ANTICOAGULATION UPDATE C AR R I E P AL M E R, D N P, RN, AN P - BC OBJECTIVES At the end of the presentation, the NP will be able to: Identify new indications for target-specific oral anticoagulants (TSOACs), aka direct oral anticoagulants (DOACs) Identify patients who are appropriate for TSOACs Describe the reversal of TSOACs in case of bleeding or the need for surgery Discuss current, relevant research in TSOACS, including reversal agents BRIEF REVIEW: CLASSES OF ORAL ANTICOAGULANTS Vitamin K antagonists (VKA) inhibits the synthesis of vitamin K-dependent clotting factors: factors II, VII, IX, and X, and the proteins C and S Warfarin (Coumadin ) Direct Thrombin Inhibitors By inhibiting thrombin, prevents the conversion of fibrinogen to fibrin, thus preventing thrombus formation Dabigatran (Pradaxa ) Factor Xa inhibitors Prevents formation of thrombin, thus preventing the conversion of fibrinogen to fibrin and thrombus formation Apixaban (Eliquis ) Rivaroxaban (Xarelto ) Edoxaban (Savaysa ) 1
INDICATIONS FOR TSOACS: DABIGATRAN Dabigatran Atrial fibrillation: Approved for stroke prevention in people with nonvalvular atrial fibrillation Venous thromboembolism (VTE): Approved for the treatment of VTE, including pulmonary embolism (PE) and deep vein thrombosis (DVT) Approved for prophylaxis of VTE in people with a history of VTE Considerations: Twice daily dosing Cannot start immediately upon diagnosing VTE; must use parenteral anticoagulation for 5-10 days 80% renally cleared No antidote INDICATIONS FOR TSOACS: APIXABAN Apixiban Atrial fibrillation: Approved for stroke prevention in people with nonvalvular atrial fibrillation VTE prophylaxis: Approved for VTE prevention in people following hip or knee replacement surgery Considerations: Can start immediately following diagnosis of VTE Twice daily dosing 25% renally cleared No antidote INDICATIONS FOR TSOACS: RIVAROXABAN Rivaroxaban: Atrial fibrillation: Approved for stroke prevention in people with nonvalvular atrial fibrillation VTE: Approved for treatment and secondary prevention of VTE Approved for prevention of VTE in people with hip and knee replacement Considerations: Can start immediately following diagnosis of VTE Once daily dosing 33% renally cleared No antidote 2
NEWLY APPROVED TSOAC: EDOXABAN Edoxaban: Atrial Fibrillation: Approved for stroke prevention in people with nonvalvular atrial fibrillation VTE: Approved for the treatment of DVT and PE in people with an active clot Considerations: CANNOT be started immediately on diagnosis of VTE; must be treated for 5-10 days with parenteral antithrombotic Once daily dosing 35% renally cleared No antidote EDOXABAN AND ATRIAL FIBRILLATION: ENGAGE AF-TIMI 48 TRIAL RCT, double-blinded study of 21,105 participants Randomized either to warfarin at INR goal 2-3, high dose (60 mg), or low dose (30 mg) Median follow up 2.8 years Inclusion: 21 years or older, diagnosis of AF, CHADS 2 score >2 Exclusion: reversible cause of AF, CrCl < 30ml/min, high bleeding risk, dual anti-platelet therapy, mod-severe mitral stenosis, other indications for anticoagulation, ACS, coronary revascularization, stroke within 30 days of randomization, or inability to adhere to study protocol Purpose: compare to warfarin in terms of prevention of stroke or systemic embolization Note: TTR of warfarin was 68.4% EDOXABAN AND ATRIAL FIBRILLATION: PRIMARY OUTCOMES Group Event Analysis Warfarin High dose Low dose 1.5% per year 1.18% per year Hazard ratio 0.79 P<0.001 for inferiority; P=0.02 for superiority 1.61% per year Hazard ratio 1.07 P=0.005 for inferiority; P=0.44 for superiority 3
EDOXABAN AND ATRIAL FIBRILLATION: SAFETY Group Total Bleeding Events/Life- Threatening Bleeding Warfarin 3.43%/0.78% High dose Low dose Analysis 2.75%/0.40% Hazard ratio 0.80 P<0.001 1.61%/0.25% Hazard ratio 0.47 P<0.001 EDOXABAN AND ATRIAL FIBRILLATION: CONCLUSIONS Edoxaban had lower rates of all bleeding compared to warfarin except GI bleeding (high-dose group) Anticoagulation-naïve patients had lower rates of stroke or embolism in the groups compared to the warfarin group Concomitant use of aspirin and amiodarone increased the efficacy of low-dose Dose reduction for kidney impairment and low body weight lowered bleeding risk in compared to warfarin High-dose is safer than and superior to warfarin for the prevention of stroke and systemic embolism in patients with AF EDOXABAN AND VENOUS THROMB0EMBOLISM RCT, double-blinded study of 4921 participants with DVT and 3319 with PE Randomized either to warfarin at INR goal 2-3, or 60 mg after initial treatment with heparin; participants with low body weight (<60kg),CrCl 30-50 ml/min, or receiving P-glycoprotein inhibitors received 30 mg Received therapy 3-12 months Inclusion: 18 years or older, DVT or PE (diagnosed with imaging) Exclusion: contraindications to anticoagulation, receiving heparin for more than 48 hours, receiving more than 1 dose of warfarin, cancer, other indications for anticoagulation, receiving aspirin more than 100 mg daily, dual antiplatelet therapy, CrCl <30 ml/min Purpose: compare to warfarin in terms of recurrence of VTE Note: TTR of warfarin was 63.5% 4
EDOXABAN AND VTE: PRIMARY OUTCOMES Group Recurrence Analysis Warfarin 3.5% overall 6.2% in participants with PE and with RV dysfunction Edoxaban 60mg 3.2% overall 3.3% in participants with PE and with RV dysfunction Participants who Wafarin: 4.2% qualified for lowdose Edoxaban: 3.0% Hazard ratio: 0.89 P<0.001 for noninferiority Hazard ratio: 0.73 EDOXABAN AND VTE: SAFETY Group Total Bleeding Events/Major Bleeding Warfarin 10.3%/1.6% High dose Participants who Warfarin: qualified for lowdose 12.8%/3.1% Edoxaban: 7.9%/1.5% Analysis 8.5%/1/4% Hazard ratio 0.81 P=0.004 for superiority Hazard ratio 0.62 EDOXABAN AND VTE: CONCLUSIONS Edoxaban once daily, following initial parenteral treatment, is noninferior to warfarin at preventing recurrence of VTE and superior to warfarin in terms of bleeding Participants were followed for 12 months, regardless of treatment period; benefits were noted at 12 months even in those who stopped treatment after 3 months per CPGs Treatment included a lead in of heparin, followed by to recruit more severe VTEs; however, this is a possible limitation to the practical use of 5
WHAT DOES NONVALVULAR MEAN? RE-LY trial: No history of valve disorder, i.e., prosthetic valve or hemodynamically relevant valve disease Rocket AF trial: Hemodynamically significant mitral valve stenosis or a prosthetic heart valve; people with valve repair were included Aristotle trial: moderate to severe mitral stenosis, or situations other than atrial fibrillation that required anticoagulation, like a prosthetic heart valve No real consensus on the definition, so it is probably wise to avoid TSOACs in those with significant valve stenosis, prosthetic valves, or a history of rheumatic heart disease NEW DATA ON TSOACS SUBPOPUL ATIONS AND C O STS SAV INGS COSTS OF TSOACS COMPARED TO WARFARIN Drug Approximate Monthly Costs Warfarin $4-$19 Dabigatran $300 Apixaban $300 Rivaroxaban $400 Edoxaban? 6
COSTS IN OTHER TERMS Analysis of Medco data of plan participants with a diagnosis of AF from Jan. 2007-Jun. 2010 23,525 participants without valvular heart disease with a CHADS 2 score >1 Measured occurrence of stroke and other major bleeding in real world patients on warfarin Compared results to bleeding rates in warfarin arms major TSOAC trials: ARISTOTLE, RE-LY, ROCKET-AF COSTS, CONTINUED Results: Stroke and other bleeds were higher in Medco patients compared to participants randomized to warfarin arms of major TSOAC trials Stroke: 3 times higher in Medco patients on warfarin than outcomes in ARISTOTLE and RE-LY and 2 times higher than in ROCKET-AF Other major bleeds: over 3 times higher in Medco patients on warfarin than outcomes in ARISTOTLE, RE-LY, and ROCKET-AF Costs savings related to stroke were higher in those with a high baseline risk: CHADS 2 >3 and older adults FINDINGS AND INTERPRETATION Drug Number of strokes avoided per 100 patient years Number of major bleeds avoided per 100 patient years Cost difference Stroke/major bleeding Apixaban 1.1 2.1 -$493/-$752 Rivaroxaban* 0.8 0.7 additional bleeds Dabigatran 1.9 1.4 additional bleeds -$358/+$502 -$806/+$251 * Rivaroxaban is the only TSOAC with additional net costs 7
TSOACS IN OLDER ADULTS Meta-analysis of RCTs comparing TSOACs (rivaroxaban, apixaban, and dabigatran) to conventional therapy in participants >75 years old Conventional therapies: warfarin, low-molecular weight heparin (LMWH), aspirin, placebo 10 trials including 25,031 older adult participants with either AF or VTE Outcomes: Safety: major or clinically relevant bleeding Efficacy: VTE, VTE-related death, stroke, systemic embolism TSOACS IN OLDER ADULTS: BLEEDING Bleeding compared to conventional Stroke/ systemic Embolism compared to conventional VTE or VTErelated death All TSOACs Rivaroxaban Apixaban Dabigatran 6.4% vs 6.3% OR 1.02 3.3% vs 4.7% OR 0.65 3.7% vs 7.0% OR 0.45 4.5% vs 4.5% OR 1.18 Noninferior, OR 0.80 Noninferior OR 0.55 5.1% vs 7.3% OR 0.80 Noninferior OR 0.49 Noninferior OR 0.21 9.3% vs 8.7% OR 1.07 Noninferior OR 0.75 Unable to estimate from RCTs TSOACS IN OLDER ADULTS: CONCLUSIONS TSOACs did not cause more bleeding than conventional agents More effective than conventional therapies in preventing stroke or systemic embolism in older adults with AF compared to conventional therapies More effective than conventional therapies in preventing VTE or VTE-related death in older adults compared to conventional therapies Bleeding risk in older adults likely attributable to comorbidities (kidney disease) rather than age 8
TSOACS AND CANCER VTEs are common in patients with cancer Current guidelines by the American Society of Clinical Oncology Initial treatment with LMWH, fondaparinux, or unfractionated heparin (UFH) After 3 months (6-12 months indefinitely in people with active cancer, inherited thrombophilia, or patients receiving chemotherapy), LMWH is preferred over VKA VKA when LMWH is not possible TSOACS Sparse data on cancer patients Ongoing trial of apixaban for prevention of VTE in patients with cancer is promising, but no data on treatment in this cohort BENEFITS OF TSOACS Rapid onset and offset, assuming normal renal function Quick onset means requiring less parenteral anticoagulation in acute settings or for prophylaxis in high-risk settings Quick offset means less need for reversal in cases of planned surgery or less severe bleeding Predictable, so no routine monitoring or dose adjustment is required LIMITATIONS OF TSOACS No reversal agents Reversal may be required in settings of emergency surgery or severe bleeding (ICH) Missed doses mean negligible anticoagulation Less clear measures of anticoagulation activity compared to warfarin Kidney function is a major consideration Renal clearance means half-life can be prolonged, especially in dabigatran 9
MEASURING EFFECT OF ANTICOAGULATION WITH TSOACS PT/INR cannot assess level of anticoagulation in TSOACs PT (but not INR) may assess anticoagulant effect of rivaroxaban, but not apixaban Anti-Xa assays can be used for factor Xa inhibitors, using a chromogenic substrate, but are not yet useful clinically Diluted thrombin time for DTIs is available in Europe (HEMOCLOT) aptt can be used to measure effect of dabigatran, but the relationship changes over the action of the dose Peak concentration, aptt is 2-3 times control values Trough concentrations (about 12 hours after the last dose), aptt is 1.3 times control values WHAT DO WE DO WHEN THERE IS BLEEDING? Determine the severity of the bleeding! Consider the timing of the last dose! Assess kidney function to understand clearance! MILD-MODERATE BLEEDING Mild Bleeding Examples: epistaxis, gum bleeds Approach: hold the next few doses of the TSOAC Moderate Bleeding Examples: GI bleeding Approach: Hold the TSOAC Circulatory support with fluids and transfusion if necessary Identify source, and treat appropriately 10
REVERSING ANTICOAGULATION May be necessary in the case of severe bleeding or unexpected invasive procedures Consider timing of the last dose Methods: Withdraw agent Administration of reversal agent (antidote) Administration of specific clotting factors REVERSING TSOACS Activated charcoal If ingestion <6 hours ago (studied in apixaban in health volunteers) Emergent dialysis Dabigatran, in overdose or renal failure Prothrombin complex concentrates 3 and 4 factor varieties reversed in healthy volunteers on rivaroxaban; 4 factors varieties reduce PT more effectively Expensive and not widely available REVERAL AGENTS APPROVED Dabigatran Rivaroxaban Apixaban Activated PCCs (apcc) Platelet concentrates in those with thrombocytopenia or long-acting antiplatelets Dialysis PCCs may reduce PT Activated charcoal 2-6 hours after ingestion of last dose 11
REVERSAL MECHANISMS UNDER INVESTIGATION Dabigatran Apixaban Rivaroxaban Parenteral monoclonal antibody that binds to and reverses drug within 5 minutes of infusions Andexanet alfa binds to factor Xa inhibitors Binding of drug, resulting in reversal HOLDING PRIOR TO PROCEDURES Apixaban Dabigatran Rivaroxaban Procedures with moderate to high risk of bleeding: discontinue at least 48 hours prior Procedure with low risk of bleeding: discontinue at least 24 hours prior Discontinue 1-2 days (CrCl 50 ml/min) or 3-5 days (CrCl <50 ml/min) before invasive or surgical procedures Consider longer times for major surgery, spinal puncture, or spinal or epidural catheter or port Discontinue at least 24 hours prior to procedure REFERENCES Amin, A., Stokes, M., Makenbaeva, D., Wiederkehr, D., Wu, N., & Lawrence, J. H. (2014). Estimated medical cost reductions associated with use of novel oral anticoagulants vs warfarin in a real-world non-valvular atrial fibrillation patient population. Journal of Medical Economics, 17, 771-781. Elyamany, G., Alzahrani, A. M., & Bukhary, E. (2014). Cancer-associated thrombosis: an overview. Clinical Medicine Insights: Oncology, 8, 129-137. Giugliano, R. P., et al, for the ENGAGE AF-TIMI 48 Investigators. (2013). Edoxaban versus warfarin in patients with atrial fibrillation. NEJM, 369, 2093-2104. The Hokusai-VTE Investigators. (2013). Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. NEJM, 369, 1406-1415. 12
REFERENCES Kasmeridis, C., Apostolakis, S., Ehlers, L., Rasmussen, L. H., Boriani, G., & Lip, G. Y. H. (2013). Cost effectiveness of treatments for stroke prevention I atrial fibrillation: focus on novel oral anticoagulants. PharmacoEconomics, 31, 971-980. Levy, J. H., Spyropoulos, A. C., Samama, C. M., & Douketis, J. (2014). Direct oral anticoagulants: new drugs and new concepts. JACC: Cardiovascular Interventions, 7, 1333-1350. Peacock, W. F. (2014). Managing bleeding and emergency revesral of newer oral anticoagulants: a review for primary care providers. Hospital Practice, 42, 75-82. Sardar, P., Chatterjee, S., Chaudhari, S., & Lip, G. Y. H. (2014). New oral anticoagulants in elderly adults: evidence from a meta-analysis of randomized trials. JAGS, 62, 857-864. 13