6Prevalence of AF by AgeFeinberg WM. Arch Intern Med. 1995;155(5):469–4736
7Budnitz D et al. N Engl J Med 2011;365:2002–12 HAZARDS OF WARFARINBudnitz D et al. N Engl J Med 2011;365:2002–12
8Budnitz D et al. N Engl J Med 2011;365:2002–12 HAZARDS OF WARFARINBudnitz D et al. N Engl J Med 2011;365:2002–12
9Efficacy and Safety Data for Target-Specific Oral Anticoagulants
10RE-LY: Time to First Stroke/SEE RR 0.91(95% CI: 0.74–1.11)p<0.001 (noninferiority)p= (superiority)0.050.04RRR34%1.69%WarfarinDabigatran etexilate 110 mgDabigatran etexilate 150 mg0.03Cumulative hazard rates1.53%0.02RR 0.66(95% CI: 0.53–0.82)p<0.001 (superiority)1.11%0.010.00.51.01.52.02.5YearsConnolly SJ et al. N Engl J Med 2009; 361:1139–51
11RE-LY Primary Efficacy Outcome Stroke and non-CNS Embolism Connolly SJ., et al. NEJM Aug 30th DOI /NEJMoa
12Hemorrhagic stroke 50 45 40 30 20 14 10 12 D110 mg BID D150 mg BID RR 0.31 (95% CI: 0.17–0.56)p<0.001 (sup)RR 0.26 (95% CI: 0.14–0.49)p<0.001 (sup)50Number of events45400.38%RRR69%RRR74%3020Both dosages of dabigatran etexilate significantly reduced the incidence of hemorrhagic stroke (one element of the primary efficacy endpoint including stroke and systemic embolism) compared to warfarin: The relative risk reduction (RRR) for dabigatran etexilate 110mg BID compared to warfarin was 69%, RRR for dabigatran etexilate 150mg was 74%.1410120.12%0.10%D110 mg BIDD150 mg BIDWarfarin6,0156,0766,022Connolly SJ., et al. NEJM published online on Aug 30th DOI /NEJMoa
13Dabigatran Etexilate vs Warfarin (RE-LY) October 19, 2010FDA Approves Pradaxa to Reduce the Risk of Stroke in Patients with Non-Valvular Atrial FibrillationPRADAXA 150 mg BID-higher rate of major (GI) bleeds and any GI bleeds compared to warfarin.In patients ≥75 years of age, the risk of major bleeding may be greater with PRADAXA than with warfarin.
14ROCKET-AF Primary Efficacy Outcome Stroke and non-CNS Embolism RivaroxabanWarfarinEvent RateHR (95% CI)P-valueOn TreatmentN= 14,1431.702.150.79 (0.65,0.95)0.015ITTN= 14,1712.122.420.88 (0.74,1.03)0.117RivaroxabanbetterWarfarin betterEvent Rates are per 100 Patient-yearsBased on Safety on Treatment or Intention-to-Treat thru Site Notification PopulationsPatel et al. NEJM 2011;365:883-91
16Safety Outcomes Rivaroxaban WarfarinEvent Rate or N (Rate)HR (95% CI)P-valueMajor>2 g/dL Hgb dropTransfusion (> 2 units)Critical organ bleedingBleeding causing death3.602.771.650.820.243.452.261.321.180.481.04 (0.90, 1.20)1.22 (1.03, 1.44)1.25 (1.01, 1.55)0.69 (0.53, 0.91)0.50 (0.31, 0.79)0.5760.0190.0440.0070.003Intracranial Hemorrhage55 (0.49)84 (0.74)0.67 (0.47, 0.94)Intraparenchymal37 (0.33)56 (0.49)0.67 (0.44, 1.02)0.060Intraventricular2 (0.02)4 (0.04)Subdural14 (0.13)27 (0.27)0.53 (0.28, 1.00)0.051Subarachnoid1 (0.01)Event Rates are per 100 patient-years Based on Safety on Treatment Population
17Primary Outcome Stroke (ischemic or hemorrhagic) or systemic embolism P (non-inferiority)<0.00121% RRRApixaban 212 patients, 1.27% per yearWarfarin patients, 1.60% per yearHR 0.79 (95% CI, 0.66–0.95); P (superiority)=0.011No. at RiskApixabanWarfarinGranger C et al. NEJM 2011;365:981–92
18Efficacy Outcomes Outcome Apixaban (N=9120) Warfarin (N=9081) HR (95% CI)P ValueEvent Rate(%/yr)Stroke or systemic embolism*1.271.600.79 (0.66, 0.95)0.011Stroke1.191.510.79 (0.65, 0.95)0.012Ischemic or uncertain0.971.050.92 (0.74, 1.13)0.42Hemorrhagic0.240.470.51 (0.35, 0.75)<0.001Systemic embolism (SE)0.090.100.87 (0.44, 1.75)0.70All-cause death*3.523.940.89 (0.80, 0.998)0.047Stroke, SE, or all-cause death4.495.040.89 (0.81, 0.98)0.019Myocardial infarction0.530.610.88 (0.66, 1.17)0.37* Part of sequential testing sequence preserving the overall type I errorGranger C et al. NEJM 2011;365:981–92
19Bleeding Outcomes Outcome Apixaban (N=9088) Warfarin (N=9052) HR (95% CI)P ValueEvent Rate(%/yr)Primary safety outcome: ISTH major bleeding*2.133.090.69 (0.60, 0.80)<0.001Intracranial0.330.800.42 (0.30, 0.58)Gastrointestinal0.760.860.89 (0.70, 1.15)0.37Major or clinically relevant non-major bleeding4.076.010.68 (0.61, 0.75)GUSTO severe bleeding0.521.130.46 (0.35, 0.60)TIMI major bleeding0.961.690.57 (0.46, 0.70)Any bleeding220.127.116.11 (0.68, 0.75)* Part of sequential testing sequence preserving the overall type I error
20You JJ et al. Chest 2012;141(2 Suppl):e531S-75S. PMID: 22315271 ACCP Recommendations for Stroke Prevention TherapyCHADS 2 score = 0 No therapy rather than antithrombotic therapy (Grade 2B) CHADS 2 score = 1 Oral anticoagulation rather than no therapy or antiplatelet therapy(Grade 1B) CHADS 2 score = 2 Oral anticoagulation rather than no therapy or other therapies (Grade 1A) For recommendations in favor of oral AC, wesuggest dabigatran 150 mg twice daily rather than VKA therapy (Grade 2B)You JJ et al. Chest 2012;141(2 Suppl):e531S-75S. PMID:
21ESC 2012 UPDATE GUIDELINES For ATRIAL FIBRILLATION Camm J et al. Eur Heart J 2012;33:2719–47
222011 ACCF/AHA/HRS Focused Update Dabigatran is useful as an alternative to warfarin for theprevention of stroke in patients with AF.Selection of patients with AF and ≥1 risk factor for stroke who couldbenefit from treatment with dabigatran as opposed to warfarin shouldconsider individual clinical features, including the ability to comply with twice-daily dosing, availability of an anticoagulation management program, patient preferences, cost, and other factorsBecause of the twice-daily dosing and greater risk of non-hemorrhagic side effects with dabigatran, patients already taking warfarin with excellent INR control may have little to gain by switching to dabigatran.Wann LS et al. Heart Rhythm 2011;8:e1–e8
24Effect of TTR on Primary Endpoints In RELY0.540.590.911.21Wallentin, et al. Lancet 20102424
2510% increase in center algorithm-consistent warfarin dosing predicted a 6.12% increase in TTR (95% CI %), and an 8% decrease in rate of the compositeclinical outcome (HR 0.92, 95% CI ).
26Translating the Results of Clinical Trials into Clinical Practice Patient selectionTherapeutic implementation Environment of the healthcare delivery system Nallamothu, et al. Circulation 2008;118:1294–303
27Will we be able to translate trial results to real-world practice? Revised Guidelines for the Management of Patients with Atrial Fibrillation were published in August 2006.
28New Oral Anticoagulants: Summary PropertyDabigatranRivaroxabanApixabanEdoxabanRoute of adminOralTargetThrombinFXaDosingTwice dailyOnce dailyMonitoring requiredNoHalf-life (hrs)12–179–128–158–11Mode of eliminationRenal 80%Renal ~36%Renal ~25%Renal ~35%
29Definitions: Chronic Kidney Disease and Renal Insufficiency Kidney Disease Outcomes Quality Initiative (KDOQI) of the National Kidney FoundationI MILD I MOD I SEVERE IRenal Insufficiency ClassificationSlide courtesy of C Cove
32JANUARY 2012 UPDATE DABIGATRAN PACKAGE INSERT Periodically assess renal function as clinically indicated (i.e., more frequently in clinical situations that may be associated with a decline in renal function) and adjust therapy accordingly.Discontinue dabigatran in patients who develop acute renal failure and consider alternative therapy.In patients with moderate renal impairment (CrCl 30–50 mL/min), concomitant use of the P-gp inhibitor dronedarone or systemic ketoconazole can be expected to produce drug exposure similar to that observed in severe renal impairment. Consider reducing the dose.
33New Oral Anticoagulants: Summary PropertyDabigatranRivaroxabanApixabanEdoxabanRoute of adminOralTargetThrombinFXaDosingTwice dailyOnce dailyMonitoring requiredNoHalf-life (hrs)12–179–128–158–11Mode of eliminationRenal 80%Renal ~36%Renal ~25%Renal ~35%
34Polypharmacy and Non-adherence Strongest predictor of non-adherence isthe # of medicationsNon-adherence rates estimated 25–50%Intentional about 75% of the timeChanges in regimen made by patients to:increase conveniencereduce adverse effects ordecrease refill expense
36Recommended Structured Follow-up First month and subsequent 3 month intervals
37Pradaxa (dabigatran etexilate mesylate): Drug Safety Communication – Safety Review of Post-Market Reports of Serious Bleeding Events UPDATED 11/02/ … bleeding rates associated with new use of Pradaxa do not appear to be higher than bleeding rates associated with new use of warfarin, which is consistent with observations from the large clinical trial used to approve Pradaxa (the RE-LY trial). FDA is continuing to evaluate multiple sources of data in the ongoing safety review of this issue.
38HAS-BLED Bleeding Risk Score Hypertension (SBP>160mmHg)Abnormal renal/liver fxn (1 pt for each)StrokeBleeding history or proneLabile INR (if on warfarin)Elderly (>65 years)Drugs (ASA, NSAIDS)/alcohol(1 pt for each)Increasing score associatedwith ISTH major bleeding(C-index 0.72)Based on 3978 patients in the EuroHeart Survey on AF with complete follow-up, all univariate bleeding risk factors in this cohort were used in a multivariate analyses along with ‘historic’ bleeding risk factors. A new bleeding risk score (acronym HAS-BLED: Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65), Drugs/alcohol concomitantly) was calculated, incorporating risk factors from the derivation cohort.Results: Fifty-three (1.5%) major bleeds occurred during 1-year follow-up. The annual bleeding rate rose with increasing risk factors. The predictive accuracy in the overall population using significant risk factors in the derivation cohort (c-statistic 0.72) was consistent when applied in several subgroups. Application of the new bleeding risk score (HAS-BLED) gave similar c-statistics except where patients were receiving antiplatelet agents alone or no antithrombotic therapy, with c-statistics of 0.91 and 0.85, respectively.Pisters R et al. Chest 2010;138:1093–100
39Optimizing Benefit and Reducing RiskHemorrhageThrombosisAF stroke associated with a 30-day mortality of 24%.
40Swedish AF Cohort; Circulation 2011; 125: 2298-2307
41Kirley K et al. Circ Cardiovasc Qual Outcomes 2012;5:615–21 Dabigatran visits,%2010Q42011Q1Q2Q3Q4Atrial fibrillation9272757163Venous thromboembolism4835Hypertensive heart disease131514Coronary artery disease96CVA/TIAValvular disordersKirley K et al. Circ Cardiovasc Qual Outcomes 2012;5:615–21
42Effective Use of TSOACs in Clinical Practice 1. Patient selection – ADHERENCEDose selection – creatinine clearanceDetermine interval follow-upAssess stability of renal functionBlood pressure controlAvoidance of concomitant antiplatelet therapyPackage insert – avoid potent drug interactions,guidance on transitions
43Procedural Management based on Bleeding Risk of Surgery DABIGATRANAPIXABAN/ RIVAROXABAN
44Novel Anticoagulants Dabigatran 150 mg BID reduced ischemic stroke Dabigatran 80% renal clearanceDabigatran is associated with small risk of MI, butreduced cardiovascular mortalityDabigatran and rivaroxaban increase GI bleedingRivaroxaban is once per day and approved Rx for VTE6. Apixaban reduced stroke, major hemorrhage, and mortality7. Well-controlled warfarin is associated with low rate of adverse events
45Gaps: Practical Considerations Translation across indicationAtrial fibrillation and valvular heart diseaseAtrial fibrillation and ACSAtrial fibrillation and DVT or PESelect situations in which monitoring would be desirableReversibility-trauma, urgent surgery, life-threatening hemorrhage
46Guide to the Management of Bleeding in Patients Taking NOAC Patients with bleeding on NOAC therapyMild bleedingModerate-SeverebleedingLife-threateningbleedingDelay next dose or discontinue treatment as appropriateMechanical compressionSurgical interventionFluid replacement and hemodynamic supportBlood product transfusionOral charcoalHemodialysis? Prothrombin Complex Concentrate?(Circulation 2011;124:1573-9)Consideration of rFVIIa or PCCCharcoal filtration? Prothrombin Complex Concentrate(Circulation 2011;124:1573-9)Hankey GJ and Eikelboom JW. Circulation. 2011; 123:
47WILL THERE BE A CONTINUING ROLE FOR WARFARIN? 1. Mechanical heart valvesCostPregnancySevere renal impairmentDrug InteractionsLack of acceptance of no monitoringReversal?Nonadherence9. Intolerant of novel anticoagulant drug47
48Novel anticoagulants may be safer in the elderly population due to their wider therapeutic index, shorter t1/2, lack of dietary interference, and fewer drug interactions.Older individuals with AF are at the highest risk of stroke, the highest risk of hemorrhage, and the highest risk of stopping therapy.Further research is needed to inform commonly encountered clinical situations to optimize the effectiveness of these novel agents in routine practice..4848