1. Impact of New Anticoagulants on the Blood Bank
January 24th, 2012
Transfusion Medicine Resident Teaching Session
Dr. Sudeep Shivakumar, Hematology

2. Objectives To briefly review the concepts of hemostasis and thrombosis
To provide an overview of anticoagulants currently in use
To discuss the new anticoagulant agents and their mechanism of action
To review the evidence for the new anticoagulants in DVT/PE and atrial fibrillation
To discuss implications of these medications for the blood bank

3. Overview Anticoagulants are widely used
Vitamin K antagonists used to be the only oral option
Times are changing…

6. Overview Big advantage: Big disadvantage: No lab monitoring
Unpredictability of coagulation tests
No reversal agents
Variety of different agents with different characteristics

7. Background What are anticoagulants? How do they do this?
Substances that prevent blood from clotting
“Blood thinners”
How do they do this?
Interfering with coagulation mechanisms

8. Hemostasis Complex process which causes bleeding to stop:
Formation of blood clot formation at the site of vessel injury
Carefully regulated system
Involves platelets and coagulation factors
Lack of coagulation factors  bleeding
Overactive coagulation cascade  thrombosis

9. Thrombosis The formation of a blood clot within a blood vessel
Can occur in the arterial or venous systems
Leads to obstruction of a blood vessel in the circulatory system
Can lead to ischemia and infarction, and even death
Can also lead to embolism
Clot within a vessel breaks free and travels through body (“embolizes”)
Thromboembolism is combination of a thrombosis and embolus

10. Atrial fibrillation Most common cardiac rhythm disorder
Affects >10% in those > 80 years old
Incidence of atrial fibrillation in 4000 male air crew recruits
Krahn et al, Am J Med, 1995

11. Atrial fibrillation
Lifetime risk for a 40 year old is ~25% (Framingham1)
Independent risk factor for ischemic stroke
Rate of stroke in those not on antithrombotic therapy is ~4.5%/year
Increases the risk of stroke 5x across all age groups
Incidence of stroke increases with age2
1.3% per year for those aged 50-59
5.1% per year for those aged 80-89
1Wolf, Stroke, 1991
2Frost, Am J Med, 2000

12. Anticoagulants in atrial fibrillation
Goal is to prevent stroke
Reduces risk to ~1% per year
Warfarin shown to be more effective than aspirin

13. Warfarin in atrial fibrillation
Better
Control
Better
AFASAK
SPAF
BAATAF
CAFA
SPINAF
EAFT
Aggregate
100%
50%
-100%
-50%
Hart R, et al. Ann Intern Med 1999;131:492

14. Anticoagulants in atrial fibrillation
Most recent Canadian Cardiovascular Society guidelines (2010):
Patients with CHADS2 score of 1 or higher should be on oral anticoagulants

17. Venous thromboembolism
Deep venous thrombosis
Pulmonary embolism

18. Venous thromboembolism
Incidence estimated at 1-2 in 1000
Known predisposing conditions – Virchow’s triad:
Venous stasis
Hypercoagulability
Vessel wall injury

19. Venous thromboembolism
Not uncommon
Longitudinal investigation of thromboembolism etiology (LITE) study1
> participants
Cohort study
Incidence of 1st time VTE = 1.92 per 1000 person years
Major cause of morbidity and mortality
JAMA study2 looking at post-mortems of hospitalized patients between 1966 and 1980
6% of deceased patients had evidence of massive pulmonary embolism
Most common preventable cause of in-hospital death
1Cushman, Am J Med, 2004
2Dismuke, JAMA, 1986

20. Pulmonary embolism Untreated PE Treated PE
Mortality rate of ~30%1
Most die within hours of diagnosis
Treated PE
Prospective NEJM study looked at 399 patients with newly diagnosed PE
94% received anticoagulant treatment
Only 2.5% (10 patients) died of PE
Treatment of PE is life-saving!
1Dalen, Prog Cardiovasc Dis, 1975
2Carson,NEJM, 1992

21. Anticoagulants in DVT/PE
Goals of treatment:
Short term:
Prevent the extension of thrombus and embolization for DVT
Reduce mortality for PE by reducing recurrent events
Relief of symptoms
Long term:
Prevent recurrent events

22. Anticoagulants currently used
Unfractionated heparin
Low molecular weight heparin
Vitamin K antagonists
Ie. warfarin

23. Warfarin Can be reversed: Vitamin K Fresh frozen plasma
Activated prothrombin complex concentrates

24. Warfarin Dosage varies because of: Monitoring by INR necessary!
Vitamin K status
Dietary factors
Nausea/vomiting
Absorption
Activity level
Other medications
Genetics
Monitoring by INR necessary!

25. Difficulties with warfarin use
Requires monitoring
Numerous drug and diet interactions
Narrow therapeutic range
Difficult to control – takes time to get in or out of the system
Role for new anticoagulants?

26. New anticoagulants Many new targets being explored
Eg. thrombin, factor Xa, tissue factor, protein C, factor V and VIII
New agents developed
Direct thrombin inhibitors
Factor Xa inhibitors
Novel anticoagulants
Oral agents increasingly in studies
Venous thromboembolism often studied first because of shorter follow up
Increasing data on dabigatran and rivaroxaban

27. New anticoagulants Ideal anticoagulant: Equally efficacious
Equally safe
No monitoring
Fewer interactions
Oral
Reversible

28. New anticoagulants Direct thrombin inhibitors Factor Xa inhibitors
Dabigatran
Factor Xa inhibitors
Rivaroxaban

29. New anticoagulants
Leung, The Hematologist, 2011

30. Dabigatran
Ximelagatran studies showed possible use for oral direct thrombin inhibitors in atrial fibrillation
Dabigatran
Oral prodrug of dabigatran etixalate
Inhibitor of thrombin
Predictable anticoagulant response
No need for monitoring
Excreted by kidneys
Less than 1% see a transaminase elevation

31. Dabigatran An ideal anticoagulant: No monitoring Fewer interactions
Oral
Reversible
Equally efficacious
Equally safe

32. Dabigatran ✓ ✓ ✓ ✗ ? ? An ideal anticoagulant: No monitoring
Fewer interactions
Oral
Reversible
Equally efficacious
Equally safe ✓ ✓ ✓ ✗ ? ?

33. Dabigatran Pharmacokinetics Half life 12-17 hours
Time to peak, plasma 1 hour
Hepatic metabolism
Not recommended for CrCl <30

34. Dabigatran Many studies for VTE prophylaxis:
REMODEL – thromboprophylaxis after knee surgery
REMOBILIZE – thromboprohylaxis after knee surgery
RENOVATE I and II – thromboprophylaxis after hip surgery
Studies for VTE treatment:
RECOVER – acute VTE treatment
REMEDY – secondary VTE prevention
Studies for atrial fibrillation:
PETRO study – phase II
RELY study – phase III

36. Dabigatran for atrial fibrillation
RELY trial
Looked at stroke prevention in patients with atrial fibrillation
Compared warfarin to dabigatran
> patients
Results:
110 mg BID dose of dabigatran as effective and less bleeding
150 mg BID dose more effective, similar bleeding
Published in NEJM in September 2009 (Connolly et al)

38. Dabigatran for atrial fibrillation
RELY trial
Note trend towards increased MI rates with dabigatran 150 mg BID
Also increased dyspepsia
Consider higher dose if <80 and low risk of bleeding

41. Dabigatran for VTE RECOVER trial
Dabigatran exilate vs warfarin in the treatment of acute thromboembolism
Randomized double blind trial
2539 patients with acute VTE
All treated initially with 5 to 11 days of LMWH or UFH
Randomized to dabigatran 150 mg BID vs warfarin
Primary outcome: objective recurrent VTE, or VTE-related death up to 6 months of treatment

42. Dabigatran for VTE RECOVER trial Results: Recurrent VTE:
34 patients (2.7%) in dabigatran group
32 patients (2.5%) in warfarin group (not significant)
Major bleeding:
20 patients (1.6%) in dabigatran group
24 patients (1.9%) in warfarin group (significant)
Deaths similar between groups
Conclusions:
Dabigatran as safe and efficacious as warfarin
Published in NEJM in December 2009 (Schulman et al)

45. Dabigatran Approved by Health Canada for atrial fibrillation
Not covered by MSI… yet
Not approved for VTE treatment
Costs $2.30 per day

46. Dabigatran and coagulation assays

47. Dabigatran and coagulation assays
aPTT affected at peak concentrations
aPTT >90 sec suggests over-dosing or accumulation
PT not affected
Fibrinogen testing underestimated results in 2 of 4 reagents
Antithrombin levels varied greatly
Overall, unpredictable results, but elevated aPTT suggested accumulation

48. Factor Xa inhibitors
Lack of direct thrombin inhibition = less bleeding?

49. Rivaroxaban Oral, direct factor Xa inhibitor
Potent (greater selectivity for factor Xa than other drugs)
Fixed, once-daily dosing
Predictable pharmacokinetics
Half life 7-11 hours
Peak concentration 4hrs after administration
Excreted via biliary and renal routes
Does have interactions CYP3A4 inhibitors
Ie. ketoconazole, macrolides

51. Rivaroxaban EINSTEIN study
NEJM study (Dec 2010)
Complicated – 2 studies in one
One study compared rivaroxaban to warfarin for DVT/PE
1700 patients
Similar outcomes in both arms for bleeding/thrombosis
No LMWH briding in rivaroxaban arm
Conclusion: rivaroxaban as safe and effective as warfarin
Not currently approved or covered for DVT/PE

53. Rivaroxaban Studied in ROCKET-AF trial
Rivaroxaban once daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation
Phase III, non-inferiority, double-blind study of rivaroxaban 20 mg OD vs. warfarin in patients with non-valvular atrial fibrillation and 2 other stroke risk factors
Recently approved by Health Canada for stroke prevention in atrial fibrillation

54. Rivaroxaban and coagulation assays

55. Rivaroxaban and coagulation assays
aPTT affected at therapeutic doses, but varied greatly
Depended on reagents used
Unpredictable
PT completely unpredictable
Antithrombin levels depended on reagent used
Fibrinogen not affected
Xa (sensitive to rivaroxaban) only affected slightly
Overall, varied, unpredictable results

56. Bleeding
~2% of patients/year on long term anticoagulants will end up with a major bleed requiring medical attention
Holding anticoagulants is the first step, but often other steps are needed
Depends on anticoagulant

58. Bleeding Warfarin Give vitamin K 5-10 mg Fresh frozen plasma Octaplex
Prothrombin complex concentrate
Works within 1 hour
More effective than plasma at reversing INR
Small volume
40 ml usually enough for most patients
$$$$$

59. Reversal of new anticoagulants
Warfarin had several predictable options for reversal:
Vitamin K
Fresh frozen plasma
Activated prothrombin complex concentrates
No reversal agents for new anticoagulants

60. Circulation, 2011

61. Reversal using PCC Randomized, double-blind, placebo controlled study
12 healthy male volunteers received rivaroxaban 20mg BID or dabigatran 150 mg BID for 2.5 days
Followed by bolus of 50IU/kg PCC (Cofact) or saline
Procedure then repeated with the other anticoagulant treatment

62. Reversal using PCC Rivaroxaban: Dabigatran: Prolonged the PT
Immediately reversed by PCC completely
Endogenous thrombin potential inhibited
Also completely normalized with PC
Dabigatran:
Affected PTT, ecarin clotting time, and thrombin time
Not reversed by PCC

65. Bleeding Dabigatran, rivaroxaban and other new agents
No known antidotes
Half-lives roughly hours
Blood product support
Fresh frozen plasma
Consider activated factor VIIa if ongoing bleed
Watch for thrombosis

66. Reversal of new anticoagulants
Suggested approach:
Transfuse as necessary
Packed red blood cells
Platelets if less than 50
Consider use of other blood products
Fresh frozen plasma
Activated factor VII
No good evidence!

68. Summary New anticoagulants are coming that may replace warfarin
Dabigatran has been approved for atrial fibrillation, and will likely be approved for DVT/PE
Rivaroxaban has been approved for atrial fibrillation, and will likely be approved for DVT/PE
No antidotes for new agents
Coagulation tests not standardized
Research needed!

69. Thank you!