3/19/2012. What is the indication for anticoagulation? Has the patient previously been on warfarin? If so, what % of the time was the INR therapeutic?

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1 Abigail E. Miller, PharmD, BCPS Clinical Specialist, Cardiology University of North Carolina Hospitals I have no personal financial relationships with the manufacturers of the products to disclose. Boehringer Ingelheim supports current research with which I am affiliated. None of the investigators receive any direct support or compensation from the manufacturer. Contact Activation (Intrinsic) Pathway Tissue Factor (Extrinsic) Pathway Summarize the evidence to support the use of new anticoagulants XII (Damaged Surface) XIIa VIII VIIa (Damaged cells) VII Describe clinical decision making in selecting new anticoagulants vs. conventional anticoagulants XI IX XIa IXa VIIIa VIIa TF TF Identify health system related issues for safe use of new anticoagulation X Prothrombin (II) Xa Va Thrombin (IIa) X XIII Explain the inpatient initiation process for new anticoagulants Fibrinogen (I) Fibrin (Ia) XIIIa (Cross linked fibrin) Slide prepared by Brent N. Reed, PharmD, BCPS Warfarin Target VKORC1 Thrombin Factor Xa Prodrug No Yes No Absorption Rapid Rapid Rapid Distribution Hydrophilic Lipophilic p Lipophilic p Metabolism CYP2C19 Esterases Glucuronidation Elimination Renal (92%) Renal (80%) T1/2: hours T1/2: hours CYP3A4/5 CYP2J2 Renal (66%) 36% unchanged Fecal (28%) 7% unchanged T1/2: 5 9 hours Coumadin Prescribing Information. Bristol Myers Squibb. Revised October What is the indication for anticoagulation? Has the patient previously been on warfarin? If so, what % of the time was the INR therapeutic? What comorbidities does the patient have? Renal dysfunction, heart failure, GI bleed, hemorrhagic stroke How does the patient pay for their medications? Does the patient have a history of non compliance? If yes, why? 1

2 D A B I G A T R A N I N P A T I E N T M A N A G E M E N T O F A N T I C O A G U L A T I O N FDA Approved Indication: Prevention of stroke and systemic embolism in patients with non valvular atrial fibrillation (AF) ACCF/AHA/HRS 2011 AF Guidelines: Recommended as an alternative to warfarin in patients with non valvular AF(IB) CHEST 2012 Guidelines: Recommended for Prevention of VTE in Orthopedic Surgery Patients (1B) AF (1A and 2B) Treatment of DVT/PE (2B) FDA Approval: October 2010 (CrCL ml/min) Recommended Starting Dose Dosage form: > < mg BID 75 mg BID Do not use 75 mg and 150 mg capsule Do NOT crush or chew, must swallow whole Adverse effects: Bleeding Gastrointestinal events JACC. 2011;57(11): Chest :2 suppl e278s e325s, e419s e494s, e531s e575s. Inclusion criteria: Non valvular AF, CrCl > 30mL/min VKA (INR 2 3) Intervention N = 6022 Patient Characteristics Median Age: 71 years Male: 63.6% Mean CHADS 2 score: 2.1 Previous vitamin K antagonist (VKA) use: 50% History of stroke, TIA, systemic embolism: 20% Time in therapeutic range (VKA): 64% N = 18, mg BID 150 mg BID N = 6015 N = 6076 Primary outcome Stroke, systemic embolism (SE) Median follow up: 2 years Non inferiority design NEJM 2009;361: Outcome (%/yr) VKA 110 mg 150 mg (%/yr) 110 mg vs.vka 150 mg vs. VKA Stroke/SE ( ) 0.66 ( ) Ischemic Stroke ( ) 0.76 ( ) Hemorrhagic ( ) 0.26 ( ) Stroke Safety MI ( ) 1.87) ( ) 1.91) Death ( ) 0.88 ( ) Bleeding Major ( ) 0.93 ( ) Intracranial ( ) 0.40 ( ) Gastrointestinal ( ) 1.50 ( ) Extracranial ( ) 1.07 ( ) Minor or Major ( ) 0.91 ( ) Dyspepsia 11.8%* 11.3%* 5.8% Discontinuation 1yr 15%* 16%* 10% Discontinuation 2yr 21%* 21%* 17% *Statistically significant difference vs. warfarin NEJM 2009;361: Outcome Net clinical benefit 110 mg %/yr 150 mg %/yr VKA %/yr 110 mg vs.vka 150 mg vs. VKA ( ) 0.91 ( ) I: N = 2564 II: N = 2568 DVT or PE Trial Design Double blind, double dummy, non inferiority Stroke/SE Bleeding Net clinical benefit Initial parenteral anticoagulation Mean (I): 10 days Primary efficacy outcome Recurrent VTE (venous thomboembolism) or related death at 6 months 150 mg BID NEJM 2009;361: I: N = 1265 II: N = 1289 VKA (INR 2 3) I: N = 1274 II: N = mg BID NEJM 2009;361: Shulman S, et al. ASH 2011 Annual Meeting; Dec San Diego, CA; Abstract

3 RE COVER I: Patient Characteristics Age (median): 56 years DVT: 69% PE: 21% DVT + PE: 9.5% 95% Previous VTE: 25% Time INR in range: 60% vs. VKA RE COVER I RE COVER II Primary outcome HR (95% CI) 2.4% vs.2.1% 1.10 ( ) Major Bleeding 1.6% vs. 1.9% 0.82 ( ) Any bleeding 16.1% vs. 21.9% 0.71 ( ) 2.4% vs. 2.2% 1.08 ( ) 1.1% vs. 1.7% 0.69 ( ) 1.6% vs. 2.2% 0.67 ( ) NEJM 2009;361: Shulman S, et al. ASH 2011 Annual Meeting; Dec San Diego, CA; Abstract 205. Trial Population Enoxaparin Primary Outcome RE NOVATE RE MODEL RE MOBILIZE CHEST Guidelines (Prevention of VTE in orthopedic surgery) Hip arthroplasty Knee arthroplasty Knee arthroplasty 40 mg SC daily X28 35 days 40 mg sc daily X6 10 days 30 mg sc BID X12 15 days 150 mg OR 220 mg daily X28 35 days 150 mg OR 220 mg daily X6 10 days 150 mg OR 220 mg daily X12 15 days 150 mg = LMWH 220 mg = LMWH 150 mg = LMWH 220 mg = LMWH 150 mg < LMWH 220 mg <LMWH 150 mg daily DVT less than LMWH one trial that used a higher dosing schedule of LMWH contributed the majority of the excess asymptomatic events The additional 2 symptomatic VTE events per 1,000 with the 150 mg dose are offset by 4 major bleeding events per 1,000 in the LMWH group, this bleeding is more likely with the higher LMWH dose Greater long term experience with LMWH still favors its use Lancet 2007;37: J Thromb Haemost 2007; 5: J Arthroplasty 2009; 24: 1 9. Agent Heparin Enoxaparin Fondaparinux Conversion to Start dabigatran at the time the heparin infusion is turned off. Start dabigatran at the time the next dose of enoxaparin was to be administered (may overlap by up to 2 hours). Start dabigatran at the time the next dose of fondaparinux was to be administered i d (may overlap by up to 2 hours). Start dabigatran at the time the next dose of rivaroxaban was to be administered. For patients at greater risk of stroke who have normal renal function, starting dabigatran up to 12 hours after the last dose of rivaroxaban may be considered. Warfarin Discontinue warfarin and start dabigatran when the INR is < 2.0. (CrCL ml/min) Recommended Starting Dose > < mg BID 75 mg BID Do not use Thromb Haemost Jun;103(6): (CrCL ml/min) Recommended Starting Dose > < mg BID 75 mg BID Do not use Dose FDA approved for AF only Conversion to Parenteral Anticoagulants > 30 Start parenteral anticoagulant 12 hours after last dabigatran dose. < 30 Start parenteral anticoagulant 24 hours after last dabigatran dose. Thromb Haemost Jun;103(6): R I V A R O X A B A N I N P A T I E N T M A N A G E M E N T O F A N T I C O A G U L A T I O N FDA Approved Indication: Prevention of stroke and systemic embolism in patients with non valvular atrial fibrillation (AF) Prophylaxis of DVT/PE in patients undergoing knee or hip replacement surgery CHEST 2012 Guidelines: Recommended for Prevention of VTE in Orthopedic Surgery Patients (1B and 2B) Treatment of DVT/PE (2B) FDA Approval: November 2011 Dosage form: 10 mg, 15 mg, 20 mg tablet Indication (Stroke Prevention) > Knee Replacement > 30 Hip Replacement > 30 Adverse effects: Bleeding Recommended Dose 20 mg once daily with evening meal 15 mg once daily with evening meal 10 mg once daily for 12 days 10 mg once daily for 35 days Discontinuation places patients with AF at an increased risk of thrombotic events Epidural or spinal hematomas have occurred in patients receiving neuraxial anesthesia or undergoing spinal puncture and may result in long term or permanent paralysis Chest :2 suppl e278s e325s, e419s e494s, e531s e575s. 3

4 Inclusion criteria: Non valvular AF, CrCl 30mL/min VKA Intervention (INR 2 3) N = 7133 Patient Characteristics Median Age: 73 years Male: 60.3% Mean CHADS 2 score: 3.47 Previous vitamin K antagonist (VKA) use: 62% History of stroke, TIA, systemic embolism: 54% Time in therapeutic range (VKA): 55% N = 14, mg or 15 mg daily N = 7131 Primary outcome Stroke, systemic embolism (SE) Median follow up: 1.9 years Non inferiority design NEJM 2011;365: Study Population Warfarin HR (95% CI) P Value Primary End Point: Event rate, #/100 pt years Noninferiority Superiority Per protocol, as treated ( ) <0.001 Safety, as treated ( ) 0.02 Intention to treat (efficacy) ( ) < During treatment (efficacy) ( ) 0.02 After discontinuation (efficacy) ( ) 0.58 Safety: Event rate, #/100 pt years Superiority Major +non major bleeding ( ) 0.44 Major bleeding ( ) 0.58 Fatal bleeding ( ) Intracranial hemorrhage ( ) 0.02 NEJM 2011;365: Trial Design Patient Characteristics LMWH + VKA (INR 2 3) N = 1718 DVT N = mg BID x 3 weeks, then 20 mg Qday N = 1731 Open label, non inferiority Primary efficacy outcome Recurrent VTE (venous thomboembolism) at 3, 6, 12 months NEJM 2010;363: Age DVT: Previous (mean): 99% VTE: 56 years PE: 1% 19% Time INR in range: 58% Outcome LMWH + VKA Recurrent VTE 2.1% 3.0% HR (95% CI), p value 0.68 ( ), <0.001 Major or clinically relevant nonmajor bleeding 8.1% 8.1% HR (95% CI), p value 0.97 ( ), 0.77 Major Bleeding 0.8% 1.2% HR (95% CI), p value 0.65 ( ), 0.21 NEJM 2010;363: Trial Population Enoxaparin DVT/PE/Death (%) 40mg SC daily 10 mg PO daily RECORD 1 Hip arthroplasty 3.7 vs. 1.1 x35 days x35 days RECORD 2 RECORD 3 RECORD 4 Hip arthroplasty 40 mg sc daily X10 14 days 10 mg PO daily X31 39 days Knee 40 mg sc daily 10 mg PO daily arthroplasty X10 14 days X10 14 days Knee arthroplasty 30 mg sc BID X10 14 days 10 mg PO daily X10 14 days 9.3 vs vs vs. 6.9 Agent Heparin Enoxaparin Fondaparinux Conversion Instructions Discontinue the heparin infusion when the first evening dose of rivaroxaban is administered. Start rivaroxaban at the time the next evening dose of enoxaparin was to be administered (may overlap by up to 2 hours). Discontinue fondaparinux. Start rivaroxaban in the evening on the following day. Start rivaroxaban 12 hours after the last morning dose of dabigatran. Warfarin Discontinue warfarin and start rivaroxaban in the evening when the INR is < 3.0. CHEST Guidelines (Prevention of VTE in orthopedic surgery) The best estimates suggest that 5 fewer symptomatic DVT per 1,000 achieved with rivaroxaban over LMWH will be offset by 9 more major bleeding events Both the possibility of increased major bleeding events and the availability of long term safety data for LMWH makes LMWH more appealing than rivaroxaban in spite of the inconvenience of subcutaneous administration NEJM 2008; 358: NEJM 2008; 358: Lancet 2008;372:31 9. Lancet 2009;373: Indication Recommended Dose > mg once daily with evening meal (Stroke Prevention) mg once daily with evening meal Knee Replacement > mg once daily for 12 days Hip Replacement > mg once daily for 35 days 4

5 Indication Recommended Dose > mg once daily with evening meal (Stroke Prevention) mg once daily with evening meal Knee Replacement > mg once daily for 12 days Hip Replacement > mg once daily for 35 days Strategy Strategy 1 (Parenteral) Strategy 2 (Oral) > 50 < 50 > Conversion Instructions Start parenteral anticoagulant hours after the last rivaroxaban dose (consider 12 hours in patients at greater risk of stroke). ±Start warfarin at the next standard administration time. Start parenteral anticoagulant 24 hours after the last rivaroxaban dose. ±Start warfarin at the next standard administration time. Start warfarin and overlap with rivaroxaban for 5 days. Discontinue rivaroxaban on day 5 or when INR is 2 3. Start warfarin and overlap for 3 days with rivaroxaban. Discontinue rivaroxaban on day 3 or when INR is 2 3. Bleeding Severity Mild Moderate A N T I D O T E Management Recommendations Delay next dose or discontinue dabigatran. Consider any of the following based on bleeding severity: Symptomatic treatment Mechanical compression Surgical intervention Fluid replacement and hemodynamic support Blood product transfusion Oral activated charcoal (if previous dose ingested within 2 hours) Dose: Liquid charcoal with sorbitol 50 g PO x 1 dose If hemostasis is not achieved with the strategies outlined above, consider the administration of 2 4 units of fresh frozen plasma (FFP). Obtain a Hematology/Coagulation consult for further recommendations. Severe or Life threatening Bleeding: Management Recommendations No agent has been shown to successfully reverse the anticoagulant effects of dabigatran, rivaroxaban, or related bleeding events. Therefore, the pharmacologic interventions below may be considered but are not required in the management of dabigatran related bleeding. A Hematology/Coagulation consult must be obtained prior to the following: 1. Prothrombin Complex Concentrate (PCC) a. Low risk for thrombotic complications: Consider activated prothrombin complex concentrate (apcc) (FEIBA ) 50 units/kg x 1. a b. High risk for thrombotic complications: Consider non activated prothrombin complex concentrate (PCC) (Profilnine ) 50 units/kg x Recombinant factor VIIa (NovoSeven ) mcg/kg IV x 1. b After several hours, additional doses of mcg/kg IV may be considered (with Hematology/Coagulation guidance) based on bleeding severity and degree of hemostasis achieved. 3. Fibrinolytic therapy (e.g., tranexamic acid, aminocaproic acid) may also be considered. 4. Fresh frozen plasma (as much as tolerated) 5. Hemodialysis To investigate potential causes of the bleeding event, obtain the following: serum creatinine, PT/INR, aptt, thrombin clotting time (TCT), CBC (platelets). What is the indication for anticoagulation? Has the patient previously been on warfarin? If so, what % of the time was the INR therapeutic? What comorbidities does the patient have? Renal dysfunction, heart failure, GI bleed, hemorrhagic stroke How does the patient pay for their medications? Does the patient have a history of non compliance? If yes, why? FDA Approval: DVT PE Treatment Post orthopedic surgery CHEST Guideline Recommendations: DVT PE Treatment Post orthopedic surgery Once daily dosing schemes: DVT PE Treatment Orthopedic surgery Reversal agent available Chest :2 suppl e278s e325s, e419s e494s, e531s e575s. New oral anticoagulants have been studied in the setting of nonvalvular AF, DVT/PE treatment, and in orthopedic surgery patients The use and selection of a new oral anticoagulant should be based on ability to match available evidence to a specific patient Health systems should define protocols for dosing, initiation, and management of adverse events Evolving evidence should clarify the ability to reverse dabigatran and rivaroxaban 5

6 Abigail E. Miller, PharmD, BCPS Clinical Specialist, Cardiology University of North Carolina Hospitals 6