8 Indications: US + + (RELY) + (ROCKET-AF) + (Aristotle) + (EINSTEIN) CoumadinDabigatrnRivaroxabanApixabanAfib++ (RELY)+ (ROCKET-AF)+ (Aristotle)+ (AVERROES)DVT/PENot yet. (RECOVER)+ (EINSTEIN)Post TKA/THADVT prophylaxis+ (RECORD 1-3)+ (ADVANCE)Not yet approved: Rivaroxaban for prophylaxis of DVT in medically ill patients(MAGELLAN). Rivaroxaban vs Enoxaparin. NI < 30 days, superior at 35 days.
9 Usual Dosing (A fib) 5 mg BID WarfarinOnce daily, titrate to INR 2-3Dabigatran150 mg BID75 mg BID (CrCl ml/min)Rivaroxaban20 mg daily15 mg daily (CrCl ml/min)Apixaban5 mg BID2.5 mg BID if any 2 of the following: age > 80, wt < 60kg, SCr > 1.5Lack of and/or limited clinical evidence for reduced doses
10 Usual Dosing (VTE) Only FDA-approved agent = rivaroxaban VTE Prophylaxis (knee/hip surgery)10mg once daily (up to 35 days)No renal dose (CrCl < 30 ml/min avoid)VTE Treatment:15 mg BID x 3 weeks then 20mg daily
11 Perioperative Recommendations DabigatranHold 1-2 days before procedureCrCl < 50 hold 3-5 daysRivaroxabanLow bleed risk hold 1 dayCrCl < 30/ low risk hold 2 daysHigh bleed risk hold 2 daysCrCl < 30/ high risk hold 4 daysApixabanLow bleed risk hold x 1 dayHigh bleed risk hold x 2 daysDabigatran PI, Blood 2012;119:
12 Major Side Effects: Bleeding: varied definition in each study. GIICHMajor (drop in Hgb by 2, life threatening).Dabigatran:Pills are made in acidic content, hence has 20% rate of GI side effects.? Observed increase risk of GI bleeding.
13 Monitoring Levels: Coumadin: INR New Oral anticoagulants: no standardized studies. No accurate quantitative measures.Dabigatran: ECT, Thrombin clotting timeRivaroxaban: special anti-Xa activityAbixaban special anti-Xa activityECT: ecarin clotting time, a thrombin clotting time assay.
14 Drug-Drug Interactions: No where as severe as with Warfarin.Dabigatran: P-glycoprotein, pro-drug.Needs acidic environment, avoid co-administration with PPI.Rivaroxaban: CYP-450 and P-glycoprotein.Caution with dual inhibitors (Ketoconazole, Itroconazole, Clarithromycin).No dose adjustments needed.Abixaban: CYP3A4 and P-glycoprotein.Decrease dose to 2.5mg bid in dual inhibitors.
15 Switching To/From Warfarin MedicationRecommendations for ConversionDabigatranStop warfarin, initiate dabigatran when INR < 2Initiate warfarin 3 days before D/C dabigatranRivaroxabanStop warfarin, initiate rivaroxaban when INR < 2-3Initiate warfarin with bridging 24 hours after D/C rivaroxabanApixabanStop warfarin, initiate apixaban when INR < 2Initiate warfarin with bridging when next apixaban dose is due.
16 Treatment of Bleeding: No evidence based guidelines.Remember that unlike Coumadin, the new OAC will continuously bind to factor Xa or thrombin, hence making FFP less useful.Current available Rx for life threatening active bleeding: based on case reports.Factor VIIPCC: 3 and 4 factor concentrates.HD: only for Dabigatran. Large volume of distribution.CharcoalPCC: prothrombin compex concentrates.Gonsalves Et al. Mayo Clinic Proc
17 Trials vs Warfarin for A Fib RE-LYDAB vs WARROCKET-AFRIV vs WARARISTOTLEAPIX vs WARComparatorDabigatranRivaroxabanApixabanDesignOpen-label,blind outcomes, noninferiorityDouble-blind, noninferioritySample sizen = 18,113n = 14,264n = 18,201RandomizationD 150mg BIDD 110mg BIDW (INR 2-3)R 20mg daily*A 5mg BID*InclusionCriteriaNonvalvular AF with increased stroke riskNonvalvular AF with prior stroke or >2 risk factorsNonvalvular AF with >1 risk factor for strokeExclusionCrCl < 30CrCl < 25* Dose reductions for renal impairment
18 Trials vs Warfarin for A fib RE-LYDAB vs WARROCKET-AFRIV vs WARARISTOTLEAPIX vs WARAverage age (yrs)717370Mean CHADS22.13.50-132%0%34%236%13%3-687%30%Prior TIA/stroke20%55%19%TTR goal)64%62%Median follow-up2 yrs1.9 yrs1.8 yrsPrimary endpointStroke (ischemic, hemorrhagic) + systemic embolism
19 Major Findings: RELY ROCKET-AF ARISTOTLE: Dabigatran 110mg NI to Warfarin (1.53% vs 1.69%).Dabigatran 150mg superior to Warfarin ONLY if compared with sub-optimal INR subgroup (1.11 % vs 1.69%).Major bleeding less with 110mg (2.71 vs 3.11%).ROCKET-AFRivaroxaban NI to Warfarin (2.1% vs 2.4%)Less ICH or fatal bleeding (0.4% vs 0.8% )ARISTOTLE:Abixaban Superior to Warfarin (1.27% vs 1.6% )Less Major bleeding (1.4% vs 2.1% )
20 Key Safety Endpoints (% per year) RE-LYROCKET AFARISTOTLED110D150WARRIVAPIX1o bleeding endpoint*2.713.113.3614.914.52.133.09Major bleed5.555.42GI bleeding1.121.511.023.22.20.760.86Intracranial hemorrhage0.230.30.740.50.70.330.8*: Primary safety endpoint:RE-LY major hemorrhageROCKET-AF major + non-major clinically relevant bleedingARISTOTLE ISTH (Int Soc Thromosis & Hemostasis) major bleeding
21 Figure 3 Forest plot for (A) major bleeding, (B) intracranial bleeding, and (C) gastrointestinal bleeding, new oral anticoagulants (NOA) versus warfarin in patients with AF.
22 Quick Review of Evidence- Based Medicine: A: Systemic review of multiple RCTs / multiple RTCsB: High quality single RTCII:A: Systemic review of cohort studiesB: High quality cohort studie(s)III:Systemic review of Case/Control studies / Case Control studiesIVCase reportsExpert opinion
23 Anticoagulation Recommendations (AF) Risk/CHADS2CHEST 2012AHA/ASALow RiskCHADS2 = 0No therapy > antithrombotic therapy (2B)Aspirin (75-325mg) > OAC (2B) or aspirin + clopidogrel (2B)Aspirin (1A)IntermediateCHADS2 = 1OAC > no therapy (1B)OAC > aspirin (2B) or aspirin + clopidogrel (2B)OAC unsuitable or pt refuses: aspirin + clopidogrel over aspirin monotherapy (2B)Warfarin (1A)Aspirin, if patient preference (1A)High RiskCHADS2 > 2OAC > no therapy (1A)OAC > aspirin (1B) or aspirin + clopidogrel (1B)OAC unsuitable or pt refuses: aspirin + clopidogrel over aspirin monotherapy (1B)Dabigatran 150mg BID > warfarin (2B)Dabigatran (1B)Rivaroxaban (2A)Apixaban (1B)Chest 2012; 141:e531S-e575SStroke 2012;43:OAC = oral anticoagulation
24 New OAC: Pros: Cons: Easy administration Immediate effect Much less food and drug interactionsOne dose fits allThe names sound so much cooler than WARFARIN.Cons:ExpensiveInability to monitor complianceShort duration: loss of effect with a single missed doseNo safe/reliable antidotes? Bleeding. Observational bias vs real difference.Renal dosing
25 Take home message:Coumadin still remains the drug of choice for many patients due to cost, past experience and known side effects.Many new OAC are in the pipeline, expect a barrage of pharma bombardments, must remain objective as many of the studies have different inclusion/exclusion criteria, definition of end points and side effects.Each patient may benefit from a different type of OAC based on comorbidities and drug side effect profile.Watch out for recall bias with the new OAC among your own colleagues.Patient compliance is a major factor: remember with the new OAC one missed dose means a lot!