It s a. of Anticoagulation. Objectives

Transcription

1 It s a New World of Anticoagulation LAURA B. RICHARDSON, PHARMD, BCPS-CV CLINICAL PHARMACIST ABBOTT NORTHWESTERN HOSPITAL Objectives Understand the key differences between the oral anticoagulants t Become familiar with the indications Identify concerning clinical situations Management of adverse effects Periprocedural considerations 1

2 KEY DIFFERENCES Indication Things to Think about... Kinetic Drug Profile (e.g. t ½ ) Renal function Adherence Issues Liver Impairment Insurance Coverage $$ 2

3 Mechanism T ½ T max Comparing & Contrasting Dabigatran (Pradaxa) Direct Thrombin Inhibitor 12 17hr ½ 2hr Rivaroxaban (Xarelto) Direct Factor X inhibitor ~10hr 1 4hr Apixaban (Eliquis) Direct Factor X inhibitor 8 15hr 1 3hr Renal 80% 33% 25% Interaction P gp CYP450, P gp CYP450, P gp Side Effects Contraindications Bleeding, GI side effects including GIB Active Bleed CrCl < 15 Prosthetic Valves Bleeding Agranulocytosis Thrombocytopenia Stevens Johnson Active Bleed Child Pugh B C CrCl < 30 in DVT CrCl < 15 in NVAF Prosthetic Valves Bleeding Nausea Skin Rash Low BP Active Bleed Severe Liver disease Prosthetic Valves Traditional Anticoagulation Traditional Anticoagulation Agents Heparin and LMWH (e.g. enoxaparin/lovenox ) Warfarin (Coumadin ) Limitations Narrow therapeutic window Time of onset/offset Variable dose response requiring lab monitoring Benefits over the Novel Oral Anticoagulants (NOAC) Reversible Ability to monitor 3

4 Newer Oral Anticoagulants They all work within a few hours no need for overlapping with IV or SQ therapies. Anti IIa Dabigatran (Pradaxa) Anti Xa Rivaroxaban (Xarelto) Apixaban (Eliquis) Anti Xa on the horizon Edoxaban (? 2014) Betrixaban (????) Ther Drug Monit Dec;32(6):673 9 INDICATIONS 4

5 dabigatran (Pradaxa ) Non Valvular Atrial Fibrillation RE LY (warfarin) VTE Treatment and reduction recurrence DVT prophylaxis hip/knee replace VTE prophylaxis in hospital and post discharge Treated with parenteral anticoag 5 10 days RE COVER (warfarin) RE COVER II (warfarin) No No RE MEDY (warfarin) RE SONATE (placebo) rivaroxaban (Xarelto ) ROCKET AF (warfarin) EINSTEIN DVT (enox/warf) EINSTEIN PE (enox/warf) EINSTEIN EXTENSION (placebo) RECORD 1 (enox) RECORD 2 (enox; placebo controlled period) RECORD 3 (enox) No apixaban ARISTOTLE AMPLIFY (enox/warf) ADVANCE 1 (enox) (warfarin) AMPLIFY EXT (placebo) ADVANCE 2 (enox) (Eliquis ) AVERROES (ASA) (as of ~8/21/14) ADVANCE3 (enox) No edoxaban 2014 approval??? ENGAGE AF TIMI 48 (warfarin) Hokusai VTE (LMWH + edoxaban vs LMWH/warf) Betrixaban Phase APEX Dabigatran (Pradaxa) 150mg BID superior efficacy Similar risk major bleeding Higher risk of GIB Atrial Fibrillation Rivaroxaban (Xarelto) Comparable non inferior efficacy Comparable major bleeding. Lower rate hemorrhagic stroke, fatal bleeds Apixaban (Eliquis) Superior efficacy to warfarin and ASA Lower risk of major bleeding 150mg BID 20 mg QD with evening meal 5mg BID 75mg BID CrCl Not recommended CrCl < 15 or HD 2012 ACCP and 2014 AHA/ACC Afib guidelines 15 mg QD with evening meal CrCl Not recommended CrCl < 15 or HD 2.5mg BID If two of the following: 80yr, 60kg, Cr 1.5 Hemodialysis: 5mg BID 80yr or 60kg 2.5mg BID 5

6 2014 AHA/ACC Afib guidelines Mechanical Heart Valve Nonvalvular Afib with prior stroke or TIA, or CHADS2 VASc 2 Nonvalvular Afib with CHADS2 VASc = 1 Cardioversion Afib 48hr or unknown duration Warfarin Warfarin recommended (INR 2 3 or ) Warfarin INR 2 3 (superior to Plavix + ASA) Warfarin Warfarin INR 2 3 Dabigatran, rivaroxaban, apixaban Do not use Patients unable to maintain therapeutic INR Not for CrCl <15 Dose may need to be adjusted for CrCl < 50 Dabigatran Rivaroxaban Apixaban Dabigatran Rivaroxaban Apixaban Other considerations Nothing or Aspirin (Plavix + ASA = greater risk of bleeding vs ASA alone) Cardioversion Dabigatran, Rivaroxaban, LMWH or IV UFH Afib < 48hr and high stroke risk Apixaban started ASAP after procedure started ASAP after procedure Cardioversion UFH or LMWH Hemodynamic instability requiring emergency cardioversion ACS with CHADS2 VASc score >/=2 Other considerations Treatment of VTE and Prevention of Recurrence Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) i Just approved for this indication ~August 2014 Require initial treatment with parenteral agent Does not require parenteral during initiation Non inferior No significant difference in major bleed 15mg BID x 21 days, then 20mg QD with food Does not require parenteral during initiation Non inferior Superior for safety Non Inferior Trend towards higher GIB risk versus warfarin 150mg BID after 5 10 days 10mg BID x 7 days, then parenteral 5mg BID Avoid in CrCl 30 Avoid in CrCl < 30 No dose adjustment Duration determined by VTE recurrent risk 6

7 Prevention VTE after hip or knee replacement Dabigatran Rivaroxaban Apixaban (Pradaxa) (Xarelto) (Eliquis) Not approved for this indication in the US All RECORD studies superior to enoxaparin No significant increases in major bleeding 10 mg daily ± food Start 6 10hr postop Hip = 35 days Knee = 12 days Avoid CrCl < 30 ADVANCE 3hip: superior to enox in preventing primary outcome events Knee: non inferior No significant increases in major bleeding 2.5mg BID ± food Start 12 24hr postop Hip = 35 days Knee = 12 days Dosing NOAC: Indication, age, weight, renal function, drug interactions Warfarin Age, weight, indication, interactions, diet, genetics ultimately on INR Consider average dose over days versus yesterdays dose and todays INR Initial prothrombotic effect, overlap with parenteral until INR therapeutic. Antithrombotic effect comes from clearance of factor products 7

8 CLINICAL SITUATIONS Degree of Renal Impairment No renal impairment and CrCl 30 ml/min Renal impairment and CrCl 30 ml/min warfarin, apixaban, rivaroxaban, dabigatran Warfarin, apixaban,?rivaroxaban CrCl 15 30ml/min warfarin, apixaban CrCl < 15 ml/min warfarin 8

9 Liver Impairment Moderate Liver Impairment Severe Liver Impairment warfarin apixaban, dabigatran warfarin Dabigatran (Pradaxa) Moderate: o large inter subject variability but no evidence of consistent change in exposure or pharmacodynamics Avoid in severe liver impairment Rivaroxaban (Xarelto) Avoid in moderate or severe liver impairment (Child Pugh B/C) or liver disease with bleeding risk Apixaban (Eliquis) Experience limited in moderate liver impairment Avoid in severe impairment Elderly Atrial Fibrillation Patients Background Facts ~10% of people > 80 yrs have afib Anticoagulation for intermediate or high risk of stroke Age risk of stroke andsevere bleeding associated with anticoagulants NOAC Lower intracranial hemorrhage risk when compared to warfarin in afib Rates may be lower than what is experienced in the general elderly population (but less than half of the patients were >75 years old, and patients excluded for high risk of bleeding) Factors to Consider Weighing risk of ischemic stroke vs intracranial hemorrhage, bleed, & fall risk Higher risk of falls Prevalence of renal disease increases with age Determine bleeding risk when determining therapy More Rx = more interaction potential 9

10 Elderly and Low Weight Patients Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) Caution in underweight Caution in underweight Afib: dose consideration in elderly & low weight RE LY 82% 65 yo 40% 75 yo Risk of stroke & bleeding increases with age, but riskbenefit profile favorable in all age groups RE LY trial: dabigatran had trend dfor higher h major bleeding (extracranial, especially GIB) for 75 yr and lower risk <75 yr ROCKET AF 77% 65 yo 38% 78yo RECORD % 65 yo 15% 75 yo EINSTEIN DVT, PE, EXT 37% 65 yo 16% 75% Efficacy in elderly ( 65) similar <65 yo. Both ARISTOTLE and AVERROES >69% 65yo >31% 75 yo ADVANCE 1, 2, 3 50% 65 yo 16% 75 yo AMPLIFY, EXT >32% 65 yo >13% 75 yo No clinically significant differences in safety/efficacy Not necessarily the answer to thrombotic reducing and intracranial bleeding hemorrhage risk associated with warfarin events higher in older patients, but risk benefit Require dose adjustments for profile age, favorable renal function, in all age less forgiving for missed doses, and lack reversible options groups when comparing age groups Patients with Cardiovascular Risks Dabigatran association with heart attacks ~ CONTROVERSIAL RE LY: risk MI (however sub analysis had no significant difference) Annual rates stroke, SE, MI, UA, CABG, PCI, arrest, cv death with dabigatran Net clinical benefit events rate with dabigatran Active controlled VTE studies: rate of clinical MI with dabigatran, placebo controlled similar rate of non fatal & fatal clinical MI reported. Possibility of risk s ll may need further inves ga on Mechanical Heart Valves NOAC should be avoided in these patients Lacking data or evidence of harm Dabigatran (RE ALIGN) terminated early due to significantly more thromboembolic events and excess major bleeding with dabigatran 10

11 Administration Considerations Unable to swallow whole tablets Do not crush: dabigatran Do not chew, break, or open capsules (bioavailability 3 7% 75%) Ok to crush/ngt: rivaroxaban, apixaban Give immediately after crushing following admin instructions Check placement (e.g. rivaroxaban to be avoided if distal to stomach) What to do about missed doses? Not as tolerable versus warfarin Package insert on when to skip or double a dose e.g. rivaroxaban 15mg BID if miss dose tk take immediately to ensure 30mg/day With or without food? ±Food: apixaban and dabigatran +Food: rivaroxaban with evening meal when dosed for afib Drug Interactions Dbi Dabigatran Rivaroxaban Apixaban (Pradaxa) (Xarelto) (Eliquis) P gp Avoid use of P pg inducers and inhibitors Rifampin contraindicated Reduce dose with dronedarone or ketoconazole (75mg BID ir CrCl 30 50) CYP3A4 & P gp Avoid use of strong CYP3A4+P gp inhibitors CYP3A4 & P gp Avoid use of strong CYP3A4+P gp inhibitors Concomitant use with antithrombotics increased bleeding risk CYP3A4 and P gp inhibitors: ketoconazole, itraconazole, ritonavir, clarithromycin increases anticoagulant CYP3A4 and P gp inducers: rifampin, carbamazepine, phenytoin, St. John s wort decrease anticoagulant 11

12 Converting Between Agents Consideration of starting warfarin and overlap for a few days before stopping NOAC Converting Between Agents Start NOAC 0 2hr before the time that the next dose of parenteral was due or at the time of d/c continuously administered dabigatran: CrCl >/= 30, wait 12hr CrCl < 30, with 24hr after the last dose of dabigatran before starting parenteral rivaroxaban and apixaban: Dc and give first dose at the time the next rivaroxaban dose would have been taken Discontinue one and begin taking the other at the next scheduled dose time 12

13 Monitoring Periodic assessment of anticoagulation appropriateness Renal function Minimum: baseline, yearly, when clinically ll indicated d More if borderline renal function for dose adjustment Monitoring Optimal range of labs to ensure safety is unknown Overdose, bleeding, surgery, compliance Prolongation of labs (Correlation of drug with concentration varies ) Potential use of labs to ensure clearance of drug Dabigatran: TT, aptt, dabigatran level Rivaroxaban: PT (anti Xa) apixaban: aptt (anti Xa) ADVERSE EFFECTS 13

14 Adverse Effects Bleeding Increased risk of bleeding, GIB Evaluate and monitor for signs of blood loss Manage risk factors that are controllable (e.g. drug interactions) Monitor Cr affects t½ and anticoagulant activity Gastrointestinal *Dabigatran Most common AE = GI related (e.g. dyspepsia, ab pain, GIB) Discontinuation rate in the RE LY trial during the 1 st and 2 nd year was 16% and 21% versus 10% and 17% for warfarin. ~Rivaroxaban Minimize GIB Risk General practice measures Use correct dose, caution for drug interactions, utilize agents approved for the indication Address modifiable risk factors Avoid NSAIDs Use ASA when clearly indicated at an appropriate dose Consider a Proton Pump Inhibitor* with other risk factors Watch Cr close, adjust for renal function when indicated If high GIB risk (*dabigatran, ~rivaroxaban) consider apixaban or warfarin *Proton Pump Inhibitor example: pantoprazole/protonix 14

15 Management of Bleeding General Measures: pressure, RBC, endoscopic procedures, pressors Specific antidote not available FFP: not adequate reversal management Vitamin K or Protamine : not expected to affect anticoagulant activity Antifibrinolytics (transexamic acid, aminocaproic acid): no experience PCC (Kcentra) or factor VII (NovoSeven) : consider if life threatening t½ Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) hr 5 9hr (11 13hr elder) ~12 hr Mean t½ increases as CrCl decreases Elimination ~80% ~33% ~25% Hemodialysis Removes ~60% Low protein binding (~35%) Consider diuresis Not removed High protein bound (95%) No impact High protein bound (87%) Activated Charcoal within 2hr of ingestion within 2hr of ingestion within 2 6hr of ingestion Reversal Consider PCC (Kcentra), alternatively factor VIIa (NovoSeven) limited experience, AE of thrombosis/dic, $$$ Example of Allina Guideline 15

16 Example of Allina Guideline Example of Allina Guideline 16

17 PERIPROCEDURAL Peri procedural Considerations Lack of consensus protocols Team based approach Be aware if patient will be having an epidural or spinal anesthesia consult with anesthesia Communication! Not all health care professionals may recognize NOACs Determine the risks of the procedure and the need to hold therapy and for how long Check renal function and determine hold based on CrCl If procedure/surgery cannot be delayed, weigh bleeding versus urgency of intervention Determine the need to bridge with parenteral 17

18 Risk of Thrombotic Events and Consideration of Bridging Risk of thrombotic complications Premature discontinuation in the absence of adequate alternative anticoagulation with any oral anticoagulant Bridging Short time to offset and onset Usually not indicated with apixaban, dabigatran, rivaroxaban If d/c for reasons other than bleeding or completion of course of therapy, consider bridge (e.g. delay in procedure, NPO) Warfarin Hold, FFP, Vitamin K, bridge, etc When to Discontinue? Diagram (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) Considerations: age, renal function, bleeding risk, thrombosis risk Invasive or surgical If decided to d/c to Invasive procedure or surgery procedures: reduce the risk of with low bleeding risk or easily Hold 1 2 days bleeding controllable bleeding Hold 3 5 days CrCl Discontinue 24hr Discontinue 24hr prior < 50 prior Consider longer if major surgery, spinal puncture, or placement of spinal or epidural Consider 2 days for procedures with higher bleeding risk epidural For CrCl < 30 hold 2 days for low bleed risk or 4 days for high bleed risk Moderate or high risk of unacceptable or clinically significant bleeding Discontinue at least 48 hours prior Bridging after discontinuation: Bridge during 24 48hr after stopping and prior to intervention is NOT generally required Restart after as soon as adequate hemostasis established, remember quick onset! Consider parenteral if PO cannot be taken after intervention 18

19 Spinal/Epidural Anesthesia or Puncture Risk of developing epidural or spinal hematoma Frequentmonitoring for signs/symptoms of neurologic impairment Consider pharmacokinetic profile and CrCl for placement and removal of indwelling epidural or intrathecal catheter Know what questions to ask! How long after the last dose can catheter be placed? When is it ok to resume after catheter removed? How long to delay administration in the case of traumatic punctures? Don t forget 19

20 Consider Patient Factors I tend to miss doses Consider warfarin Cost is a potential adherence barrier Confusion Issues Issues with INR adherence, history of difficult to control INR Check with insurance coverage first! Potential for discounted NOAC programs Remember... warfarin is still an option Avoid alternating warfarin doses Daily NOAC rather than BID dosing dabigatran, rivaroxaban, apixaban Suggest strategies to improve adherence OTC that affect hemostasis & increase bleed risk Sign/symptom blood loss When to go to the ER Still need to monitor Cr, drug interactions, compliance, AE Patient Counseling 20

21 SUMMARY Warfarin (Coumadin) Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) Afib QD BID QD BID VTE QD BID, after 5 10 days parenteral BID x 21 days, then QD Ortho QD Not approved QD BID Renal excretion Hepatic Can give in renal insufficiency or HD, monitoring INR Affects INR/warfarin dose, dose adjust 80% Not recommended CrCl < 15 or HD 33% Not recommended CrCl < 15 or HD BID 25% HD dosing considerations Avoid in severe Avoid in moderate or severe Avoid in severe Reversal Vit K, FFP, PCC, VII None None None Efficacy High Experience Monitor Monitoring No Monitoring No Monitoring No Monitoring DI Not a substrate for CYP450 CYP450 substrate CYP450 substrate Miss dose LOTS of Interactions Not a large impact from missed dose P gp substrate P gp substrate P gp substrate Impact with missed dose(s) Impact with missed dose(s) Impact with missed dose(s) Diet Consistent Diet ± food Afib: give with evening meal (± food for VTE indications) Crush Ok to crush Do not crush Ok to crush Ok to crush AE Higher GIB/gastritis AMI risk? ± food 21

22 We may look alike... But when you line us up we are not all the same! References Hellwig T and Gulseth M. New oral therapies for the prevention and treatment of venous thromboembolism. Am J Health Syst Pharm. 2013;70: January CT, Wann LS, Alpert JS, et al AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and Heart Rhythm Society. Circulation 2014 Mar 28 Miller CS, Grandi SM, Shomony A, et al. Meta Analysis of Efficacy and Safety of New Oral Anticoagulants (Dabigatran, Rivaroxaban, Apixaban) Versus Warfarin in Patients with Atrial Fibrillation. Am J Cardiol 2012;110: Product Information for Eliquis. Bristol Myers Squibb Company. Princeton, NJ August Product Information for Xarelto. Bayer Inc. Toronto, ON M9W 1G6. August Product Information for Pradaxa. Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT April 2014 PL Detail Document, Appropriate Use of Oral Anticoagulants. Pharmacist s Letter/Prescriber s Letter. July PL Detail Document, Considerations for Anticoagulant Use in Elderly A.Fib Patients. Pharmacist s Letter/Prescriber s Letter. August PL Detail Document, Stopping Antithrombotics Before Surgery. Pharmacist s Letter/Prescriber s Letter. January Sardar P, Chatterjee S, Chaudhari S, et al. New Oral Anticoagulants in Elderly Adults: Evidence from a Meta Analysis of Randomized Trials. J Am Geriatr Soc 2014;62: Skeik N, Murphy CJ, Porten BR. The role of novel anticoagulants in the management of venous thromboembolism. Vascular Medicine. 2014;19(3): Skeik N, Rumery K, Rodriguez G. The New Era of Anticoagulation. Ann Vasc Surg 2013: 1 12 Wells PS, Forgie MA, Rodger MA, et al. Treatment of Venous Thromboembolism. JAMA. 2014;311(7): Tsu LV and Dager WE. Safety of New Oral Anticoagulants with Dual Antiplatelet Therapy in Patients with Acute Coronary Syndromes. The Annals of Pharmacotherapy. 2013;47:573 7 Weitz JI, Healey JS, Skanes AC, et al. Periprocedural Management of New Oral Anticoagulants in Patients Undergoing Atrial Fibrillation Ablation. Circulation. 2014;129:

23 Thank You 23