. Food and Drug Administration Web site. PressAnnouncements/ ucm htm. October 21, Accessed October 14, 2012.
7. Healey JS, Eikelboom J, Douketis J, et al. Periprocedural Bleeding and Thromboembolic Events With Dabigatran Compared With Warfarin : Results From the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Randomized Trial. Circulation. 2012;126:
8. Highlights of Prescribing Information. Prescribing Information. Pradaxa Web site. =renetnt&folderPath = /Prescribing%20Information /PIs/ Pradaxa/ Pradaxa.pdf. May 2012, Accessed October 10, 2012.
9. Ryan L. Thompson of Watts Guerra Craft LLP Moves to Consolidate Pradaxa Lawsuits in MDL No July 16, 2012, Accessed October 14, 2012.
10. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism. N Engl J Med. 2009;361(24):
11. Stangier J, Rathgen K, Stähle H, Gansser D, Roth W. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol. 2007;64(3):292–303.
12. Truumees E, Gaudu T, Dieterichs C, Geck M, Stokes J, Epidural Hematoma and Intraoperative Hemorrhage in a Spine Trauma Patient on Pradaxa (Dabigatran). Spine.2012;37(14): E863–E /pubmed/ Accessed October 17,2012.
13. University of Utah Healthcare. Pradaxa (dabigatran etexilate) Peri- procedural Guideline. edu/thrombosis /newagents/TS.Dabi_PeriProc.pdf. Accessed Nov 20, 2012.
14. University of Washington Medical Center (UWMC). ANTICOAGULATION GUIDELINES FOR NEURAXIAL PROCEDURES. vte.washington.edu/docs/VTE_neuraxial_pathway.pdf. Accessed Nov 20, 2012.
Two double-blind, randomized trials, with a single dose of mg (n=40), and with multiple dose of mg TID (n=40). Peak dabigatran plasma concentrations at a median tmax of 1.25–1.5 h. After single oral dose oral of 100, 200 or 400 mg, the t1/2 was 7–9 h. Multiple dose study: The t1/2 of dabigatran was approximately 14–17 h and was not dose-dependent. Steady-state concentration was reached on day 3 with TID dose. Elimination: predominantly (up to 80%) via the renal pathway. Dabigatran undergoes conjugation with glucuronic acid to form acylglucuronides. These conjugates were shown to be pharmacologically active, demonstrating almost identical PD properties to free, nonconjugated dabigatran. INR, TT and ECT increased in direct proportion to dabigatran plasma concentration, whereas aPTT prolongation was linearly related to the square root of the plasma concentration. TT and ECT exhibited the greatest sensitivity and precision within the anticipated therapeutic dose range. These data suggest that dabigatran etexilate has a predictable pharmacokinetics and pharmacodynamics.[11]
TT= Trombin time [14-16 sec.], ECT=Ecarin Clotting Time [ sec], aPTT= activated Partial Thromboplastin time [25-35sec]
Method
CONCLUSIONS
Patients older than 74 years taking oral anticoagulant Pradaxa (Dabigatran) are at increased risk of extracranial bleeding compared to those taking Warfarin. Major GI bleeding events has been reported especially in elderly patients (>=75 yrs old). Additionally, patients with decreased renal function have increased bleeding risks with Pradaxa. Perioperative hematology consults has been recommended for those patients with CrCL <30 ml per minute taking Pradaxa. Considering the fact that Pradaxa is an irreversible direct thrombin inhibitor, anesthesia providers might find it difficult to control bleeding in patients taking Pradaxa. On the other hand, holing Pradaxa for 49 hrs prior to surgery was associated with similar bleeding events with those patients holing their Warfarin doses for 114 hrs.
Due to the fact that Pradaxa is a relatively new oral anticoagulant and most of the experimental studies have been done during phase III of the study, anesthesia providers need to follow-up on future phase IV studies and case reports. Current studies and case reports limits the scope of this literature review to reflect the guidelines by American Society of Regional Anesthesia, and other healthcare institutes.
An extensive literature review to consolidate pharmacokinetics, pharmacodynamics, clinical trials, and case reports regarding Pradaxa