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

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

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

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

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

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

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

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

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

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

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

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

Venous thromboembolism Deep venous thrombosis Pulmonary embolism

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

Venous thromboembolism Not uncommon Longitudinal investigation of thromboembolism etiology (LITE) study1 >21 000 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 3 412 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

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

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

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

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

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!

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?

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

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

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

New anticoagulants Leung, The Hematologist, 2011

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

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

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

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

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

Dabigatran for atrial fibrillation RELY trial Looked at stroke prevention in patients with atrial fibrillation Compared warfarin to dabigatran >18 000 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)

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

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

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)

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

Dabigatran and coagulation assays

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

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

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

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

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

Rivaroxaban and coagulation assays

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

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

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 $$$$$

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

Circulation, 2011

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

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

Bleeding Dabigatran, rivaroxaban and other new agents No known antidotes Half-lives roughly 11-14 hours Blood product support Fresh frozen plasma Consider activated factor VIIa if ongoing bleed Watch for thrombosis

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!

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!

Thank you! shivakumars@cdha.nshealth.ca