報告者 : 輔醫M6 李英誠

指導老師：蔡忠芬醫師
This article was published on July 11, 2017, at NEJM.org.
DOI: 10.1056/NEJMoa1707278
Copyright © 2017 Massachusetts Medical Society.
1
Introduction
 Idarucizumab, a monoclonal antibody fragment, can
reverse the anticoagulant effect of dabigatran(Pradaxa)

2
Method
 Multicenter, prospective, single-cohort study
 Patient : two groups, receiving dabigatran, Age>18,
 Group A - uncontrollable or life-threatening bleeding
 ICH / GI bleeding / Trauma
 Group B - undergo surgery or other invasive procedures
that could not be delayed for at least 8 hours
 Acute abdomen / Fracture
 Treatment
 IV 5g idarucizumab, two 50-ml bolus infusions
 (2.5g each), no more than 15 minutes
3
 Method-2
• Primary end point
• Maximum percentage reversal of the anticoagulant effect
of dabigatran, 1st infusion ~ 4hr
• Complete reversal – decrease Dtt or Ect to a normal level
• 1. Diluted thrombin time 2. Ecarin clotting time
• 3. aPTT 4. Concentration of unbound Dabigatran
first infusion 10 - 30(min) 1 2 4 12 24 (hr)

• Treating clinicians were unaware of the result

• A second 5-g was permitted
4
 Method-3
• Secondary end point (Clinical outcome, clinician)
• Group A – extent of bleeding and hemodynamic stability
• Group B – periprocedural hemostasis
• Classified as Normal / Mildly / Moderately / Severely
• Adverse event (within 5 days)
• Thrombotic event
• Mortality 30 and 90 days (Vascular or nonvascular)

5
Statistic Analysis
 Primary end point
 Pretreatment Dtt or Ect above normal limit are assessed
at a central lab
 Confidence interval or percentile

6
Result
• Characteristric of Patient
• June 2014 - July 2016, total 503 patients
(301 in group A and 202 in group B)
• 95% of the patients were receiving dabigatran for stroke
prevention (+Af), median age 78
• last dose of dabigatran to the first infusion of
idarucizumab group A (14.6 hr), group B(18.0 hr)
• 43.3% had a creatinine clearance less than 50 ml per
minute

7
Result-2
• Group A (301)
• 137 (45.5%) gastrointestinal bleeding
• 98 (32.6%) had intracranial hemorrhage
• 78 (25.9%) had trauma
• Group B(202)
• 197 (97.5%) underwent the intended surgery or
intervention
• median time from the first infusion to the procedure was
1.6hr

8
Result-3
 Primary end point - Reversal of anticoagulation

 Median maximum percentage reversal within 4 hours after

the administration of idarucizumab was 100%
 Independently of age, sex, renal function, and dabigatran
concentration at baseline.
9
Result-4
 Primary end point - Reversal of anticoagulation

10
Result-4
 Dabigatran Concentration

114/497 11
Result-5
• Secondary end point – clinical outcome
• Group A, 301
• 98 patients with intracranial bleeding
time to cessation of bleeding ???
• Remaining 203 patients in group A, 134 (67.7%) had
confirmed bleeding cessation within 24 hours
• Median time to hemostasis 2.5 hours
• Could not be determined in 67 patients
• Bleeding stopped before treatment in 2 patients

12
Result-5
 Secondary end point – clinical outcome
 Group B, 202
 197 patients underwent surgery or an intervention,
periprocedural hemostasis was assessed
 normal in 184 patients (93.4%),
 mildly abnormal in 10 (5.1%),
 moderately abnormal in 3 (1.5%)
 no patients had severely abnormal hemostasis.

13
Result-5
 Mortality rate
Mortality Group A Group B
30day 13.5% 12.6%
90day 18.8% 18.9%
within 5 days 6.3% 7.9%

Mortality ICH GI bleeding Bleeding at

other site

30day 16.4% 11.1% 12.7%

14
Result-6
 Thrombotic event
 Within 30 days - 24 / 503 patients (4.8%; 14 in group A
and 10 in group B)
 Within 90 days - 34 / 503 patient (6.8%; 19 in group A
and 15 in group B)

15
Result-6
 Thrombotic
event

16
Result-7
 Immunogenicity
 Anti-idarucizumab antibodies were detected in 28
(5.6%) of the 501 patients
 19 before infusion, 9 developed during treatment
 Titer gernerally low
 Hypersensitivity
 Rash*1 (+ ondansetron / tramadol 2 days before)
 Vomiting and loss of conciousness in ICH patient
 Hypotention during infusion
 Anaphylaxis*1 (+amoxicillin)
17
Result-8
 Other safety outcome (within 5 days)
 Serious adverse events - 117 patients (23.3%)
 66 (23.3%) in Group A, 51 (25.2%) in Group B
 Most Frequent
 Delirium
 Cardiac arrest
 Septic shock

18
Discussion
 Idarucizumab reversed anticoagulation rapidly and
completely (100%) in 503 patient,
• Group A : overt bleeding evaluation, stop in 2.5hr
• Group B : enable 197/202 going to surgery 1.6hr

19
Discussion-2
• Matained for 24hr in most of the patient (114/497)
• Recurrent elevation in clotting time, between 12 and 24
hour in 114 patients
• redistribution of unbound dabigatran
• (extravascular to the intravascular )
 Safe to use even if patients have little circulating
dabigatran.

20
Discussion 3
 30-day, 90-day mortality rate was similar in group A
and group B
 related to the severity or coexisting conditions
 30-day mortality rate lower compared to other wafarin
study Mortality Group A Group B
30day 16.4% (ICH) 12.6%
30day(wafarin) 50% (ICH) 30%

 Similar to Andexanet (reversal of Factor Xa )study

 15%, in serious bleeding
21
Discussion-4
 Thrombotic event 4.8% at 30 days and 6.8% at 90 days
 similar in group A(5.0%) and group B(4.6%)
 consistent with major bleeding or major surgery
 Half-life of idarucizumab : 45min

22
Discussion-5
 Strength
 Broad inclusion criteria
 Useful clinical practice
 Limitation
 Lack of control group

23
Conclusion
 Idarucizumab is effective for dabigatran reversal
within 4 hr (100%)
 uncontrolled bleeding
 urgent surgery

24
Thanks for your listening!

25