abelacimab for prevention of venous

1. Abelacimab for Prevention of
Venous
Thromboembolism
Authors Peter Verhamme, M.D., B.
Alexander Yi, M.D., Ph.D., Annelise
Segers, M.D Et all
NEJM August 2021

3. Current recommendation
• For post op VTE prophylaxis current
recommendation
LMWH - SubQ: 40 mg once daily; continue for
length of hospital stay or until patient is fully
ambulatory and risk of VTE has diminished
(ACCP [Kahn 2012]; ASCO [Key 2020])

4. LMWH
• Total hip arthroplasty or hip fracture surgery:
• SubQ: 40 mg once daily or 30 mg every 12
hours, with initial dose administered ≥12
hours preoperatively or ≥12 hours
postoperatively once hemostasis is achieved
(ACCP [Falck-Ytter 2012]; Eriksson 2001; Pai
2020).

5. UFH
• Venous thromboembolism prophylaxis
(alternative agent):
• SubQ: 5,000 units every 8 to 12 hours, with initial
dose given ≥2 hours prior to surgery.
Alternatively, may postpone pharmacologic
prophylaxis until after surgery (eg, high bleeding
risk) when it is safe to initiate. Continue until fully
ambulatory and risk of VTE has diminished
(typically up to 10 days) (ACCP [Gould 2012]; Pai
2019b).

6. UFH
• Orthopedic surgery (eg, hip fracture surgery,
total hip arthroplasty, total knee
arthroplasty): SubQ: 5,000 units every 8 to 12
hours, with initial dose administered ≥12
hours preoperatively or ≥12 hours
postoperatively once hemostasis is achieved;
optimal duration of prophylaxis is unknown,
but it is usually given for a minimum of 10 to
14 days and can be extended for up to 35 days

7. NOAC Rivoroxaban
• Nonmajor orthopedic surgery of lower limb
(alternative therapy) (off-label use):
• Oral: 10 mg once daily initiated ≥6 to 10 hours
after surgery; continue for the duration of
immobilization (Pai 2020; Samama 2020).

8. • Total hip arthroplasty or total knee
arthroplasty :
• Oral: 10 mg once daily initiated ≥6 to 10 hours
after surgery or when hemostasis established.
• Duration: Optimal duration of prophylaxis is
unknown but it is usually given for a minimum
of 10 to 14 days and can be extended for up to
35 days (ACCP [Falck-Ytter 2012]; Eikelboom
2001);

9. • Aspirin is also being considered in VTE
prophylaxis in pts specifically or lower limb ortho
surg
• Ref : Aspirin versus enoxaparin for the initial
prevention of venous
thromboembolism following elective arthroplasty
of the hip or knee:
A systematic review and meta-analysis
Elsivier journal Aug 2020

10. Coagulation Cascade

11. It was observed that…
•
Patients with congenital factor XI deficiency are
at lower risk for venous thromboembolism than
patients with normal factor XI levels, and they
rarely have spontaneous bleeding. Factor
XI can be activated by factor XIIa or by thrombin
and is important for thrombus growth and
stabilization. Abelacimab inhibits the activation of
factor XI by either activator

12. Abelacimab was developed…
• Abelacimab (MAA868) is a fully human
monoclonal antibody that binds to the catalytic
domain
of factor XI and locks it in the zymogen (inactive
precursor) conformation, thereby preventing its
activation by factor XIIa or thrombin.6 The
intravenous infusion of abelacimab almost
immediately reduces the functional factor XI level
in a dose-dependent manner

13. This study AIM
• To compared the efficacy
and safety of abelacimab administered
postoperatively with the efficacy and safety of
enoxaparin in patients undergoing total knee
arthroplasty

14. Methodology
• Trial Design
• phase 2, prospective, randomized, parallel
group trial
• Inclusion Criteria
• 18-80yr age
• Undergoing total knee arthoplasty

16. Exclusion criteria
• The main exclusion criteria were active
bleeding or a high risk of bleeding, a history of
venous thromboembolism
• eGfr <60/1.72m2
• clinically significant
liver disease.

17. Randomisation
• Before surgery, patients were randomly
assigned
in a 1:1:1:1 ratio to receive one of three
regimens
of abelacimab (30 mg, 75 mg, or 150 mg) or
enoxaparin

18. Dose
• Abelacimab, administered in a single intravenous
infusion over
a period of 30 to 60 minutes, was started 4 to
8 hours after surgery.
• Enoxeparin as 40 mg administered subcutaneously
once daily,
was started either the evening before or approximately
12 hours after surgery and was to be
continued until venography was performed.

19. Endpoints
• Day 30 and 110 of study
• Major bleed event (clinically relevent)
• defined as fall in Hb 2 mg due to bleed
• Needing 2 unit RCC
• Resulting in intervention or fatal,
caused hemodynamic instability, or caused
hemarthrosis that delayed mobilization or wound
healing and resulted in prolonged hospitalization
or deep wound infection.

20. Endpoints
Clinically relevant non-major bleeding was
defined as overt bleeding that did not meet the
criteria for major
bleeding but resulted in a medical examination
or an intervention or had clinical consequences

21. Data points
• The activated partial-thromboplastin time
and plasma concentration of abelacimab were
determined before surgery and after surgery on days 3,
10, 30, 50, and 110
• Factor XI activity
and the free factor XI level, which indicates the
concentration of factor XI without bound abelacimab,
were quantified before surgery and after
surgery on days 3, 10, and 30

22. Surveillance and Follow-up
• Patients were evaluated the day before
surgery
and after surgery on days 1, 3, 6, and 10 and
were
contacted on days 30, 50, and 110

23. Results
• Venogram was performed
• Venous thromboembolism occurred in 13 of
102 patients (13%) in the 30-mg abelacimab group
• 5 of 99 patients (5%) in the 75-mg abelacimab
group
• 4 of 98 patients (4%) in the 150-mg
abelacimab group
• 22 of 101
patients (22%) in the enoxaparin group

24. Results
• All three abelacimab regimens met the
criterion for non-inferiority to enoxaparin
• While 75 and 150 mg regime achieve
superiority criteria to enoxaparin (p-<0.001)

25. Major Bleeding
• Clinically relevant bleeding through day 30 occurred in
• 2 of 102 patients (2%) in the 30-mg abelacimab group,
•
• 2 of 104 patients (2%) in
the 75-mg abelacimab group,
• None of 99 patients in the 150-mg abelacimab group
• None of 104 patients in the enoxaparin group

26. Non Major Bleed
• The 2 patients in the 30-mg abelacimab
• One patient in the 75-mg abelacimab group
• Serious A/E
• Serious adverse events occurred during the trial
intervention in 1%, 3%, and 1% of the patients
in the 30-mg, 75-mg, and 150-mg abelacimab
groups, respectively, and in none of the patients
in the enoxaparin group

27. Pharmacodynamics

28. • The levels were low on day 3 with all three
abelacimab regimens and remained low on
day 10 , with the 75-mg and 150-mg regimens
but not with the 30-mg regimen.

29. Discussion
• This trial showed that the single 30-mg dose of
abelacimab was noninferior to enoxaparin for the
prevention of postoperative venous
thromboembolism, and the single 75-mg and 150-mg
doses of abelacimab were superior to enoxaparin, with
incidences of venous thromboembolism of 22%
in the enoxaparin group, 13% in the 30-mg abelacimab
group, 5% in the 75-mg abelacimab
group, and 4% in the 150-mg abelacimab group
The rate of major or clinically relevant nonmajor
bleeding was low in all the trial groups.

30. Summary
• Abelacimab reduced the risk of
postoperative thromboembolism to a greater
extent than conventional anticoagulants such as
enoxaparin, without increasing the risk of
bleeding. Further studies are needed to
determine
whether anticoagulant strategies targeting factor
XI can act as thrombolytic agent?