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Impact of New Anticoagulants on the Blood Bank

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Presentation on theme: "Impact of New Anticoagulants on the Blood Bank"— Presentation transcript:

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!

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