The DOACs - How and in Whom

Transcription

1 The DOACs - How and in Whom Scott C. Woller, MD Medical Director, Anticoagulation Management, Intermountain Healthcare Cenral Region, Co-Director Venous Thromboemolism Program, Intermountain Medical Center; Associate Professor, Internal Medicine, University of Utah School of Medicine; Salt Lake City, Utah Objectives: Discuss and outline a strategy to select among the available DOAC medications for patients with VTE and various characteristics and comorbidities. Indicate the available reversal agents for DOACs and review management strategies to address bleeding in patients taking DOACs. Describe limitations to the understanding of DOAC interruption, and describe a standardized approach to peri-procedural interruption of DOACs.

2 Direct oral anticoagulants: How to use DOACs and in whom? Scott C. Woller, MD Co-Director Thrombosis Program, Intermountain Medical Center Associate Professor of Clinical Medicine, University of Utah School of Medicine Thrombosis Guidelines Symposium Intermountain Medical Center April 22, 2016

3 Disclosures Panelist for the American College of Chest Physicians 10 th edition Guideline for Antithrombotic Therapy for VTE Disease Panelist for the Anticoagulation Forum Clinical Guidance Management of venous thromboembolism initiative I have been awarded grant funding paid to my employer (Intermountain Healthcare) from Bristol-Meyers Squibb

4 Learning Objectives At the conclusion of this activity, participants should be able to: Outline a strategy to select among the available DOAC medications for patients with VTE and various characteristics and comorbidities. Indicate the available reversal agents for DOACS and review management strategies to address bleeding in patients taking DOACs. Describe limitations to the understanding of DOAC interruption, and describe a standardized approach to their peri-procedural interruption.

5 Naming a new class of medicines NOAC: Non Vitamin K Oral Anticoagulant ISTH Guidance Statement J Thromb Haemost Jun;13(6):1154-6

6 The Direct Oral Anticoagulants (DOACs)

7 DOACs TF VIIa Va sciencecodex.com

8 Nomenclature of venous thromboembolism therapy Acute therapy represents the initial phase which often includes a higher dose or parenteral drug. The minimum duration of anticoagulant therapy for DVT or PE is usually three months, and this period of treatment is referred to as "long-term therapy". A decision to treat patients for longer than 3 months is referred to as "extended therapy. Kearon C. Chest doi: /j.chest

9 The Direct Oral Anticoagulants Rivaroxaban Apixaban Edoxaban Dabigatran BRAND NAME PHARMACEUTICAL Xarleto Bayer Eliquis BMS & Pfizer Savaysa Daiichi Sankyo Pradaxa Boehringer Ingelheim TARGET Factor Xa Factor Xa Factor Xa Factor IIa BIOAVAILABILITY (%) ~80 ~ TIME TO PEAK (h) HALF-LIFE (h) RENAL EXCRETION (%) >80 EFFECT ON aptt/pt* 1.8/ /~2 yes 2.3/NR EFFECT ON Xa 68% NR NR No Effect DRUG INTERACTIONS CYP3A4 IND/INH CYP3A4 INH P-gp INH/CYP3A4 Verapamil/rifampin Derived from: Crowther. Blood. 2008;111: ; Garcia, D. Blood. 2010;115:15-20; Schulman Thromb Haemost 2014; 111:

10 Metabolism of DOACs Heidbuchel 2013 Nutescu J Thromb Thrombolysis (2016) 41:15 31

11 DOACs for VTE: The Long-term Treatment Clinical Trials DRUG RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN TRIAL EINSTEIN-PE+DVT AMPLIFY HOKUSAI RE-COVER Dose 15mg BID x 21d; 20mg QD 10mg BDX x 7d; 5mg BID LMMH then 60mg QD (30mg CrCl30-50;<60kg) LMWH then 150mg BID x 6 mo. Comparator/TTR% LWWH + Warf / 61% LWWH + Warf / 61% LMWH + Warf / 63.5% LWWH + Warf / 60% Condition (%) PE 61% DVT 64% DVT 65 PE 25 B 10 DVT 60 PE 40 B24 DVT 70 PE 20 B 10 Enrolled Design R OL NI R DB NI R DB NI R DB NI Age/ % 57 yrs / 55% 57 / 61% 55.8 / 57% 55 yrs / 58% Cancer 5% 2.5% 9.2% 5% 1 o Efficacy Recurrent VTE Recur. VTE + VTE death Recur. VTE + VTE death Recur. VTE + death Primary Safety MB + CRNMB MB + CRNMB MB+CRNMB Bleeding/ACS/LFT Efficacy Outcome 2.3 v. 2.1; RR 0.9 ( ) p<0.003 NI Major Bleeding 1.7 v. 2.2 RR 0.55 ( ) p=<0.05 sup 2.3 vs. 2.7 RR 0.84 ( ) p<0.001 NI 0.6 vs. 1.8 RR 0.31 ( ) p<0.001 sup 3.2 vs. 3.5 RR 0.89 ( ) p<0.001 NI 1.4 vs. 1.6 RR 0.84 ( ) p=0.35 sup 2.4 v. 2.1; RR 1.1 ( ) 1.6 v. 1.9 RR 0.82 (ns) Any bleeding 10.3 vs. 11.4% CRB: 4.3 vs. 9.7% 21.7% vs. 25.6% HR 0.71 ( ) Summary Non-inferior; QD dose Non-inferior and safer Non-inferior, QD Non-inferior Schulman NEJM 2009;361:2342; EINSTEIN Investigators NEJM Dec 4, 2010; AMPLIFY NEJM 1 Jul 2013; HOKUSAI NEJM 1 Sept 2013

12 AT10: Choice of anticoagulant for long-term treatment of DVT and PE: DOAC vs. warfarin RESOURCES FOR AT10 GUIDELINE STATEMENT Dabigatran for long-term treatment of VTE RE-COVER N Engl J Med Dec 10;361(24): RE-MEDY/RE-SONATE N Engl J Med Feb 21;368(8): RE-COVER II Trial Investigators. Circulation Feb 18;129(7): Rivaroxaban for acute and long-term treatment of VTE Prins MH, etal. Thromb J Sep 20;11(1):21 EINSTEIN Investigators. N Engl J Med Dec 23;363(26): EINSTEIN PE Investigators. N Engl J Med Apr 5;366(14): Apixaban for acute and long term treatment of VTE AMPLIFY Investigators. N Engl J Med Aug 29;369(9): Edoxaban for long-term treatment of VTE Hokusai-VTE Investigators. N Engl J Med Oct 10;369(15): Kearon C. Chest doi: /j.chest

13 AT10 Summary of evidence: Recurrent VTE NOAC n (studies) QUESTION: Should a DOAC or warfarin be used for acute and long-term treatment of VTE? Quality assessment Risk of bias Overall quality of evidence Study event rates (%) With LMWH and VKA With NOAC Summary of Findings Relative effect (95% CI) Risk w/ LMWH &VKA Anticipated absolute effects Risk difference with NOACs (95% CI) Recurrent VTE RIVAROXABAN 8281 (2 studies) no serious risk of bias MODERATE due to imprecision 95/4131 (2.3%) 86/4150 (2.1%) RR 0.90 (0.68 to 1.2) 23 per fewer per 1000 (from 7 fewer to 5 more) DABIGATRAN 5107 (2 studies) no serious risk of bias MODERATE due to imprecision 55/ /2553 (2.2%) 2 (2.4%) RR 1.12 (0.77 to 1.62) 22 per more per 1000 (from 5 fewer to 13 more) APIXABAN 5244 (1 study) no serious risk of bias MODERATE due to imprecision 71/2635 (2.7%) 59/2609 (2.3%) RR 0.84 (0.6 to 1.18) 27 per fewer per 1000 (from 11 fewer to 5 more) EDOXABAN 8240 (1 study) no serious risk of bias MODERATE due to imprecision 146/ /4118 (3.5%) 3 (3.2%) RR 0.83 (0.57 to 1.21) 35 per fewer per 1000 (from 15 fewer to 7 more)

14 AT10 Summary of evidence: Major Bleeding NOAC n (studies) QUESTION: Should a DOAC or warfarin be used for acute and long-term treatment of VTE? Quality assessment Risk of bias Overall quality of evidence Study event rates (%) With LMWH and VKA With NOAC Summary of Findings Relative effect (95% CI) Anticipated absolute effects Risk with LMWH and VKA Risk difference with NOACs (95% CI) Major Bleeding RIVAROXABAN 8246 (2 studies) no serious risk of bias HIGH 72/ /4130 (1.7%) 4 (0.97%) RR 0.55 (0.38 to 0.81) 17 per fewer per 1000 (from 3 fewer to 11 fewer) DABIGATRAN 5107 (2 studies) no serious risk of bias MODERATE due to imprecision 51/ /2553 (2%) 2 (1.4%) RR 0.73 (0.48 to 1.1) 20 per fewer per 1000 (from 10 fewer to 2 more) APIXABAN 5365 (1 study) no serious risk of bias HIGH 49/2689 (1.8%) 15/2676 (0.56%) RR 0.31 (0.17 to 0.55) 18 per fewer per 1000 (from 8 fewer to 15 fewer) EDOXABAN 8240 (1 study) no serious risk of bias MODERATE due to imprecision 66/4122 (1.6%) 56/4118 (1.4%) RR 0.85 (0.6 to 1.21) 16 per fewer per 1000 (from 6 fewer to 3 more)

15 AT10 Choice of anticoagulant for long-term treatment of DVT and PE: DOAC vs. warfarin Evaluation of Individuals with Pulmonary Nodules: General Approach Despite the lack of an antidote for the DOACs, the risk that a major bleed will be fatal appears to be no higher than that for warfarin The risk of bleeding (particularly intracranial bleeding) with the NOACs is less than with VKA therapy Cost and coverage will represent an important real-world patient important factor in choosing long-term anticoagulant

16 AT10 Choice of anticoagulant for long-term treatment of DVT and PE: DOAC vs. warfarin Evaluation of Individuals with Pulmonary Nodules: General Approach Recommended therapy for VTE takes into consideration efficacy, safety, and burden of treatment. This also can include cost. Is there evidence to recommend 1 DOAC over another? DOACs have not been compared head-to-head for patient-important outcomes. Based on indirect comparisons these outcomes appear to be similar with all of the NOACs Individual patient characteristics (including cost and insurance coverage) will likely drive choice of anticoagulant for the initial 3 months of therapy

17 AT10 Choice of anticoagulant for long-term treatment of DVT and PE: DOAC vs. warfarin Evaluation of Individuals with Pulmonary Nodules: General Approach AT10 Guideline Statement: In patients with DVT of the leg or PE and no cancer, as long-term (first 3 months) anticoagulant therapy, we suggest apixaban or edoxaban or rivaroxaban or dabigatran over VKA therapy (Grade 2B). Remarks: Acute therapy with parenteral anticoagulation is given before dabigatran and edoxaban. For the first time an alternative to usual care with low molecular weight heparin and warfarin has been suggested for the long-term treatment of PE and DVT. Kearon C. Chest doi: /j.chest

18 Who is a candidate for a DOAC therapy to treat VTE? Who is not? From the clinical trials: Need for thrombolytic therapy An indication for anticoagulation for which DOAC approval does not exist High risk of bleeding Significant liver disease (acute or chronic hepatitis, cirrhosis, or AST/ALT 3x ULN) Creatinine clearance 30 ml/min (for apixaban the threshold was 25 ml/min) Aspirin use (100 mg/day) Concomitant use of interacting medications Uncontrolled hypertension Schulman S (2013) N Engl J Med 368: EINSTEIN Investigators (2010) N Engl J Med 363: Agnelli G (2013) N Engl J Med 368: Schulman S (2009) N Engl J Med 361: Schulman S (2014) Circulation 129: EINSTEIN PE Investigators (2012). N Engl J Med 366: Agnelli G (2013) N Engl J Med 369: Hokusai-VTE Investigators (2013) N Engl J Med 369:

19 Who is a candidate for a DOAC therapy to treat VTE? Who is not? From the school of hard knocks: Patients who struggle with compliance (unless related to transportation for INRs) Warfarin is likely favorable to allow ascertainment of and anticoagulant effect Financial barriers to longitudinal compliance After 1.1 year f/u <50% prescribed DOAC picked up adequate drug to cover 80% days Kearon C AT10 Chest 2016; Yao, X Chest Physician Vol. 11, No. 2 Feb. 2016

20 Candidates for a DOAC therapy: Special populations

21 Candidates for a DOAC therapy: Special populations Pregnancy + Dabigatran or rivaroxaban = Apixaban has no human data in pregnancy, but showed no maternal or fetal harm in animal studies Edoxaban animal studies demonstrated no fetal harm DOAC excretion in breast milk is not known. XARELTO-PM-ENG-10JUL pdf. BoehringerIngelheim Canada Ltd (2014) Pradaxa product monograph. images from: colorbox.com; dailykos.com

22 Candidates for a DOAC therapy: Special populations Pregnancy dailykos.com

23 Candidates for a DOAC therapy: Special populations Extremes of weight Evidence is limited Patients <50 60 kg were 2 13 % of DOAC study populations & 16 % of patients were >100 kg 1 meta-analysis showed that for patients >100kg recurrent VTE risk was 0.9 (95% CI ) Dabigatran does not appear to be affected by extremes of weight Weight may affect kinetics of anti-xa s but the clinical significance is unknown. Schulman NEJM 2009; EINSTEIN Investigators NEJM 2010; AMPLIFY NEJM 2013; HOKUSAI NEJM 2013; StangierDJ Clin Pharmacokinet 2008; Frost J. thromb Haemost 2009; Upreti VV 2013 Br J Clin Pharmacol; Kubitza D 2007 J Clin Pharmacol; clipartbest.com; van Es Blood. 2014

24 Candidates for a DOAC therapy: Special populations Extremes of weight dailykos.com

25 Candidates for a DOAC therapy: Special populations Elderly Evidence from a meta-analysis of the Phase 3 trials studying VTE Pooled DOAC vs. VKA for age 75 years for recurrent VTE or VTE-related death: HR 0.56 (95% CI ) p=0.003 Pooled DOAC vs. VKA for age 75 years for Major bleeding: HR 0.49 (95% CI ) p=0.04 van Es N. Blood. 2014; pintrest.com

26 Candidates for a DOAC therapy: Special populations Elderly van Es N. Blood. 2014; pintrest.com

27 Candidates for a DOAC therapy: Special populations Thrombophilias Evidence is limited Patients with thrombophilias comprised 2-18% of those enrolled in DOAC trials Post-hoc dabigatran data shows no difference in recurrent VTE Exception: APS--3 ongoing studies RAPS (Canada), TRAPS (Italy), ASTRO-APS (USA) Schulman S (2013) N Engl J Med 368: EINSTEIN Investigators (2010) N Engl J Med 363: Agnelli G (2013) N Engl J Med 368: Schulman S (2009) N Engl J Med 361: Schulman S (2014) Circulation 129: EINSTEIN PE Investigators (2012). N Engl J Med 366: Agnelli G (2013) N Engl J Med 369: Hokusai-VTE Investigators (2013) N Engl J Med 369: ; Schulman S et al (2014) ASH 56th annual meeting Dec 2014, session 332 abstract 1544

28 Candidates for a DOAC therapy: Special populations Thrombophilias

29 Candidates for a DOAC therapy: Special populations Thrombophilias APS =

30 Candidates for a DOAC therapy: Special populations Cancer No dedicated RCT evidence for cancer patients exists Systematic reviews of the cancer subgroup from the clinical trials suggest DOACs are similar to VKA for VTE recurrence risk reduction and no difference in MB/CRNMB 1 meta-analysis suggested for VTE recurrence RR 0.57 (95% CI ; p=0.02) Schulman S 2013 NEJM EINSTEIN Investigators 2010 NEJM ; Agnelli G 2013 NEJM; Schulman S 2009 NEJM; Schulman S 2014 Circulation; EINSTEIN PE Investigators 2012 NEJM; Agnelli G 2013 NEJM; Hokusai-VTE Investigators 2013 NEJM; Castellucci LA JAMA; Carrier M Thromb Res; Vedovati MC Chest; Di Minno MN J Thromb Haemost; Franchini M.2015 Thromb Res

31 Candidates for a DOAC therapy: Special populations Cancer Schulman S 2013 NEJM EINSTEIN Investigators 2010 NEJM ; Agnelli G 2013 NEJM; Schulman S 2009 NEJM; Schulman S 2014 Circulation; EINSTEIN PE Investigators 2012 NEJM; Agnelli G 2013 NEJM; Hokusai-VTE Investigators 2013 NEJM; Castellucci LA JAMA; Carrier M Thromb Res; Vedovati MC Chest; Di Minno MN J Thromb Haemost; Franchini M.2015 Thromb Res; va Es 2015; Kearon C AT

32 Candidates for a DOAC therapy: Special populations Cancer AT10 states that For VTE and cancer, we suggest LMWH over VKA (Grade 2B), dabigatran (Grade 2C), rivaroxaban (Grade 2C), apixaban (Grade 2C), or edoxaban (Grade 2C). No comparison of DOAC with LMWH to date 5 ongoing trials (rivaroxaban=2, apixaban=2, edoxaban=1) clinicaltrials.gov accessed 12 MAR 2016 Kearon C AT

33 Candidates for a DOAC therapy: Special populations Cancer

34 Choosing between DOACs for VTE: Summary Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban Cost Compliance Bleeding risk (+)* Renal Dysfunction QOL *perhaps an increased GIB signal

35 Monitoring of DOACs youtube.com

36 Monitoring of DOACs DOAC monitoring is not routinely recommended Detect clinically relevant levels of DOACs Urgent or emergent invasive procedure Hemorrhage Neuraxial anesthesia Major trauma Potential thrombolysis in acute thromboembolism Derived from: Burnett AE J Thromb Thrombolysis (2016) 41:

37 Monitoring of DOACs DOAC monitoring is not routinely recommended Detect expected on-therapy levels of DOACs Event on therapy Questions surrounding adherence Derived from: Burnett AE J Thromb Thrombolysis (2016) 41:

38 Monitoring of DOACs DOAC monitoring is not routinely recommended Detect of excessive levels of DOACs Hemorrhage Overdose Hepatic/renal impairment Drug interactions Derived from: Burnett AE J Thromb Thrombolysis (2016) 41:

39 Monitoring of DOACs DOAC monitoring is not routinely recommended Most circumstances that would trigger a desire to monitor effect are urgent Major Bleeding: Supportive care Administration of blood products As applicable, administration of antidote Derived from: Burnett AE J Thromb Thrombolysis (2016) 41:

40 Dabigatran: Clotting Assay Summary Expected median therapeutic drug concentrations TT Expected 95 th percentile therapeutic drug concentrations ECT Clotting Time (sec) Dabigatran Concentration aptt PT/INR Slide courtesy of R. Pendleton

41 Evaluation of anticoagulant effect of Dabigatran aptt ratio Dabigatran effect on aptt Dabigatran Concentration (ng/ml) Derived from van RynThromb Haemost 2010; 103: 1116

42 Monitoring of DOACs: Summary DOAC monitoring is not routinely recommended It may be occasionally helpful to ascertain a qualitative affect of DOACs PTT (dabigatran) PT (rivaroxaban,?apixaban) Quantitative measurement may become more widely available dtt, ECT (dabigatran) DOAC anti-xa (apixaban, rivaroxaban, edoxaban) LMWH anti-xa (apixaban, rivaroxaban, edoxaban) The clinical value of monitoring may be uncertain Derived from: Burnett AE J Thromb Thrombolysis (2016) 41:

43 Monitoring of DOACs: Summary Assess for on-therapy (quantitative) Interpretation dabigatran dtt, ECT NL TT excludes rivaroxaban Anti-Xa* NL anti-xa excludes apixaban Anti-Xa* NL anti-xa excludes edoxaban Anti-Xa* NL anti-xa excludes Assess for on-therapy (qualitative) PTT PT Qualitative assessment for drug NL may be unreliable NL likely excludes * Standard chromogenic anti-xa calibrated to UFH or LMWH may be used as a qualitative alternative Derived from Burnett J Thromb Thrombolysis (2016) 41:206

44 Reversal of DOAC effect Is there a role for reversal agents for the DOACs? Short t 1/2 Clinical trials demonstrate that regardless of the absence of an antidote clinically important bleeding appears no more frequently and may occur less with DOACs compared with VKA Burnett AE J Thromb Thrombolysis (2016) 41: ; Wu C Thromb Res. 2015; Castellucci LA, JAMA 2014; Chai-Adisaksopha C. Blood 2014

45 Reversal of DOAC effect Is there a role for reversal agents for the DOACs? Evidence against the routine need for DOAC monitoring AT10 summary of bleeding risk Real-world experience Dresden registry of 1776 patients followed 1.1 years 1082 bleeding events occurring in 762 patients were evaluated 3.4% experienced major bleeding (ISTH criteria) 62% treated conservatively 38% required surgery or an intervention FFP or PCC given in 6 patients (no rfvii given) 1 death at a week Conclusion: In real life, rates of rivaroxaban-related MB may be lower & at least not worse than VKA Beyer-Westendorf J. Blood. 2014;124(6): )

46 Reversal of DOAC effect Is there a role for reversal agents for the DOACs? In VTE patients: The per-100 patient year incidence rate of major bleeding of DOAC vs. VKA: 0.35 (95% CI, , p=0.0023). IN all DOACs: Wu C Thromb Res. 2015; Castellucci LA, JAMA 2014; Chai-Adisaksopha C. Blood 2014

47 Reversal of DOAC effect Is there a role for reversal agents for the DOACs? IN all DOACs: Wu C Thromb Res. 2015; Castellucci LA, JAMA 2014; Chai-Adisaksopha C. Blood 2014

48 Reversal of DOAC effect Is there a role for reversal agents for the DOACs? IN all DOACs: Wu C Thromb Res. 2015; Castellucci LA, JAMA 2014; Chai-Adisaksopha C. Blood 2014

49 Reversal of DOACs

50 Reversal of DOACs: Idarucizumab Idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes FDA Approved October 16, 2015 N EnglJ Med 2015;373:

51 Andexanet alpha Recombinant competitive inhibitor of Factor Xa From NEJM.org

52 Andexanet Alfa for the Reversal of Xa Inhibitors RESULTS % -21 anti-xa activity Thrombin restoration apixaban placebo rivaroxaban placebo2 Siegal DM NEJM 2015;373:2413

53 Reversal of DOACs: Aripazine (PER977) Small water soluble molecule that non-covalently bends the binding site of all anticoagulants accessed 18 Nov 2015

54 Reversal of DOACs: Aripazine (PER977) rosphe re.pdf accessed 18 Nov 2015

55 Perioperative interruption: The DOACs About 2.5M Americans require long-term anticoagulation About 10% require interruption annually Generally, interrupt 4-5 half-lives before HBR procedure OK to interrupt 2-3 half-lives before LBR procedure Half-life increases as creatinine clearance declines Anderson M Clev. Clin J Med, 2014, 8; 629;

56 Interruption of DOACs How many doses do I hold before a procedure? Rivaroxaban Apixaban Edoxaban Dabigatran Procedure: interruption: CrCl > 80 CrCl CrCl CrCl LowBleed Risk High Bleed risk Low Bleed Risk High Bleed risk Low Bleed Risk High Bleed risk Low Bleed Risk High Bleed risk 2-3 t 1/2 4-5 t 1/2 2-3 t 1/2 4-5 t 1/2 2-3 t 1/2 4-5 t 1/2 2-3 t 1/2 4-5 t 1/ Derived from Burnett J Thromb Thrombolysis (2016) 41:206

57 Interruption of DOACs How many doses do I hold before a procedure? Rivaroxaban Apixaban Edoxaban Dabigatran Procedure: interruption: CrCl > 80 CrCl CrCl CrCl LowBleed Risk High Bleed risk Low Bleed Risk High Bleed risk Low Bleed Risk High Bleed risk Low Bleed Risk High Bleed risk 2-3 t 1/2 4-5 t 1/2 2-3 t 1/2 4-5 t 1/2 2-3 t 1/2 4-5 t 1/2 2-3 t 1/2 4-5 t 1/ Derived from Burnett J Thromb Thrombolysis (2016) 41:206

58 Interruption of DOACs How many doses do I hold before a procedure? Rivaroxaban Apixaban Edoxaban Dabigatran Procedure: interruption: CrCl > 80 CrCl CrCl CrCl LowBleed Risk High Bleed risk Low Bleed Risk High Bleed risk Low Bleed Risk High Bleed risk Low Bleed Risk High Bleed risk 2-3 t 1/2 4-5 t 1/2 2-3 t 1/2 4-5 t 1/2 2-3 t 1/2 4-5 t 1/2 2-3 t 1/2 4-5 t 1/ Derived from Burnett J Thromb Thrombolysis (2016) 41:206

59 Interruption of DOACs How many doses do I hold before a procedure? Rivaroxaban Apixaban Edoxaban Dabigatran Procedure: interruption: CrCl > 80 CrCl CrCl CrCl LowBleed Risk High Bleed risk Low Bleed Risk High Bleed risk Low Bleed Risk High Bleed risk Low Bleed Risk High Bleed risk 2-3 t 1/2 4-5 t 1/2 2-3 t 1/2 4-5 t 1/2 2-3 t 1/2 4-5 t 1/2 2-3 t 1/2 4-5 t 1/ Derived from Burnett J Thromb Thrombolysis (2016) 41:206

60 Follow-up for patients on a DOAC Follow-up visits should focus on 3 objectives: Ensuring proper DOAC Maximizing adherence Minimizing bleeding. A (adherence) B (bleeding) C (creatinine clearance) D (drug interactions) E (examination) F (follow-up) Gladstone DJ Ann Intern Med. 2015;163:

61 Follow-up for patients on a DOAC Gladstone DJ Ann Intern Med. 2015;163:

62 Summary DOACs are effective and safe for the long-term treatment of VTE For the 1 st time a major guideline recommends a treatment other than VKA for VTE Patients should be considered on a case by case basis for the 1 st line use of DOACs Beware of DOAC use among special populations Routine monitoring of DOACs is not recommended Reversal agents for the DOACs are here (with more to come) Anticoagulants are dangerous drugs that require thoughtful use and follow-up