Presentation on theme: "Impact of New Anticoagulants on the Blood Bank"— Presentation transcript:
1 Impact of New Anticoagulants on the Blood Bank January 24th, 2012Transfusion Medicine Resident Teaching SessionDr. Sudeep Shivakumar, Hematology
2 Objectives To briefly review the concepts of hemostasis and thrombosis To provide an overview of anticoagulants currently in useTo discuss the new anticoagulant agents and their mechanism of actionTo review the evidence for the new anticoagulants in DVT/PE and atrial fibrillationTo discuss implications of these medications for the blood bank
3 Overview Anticoagulants are widely used Vitamin K antagonists used to be the only oral optionTimes are changing…
6 Overview Big advantage: Big disadvantage: No lab monitoring Unpredictability of coagulation testsNo reversal agentsVariety 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 injuryCarefully regulated systemInvolves platelets and coagulation factorsLack of coagulation factors bleedingOveractive coagulation cascade thrombosis
9 Thrombosis The formation of a blood clot within a blood vessel Can occur in the arterial or venous systemsLeads to obstruction of a blood vessel in the circulatory systemCan lead to ischemia and infarction, and even deathCan also lead to embolismClot 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 oldIncidence of atrial fibrillation in 4000 male air crew recruitsKrahn et al, Am J Med, 1995
11 Atrial fibrillationLifetime risk for a 40 year old is ~25% (Framingham1)Independent risk factor for ischemic strokeRate of stroke in those not on antithrombotic therapy is ~4.5%/yearIncreases the risk of stroke 5x across all age groupsIncidence of stroke increases with age21.3% per year for those aged 50-595.1% per year for those aged 80-891Wolf, Stroke, 19912Frost, Am J Med, 2000
12 Anticoagulants in atrial fibrillation Goal is to prevent strokeReduces risk to ~1% per yearWarfarin shown to be more effective than aspirin
13 Warfarin in atrial fibrillation BetterControlBetterAFASAKSPAFBAATAFCAFASPINAFEAFTAggregate100%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 thrombosisPulmonary embolism
18 Venous thromboembolism Incidence estimated at 1-2 in 1000Known predisposing conditions – Virchow’s triad:Venous stasisHypercoagulabilityVessel wall injury
19 Venous thromboembolism Not uncommonLongitudinal investigation of thromboembolism etiology (LITE) study1> participantsCohort studyIncidence of 1st time VTE = 1.92 per 1000 person yearsMajor cause of morbidity and mortalityJAMA study2 looking at post-mortems of hospitalized patients between 1966 and 19806% of deceased patients had evidence of massive pulmonary embolismMost common preventable cause of in-hospital death1Cushman, Am J Med, 20042Dismuke, JAMA, 1986
20 Pulmonary embolism Untreated PE Treated PE Mortality rate of ~30%1Most die within hours of diagnosisTreated PEProspective NEJM study looked at 399 patients with newly diagnosed PE94% received anticoagulant treatmentOnly 2.5% (10 patients) died of PETreatment of PE is life-saving!1Dalen, Prog Cardiovasc Dis, 19752Carson,NEJM, 1992
21 Anticoagulants in DVT/PE Goals of treatment:Short term:Prevent the extension of thrombus and embolization for DVTReduce mortality for PE by reducing recurrent eventsRelief of symptomsLong term:Prevent recurrent events
22 Anticoagulants currently used Unfractionated heparinLow molecular weight heparinVitamin K antagonistsIe. 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 statusDietary factorsNausea/vomitingAbsorptionActivity levelOther medicationsGeneticsMonitoring by INR necessary!
25 Difficulties with warfarin use Requires monitoringNumerous drug and diet interactionsNarrow therapeutic rangeDifficult to control – takes time to get in or out of the systemRole for new anticoagulants?
26 New anticoagulants Many new targets being explored Eg. thrombin, factor Xa, tissue factor, protein C, factor V and VIIINew agents developedDirect thrombin inhibitorsFactor Xa inhibitorsNovel anticoagulantsOral agents increasingly in studiesVenous thromboembolism often studied first because of shorter follow upIncreasing data on dabigatran and rivaroxaban
28 New anticoagulants Direct thrombin inhibitors Factor Xa inhibitors DabigatranFactor Xa inhibitorsRivaroxaban
29 New anticoagulantsLeung, The Hematologist, 2011
30 DabigatranXimelagatran studies showed possible use for oral direct thrombin inhibitors in atrial fibrillationDabigatranOral prodrug of dabigatran etixalateInhibitor of thrombinPredictable anticoagulant responseNo need for monitoringExcreted by kidneysLess than 1% see a transaminase elevation
31 Dabigatran An ideal anticoagulant: No monitoring Fewer interactions OralReversibleEqually efficaciousEqually safe
32 Dabigatran ✓ ✓ ✓ ✗ ? ? An ideal anticoagulant: No monitoring Fewer interactionsOralReversibleEqually efficaciousEqually safe✓✓✓✗??
33 Dabigatran Pharmacokinetics Half life 12-17 hours Time to peak, plasma 1 hourHepatic metabolismNot recommended for CrCl <30
34 Dabigatran Many studies for VTE prophylaxis: REMODEL – thromboprophylaxis after knee surgeryREMOBILIZE – thromboprohylaxis after knee surgeryRENOVATE I and II – thromboprophylaxis after hip surgeryStudies for VTE treatment:RECOVER – acute VTE treatmentREMEDY – secondary VTE preventionStudies for atrial fibrillation:PETRO study – phase IIRELY study – phase III
36 Dabigatran for atrial fibrillation RELY trialLooked at stroke prevention in patients with atrial fibrillationCompared warfarin to dabigatran> patientsResults:110 mg BID dose of dabigatran as effective and less bleeding150 mg BID dose more effective, similar bleedingPublished in NEJM in September 2009 (Connolly et al)
41 Dabigatran for VTE RECOVER trial Dabigatran exilate vs warfarin in the treatment of acute thromboembolismRandomized double blind trial2539 patients with acute VTEAll treated initially with 5 to 11 days of LMWH or UFHRandomized to dabigatran 150 mg BID vs warfarinPrimary 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 group32 patients (2.5%) in warfarin group (not significant)Major bleeding:20 patients (1.6%) in dabigatran group24 patients (1.9%) in warfarin group (significant)Deaths similar between groupsConclusions:Dabigatran as safe and efficacious as warfarinPublished in NEJM in December 2009 (Schulman et al)
47 Dabigatran and coagulation assays aPTT affected at peak concentrationsaPTT >90 sec suggests over-dosing or accumulationPT not affectedFibrinogen testing underestimated results in 2 of 4 reagentsAntithrombin levels varied greatlyOverall, unpredictable results, but elevated aPTT suggested accumulation
48 Factor Xa inhibitorsLack 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 dosingPredictable pharmacokineticsHalf life 7-11 hoursPeak concentration 4hrs after administrationExcreted via biliary and renal routesDoes have interactions CYP3A4 inhibitorsIe. ketoconazole, macrolides
51 Rivaroxaban EINSTEIN study NEJM study (Dec 2010)Complicated – 2 studies in oneOne study compared rivaroxaban to warfarin for DVT/PE1700 patientsSimilar outcomes in both arms for bleeding/thrombosisNo LMWH briding in rivaroxaban armConclusion: rivaroxaban as safe and effective as warfarinNot 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 fibrillationPhase 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 factorsRecently approved by Health Canada for stroke prevention in atrial fibrillation
55 Rivaroxaban and coagulation assays aPTT affected at therapeutic doses, but varied greatlyDepended on reagents usedUnpredictablePT completely unpredictableAntithrombin levels depended on reagent usedFibrinogen not affectedXa (sensitive to rivaroxaban) only affected slightlyOverall, varied, unpredictable results
56 Bleeding~2% of patients/year on long term anticoagulants will end up with a major bleed requiring medical attentionHolding anticoagulants is the first step, but often other steps are neededDepends on anticoagulant
58 Bleeding Warfarin Give vitamin K 5-10 mg Fresh frozen plasma Octaplex Prothrombin complex concentrateWorks within 1 hourMore effective than plasma at reversing INRSmall volume40 ml usually enough for most patients$$$$$
59 Reversal of new anticoagulants Warfarin had several predictable options for reversal:Vitamin KFresh frozen plasmaActivated prothrombin complex concentratesNo reversal agents for new anticoagulants
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 daysFollowed by bolus of 50IU/kg PCC (Cofact) or salineProcedure then repeated with the other anticoagulant treatment
62 Reversal using PCC Rivaroxaban: Dabigatran: Prolonged the PT Immediately reversed by PCC completelyEndogenous thrombin potential inhibitedAlso completely normalized with PCDabigatran:Affected PTT, ecarin clotting time, and thrombin timeNot reversed by PCC
65 Bleeding Dabigatran, rivaroxaban and other new agents No known antidotesHalf-lives roughly hoursBlood product supportFresh frozen plasmaConsider activated factor VIIa if ongoing bleedWatch for thrombosis
66 Reversal of new anticoagulants Suggested approach:Transfuse as necessaryPacked red blood cellsPlatelets if less than 50Consider use of other blood productsFresh frozen plasmaActivated factor VIINo 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/PERivaroxaban has been approved for atrial fibrillation, and will likely be approved for DVT/PENo antidotes for new agentsCoagulation tests not standardizedResearch needed!