Updates in Anticoagulation. Megan Labreck, PharmD, BCPS, CACP Kristian Navickas, PharmD, BCPS, BCACP Tara Schreck, PharmD, BCACP

Transcription

1 Updates in Anticoagulation Megan Labreck, PharmD, BCPS, CACP Kristian Navickas, PharmD, BCPS, BCACP Tara Schreck, PharmD, BCACP

2 Pharmacist Learning Objectives At the end of this program, the learner will be able to: 1. Discuss the updates to the 2016 CHEST Guidelines on Antithrombotic Therapy for VTE Disease 2. Review the current indications and dosing for NOACs 3. Explore the emerging roles of NOACs in CAD, PCI, and cardioversion 4. Review the updates to the ACC recommendations on the management of bleeding in patients on oral anticoagulation

3 Pharmacy Technician Objectives At the end of this program, the learner will be able to: 1. Understand the similarities and differences between oral anticoagulants 2. Identify the generic and brand names for oral anticoagulants 3. State the contraindications to oral anticoagulants

4 Patient Case BC is a 26 yo male diagnosed with a DVT in his left popliteal vein. PMH includes a h/o HTN, treated with lisinopril 10mg daily (patient admits to non-adherence) Patient has commercial insurance through his employer Patient admits he recently returned from a trip to New Zealand (spent 20+ hours on airline)

5 Patient Case Things to consider: Cause of VTE Insurance Adherence to medications Decisions to make: Choice of therapy Duration of therapy

6 A Brief History of Oral Anticoagulants 1930s 1951 Suicide attempt draws attention to warfarin s clinical effects 1954 Coumadin approved by Endo Pharmaceuticals 1955 Warfarin given to President Eisenhower after heart attack 1980s INR developed, optimal range introduced 1990s Optimal anticoagulation duration introduced The Pharmaceutical Journal, Vol. 284, p189 URI: BJH. 2008; 141:

7 A Brief History of Oral Anticoagulants (AC), cont. 2000s First NOACs developed: direct thrombin inhibitors (DTIs) and Factor Xa inhibitors (FXaIs) Ximelagatran halted in 2006 due to liver toxicity Dabigatran approved in 2010 Rivaroxaban approved in 2011 Apixaban approved in 2012 Edoxaban approved in 2015 The Pharmaceutical Journal, Vol. 284, p189 URI: BJH. 2008; 141:

8 Keeping Safety in Mind Joint Commission 2018 National Patient Safety Goals: NPSG Reduce the likelihood of patient harm associated with anticoagulant therapy Use approved protocols for initiation/maintenance Baseline INR must be obtained for patients on warfarin, and policies in place for monitoring of anticoagulation Provide education regarding anticoagulant therapy to prescribers, staff, patients, and caregivers The Joint Commission

9 Updates to Venous Thromboembolism (VTE) Guidelines CHEST. 2016; 149(2):

10 2016 CHEST VTE Guidelines: Select Key Changes Topic New Changed New evidence but no change Choice of long-term and extended AC therapy ASA for extended treatment of VTE Management of recurrent VTE on AC therapy Duration of treatment CHEST. 2016; 149(2):

11 VTE Risk Factors Surgery Trauma Increasing age Obesity History VTE Cancer Immobility Photo credit: American Society of Hematology Pregnancy Estrogen-containing oral contraceptives or hormone replacement Inherited or acquired thrombophilia CHEST. 2016; 149(2):

12 Choice of AC Therapy - Acute & Long- Term Deep vein thrombosis (DVT) of leg or pulmonary embolism (PE) without active cancer Extended treatment with NOACs reduce recurrent VTE and is associated with less bleeding risks NOACs preferred over warfarin (Grade 2B) No one NOAC is preferred over the other Rivaroxaban, apixaban (No bridging needed) Dabigatran, edoxaban (Start with parenteral AC x5d) Warfarin preferred over LMWH (Grade 2C) Overlap with parenteral anticoagulation x5 days and INR >2 for 24 hours CHEST. 2016; 149(2):

13 Choice of AC Therapy - Acute & Long- Term, Cont. DVT of leg or PE with active cancer LMWH preferred over warfarin (Grade 2C) LMWH preferred over NOACs (Grade 2C) In patients with VTE and cancer who are not treated with LMWH, there is no preference for either a NOAC or VKA CHEST. 2016; 149(2):

14 Choice of AC Therapy - Extended Therapy No need to change choice of AC after the first 3 months Reassess in periodic intervals Annually Risk vs Benefit Consideration Reduction in recurrent VTE CHEST. 2016; 149(2):

15 AC Considerations for Initial and Long-Term Treatment Factor Cancer Parenteral therapy to be avoided Once daily oral therapy preferred Liver disease and coagulopathy Renal disease; CrCl <30mL/min Coronary Artery Disease Dyspepsia or h/o GI bleeding Poor adherence Reversal agent needed Pregnancy or risk of pregnancy Cost Preferred AC LMWH Rivaroxaban; apixaban Rivaroxaban; edoxaban; warfarin LMWH Warfarin Warfarin; rivaroxaban; apixaban; edoxaban Warfarin; apixaban Warfarin Warfarin; UFH LMWH Varies CHEST. 2016; 149(2):

16 NOAC Trials in VTE Treatment Comparison Trials Study Design Dabigatran Rivaroxaban Apixaban Edoxaban RECOVER I RECOVER II Randomized, double-blind, noninferiority, parallel group EINSTEIN DVT EINSTEIN PE Randomized, open-label, event-driven, noninferiority, parallel group AMPLIFY Randomized, double-blind, parallel group HOKUSAI VTE Randomized, double-blind, noninferiority parallel group Primary Efficacy Endpoint Recurrent symptomatic VTE or death related VTE Recurrent symptomatic VTE Recurrent symptomatic VTE or death related VTE Recurrent symptomatic VTE Primary Safety Endpoint Major bleeding Major or CRNM bleeding Major bleeding Major or CRNM bleeding Drugs. 2014;74:

17 NOAC Trials in VTE Treatment Comparison Dabigatran Rivaroxaban Apixaban Edoxaban Sample Size (n) % DVT Patients 69% 99% (EINSTEIN DVT) 66% 60% % PE Patients 22% 75% (EINSTEIN PE) 25% 30% % PE and DVT Patients 9% 15% 9% 10% % Active Cancer 4% 5% 3% 3% % Unprovoked N/A 63% 90% 66% Drugs. 2014;74:

18 NOAC Trials in VTE Treatment Comparison Dabigatran Rivaroxaban Apixaban Edoxaban Intervention 150mg BID 150mg BID 15mg BID x21 days 20mg once daily 10mg BID x7 days 5mg BID 60mg or 30mg once daily Comparator Warfarin Enoxaparin warfarin Enoxaparin warfarin Warfarin Parenteral AC (UFH, LMWH, fondaparinux) Duration of Treatment Mandatory, 5 day Optional, max 48h Optional, max 36h Mandatory, 5 day 6 mos 3, 6, or 12 mos 6 mos 3, 6, or 12 mos Drugs. 2014;74:

19 NOAC Trials in VTE Treatment Comparison Dabigatran Rivaroxaban Apixaban Edoxaban Primary efficacy endpoint (%) 2.4 vs vs vs vs vs vs 3.5 Major Bleeding (%) 1.6 vs vs vs vs vs vs 1.6 CRNM Bleeding (%) 4 vs vs vs vs vs vs 8.9 Major and CRNM Bleeding (%) 5.6 vs vs vs vs vs vs 10.3 Drugs. 2014;74:

20 Aspirin (ASA) for Extended treatment of VTE In patients with an unprovoked DVT or PE who are stopping AC treatment and have no contraindication to ASA: ASA preferred over no ASA (Grade 2C) Study population = patients completing 3 months of initial AC therapy after 1 st unprovoked DVT/PE Less effective at preventing recurrent VTE than anticoagulants Balance with ASA s risk of bleeding and inconvenience Better than no therapy CHEST. 2016; 149(2):

21 Management of VTE Despite AC Therapy If on therapeutic warfarin or NOAC, then switch to LMWH temporarily (minimum 1 month) (Grade 2C) If on long-term LMWH and compliant, recommendation is to increase the dose by 25-33% (Grade 2C) Reason for recurrence Non-adherence Subtherapeutic warfarin Drug interaction (reducing AC effect) Patient factors (active cancer, antiphospholipid syndrome, hormones) CHEST. 2016; 149(2):

22 Duration of AC Treatment Based on Type of VTE Type of VTE Recommended Duration of Treatment 2012 Recommended Duration of Treatment 2016 Proximal DVT (leg) or PE provoked by surgery DVT (leg) or PE provoked by nonsurgical transient risk factor Isolated distal DVT (leg) provoked by surgery or nonsurgical transient risk factor 3 months 3 months 3 months 3 months 3 months 3 months Unprovoked PE or DVT (leg) At least 3 months At least 3 months Pt s first DVT that is an unprovoked proximal DT (leg) or PE At least 3 months Extended therapy (no scheduled stop date) CHEST. 2016; 149(2):

23 Duration of AC Treatment Based on Type of VTE Type of VTE In patients with second unprovoked VTE with a low bleeding risk In patients with second unprovoked VTE with a moderate bleeding risk In patients with second unprovoked VTE with a high bleeding risk Patients with DVT (leg) and active cancer w/ or w/o high risk of bleeding Recommended Duration of Treatment 2012 Recommended extended therapy Suggested extended therapy Suggest 3 months Extended therapy Recommended Duration of Treatment 2016 Extended therapy (no scheduled stop date) At least 3 months 3 months Extended therapy (no scheduled stop date) CHEST. 2016; 149(2):

24 Review: NOAC Indications and Dosing

25 PHOTO CREDIT:

26 NOAC: Renal Exclusions Dabigatran: Avoid in CrCl <15 ml/min Rivaroxaban: Avoid non-valvular AF treatment in CrCl <15 ml/min Avoid DVT/PE treatment and prophylaxis in CrCl <30 ml/min Pradaxa (dabigatran) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; August Xarelto (rivaroxaban) [prescribing information]. Gurabo, PR: Janssen Pharmaceuticals Inc; September 2014.

27 NOAC: Renal Exclusions Apixaban: DVT/PE Treatment excluded CrCl <25 ml/min or SCr >2.5 from trials DVT prophylaxis excluded CrCl <30 ml/min from trial Edoxaban: Avoid non-valvular AF treatment in CrCl <15 ml/min or >95 ml/min Avoid DVT/PE treatment in CrCl <15 ml/min Eliquis (apixaban) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; March Savaysa (edoxaban) [prescribing information]. Tokyo, Japan: Daiichi Sankyo; January 2015.

28 NOAC: Half-Life T1/2 much shorter than warfarin Compliance is crucial to NOAC success Dabigatran Apixaban Edoxaban Rivaroxaban T 1/2 (hours)

29 Cost Comparison; Monthly Dabigatran: $387 Rivaroxaban: $425 Apixaban: $425 Edoxaban: $342 Warfarin: $4 PT/INR (self pay): $17.55 Drug prices obtained from

30 Betrixaban New NOAC Direct factor Xa inhibitor Indication: VTE prevention Acutely ill medical, non-surgical patients Moderate or severely limited mobility plus other VTE risk factors Not recommended for use in AF, VTE treatment, after hip/knee surgery, long-term VTE prevention in cancer or prior VTE Product information for Bevyxxa. Portola Pharmaceuticals. South San Francisco, CA March 2018.

31 Betrixaban New NOAC LMWH 160mg x1 then 80mg once daily with food for days Renal dosing: 80mg x1 then 40mg once daily with food for days APEX clinical trial prevents small number of symptomatic VTEs, increases risk of CRNM Expensive ($630 for 6 weeks therapy) Product information for Bevyxxa. Portola Pharmaceuticals. South San Francisco, CA March 2018.

32 Emerging Roles of NOACs

33 NOACs in CAD: COMPASS Trial Clinical question In patients with established stable atherosclerotic disease, is rivaroxaban plus aspirin more effective than aspirin alone in reducing cardiovascular death, stroke, or nonfatal MI? NEJM. 2017; 377(14):

34 NEJM. 2017; 377(14):

35 COMPASS Summary Rivaroxaban dose is vascular dose Rivaroxaban 2.5mg twice daily + aspirin 100mg daily Reduces CV death, stroke, MI Increases major bleeding without a significant increase in fatal or intracranial bleeding No significant benefit vs. rivaroxaban alone NEJM. 2017; 377(14):

36 COMPASS Summary Rivaroxaban dose Take is vascular Away: dose Rivaroxaban 2.5mg dose is twice not approved daily + aspirin worldwide 100mg daily Early termination: this may overestimate the Reduces degree CV death, of benefit stroke, of MI riva+aspirin Increases major bleeding without a significant increase in fatal or intracranial bleeding No significant benefit vs. rivaroxaban alone NEJM. 2017; 377(14):

37 NOACs in PCI: RE-DUAL PCI Clinical question In patients with nonvalvular atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) for coronary artery disease, is dual therapy with a thienopyridine antiplatelet and dabigatran associated with less bleeding when compared to triple therapy with aspirin, a thienopyridine antiplatelet, and dabigatran? Is dual therapy associated a higher rate of thrombosis? NEJM. 2017; 377(16):

38 NEJM. 2017; 377(16):

39 RE-DUAL PCI: Summary In AF patients who underwent PCI Dabigatran + P2Y12 (dual therapy) antagonist significantly reduced risk of bleeding vs. warfarin triple therapy Non-inferiority for thrombotic events Dabigatran doses used are (110mg vs 150mg) approved worldwide for stroke prevention LIMITATIONS The initial goal sample size of 8520 patients (powered to assess for thromboembolic events) was not reached due to feasibility. As a result, the trial is underpowered to robustly assess for thrombotic events. Only 12% of study patients received ticagrelor, limiting generalizability of these findings to use of this drug. NEJM. 2017; 377(16):

40 RE-DUAL PCI: Summary In AF patients who underwent PCI Dabigatran + P2Y12 (dual therapy) antagonist significantly reduced risk of bleeding vs. warfarin triple therapy Non-inferiority for thrombotic events Dabigatran doses used are Take (110mg Away: vs 150mg) approved worldwide for stroke prevention Dabigatran + P2Y12 (dual therapy) is non-inferior to triple therapy and may be an option in AF LIMITATIONS The initial goal sample size of 8520 patients (powered to assess for thromboembolic events) was not reached due to feasibility. As a result, the trial is underpowered to robustly assess for thrombotic events. patients undergoing PCI Only 12% of study patients received ticagrelor, limiting generalizability of these findings to use of this drug. NEJM. 2017; 377(16):

41 NOACs in PCI: PIONEER-AF PCI Clinical question Among patients with nonvalvular AF undergoing PCI with stent placement, does low-dose rivaroxaban plus either single or dual antiplatelet therapy reduce risk of bleeding when compared to warfarin plus dual antiplatelet therapy? NEJM. 2016; epub Nov 2016: 1-12.

42 NEJM. 2016; epub Nov 2016: 1-12.

43 PIONEER-AF PCI Summary In patient with AF undergoing PCI for stent placement Rivaroxaban based therapy was associated with less clinically significant bleeding TIMI major bleeding was similar between the three groups Major ADE (ie: cardiac events, stent thrombosis) was similar between groups All cause mortality and re-hospitalization was lower with rivaroxaban vs. warfarin/dapt Limitations Not blinded, not powered for efficacy, smaller sample size than NOAC trials NEJM. 2016; epub Nov 2016: 1-12.

44 PIONEER-AF PCI Summary In patient with AF undergoing PCI for stent placement Take Away: Rivaroxaban based therapy had less clinically Rivaroxaban based therapy was associated with less clinically significant bleeding TIMI major bleeding was similar between the three groups significant Major ADE (ie: bleeding cardiac events, compared stent thrombosis) to VKA was based similar between groups All cause mortality and therapies. re-hospitalization was lower with rivaroxaban vs. warfarin/dapt Not powered for efficacy- is this clinically significant? Limitations Not blinded, not powered for efficacy, smaller sample size than NOAC trials NEJM. 2016; epub Nov 2016: 1-12.

45 NOACs in Cardioversion: EMANATE Clinical Question: The goal of the trial was to evaluate short-duration apixaban compared with warfarin with among patients undergoing cardioversion. Am Heart Journal. 2016; 179:

46 Am Heart Journal. 2016; 179:

47 Am Heart Journal. 2016; 179:

48 EMANATE Trial Summary Bleeding rates were similar across both the apixaban and warfarin groups. EMANATE was underpowered Their findings support the use of apixaban in patients with AFib undergoing cardioversion. Am Heart Journal. 2016; 179:

49 EMANATE Trial Summary Bleeding rates were similar across both the Take Away: apixaban and warfarin groups. This study supports the use of apixaban prior to EMANATE was underpowered cardioversion. Stay tuned for full publication Their findings support the use of apixaban in patients with AFib undergoing cardioversion. Am Heart Journal. 2016; 179:

50 Managing Bleeding

51 New Guidance for Managing Bleeding American College of Cardiology (ACC) released expert consensus decision pathway in 2017 Provides guidance to clinicians who are managing bleeding in the setting of warfarin and NOACS Considers: Severity of bleeding Acute medical and surgical management Need for reversal Appropriateness of restarting anticoagulation JACC. 2017; 70(24):

52 Assessment and Treatment Strategies Major bleeding: Bleeding at critical site Hemodynamically unstable Clinically overt bleeding Minor bleeding: Everything else Treatment recommendations: Major bleeding: Stop OAC, initiate appropriate measures to stop bleeding Minor bleeding: Stop OAC in patients requiring hospitalization, a surgical intervention, or a transfusion JACC. 2017; 70(24):

53 Laboratory Assessment All anticoagulated patients: PT and aptt VKA: INR Dabigatran: Dilute thrombin time, ecarin clotting time, ecarin chromogenic assay Thrombin time (TT): Normal value can rule out relevant dabigatran levels FXa-Inhibitors: Chromogenic anti-xa assay, PT (edoxaban and rivaroxaban) JACC. 2017; 70(24):

54 Assessment and Treatment Strategies VKA (Warfarin) -Vitamin K oral (non-major) or IV (major/critical) -Administer 4F-PCC -INR 2-4: 25u/kg -INR 4-6: 35u/kg -INR >6: 50u/kg - Alternative 4F-PCC dosing -Low fixed-dose option (1000units) -1500u for ICH DTI (Dabigatran) -Consider activated charcoal for ingestion w/in 2-4 hours -Administer 5g idarucizumab IV -If idarucizumab IV not available, administer 4F-PCC or apcc 50u/kg IV FXa-Inhibitors (Apixaban, edoxaban, rivaroxaban) -Consider activated charcoal for ingestion w/in 2-4 hours -Administer 4F-PCC 50u/kg IV -If 4F-PCC not available, administer apcc 50u/kg IV JACC. 2017; 70(24):

55 Patient Case Remember BC? Things to consider: Cause of VTE likely related to his travel (provoked cause) Insurance (high-deductible not met) Patient endorses a desire to improve adherence and overall health, thinks he might be more successful with once-daily therapy.

56 Patient Case Remember BC? Which choice of therapy is recommended for BC at this time? A. Weight-based LMWH B. Warfarin C. NOAC (no specific agent preferred) D. NOAC (specific agent preferred)

57 Patient Case Remember BC? Which duration of anticoagulation therapy is recommended for BC at this time? A. Indefinite B. At least 3 months C. At least 1 year D. At least 2 weeks, then reevaluate

58 Patient Case Remember BC Should BC be on ASA after his anticoagulation therapy is complete? Guidelines recommend after first 3 months (grade 2C) Studies involved 1 st unprovoked VTE Does BC need bridging with LMWH prior to starting oral anticoagulation? No rivaroxaban, apixaban Yes dabigatran, edoxaban

59 Updates in Anticoagulation Megan Labreck, PharmD, BCPS, CACP Kristian Navickas, PharmD, BCPS, BCACP Tara Schreck, PharmD, BCACP

60 Betrixaban New NOAC Direct factor Xa inhibitor Indication: VTE prevention Acutely ill medical, non-surgical patients Moderate or severely limited mobility plus other VTE risk factors Not recommended for use in AF, VTE treatment, after hip/knee surgery, long-term VTE prevention in cancer or prior VTE Product information for Bevyxxa. Portola Pharmaceuticals. South San Francisco, CA March 2018.

61 Betrixaban New NOAC LMWH 160mg x1 then 80mg once daily with food for days Renal dosing: 80mg x1 then 40mg once daily with food for days APEX clinical trial prevents small number of symptomatic VTEs, increases risk of CRNM Expensive ($630 for 6 weeks therapy) Product information for Bevyxxa. Portola Pharmaceuticals. South San Francisco, CA March 2018.