Anticoagulation: Novel Agents

Transcription

1 Anticoagulation: Novel Agents Scott C. Woller, MD Medical Director, Anticoagulation Management, Intermountain Healthcare Central Region, co-director Venous Thromboembolism Program, Intermountain Medical center; Intermountain Healthcare; Associate Professor, Internal Medicine, University of Utah School of Medicine Objectives: Review the role of direct oral anticoagulants (DOACs) for the treatment of atrial fibrillation and venous thrombosis Discuss an approach to transitioning patients from warfarin anticoagulation to anticoagulation with a DOAC Discuss an approach to interruption of a DOAC for a procedure that requires interruption of anticoagulation List recent advances in the evident for interruption of warfarin for procedures ("bridging")

2 Direct Oral anticoagulants (DOACs) in clinical practice Scott C. Woller, MD Co Director, Thrombosis Program Intermountain Medical Center Associate Professor of Medicine University of Utah School of Medicine North Region Clinical Learning Day McKay Dee Hospital 11 September 2015

3 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)

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

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) who masterpiece collection gold dalek/

7 DOACs TF VIIa Va sciencecodex.com

8 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:

9 TRIAL RE LY ROCKET AF ENGAGE AF TIMI ARISTOTLE Drug Dabigatran Rivaroxaban Edoxaban Apixaban Dose The Direct Oral Anticoagulants: Atrial Fibrillation 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.

10 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:

11 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.

12 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:

13 Atrial Fibrillation TRIAL RE LY ROCKET AF ENGAGE AF TIMI 48 ARISTOTLE Drug Dabigatran Rivaroxaban Edoxaban Apixaban Dose 110mg or 20 mg daily 60 mg QD # 5 mg BID 150mg BID (15 mg daily RI) (30 mg QD)* (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

14 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) Giugliano, NEJM 2013;369:

15 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.

16 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

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

18 DRUG RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN TRIAL EINSTEIN PE 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 / 62.7% LWWH + Warf / 61% LMWH + Warf / 63.5% LWWH + Warf / 60% Condition (%) PE 100% B 25% 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/ % 58 yrs / 54% 57 / 61% 55.8 / 57% 55 yrs / 58% Cancer 4.6% 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 2.1 v. 1.8; RR 1.12 ( ) p<0.003 NI Major Bleeding 1.1 v. 2.2 RR 0.49 p=0.11(ns) [PE: 0.49] DOACs for VTE 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 8.5 vs RR 0.81 ( ) p=0.004 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, safer; QD Non inferior Schulman NEJM 2009;361:2342; EINSTEIN Investigators NEJM Dec 4, 2010; AMPLIFY NEJM 1 Jul 2013; HOKUSAI NEJM 1 Sept 2013

19 Choosing between DOACs in VTE Castellucci JAMA. 2014;312(11):

20 Choosing between DOACs: Summary Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban Cost Compliance Bleeding risk Renal Dysfunction QOL

21 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;

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

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

24 Transitioning between anticoagulants Warfarin DOAC

25 Package inserts of the DOACs vary Representative of expert opinion Recommendation: Stop warfarin. Start apixaban, dabigatran, edoxaban, or rivaroxaban as soon as INR is less than 2.5.

26 Transitioning between anticoagulants DOAC Warfarin

27 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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29 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:

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

31 Summary The Direct Oral Anticoagulants Atrial fibrillation Venous thromboembolism Choice of drug 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

32 Thank you