1. Dabigatran and other NOAC in the treatment of DVT
Dr Khalid AlHashmi
MD, FRCSPC
Internal Medicine/Hematology/Medical Oncology

2. VTE
- The third most common cause of vascular death after myocardial infarction and stroke. - The current standard treatment is rapidly acting parenteral anticoagulation for 5 to 7 days followed by at least 3 months of treatment with a vitamin K antagonist.

3. Incidence of VTE
- Estimated to affect 350,000 to 600,000 Americans annually. • Contributing to at least 100,000 deaths per year • increases with ageing population.

5. Boulay, F. et al. BMJ 2001;323:

6. Thrombophilia and risk
FII MUTATIO
FVL
PROTEIN S
PROTEIN C
ANTITHROMBIN
DEFECT
2-4
2.10
0.02
Prevalence
*3-4
*4-5
*10
Risk of VTE increased by
Increased?
Increased
Not Increased
Thromboembolism
Increased risk for VTE by
Neonatel Purpura Fulminans
Often Lethal
Homozygous form

7. NEW ORAL ANTICOAGULANTS VS WARFARIN
New Agents
Warfarin
Features
rapid
slow
onset
fixed
variable
Dosing
same
indications no
yes
Food effect
Drug interaction
Monitoring
short
long
Half-life
antidote

8. Some of the New Anticoagulants O:Oral, P:Parenteral
Anti-FXa
Anti-Flla (anti-thrombin)
Rivaroxaban (o) Apixaban (o) Edoxaban (o) Otamixaban (p) LY (o) DX-9065a (p) Betrixiban (o) TK-442 (o)
Dabigatran (o) Odiparcil (o) Flovagatran (p) Pegmusirudin (p) Peg-hirudin (p) Desirudin (p)

14. Thrombin (IIa) inhibition
-Important : - The last enzymatic step in coagulation. - Thrombin also involved in platelet activation. - Activates fibrinogen. - Activates thrombomodulin. - back-activation of F XI, F V and F VIII

15. The New Oral Anticoagulants: Similar Yet Different
DABGATRAN Etexilate
APIXABAN
RIVARXABAN
FEATURES
IIa Xa
Target
628
460
436
Molecular Weight
Yes No
Prodrug 6 50 80
Bioavailability % 2 3
Time to peak
12-17
9-14 9
Half-life (h) 25 65
Renal excretion (%)
none
antidote

16. NOAC
DVT Prophylaxis. VTE treatment. Post surgical prophylaxis. Stroke prevention in AF. ACS.

17. Dabigatran Etexilate Pradaxa®
Specific, competitive, reversible univalent thrombin inhibitor Rapid onset within 2 hours Low protein binding Half life hours Renal clearance as glucuronic acid conjugate: 85% Metabolized by esterase catalyzed hydrolysis and P-gp transport mechanisms

18. Dabigatran: Clinical Development
ACS
Stroke prevention in AF
DVT
Treatment
Postsurgical prophylaxis of DVT
RE-DEEM
Unpublished
RE-LY
RE-COVER
RE-MODEL
RE-MEDY
RE-MOBIZE
RE-SONATE
RE-NOVATE
RE-NOVATE 2

19. -228 clinical centers in 29 countries
-228 clinical centers in 29 countries. - Recurrent thromboembolism: -30/1274 ((2.4%) dabigatran - 27/1265 (2.1%) warfarin . P value < Major bleeding -20 (1.6%) dabigatran -24 (1.9%) warfarin. HR The numbers of deaths, acute coronary syndromes, and abnormal liver-function tests were similar in the two groups.
Dabigatran versus Warfarin in the Treatment of Acute Venous
Thromboembolism
Sam Schulman,
RE-COVER Study Group
N Engl J Med 2009;
December 10, 2009

20. RE-COVER

21. RE-COVER

22. RE-COVER

23. RE-COVER

24. RE-COVER

25. -completed at least 3 initial months of therapy
In the active-control study,
Recurrent venous thromboembolism :
-26 of 1430 patients in the dabigatran group (1.8%)
-18 of 1426 patients in the warfarin group (1.3%) (hazard ratio with dabigatran, 1.44).
Major bleeding :
-13 patients in the dabigatran group (0.9%)
-25 patients in the warfarin group (1.8%)
(hazard ratio, 0.52; 95% CI, 0.27 to 1.02).
Major or clinically relevant bleeding was less frequent with dabigatran (hazard ratio, 0.54).
Acute coronary syndromes
-13 patients in the dabigatran group (0.9%) and patients in the warfarin group (0.2%) (P=0.02).
================================================
In the placebo-control study,
Recurrent venous thromboembolism
- 3 of 681 patients in the dabigatran group (0.4%)
- 37 of 662 patients in the placebo group (5.6%) (hazard ratio, 0.08; P<0.001).
Major or clinically relevant bleeding
-36 patients in the dabigatran group (5.3%)
- 12 patients in the placebo group (1.8%)
(hazard ratio, 2.92).
Acute coronary syndromes occurred in 1 patient each in the dabigatran and placebo groups.
Extended Use of Dabigatran, Warfarin, or Placebo in Venous Thromboembolism
-Sam Schulman,
-completed at least 3 initial months of therapy
-N Engl J Med 2013;
368:
-RE-MEDY and the RE-
SONATE Trials

27. RE-MEDY and the RE-SONATE Trials

28. RE-MEDY and the RE-SONATE Trials

29. RE-MEDY and the RE-SONATE Trials

30. RE-MEDY and the RE-SONATE Trials

31. 2589 patients with acute VTE treated with low-molecular-weight or unfractionated heparin for 5 to 11 days.
Patients were assigned in a 1:1 ratio to receive active fixed-dose dabigatran 150 mg twice daily and warfarin-like placebo or active warfarin and dabigatran-like placebo
The primary outcome, recurrent symptomatic, objectively confirmed VTE and related deaths during 6 months :
30 of the 1279 dabigatran patients (2.3%)
28 of the 1289 warfarin patients (2.2%)
hazard ratio, 1.08; 95%; P<0.001
major bleeding,
15 patients receiving dabigatran (1.2%)
22 receiving warfarin (1.7%)
hazard ratio, 0.69; 95% CI, 0.36–1.32).
Deaths, adverse events, and acute coronary syndromes were similar in both groups.
Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis.
More Asian
Circulation Feb
18;129(7):764-72
Sam Schalman
RE-COVER II

32. Recover -II

33. RECOVER -II

34. RECOVER-II

35. RECOVER-II
- Dabigatran was noninferior to warfarin for the prevention of recurrent or fatal VTE (P<0.001 for both hazard ratio and difference in absolute risk criteria). - The incidence of different categories of adverse events was similar in the 2 treatment groups. - Dyspepsia was the only drug related adverse event that was more common in the dabigatran group (1.0%).

36. Xarelto® Rivaroxaban
Direct, specific, competitive factor Xa inhibitor Rapid onset within 2-4 hours High bioavailability of >80% Metabolized via the CYP3A4, CYP211, and P-gp transport mechanisminteractions with drugs using the same metabolic pathways Renal and fecal elimination

37. Rivaroxaban: Clinical Development
ACS
STROKE
Prevention in AF
DVT TREATEMNT
POST SURGICAL PROPHYLAXIS
ATLAS
ROCKET-AF
EINSTEIN-DVT
ODIXa-KNEE
ROCKET-J
EINSTEIN-EXT
ODIXa-HIP
EINSTEIN-PE
RECORD-1
RECORD-2
RECORD-3
RECORD-4

38. EINSTEIN

39. EINSTEIN

40. EINSTEIN

41. Noninferiority study
rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) VS subcutaneous enoxaparin followed by a vitamin K antagonist (either warfarin or acenocoumarol).
given rivaroxaban and 1718 given enoxaparin plus a vitamin K antagonist.
- Rivaroxaban (36 events/ 1730) (2.1%).
- Enoxapain/warfarin (51 events/1718 )(3.0%]
HR 0.68; P<0.001.
Oral Rivaroxaban for Symptomatic Venous Thromboembolism
The EINSTEIN Investigators
N Engl J Med 2010; 363:
December 23, 2010

42. EINSTEIN

43. Direct, reversible FXa inhibitor Rapid onset, peak within 3 hrs
Apixaban Eliquis
Direct, reversible FXa inhibitor
Rapid onset, peak within 3 hrs
Bioavailability of %
Long half life, slightly longer in elderly (15 hrs)
Multiple elimination pathways
25% renal
75% biliary
Metabolism via CYP3A4, SULT1AA pathways

44. Apixaban: Clinical Development
ACS
Stroke Prevention In AF
DVT Treatment
Post surgical Prophylaxis of DVT
APPRAISE-1
ARISTOTOLE
Botticelli DVT
Dose ranging study
APROPOS
APPRAIS-2
Terminated-bleedin
AVERROES
AMPLIFY
ADVANCE-1
APPRAISE-Japan
terminated
ADVANCE-2
ADVANCE-3

45. THANK YOU

46. In the continued-treatment study (had been treated for 6 or 12 months with a vitamin K antagonist or rivaroxaban were randomly assigned to receive continued treatment with rivaroxaban or placebo)
-602 patients in the rivaroxaban group
-594 in the placebo group,
rivaroxaban had superior efficacy (8 events [1.3%], vs. 42 with placebo [7.1%]; hazard ratio, 0.18; 95% CI, 0.09 to 0.39; P<0.001).
- Four patients in the rivaroxaban group had nonfatal major bleeding (0.7%), versus none in the placebo group (P=0.11

47. Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism
Noninferiority trail Recurrent venous thrombosis: Rivaroxaban group (2.1%) Standard-therapy group ( (1.8%) (hazard ratio, 1.12) Major bleeding: (1.1%) in the rivaroxaban (2.2%) standard-therapy group (hazard ratio, 0.49)
The EINSTEIN–PE Investigators
N Engl J Med 2012