Anticoagulation Update: VTE Guidelines update, DOACs, procedural warfarin interruption, and icentra (whew!)

Transcription

1 Anticoagulation Update: VTE Guidelines update, DOACs, procedural warfarin interruption, and icentra (whew!) Clinical Learning Day 2017 Scott C. Woller, MD Co-Director, Thrombosis Program Intermountain Medical Center Professor of Medicine University of Utah School of Medicine

2 Disclosures Investigator initiated grant recipient: Bristol-Myers-Squibb (paid to Intermountain Healthcare) Panelist American College of Chest Physicians (ACCP) Clinical Practice Guideline: Antithrombotic therapy for venous thromboembolic disease (AT10)

3 Objectives DOAC limitations & use in routine clinical care Special populations AT10 Updates for Venous Thromboembolism Warfarin interruption for procedures ( bridging ) Why clinical decision support for anticoagulation matters in icentra

4 The Direct Oral Anticoagulants

5 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:

6 Choosing a DOAC vs. warfarin in AF Ruff CT et al. Lancet 2014; 383:

7 Choosing a DOAC vs. warfarin in AF * *TTR > 66% Ruff CT et al. Lancet 2014; 383:

8 AT10 Choice of anticoagulant for long-term treatment of DVT and PE: DOAC vs. warfarin AT10 Guideline Statement: Evaluation of Individuals with Pulmonary Nodules: General Approach 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

9 AT10 Choice of anticoagulant for long-term treatment of DVT and PE: DOAC vs. warfarin Recommended therapy for VTE takes into consideration efficacy, Evaluation of Individuals with Pulmonary Nodules: General Approach 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. Based on indirect comparisons outcomes appear similar with all Individual patient characteristics (including cost and insurance coverage) will likely drive choice of anticoagulant for the initial 3 months of therapy

10 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 no DOAC approval exists High risk of bleeding Significant liver disease (acute or chronic hepatitis, cirrhosis, or AST/ALT 3x ULN) Creatinine clearance 30 ml/min (apixaban 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:

11 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

12 DOAC therapy: Special Populations

13 Candidates for a DOAC therapy: Special populations Pregnancy + Dabigatran or rivaroxaban = Apixiban has no human data in pregnancy, but showed no maternal or fetal harm in animal studies Ex vivo drug concentration across placenta F:M ration 0.9 Edoxaban animal studies demonstrated no fetal harm DOAC excretion in breast milk is not known XARELTO-PM-ENG-10JUL pdf. Boehringer Ingelheim Canada Ltd (2014) Pradaxa product monograph. images from: colorbox.com; dailykos.com; Bapat P et al.. J Thromb Haemost 2016; 14: ; Bapat P etal. Obstet Gynecol 2014; 123: 1256; 15 Bapat P etal. Am J Obstet Gynecol 2015; 213: 710.e1 6.

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

15 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. ISTH and AC Forum suggest against use based on PK/PD in obese Schulman NEJM 2009; EINSTEIN Investigators NEJM 2010; AMPLIFY NEJM 2013; HOKUSAI NEJM 2013; Stangier DJ 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; Martin K etal. J Thromb Haemost 2016; 14: ; Burnett etal. J Thromb Thrombolysis (2016) 41:

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

17 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

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

19 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

20 Candidates for a DOAC therapy: Special populations Thrombophilias

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

22 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) Castellucci LA JAMA; Carrier M Thromb Res; Vedovati MC Chest; Di Minno MN J Thromb Haemost; Franchini M.2015 Thromb Res

23 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

24 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

25 Candidates for a DOAC therapy: Special populations Cancer

26 Choosing between DOACs: Summary Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban Cost Compliance Bleeding risk Renal Dysfunction QOL : Less favorable +++: More favorable

27 Aspirin for extended treatment VTE?

28 Aspirin for the secondary prevention of VTE AT10 Guideline Statement: In patients with an unprovoked proximal DVT or PE who are stopping anticoagulant therapy and do not have a contraindication to aspirin, we suggest aspirin over no aspirin to prevent recurrent VTE (Grade 2B) Kearon C. CHEST 2016; 149(2):

29 Aspirin for the secondary prevention of VTE Studies: 2 Participants: 1,224 Quality Evidence (GRADE) Hazard Ratio Difference Per 1,000 VTE Major Bleeding Mortality

30 Aspirin for the secondary prevention of VTE Anticoagulants reduce VTE >90% DOACS suggested if unprovoked & low risk bleeding Bleeding may be similar with ASA & DOACs SUMMARY Unprovoked proximal DVT or PE and stop AC & no contraindication then aspirin over no aspirin (Grade 2B)

31 Warfarin interruption for procedures Bridging en.wikipedia.org

32 Warfarin interruption for procedures Bridging About 2.5M Americans require long-term anticoagulation About 10% require interruption annually Anderson M Clev. Clin J Med, 2014, 8; 629;

33 Warfarin interruption for procedures Bridging Bridge Trial RDBPCT 1884 pts. with AF Dalteparin or Placebo From 3 days before until AM before the procedure and then for 5-10 days after Demographics: mean age 72; 97.2% with CHADS 4 Time to first post-procedure dose: 53h (H) 21h (L) Mean # Post-Procedure doses: 16 Douketis JD etal. NEJM online 22 June 2014

34 Warfarin interruption for procedures Bridging Bridge Trial Results The incidence of arterial TE 0.4% in the no-bridging group and 0.3% in the bridging group (95% CI ; P = 0.01 for noninferiority). The incidence of major bleeding was 1.3% in the nobridging group and 3.2% in the bridging group RR 0.41 (95% CI ; p= for superiority). Conclusion: Forgoing bridging in AF patients was noninferior to bridging for stroke and decreased the risk of major bleeding. Douketis JD etal. NEJM online 22 June 2014

35 Warfarin interruption for procedures Bridging Warehouse Study Retrospective cohort study at Kaiser Colorado 1187 pts. on indefinite anticoagulation for VTE Demographics: omean age 66; 46% M o56% DVT 44% PE o79% low risk for recurrence at time of interruption o98.7% with VTE 3 mo. prior oprocedures: GI Endo (37%) ortho (14%) spine (10%) abd sx (9%) Outcome: 30-d clinically relevant bleeding, recurrent VTE, and all-cause mortality. Clark NP etal. JAMA Intern Med. Online May 26, 2015.

36 Warfarin interruption for procedures Bridging Warehouse Study Results There was no significant difference in the rate of recurrent VTE between groups (0 vs 3; P =.56). No deaths occurred in either group 30d bleeding in the bridge therapy and non bridge groups occurred in 15 patients (2.7%) and 2 patients (0.2%), respectively (hazard ratio, 17.2; 95%CI ). Conclusion: Bridge therapy was associated with an increased risk of bleeding during warfarin interruption among VTE patients and is likely unnecessary for most. Clark NP etal. JAMA Intern Med. Online May 26, 2015.

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38 Why use warfarin decision-support?

39 Anticoagulation management: icentra Why Clinical Decision Support in icentra? AT 9 Guideline For dosing decisions during maintenance VKA therapy, we suggest using validated decision support (e.g. computerized programs) rather than no decision support. Anticoagulation Forum When determining warfarin doses during VTE treatment we suggest using computer-aided warfarin dosing programs over an ad hoc approach. Holbrook CHEST 2012; 141(2)(Suppl):e152S e184s; Witt D etal. J Thromb Thrombolysis (2016) 41:

40 CDS outcomes within Intermountain

41 Pre-Post warfarin management with CAC CDS Patient enrolled in CAC Time that the patient is taking warfarin INRs before CDS INRs after CDS n=2591 Woller, SC et al. Clin Appl Thromb Hemost Apr;21(3):197-20

42 Results TTR=64% TTR=65.1% Woller, SC et al. Clin Appl Thromb Hemost Apr;21(3):197-20

43 Results: Secondary Outcomes Major Complications Events, n BEFORE CDS Events/ 100 Pt. yrs. Events, n AFTER CDS Events/ 100 Pt. yrs. Percent Δ p-value PE % < VTE with hospitalization % < Stroke NA Major Bleed % ED visit % < Hospitalization % < Woller, SC et al. Clin Appl Thromb Hemost Apr;21(3):197-20

44 Ability to receive Alerts for patients enrolled in the protocol Types of Alerts Reporting of INR with decision support suggested warfarin dosing Late for INR Hospitalization/ER admission Hospital D/C New drug interaction with warfarin

45 Comprehensive Anticoagulation CDS in icentra Initiation protocol Chronic protocol Bridging protocol DOAC Management (2017)

46 Summary The Direct Oral Anticoagulants Special populations AT10 Updates for treatment of VTE Peri-procedural interruption of the warfarin Not so much bridging anymore! Why anticoagulation management in icentra