3History of anticoagulant therapy Oral thrombin and Xa inhibitorsWarfarin mechanism elucidated (J. Suttie)Warfarin clinical trialsAnticoagulant in spoiled sweet clover (K.P. Link)First clinical use of 4-hydroxycoumarin (O. Meyer et al)Warfarin dosing/INRParenteral anticoagulants – heparin early 20th C. Incredible shrinking drug; heparin derivatives still drugs of choice for treatment of acute VTE, in-hospital prophyOral anticoagulants – Wisconsin connectionHeparin discovered by medical student (McLean)Clinical use of heparinCont infusion of heparin; aPTT monitoringLMWH trialsRequirement for plasma cofactor discovered(K. Brinkhous)LMWH(J. Hirsch)Fondaparinux trials
4New oral anticoagulants Dabigatran (Pradaxa®) – thrombin inhibitorFDA approval 2010: stroke prevention in non-valvular AfibRivaroxaban (Xarelto®) – Xa inhibitorFDA approval 2010/11: postop VTE prophylaxis, stroke prevention in Afib, treatment of VTEApixaban (Eliquis®) – Xa inhibitorFDA approval 2012: stroke prevention in Afib; approved 2014 for VTE prophylaxis after major orthopedic surgeryEdoxaban – Xa inhibitorNot yet FDA approved
5Anticoagulant drug mechanisms Indirect inhibitorsDirect inhibitorsIndirect vs direct inhibitors. Parenteral vs oral. Thrombin vs Xa. Note that warfarin doesn’t block actions of clotting factors but just lowers blood levels.Ansell, 2011 HTRS meeting
7Pharmacology of oral anticoagulant drugs WarfarinNew agentsBioavailability99%6-80% (some active drug in large bowel)Tmax72-96 hours2-4 hoursHalf-life40 hours5-17 hoursMetabolismCytochrome P450Biliary/RenalDrug InteractionsManyNot so manyFood InteractionsYesNoGenetic VariationMajor effectsMinor effects (?)MonitoringPT/INRNoneReversalVit K/PCC/FFPPCC?Dialysis?
8Cost per month of oral anticoagulants Rivaroxaban (20 mg/day) : $290Dabigatran (150 mg bid): $290Apixaban (5 mg bid): $147Warfarin (7.5 mg/day): $31About 10x as expensive as warfarin, but much cheaper than LMWH.Source: UWHC Pharmacy
9Dabigatran Dose Stroke prevention in A fib: 110-150 mg bid 110 mg dose not available in USFor patients with CrCl 15-30: 75 mg bidNot recommended for CrCl < 15 or dialysis dependentPostop VTE prophylaxis*: mg once dailyPrevention of recurrent VTE*: 150 mg bidLess than 10% absorbed; relatively high rate of GI side effectsCrosses the placenta – do not use during pregnancyDrug may degrade over time after exposure to air – must be kept in original packagingUnused tablets should be discarded after 90 days* Not FDA-approved indication
10Rivaroxaban Dose: Stroke prevention in Afib: 15-20 mg once daily Post op VTE prophylaxis: 10 mg once dailyAcute VTE treatment: 15 mg twice dailySecondary prevention of VTE: 20 mg once dailyAcute coronary syndrome*: mg twice dailyUse with caution in moderate renal impairment (CrCL 30-49); 15 mg/day dose recommendedAvoid use if CrCl < 30 (not dialyzable)Avoid use in severe liver disease*Not FDA-approved indicationTreatment trials have used higher/BID doses of R initially
11Apixaban Dose: Stroke prevention in Afib: 5 mg bid 2.5 mg bid if age >80, weight < 60 kg, or serum creatinine > 1.5Post op VTE prophylaxis*: 2.5 mg bidSecondary prevention of VTE*: mg bidTreatment of acute VTE*: 10 mg bidSecondary prevention of VTE*: 5 mg bidAvoid use in severe liver disease (75% biliary excretion)Less dependent on renal excretion – safer in pts with renal insuff? Less safe in pts with liver dz?*Not FDA-approved indication
13NEW ORAL ANTICOAGULANTS VS WARFARIN IN NON-VALVULAR ATRIAL FIBRILLATION Drug being compared# subjectsCHADS2(mean)TTR(median)RE-LYDabigatran(two doses)18,1132.167%ROCKET-AFRivaroxaban14,2643.558%ARISTOTLEApixaban18,20166%ENGAGEAF-TIMI 48Edoxaban21,1052.868%All randomized; RE-LY unblindedAll designed as non-inferiority trialsPrimary outcome was stroke or embolismAll funded by drug manufacturerNEJM 2009; 361: 1139NEJM 2011; 365:883NEJM 2011; 365:981
14NEW ORAL ANTICOAGULANTS VS WARFARIN: RISK OF STROKE OR EMBOLISM Dabigatran 150 mg bidRivaroxaban 20 mg qdApixaban 5 mg bidEdoxaban 60 mg qdCombinedRuff et al, Lancet 2013
15NEW ORAL ANTICOAGULANTS VS WARFARIN: SECONDARY EFFICACY AND SAFETY OUTCOMES Ruff et al, Lancet 2013
16NEW ORAL ANTICOAGULANTS VS WARFARIN: RISK OF MAJOR BLEEDING Dabigatran 150 mg bidRivaroxaban 20 mg qdApixaban 5 mg bidEdoxaban 60 mg qdCombinedRuff et al, Lancet 2013
17Bleeding rates with dabigatran vs warfarin as a function of age Intracranial bleeding lower with dabigatran at all agesExtracranial bleeding rates higher with dabigatran above age 75Circulation 2011;123:2363
18Dabigatran use associated with higher risk of coronary events ←Risk lower with dabigatran Risk higher with dabigatran→Arch Intern Med 2012;172:397
19LESSONS FROM AF TRIALS WITH NEW ORAL AGENTS Main result: New agents at least as effective as warfarin, can be given without routine monitoringOther/unexpected findings:Reduction in intracranial bleedingHigher MI rates (dabigatran)Higher rates of GI bleeding (active drug in lower intestine)Extracranial bleeding risk higher in older patients
20Relative efficacy and safety of apixaban vs warfarin, according to adequacy of individual INR controlFavors apixaban Favors warfarinThe benefit of switching from warfarin to a NOAC appears to be greatest in patients with relatively poor INR controlThis is patient-level data comparing outcomes with apixaban and warfarin (in Afib) vs adequacy of anticoagulant control in warfarin pts vs matched controls. Bottom group is all adverse outcomes (bleeding or clotting), note that the benefit of apixaban greatest when warfarin control is worstWallentin et al, Circulation 2013
21Can the new oral agents be used in patients with mechanical valves? Randomized trial of dabigatran vs warfarin in patients with mechanical valves showed more thrombotic complications (5% vs 0) and more bleeding (4% vs 2%) with dabigatran (Eikelboom et al, NEJM 2013; 369:1206)DO NOT USE NOACs IN PATIENTS WITH MECHANICAL VALVES
27Less thrombosis, more bleeding with NOACs NOACs vs LMWH after total hip or knee arthroplasty A systematic review of the literatureDabigatran vs LMWHXa inhibitors vs LMWHMortalityLess thrombosis, more bleeding with NOACsSymptomatic DVTNonfatal PEMajor bleedingAnn Intern Med 2013;159:275
29New oral anticoagulants plus antiplatelet therapy in ACS: meta-analysis Favors NOA Favors placeboNon-significant decrease in overall mortality, large increase in risk for major bleedingFour trials of R vs E in high risk ortho surgery all showed better efficacy for R. Note bleeding rates for R are somewhat higher across the board.Arch Intern Med 2012; 172:1537
31Effects of NOACs on routine coag tests PT/INR and PTT are relatively insensitive to the effects of these drugsReagent-dependent – results will vary among labsNormal PT and PTT do not rule out significant blood level of NOACIf PT or PTT elevated → assume significant blood levels of NOACThrombin time very sensitive to dabigatran effect – normal TT implies no drug on boardRivaroxaban & apixaban do not affect TT
32Measuring blood levels of NOACs Dabigatran:Modified thrombin time assay (Hemoclot®)Rivaroxaban and apixaban:Anti-Xa activity (similar to LMWH assay)Neither assay FDA-approved or widely available nowWhen to consider measuring drug level:Detect/quantify overdoseScreen for drug accumulation (eg, impaired renal or liver function)Assure low drug level prior to surgeryLimited usefulness for assessing compliance due to short drug half-livesDabigatran assays likely to be available only via send-out for most hospitals. More hospitals doing anti-Xa assays but still not routinely available most places. Compliance testing dicey due to rapid onset and short duration of drug effect. Probably better off counting pills.
33REVERSAL? No specific antidote for any of the new OACs New agents in development may solve this problemActivated charcoal will reduce drug absorption if administered within a few hours of ingestionRivaroxaban & apixaban effect may be reversed by giving prothrombin complex concentrate (PCC) (limited data)Dabigatran is dialyzable60% removed/3 hours, with rebound effectCase reports suggest that recombinant factor VIIa (NovoSeven™) is ineffective vs dabigatran (Thromb Haemost 2012;108:585)
34Risk-benefit profile of NOACs vs warfarin remains favorable in patients with moderate renal insufficiency (GFR < 50) Meta-analysis of 9 phase III trialsThrombotic eventsMajor bleeding% of drug excreted by kidneys →VKA betterNOAC betterFour trials of R vs E in high risk ortho surgery all showed better efficacy for R. Note bleeding rates for R are somewhat higher across the board.J Thromb Haemost 2014;12:337
36Transitioning to NOACs Unfractionated heparin to NOAC:Start NOAC when UFH infusion stoppedLMWH to NOAC:Start NOAC 2 h before next scheduled sq dose of LMWHWarfarin to NOAC:When INR < 2.0Note that delay between stopping dabigatran and starting another anticoagulant should be longer if there is any degree of renal insufficiency. Note also that INR may be affected by dabigatran for a day or two after stopping the drug.
37Transitioning from NOACs NOAC to parenteral anticoagulant:CrCl >30: start 12 hours after last NOAC doseCrCl <30: start 24 hours after last NOAC doseNOAC to warfarin:CrCl >50: start warfarin 3 days before NOAC stoppedCrCl 31-50: start warfarin 2 days before NOAC stoppedCrCl 15-30: start warfarin 1 day before NOAC stoppedRemember that NOACs can prolong PT/INRNote that delay between stopping dabigatran and starting another anticoagulant should be longer if there is any degree of renal insufficiency. Note also that INR may be affected by dabigatran for a day or two after stopping the drug.
38When to stop drug before surgery Stop NOAC at least 3 drug half-lives prior to surgeryDabigatran: hRivaroxaban: hApixaban: hAllow more time if:Age > 75Impaired renal or liver functionHigh bleeding risk
39Who are the best candidates for new oral anticoagulants? Patients who have unstable INR on warfarin not due to poor complianceReasonably good renal & hepatic functionNo mechanical valveNot pregnant (drugs cross placenta)< 75 years oldNo history of lower GI bleedingNot at high risk for ACS (dabigatran)