Praxbind® : Clinical Efficacy

Akpan Anani, Mercer University College of Pharmacy

While oral anticoagulants are used for the prevention or treatment of thrombotic events, certain life-threatening scenarios may warrant interventions in which anticoagulant reversal is needed to achieve hemostasis. Consequently, the availability and efficacy of reversal agents can have a large impact on the decision making of healthcare providers in regards to the anticoagulant therapy regimen being utilized by patients. Pradaxa® (dabigatran) is an oral anticoagulant approved in the U.S. in 2010 for the treatment and prevention of different thrombotic events. [1] Conversely, Praxbind® (idarucizumab) is an aptly named humanized monoclonal antibody fragment that binds to dabigatran and reverses its anticoagulant activity. [2] Idarucizumab has been licensed in numerous countries (first approved in the U.S. in 2015) [3] based on preliminary results from the first 90 patients enrolled in the Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD) trial. [4]

Idarucizumab for Dabigatran Reversal — Full Cohort Analysis [5]
Design A multicenter, prospective, single-cohort study; N= 503
Objective To determine whether 5 g of intravenous Praxbind® (idarucizumab) would be able to reverse the anticoagulant effect of dabigatran in patients with either uncontrolled bleeding or those about to undergo an urgent procedure
Study Groups Group A (uncontrolled bleeding); n= 301

Group B (urgent surgery); n= 202

Methods Eligible patients were adults currently receiving dabigatran and falling into one of the following two groups:

·       Group A – patients with uncontrollable or life-threatening bleeding requiring rapid anticoagulant reversal

·       Group B – patients about to undergo invasive surgical procedures that could not be delayed for at least eight hours and requiring normal hemostasis

All patients received 5g of intravenous (IV) idarucizumab, administered as two 50 ml bolus infusions, 15 minutes apart.

Duration June 2014 – July 2016
Primary Outcome Measure The maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours of idarucizumab administration
Baseline Characteristics
Characteristic Group A (n= 301) Group B (n= 202) Total (n=503)
Age, yr
    Median 79 77 78
    Range 24 – 96 21- 96 21- 96
Male sex, no. (%) 172 (57.1) 102 (50.5) 274 (54.5)
Weight, kg
    Median 74 77 75
    Range 35-231 39- 169 35- 231
Race/ethnicity, no. (%)
    White 239 (79.4) 175 (86.6) 414 (82.3)
    Asian 29 (9.6) 8 (4.0) 37 (7.4)
    Hawaiian/Pacific Islander 16 (5.3) 14 (6.9) 30 (6.0)
    Other 17 (5.6) 5 (2.5) 22 (4.4)
Coexisting condition, no. (%)
    Hypertension 237 (78.7) 157 (77.7) 394 (78.3)
    Congestive heart failure 117 (38.9) 65 (32.2) 182 (36.2)
    Diabetes 95 (31.6) 57 (28.2) 152 (30.2)
    Coronary artery disease 110 (36.5) 68 (33.7) 178 (35.4)
    Previous stroke 73 (24.3) 36 (17.8) 109 (21.7)
    Previous transient ischemic       attack 27 (9.0) 20 (9.9) 47 (9.3)
    Previous systemic embolism 20 (6.6) 16 (7.9) 36 (7.2)
    Previous major bleeding 27 (9.0) 10 (5.0) 37 (7.4)
    Current cancer 23 (7.6) 20 (9.9) 43 (8.5)
Creatinine clearance
    Value, ml/min
   Median 50.8 56.0 52.6
   Range 6.1-216.9 7.9 – 198.7 6.1-216.9
    Distribution
   ≥80 ml/min 58 (19.3) 50 (24.8) 108 (21.5)
   50 to <80 ml/min 95 (31.6) 68 (33.7) 163 (32.4)
   30 to <50 ml/min 86 (28.6) 41 (20.3) 127 (25.2)
   <30 ml/min 53 (17.6) 38 (18.8) 91 (18.1)
   Missing data 9 (3.0) 5 (2.5) 14 (2.8)
Dose of dabigatran, no. (%)
    150 mg twice daily 94 (31.2) 57 (28.2) 151 (30.0)
    110 mg twice daily 185 (61.5) 126 (62.4) 311 (61.8)
    75 mg twice daily 16 (5.3) 8 (4.0) 24 (4.8)
    Other 3 (1.0) 11 (5.4) 14 (2.8)
Indication for dabigatran, no. (%)
    Atrial fibrillation 288 (95.7) 190 (94.1) 478 (95.0)
    Orthopedic surgery 0 3 (1.5) 3 (0.6)
    Venous thromboembolism 5 (1.7) 4 (2.0) 9 (1.8)
    Other 8 (2.7) 5 (2.5) 13 (2.6)
Time since last intake of dabigatran, hr
    Median 14.6 18.0 15.6
    Range 1.5- 90.4 2.6- 105.8 1.5- 105.8
Elevated ecarin clotting time at baseline, no. (%) 276 (91.7) 185 (91.6) 461 (91.7)
Elevated diluted thrombin time at baseline, no. (%) 244 (81.1) 152 (75.2) 396 (78.7)
Elevated ecarin clotting time or diluted thrombin time at baseline, no. (%) 276 (91.7) 185 (91.6) 461 (91.7)
Results For dabigatran patients (N= 503) with either uncontrolled bleeding or about to undergo an urgent procedure and having a prolonged diluted thrombin time at baseline, idarucizumab reversed anticoagulation rapidly (within four hours) and completely (to a median maximum percentage of 100%, 95% CI 100 to 100) in more than 98% of the patients. No p values were given.
Adverse Effects Common: N/A
Serious: N/A
Percentage that discontinued due to adverse events: N/A
Study Author Conclusions Idarucizumab is a rapid, safe, and efficacious agent for the reversing the anticoagulant effect of dabigatran in emergency situations.

Given the widespread need for antithrombotic therapy, the utility of rapid, safe, and efficacious reversal agents for all of the oral anticoagulants cannot be overstated. Idarucizumab provides exactly that for dabigatran, and is one of the major benefits that dabigatran can currently boast over the other new oral anticoagulants. While the reported results are overwhelmingly conclusive in favor of idarucizumab’s effectiveness, its use is obviously tied to the prescribing frequency of dabigatran; if dabigatran is not the oral agent prescribed, then idarucizumab could not be indicated for. And although no adverse events were reported in the trial, only a small amount of time has transpired since the study was published; additional post-marketing surveillance is needed to ensure that no untoward effects stem from idarucizumab usage.

References

[1] PRADAXA® (dabigatran) oral capsules [Prescribing Information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, 2012.

[2] Schiele F, van Ryn J, Canada K, et al. A specific antidote for dabigatran: functional and structural characterization. Blood 2013;121:3554-3562.

[3] PRAXBIND® (idarucizumab) intravenous injection. [Prescribing Information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, 2015.

[4] Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015;373:511-520.

[5] Pollack CV, Reilly PA, Van ryn J, et al. Idarucizumab for Dabigatran Reversal – Full Cohort Analysis. N Engl J Med. 2017; 377:431-441.

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