7/13/2017. The Process. To Bridge Or Not To Bridge. Periprocedural Management of Anticoagulation in Nonvalvular Atrial Fibrillation: The Problem

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1 Periprocedural Management of Anticoagulation in Nonvalvular Atrial Fibrillation: The Problem 35 million prescriptions written annually in the United States for oral anticoagulation (OAC) 15-20% of these prescriptions are potentially interrupted in a given year placing patients at risk of thrombo-embolic events (TE), bleeding, or death Management of such patients is spread across providers with poor coordination in decision making To Bridge Or Not To Bridge The risk of a TE with an interruption Based on pooled data: (non-randomized in most studies) 0.52% for interruption without bridging 0.94% for those interrupted and bridged In BRIDGE trial alone: 0.4% for interruption without bridging 0.3% for those interrupted and bridged The Process Should the patient be anti-coagulated in the first place? Assess TE risk of interruption (patient specific) Assess risk of bleeding (procedure specific) Are some procedures such low risk that clinicians can fast track decision not to interrupt Are there procedures of sufficient bleeding risk that we would always interrupt? 1

2 The Process Recognize that there are instances where clinical judgment needs to prevail Attempt to give guidance that is procedure-specific 2

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4 Guidance Statement for consideration of postprocedural parenteral anticoagulation: 1. Postprocedural bridging with a parenteral agent can be considered in patients with moderate or high risk of stroke or thromboembolic event. 2. VKA therapy should be resumed (in most cases at the patient s usual therapeutic dose) without use of parenteral anticoagulation in cases associated with high risk for bleeding. Guidance Statement for the initiation of postprocedural therapeutic parenteral anticoagulation in patients with moderate or high thrombotic risk: 1. Establish that hemostasis has been achieved, procedure-specific bleeding complications have been considered, patient-specific bleeding factors have been evaluated, and the proceduralist and the primary managing service are involved in the decision to restart anticoagulation. 2. Following procedures with a lower postprocedural risk of bleeding, therapeutic parenteral anticoagulation, if indicated, can be started within the first 24 hours after the procedure in collaboration with the proceduralist and care team. Guidance Statement for the initiation of postprocedural therapeutic parenteral anticoagulation in patients with moderate or high thrombotic risk: 3. Following procedures with a higher post procedural risk of bleeding, therapeutic parenteral anticoagulation should be delayed for at least hours after the procedure. 4. When VKA therapy is reinitiated, careful monitoring of the INR during bridging is required to mitigate bleed risk. 4

5 Guidance Statement for restarting DOAC therapy post procedure: 1. Establish that hemostasis has been achieved, procedure-specific bleeding complications have been considered, patient-specific bleeding factors have been evaluated, and the proceduralist and primary managing service have been involved in the decision to restart anticoagulation. 2. Following procedures with low postprocedural bleed risk where TI is indicated, it is reasonable to resume DOAC therapy at full dose on the day following the procedure. Guidance Statement for restarting DOAC therapy postprocedure: 3. Following high postprocedural bleed risk procedures, it is reasonable to wait at least hours before resuming DOAC therapy at full dose if complete hemostasis has been achieved. 4. DOAC dosing should reflect postprocedural renal function. Bridging therapeutic anticoagulation with a parenteral agent is generally not required Implications of Pathway Primary goal was to provide a framework for the multiple decisions that are made when managing the anticoagulated patient undergoing a procedure Currently an area of high case volume handled with high variability Management of anticoagulation crosses many specialties Literature informed guidance when possible In areas where clinical judgment is needed, the pathway provided guidance by expert consensus Use of app provides point-of-care guidance available to multiple specialties 5

6 Effectiveness and Safety of Novel Oral Anticoagulants (NOACs) in VTE Treatment JOSHUA A. BECKMAN, MD, FACC, FAHA, MSVM DIRECTOR, SECTION OF VASCULAR MEDICINE VANDERBILT UNIVERSITY MEDICAL CENTER Disclosures Consulting: Astra Zeneca, Janssen, Aralez, Abbott Research Grant: Merck Board: VIVA While Mortality Decreases, Readmission Rate Remains High Retrospective cohort study of 100% Medicare fee-for-service beneficiaries hospitalized from 1999 to 2010 with a principal discharge diagnosis code for PE. Minges, KE. AJC 2015;116(9):

7 New Anticoagulants ORAL TTP889 X TF/VIIa IX PARENTERAL TFPI (tifacogin) Rivaroxaban Apixaban Edoxaban YM150 DU-176b Betrixaban TAK 442 IXa VIIIa Va Xa II AT APC (drotrecogin alfa) stm (ART-123) Fondaparinux Idraparinux DX-9065a Dabigatran IIa Fibrinogen Fibrin Adapted from Weitz & Bates, J Thromb Haemost 2007 Disadvantages of Warfarin Delayed onset/offset Variable dose response Narrow therapeutic window Drug-drug, drug-food interactions Inconvenient monitoring High bleeding rate Emergency Hospitalizations for Adverse Drug Events in Older U.S. Adults ( ) Budnitz DS, et al. N Engl J Med 2011;365:2002 2

8 The Ideal Oral Anticoagulant Oral, preferably once daily Rapid onset and offset of action Predictable PK and PD Low propensity for food and drug interactions Fixed doses Wide therapeutic window Easy to use with no need for monitoring RE-COVER: Dabigatran for VTE Recurrent VTE or VTE-related death 2,564 patients with objectively confirmed VTE were randomized to parenteral anticoagulation followed by fixed-dose dabigatran or dose-adjusted warfarin. p < for noninferiority Major or any bleeding p < p = 0.38 Schulman S, et al. N Engl J Med 2009;361:2342 EINSTEIN-DVT: Rivaroxaban for DVT Immediate initiation with rivaroxaban and no parenteral anticoagulant required n = 2,449 N Engl J Med 2010;363:2499 3

9 EINSTEIN-PE: Rivaroxaban for PE 4,832 patients with objectively confirmed PE were randomized to oral rivaroxaban (15 mg 2x/d for 3 weeks and then 20 mg daily) or parenteral anticoagulation followed by doseadjusted warfarin. Symptomatic Recurrent VTE p = p = for noninferiority N Engl J Med 2012;366:1287 AMPLIFY: Oral Apixaban for Treatment of VTE Agnelli G, et al. N Engl J Med. 2013; 369:799 Hokusai-VTE: Edoxaban vs. Warfarin NOTE: Among 938 patients with PE and RV dysfunction, the rate of recurrent VTE was 3.3% in the edoxaban group and 6.2% in the warfarin group (HR, 0.52; 95% CI, 0.28 to 0.98) p < for noninferiority p = for superiority The Hokusai-VTE Investigators. N Engl J Med 2013;369:1406 4

10 Anticoagulation Strategy in Evolution Overlapping LMWH/Warfarin Bridge UFH/Warfarin Bridge Switching LMWH to Dabigatran (RE-COVER) LMWH to Edoxaban (HOKUSAI-VTE) Oral Monotherapy Rivaroxaban (15 mg 2x/d for 3 wks, then 20 mg/d) (EINSTEIN) Apixaban (10 mg 2x/d for 1 wk, then 5 mg 2x/d) (AMPLIFY) Efficacy of NOACs for VTE Treatment: Meta-Analysis van der Hulle T, et al. J Thromb Haemost. 2014;12:320 Safety of NOACs for VTE Treatment: Meta-Analysis 1.2 Relative Risk Major Bleed Clin Rel Non Major Nonfatal ICH Fatal Bleed van der Hulle T, et al. J Thromb Haemost. 2014;12:320 5

11 Optimal Anticoagulation for Treatment of Acute VTE NOACs offer similar efficacy but improved safety compared with warfarin. NOACs may facilitate home therapy of patients presenting with low-risk VTE to the outpatient and Emergency Department settings. Optimal Anticoagulation for Acute VTE: 2016 CHEST Guideline Update In patients with DVT of the leg or PE and no cancer, as long-term (first 3 months) anticoagulant therapy, we suggest dabigatran, rivaroxaban, apixaban or edoxaban over VKA therapy (all Grade 2B). Kearon C, et al. CHEST (2016), doi: /j.chest

12 6/28/2017 Effectiveness and Safety of Direct Oral Anticoagulants (DOACs) Versus Warfarin in Nonvalvular Atrial Fibrillation Ty J. Gluckman, MD, FACC, FAHA Medical Director, Clinical Transformation Providence Heart and Vascular Institute Portland, Oregon Disclosures Boehringer-Ingelheim Consultant Efficacy, Safety, and Practical Considerations Items to consider when choosing an antithrombotic agent Reduced Risk of Stroke or Systemic Embolism Increased Risk of Bleeding Pharmacokinetics Risk of Drug-Food and Drug-Drug Interactions Availability of a reversal agent Ease of dosing Cost 1

13 Percent/Year Percent/Year 6/28/2017 Aspirin or Warfarin in Nonvalvular Atrial Fibrillation (NVAF) Pooled analyses comparing the impact of aspirin to placebo and warfarin to placebo on rates of ischemic stroke Aspirin vs. Placebo Warfarin vs. Placebo Atrial Fibrillation Investigators. Arch Intern Med. 1994;154: Dabigatran versus Warfarin in NVAF RE-LY Trial 18,113 patients with NVAF randomized to warfarin (INR of 2-3), dabigatran (150 mg BID), or dabigatran (110 mg BID) for a median of 2 years P= P=0.31 Dabigatran 150 mg BID 3.5 Warfarin, TTR=64% 3.0 Superiority 2.5 Noninferiority 2.0 P= Stroke or Systemic Embolism Ischemic Stroke Connolly SJ et al. NEJM 2009;361: Hemorrhagic All Cause Stroke Mortality Major Bleed Intracranial Hemorrhage Major GI Bleed Rivaroxaban versus Warfarin in NVAF ROCKET AF Trial ,264 patients with NVAF randomized to warfarin (INR of 2-3) or rivaroxaban (15-20 mg QD) for 1.6 years Superiority P=0.12 Noninferiority Stroke or Systemic Embolism P=0.58 Ischemic Stroke Patel MR et al. NEJM 2011;365: Rivaroxaban 20 mg QD Warfarin, TTR=55% P=0.024 P=0.07 Hemorrhagic All Cause Stroke Mortality P=0.58 Major Bleed P=0.02 Intracranial Hemorrhage Major GI Bleed 2

14 Percent/Year Percent/Year 6/28/2017 Apixaban versus Warfarin in NVAF ARISTOTLE Trial ,201 patients with NVAF randomized to warfarin (INR of 2-3) or apixaban (5 mg BID) for 1.8 years Superiority P=0.01 Noninferiority Stroke or Systemic Embolism P=0.42 Ischemic Stroke Granger CB et al. NEJM 2011;365: P=0.047 Hemorrhagic All Cause Stroke Mortality Major Bleed Apixaban 5 mg BID Warfarin, TTR=66% Intracranial Hemorrhage P=0.37 Major GI Bleed Edoxaban versus Warfarin in NVAF ENGAGE AF Trial ,105 patients with NVAF randomized to warfarin (INR of 2-3) or edoxaban (30 or 60 mg QD) for 2.8 years Noninferiority P=0.005 Superiority P=0.44 Stroke or Systemic Embolism Ischemic Stroke Giugliano RP et al. NEJM 2013;369: P=0.08 P=0.006 Noninferiority Superiority P=0.02 P=0.97 Hemorrhagic Stroke All Cause Mortality Major Bleed Intracranial Hemorrhage Edoxaban 30 mg QD Edoxaban 60 mg QD Warfarin, TTR=68% P=0.03 Major GI Bleed DOACs and Risk of Intracranial Hemorrhage Meta-analysis of 6 randomized controlled trials of antithrombotic therapy in NVAF Favors DOACs Favors Comparators Chatterjee S et al. JAMA Neurol 2013;70:

15 Major bleeding rate (%) 6/28/2017 Efficacy and Safety of DOACs in Nonvalvular Atrial Fibrillation Meta-analysis comparing the impact of the direct oral anticoagulants (DOACs) to warfarin on rates of stroke or system embolism and major bleeding Stroke or system embolism Major bleeding Ruff CT et al. Lancet 2014;383: Real World Efficacy of DOACs in Nonvalvular Atrial Fibrillation Real-world cohort of 61,678 nonvalvular atrial fibrillation Danish patients comparing the impact of the direct oral anticoagulants (DOACs) to warfarin on outcomes Ischemic Stroke or Systemic Embolism All-cause Death Larsen TB et al. BMJ 2016;353:i3189 Years Since Start of Treatment Apixaban Dabigatran Rivaroxaban Warfarin Real World Safety of DOACs in Nonvalvular Atrial Fibrillation Real-world cohort of 54,321 nonvalvular atrial fibrillation Danish patients comparing the impact of the direct oral anticoagulants (DOACs) to warfarin on major bleeding Compared to apixaban: HR for rivaroxaban=1.49 ( ) HR for warfarin=1.23 ( ) HR for dabigatran=1.17 ( ) Follow-up (Years) Lamberts M et al. JAHA 2017;Epub aheadof print 4

16 6/28/2017 Advantages and Disadvantages of DOACs Superior (apixaban, dabigatran, edoxaban [60 mg]) or comparable (rivaroxaban and edoxaban [30 mg]) efficacy in RCTs Significantly lower risk of ICH Rapid onset and offset No need for anticoagulation monitoring Minimal risk of drug-food interaction Lower risk of drug-drug interaction Compared to warfarin, the DOACs have: Higher risk of GI bleeding with some agents (dabigatran, rivaroxaban, and edoxaban [60 mg] but not apixaban or edoxaban [30 mg]) in RCTs Lack of an FDA approved reversal agent (except for dabigatran) Higher cost In spite of this, both types of agents are significantly underutilized Contemporary Antithrombotic Practice Patterns Cohort study of 655,000 nonvalvular atrial fibrillation patients from the NCDR PINNACLE registry with CHA 2 DS 2 -VASc score >1 Warfarin Dabigatran Rivaroxaban Apixaban Marzec LN et al. JACC 2017;69: Questions and Discussion 5

17 Clinical Advances in Anticoagulation in AF and VTE: Anticoagulant Reversal Agents George A. Davis, PharmD, BCPS UK HealthCare Gill Heart and Vascular Institute UK College of Pharmacy University of Kentucky July 17, 2017 Objective Discuss potential treatment strategies for anticoagulant reversal Goals of Anticoagulation Reversal Optimize Benefits, Minimize Risk Excessive Reversal Unnecessary interruption Increase thrombosis risk Inadequate Reversal Mortality Functional outcomes Hematoma expansion Surgical/procedural bleeding Choose an evidence-based reversal regimen Reversal warranted based on clinical status, urgency, and anticoagulant characteristics Appropriate dosage Appropriate monitoring An ideal anticoagulation reversal will provide the greatest reduction in further bleeding complications with the lowest incidence of thromboembolism. 1

18 Conventional anticoagulants and approve specific reversal and investigational agents Drug characteristic Oral warfarin unfractionated heparin Parenteral Anticoagulants low-molecular fondaparinux argatroban bivalirudin weight heparin Mode of action inhibition of vitamin K dependent carboxylation of clotting factors antithrombin-mediated inhibition of serine proteases (predominantly factor IIa and Xa inhibition) antithrombin-mediated inhibition of serine proteinases (predominantely factor Xa inhibition) antithrombinmediated factor Xa inhibition reversible factor IIa inhibition factor IIa inhibition Half-life h min 3-6 h 17 h 45 min 30 min Clearance hepatic and renal phagocytosis renal renal hepatic renal Approved specific direct reversal vitamin K, FFP PCC protamine partial reversal by protamine none modified thrombin none Investigational specific direct reversal none ciraparantag (PER977) andexanet alpha, ciraparantag (PER977) andexanet alpha none none Hematology Am Soc Hematol Educ Program Dec 2;2016(1): NOAC Reversal Practical consideration: Factors that impact PK/PD onset/offset Patient specific factors to assess last NOAC dose and half-life Time of last dose? Indication for reversal? How urgent is reversal? Indication for anticoagulant? Age Body weight Creatinine - Renal function Drug-drug interactions Dabigatran Rivaroxaban Apixaban Edoxaban Betrixaban Drug target Thrombin Factor Xa Factor Xa Factor Xa Factor Xa Time to max h 2h 3-4h 1-2h 3-4h effects Half-life 12-17h 5-9h 8-15h 8-10h 19-27h Plasma protein 35% 92-95% 87% 40-59% 60% binding Volume L 50 L Low >300 L >200 L distribution Renal 80% 33% 25% 35-39% 11% Elimination Pgp, Pgp, Drug interactions Pgp Pgp, CYP3A4 Pgp CYP3A4 CYP3A4 Arterioscler Thromb Vasc Biol. 2015;35: ; Vasc Health Risk Manag. 2015;11: ; BEVYXXA (betrixaban) [prescribing information], Portola Pharmaceuticals Inc, 6/2017. Renal impairment increases NOAC half-life Property Dabigatran Rivaroxaban Apixaban Edoxaban Betrixaban Renal clearance of absorbed dose, % Half-life in renal impairment, h CrCl >80 ml/min CrCl ml/min NA CrCl ml/min NA CrCl <30 ml/min NA Dialyzable Yes No Yes No NA Nutescu EA. Am J Health-Syst Pharm. 2013;70(Suppl 1):S3-11. Pradaxa (dabigatran etexilate mesylate) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc.; 11/2015. Xarelto (rivaroxaban) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 5/2016. Eliquis (apixaban) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 9/2015. Savaysa (edoxaban) [prescribing information]. Parsippany, NJ: Daiichi Sankyo, Inc; 9/2015. DeVriese AS et al. Am J Kidney Dis. 2015;66(1): Heidbuchel H et al. Europace. 2015;17(10): ; BEVYXXA (betrixaban) [prescribing information], Portola Pharmaceuticals Inc, 6/

19 NOAC reversal: Potential strategies to date Strategy Removal Bypassing Example Activated charcoal after recent ingestion (with caution) Hemodialysis (dabigatran only, probably not necessary with target specific reversal agent) Prothrombin complex concentrate (PCC) Activated PCC rfviia (not recommended by some guidelines) Sequestration Idarucizumab (dabigatran only) Andexanet alfa (FXa inhibitors only; in development, not FDA approved but possible approval by YE2017) Ciraparantag (in development, not FDA approved) 2016 ISTH NOAC Reversal Guidelines: Indications for Reversal Life-threatening bleeding ICH, symptomatic or expanding extradural hemorrhage or uncontrolled hemorrhage Bleeding in a closed space or critical organ Intraspinal, intraocular, pericardial, pulmonary, retroperitoneal, or intramuscular with compartment syndrome Persistent major bleeding despite local hemostatic measures, or risk of recurrent bleeding because of delayed NOAC clearance or NOAC overdose Urgent reversal for procedural Need for urgent intervention that associated with high risk of bleeding, cannot be delayed to allow for drug clearance Emergency surgery, intervention in patients at high risk for procedural bleeding Neurosurgery (intracranial, extradural, spinal), lumbar puncture, cardiac or vascular surgery (aortic dissection/aneurysm repair), hepatic or other major organ surgery Potential indication for use Need for urgent surgery, intervention in patients with acute kidney injury Reversal agents should NOT be used Elective surgery GI bleeds that respond to supportive measures High drug levels, excessive anticoagulation without associated bleeding Need for surgery or intervention that can be delayed long enough to permit drug clearance Levy JH, et al. J Thromb Haemost. 2016;14: NOAC Reversal Guidelines: Lab testing Drug Class Laboratory testing for NOACs Normal aptt makes it unlikely dabigatran is major contributor to bleeding Normal TT indicates absence of dabigatran Normal PT does not exclude significant apixaban effects Quantification NOAC Chromogenic anti-fxa assay may be used for apixaban, edoxaban, rivaroxaban (if available) Conventional Coagulation Testing dtt, ECT, ecarin chromogenic assay may be used for dabigatran Specialized Coagulation Testing PT aptt TT dtt ECT/ECA Anti-Xa Activity Direct thrombin inhibitor dabigatran / N/A Factor Xa Inhibitor rivaroxaban / / N/A N/A N/A apixaban / / N/A N/A N/A edoxaban / / N/A N/A N/A betrixaban / / N/A N/A N/A, increase;, decrease;, no change; N/A, not advised; Color key: red, inappropriate testing; yellow, may be useful for excluding clinically relevant drug levels and may approximate drug levels; green, best test available. Do not wait for laboratory tests for lifethreatening bleeding Determine time of last dose if possible Estimate drug half-life with CrCl For patients with CrCl >60 ml/min, half-lives are no longer than 12 hr Consider if NOAC levels rising or falling if available J Thromb Haemost. 2016;14: ; Hematology Am Soc Hematol Educ Program Dec 2;2016(1):

20 NOAC Reversal Guidelines (AC Forum, 2016) Non-specific reversal strategies PCC (Factors II, VII, IX, and X) as non-activated PCC 50u/kg (e.g. KCentra) or activated 80u/kg (e.g. FEIBA) Limited to in-vitro studies, animal models, or healthy volunteers Conflicting results Evidence remains low quality, limited data on clinical outcomes (hemostasis, mortality) Recombinant Factor VIIa is generally not recommended as first line agent for NOAC reversal FFP may not be practical due to volume required to reverse thrombin or FXa may lead to fluid overload 2017 status: Further comparative effectiveness studies are needed to understand the risks/benefits of PCC for NOAC reversal J Thromb Thrombolysis (2016) 41: ; Specific Reversal Agents for NOACs: Approved and in Development Idarucizumab FDA approved Andexanet alfa Investigational Ciraparantag Investigational Reverses dabigatran Approved Oct 2015 for rapid reversal of dabigatran for emergency procedures or lifethreatening or uncontrolled bleeding Reverses factor Xa inhibitors Phase 3: apixaban, rivaroxaban, enoxaparin Phase 2: edoxaban; planned for betrixaban August 2016 PDUFA date: FDA asked for more data; projected FDA approval in YE2017 Reverses all NOACs (broad-spectrum) FDA Fast Track Status Phase 2: edoxaban, enoxaparin PDUFA, Prescription Drug User Fee Act; Praxbind (idarucizumab) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. 10/2015. Portola Pharmaceuticals. [news release]. 1/8/ Accessed 5/11/16. Perosphere. Accessed 5/11/16. Specific Reversal Agents for NOACs: Characteristics Idarucizumab Andexanet alfa Ciraparantag Monoclonal antibody Mechanism of Action fragment that binds dabigatran 350X more than between dabigatran and Decoy Xa molecule that binds FXa inhibitor anticoagulants restoring function of endogenous FXa Anticoagulant binding via noncovalent hydrogen bonds and charge-charge interactions thrombin NOAC(s) reversed Dabigitran Apixaban, Edoxaban, Rivaroxaban Dabigatran, Apixaban, Edoxaban, Rivaroxaban Apixaban: 400mg IV bolus + 480mg Studied doses 5gm IV given as two 2.5gm boluses over 5-10 min within 15min infusion over 2h Rivaroxaban, edoxaban: 800mg IV bolus + 960mg infusion over 2h; if < 7hrs since last rivaroxaban dose, mg IV single dose dose decrease by 50% Onset of action <5min <2min 5-10min Half-life Biphasic, Initial 45min; Terminal ~10hrs 1h Duration of action: 24h Elimination Renal Not reported Renal 4

21 Idarucizumab: Summary of REVERSE-AD32 Phase III multicenter, prospective cohort n=494 adult patients on dabigatran requiring: Reversal for life threatening bleeding (Group A; n=298) Need for urgent surgery (Group B, n=196) Primary outcome Maximal % reversal of anticoagulant effect (dtt) Group A (235/238; >98%); Group B (141/143; >98%) Similar results for ECT Secondary outcomes Time to hemostasis Group A: 3.5 h Group B: 4-5 h Periprocedural hemostasis 178/191 (93%) Thrombotic events 30d: Group A (4.4%); Group B (4.6%) 90d: Groups A and B (6.3%) 7 MI, 8 CVA, 15 VTE, 1 systemic embolism ~2/3 occurred OFF antithrombotic therapy Mortality 30d: Group A (12.3%); Group B (12.4%) 90d: Group A (18.7%); Group B (18.5%) Pollack et al., N Engl J Med 2015;373:511; AHA 2016 available at downloadable/ucm_ pdf Idarucizumab: Summary of REVERSE-AD32: Remaining questions Does idarucizumab improve clinical outcomes in bleeding patients? How should patients be selected to receive idarucizumab (up to 25% had insignificant dabigatran levels at study entry)? What is the significance of increased dabigatran levels at 12 and 24 hrs? Should these patients be re-dosed? Cost not discussed but current reversal strategies are expensive Our institution approach: Criteria based, restrictive use of reversal agents per hospital-specific guidelines reviewed by Anticoagulation Subcommittee of P&T Pharmacist evaluation at time of order (provided 24/7/365) to assess criteria and prepare dose/delivery in timely manner Pollack et al., N Engl J Med 2015;373:511; AHA 2016 available at downloadable/ucm_ pdf NOAC Reversal Summary Era of specific reversal agents is on the horizon Most associated bleeding (minor to moderate) can be managed by supportive care Pertinent laboratory parameters and clinical response should be considered but warrant further study Baseline TT, aptt, Factor Xa If NOAC reversal is indicated: FXa inhibitors: Consider PCC 50 units/kg; andexanet approval pending and ciraparantag in the pipeline Dabigatran: Use idarucizumab 5g Consider developing hospital-based guidance Re-initiation of anticoagulant after bleeding event warrants further study 5

22 Extended Use of Anticoagulation in Patients Previously Not Considered for Long-term Therapy Rachel P. Rosovsky, MD, MPH July 17, 2017 Conflicts of Interest Research support: Janssen and Daiichi Sanko 2 Scope of the problem What is the risk of recurrent VTE after stopping anticoagulation? 3 1

23 Risk of recurrent VTE Type of VTE 1 year risk 5 year risk Provoked by surgery 1% 3% Provoked by non surgical reversible risk 5% 15% Unprovoked VTE 10% 30% Cancer associated 15% 4 * Not predicted due to high mortality rate from cancer VTE = venous thromboembolism Kearon et al. CHEST Risk of recurrent VTE Cumulative incidence of recurrent thromboembolism in patients with idiopathic and secondary VTE. Key points: 1. At 10 years, risk is over 50% in unprovoked patients 2. Even at 10 years, risk increasing VTE = venous thromboembolism 5 Prandoni, Hematologica Who warrants long term anticoagulation? Depends on: patient-specific bleeding risks patient-specific thrombotic risks patient values and preferences 6 2

24 Who warrants long term anticoagulation? Most likely to benefit Idiopathic VTE Active cancer Antiphospholipid syndrome Recurrent VTE high risk thrombophilia Possible benefit Provoked VTE with persistent risk factors Unprovoked isolated distal DVT with persistent risk factors Unprovoked incidental PE 7 VTE = venous thromboembolism Clinical features associated with recurrent risk Several clinical features associated with recurrence; however, not completely defined on how to weigh each one. proximal location of DVT or PE obesity male sex several thrombophilic defects D-dimer residual vein thrombosis IVC filter 8 Recurrent Risk Prognostic Models HERDOO2 Ddimer, age, BMI, post thrombotic signs Vienna Ddimer, sex, site of index event DASH Ddimer, age, sex, hormones DAMOVES Ddimer, age, mutation, obesity, varicose veins, eight, sex 9 3

25 Bleeding Prediction Scores VTE bleeding scores Kuijer RIETE Atrial fibrillation bleeding scores HAS-BLED ATRIA HEMORR 2 HAGES 10 VTE = venous thromboembolism RIETE score Score for fatal bleeding in patients on anticoagulation for VTE 11 Nieto et al. JTH and Thrombosis Research RIETE Score Risk categories of patients according to score, and corresponding rates of fatal bleeding. 12 Nieto et al. Thrombosis Research

26 Bleeding Risk 13 Kearon et al. CHEST Who warrants long term anticoagulation How do we decide who to anticoagulated and with what? 14 Trials of long term anticoagulation Warfarin (vs placebo) Aspirin (vs placebo) Dabigatran RE-MEDY (vs warfarin): non inferior RE-SONATE (vs placebo) Apixaban Amplify Extension (vs placebo) Rivaroxaban Einstein Extension (vs placebo) Einstein Choice (vs aspirin) Primary efficacy: symptomatic recurrent fatal or nonfatal VTE Principal safety: major bleeding. Equipoise 15 5

27 RE-SONATE: Dabigatran 1343 patients, completed 6-12 months of anticoagulation (equipoise) randomized to dabigatran 150 mg bid or placebo. Dabigatran reduced the risk of recurrent VTE compared to placebo with an increase in bleeding Agnelli et al. NEJM AMPLIFY Extension: Apixaban 2482 patients, completed 6-12 months of anticoagulation (equipoise) randomized to apixaban 5 mg (treatment dose) or 2.5 mg (prophylactic dose) or placebo. Apixaban reduced the risk of recurrent VTE without increasing the rate of major bleeding Agnelli et al. NEJM Einstein Extension: Rivaroxaban 1196 patients, completed 6-12 months of anticoagulation remained on 20 mg, the continued-treatment study. Rivaroxaban had superior efficacy and no significant difference in bleeding Einstein Investigators. NEJM

28 Einstein CHOICE: Rivaroxaban 3396 patients, completed 6-12 months AC, randomized to either once-daily rivaroxaban (20 mg or 10 mg) or 100 mg of aspirin. Equipoise regarding need for continued AC. AC = anticoagulation Weitz et al. NEJM Einstein CHOICE: Rivaroxaban Risk of recurrent event was significantly lower with rivaroxaban both 20 mg (treatment dose) and 10 mg (prophylactic dose) compared to aspirin, without a significant increase in bleeding rates. Weitz et al. NEJM Einstein CHOICE: Rivaroxaban Weitz et al. NEJM

29 Question: What do all these studies tell us? Appears that DOACs (dabigatran, apixaban and rivaroxaban) decrease risk of recurrent VTE when compared to placebo in extension studies where there is equipoise in deciding on whether to continue AC. Apixaban and rivaroxaban had no significant increase in major bleeding. AC = anticoagulation 22 Have these studies changed guidelines? 23 Jaff et al. Circulation Have these studies changed guidelines? It is not possible to give a definitive guidance statement as to which patients should or should not receive long-term anticoagulant therapy after an episode of an unprovoked PE or DVT. Patients should be assessed on an individual basis, taking into consideration factors contributing to thrombosis recurrence risk and bleeding risk, and should be offered information outlining the risks and benefits of long-term anticoagulation. Moreover, patients values and preferences should be considered, relating to the impact of thrombosis recurrence (if anticoagulation is stopped) and bleeding (if anticoagulation is continued). 24 Baglin et al. JTH

30 Have these studies changed guidelines? Remarks: Patient sex and D-dimer level measured a month after stopping anticoagulant therapy may influence the decision to stop or extend anticoagulant therapy. In all patients who receive extended anticoagulant therapy, continuing use of treatment should be reassessed at periodic intervals (eg, annually). 25 Kearon et al. CHEST How do I apply these results to my patients? Provoked vs unprovoked Dose Equipoise What about needing to wait the 6 months One possible algorithm Kearon et al. Blood

31 Who warrants long term anticoagulation? Individualize treatment decision Risk of recurrent VTE Risk of bleed Patient preference and values Availability of drug Re-evaluate Thank you 10