Optimal Anticoagulation: New Drugs, Indications, and Reversal

Roy E. Smith, M.D., M.S.Department of Medicine

Division of Hematology and Medical OncologyUniversity of Pittsburgh Medical Center

10/21/19 1

Objectives:

• Understand the mechanisms of action and differences of the new oral

anticoagulants

• Know indications for each new oral anticoagulant

• Increase knowledge of use of each new oral anticoagulant in special

circumstances.

• Understand useful reversal strategies for each new oral anticoagulant

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Tyranny of Choice – Current Challenges

• DOACs differ in a number ways

• Must consider drug and patient characteristics

• No randomized comparisons of DOACs

• Safety and efficacy similar to warfarin and with reduced risk of spontaneous ICH

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Differences in DOACS

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Dabigatran Rivaroxaban Apixaban Edoxaban BetrixabanHip replacement

Knee replacement

Stroke/SE in NVAF

Acute VTE

Extended VTE

CAD/PAD

VTE ppx

Yes yes yes

yes yes

yes yes

yes yes yes yes

yes yes yes

yes

yes

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Makan et al. PLOS one 2018

Efficacy and Safety of DOACs vs Warfarin

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Makan et al. PLOS one 2018

Efficacy and Safety of DOACs vs Warfarin in NVAF

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Makan et al. PLOS one 2018

Efficacy and Safety of DOACs vs Warfarin in VTE

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VTE ppx for THR or TKR vs Enoxaparin

Rivaroxaban Superior with no difference in bleeding

Edoxaban Not approved for these indication

RE-NOVATE I and II THRDabigatran

Lassen et al. NEJM 2010Eriksson et al. NEJM 2008Kakkar et al. Lancet 2008Eriksson et al. Lancet 2007Eriksson et al. J thromb Haemost 2007

Apixaban Advance 3 THR Superior with no difference in bleeding

Record 1 and 2 THR

Non-inferior

Apixaban Superior with no difference in bleedingAdvance 2 TKR

Rivaroxaban Superior with no difference in bleedingRecord 1 and 2 TKR

TKR Not approved for this IndicationDabigatran

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Evidence for VTE Risk Reduction after Treatment

Edoxaban Not approved for this indication

Agnelli et al. NEJM 2012Weitz et al NEJM 2017Buller Blood 2009Schulman et al. NEJM 2013

Apixaban AMPLIFY - EXT Superior: vs placebo with similar bleeding

Rivaroxaban EINSTEIN – EXT and CHOICE • Superior: vs placebo with higher bleeding major bleeding

• 10mg and 20mg better than ASA

RE - MEDY and RE - SONATEDabigatran • Non-inferior vs warfarin with similar bleeding

• Superior vs placebo, higher major bleeding

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Reduction of Risk of Major Cardiovascular Events in Patients with Chronic CAD or PAD

COMPASS TRIAL

Ischemic stroke 0.51 (0.38, 0.69)Coronary heart disease death 0.73 (0.55, 0.96)Acute limb ischemia 0.55 (0.32, 0.92)Lower extremity amputations 0.45 (0.26, 0.89)

N = 9152 N = 9126

Rivaroxaban 2.5mg + ASA 100mg ASA 100mg alone

Patients with CAD and PAD

Patients with PAD

Acute limb ischemia 0.56 (0.32, 0.99)

Eikelboom et al. NEJM 2017

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APEX: a multinational pivotal trial of extended VTE prophylaxis in acutely ill

medical patients (N=7513)1,*

Extended-duration Bevyxxa (35 to 42 days) vs enoxaparin (6 to 14 days) + placebo

Cohen et al. NEJUM 2016

Primary Efficacy Endpoint: Asymptomatic proximal DVT + symptomatic DVT

0.76 (95%CI 0.63, 0.92); p=0.006

Principle safety outcome: Major bleeding

1.19 (95% CI 0.67, 2.12); p=0.55

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Why DOACs are preferred for most patients with VTE

• More convenient • No routine monitoring or dose adjustment • No dietary (and few drug-drug) interactions

• Simplified peri-procedural anticoagulation

• As effective as warfarin and safer

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• Pro-thrombotic states: e.g. APLS

• Severe renal impairment (CrCl< 30 ml/min)

• Moderate to severe hepatic impairment

• Clinically significant drug interactions

• Extremely high body weight (> 120 kg ?)

• Prohibitive cost

When should a DOAC not be the first choice?

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The folly of monitoringSchematic of drug effect: warfarin vs DOACs

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Measuring DOACs: When

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Lab Measurement for DOACs

• DOACs can (but do not always) prolong “traditional” clotting times (PTT or PT)

• Thrombin time (TT) is very sensitive to (even low concentrations of) dabigatran –a normal thrombin time excludes dabigatran

10/21/19 19Cuker et al JACC 2014

Measuring DOACs: How

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Best tests for DOACsDabigatran: dilute thrombin time (calibrated for dabigatran)

Fxa inhibitors: anti-Xa assay (calibrated for a particular DOAC)

• Therapeutic ranges are not established

• “expected” trough: ~ 50 ng/mL

• “expected” peak: 150 –250 ng/mL

• “Safe” trough levels < 30 – 50ng/mL

Samuelson et al. Chest. 2016

Douxfils et al. JTH 2017

Levy et al. JTH 2015

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FXa Inhibitory Profile of DOACS Does Fully Reflect Their Biologic Spectrum

Siddiqui et al. Clin Appl Thomb Hemost. 2019

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DOACs and Heparins

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Macedo et al. Annals of Pharmacotherapy 2018

Influence of of DOACs on Anti-FXa Measurements

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Initiation of AC in Patients with Liver Disease

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• Extreme obesity—also referred to as severe, grade III, or morbid obesity• BMI > 40 kg/m2

• 7.7% of the adult US population.

• 20 million extremely obese adults living in the US

• 500 000 extremely obese individuals in the US with AF have an indication or are receiving AC.

• 70 000 extremely obese patients in the US with VTE require AC

DOACs and the Obese Patient

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PK /PD Studies in Obese Patients

Apixaban: • >120 kg vs 65-85 kg• 31% lower mean [peak]; 144ng/mL vs 207ng/mL• 24% higher Vd; 76 L vs 61 L• 20% decreased AUC• Authors considered differences in to be unimportant

Rivaroxaban• >120 kg vs 70-80 kg• Similar [peak} and AUC• Weight has no effect

Rivaroxaban pooled form Einstein DVT an ODIXa – DVT)• No difference in [peak]• High wt individuals have increase VD

Upreti et al. Br J Clin Pharmacol 2013Kubitza et al. J Clin Pharmacol 2007Meuck et al. Clin Pharmacokinet 2011

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PK /PD Studies in Obese Patients

• Subgroup Analysis of Available PK data from large clinical trials

• PK/PD data suggests reduced drug exposure, lower [peak] and shorter t/2

• High interpatient patient variability by dose and indication

• Also there is large intra-patient variability for dabigatran

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The International Society on Thrombosis and Haemostasis (ISTH)

• Subgroup analyses of obese patients from the large phase III DOAC vs warfarin trials suggest that DOACs are efficacious and safe in obese patients

• F <20% of patients in clinical trials had body weight ≥ 100kg

• Few patients with BMI >40 kg/m2 and PK data

• Suggest that DOACs not be used in patients with a BMI > 40 kg/m2 or a weight >120 kg

• If a DOAC is used , peak and trough levels should be measured

Piran et al. Res Pract Thromb Haemost. 2018Martin et al. JTH 2016

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DOACs and APLS

TRAPS H/O thrombosis (VAM) plus Triple + Rivaroxaban vs warfarin 19% vs 3%

Events

ASTRO- APS H/O thrombosis ≥ 6 months on AC and APS Apixaban vs warfarin

Pengo et al. Blood 2008

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DOACs and Patients with a History of GI Bleeding• The incidence of major GI bleeding varies among the DOACS

• RE-LY Trial• Dabigatran 150 vs warfarin 1.51 vs 11,02%/year; p<0.001• Dabigatran 110 vs warfarin 1.12 vs 1.02 %/year; p = 0.43

• Rocket-AF• Rivaroxaban vs warfarin 3.61 events /100 pt-yrs vs 2.60 events/pt-yrs

• ARISTOTLE • Apixaban vs warfarin no difference

• ENGAGE-TIMI-AF 48• Edoxaban 60 vs warfarin 1.51% va 1.23%; p = 0.03• Edoxaban 30 vs warfarin 0.82% p < 0.001

Czuprynska et al. BJH. 2017

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Cancer Associated Venous ThrombosisDOAC vs dalteparin

RVTE %

Death (%)

Hokusai VTE Cancer(edoxaban)

Select-D VTE Cancerrivaroxaban

Pts

E 522

D 524

R 203

D 203

Duration

12 months

6 months

Major Bleeding%

6.9

4.0

6

4

7.9

11.3

4

11

39.5

36.6

25

30

Raskob et al. NEJM 2018Young et al. JCO 2019

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DOACs to Prevent Cancer Associated Venous ThrombosisRandomized DOAC vs Placebo

AVERT Apixaban 2.5 4.2% vs 10.2% 0.41 (CI 0.26 – 0.65); P<0.001

Cassini Rivaroxaban 10 6.0% vs 8.8% 0.66 (CI 0.40 – 1.09); P<0.1

Major bleeding 3.5% vs 1.8%; p = 0.046

Major bleeding 4.7% vs 3.0%; p = 0.24

• apixaban – less VTE, more bleeding

• rivaroxaban – no change in VTE, more bleeding

Khorana et al. NEJM. 2019Carrier et al. NEJM. 2019

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Heparin-induced Thrombocytopenia and Thrombosis

• 56 patients treated with DOACs and LAC

• Patients received • upfront DOAC, • after lead in AC• After platelet recovery

• 36 rivaroxaban; 12 apixaban, 11 dabigatran• 0 bleeds, 1 thrombotic event

Warkentin et a;l. Blood 2017

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Barlow egt al. Pharmacotherapy 2019Cuker et al Blood Advances 2018Ng Thromb Res 2015

American Society of Hematology 2018 Guidelines for HIT

• DOACs (apixaban, dabigatran, rivaroxaban) conditional recommendation

• Stable patients without life or limb threatening VTE

• Patients with HIT characterized by platelet recovery

• Based on small case series and indirect evidence of less bleeding and similar efficacy to warfarin in VTE patients

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American Society of Hematology HIT Guidelines

DOAC Pharmacokinetics

• Dabigatran• T1/2 CrCl > 50; 12-18 hours• T1/2 CrCl 30-50; 13-23 hours

• Rivaroxaban• T1/2 CrCl > 50; 7-10 hours• T1/2 CrCl 30-50; 9-13 hours

• Apixaban• T1/2 CrCl > 50; 7-10 hours• T1/2 CrCl 30-50; 9-13 hours

• Edoxaban• T1/2 CrCl > 50; 12-18 hours• Dosed reduced CrCl 30-50

Tafur et al et al Heart 2018

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DOACS in Renal Impairment and Dialysis

Moll et al. The Hematologist 2017

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DOACS in Renal Impairment and Dialysis

Moll et al. The Hematologist 2017Mavrakanas et al. J Am Soc Nephrol. 2017

• Patients on HD received 2.5 mg of apixaban

• AUC increased 2 -5.4 times between day 2 and day 8; p<0.001

• AUC was similar to 5mg dose in patients with preserved renal function

• Cmin and Cmax increased significantly

• Only 4% of drug removed during HD

• No significant data with other DOACs

Perioperative AC Use for Surgery Evaluation (PAUSE) Study

Presumes• A standardized protocol would be both easier and safe

• Obviates the need for heparin bridging and preoperative coagulation testing

• A low rate of major bleeding (1%) and arterial thrombosis (0.5%)

• >90% of patients will have minimal or non-detectable DOAC levels at surgery

Douketis et al ASH 201810/21/19 39

Patient Recruitment

N = 1082rivaroxaban cohort

3,640 patients screened

663 (17.4%) excluded

N = 1257apixaban cohort

N = 668dabigatran cohort

Mean age 72.533% HBR

Perioperative AC Use for Surgery Evaluation (PAUSE) Study

Eligibility• DOACs a sustained time• Creatinine Clearance >30 mL/min (apixaban >25)• Bleeding and thrombotic risk assessment by surgery

• Aim: Establish Safe standardized protocol for the perioperative management of patients with AF who are DOACs

• Design: Multi-center prospective observational cohort

• Patients: N=3300 with AF (1100/DOAC)

10/21/19 40Douketis et al ASH 2018

Perioperative AC Use for Surgery Evaluation (PAUSE) Study

RivaroxabanApixaban

Dabigatran

Bleeding risk LOW HIGH

STOP Id BEFORE STOP 2d BEFORE

LOW HIGH

CrCl ≥ 50<50≥ 50 <50

STOP Id BEFORE STOP 2d BEFORE STOP 4d BEFOREDouketis et al ASH 201810/21/19 41

PAUSE STUDY RESULTS

• Major Bleeding: apixaban 1.35%, dabigatran 0.9%, rivaroxaban 1.85%

• Arterial thromboembolism: apixaban 0.16%, dabigatran 0.6%, rivaroxaban 0.37%

• DOAC < 50ng/ml: apixaban 90.5%, dabigatran 96.8%, rivaroxaban 98.8%

• Standardized approach was safe and effective:• High bleeding risk: hold for 48h before; restart 48h after• Low bleeding risk: hold for 24h before; restart 24h after

• Bridging not needed

10/21/19 42Douketis et al ASH 2018

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Idarucizumab: specific reversal agent for dabigatran

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Idarucizumab: specific reversal agent for dabigatran

Glund S et al. AHA 2013

Healthy volunteer study: immediate, dose-dependent reversal of dabigatran anticoagulation

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Clinical Outcomes

Group A

3 of 51 patients died from bleeding within 30 days

Group BNormal intraoperative hemostasis: 33

Mildly abnormal hemostasis: 2

Moderately abnormal hemostasis: 1

No evidence of prothrombotic or immunologic effect

Pollock et al. NEJM 2015

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Andexanet: (FXa Decoy)Siegal et al. NEJM 2015

Binds and sequesters the factor Xa inhibitors,

rivaroxaban and apixaban

Binds and inhibits the activity of Tissue

Factor Pathway Inhibitor (TFPI) leading to

increased tissue factor-initiated thrombin

generation

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Mechanism of Action of Prothrombin Complex Concentrates

Brinkman InTechOpen 2016

Reversal Agent OutcomesReversal Agent ANNEXA-4

Andexxa®Schulman et al. PCCs RE-VERSE AD

Praxbind®UPRATE

PCCs

Oral anticoagulant RivaroxabanApixaban

RivaroxabanApixaban

Dabigatran(Group A)

RivaroxabanApixaban

Study design Prospective, open-labelProspective,

observationalProspective, open-label

Prospective,

observational

Efficacy Population (N) 254 66 301 84

Age in years 77 (mean) 77 (mean) 79 (median) 75 (median)

Intracranial bleeding 67% 55% 33% 70%

Gastrointestinal bleeding 24% 24% 46% 16%

Ineffective hemostasis 18%* 32% 22% 31%

Safety Population (N) 352 66 301 84

Death 14% 14% 14% 32%

Thrombotic event 10% 8% 5% 4%

48*5 patients not included in analysis of hemostatic efficacy for administrative reasons.

NEJM 2019; 380(14): 1326-35.

Thromb Haemost 2018; 118(05): 842-51.

Blood 2017; 130(5): 1706-12.

NEJM 2017; 377(5): 431-41.

Direct Cost ComparisonReversal Agent Regimen Drug Cost per Unit Cost per Treatment*

Andexxa®Low Dose

$2750/100 mg$24,750

High Dose $49,500

Kcentra® 50 units/kg $1.60/unit $6400

FEIBA NF® 50 units/kg $1.70/unit $6800

Reimbursement Program for Andexxa®• New Technology Add-On Payment (NTAP)

reimbursement

*For 80 kg patient with INR > 6Cost Reflective As Of: 6/2019 Source: HC Pharmacy

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Summary

• DOACs have differing biological properties

• In general appear to be similar to warfarin and LMWH in efficacy and less bleeding

• Rivaroxaban + aspirin has benefit for CAD and PAD

• My be ineffective or hazardous among special populations• Renal impairment, dialysis, APLS, Cancer patients

• Bleeding may be effectively reversed with specific antidotes, 4 factor PCCs, or by removal