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What are all of these blood thinners? A review of oral anticoagulation options. Janet Friant, MSN, APN-BC, AACC University of Chicago Medical Center Chicago, IL Objectives • Provide an overview of coagulation and highlight potential targets for pharmacotherapy in thrombosis • Detail the MOA of warfarin and the novel oral anticoagulants (NOACs) with a focus on practical considerations related to anticoagulation • Review the data for use of NOACs in approved clinical indications • Outline initiation and transition strategies 3 Objectives • Provide an overview of coagulation and highlight potential targets for pharmacotherapy in thrombosis • Detail the MOA of warfarin and the novel oral anticoagulants (NOACs) with a focus on practical considerations related to anticoagulation • Review the data for use of NOACs in approved clinical indications • Outline initiation and transition strategies 4 Definitions • Coagulation - The physiologic process by which blood clots • Hemostasis - Physiologic clotting of blood in response to injury or vascular leakage (“Keeping blood where it belongs”) • Thrombosis - Pathologic clotting of blood (“Hemostasis in the wrong place”) 5 Coagulation in perspective: Thrombosis vs. hemostasis Issues of thrombosis and hemostasis often coexist in the very same patient “BAD CLOT” “GOOD CLOT” 6 Coagulation and platelet cascades 7 Nathan S, Swamy R. U.S. Cardiology 2008. Oral anticoagulation Clinical indications • Venous thromboembolism • Treatment • Prophylaxis • Arterial thrombosis (including PE) • LV thrombus / post-myocardial infarction • Atrial fibrillation (valvular, nonvalvular) • Prosthetic heart valves • CVA (stroke) 8 Nonvalvular atrial fibrillation • NVAF is the most common sustained cardiac arrhythmia in the U.S. affecting an estimated 2.7 million to 6.1 million adults in the United States and over 15 million patients worldwide. • It is widely believed that the incidence and prevalence of atrial fibrillation will continue to rise, perhaps doubling over the next 25 years. • The lifetime risk of developing atrial fibrillation after the age of 40 is as high as 25%, and is influenced by a variety of factors such as the development or coexistence of thyroid disease, diabetes, hypertension, obesity, sleep apnea, heart failure, myocardial ischemia and structural heart disease. 9 Nathan S, Shah AP. The Journal of Cardiothoracic and Vascular Anesthesia 2014. In press. Projected incidence of NVAF in the U.S. 10 Miyasaka Y, et al. Circulation 2006; 114: 119. Nonvalvular atrial fibrillation • Thromboembolic disease, in particular stroke, remains the most significant and feared complication of atrial fibrillation. • Atrial fibrillation is associated with 15% of strokes in people of all ages and 30% of strokes in people > 80 y.o. • There are an estimated 500,000 hospitalizations primarily for atrial fibrillation annually in the U.S. • It is estimated that atrial fibrillation contributes to at least 100,000 deaths per year, many as a consequence of stroke. 11 Nathan S, Shah AP. The Journal of Cardiothoracic and Vascular Anesthesia 2014. IDEM. Atrial fibrillation” a major contributor to stroke in the elderly; the Framingham Study. Arch Intern Med 1987; 147; 1561-4. Clinical Calculation Tools Clinical Calculation Tools: Qx Calculate Objectives • Provide an overview of coagulation and highlight potential targets for pharmacotherapy in thrombosis • Detail the MOA of warfarin and the novel oral anticoagulants (NOACs) with a focus on practical considerations related to anticoagulation • Review the data for use of NOACs in approved clinical indications • Outline initiation and transition strategies • Briefly highlight pipeline agents and combination therapies 14 Oral anticoagulants Warfarin Dabigatran 15 Rivaroxaban Apixaban Edoxaban Warfarin Wisconsin Alumni Research Foundation 16 Warfarin Kinetics Absorption 17 Oral: Rapid, complete Metabolism Hepatic, primarily via CYP2C9; minor pathways include CYP2C8, 2C18, 2C19, 1A2, and 3A4 Excretion Urine (92%, primarily as metabolites) Half-life Dosing 20-60 hours Variable Warfarin Key considerations 18 Onset of therapeutic effect 5-7 days May requiring bridging with indirect antithrombins Antidote Vitamin K, FFP, PRBC Factors influencing warfarin response Vitamin K balance, drug interactions, genetic variations, impaired hepatic function, hypermetabolic states, co-morbid medical conditions Adverse drug reactions Bleeding/Hemorrhage/Hematuria Vasculitis Dermatitis, pruritus, urticaria Abdominal pain, N/V/D Anemia Skin necrosis, gangrene, “purple toes” syndrome Indications for warfarin and recommended therapeutic range 19 Limitations of warfarin Only 55% of nonvalvular AF patients without contraindications receive warfarin*1 Mean TTR is low in patients receiving warfarin Rose et al 2 58% Patients (%) (N=124,551) 55% overall use1 Baker et al 3 55% (N=22,237) Rose et al 4 67% (N=3104) Sarawate et al 5 29% (N=470) McCormick et al 6 (n=1064) (n=1596) (n=3707) (n=3752) 0 Age (y) 20 (n=963) 51% (N=174) 20 40 60 Mean TTR (%) 1. 2. 3. 4. 5. 6. 7. Go AS et al. Ann Intern Med. 1999;131(12):927-934. Rose AJ et al. Circ Cardiovasc Qual Outcomes. 2011;4(1):22-29. Baker WL et al. J Manag Care Pharm. 2009;15(3):244-252. Rose AJ et al. J Thromb Haemost. 2008;6(10):1647-1654. Sarawate C et al. J Thromb Thrombolysis. 2006;21(2):191-198. McCormick D et al. Arch Intern Med. 2001;161(20):2458-2463 Bungard et al. Arch Intern Med. 2000; 160; 41-46. 80 100 Warfarin vs. placebo in stroke prevention in patients with NVAF Favors Favors Warfarin Placebo AFASAK SPAF BAATAF CAFA SPINAF EAFT All Trials 100% 50% 0 -50% -100% Relative Risk Reduction (95% CI) AFASAK = Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study; BAATAF = Boston Area Anticoagulation Trial for Atrial Fibrillation CAFA = Canadian Atrial Fibrillation Anticoagulation Study; EAFT = European Atrial Fibrillation Trial; SPAF = Stroke Prevention in Atrial Fibrillation Study; SPINAF = Stroke Prevention in Nonrheumatic Atrial Fibrillation. 21 Hart RG et al. Ann Intern Med. 1999;131(7):492-501. NOACs: “Are we there yet?” 22 Objectives • Provide an overview of coagulation and highlight potential targets for pharmacotherapy in thrombosis • Detail the MOA of warfarin and the novel oral anticoagulants (NOACs) with a focus on practical considerations related to anticoagulation • Review the data for use of NOACs in approved clinical indications • Outline initiation and transition strategies • Briefly highlight pipeline agents and combination therapies 23 Pros and cons of NOACs 24 Advantages Rapid onset/offset of action Disadvantages Use is contraindicated or dose reduction is required in patients with severe CKD Absence of food interactions Limited availability of assays for measuring drug levels Limited hepatic metabolism/few strong DDIs Wide therapeutic window Lower risk of intracranial hemorrhage Lower potential risk of bleeding complications Higher drug acquisition costs Rapid decline in effect if doses are missed No specific antidote Increased risk for GI bleeding Fixed dosing Contraindicated in patients with mechanical heart valves Direct oral thrombin inhibition XIIa VIIa XIa Tissue factor IXa Xa II × Factor IIa (thrombin) 25 Dabigatran Dabigatran Kinetics Absorption 26 Rapid; initially slow postoperatively Metabolism Hepatic; rapidly and completely hydrolyzed to active form by plasma and hepatic esterase Excretion Renal (80%) Half-life Dosing 12-17 hours 150mg twice daily if CrCl >30 ml/min 75mg twice daily is CrCl 15-30 ml/min Dabigatran • Onset: 1 hour, delayed by food • Antidote: None • Contraindications – Hypersensitivity to dabigatran or any component – Active bleeding • Warnings/Precautions – Bleeding – Renal impairment – Anticoagulants – Invasive/surgical invasions – P-gp inducers/inhibitors • ADRs – Bleeding (8% to 33%; major ≤ 6%) – Dyspepsia (11%) 27 Dabigatran vs. warfarin in the RELY trial 28 Connolly SJ, et al. N Engl J Med 2009;361:1139-51. RELY: Cumulative hazard rates for the primary outcome of stroke or systemic embolism, according to treatment group 29 Connolly SJ, et al. N Engl J Med 2009;361:1139-51. RELY: Safety outcomes according to treatment group 30 Connolly SJ, et al. N Engl J Med 2009;361:1139-51. RELY: Conclusions • In patients with atrial fibrillation, dabigatran given at a dose of 110 mg BID was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major haemorrhage • Dabigatran administered at a dose of 150 mg BID, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major haemorrhage 31 Recommended use of dabigatran 32 Direct oral Xa inhibition Tissue factor XIIa XIa VIIa IXa × Xa Rivaroxaban Apixaban Edoxaban Factor II (prothrombin) Fibrinogen 33 Fibrin clot Rivaroxaban Kinetics Absorption 34 Intestines, rapid Recommended to take with food Metabolism Hepatic CYP3A4/5 and CYP2J2 Excretion Renal (65%) Half-life Dosing 5-9 hours 20 mg once daily if CrCl > 50 ml/min 15mg once daily if CrCl 15-50 ml/min ROCKET-AF: Rivaroxaban vs. warfarin in NVAF at mod-high risk of stroke Nonvalvular AF Randomized double-blind/ double-dummy (N=14,264) CHADS2 Risk Factors •Prior stroke, TIA, or non–CNS systemic embolus – OR – •CHF or LVEF ≤35% At least 2 •Hypertension required •Age ≥75 years •Diabetes Rivaroxaban Warfarin 20 mg/d (15 mg/d for CrCl 30 to <50 mL/min) INR target: 2.0 to 3.0 inclusive Monthly assessments* Warfarin management was determined by clinician Enrollment of subjects without prior stroke, TIA, or systemic embolism and only 2 factors capped at 10% CHADS2 = congestive heart failure, hypertension, age, diabetes, prior stroke or TIA; CHF = congestive heart failure; CNS = central nervous system; INR = international normalized ratio; TIA = transient ischemic attack. *Patients seen at weeks 1, 2, and 4, then as clinically indicated but at least monthly thereafter. 35 1. Patel MR et al. N Engl J Med. 2011;365(10):883-891. 2. Online supplement to: Patel MR et al. N Engl J Med. 2011;365(10):883-891. http://www.nejm.org/doi/suppl/10.1056/NEJMoa1009638/suppl_file/nejmoa1009638_appendix.pdf. Accessed February 28, 2012. 3. ROCKET AF Study Investigators. Am Heart J. 2010;159(3):340-347. ROCKET AF: Primary endpoint (per protocol) 36 Patel MR et al. N Engl J Med 2011;365:883-891. ROCKET AF: Primary endpoint (intention to treat) 37 Patel MR et al. N Engl J Med 2011;365:883-891. Rivaroxaban vs. warfarin in NVAF: ROCKET AF trial The overall results for the primary composite endpoint (time to first occurrence of stroke (any type) or non–CNS systemic embolism) were noninferior between rivaroxaban and warfarin XARELTO® (n=7081)* Rate/ No. (%) 100 PTY Warfarin (n=7090)* Rate/ No. (%) 100 PTY HR (95% CI) Primary composite endpoint† 269 (3.8) 2.1 306 (4.3) 2.4 0.88 (0.74-1.03) Stroke 253 (3.6) 2.0 281 (4.0) 2.2 – 33 (0.5) 0.3 57 (0.8) 0.4 – 206 (2.9) 1.6 208 (2.9) 1.6 – 19 (0.3) 0.2 18 (0.3) 0.1 – 20 (0.3) 0.2 27 (0.4) 0.2 – Hemorrhagic stroke Ischemic stroke Unknown stroke type Non–CNS systemic embolism *Data are shown for all randomized patients followed to site notification. †The primary endpoint was the time to first occurrence of stroke (any type) or non–CNS systemic embolism. 1. Online supplement to: Patel MR et al. N Engl J Med. 2011;365(10):883-891. http://www.nejm.org/doi/suppl/10.1056/NEJMoa1009638/suppl_file/nejmoa1009638_appendix.pdf. 38 ROCKET AF: Secondary endpoints Rivaroxaban (n=7081)* Rate/ No. (%) 100 PTY HR (95% CI) Stroke, systemic embolism, and vascular death 572 (8.1) 4.5 609 (8.6) 4.8 0.94 (0.84-1.05) Stroke, systemic embolism, MI, and vascular death 659 (9.3) 5.2 709 (10.0) 5.7 0.93 (0.83-1.03) 33 (0.5) 206 (2.9) 19 (0.3) 0.3 1.6 0.2 57 (0.8) 208 (2.9) 18 (0.3) 0.4 1.6 0.1 0.58 (0.38-0.89) 0.99 (0.82-1.20) 1.05 (0.55-2.01) 20 (0.3) 0.2 27 (0.4) 0.2 0.74 (0.42-1.32) 130 (1.8) 1.0 142 (2.0) 1.1 0.91 (0.72-1.16) 582 (8.2) 4.5 632 (8.9) 4.9 0.92 (0.82-1.03) Stroke type Hemorrhagic Ischemic Unknown Systemic embolism MI All-cause mortality 39 Warfarin (n=7090)* Rate/ No. (%) 100 PTY Comparable major and nonmajor bleeding in ROCKET AF for rivaroxaban and warfarin Bleeding Major and nonmajor clinically relevant Major Nonmajor clinically relevant Rivaroxaban (n=7111)* Rate/ No. (%) 100 PTY Warfarin (n=7125)* Rate/ No. (%) 100 PTY HR (95% CI) 1475 (20.7) 14.9 1449 (20.3) 14.5 1.03 (0.96-1.11) 395 (5.6) 3.6 386 (5.4) 3.5 1.04 (0.90-1.20) 1185 (16.7) 11.8 1151 (16.2) 11.4 1.04 (0.96-1.13) *Safety population on-treatment. 40 Patel MR et al. N Engl J Med. 2011;365(10):883-891. ROCKET-AF: Conclusions • Rivaroxaban was noninferior to warfarin for prevention of stroke or systemic embolism. • Rivaroxaban group had less intracranial and fatal bleeding that the warfarin group. 41 Apixaban Kinetics Absorption Metabolism 15% liver metabolism CYP3A4 Excretion Primarily Biliary/Fecal (73%) Renal (27%) unchanged 8 to 15 hours Half-life Dosing 42 Rapid; Intestines Dose: 5mg twice daily Dose reduction to 2.5mg twice daily if 2+ of the following: ≥80 years;, weight ≤60kg, Cr ≥1.5mg/dl Apixaban vs. warfarin in NVAF 43 Granger CB et al. N Engl J Med 2011;365:981-992. Apixaban vs. warfarin in NVAF 44 Granger CB et al. N Engl J Med 2011;365:981-992. Apixaban vs. warfarin in NVAF 45 Granger CB et al. N Engl J Med 2011;365:981-992. Apixaban vs. warfarin in NVAF 46 Granger CB et al. N Engl J Med 2011;365:981-992. Apixaban vs. warfarin in NVAF 47 Granger CB et al. N Engl J Med 2011;365:981-992. Apixaban vs. warfarin in NVAF Treatment with apixaban as compared to warfarin in patients with AF and at least one additional risk factor for stroke: • Reduces stroke and systemic embolism by 21% (p=0.01) • Reduces major bleeding by 31% (p<0.001) • Reduces mortality by 11% (p=0.047) with consistent effects across all major subgroups and with fewer study drug discontinuations on apixaban than on warfarin, consistent with good tolerability. 48 Granger CB et al. N Engl J Med 2011;365:981-992. Apixaban vs. warfarin in NVAF In patients with atrial fibrillation, apixaban is superior to warfarin at preventing stroke or systemic embolism, causes less bleeding, and results in lower mortality. 49 Granger CB et al. N Engl J Med 2011;365:981-992. Edoxaban Kinetics Absorption Rapid; Intestines Peak in 1-2 hours Metabolism Predominant metabolite is active Hepatic clearance- 50%, 50% renal Minimal via hydrolysis Excretion Urine (primarily unchanged) Half-life 10-14 hours Dosing Dose: 30 mg daily Dose increased if CrCl >50 to 95ml/min to 60mg -AVOID in CrCl >95 ml/min or < 15ml/min 50 Edoxaban vs. Wafarin in NVAF Giugliano PR et al. N Engl J Med 2013;369:2093-104.. Edoxaban Stroke or Embolic Event Giugliano PR et al. N Engl J Med 2013;369:2093-104.. Edoxaban Major Bleeding Event Giugliano PR et al. N Engl J Med 2013;369:2093-104.. ENGAGE AF TIMI 48: Conclusions • Both once-daily regimens of edoxaban were noninferior to warfarin for stroke and systemic embolic protection in patients with non valvular atrial fibrillation. • Both does were associated with significantly lower rate of bleeding and death from CV causes. 54 Trials of NOACs (vs. warfarin) in NVAF NOTE: Because these clinical trials were conducted with different designs and evaluated different populations, direct comparisons of their results cannot be made. Subjects, % ENGAGE AF –TIMI 48 (N=21,105) ROCKET AF (N=14,264)1 RE-LY (N=18,113)2 ARISTOTLE (N=18,201)3 3.5 2.1 2.1 2.8 0 or 1 <0.1* 31.9 34.0 <0.1 2 13.0 35.6 35.8 46 3-6 86.9 32.5 30.2 53.9 Prior VKA use 62.4 49.6 57.1 58.8 CHF 62.5 32.0 35.4 58.2 Hypertension 90.5 78.9 87.4 93.7 Diabetes mellitus 40.0 23.3 25.0 36.4 Prior stroke/TIA/embolis m 54.8 20.0 19.4 28.1 Prior MI 17.3 16.6 14.2 CHADS2 score (mean) *Three subjects with a CHADS2 score of 0 or 1 were enrolled in ROCKET AF in violation of the study protocol. 1. Patel MR et al. N Engl J Med. 2011;365(10):883-891. 2. Connolly SJ et al. N Engl J Med. 2009;361(12):1139-1151. 3. Granger CB et al. N 55 Engl J Med. 2011;365(11):981-992 4. Giugliano RP et al. N Engl J Med. 2013; 369: 2093-104. NOACs in NVAF: Comparison of trials Comparative pharmacology of oral anticoagulants 57 NOACs in NVAF: Primary endpoints Study NOAC VKA Outcome RE-LY Dabigatran 1.1% Warfarin 1.7% RR 0.66 95% CI 0.53-0.82 P < 0.001 superiority ARISTOTLE Apixaban 1.3% Warfarin 1.6% HR 0.79 95% CI 0.66-0.95 P= < 0.001 Non- I P= 0.01 Superiority ROCKET-AF Rivaroxaban 1.7% Warfarin 2.2% HR 0.79 95% CI 0.66-0.96 P = <0.001 Non-Inferiority ENGAGE AF-TIMI 48 HD Edoxaban 1.18% LD Edoxaban 1.61% Warfarin 1.5% HR HD 0.79 95%CI 0.63-0.99 HR LD 1.07 95% CI 0.87-1.31 Non-Inferiority NOACs in NVAF: Bleeding 59 Study NOAC VKA Outcome RE-LY Dabigatran 3.3% Warfarin 3.6% RR 0.93 95% CI 0.81-1.07 P = 0.31 ARISTOTLE Apixaban 2.1% Warfarin 3.1% HR 0.69 95% CI 0.60-0.8 P = < 0.001 ROCKET-AF Rivaroxaban 5.6% Warfarin 5.4% HR 1.04 95% CI 0.90-1.20 P = 0.58 ENGAGE AFTIMI 48 HD Edoxaban 2.75% LD Edoxaban 1.61% Warfarin 3.4% HD HR 0.80 95 % CI 0.71-0.91 LD HR 0.47 95% CI 0.41-0.55 NOACs in NVAF: Intracranial hemorrhage 60 Study NOAC VKA Outcome RE-LY Dabigatran 0.3% Warfarin 0.7% RR 0.40 95% CI 0.27-0.60 P= <0.001 ARISTOTLE Apixaban 0.3% Warfarin 0.8% HR 0.42 95% CI 0.30-0.58 P = <0.001 ROCKET-AF Rivaroxaban 0.5% Warfarin 0.7% HR 0.67 95% CI 0.47-0.93 P = 0.02 ENGAGE EFTIMI 48 HD Edoxaban 0.39% LD Edoxaban 0.26% Warfarin 0.85% HD HR 0.47 95 % CI 0.64-0.63 LD HR 0.30 95% CI 0.21-0.43 NOACs in NVAF: Dosing recommendations 61 Agent Dosing Recommendations Dabigatran 75mg, 150mg CrCl > 30 cc/min: 150 mg, BID CrCl 15 to 30 cc/min: 75 mg, BID Avoid < 15 cc/min Apixaban 2.5mg, 5mg CrCl > 15 cc/min: 5 mg, BID Any 2 ( > 80 yrs, < 60 kg, SCr > 1.5mg/dL: 2.5 mg, BID) Avoid < 15 cc/min Rivaroxaban 10mg, 15mg, 20mg CrCl > 50 cc/min: 20 mg, Qday CrCl 15-50 cc/min: 15 mg, Qday Avoid CrCl < 15 cc/min Edoxaban 30mg, 60mg CrCl > 50 to < 95mL/min: 60 mg daily CrCl 15 to 50mL/min: 30 mg daily Avoid CrCl < 15cc/min and > 95cc/min Oral anticoagulation Clinical indications • Venous thromboembolism • Treatment • Prophylaxis • Arterial thrombosis (including PE) • LV thrombus / post-myocardial infarction • Atrial fibrillation (valvular, nonvalvular) • Prosthetic heart valves • CVA (stroke) 62 Oral anticoagulation Clinical indications for Pulmonary Embolus and Deep Vein Thrombosis Comparison of NOAC in VTE Treatment FDA Approved 1-8-2015 Objectives • Provide an overview of coagulation and highlight potential targets for pharmacotherapy in thrombosis • Detail the MOA of warfarin and the novel oral anticoagulants (NOACs) with a focus on practical considerations related to anticoagulation • Review the data for use of NOACs in approved clinical indications • Outline initiation and transition strategies • Briefly highlight pipeline agents and combination therapies 66 Medication Transition Triple therapy and risk of bleeding 68 Sørensen R, et al. Lancet 2009; 374: 1967–1974. Factors when choosing a NOAC Summary • Systemic anticoagulation has demonstrated significant benefit (reduced vascular morbidity/mortality) across a wide range of thrombosis states • NVAF remains a large (and growing) global medical problem which exacts in large part, through increased thromboembolic risk • AF-associated CVAs are more likely to be more morbid and more likely fatal than non-AF associated CVAs • Warfarin anticoagulation has proven benefit across a wide variety of thrombosis states but is frequently associated with unacceptably low TTR and management challenges 70 Summary • The novel oral anticoagulants (NOACs) when used appropriately, offer more homogeneous treatment effect than dose-adjusted warfarin with comparable or lower rates of major bleeding • Hepatic function, renal function and co-administration of medications impacting NOAC metabolism serve as important considerations when electing to switch to a NOAC • Co-administration of oral anticoagulants with oral antiplatelet therapy increases the risk of major bleeding 71