Survey
* Your assessment is very important for improving the work of artificial intelligence, which forms the content of this project
Download click here for presentation
Document related concepts
no text concepts found
Transcript
Novel Oral An,coagulant Agents: An Update in Pharmacotherapy David Stewart, PharmD, BCPS Associate Professor of Pharmacy Prac,ce East Tennessee State University Bill GaEon College of Pharmacy [email protected] Disclosures Speaker’s Bureau for: Boehringer-‐Ingelheim Pharmaceu,cals Janssen Pharmaceu,cals At the conclusion of this program, the audience should be able to: • List the new oral an,coagulant medica,ons currently approved or in the approval process by the United States Food and Drug Administra,on • Communicate basic principles of pharmacokine,cs to other healthcare providers • Iden,fy appropriate indica,ons for the use of new oral an,coagulant medica,ons • Develop pa,ent specific plans u,lizing newly approved oral an,coagulant agents for the treatment and preven,on of venous thromboembolic events in various pa,ent popula,ons An,coagulant Timeline 1943 Heparin 2010 Dabigatran 1954 Warfarin 2012 Apixaban 2011 Rivaroxaban Coagula,on Cascade Intrinsic Pathway (PTT) XII XIIa XI XIa IX Warfarin Rivaroxaban & Apixaban Extrinsic Pathway (PT) VIIa VII IXa VIII Xa Va X II Dabigatran Fibrinogen IIa XIII XIIIa Fibrin Summary Table Parameter Apixaban Dabigatran Rivaroxaban Target Protein Factor Xa Thrombin (IIa) Factor Xa No Yes (etexilate) No CYP3A4/P-‐gp Renal CYP3A4/P-‐gp Avoid < 15 ml/min ↓ 15-‐30 ml/min Avoid < 15 ml/min ↓ 15-‐50 ml/min Avoid < 15 ml/min1 CYP3A4/P-‐gp P-‐gp CYP3A4/P-‐gp Onset of ac,vity 3-‐4 hrs 1-‐2 hrs 2-‐4 hrs t½ 8-‐15 hrs 12-‐18 hrs 5-‐9 hrs Dosing interval Twice daily Twice daily Daily Measuring tests PT/An,-‐factor Xa ECT, TT, +/-‐ aPTT PT/An,-‐factor Xa Pro-‐Drug 1˚ Elimina,on Renal Adjustment Drug-‐Drug Interact. 1Indica,on Specific. For VTE no adjustment and avoid use < 30 ml/min. Monitoring vs. Measuring Measuring Dabigatran Thromb Haemost 2010;103:1116-‐27. Measuring Rivaroxaban & Apixaban • Role of aPTT & PT/INR • An,-‐Xa Assays – Chromagenic an,-‐Xa assays may be useful • Different assays vary in sensi,vity • Must calibrate standard curve based on drug concentra,on – HepTest® accurate when modified for rivaroxaban (and likely apixaban) • Incuba,on period too long • Modified HepTest® may be useful Ther Drug Monit 2010;32:673-‐9. Measuring Rivaroxaban PT is sensi,ve (Don’t rely on INR) aPTT not sensi,ve Highlights peak concentra,ons J Thromb Haemost 2011;9:133-‐9. Reversal of New An,coagulants • Universal Xa an,dote (PRT4445) in Phase 2 trials • FFP – No data, unclear/unknown benefit • 3 factor PCC – Unknown • 4 factor PCC – Reverse rivaroxaban but not dabigatran (not available in US) • aPCC – Baboon data showed transient reversal of rivaroxaban • Recombinant Factor VIIa – Case reports only • Risk of arterial thrombosis – All PCC’s and RFVIIa increase the risk of arterial thrombo,c events in non-‐ hemophiliac pa,ents – Must weigh poten,al risks with poten,al benefits • These effects may all be only transient Portola Pharmaceu,cals. Press Release: 10 December 2012. Am J Hematol. 2012;84:S141-‐5. Am J Health-‐Syst Pharm. 2012;69:1473-‐84. Circula,on. 2011;124:1573-‐79. Issues with New An,coagulants Summary of Afib Data Apixaban (ARISTOTLE) Dabigatran (RE-‐LY) Rivaroxaban (ROCKET – AF) > 18,000 > 18,000 > 14,000 Mean CHADS2 ≈ 2 ≈ 2 ≈ 3.5 TTR 62% 64% 55% Superior Superior1 Non-‐Inferior Decreased Similar Similar # Pa,ents Efficacy vs. VKA Bleeding2 vs. VKA 1Dabigatran 150 mg BID group. 2Major bleeding per study design. New Engl J Med 2009;DOI:10.1056/NEJMoa0905561. New Engl J Med 2011;DOI:10.1056/NEJMoa1009638. New Engl J Med 2011;DOI:10.1056/NEJMoa1107039. Use of Concomitant An,platelet Agents in Afib Studies AnAplatelet Agents ARISTOTLE (Apixaban) RELY (Dabigatran) ROCKET-‐AF (Rivaroxaban) < 165 mg/day Yes < 100 mg/day Clopidogrel Yes Yes Yes Combina,on No Yes No Aspirin Use (%) 31% 40% 36% ASA Trials for other indica,ons were similar. New Engl J Med 2009;361:1139-‐51. New Engl J Med 2011;365:883-‐91. New Engl J Med 2011;365:981-‐92. Treatment of VTE Apixaban Dabigatran Rivaroxaban Comparator(s) Placebo Warfarin/Placebo Warfarin/Placebo Treatment Type Chronic Acute/Chronic Acute/Chronic N/A ≈ warfarin ≈ warfarin > Placebo (both doses) ≈ warfarin & > placebo > placebo 12 months Up to 36 months Up to 24 months Bleeding Outcomes (Acute) N/A ≈ warfarin ≈ warfarin Bleeding Outcomes (Chronic) ≈ or > placebo (dose dependent) < warfarin & > placebo > placebo Acute Results Chronic Results Follow-‐Up N Engl J Med 2012;DOI:10.1056/NEJMoa1113572. N Engl J Med 2010;DOI:10.1056/NEJMoa1007903. N Engl J Med 2009;DOI:10.1056/NEJMoa0906598. N Engl J Med 2013;368:699-‐708. N Engl J Med 2013;368:709-‐18. Summary of Acute VTE Treatment Data Dabigatran (RE-‐COVER) Rivaroxaban (EINSTEIN) > 2,500 > 3,400 6 months 6 months LMWH Rivaroxaban 60% 58% Efficacy vs. VKA Non-‐Inferior Non-‐Inferior Bleeding vs. VKA Similar Similar DVT & PE DVT & PE # Pa,ents Treatment Dura,on Ini,al Therapy1 TTR VTE Type 1Ini,al therapy in study group, both studies “bridged” control group. New Engl J Med 2012;DOI:10.1056/NEJMoa1113572. New Engl J Med 2010;DOI:10.1056/NEJMoa1007903. New Engl J Med 2009;DOI:10.1056/NEJMoa0906598. Summary of Orthopedic VTE Data1 Comparator Apixaban Dabigatran Edoxaban (2.5 mg q12h) (150 or 220mg/day) (30 mg/day) Rivaroxaban (10 mg/day) Enoxaparin 40 mg daily Superior Non-‐Inferior -‐-‐-‐ Superior Enoxaparin 20 mg q12h -‐-‐-‐ -‐-‐-‐ Superior -‐-‐-‐ Enoxaparin 30 mg q12h Non-‐Inferior Inferior -‐-‐-‐ Superior Bleeding vs. Enoxaparin Similar Similar Similar Similar 1Includes pa,ents undergoing both TKA and THA. Most studies excluded pa,ents with CrCl < 30 ml/min. Summary of these data available in: Pharmacother 2011;31:1175-‐91. Addi,onal Therapeu,c Uses • VTE Prophylaxis in Medical Pa,ents – Only evaluated in extended dura,ons vs. enoxaparin – No benefit for extended prophylaxis • Acute Coronary Syndrome – Apixaban significantly increased risk of bleeding – Rivaroxaban (evaluated 2.5 mg and 5 mg BID) • Primary Endpoint (CV Death, MI or CVA) showed benefit • TIMI Major Bleeding higher with rivaroxaban • Intracranial Hemorrhage higher with rivaroxaban New Engl J Med 2011;365:2167-‐77. New Engl J Med 2012;366:9-‐19. New Engl J Med 2011 Online;DOI:10.1056/NEJMoa1110899. Rivaroxaban • ATLAS-‐ACS 2 TIMI 51 Trial • All pa,ents received low dose ASA with either: – – – – Rivaroxaban 2.5 mg twice daily or Rivaroxaban 5 mg twice daily Groups were stra,fied based on clopidogrel use Large number of pa,ents from Eastern Europe (40%); however North America data were independently consistent/significant • Results – Primary Endpoint (CV Death, MI or CVA) • Both doses beEer than placebo – TIMI Major Bleeding • Rivaroxaban 2.5 mg BID vs Placebo: HR = 3.46 (2.08-‐5.77) • Rivaroxaban 5 mg BID vs Placebo: HR = 4.47 (2.71-‐7.36) – Intracranial Hemorrhage • Rivaroxaban 2.5 mg BID vs Placebo: HR = 2.83 (1.02-‐7.86) • Rivaroxaban 5 mg BID vs Placebo: HR = 3.74 (1.39-‐10.07) • Summary – Improved outcomes but 3-‐fold increased risk of major bleeding New Engl J Med 2012;366:9-‐19. Dabigatran and Myocardial Infarc,on • Meta-‐analysis (January 2012) – 30,514 pa,ents included – Mul,ple indica,ons/popula,ons – Dabigatran vs. Warfarin • MI – RR: 1.33 (1.03-‐1.71); AR: 0.40% • Mortality – RR: 0.89 (0.80-‐0.99); AR: 0.19% • Long-‐term VTE Treatment • Dabigatran vs. Warfarin – RR: 4.5 (13 events vs. 3 events); p = 0.02 Arch Intern Med. Online Jan 9, 2012;DOI:10.101/archinternmed.2011.1666. N Engl J Med 2013;368:709-‐18. Warfarin + ASA + Clopidogrel • Triple therapy – Assumed appropriate for many pa,ents post PCI – Lack of data to support use or non-‐use • Un,l now – the WOEST Study – – – – Clopidogrel + Warfarin vs. Clopidogrel + Warfarin + ASA Pa,ents on warfarin undergoing PCI ≈ 65% DES Primary Endpoint – Any bleeding event • Any bleeding Event – HR (95% CI): 0.36 (0.26-‐0.50) • TIMI Major – HR (95% CI): 0.56 (0.25-‐1.27) • TIMI Major and minor – HR (95% CI): 0.40 (0.27-‐0.58) – Secondary Endpoint – Composite of death, MI, CVA, Target-‐vessel revasculariza,on, and stent thrombosis • Lower event rate in DOUBLE therapy group (p = 0.025) • All-‐cause mortality individually lower • Cardiac death, Any MI, STEMI, NSTEMI, CVA all numerically lower in DOUBLE therapy group – Main limita,on is open-‐label design Lancet online early February 13, 2013 – DOI: 10.1016/S0140-‐6736(13)60054-‐9. Take Home Points for Providers • Several new op,ons currently or will exist to replace warfarin • Current approved indica,ons include: – Prophylaxis of VTE in orthopedic pa,ents – Preven,on of stroke in pa,ents with Afib – Acute and chronic treatment of VTE • Adverse event rates are high when not used/dosed appopriately • Agents vary based on various pharmacologic and pharmacokine,c parameters – – – – None of the new agents require monitoring Would base choice of agent on pa,ent specific factors All of them can be “measured” if needed Best technique for reversal is unknown for most at this ,me but likely is either expensive, locally unavailable, or both • Cost will be a limita,on if not covered by insurance FDA Approved Dosing Parameter Dabigatran Rivaroxaban Apixaban 150 mg BID 20 mg QD Dosing Non-‐valvular Atrial fibrilla,on Orthopedic VTE Px Treatment DVT/PE Timing of Dose (CrCl 15-‐30 ml/min) (CrCl 15-‐50 ml/min) 5 mg BID (2.5 mg BID if age ≥ 80, weight ≤ 60 kg, or SCr ≥ 1.5 mg/dl) N/A 10 mg QD N/A N/A 15 mg BID X 21 days, then 20 mg QD (CrCl ≥ 30 ml/min) N/A Any,me (With or Without Food) 15, 20 mg Dose – With Food 10 mg Dose – Any,me Any,me (With or Without Food) (CrCl > 30 ml/min) (CrCl > 50 ml/min) 75 mg BID 15 mg QD Pa,ent Educa,on • Dabigatran – Store in original container – Discard opened product a•er 4 months – Dyspepsia most common side effect (up to 30%) – Do not open capsule – Comprehensive Pa,ent Guide Available Online1 • Rivaroxaban – Take with food 1Circ 2011;124:e209-‐e211. (DOI: 10.1161/CIRCULATIONAHA.111.019786) Novel Oral An,coagulant Agents: An Update in Pharmacotherapy David Stewart, PharmD, BCPS Associate Professor of Pharmacy Prac,ce East Tennessee State University Bill GaEon College of Pharmacy [email protected] Summary Table Parameter Apixaban Dabigatran Rivaroxaban Target Protein Factor Xa Thrombin (IIa) Factor Xa No Yes (etexilate) No CYP3A4/P-‐gp Renal CYP3A4/P-‐gp Avoid < 15 ml/min ↓ 15-‐29ml/min Avoid < 15 ml/min Adjust < 50 ml/min Avoid < 15 ml/min1 CYP3A4/P-‐gp Rifampin (P-‐gp) CYP3A4/P-‐gp Onset of ac,vity 3-‐4 hrs 1-‐2 hrs 2-‐4 hrs t½ 8-‐15 hrs 12-‐18 hrs 5-‐9 hrs Twice daily Twice daily Daily Monitoring tests An,-‐factor Xa ECT, TT, +/-‐ aPTT An,-‐factor Xa FDA Indica,ons None Non-‐valvular Afib. Non-‐valvular Afib. Ortho VTE Proph. Afib Ortho VTE Proph Afib, VTE Afib, Ortho VTE Proph, VTE Pro-‐Drug 1˚ Elimina,on Renal Adjustment Drug-‐Drug Interact. Dosing interval Clinical Uses 1Orthopedic VTE prophylaxis doses (10 mg daily) do not require renal adjustment; do not use if CrCl < 30 ml/min. Use of Concomitant An,platelet Agents AnAplatelet Agents ARISTOTLE (Apixaban) RELY (Dabigatran) ROCKET-‐AF (Rivaroxaban) < 165 mg/day Yes < 100 mg/day Clopidogrel Yes Yes Yes Combina,on No Yes No Aspirin Use (%) 31% 40% 36% ASA New Engl J Med 2009;361:1139-‐51. New Engl J Med 2011;365:883-‐91. New Engl J Med 2011;365:981-‐92. RE-‐LY -‐ Results Event Dabi 110 vs Warf HR (95% CI) Dabi 150 vs Warf HR (95% CI) Dabi 150 vs Dabi 110 HR (95% CI) Efficacy 1˚ Endpoint* 0.91 (0.74-‐1.11) 0.66 (0.53-‐0.82) 0.73 (0.58-‐0.91) All stroke 0.92 (0.74-‐1.13) 0.64 (0.51-‐0.81) 0.70 (0.56-‐0.89) Ischemic Stroke 1.11 (0.89-‐1.40) 0.76 (0.60-‐0.98) 0.69 (0.54-‐0.88) Hemorrhagic Stroke 0.31 (0.17-‐0.56) 0.26 (0.14-‐0.49) 0.85 (0.39-‐1.83) MI published 1.35 (0.98-‐1.87) 1.38 (1.00-‐1.91) 1.02 (0.76-‐1.38) MI revised 1.29 (0.96-‐1.75) 1.27 (0.94-‐1.71) Not available All cause mortality 0.91 (0.80-‐1.03) 0.88 (0.77-‐1.00) 0.97 (0.85-‐1.11) Safety Major bleeding 0.80 (0.69-‐0.93) 0.93 (0.81-‐1.07) 1.16 (1.00-‐1.34) GI bleeding 1.10 (0.86-‐1.41) 1.50 (1.19-‐1.89) 1.36 (1.09-‐1.70) All bleeding 0.78 (0.74-‐0.83) 0.91 (0.86-‐0.97) 1.16 (1.09-‐1.23) IC bleeding 0.31 (0.20-‐0.47) 0.40 (0.27-‐0.60) 1.32 (0.80-‐2.17) New Engl J Med 2009;361:1139-‐51. New Engl J Med 2010;363:1875-‐76. *Non-‐inferiority margin = 1.46 RE-‐LY Summary • Dabigatran 110 mg BID vs. warfarin – Non-‐Inferior Efficacy – Lower major and overall bleeding rates – Similar GI bleeding rates • Dabigatran 150 mg BID vs. warfarin – Superior efficacy – Lower overall bleeding rates – Similar major bleeding rates – Elevated rates of GI bleeding • Both doses showed decreased ICH compared to warfarin (60-‐70% RRR) ROCKET-‐AF Results Event Rivaroxaban (% per year) Warfarin (% per year) HR (95% CI) Efficacy 1˚ Endpoint* 2.1 2.4 0.88 (0.75-‐1.03) All stroke 1.65 1.96 0.85 (0.70-‐1.03) Ischemic Stroke 1.34 1.42 0.94 (0.75-‐1.17) Hemorrhagic Stroke 0.26 0.44 0.59 (0.37-‐0.93) MI 0.91 1.12 0.81 (0.63-‐1.06) All-‐cause mortality 1.87 2.21 0.85 (0.70-‐1.02) Safety Major bleeding 3.6 3.4 1.04 (0.90-‐1.20) All bleeding 14.9 14.5 1.03 (0.96-‐1.11) 3.2 (% overall) 2.2 (% overall) p < 0.001 0.5 0.7 0.67 (0.47-‐0.93) Major GI bleeding IC bleeding *Non-‐inferiority margin = 1.46 New Engl J Med 2011;365:883-‐91. ROCKET-‐AF Summary • Rivaroxaban vs. warfarin – Non-‐Inferior Efficacy – Similar bleeding rates – Lower ICH rates • High risk pa,ent popula,on (Mean CHADS2 score > 3) • TTR 55% New Engl J Med 2011;365:883-‐91. ARISTOTLE Results Event Apixaban (% per year) Warfarin (% per year) HR (95% CI) Efficacy 1˚ Endpoint* 1.27 1.60 0.79 (0.66-‐0.95) All stroke 1.19 1.51 0.79 (0.65-‐0.95) Ischemic Stroke 0.97 1.05 0.92 (0.74-‐1.13) Hemorrhagic Stroke 0.24 0.47 0.51 (0.35-‐0.75) MI 0.53 0.61 0.88 (0.66-‐1.17) All-‐cause mortality 3.52 3.94 0.89 (0.80-‐0.998) Safety Major bleeding 4.07 6.01 0.68 (0.61-‐0.75) All bleeding 18.1 25.8 0.71 (0.68-‐0.75) IC bleeding 0.33 0.80 0.42 (0.30-‐0.58) *Non-‐inferiority margin = 1.38 New Engl J Med 2011;365:981-‐92. ARISTOTLE Summary • Apixaban vs. warfarin – Superior efficacy with apixaban – ↓ overall mortality with apixaban (NNT = 238) – Lower bleeding rates with apixaban – Lower ICH rates • Apixaban vs. Aspirin – 6,000 high-‐risk pa,ents (mean CHADS2 = 2) – Not candidates for warfarin – 1 year follow-‐up – Superior efficacy to aspirin – Similar bleeding (including ICH) rates New Engl J Med 2011;365:981-‐92. New Engl J Med 2011;364:806-‐17. Summary of Afib Data Apixaban (ARISTOTLE) Dabigatran (RE-‐LY) Rivaroxaban (ROCKET – AF) > 18,000 > 18,000 > 14,000 Mean CHADS2 ≈ 2 ≈ 2 ≈ 3.5 TTR 62% 64% 55% Superior Superior1 Non-‐Inferior Decreased Similar Similar CYP3A4/P-‐gp Renal CYP3A4/P-‐gp/Renal # Pa,ents Efficacy vs. VKA Bleeding2 vs. VKA Elimina,on 1Dabigatran 150 mg BID group. 2Major bleeding per study design. Use of Concomitant An,platelet Agents AnAplatelet Agents ARISTOTLE (Apixaban) RELY (Dabigatran) ROCKET-‐AF (Rivaroxaban) < 165 mg/day Yes < 100 mg/day Clopidogrel Yes Yes Yes Combina,on No Yes No Aspirin Use (%) 31% 40% 36% ASA New Engl J Med 2009;361:1139-‐51. New Engl J Med 2011;365:883-‐91. New Engl J Med 2011;365:981-‐92.
Related documents