Getting the Most from DOAC Therapy:

Transcription

1 Getting the Most from DOAC Therapy: Minimizing Risk and Maximizing Adherence Brent N. Reed, Pharm.D., BCPS AQ Cardiology University of Maryland School of Pharmacy Stuart T. Haines, Pharm.D., BCPS, BCACP, BC ADM University of Mississippi School of Pharmacy Annual Meeting & Exposition Seattle, Washington March 22 25

2 Disclosures Brent N. Reed declares that he has no financial or other conflicts of interest related to the content of this presentation. Stuart T. Haines declares that he has no financial or other conflicts of interest related to the content of this presentation. 2

3 CPE Information Target Audience: Pharmacists ACPE#: L01 P Activity Type: Application based 3

4 Supporter This activity is supported by independent educational grants from Pfizer Inc. a

5 Learning Objectives At the completion of this application based activity, participants will be able to: Develop an evidence based patient care plan for a patient requiring treatment with a direct oral anticoagulant (DOAC). Identify patients who are at high risk for adverse events associated with DOAC therapy and strategies for managing these patients. List strategies for reversal of a DOAC overdose. Evaluate strategies that optimize adherence and persistence for patients receiving DOAC therapy. 5

6 Anticoagulation Landscape Today

7 Assessment Question #1 KL is a 57 year old female who has been diagnosed with a DVT. This is her third VTE in the past 5 years. Which of the following is a potential reason to recommend apixaban over edoxaban in the case of KL? A. Apixaban has fewer potential drug drug interactions than edoxaban. B. Apixaban is more effective than edoxaban in terms of preventing recurrent VTE. C. Apixaban can be dosed once daily; edoxaban must be taken twice daily for the first 3 weeks. D. Apixaban can be used for acute and long term treatment; an injectable anticoagulant must be used before transitioning to edoxaban. 7

8 Oral Anticoagulation Timeline 1954 Warfarin approved 1963 JFK assassinated 1974 President Nixon resigns 2001 Terrorist attacks on the Pentagon and WTC 2005 Hurricane Katrina 2011 Rivaroxaban approved 2015 Edoxaban approved 2017 Betrixaban approved 1969 Neil Armstrong walks on the moon 1987 Stock Market Crash Black Monday 2008 Great Recession Begins 2010 Dabigatran approved 2012 Apixaban approved

9 What s In A Name? DOAC vs NOAC vs TSOAC DOAC = Direct Oral Anticoagulant (preferred terminology) NOAC Novel Oral Anticoagulant or Non vitamin K Oral Anticoagulant TSOAC = Target specific oral anticoagulant Direct Xa Inhibitors (apixaban, betrixaban, edoxaban, rivaroxaban) Direct Thrombin Inhibitor (dabigatran) Barnes CD et al. J Thrombosis Haemost. 2015; 13:

10 Direct Oral Anticoagulants (DOACs) Pharmacokinetics & Pharmacodynamics Property Dabigatran Rivaroxaban Apixaban Edoxaban Betrixaban MOA Direct Thrombin Inhibitor Direct Xa Inhibitor Direct Xa Inhibitor Direct Xa Inhibitor Direct Xa Inhibitor Bioavailability 6 7% 80% 50% 62% 35% Tmax 1.5 hours 2 4 hours 2 3 hours 1 2 hours 3 4 hours T½ hours 9 13 hours 8 15 hours 8 11 hours hours CPY450 Metabolism No Yes Yes No No Drug Interactions P gp P gp P gp P gp P gp + CYP3A4 + CYP3A4 Dialyzable Yes No No No No Renal Elimination 80% 35% 25% 40% <10% Renal Dose Adjust Yes Yes No? Yes Yes Antidote Yes Yes Yes Yes? Yes? J Am Coll Cardiol Intv 2014;7: ; P&T 2018; 43:

11 Anticoagulation Therapy Indications Prevention of Venous Thromboembolism Treatment of Venous Thromboembolism Stroke Prevention in Atrial Fibrillation Images from NIH MedLine Plus. National Institutes of Health, U.S. Library of Medicine.

12 Treatment of Venous Thromboembolism 12

13 American College of Chest Physicians Evidence Based Clinical Practice Guidelines, 10 th ed (2012) Indication DVT or PE Duration LMWH (preferred, once daily) Fondaparinux (preferred) Intravenous UFH or SC UFH Recommendation (initial treatment) Oral VKA starting day 1 or 2, minimum overlap 5 days, INR > 2.0 LMWH preferred long term to new oral AC in patients not receiving VKA Provoked (surgical or nonsurgical, proximal or distal): 3 months over a shorter or longer duration Unprovoked, first episode: 3 months, consider long term therapy Unprovoked, second episode: long term preferred unless high bleeding risk Evidence Grade 1B 1B 1B, 2B 1B, 2B Kearon C et al. Chest. 2012; 141(suppl 2):e419S e494s.

14 Are the Direct Oral Anticoagulants First Line? In the absence of direct comparisons between DOACs no preference for one DOAC over another DOAC. Kearon C et al. Chest. 2016; 149:

15 Phases of Treatment for VTE Initiation (5 21 days) UFH, LMWH, fondaparinux Rivaroxaban 15 mg BID Apixaban 10 mg BID Early Maintenance (3 6 months) Warfarin (INR ) Rivaroxaban 20 mg daily Apixaban 5 mg BID Dabigatran 150 mg BID Edoxaban 60 mg daily Extension (up to indefinite) Warfarin (INR ) Rivaroxaban 20 mg daily Rivaroxaban 10 mg daily Apixaban 2.5 mg BID Dabigatran 150 mg BID Warfarin (INR ) Aspirin 81 mg daily Blondon M et al. Circulation. 2015; 132:

16 Acute VTE Treatment Options Conventional VTE Treatment Dabigatran Edoxaban LMWH or UFH + VKA (overlap) Day 1 Day 1 LMWH LMWH VKA At least 3 months Switching Day 6 11 Dabigatran 150 mg BID Edoxaban 60 mg daily At least 3 months Rivaroxaban Apixaban Rivaroxaban 15 mg BID x 3 wk, then 20 mg daily Apixaban 10 mg BID x 1 wk, then 5 mg BID UFH = unfractionated heparin LMWH = low molecular weight heparin or fondaparinux VKA = vitamin K antagonists Streiff MB et al. J Thromb Thrombolysis. 2016; 41:32 67.

17 Extended VTE Treatment & DOACs: Outcomes Recurrent VTE, HR (95% CI) W(fixed) Major Bleeding VTE related Death EINSTEIN EXT 0.19 ( ) 0.20 AMPLIFY EXT 2.5 mg 0.19 ( ) 0.32 AMPLIFY EXT 5.0 mg 0.20 ( ) RE SONATE 0.08 ( ) Kearon ( ) Meta analysis (n=3,015) R (95% CI) W(fixed) 8.80 ( ) ( ) ( ) ( ) ( ) Fixed Effect 0.17 ( ) ( ) Favors DOAC Favors VKA 83% relative risk reduction of recurrent VTE or VTE related death (CI: , p<0.0001) Favors DOAC Favors VKA No significant increase in the risk of major bleeding (CI: , p=0.38) Sindet Pedersen C et al. Thromb Res. 2015; 136:732 8.

18 Prescribing Highlights: Indications Apixaban Dabigatran Edoxaban Rivaroxaban Treatment of DVT, PE Reduction in risk of recurrence of DVT, PE in patients who have been previously treated Treatment of DVT, PE following 5-10 days of initial therapy with a parenteral anticoagulant Reduction in risk of recurrent DVT, PE following initial therapy Initial treatment Prevent Recurrent VTE Treatment of DVT, PE in patients who have been treated with a parenteral anticoagulant for 5-10 days Not indicated Treatment of DVT, PE Take tablets with food Reduction in risk of recurrence of DVT, PE Take tablets with food Pradaxa (dabigatran etexilate mesylate) prescribing information Nov. Xarelto (rivaroxaban) prescribing information Aug. Eliquis (apixaban) prescribing information Jul. Savaysa (edoxaban) [prescribing information Sep.

19 Prescribing Highlights: Dosing Apixaban Dabigatran Edoxaban Rivaroxaban 10 mg orally BID for 7 days, followed by 5 mg orally BID If CrCl >30 ml/min: 150 mg orally, BID after 5-10 day parenteral anticoagulation Initial treatment 60 mg daily 30 mg day if CrCl ml/min, body weight 60 kg, or who use certain P-gp inhibitors Prevent Recurrent VTE 2.5 mg orally BID If CrCl >30 ml/min: 150 mg orally, BID after initial treatment Not indicated 15 mg orally BID with food for first 21 days for initial treatment of acute DVT, PE After initial treatment period, 20 mg orally daily with food for long-term reduction in risk of recurrence Pradaxa (dabigatran etexilate mesylate) prescribing information Nov. Xarelto (rivaroxaban) prescribing information Aug. Eliquis (apixaban) prescribing information Jul. Savaysa (edoxaban) [prescribing information Sep.

20 Stroke Prevention in Atrial Fibrillation 20

21 Atrial Fibrillation By the Numbers Atrial Fibrillation Prevalence (Millions) Current Trend Projected Growth Approximately 6 million patients in the US have AF Year Estimated prevalence expected to exceed 12 million by 2030 Atrial fibrillation increases the overall risk of stroke by 5 fold Adapted from data in Circulation Mar 7;135(10):e

22 CHA 2 DS 2 VASc Risk Stratification Score C Chronic heart failure (1 point) H Hypertension (1 point) A 2 Age >75 years (2 points) D Diabetes mellitus (1 point) S 2 Stroke or TIA (2 points) V Vascular disease (1 point) A Age years (1 point) Sc Sex category (women get 1 point) TIA transient ischemic attack

23 Antithrombotic Therapy Selection 1 CHA 2 DS 2 VASc Score Risk of Stroke / Systemic Embolism No therapy If male (Strong, Moderate) If female (Strong, Moderate) Oral Anticoagulation: DOAC Preferred (Strong, Moderate) Warfarin (Strong, Moderate) Use SAMe TT 2 R 2 (Consensus) Strong = Strong Recommendation Moderate = Moderate Quality Evidence Less than half of eligible patients are prescribed an oral anticoagulant. 2 1 Lip GYH et al. Chest. 2018; Ahead of Print: /j.chest JAMA Cardiol Apr 1;1(1):55 62.

24 Are the Direct Oral Anticoagulants First Line? Lip GYH et al. Chest. 2018; Ahead of Print: /j.chest

25 DOACs versus Warfarin in AFib Characteristic Apixaban (Eliquis ) Dabigatran (Pradaxa ) Edoxaban (Savaysa ) Rivaroxaban (Xarelto ) Landmark Trial ARISTOTLE 1 RE LY 2 ENGAGE AF 3 ROCKET AF 4 Major Inclusion >1 stroke risk factor >1 stroke risk factor CHADS 2 >2 >2 stroke risk factors Exclusions for Renal Impairment SCr > 2.5 or CrCl < 25 ml/min < 30 ml/min < 30 ml/min < 30 ml/min Mean CHADS 2 Score Warfarin Mean TTR 66% 64% 68% 55% Overall Efficacy Superior Superior* Non inferior Non inferior Overall Safety Superior Similar* Superior Similar Other Notable Outcomes ICH ICH GIB* ICH fatal bleeding GIB ICH fatal bleeding GIB *Dabigatran 150 mg twice daily. Increased risk of stroke in pa ents with CrCl > 95 ml/min. CrCl creatinine clearance, DOAC direct acting oral anticoagulant, ICH intracranial hemorrhage, NVAF non valvular atrial fibrillation, SCr serum creatinine, TTR time in therapeutic range, (1) N Engl J Med Sep 15;365(11): (2) N Engl J Med Sep 17;361(12): (3) N Engl J Med Nov 28;369(22): (4) N Engl J Med Sep 8;365(10):

26 DOAC Dosing in AFib Characteristic Apixaban (Eliquis ) Dabigatran (Pradaxa ) Edoxaban (Savaysa ) Rivaroxaban (Xarelto ) Standard Dosing 5 mg twice daily 150 mg twice daily Determine renal function first 20 mg once daily with evening meal Renal Function Adjustments Reduce to 2.5 mg twice daily if SCr > 2.5 mg/dl and age > 80 years or weight < 60 kg Reduce to 75 mg twice daily if CrCl ml/min 60 mg once daily if CrCl ml/min Reduce to 30 mg once daily if CrCl ml/min Reduce to 15 mg once daily with evening meal if CrCl ml/min Renal Function Contraindications None* Avoid if CrCl < 15 ml/min or receiving dialysis Avoid if CrCl > 95 ml/min or < 15 ml/min Avoid if CrCl < 15 ml/min or receiving dialysis CrCl creatinine clearance, DOAC direct acting oral anticoagulant, NVAF non valvular atrial fibrillation, SCr serum creatinine *Safety in end stage renal disease and hemodialysis limited to small studies

27 High Risk Patient Groups Special Considerations for DOACs in Certain Populations 27

28 Assessment Question #2 A 62 year old man with atrial fibrillation on warfarin (CHA 2 DS 2 VASc = 4) and end stage renal disease on hemodialysis asks if he is a candidate for DOAC therapy. Which of the following would be most appropriate? A. Switch to apixaban 5 mg twice daily. B. Switch to dabigatran 75 mg twice daily. C. Switch to edoxaban 60 mg once daily. D. Continue warfarin due to the lack of evidence with DOACs. 28

29 High Risk Patient Groups Cancer Obesity Renal dysfunction Interacting drugs Triple antithrombotic therapy 29

30 VTE Treatment in Cancer Patients with cancer are at an increased risk of thromboembolism compared to the general population LMWH shown to be superior to VKA in this setting Meta analyses suggested that DOACs may be superior to LMWH while increasing the risk of bleeding Abbreviations: LMWH low molecular weight heparin, VKA vitamin K antagonist 30

31 DOACs for VTE Treatment in Cancer Edoxaban vs. Dalteparin Hokusai VTE Cancer Trial Patients with Recurrent Venous Thromboembolism (%) Number at risk Edoxaban Dalteparin Recurrent VTE Events HR 0.71 (95% CI ) Months Edoxaban Dalteparin Duration of treatment longer with edoxaban (211 vs. 184 days, p = 0.01) Primary endpoint: non inferior with respect to composite of VTE events and bleeding (p = 0.006) Numerically lower risk of VTE events (7.9% vs. 11.3%, p = 0.09) (left) Significantly higher risk of major bleeding (6.9% vs. 4.0%, p = 0.04) Abbreviations: CI confidence interval, HR hazard ratio N Engl J Med Feb 15;378(7):

32 DOACs for VTE Treatment in Cancer Rivaroxaban vs. Dalteparin SELECT D Trial Patients with Recurrent Venous Thromboembolism (%) Number at risk Rivaroxaban Dalteparin Recurrent VTE Events HR 0.43 (95% CI ) Months Rivaroxaban Dalteparin No differences in duration of therapy Lower risk of VTE events (4% vs. 11%) (see left) Numerically higher risk of major bleeding (HR 1.83, 95% CI ) Significantly higher risk of clinically relevant nonmajor bleeding (HR 3.76, 95% CI ) Defined as bleeding events that were not major but required escalation of care Abbreviations: CI confidence interval, HR hazard ratio J Clin Oncol Jul 10;36(20):

33 ISTH Recommendations for Cancer VTE Individualize treatment based on shared decision making with patient. Low risk of bleeding High risk of bleeding Edoxaban or rivaroxaban suggested (if no DDIs) LMWH suggested LMWH is an acceptable alternative Edoxaban or rivaroxaban are acceptable (if no DDIs) Abbreviations: DDIs drug drug interactions, LMWH low molecular weight heparin J Thromb Haemost Sep;16(9):

34 Pharmacokinetic Effects on DOACs Absorption Distribution Metabolism Elimination P glycoprotein Efflux pump, which can be inhibited ( DOAC) or induced ( DOAC). Weight / Obesity Affects volume of distribution and total clearance. Hepatic Metabolism CYP mediated, which can be inhibited ( DOAC) or induced ( DOAC). Renal Clearance Affected by underlying renal function. 34

35 Dosing Matters: Outcomes in AF Baseline Dosing Outcomes 87.0% 3.4% 9.4% Events During Follow Up (100 Patient Years) p = NS p = p = 0.04 for overdose Recommended Dose Over Dosed Under Dosed 0 Major Bleeding CV Hospitalization Mortality Recommended Dose Over Dosed Under Dosed CV cardiovascular, DOAC direct acting oral anticoagulant, NVAF nonvalvular atrial fibrillation Adapted from J Am Coll Cardiol Dec 20;68(24):

36 Pharmacokinetic Data in Obesity Drug Data Source Obesity Findings Apixaban Single 10 mg dose in healthy volunteers of reference (n=18) vs. high weight (n=19) 1 > 120 kg Decreased C max Decreased AUC Decreased t 1/2 Dabigatran Subgroup analysis of RE LY trial comparing reference (n=6852) vs. high weight (n=1433) 2 > 100 kg Decreased geometric mean trough* Rivaroxaban Single 10 mg dose in healthy volunteers of reference (n=12) vs. high weight (n=12) 3 > 120 kg No change in Cmax No change in AUC No change in t 1/2 No dosing recommendations are provided in the labeling for any of the DOACs. No data on edoxaban were available at the time of this presentation. *Geometric mean troughs are used for log normal distributions. Abbreviations: AUC area under the curve. Data from (1) Br J Clin Pharmacol. 2013;76: (2) J Am Coll Cardiol Feb 4;63(4): (3) J Clin Pharmacol. 2007;50:

37 Clinical Data in Obesity Recurrent Thromboembolic Events in VTE Trials 1 Study or Subgroup DOACs VKA Risk Ratio Risk Ratio Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI AMPLIFY % 0.61 (0.29, 1.28) EINSTEIN-DVT % 0.99 (0.43, 2.26) EINSTEIN-PE % 1.28 (0.56, 2.90) HOKUSAI % 1.02 (0.58, 1.82) RECOVER-I&II % 1.16 (0.58, 2.29) Total (95% CI) % 0.98 (0.72, 1.35) Total events Heterogeneity: Tau 2 = 0.00, Chi 2 = 2.23, df = 4 (P = 0.69), I 2 = 0% Test for overall effect: Z = 0.10 (p = 0.92) Favors DOACs Favors VKA Bleeding Related Outcomes in VTE Trials 1 Study or Subgroup DOACs VKA Risk Ratio Risk Ratio Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI AMPLIFY % 0.10 (0.01, 0.77) EINSTEIN-DVT % 0.78 (0.50, 1.23) EINSTEIN-PE % 1.09 (0.79, 1.52) HOKUSAI % 1.07 (0.75, 1.54) Total (95% CI) % 0.93 (0.65, 1.32) Total events Heterogeneity: Tau 2 = 0.06, Chi 2 = 6.46, df = d (P = 0.09), I 2 = 54% Test for overall effect: Z = 0.43 (p = 0.67) Favors DOACs Favors VKA A different meta analysis also suggests high body weight did not reduce DOAC efficacy in atrial fibrillation. 2 Threshold for obesity was > 100 kg in 4 trials and > 90 kg in 2 trials. Abbreviations: venous thromboembolism (1) Ann Med Feb;47(1):61 8. (2) J Thromb Haemost Jul;15(7):

38 ISTH Recommendations for Obesity 1. DOACs should not be used in patients with a BMI > 40 kg/m 2 or a weight > 120 kg. 2. If a DOAC is used, obtain peak and trough levels; VKA should be considered if the trough falls below the expected range. Drug Dose Trough (ng/ml) Median (5 th to 95 th percentile) Peak (ng/ml) Median (5 th to 95 th percentile) Dabigatran 150 mg twice daily 90 (31 225) 184 (64 443) Rivaroxaban 20 mg once daily 26 (6 87) 270 ( ) Apixaban 5 mg twice daily 103 (41 230) 171 (91 321) Edoxaban 60 mg once daily 22 (10 40) 170 ( ) Abbreviations: BMI body mass index, ISTH International Society on Thrombosis and Haemostasis, VKA vitamin K antagonist J Thromb Haemost. 2016; 14: Hematology Am Soc Hematol Educ Program 2015;2015:

39 DOAC Renal Dose Adjustments Indication Apixaban* Dabigatran Edoxaban Rivaroxaban Atrial Fibrillation Reduce if SCr >1.5 mg/dl and either weight < 60 kg or age > 80 years Reduce if CrCl ml/min Avoid if CrCl < 15 ml/min VTE Treatment No dose reduction Avoid if CrCl < 30 ml/min Avoid if CrCl > 95 ml/min Reduce if CrCl ml/min Avoid if CrCl < 15 ml/min Reduce if CrCl < ml/min Avoid if CrCl < 15 ml/min Reduce if CrCl < 50 ml/min* Avoid if CrCl < 30 ml/min *Trials did not enroll patients with CrCl < 15 ml/min or end stage renal disease. No dose reduc on needed for 2.5 mg bid dosing in vascular disease, Abbrevia ons: CrCl creatinine clearance, SCr serum creatinine 39

40 Anticoagulation for AF in ESRD Increased ASCVD Risk Endothelial dysfunction Increased pro coagulant concentrations RAAS activation Platelet dysfunction Impaired prostaglandin synthesis Studies with warfarin aren t that great either Anticoagulate Do Not Anticoagulate Anticoagulation in AF not routinely recommended per 2011 KDIGO guidelines Abbreviations: AF atrial fibrillation, ASCVD atherosclerotic cardiovascular disease, KDIGO Kidney Disease: Improving Global Outcomes, RAAS renin angiotensin aldosterone system. Kidney Int Sep;80(6):

41 Summary of Data in ESRD and Dialysis Apixaban 1 3 Edoxaban 4 Rivaroxaban 5 6 Dialyzability* 6% 9% 5% Available Studies Single dose and steady state PK/PD studies Observational clinical studies Single dose PK study Single dose and multiple daily dose PK/PD studies Data Summary Single dose: 5 mg bid regimen comparable to healthy volunteers Steady state: supra therapeutic levels with 5 mg bid regimen Clinical studies: reduced bleeding with both doses; reduced thromboembolic outcomes with 5 mg bid Single dose: 15 mg welltolerated ; PK/PD not compared to healthy volunteers Single dose: 15 mg comparable to 20 mg in healthy volunteers Multiple daily dose: 10 mg regimen comparable to 20 mg regimen in healthy volunteers *May vary by dialysis method, session duration, and type of filter used. Abbreviations: PK pharmacokinetic, PD pharmacodynamic (1) J Clin Pharmacol May;56(5): (2) J Am Soc Nephrol Jul;28(7): (3) Circulation Oct 9;138(15): (4) Thromb Haemost Apr;113(4): (5) Am J Nephrol. 2016;43(4): (6) Am J Kidney Dis Jul;66(1):

42 Labeling Recommendations in ESRD Indication Apixaban Edoxaban Rivaroxaban Atrial Fibrillation 5 mg bid unless also < 60 kg or > 80 years of age (although it is unknown whether this produces similar clinical effects) Not recommended 15 mg once daily VTE Treatment No dose adjustment Not recommended Avoid use (although it is unknown whether this produces similar clinical effects) 42

43 Drug Drug Interactions P glycoprotein drug efflux pump Hepatic CYP3A4 Metabolism Lumen CYP3A4 Intestinal wall Inhibitors: efflux, DOAC Inducers: efflux, DOAC Inhibitors: metabolism, DOAC Inducers: metabolism, DOAC May also have combined effects 43

44 Drug Drug Interaction Potential Indication Apixaban Dabigatran Edoxaban Rivaroxaban Bioavailability 50% 3 7% (also subject to hydrolysis) 62% 66% (100% when taken with food) P glycoprotein substrate Yes Yes Yes Yes Hepatic metabolism 73% (CYP3A4) 20% (not CYP3A4) 50% (only 4% CYP3A4) Renal clearance 27% 80% 50% 35% 65% (CYP3A4 and CYP2J3) Europace Oct;17(10):

45 Common Interacting Drugs (FYI) P gp Inducers P gp Inhibitors P gp + Strong CYP3A4 Inhibitors P gp + Strong CYP3A4 Inducers P gp + Moderate CYP3A4 Inhibitors Barbiturates Phenytoin Carbamazepine Rifampin St. John s wort Amiodarone Dronedarone Diltiazem Verapamil Clarithromycin Grapefruit juice Cyclosporine Tacrolimus Ketoconazole Itraconazole Ritonavir Barbiturates Phenytoin Carbamazepine Rifampin St. John s wort Clarithromycin Grapefruit juice Ketoconazole Itraconazole Ritonavir Dronedarone Diltiazem Verapamil Azithromycin 45

46 Managing Drug Drug Interactions Interaction Apixaban Dabigatran Edoxaban Rivaroxaban P gp inducers Avoid Avoid P gp inhibitors P gp plus strong CYP3A4 inducers P gp plus strong CYP3A4 inhibitors P gp plus moderate CYP3A4 inducers Use with caution, avoid in renal impairment* Use with caution, avoid in renal impairment Avoid Avoid Avoid Avoid Dose reduce; avoid if already on lower dose Avoid Avoid Avoid Avoid Avoid Use with caution, especially in renal impairment *For dronedarone and ketoconazole, label specifically notes to dose reduce dabigatran or avoid if co existing renal impairment is present. Abbreviations: P gp p glycoprotein 46

47 Triple Antithrombotic Therapy Patients requiring dual antiplatelet therapy (aspirin plus P2Y12 inhibitor) and indication for oral anticoagulation Practical strategies have varied: Warfarin to target an INR of Using clopidogrel over newer P2Y12 inhibitors Selecting alternative stents (BMS > DES) WOEST trial: VKA plus clopidogrel reduced bleeding vs. triple antithrombotic therapy (44.4% vs. 19.4%, p < ) Abbreviations: BMS bare metal stent, DES drug eluting stent, INR international normalized ratio, VKA vitamin K antagonist Adapted from Lancet Mar 30;381(9872):

48 DOAC Dual Therapy vs. Triple Therapy Event (%) Event (%) HR 0.52 (95% CI ) p < for non inferiority HR 0.72 (95% CI ) p < for non inferiority Triple therapy Dabigatran 110 mg DT Number at risk Months DBG 110 DT TT Triple therapy Dabigatran 150 mg DT Number at risk Months DBG 150 DT TT Dabigatran Dual Therapy vs. VKA Triple Therapy RE DUAL PCI Trial Triple therapy (TT; aspirin + P2Y12i+ VKA) vs. dual therapy (DT; P2Y12i + dabigatran 110 mg or 150 mg bid) Primary endpoint: major or clinically relevant non major bleeding Dabigatran 110 mg DT: non inferior and superior vs. TT (top left) Dabigatran 150 mg DT: non inferior vs. TT (bottom left) Not powered for thrombotic events Abbreviations: bid twice daily, CI confidence interval, DBG dabigatran, DT dual therapy, HR hazard ratio, P2Y12i P2Y12 inhibitor VKA vitamin K antagonist, TT triple therapy. N Engl J Med Oct 19;377(16):

49 DOAC Dual Therapy vs. Triple Therapy Cumulative Incidence of Primary Endpoint (%) Number at risk RVX DT vs. VKA TT: HR 0.59 (95% CI ) RVX TT vs. VKA TT: HR 0.63 (95% CI, ) Months VKA TT Rivaroxaban TT Rivaroxaban DT RVX DT RVX TT VKA TT Two Rivaroxaban Strategies vs. VKA Triple Therapy PIONEER Trial Patients randomized to three arms: Rivaroxaban 15 mg qday + P2Y12i (DT) Rivaroxaban 2.5 mg bid + P2Y12i + aspirin (TT) VKA + P2Y12i + aspirin (TT) Both rivaroxaban arms reduced primary endpoint of clinically significant bleeding Not powered for thrombotic events Abbreviations: CI confidence interval, DT dual therapy, HR hazard ratio, P2Y12i P2Y12 inhibitor, RVX rivaroxaban, TT triple therapy, VKA vitamin K antagonist. N Engl J Med Dec 22;375(25):

50 DOAC Dual Therapy vs. Triple Therapy Dual therapy regimens (DOAC + P2Y12i) seem reasonable in patients requiring PCI plus OAC Rivaroxaban triple therapy (2.5 mg bid + P2Y12i + aspirin) reasonable short term, but patients should be converted to appropriate dose when indication for DAPT is complete Safety of above regimens unclear with newer P2Y12i Trials with apixaban and edoxaban are ongoing Abbreviations: bid twice daily DAPT dual antiplatelet therapy, OAC oral anticoagulant, P2Y12i P2Y12 inhibitor 50

51 Reversing DOAC Activity When to Reverse and DOAC Reversal Strategies 51

52 Assessment Question #3 A 72 year old woman with atrial fibrillation on apixaban 5 mg twice daily presents to the emergency department with blurry vision, and initial imaging is suggestive of intracranial hemorrhage. Which of the following therapies would be most appropriate to administer at this time? A. 4 Factor prothrombin complex concentrates 50 units/kg IV. B. Andexanet alfa 400 mg IV once, then 4 mg/min x 120 minutes. C. Idarucizumab 5 mg IV x 2, given no more than 15 minutes apart. D. Vitamin K 10 mg IV once followed by 5 mg IV in 6 hours. 52

53 Periprocedural Interruption of DOACs No Procedural bleeding risk? Increased baseline bleeding risk? Yes for any of the following: Major bleed or ICH < 3 months Platelet abnormality (including concurrent aspirin use) Prior bleed during bridging No clinically important risk Low Uncertain, moderate, or high Do not interrupt. Time at DOAC trough if possible Interrupt based on CrCl (see table on next slide) Use clinical judgment. Interrupt by at least as long as determined by CrCl (see table). Abbreviations: CrCl creatinine clearance, DOAC direct acting oral anticoagulant, ICH intracranial hemorrhage Adapted from J Am Coll Cardiol Feb 21;69(7):

54 Periprocedural Holding Recommendations Dabigatran Apixaban, Edoxaban, and Rivaroxaban CrCl (ml/min) > < 15 > < 15 Low bleeding risk >24 hours >36 hours >48 hours >72 h Consider dtt and/or holding >96 hours* >24 h >36h Consider anti Xa and/or holding >48hours* Uncertain, moderate, or high bleeding risk >48 hours >72 hours >96 hours > 120 hours Consider dtt* > 48 h Consider anti Xa and/or holding >48hours* *No data in these scenarios. Abbreviations: CrCl creatinine clearance, DOAC direct acting oral anticoagulant, dtt dilute thrombin time Adapted from J Am Coll Cardiol Feb 21;69(7):

55 Restarting DOACs Post Procedure No Complete hemostasis achieved with no bleeding complications, no high risk features for bleeding, and no potentially catastrophic bleed location? Yes Low post procedural bleeding risk High post procedural bleeding risk Use clinical judgement. Re initiate DOAC within 24 hours of the procedure.* Consider temporary use of parenteral agent if unable to tolerate oral medications. Re initiate DOAC within hours after procedure. Consider temporary use of parenteral agent if unable to tolerate oral medications. Abbreviations: CrCl creatinine clearance, DOAC direct acting oral anticoagulant, ICH intracranial hemorrhage Adapted from J Am Coll Cardiol Feb 21;69(7):

56 DOAC Laboratory Monitoring Standard Assays Specialized Assays Assays Interpretation Assays Interpretation Dabigatran Apixaban Edoxaban Rivaroxaban TT, aptt PT Excludes clinically relevant levels if normal (TT > aptt) Cannot exclude clinically relevant levels if normal Prolonged PT suggests ontherapy or supratherapeutic levels dtt, ECT, ECA Anti Xa* Excludes clinically relevant levels if results are normal Can be used to measure on therapy or supratherapeutic levels *Must be calibrated for specific drug Abbreviations: aptt activated partial thromboplastin time, dtt dilute thrombin time, ECA ecarin chromogenic assay, ECT ecarin clotting time, PT prothrombin time, TT thrombin time Adapted from J Am Coll Cardiol Dec 19;70(24):

57 Bleeding Management Overview Bleeding at a critical site, hemodynamic instability, decrease in Hgb >2 g/dl, or >2 units of RBCs needed? No Non major bleeding Is an escalation of care required? Yes Major bleeding Is it at a critical site* or lifethreatening? No Yes No Yes Control bleeding but continue DOAC Control bleeding and STOP DOAC Control bleeding and STOP DOAC Control bleeding and STOP DOAC Is the bleeding controlled? No Administer antidote based on DOAC taken *Critical site bleeds include central nervous system bleeding, pericardial tamponade, airway bleeding, hemothorax, intra abdominal bleeding, retroperitoneal hematoma, and intramuscular/intra articular extremity bleeding. Abbreviations: Hgb hemoglobin, RBCs red blood cells Adapted from J Am Coll Cardiol Dec 19;70(24):

58 DOAC Reversal Strategies Which DOAC? Dabigatran Apixaban or rivaroxaban* Idarucizumab (consider activated charcoal if ingested within 2 4 hours) Andexanet alfa (consider activated charcoal if ingested within 2 4 hours) Alternatives: 4 Factor PCC or apcc 50 units/kg IV Alternatives: 4 Factor PCC 50 units/kg IV (preferred over apcc) *Case studies suggest that andexanet alfa may also be effective for reversing edoxaban and betrixaban Abbreviations: apcc activated prothrombin complex concentrates, PCC prothrombin complex concentrates Adapted from J Am Coll Cardiol Dec 19;70(24):

59 DOAC Antidotes \Idarucizumab Mechanism Monoclonal antibody to dabigatran Idarucizumab (Praxbind ) Clinical Trial Results Dosing Comments Reversed anticoagulation parameters within 4 hours Dabigatran reappeared in 23% of patients at hours Hemostasis obtained within 2.5 hours in most patients (68%) 5 g IV administered as two 2.5 g doses no more than 15 minutes apart Additional 5 mg IV may be necessary if coagulation parameters re elevate or re bleeding occurs Monitor aptt at 2 hours and every 12 hours until normal Risk of thrombosis likely driven by withholding DOAC after reversal Abbreviations: aptt activated partial thromboplastin time N Engl J Med Aug 3;377(5):

60 DOAC Antidotes \ Andexanetalfa Andexanet alfa (Andexxa ) Mechanism Inactivated factor Xa, which binds to apixaban and rivaroxaban Clinical Trial Results Dosing Factor Xa activity decreased by nearly 90% after bolus and remained 30 40% below baseline activity at 4 hours after infusion Hemostasis deemed as good or excellent in 79% of patients Unknown time of last dose: high dose < 8 hours of rivaroxaban > 10 mg or apixaban > 5 mg: high dose < 8 hours of rivaroxaban <10 mg or apixaban <5 mg: standard dose >8 hours of last dose: standard dose High dose: 800 mg IV bolus (30 mg/min), then 8 mg/min for up to 120 minutes Standard dose: 400 mg IV bolus (30 mg/min), then 4 mg/min for up to 120 minutes Comments Risk of thrombosis likely driven by withholding DOAC after reversal N Engl J Med Sep 22;375(12):

61 Resuming DOAC Therapy Assess: bleeding occurred at a critical site, patient is at high risk for re bleeding, invasive procedure is planned, or patient declines to restart? No Yes Examples: Drug drug interactions Renal function No No Other factors that increased risk of bleeding with DOAC? Is patient on antiplatelet therapy? Yes Delay Yes Reassess need for antiplatelet therapy Factors to consider: Patient preferences Need for surgery/invasive procedures Site of bleeding Risk of re bleeding Risk of thrombosis Resume DOAC Consider alternative DOAC or VKA Abbreviations: VKA vitamin K antagonist Adapted from J Am Coll Cardiol Dec 19;70(24):

62 Adherence and Persistence 62

63 Assessment Question #4 JP is a 68 year old African American male recently diagnosed with atrial fibrillation and prescribed rivaroxaban for stroke prevention. Which of the following strategies would most likely increase his adherence and persistence to DOAC therapy? A. Give JP a 7 day pill box. B. Ask JP about what the prescriber explained about the risk and benefits of rivaroxaban. C. Schedule regular follow up visits or calls with JP to interview him and check BP and kidney function. D. Explain the importance of taking rivaroxaban every day missing just one dose can increase his risk of stroke. 63

64 Terminology Adherence Degree to which a patient adheres to the recommended treatment regimen. Example of nonadherence: running out of a medication for a few days before getting it refilled. Persistence Continuation for the full intended duration of treatment (which may differ by indication). Example of non persistence: discontinuing treatment prior to completing at least 3 month duration for provoked VTE. Adherence and persistence are not synonymous. A patient can be persistent but not (sufficiently) adherent to receive the benefits of DOAC therapy. Or vice versa.

65 Practical Consideration: DOACs vs. Warfarin Given their shorter duration of effect, DOACs are less forgiving than warfarin when doses are missed DOACs are less prone to drug drug and drug food interactions DOACs require less frequent laboratory monitoring tests Measuring the response to therapy can provide clinician and patient helpful feedback (warfarin) Patient preference is a key consideration patients should be included in the decision making process Once daily dosing (edoxaban, rivaroxaban, warfarin) vs. twice daily dosing (apixaban, dabigatran, rivaroxaban [acute VTE]) Burnett AE et al. J Thromb Thrombolysis. 2016; 41:

66 Nonadherence Causes & Contributors Patient Factors Provider / System Factors

67 Antithrombotic therapy should be individualized based on shared decision making (Class I, Level of Evidence C) 1 Provider Preferences Patient Preferences Perceptions regarding the extent to which decisions are shared between patients and providers do not match. 2 3 (1) J Am Coll Cardiol Dec 2;64(21):e1 76. (2) Thromb Haemost Jan 26;117(2): (3) Patient Educ Couns Aug;88(2): c

68 Patient Factors Non Modifiable Demographics (e.g. age, gender) Socioeconomic status Treatment experience Personal beliefs and values Comorbidities Modifiable? Capability (e.g., patient understanding, ability/tools to manage medications) Motivation (e.g., perceived risks and benefits of therapy) Social determinants of health (e.g., cost, medication access) Medication complexity (inverse U shaped curve) Br J Haematol Jul;174(1): Thromb Res Oct;136(4):

69 Adherence Problems! An estimated 30 50% of patients prescribed DOACs do not take at least 80% of prescribed doses in the first year Adherence to DOAC declines over time Younger patients, those who take fewer medications, and those who are AC naïve are less likely to be adherent Lower adherence to DOACs has been associated with an increased risk of mortality and stroke (HR = 1.07 per 0.10 decline in PDC) Manzoor BS et al. Pharmacotherapy 2017; 37: Maura G et al. Pharmacoepidemol. 2017; 26: Bome RT et al. BMC Cardiovasc Disorders 2017; 17:

70 DOAC Persistence Rates 40% Discontinuation Rates in Major NVAF Trials 1 30% 20% 34.4% 10% 25.3% 21.9% 25.3% 3.0% 2.7% 4.0% 4.2% 0% Apixaban (ARISTOTLE) Dabigatran (RE LY) Edoxaban (ENGAGE AF) Rivaroxaban (ROCKET AF) Discontinuation ADR Related Discontinuation Additionally, observational studies show adherence/persistence rates as good or better than warfarin (> 70% vs %). 1 2 DOAC direct acting oral anticoagulant, NVAF non valvular atrial fibrillation (1) Adapted from: Thromb Haemost Jan 26;117(2): (2) Br J Haematol Jul;174(1):30 42.

71 Comparative Adherence Rates Among DOACs 1 100% No single DOAC is consistently better although adherence to apixaban and rivaroxaban tends to be higher than with dabigatran. 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Forslund, et al. (2) McHorney, et al. (3) Beyer Westerndorf, et al. (4) Coleman, et al. (5) Yao, et al. (6) Apixaban Dabigatran Rivaroxaban DOAC direct acting oral anticoagulant (1) Adapted from: Thromb Haemost Jan 26;117(2): (2) Eur J Clin Pharmacol 2016; 72: (3) Curr Med Res Opin 2015; (4) Europace 2016; euv421. (5) Int J Cardiol 2016; 212: (6) J Am Heart Assoc 2016; 5: pii: e

72 Impact of Early Non Persistence in Afib Drug/Outcome Hazard Ratio (95% CI) Dabigatran Composite outcome 1.76 ( ) Cerebrovascular event 3.75 ( ) Rivaroxaban Composite outcome 1.89 ( ) Cerebrovascular event 6.25 ( ) Hazard Ratio (95% CI) CI confidence interval, NVAF non valvular atrial fibrillation Adapted from: Heart Br Card Soc Sep;103(17):

73 Improving Adherence and Persistence The support structures available to clinicians and patients can significantly improve adherence to DOACs Appropriate selection assessing candidates for DOAC therapy and involving patients in the decision to use a DOAC; access to medication Patient education regarding the purpose and importance of DOAC therapy, potential adverse events, administration, and adherence strategies Ongoing Patient Monitoring adherence, adverse events, renal function, and drugdrug interactions; either face to face or telephone f/u Shore S et al. JAMA 2015; 313: Al Khalili F et al. Clin Trial Reg Sci Card 2016: 18:

74 Monitoring DOACs Adherence Assessment Direct questioning followed by patient education Refill history Bleeding Risk Assessment GI bleeding? EtOH use? Falls? Renal function / creatinine clearance Drug interactions (especially NSAIDs and aspirin!) Physical Examination Bruises and overt bleeding Blood pressure Gait and balance Gladstone DJ et al. Ann Intern Med. 2015; 163:

75 Closing Remarks/Conclusion Direct oral anticoagulants have increasingly replaced warfarin therapy for VTE treatment and stroke prevention DOACs have different pharmacodynamic and pharmacokinetic properties which must be considered when used in high risk populations Reversal strategy depends on the DOAC and the urgency with which the anticoagulation effects must be abated Adherence and persistent to DOAC therapy is often poor systematic follow up monitoring can improve outcomes 75

76 Assessment Question #1 KL is a 57 year old female who has been diagnosed with a DVT. This is her third VTE in the past 5 years. Which of the following is a potential reason to recommend apixaban over edoxaban in the case of KL? A. Apixaban has fewer potential drug drug interactions than edoxaban. B. Apixaban is more effective than edoxaban in terms of preventing recurrent VTE. C. Apixaban can be dosed once daily; edoxaban must be taken twice daily for the first 3 weeks. D. Apixaban can be used for acute and long term treatment; an injectable anticoagulant must be used before transitioning to edoxaban. 76

77 Assessment Question #2 A 62 year old man with atrial fibrillation on warfarin (CHA 2 DS 2 VASc = 4) and end stage renal disease on hemodialysis asks if he is a candidate for DOAC therapy. Which of the following would be most appropriate? A. Switch to apixaban 5 mg twice daily. B. Switch to dabigatran 75 mg twice daily. C. Switch to edoxaban 60 mg once daily. D. Continue warfarin due to the lack of evidence with DOACs. 77

78 Assessment Question #3 A 72 year old woman with atrial fibrillation on apixaban 5 mg twice daily presents to the emergency department with blurry vision, and initial imaging is suggestive of intracranial hemorrhage. Which of the following therapies would be most appropriate to administer at this time? A. 4 Factor prothrombin complex concentrates 50 units/kg IV. B. Andexanet alfa 400 mg IV once, then 4 mg/min x 120 minutes. C. Idarucizumab 5 mg IV x 2, given no more than 15 minutes apart. D. Vitamin K 10 mg IV once followed by 5 mg IV in 6 hours. 78

79 Assessment Question #4 JP is a 68 year old African American male recently diagnosed with atrial fibrillation and prescribed rivaroxaban for stroke prevention. Which of the following strategies would most likely increase his adherence and persistence to DOAC therapy? A. Give JP a 7 day pill box. B. Ask JP about what the prescriber explained about the risk and benefits of rivaroxaban. C. Schedule regular follow up visits or calls with JP to interview him and check BP and kidney function. D. Explain the importance of taking rivaroxaban every day missing just one dose can increase his risk of stroke. 79