ASH Clinical News September 2017 New | Page 39

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CLINICAL NEWS

Is Idarucizumab the First “ Antidote ” to a Direct Oral Anticoagulant ?

Idarucizumab “ rapidly and completely ” reversed the bloodthinning effects of the direct oral anticoagulant dabigatran in patients who had uncontrolled bleeding or were about to undergo an emergency procedure , according to results from the RE-VERSE AD ( Reversal Effects of Idarucizumab on Active Dabigatran ) trial published in the New England Journal of Medicine .
In the multicenter , prospective , single-cohort trial , Charles V . Pollack Jr ., MD , from Thomas Jefferson University in Philadelphia , Pennsylvania , and co-authors enrolled 503 adult patients ( median age = 78 years ; range = 21-96 years ) who were receiving dabigatran between June 2014 and July 2016 : 301 had uncontrollable or life-threatening bleeding that required rapid anticoagulant reversal ( group A ), and 202 were about to undergo surgery or an invasive procedure that required normal hemostasis ( group B ).
The study inclusion criteria were kept intentionally broad to reflect real-world clinical practice , the authors noted , adding that the protocol “ was designed to mimic routine emergency care ,” and patients received idarucizumab without coagulation studies and regardless of clinical presentation .
In group A , most bleeding events were gastrointestinal ( n = 137 ; 45.5 %) or intracranial ( n = 98 ; 32.6 %). In group B , the most common reasons for an urgent procedure were abdominal condition or infection ( n = 49 ; 24.3 %), fracture or septic arthritis ( n = 41 ; 20.3 %), and cardiovascular condition ( n = 37 ; 18.3 %). Most patients ( n = 478 ; 95 %) were receiving dabigatran for atrial fibrillation .
Idarucizumab 5 g was administered intravenously as two 50 mL bolus infusions , each containing 2.5 g of idarucizumab and given no more than 15 minutes apart . The median patient-reported time from last dabigatran dose to idarucizumab infusion was 15.6 hours ( range = 1.5-105.8 hours ).
A total of 461 patients ( 97.1 %; 276 in group A and 185 in group B ) had coagulation measurements ( diluted thrombin time or ecarin clotting time ) available at baseline and were included in the primary efficacy analysis . Within four hours of idarucizumab administration , the median maximum percentage reversal of dabigatran ( primary endpoint ) was 100 percent ( 95 % CI 100-100 ) in 98 percent of patients . “ Reversal was rapid and occurred independently of age , sex , renal function , and dabigatran concentration at baseline ,” the authors reported .
Before idarucizumab was administered , the median baseline concentration of unbound dabigatran was 110 ng / mL in group A and 73.6 ng / mL in group B ; after idarucizumab , the concentration dropped to ≤20 ng / mL in all but three patients . These concentrations remained at ≤20 ng / mL for 24 hours in the majority of patients but increased in 23 percent of patients ( n = 114 / 497 ), mostly after 12 hours . Sixty-seven patients had elevated levels only at the 24-hour measurement .
Elevated dabigatran concentration levels that persisted for more than 24 hours were associated with recurrent or continuous bleeding

“ Reversal was rapid and occurred independently of age , sex , renal function , and dabigatran concentration at baseline .”

— CHARLES V . POLLACK JR ., MD in 10 patients in group A ( none in group B ), three of whom received an additional dose of idarucizumab . After 24 hours , their median idarucizumab concentration decreased to < 1 percent of the peak median , “ a finding consistent with the short half-life of idarucizumab ,” the authors noted .
Nine patients ( 1.8 %) in the entire cohort received > 5 g of idarucizumab , including three in group A who had recurrent bleeding .
Ninety-eight patients in group A were not evaluable for cessation of bleeding ; among the other 203 patients , 134 ( 67.7 %) had confirmed bleeding cessation within 24 hours , and the median time to hemostasis after idarucizumab was 2.5 hours ( 95 % CI 2.2-3.9 ).
In group B , 197 patients underwent their planned procedure a median of 1.6 hours after idarucizumab administration ( range not provided ), and 184 of those patients ( 93.4 %) had normal hemostasis after surgery . The remaining patients had mildly abnormal ( 5.1 %) or moderately abnormal ( 1.5 %) hemostasis .
The 30-day mortality rate was 13.5 percent in group A and 12.6 percent in group B , and the 90-day mortality rates were 18.8 percent and 18.9 percent , respectively . Nineteen patients in group A ( 6.3 %) and 16 in group B ( 7.9 %) died within five days of idarucizumab treatment .
Idarucizumab did not appear to have a “ procoagulant ” effect , with thrombotic events occurring in 24 patients ( 4.8 %) within
30 days of treatment ( 14 in group A and 10 in group B ). Three days after idarucizumab infusion , 22.9 percent of patients in group A and 66.8 percent of patients in group B restarted anticoagulation or antiplatelet therapy .
Within five days of idarucizumab administration , 117 patients

“ The safety of idarucizumab ... supports its urgent use , even if patients later prove to have had little or no circulating dabigatran .”

— CHARLES V . POLLACK JR ., MD
( 23.3 %) experienced serious adverse events ( AEs ). In group A , the most common AE was delirium ( 2.3 %), and in group B the most common AEs were cardiac arrest ( 3.5 %) and septic shock ( 3.0 %). The other most frequently reported AEs were worsening of the index event or a coexisting condition .
Overall , the researchers did not observe any “ serious adverse safety signals ” with idarucizumab . “ The safety of idarucizumab observed in this study supports its urgent use , even if patients later prove to have had little or no circulating dabigatran .”
The study is limited by its lack of a control group , and some patients had normal clotting times at study entry . Because experience with direct oral anticoagulants is limited , there also are no standardized measures for determining effective and ineffective anticoagulation reversal .
Dr . Pollack and contributing authors report financial support from Boehringer Ingelheim , which supported the study and is the manufacturer of idarucizumab .
REFERENCE
Pollack CV , Reilly PA , van Ryn J , et al . Idarucizumab for dabigatran reversal — full cohort analysis . N Engl J Med . 2017 ; 377:431-41 .
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