Anticoagulation with Direct oral anticoagulants (DOACs) and advances in peri-procedural interruption of anticoagulation-- Bridging

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1 Anticoagulation with Direct oral anticoagulants (DOACs) and advances in peri-procedural interruption of anticoagulation-- Bridging Scott C. Woller, MD Co-Director, Thrombosis Program Intermountain Medical Center Associate Professor of Medicine University of Utah School of Medicine Clinical Learning Day Intermountain Medical Center 29 January 2016

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 The Direct Oral anticoagulants (DOACs) Atrial fibrillation Venous thromboembolism Choice of drug Reversal of the DOACs Peri-procedural interruption of the DOACs Transition from: DOAC warfarin Warfarin DOAC Longterm management of DOACs Warfarin interruption ( Bridging )

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

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 The Direct Oral Anticoagulants: Atrial Fibrillation TRIAL RE-LY ROCKET-AF ENGAGE-AF-TIMI ARISTOTLE Drug Dabigatran Rivaroxaban Edoxaban Apixaban Dose 110mg or 150mg BID 20 mg daily (15 mg daily RI) 60 mg QD # (30 mg QD)* 5 mg BID (2.5mg BID)* Comparator/TTR Warfarin/ 67% Warfarin/ 55% Warfarin/ 68% Warfarin/ 62% Condition AF 6 mo + 1RF AF 6 mo + 2RF AF 6 mo + 1RF AF + 1RF Enrolled 18,113 14,000 21,105 18,201 Design R OL R DB DD R DB DD R BD DD Age/ % 72 yrs / 64% 73 yrs / 60% 72 yrs / 62% 70 yrs / 65% Mean CHADS Prior Stroke/TIA 20% 55% 28% 19.2% Primary Outcome Stroke/SE Stroke/SE Stroke/SE Stroke/SE Median follow-up 2 yrs 1.9 yrs 2.8 yrs 1.8 yrs SE: acute vascular occlusion of an extremity or organ, documented by means of imaging, surgery, or autopsy.

7 RE-LY: Summary Comparison of Dabigatran to Warfarin Dabigatran 150 mg BID was superior to warfarin Systemic Embolism or Stroke: RR 0.66 ICH: RR 0.4 Major bleeding did not differ RR 0.93 NNT to prevent one stroke: 357 NNT to prevent one hemorrhagic stroke: 370 Dabigatran 75mg BID CrCl ml/min Connolly NEJM 2009;361:

8 Atrial Fibrillation TRIAL RE-LY ROCKET-AF ENGAGE-AF-TIMI ARISTOTLE Drug Dabigatran Rivaroxaban Edoxaban Apixaban Dose 110mg or 150mg BID 20 mg daily (15 mg daily RI) 60 mg QD # (30 mg QD)* 5 mg BID (2.5mg BID)* Comparator/TTR Warfarin/ 67% Warfarin/ 55% Warfarin/ 68% Warfarin/ 62% Condition AF 6 mo AF 6 mo + 2RF AF 6 mo + 1RF AF + 1RF Enrolled 18,113 14,000 21,105 18,201 Design R OL R DB DD R DB DD R BD DD Age/ % 72 yrs / 64% 73 yrs / 60% 72 yrs / 62% 70 yrs / 65% Mean CHADS (87% 3 ) Prior Stroke/TIA 20% 55% 28% 19.2% Primary Outcome Stroke/SE Stroke/SE Stroke/SE Stroke/SE Median follow-up 2 yrs 1.9 yrs 2.8 yrs 1.8 yrs SE: acute vascular occlusion of an extremity or organ, documented by means of imaging, surgery, or autopsy.

9 ROCKET-AF: Summary Comparison of Rivaroxaban to Warfarin Non-inferiority achieved in per-protocol as treated Superiority ITT (2.1% vs. 2.4% p=0.12) not achieved No difference in Major and NMCR bleeding seen Significantly fewer ICH & fatal bleeds with rivaroxaban CHADS2 mean 3.5 Higher risk population TTR for the comparator group was 55% Once daily dosing is meritorious Compliance of 88% vs. 74% in setting chronic therapy Patel NEJM Aug 10, 2011 Corda RS. South Med J 2000; 93:

10 Atrial Fibrillation TRIAL RE-LY ROCKET-AF ENGAGE-AF-TIMI-48 ARISTOTLE Drug Dabigatran Rivaroxaban Edoxaban Apixaban Dose 110mg or 150mg BID 20 mg daily (15 mg daily RI) 60 mg QD # (30 mg QD)* 5 mg BID (2.5mg BID)^ Comparator/TTR Warfarin/ 67% Warfarin/ 55% Warfarin/ 68% Warfarin/ 62% Condition AF 6 mo AF 6 mo + 2RF AF 6 mo + 1RF AF + 1RF Enrolled 18,113 14,000 21,105 18,201 Design R OL R DB DD R DB DD R BD DD Age/ % 72 yrs / 64% 73 yrs / 60% 72 yrs / 62% 70 yrs / 65% Mean CHADS Prior Stroke/TIA 20% 55% 28% 19.2% Primary Outcome Stroke/SE Stroke/SE Stroke/SE Stroke/SE Median follow-up 2 yrs 1.9 yrs 2.8 yrs 1.8 yrs #verboten if CrCl > 95 ml/min *CrCl ml/min

11 ENGAGE-AF-TIMI 48: Summary Comparison of Edoxaban to warfarin Edoxaban was noninferior to warfarin 1.18% vs. 1.5% (95% CI ; p<0.001) for 60mg QD (30mg QD HR=1.07) Edoxaban was superior to warfarin for major bleeding 2.75% (LD 1.61%) vs. 3.43% (p< 0.001) (HR 0.8 & 0.47) Edoxaban was superior to warfarin for Composite Endpoint: 3.85% * (LD 4.23%) vs. 4.43% (HR 0.87; p=0.005 * ) Net Clinical Outcome Benefit favors Edoxaban 7.26% (LD 6.79%) % vs. 8.11% (p 0.003) Primary endpoint: stroke or systemic embolism: Noninferior *Composite endpoint: stroke, systemic embolism, CV death Giugliano, NEJM 2013;369:

12 Atrial Fibrillation TRIAL RE-LY ROCKET-AF ENGAGE-AF-TIMI ARISTOTLE Drug Dabigatran Rivaroxaban Edoxaban Apixaban Dose 110mg or 150mg BID 20 mg daily (15 mg BID RI) 60 mg QD # (30 mg QD)* 5 mg BID (2.5mg BID)^ Comparator/TTR Warfarin/ 67% Warfarin/ 55% Warfarin/ 68% Warfarin/ 62% Condition AF 6 mo AF 6 mo + 2RF AF 6 mo + 1RF AF + 1RF Enrolled 18,113 14,000 21,105 18,201 Design R OL R DB DD R DB DD R BD DD Age/ % 72 yrs / 64% 73 yrs / 60% 72 yrs / 62% 70 yrs / 65% Mean CHADS Prior Stroke/TIA 20% 55% 28% 19.2% Primary Outcome Stroke/SE Stroke/SE Stroke/SE Stroke/SE Median follow-up 2 yrs 1.9 yrs 2.8 yrs 1.8 yrs ^if 2 of: age>80, wt <60kg, Cr >1.5 SE: acute vascular occlusion of an extremity or organ, documented by means of imaging, surgery, or autopsy.

13 ARISTOTLE: Summary Comparison of Apixaban to Warfarin Apixaban reduced the risk of stroke or systemic embolism by 21%, major bleeding by 31%, and death by 11%. For each 1000 patients treated for 1.8 years, apixaban prevented 6 strokes 15 major bleedings and 8 deaths. Net Clinical Outcome Benefit favors apixaban 6.13% vs. 7.2% p < Granger NEJM 2011;365:981-92

14 DOACs vs. warfarin in AF * *TTR > 66% Ruff CT et al. Lancet 2014; 383:

15 DOACs for VTE

16 Choice of anticoagulant for long-term treatment of DVT and PE: NOAC vs. warfarin AT10 Guideline Statement: In patients Evaluation with DVT of Individuals of the leg with or Pulmonary PE and no Nodules: cancer, General as long-term Approach (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. What evidence exists for the comparative effectiveness of Non-vitamin K oral anticoagulants (NOACs) vs. warfarin? Kearon C. Chest doi: /j.chest

17 Choice of anticoagulant for long-term treatment of DVT and PE: NOAC 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

18 Choice of anticoagulant for long-term treatment of DVT and PE: NOAC vs. warfarin Summary of evidence: Recurrent VTE NOAC n (studies) RIVAROXABAN 8281 (2 studies) DABIGATRAN 5107 (2 studies) APIXABAN 5244 (1 study) EDOXABAN 8240 (1 study) QUESTION: Should a NOAC or warfarin be used for acute and long-term treatment of VTE? Quality assessment Summary of Findings Risk of bias no serious risk of bias no serious risk of bias no serious risk of bias no serious risk of bias Overall quality of evidence MODERATE due to imprecision MODERATE due to imprecision MODERATE due to imprecision MODERATE due to imprecision Study event rates (%) With NOAC Relative effect (95% CI) Anticipated absolute effects Risk w/ LMWH &VKA With LMWH and VKA Recurrent VTE 95/4131 (2.3%) 55/2554 (2.2%) 2 71/2635 (2.7%) 146/4122 (3.5%) 3 86/4150 (2.1%) 60/2553 (2.4%) 59/2609 (2.3%) 130/4118 (3.2%) RR 0.90 (0.68 to 1.2) RR 1.12 (0.77 to 1.62) RR 0.84 (0.6 to 1.18) RR 0.83 (0.57 to 1.21) Risk difference with NOACs (95% CI) 23 per fewer per 1000 (from 7 fewer to 5 more) 22 per more per 1000 (from 5 fewer to 13 more) 27 per fewer per 1000 (from 11 fewer to 5 more) 35 per fewer per 1000 (from 15 fewer to 7 more)

19 Choice of anticoagulant for long-term treatment of DVT and PE: NOAC vs. warfarin Summary of evidence: Major Bleeding NOAC n (studies) RIVAROXABAN 8246 (2 studies) DABIGATRAN 5107 (2 studies) APIXABAN 5365 (1 study) EDOXABAN 8240 (1 study) QUESTION: Should a NOAC or warfarin be used for acute and long-term treatment of VTE? Quality assessment Risk of bias no serious risk of bias no serious risk of bias no serious risk of bias no serious risk of bias Overall quality of evidence HIGH MODERATE due to imprecision HIGH MODERATE due to imprecision Summary of Findings Study event rates (%) Relative effect Anticipated absolute effects With LMWH With NOAC (95% CI) Risk with Risk difference and VKA LMWH and with NOACs VKA (95% CI) Major Bleeding 72/4116 (1.7%) 4 51/2554 (2%) 2 49/2689 (1.8%) 66/4122 (1.6%) 40/4130 (0.97%) 37/2553 (1.4%) 15/2676 (0.56%) 56/4118 (1.4%) RR 0.55 (0.38 to 0.81) RR 0.73 (0.48 to 1.1) RR 0.31 (0.17 to 0.55) RR 0.85 (0.6 to 1.21) 17 per fewer per 1000 (from 3 fewer to 11 fewer) 20 per fewer per 1000 (from 10 fewer to 2 more) 18 per fewer per 1000 (from 8 fewer to 15 fewer) 16 per fewer per 1000 (from 6 fewer to 3 more)

20 Choice of anticoagulant for long-term treatment of DVT and PE: NOAC vs. warfarin Despite the lack of an antidote for the NOACs, the risk that a major bleed will be fatal appears to be no higher than that for warfarin Evaluation of Individuals with Pulmonary Nodules: General Approach 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

21 Choice of anticoagulant for long-term treatment of DVT and PE: NOAC 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 NOAC over another? NOACs have not been compared head-to-head for patientimportant 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

22 Choice of anticoagulant for long-term treatment of DVT and PE: NOAC vs. warfarin SUMMARY Evaluation of Individuals with Pulmonary Nodules: General Approach For the first time an alternative to usual care with low molecular weight heparin and warfarin has been suggested for the long-term ( initial ) treatment of PE and DVT. This is a weak recommendation.

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

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

25 Andexanet alpha Recombinant competitive inhibitor of Factor Xa

26 Andexanet alpha Modified competitive inhibitor of Factor Xa

27 Andexanet alpha Modified competitive inhibitor of Factor Xa

28 Andexanet alpha Modified competitive inhibitor of Factor Xa

29 Andexanet alpha

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

31 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 increases Anderson M Clev. Clin J Med, 2014, 8; 629;

32 Preoperative interruption of DOACs Adapted from Gladstone DJ Ann Intern Med. 2015;163:

33 Douketis J. Current Pharmaceutical Design, 2010, 16,

34 Transitioning between anticoagulants Warfarin DOAC

35 Package inserts of the DOACs vary Representative of expert opinion Recommendation: Obtain an INR. Stop warfarin & start apixaban, dabigatran, edoxaban, or rivaroxaban as soon as INR is less than 2.5.

36 Transitioning between anticoagulants DOAC Warfarin

37 Transitioning from DOAC warfarin Post hoc analysis of the ROCKET-AF Rivaroxaban warfarin: Increased risk of stroke HR 3.72 (95% CI ); P = Retrospective analysis of ARISTOTLE Apixaban warfarin: Increased risk of stroke HR 4.07 (95% CI ) Especially those with a high CHADS2 score Patel MR, etal. J Am Coll Cardiol 61(6):651 Granger CB etal. Eur Heart J 33(suppl 1):685

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39 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:

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

41 BRIDGE Study RDBPCT assigned 1884 AF pts to bridging LMWH or matching placebo administered subcutaneously twice daily, from 3 days before the procedure until 24 hours before the procedure and then for 5 to 10 days after. 30-day rate of arterial TE (stroke, systemic embolism, or TIA) and major bleeding RESULTS Incidence of arterial TE was 0.4% in the no-bridging group and 0.3% in the bridging group. MB was 1.3% in the no-bridging group and 3.2% in the bridging group (relative risk, 2.46; 95% P = for superiority). Douketis JD N Engl J Med 2015;373:

42 WAREHOUSE Study Retrospective cohort study 1178 patients receiving AC for VTE from KP database between January 1, 2006, and March 31, 2012 RESULTS 30-day relevant bleeding, recurrent VTE, & all-cause mortality 30-day clinically relevant bleeding: Bridge: 2.7% Non-bridge: 0.2% HR 17.2 (95%CI, ) No significant difference in recurrent VTE groups 0 vs 3 p = No deaths occurred in either group Clark NP JAMA Intern Med. Published online May 26,

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44 Summary The Direct Oral Anticoagulants Atrial fibrillation Venous thromboembolism Choice of drug Reversal agents are here (and more are coming.) Peri-procedural interruption of the DOACs Drug, procedure, renal function Transition from: DOAC warfarin Warfarin DOAC While monitoring and dose adjustment is not required, DOAC patients merit routine follow-up Should likely be bridging fewer, select patients