updates in oral anticoagulation: an€¦ · updates in oral anticoagulation: an evidence ‐based...

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Updates in Oral Anticoagulation: An Evidence‐Based Review

Mona A. Ali, Pharm.D., BCPS

Jenna M. Holzhausen, Pharm.D., BCPS

Disclosure Statement

The presenters have no actual or potential conflict of interest in relation to this

presentation.

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Objectives

• Describe pharmacokinetic and pharmacodynamiccharacteristics of the direct oral anticoagulants (DOACs)

• Evaluate the available literature regarding DOAC use in special populations

• Discuss treatment options for the management of DOAC reversal

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Available Oral Anticoagulants

Fibrinogen

Factor II(Prothrombin)

Fibrin

Factor IIa(Thrombin)

Factor X

Factor IX Factor VII

Anti‐Xa drugs• Apixaban• Edoxaban• Rivaroxaban• Betrixaban

Anti‐IIa drug• Dabigatran

Factor Xa

VKA drug• Warfarin

FVIIa

FIXa

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Warfarin

Pros

• Effective

• Inexpensive

• Prescriber familiarity

• Wide range of indications

• Long term safety established

• Ability to measure coagulation intensity

• Antidote

Cons

• Slow onset

• Individualized dosing

• Narrow therapeutic range

• Frequent INR monitoring

• Drug interactions

• Dietary interactions

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Consistent Nomenclature

• What should we call the “novel” agents?• NOACs – New/Novel/Non‐VKA Oral Anticoagulants

• TSOACs – Target‐Specific Oral Anticoagulants

• DOACs – Direct‐Acting Oral Anticoagulants

Barnes GD, et al. J Thromb Haemost. 2015;13:1154‐1156.

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Currently Available DOACsDabigatran (Pradaxa®)

Rivaroxaban (Xarelto®)

Apixaban(Eliquis®)

Edoxaban(Savaysa®)

Betrixaban(Bevyxxa®)

Mechanism of Action

Direct thrombin inhibitor (DTI)

Factor Xa Inhibitor Factor Xa Inhibitor Factor Xa Inhibitor Factor Xa Inhibitor

FDA‐Approved Indications

• Nonvalvular AF• DVT/PE• Postoperative

VTE Prophylaxis


VTE Prophylaxis


VTE Prophylaxis

• Nonvalvular AF• DVT/PE

• Postoperative VTE Prophylaxis

Absorption P‐glycoprotein mediated

Bioavailability 3 – 7% ~66% without food80‐100% with food

~50% 62% 34%; influenced by food

Peak Onset 1 – 2 hours 2 – 4 hours 3 – 4 hours 1 – 2 hours 3 – 4 hours

Half‐Life 12 – 17 hours 5 – 9 hours 8 – 15 hours 10 – 14 hours 19 – 27 hours

Metabolism Plasma and hepatic esterases

CYP3A4/5, CYP2J2 CYP3A4/5, other CYP enzymes

CYP3A4 Minimal viahydrolysis

Renal Excretion 80% 66%36% unchanged

27% 50% 11%

Dialyzable Yes No No No No

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Product Package Inserts

DOAC Dosing for Atrial FibrillationDabigatran (Pradaxa®)


Apixaban(Eliquis®)

Edoxaban(Savaysa®)

Dose 150 mg BID20 mg daily with evening meal

5 mg BID 60 mg daily

Adjustments for Renal Dysfunction

CrCl 15 ‐ 30 ml/min: 75 mg BID

CrCl < 15 ml/min: Notrecommended

CrCl 15 – 49 ml/min: 15 mg daily with evening meal

CrCl < 15 ml/min: Not recommended

2.5 mg BID if any two of the following:• Age ≥ 80 yrs• Weight ≤ 60 kg• SCr ≥ 1.5 mg/dL

CrCl 15 – 50 ml/min: 30 mg daily


Trial CrClExclusion

CrCl < 30 ml/min CrCl < 30 ml/min CrCl < 25 ml/min CrCl < 30 ml/min

End‐Stage Renal Disease

Not recommended Not recommended

5 mg BID

2.5 mg BID if:• Age ≥ 80 yrs or • Weight ≤ 60 kg

Not recommended

Upper CrClLimit

None None NoneContraindicated with CrCl > 95 ml/min

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DOAC Dosing for VTE TreatmentDabigatran (Pradaxa®)


Apixaban(Eliquis®)

Edoxaban(Savaysa®)

Mono‐Therapy?

Preceded by 5 – 10 days parenteral therapy

Yes YesPreceded by 5 ‐ 10 days parenteral therapy

Dose

150 mg BID

Extended tx: 150 mg BID

15 mg BID x 21 days, then 20 mg daily

Extended tx: 20 mg daily

10 mg BID x 7 days, then 5 mg BID

Extended tx: 2.5 mg BID

60 mg daily*

Extended tx: 60 mg daily

DoseAdjustments for Renal Dysfunction

None None None

CrCl 15 – 50 ml/min: 30 mg daily


Trial CrClExclusion

CrCl < 30 ml/min CrCl < 30 ml/min CrCl < 25 ml/min CrCl < 30 ml/min

Upper CrClLimit

None None None None

*Reduce edoxaban to 30 mg daily if weight ≤ 60 kg

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Ideal DOAC Candidates

Good AdherencePoor INR Control on Warfarin (TTR < 60) or INR Monitoring

Inconvenient

Stable Renal and Hepatic Function

Accepting of DOAC Cost

DOAC

Candidate

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Patients in Whom DOACs Should be Avoided or Are Not Well‐StudiedAVOID DOACs

• Mechanical Heart Valves

• Following Acute Coronary Syndrome

• Interacting Medications

• Non‐Bleeding Adverse Events• Allergy

• Rash

• Dyspepsia

• Pregnancy / Breastfeeding• Category C, except apixaban (B)

• Children (no data)

DOACs Not Well‐Studied

• Valvular Atrial Fibrillation

• Hypercoagulable States

• Cancer‐Associated VTE

• Left‐Ventricular Thrombus

• Heparin‐Induced Thrombocytopenia (HIT)

• Triple Antithrombotic Therapy

• Elderly

• End‐Stage Renal Disease (ESRD)

• Extremes of Body Weight

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DOAC USE: END‐STAGE RENAL DISEASE

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5

Effect of Renal Function on DOAC Clearance

Creatinine Clearance(ml/min)

Dabigatran Half‐Life

Rivaroxaban Half‐Life

ApixabanHalf‐Life

EdoxabanHalf‐Life

> 80 13.8 hours 8.3 hours 15.1 hours 8.6 hours

50 – 80 16.6 hours 8.7 hours 14.6 hours Not reported

30 – 49 18.7 hours 9.0 hours 17.6 hours 9.4 hours

< 30 27.5 hours 9.5 hours 17.3 hours 16.9 hours

Kaatz S, et al. Am J Hematol. 2012;87:s141‐145.Ridout G, et al. J Clin Pharmacol. 2009;49:1124 (abstract 144).

Stangler J, et al. Clin Pharmacokinetics. 2010;49:259‐268.

Minimal increase

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Pharmacokinetic Data in ESRD Patients on Hemodialysis

Apixaban Dabigatran Edoxaban Rivaroxaban

Number of Patients 8 6 6 8

Dose 5 mg 50 mg 15 mg 15 mg

Given Prior to HD*AUCCmax

↑ 17%↓ 21%

↓ 32%↓84%

‐‐‐‐‐‐‐‐‐‐

↑ 47%↓ 9%

Given After HD*AUCCmax

↑ 36%↓ 10%

‐‐‐‐‐‐‐‐‐‐

‐‐‐‐‐‐‐‐‐‐

↑ 56%↑ 18%

Exposure Reduction Post‐Hemodialysis

14% 62 – 68% 8.7% 5%

Half‐Life ~12.5 hours 34.1 hours ~10.5 hours 12.2‐13.2 hours

Dias C, et al. Am J Nephrol. 2016;43:229‐236.Stangler J, et al. Clin Pharmacokinetics. 2010;49:259‐268.

Wang X, et al. J Clin Pharmacol. 2016; 56(5):628‐636.

*Compared to healthy subjects

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Apixaban vs. Warfarin in Patients with Severe Renal Impairment

• Single‐center

• Retrospective

• Matched cohort

Study Design

• Adults receiving ≥1 dose of apixaban or warfarin

• CrCl < 25 ml/min, SCr > 2.5 mg/ml, or HD/CAPD

Inclusion Criteria

• Inability to assess dose or renal function

• Continuous renal replacement therapy

Exclusion Criteria

• N = 73 in each group

• Mean age: 79 yrs

• Mean weight: 82 kg

Renal function stratification

• Severe renal impairment: 63%

• ESRD: 9.6%

• ESRD on dialysis: 27.4%

Anticoagulation indication

• Atrial fibrillation: 72.6%

• VTE: 26%

• Thromboprophylaxis: 1.4%

Stanton BE, et al. Pharmacotherapy. 2017;37(4):412‐419.

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Study Outcomes

9.6%

11.0%

1.4%

21.9%

7.5%

17.8%

8.2%

2.7%

27.4%

7.5%

0.0%

5.0%

10.0%

15.0%

20.0%

25.0%

30.0%

Major Bleed ClinicallyRelevant Bleed

Minor Bleed CompositeBleed Events

Stroke in NVAF

Occurrence of Clinical Outcomes

Apixaban Warfarin

• Screened for bleeding at least 5 months post‐discharge

• No statistically significant differences

• Major bleeds mainly gastrointestinal

• No recurrent VTE events in either group

Stanton BE, et al. Pharmacotherapy. 2017;37(4):412‐419.

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Apixaban Pharmacokinetics at Steady State in Hemodialysis Patients

Day 1: Start apixaban2.5 mg BID

Day 8

Parameter*Day 8

(2.5 mg BID)Day 22

(5 mg BID)p‐value Reference Level

AUC0‐24, ng h/ml 2019.7 (30.7%) 6053.2 (46.6%) 0.03 3370 (2070‐5250)

Cmax, ng/ml 131.5 (31.1%) 307.0 (39.4%) 0.02 171 (91‐321)

Cmin, ng/ml 58.0 (31.2%) 217.5 (51.9%) 0.03 107 (56‐203)

Day 9: Last apixaban

dose4 hours HD

Days 10‐14: Washout period

Day 15: Start apixaban 5 mg BID

Day 22(last day)

Days 1 – 8 on Apixaban 2.5 mg BID:• Mean AUC24 increased 3.4 fold• Mean Cmax increased 2.9 fold• Mean Cmin increased 2.6 fold

p < 0.001 for all

Note: Day 8 values similar to those in patients without advanced CKD

Mavrakanas TA, et al. J Am Soc Nephrol. 2017;28:2241‐2248.

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*Reported as mean (coefficient of variation)

ESRD Conclusions

• Apixaban is the only FDA‐approved DOAC for use in patients with ESRD

• My opinion: It’s too early to say apixaban is safe and effective in ESRD

• Recommend utilizing warfarin in this population until prospective, long‐term data is available

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DOAC USE: EXTREMES OF BODYWEIGHT

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Extremes of Body Weight in DOAC Trials

Trial Indication Dosing Total N BW ≤ 60 kg BW > 100 kg

DabigatranRECOVER I/IIRE‐LY

VTEAF

150 BID150/110 BID

510718113

57376 (< 50kg)

8323099

RivaroxabanEINSTEIN‐DVT/PEROCKET‐AF

VTEAF

15 BID x 21d, 20 QD20 QD

828114262

167341

13931017

ApixabanAMPLIFYARISTOTLE

VTEAF

10 BID x 7d, 5 BID5 BID

539518201

4571985

1017N.R

EdoxabanHOKUSAIENGAGE‐AF

VTEAF

60 QD60/30 QD

824021105

10432071

1265N.R.

Boonyawat K, et al. J Thromb Haemost. 2017;15:1322‐1333.

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Meta‐Analyses of Phase III Trials

Event Body Weight

DOAC Events (%)

VKA Events (%)

Risk Ratio [95% CI] p‐Value

Recurrent VTE or VTE‐Related Death

Low 2.6% 3.1% 0.84 [0.57 – 1.24] 0.38

Normal 2.4% 2.6% 0.91 [0.75 – 1.09] 0.30

High 2.7% 2.8% 0.98 [0.72 – 1.35] 0.92

Major or CRNMB

Low 8.4% 10.1% 0.80 [0.54 – 1.20] 0.29

Normal 6.5% 7.9% 0.82 [0.67 – 1.00] 0.05

High 6.7% 7.1% 0.93 [0.65 – 1.32] 0.67

• Meta‐analysis of all phase III trials revealed

• Increased risk of thromboembolic events in low body weight group

• Comparable bleeding outcomes between groups

• Results of meta‐analysis of phase III VTE trials:

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CRNMB = Clinically relevant non‐major bleedingDi Minno, et al. Ann Med. 2015;47:61‐68.

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Existing PK/PD Data with DOACs

Type of Data Drug Intervention Weight Categories

Single‐Dose Studies

RivaroxabanSingle 10 mg dose of rivaroxaban or placebo

1. ≤ 50 kg2. 70 to 80 kg3. >120 kg

ApixabanSingle 10 mg dose of apixaban

1. ≤ 50 kg2. 65 to 85 kg3. ≥ 120 kg

SubgroupAnalysis

DabigatranDabigatran 110 or 150 mg twice daily

1. < 50 kg2. 50 to < 100 kg3. > 100 kg

Kubitza D, et al. J Clin Pharmacol. 2007;47:218‐226.Reilly PA, et al. J Am Coll Cardiol. 2014;63:321‐328.

Upreti VV, et al. Br J Pharmacol. 2013;76(6):908‐916.

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Effect of Extremes of Body Weight on Rivaroxaban

Subject Demographics

Parameter*

Placebo (n = 12)

Rivaroxaban 10 mg

≤ 50 kg(n = 12)

70 – 80 kg(n = 12)

> 120 kg(n = 12)

Age, yrMeanRange

34.320 – 50

35.322 – 46

32.320 – 54

37.1 22 – 47

Male, n (%) 4 (33) 0 (0) 6 (50) 6 (50)

Weight, kg 81.7 ±34.4

48.3 ± 0.9 74.0 ± 2.2 132.2 ± 9.9

BMI, kg/m2 28.5 ±10.4

19.3 ± 1.1 24.3 ± 2.3 43.5 ±4.2

• Single‐blind, randomized, placebo‐controlled, parallel group

•Compared subjects with extremes of body weight

Study Design

•Rivaroxaban 10 mg or placebo x 1 dose

•Blood and urine samples for 48 hours

Intervention

•Pharmacokinetic and pharmacodynamicparameters stratified by bodyweight

Outcomes

Kubitza D, et al. J Clin Pharmacol. 2007;47:218‐226.

*Weight and BMI reported as mean ± SD

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Rivaroxaban Results

• AUC and Factor Xa inhibition similar between weight groups

• Cmax increased 24% in the low body weight group (p = 0.04)

• No difference in Cmax observed with high body weight compared to 70 –80 kg group

Parameter* ≤ 50 kg (n = 12)

> 120 kg (n = 12)

AUC 1.14 (0.98‐1.30) 1.12 (0.98‐1.28)

Cmax 1.24 (1.07‐1.44) 1.04 (0.90‐1.20)

*LS‐Means Ratio versus the 70 to 80 kg group (90% confidence interval)

Author’s Conclusion: It is thought unlikely dose adjustments of rivaroxaban will be necessary for subjects with extreme body weight.


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Effect of Extremes of Body Weight on Apixaban

Subject Demographics

Parameter

Apixaban 10 mg

≤ 50 kg(n = 18)

65 – 85 kg(n = 18)

> 120 kg(n = 19)

Age, yrMean ± SDRange

23 ± 418 ‐ 31

28 ± 718 ‐ 43

29 ± 819 ‐ 41

Male, n (%) 2 (11) 8 (44) 16 (84)

Weight, kgMean ± SDRange

47 ± 3.638 – 50

75 ± 5.567 – 84

137 ± 18.3120 ‐ 175

BMI, kg/m2

Mean ± SDRange

18.8 ± 217 ‐ 22

26.3 ± 222 ‐ 30

42.6 ± 632 ‐ 54

•Open label, parallel group, two center trial

• Compared subjects with extremes of body weight

Study Design

•Apixaban 10 mg x 1 dose after overnight fast

•Blood and urine samples for 72 hour

Intervention

•Pharmacokinetic and pharmacodynamics parameters stratified by bodyweight

Outcomes


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Apixaban Results

• Inverse relationship between apixaban exposure and body weight (p < 0.001 for Cmax and AUC)

• Similar relationship between Cmax and AUC and BMI

Parameter* ≤ 50 kg (n = 18)

> 120 kg (n = 19)

AUC (ng mL‐1 h) 1.198 (1.011‐1.419) 0.771 (0.652‐0.912)

Cmax (ng mL‐1) 1.272 (1.075‐1.506) 0.692 (0.586‐0.818)

Upreti VV, et al. Br J Pharmacol. 2013;76(6):908‐916.

*Geometric Mean Ratio versus the 65 – 85 kg group (90% confidence interval)

Author’s Conclusion: The modest change in apixaban exposure is unlikely to require dose adjustment based on body weight

alone.

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Dabigatran PK in RE‐LY Trial Patients

• Inverse relationship between concentration and weight

• 21% higher concentration for low BW group

• 21% lower concentration for high BW group

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Reilly PA, et al. J Am Coll Cardiol. 2014;63:321‐328.

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ISTH Guidance Statement

• Recommend appropriate standard dosing of DOACs in patients with BMI ≤ 40 kg/m2 and weight ≤ 120 kg

• Suggest DOACs should NOT be used in patients with BMI > 40 kg/m2 or weight > 120 kg• Limited clinical data available

• PK/PD evidence suggests:• Decreased drug exposures

• Reduced peak concentrations

• Shorter half‐lives

• If used in obese patients, suggest checking peak/trough level• If below expected range, suggest changing to VKA rather than adjusting DOAC dose

Martin K, et al. J Thromb Haemost. 2016;14(6):1308‐1313.

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Anticoagulation Forum Guidance Statement

• Suggest avoiding DOACs for VTE in patients at extremes of weight (e.g., < 50 kg, > 120 kg or BMI ≥ 35 kg/m2)

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Burnett AE, et al. J Thromb Thrombolysis. 2016;41:206‐232.

Extremes of Body Weight Conclusions

• Limit DOAC use in patients < 50 kg or > 120 kg to those who cannot tolerate warfarin

• Increased DOAC exposure in low body weight patients

• Potential for decreased exposure in obese patients

• Proposed management:• < 50 kg: Avoid DOAC use

• 50 kg – 120 kg: DOAC use appropriate

• 121 kg – 150 kg: Limited evidence; may consider DOAC

• > 150 kg: Avoid DOAC unless warfarin not an option

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DOACS FOR THE TREATMENT OF CANCER‐ASSOCIATED VTE

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Epidemiology of Cancer‐Associated VTE

• Cancer increases risk of developing VTE four‐ to seven‐fold

• VTE is associated with high mortality• 2nd leading cause of death in cancer patients

• During anticoagulation, patients with cancer‐associated VTE are at increased risk for:

• VTE recurrence

• Bleeding complications

• Once anticoagulation is withdrawn, risk of VTE recurrence is ≥ 15% per year

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Prandoni P, et al. Blood. 2002;100(10):3484 – 3488.Timp JF, et al. Blood. 2013;122:1712‐1723.

Verso M, et al. Intern Emerg Med. 2015;10:651‐656.

Risk Factors for Cancer‐Associated VTE

Patient‐Related

• Age

• Race

• VTE history

• Obesity

• Platelet count

• Comorbid conditions

Treatment‐Related

• Surgery

• Hospitalization

• Catheters

• Choice of therapy• Chemotherapy

• Hormonal therapy

• Antiangiogenic agents

• Erythropoiesis‐stimulating agent

Cancer‐Related

• Primary site

• Histology

• Stage

• Grade

• Time since diagnosis

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Eichinger S. Thromb Res. 2016;140 Suppl 1:S12‐17.

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Risk of VTE Based on Primary Site

Relative VTE Risk Range: 1.02 to 4.34

Stein PD, et al. Am J Med. 2006;119:60‐68.

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Guideline Recommendations Specific to Cancer‐Associated VTE

CHEST

• LMWH recommended over VKA (Grade 2B) or any DOAC (Grade 2C) for the first 3 months

• Extended anticoagulant therapy (no stop date) is recommended for patients with low‐moderate (Grade 1B) or high (Grade 2B) bleed risk

• In patients not treated with LMWH, no preference stated for VKA vs. DOAC

ASCO

• LMWH recommended for first 5 – 10 days of treatment as well as for long‐term secondary prophylaxis for at least 6 months

• Use of DOACs not recommended for patients with malignancy and VTE due to lack of evidence

NCCN

• LMWH preferred for the first 6 months as monotherapy

• For non‐catheter associated VTE, recommend indefinite anticoagulation while cancer is active, under treatment, or if risk factors for recurrence persist

• For patients who refuse LMWH, a DOAC is an acceptable alternative for management of VTE

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Kearon C, et al. CHEST. 2016;149(2):315‐352. Lyman GH, et al. J Clin Oncol. 2015;33:654‐656.Streiff M, et al. NCCN Guidelines for Cancer‐Associated Venous Thromboembolic Disease (VTE) V.1.2017. NCCN.org.

Evidence Supporting LMWH

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65.6

6.6 6.9

2.8

15.8

109.1

10 10

4

0

2

4

6

8

10

12

14

16

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CLOT LITE Romera ONCENOX CATCH CANTHANOX

Risk of Recurrent VTE with LMWH vs. VKA

LMWH VKA

Outcome RR (95% CI) and p‐value

Recurrent VTE 0.60 (0.45 – 0.79)

p < 0.001

Major Bleed 1.07 (0.66 – 1.73)

p = 0.80

Posch F, et al. Thromb Res. 2015;136:582‐589.

Meta‐Analysis Results

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Recurrent V

TE (%)

13

Practical Issues With LMWH Use

Drug cost

Parenteral administration

Dosing frequency

Lack of long‐term efficacy and safety data

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Why Consider DOACs?

Compared to LMWH

• Ease of administration

• Less expensive

Compared to Warfarin

• No routine laboratory monitoring required

• Fewer drug‐drug and drug‐food interactions

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Active Cancer in DOAC Trials

DOAC Trial Indication DOAC Dosing Treatment Duration (Months)

Total N Active Cancer, n (%)

DabigatranRECOVER IRECOVER II

VTEVTE

150 BID150 BID

66

25392589

121 (4.8)100 (3.9)

RivaroxabanEINSTEIN‐DVTEINSTEIN‐PE

DVTPE

15 BID x 21d, 20 QD15 BID x 21d, 20 QD

3, 6, 123, 6, 12

34494832

207 (6.0)223 (4.6)

ApixabanAMPLIFY VTE 10 BID x 7d, 5 BID 6 5395 169 (3.1)

EdoxabanHOKUSAI VTE 60 QD 3 ‐ 12 8240 208 (2.5)

Vedovati MC, et al. CHEST. 2015;147(2):475‐483.Verso, et al. Intern Emerg Med. 2015;10:651‐656.

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VTE Recurrence in Patients with Cancer: DOAC vs. VKA

AMPLIFY

EINSTEIN‐DVT

EINSTEIN‐PE

HOKUSAI

RECOVER I & II

Favors DOAC Favors VKA

OR (95% CI): 0.63 (0.37 – 1.10)

p = 0.10

Vedovati MC, et al. CHEST. 2015;147(2):475‐483.

N = 1132Event rate: 3.9% (DOAC) vs. 6% (VKA)

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Major and Clinically Relevant Bleeding in Patients with Cancer‐Associated VTE

Major Bleeding Clinically Relevant Bleeding

Favors DOAC Favors VKA Favors DOAC Favors VKA

AMPLIFY EINSTEIN‐DVT/PE HOKUSAIRECOVER I & II

AMPLIFY EINSTEIN‐DVTEINSTEIN‐PE HOKUSAIRECOVER I & II

N = 1114Event rate: 3.2% (DOAC) vs. 4.2% (VKA)OR (95% CI): 0.77 (0.41 – 1.44); p = 0.42

N = 1114Event rate: 14.5% (DOAC) vs. 16.5% (VKA)OR (95% CI): 0.85 (0.62 – 1.18); p = 0.34

Vedovati MC, et al. CHEST. 2015;147(2):475‐483.

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DOAC vs. LMWH?

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Posch F, et al. Thromb Res. 2015;136:582‐589.

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Definition of Active Cancer

Trial DOAC Active Cancer Definition

RECOVER I/II Dabigatran Diagnosis of or any treatment for cancerwithin the last five years

EINSTEIN‐DVT/PE Rivaroxaban Cancer that was diagnosed or treated within the 6 months prior to enrollment or recurrent or metastatic cancer

AMPLIFY Apixaban Cancer that was diagnosed or treated within the 6 months prior to enrollment

HOKUSAI Edoxaban Physician discretion at time of enrollment

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Büller HR, et al. N Engl J Med. 2012;366(14):1287‐97. Schulman S, et al. N Engl J Med. 2009;361(24):2342‐52.Agnelli G, et al. N Engl J Med. 2013;369(9):799‐808. Büller HR, et al. N Engl J Med. 2013;369(15):1406‐15.

Efficacy and Safety of Rivaroxaban in Patients with VTE and Active Malignancy

Type of Cancer n (%)

Genitourinary 28 (23.6)

Gastrointestinal 24 (20.3)

Lung 16 (13.5)

Hematologic/Myeloma 12 (10.1)

Breast 11 (9.3)

Pancreatic 10 (8.4)

Renal 8 (6.7

Sarcoma 2 (1.6)

Brain 2 (1.6)

Other* 5 (4.2)

Bott‐Kitslaar DM, et al. Am J Med. 2016;129(6):615‐619.

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• Single center prospective follow‐up study

• n = 296 patients prescribed rivaroxaban for treatment of VTE

*Includes thyroid, oral, metastatic melanoma, and uncertain primary site

Variable Cancer (n = 118)

No Cancer(n = 178)

p‐Value

VTE recurrence, n(%) 4 (3.3)* 5 (2.8) 0.53

Major Bleed, n(%) 3 (2.5) 0 (0.0) 0.06

NMCRB, n(%) 4 (3.4) 1 (0.6) 0.08

Major and NMCRB, n(%) 7 (5.9) 1 (0.6) 0.008

Minor Bleed, n(%) 3 (2.5) 3 (1.7) 0.69

Death, n(%) 37 (31) 0 (0.0) < 0.0001

*Includes two events that occurred during anticoagulation interruption for an invasive procedure

Patients With and Without Cancer: 3 Month Outcomes

Safe and Effective Use of Rivaroxaban for Treatment of Cancer‐Associated Thromboembolic Disease

New or recurrent VTE, major bleeding, CRNMB leading to rivaroxaban d/c, or

death

Age < 75: Rivaroxaban 15 mg BID x 3 wk, then 20 mg daily.

Age ≥ 75 or PLT 25,000 to 50,000/mcL: Rivaroxaban 10 mg BID x 3 wk, then 15

mg daily

200 patient cohort with cancer‐associated VTE treated with rivaroxaban

Endpoint Mantha, et al Cohort (n=200)

EINSTEIN Cancer Subgroup (n=354)

VTE 4.4% 4.5%

Major Bleed 2.2% 2.3%

CRNMB 3.8% 13.6%

Death 17.6% 7.1%

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Mantha S, et al. J Thromb Thrombolysis. 2017;43:166‐171.Prins MH, et al. Lancet Haematol. 2014;1:e37‐46.

6 month follow‐up

Type of Cancer n (%)

Pancreas 34 (17)

Gynecological 26 (13)

Lung 23 (11.5)

Breast 22 (11)

Genitourinary 21 (10.5)

Colorectal 18 (9)

Hematological 17 (8.5)

Stomach/Esophagus 6 (3)

Other 33 (16.5)

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Limitations to Use of DOACs for Cancer‐Associated VTE

Lack of efficacy / safety data in this population compared to standard of care

Unreliable administration and absorption in patients with nausea/vomiting, diarrhea, and mucosal erosion

Renal and hepatic impairment are common

Lack of experience managing procedures and thrombocytopenia

Potential drug‐drug interactions

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Drug Interaction Concerns

CYP3A4 / P‐glycoprotein INDUCERS CYP3A4 / P‐glycoprotein INHIBITORS

Carbamazepine

Dexamethasone

Doxorubicin

Phenobarbital

Phenytoin

Rifampin

St. John’s Wort

Vinblastine

AmiodaroneClarithromycin

DiltiazemFluconazoleRitonavirTacrolimusTamoxifen

TKIsVerapamil

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Ongoing DOAC Cancer TrialsTrial Title

CALLISTO Cancer Associated Thrombosis – Exploring Solutions for Patients Through Treatment and Prevention with Rivaroxaban

CANVAS Direct Oral Anticoagulants Versus LMWH +/‐Warfarin for VTE in Cancer

CAP Apixaban as Treatment of Venous Thrombosis in Patients With Cancer

CASTA‐DIVA Cancer Associated Thrombosis, a Pilot Treatment Study Using Rivaroxaban

Catheter 2 Study in Cancer Patients with Central Line Associated Clots in the Upper Extremity Treated with Rivaroxaban

CONKO‐011 Rivaroxaban in the Treatment of VTE in Cancer Patients – A Randomized Phase III Study

COSIMO A Non‐Interventional Study on Xarelto for Treatment of VTE and Prevenetion of Recurrent VTE in Patients with Active Cancer

Hokusai‐VTECancer

Edoxaban for Treatment of Venous Thromboembolism in Patients with Cancer

NCT02583191 Rivaroxaban in the Treatment of VTE in Cancer Patients

NCT02585713 Apixaban or Dalteparin in Reducing Blood Clots in Patients with Cancer Related VTE

PRIORITY A Randomised Phase II Study to Compare the Safety and Efficacy of Dalteparin vs. Rivaroxaban for Cancer‐Associated VTE

SELECT‐D Anticoagulation Therapy in SELECTeD Cancer Patients at Risk of Recurrence of VTE

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17

DOACs for Cancer‐Associate Thrombosis Summary

• Recommend LMWH remain first‐line

• If LMWH not utilized, may consider DOACs

• Factors to consider:

• Active cancer vs. history of cancer

• Primary site of cancer

• Ability to eat consistently

• Drug‐drug interactions

• Awaiting results of ongoing studies to guide care

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DOAC USE IN THE SETTING OF HEPARIN‐INDUCED THROMBOCYTOPENIA (HIT)

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Heparin‐Induced Thrombocytopenia

• Immunologic reaction due to heparin‐platelet factor 4 (PF4) complexes

• Results in prothrombotic state

• Incidence 1 – 5% based on type of heparin product administered

• 4T Score predicts positive HIT antibody• Thrombocytopenia

• Timing of platelet count fall following heparin initiation

• Thrombosis

• oTher

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Lo GK, et al. J Thromb Haemost. 2006;4:759 – 765.Tran PN, et al. Clin Appl Thromb Hemost. 2017. [epub ahead of print].

18

Current HIT Management

Initial

• STOP heparin / LMWH product

• START one of the following:

• Argatroban

• Bivalirudin

• Fondaparinux

Long‐Term Management

• Warfarin

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Until platelet count > 150,000/mcL

Rationale Supporting DOAC Use

• DOACs have been proven NOT to interact with PF4 or reduce protein C natural anticoagulant activity

• Represent simplified management option

• Fixed dosing

• Rapid onset

• Minimal monitoring

• Decreased cost vs. parenteral therapy

• Majority of evidence: case reports and case series

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DOACs for Treatment of HIT: Update of Hamilton Experience and Literature Review

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• Observational study and literature review

• Probable HIT treated with DOAC

• Rivaroxaban (n = 53), apixaban (n = 15), dabigatran (n = 12)

Study Design

• 30‐day incidence of new symptomatic, objectively confirmed venous and arterial thromboembolism in patients with “acute HIT”

Primary Outcome

• Incidence of symptomatic thromboembolism, venous and arterial thromboembolism, major bleeding, and time to platelet recovery

Secondary Outcomes

Warkentin TE, et al. Blood. 2017;130(9):1104‐1113.

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55

First non‐heparin anticoagulant used to treat

acute HIT?

DOAC

Group A1 (n=25)

DOAC started when platelet count < 150

Group A2 (n=5)

Platelet count never < 150

Non‐DOAC

Group B (n=39)

DOAC started before platelet count > 150

Group C (n=11)

DOAC started after platelet count > 150

Warkentin TE, et al. Blood. 2017;130(9):1104‐1113.

Primary DOAC Treatment

Secondary DOAC Treatment

Acute HIT Subacute HIT

Treatment of Acute HIT Outcomes

Rivaroxaban (n = 46)

Apixaban (n = 12)

Dabigatran (n = 11)

Thromboembolism 1 (2.2%) 0 (0.0%) 1 (9.1%)

Major Bleed 0 (0.0%) 0 (0.0%) 0 (0.0%)

Remaining Questions with DOACs

Optimal dosing strategy

Safety / efficacy of individual agents compared to conventional therapy

Need for initial parenteral treatment course

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DOAC Use in the Setting of HIT Summary

• Limited evidence suggests DOACs may be safe and effective for treatment of HIT

•Choose agent based on patient‐ and drug‐specific factors

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Consider DOAC ‐ Clinically stable‐ Low – moderate bleed risk‐ No contraindications to DOAC

Parenteral Therapy Preferred ‐ Arterial thromboembolism‐ Critical illness‐ High bleed risk‐ Potential need for urgent procedures

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DOAC Use in Special Populations Summary

• The role of DOACs continues to expand

•Warfarin or LMWH may still be preferred for select populations

• Treatment selection should be based on patient, drug, and disease‐specific factors

•Prospective, randomized controlled trials are needed to help guide therapy

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REVERSAL OF DIRECT ORAL ANTICOAGULANTS

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Goal of Anticoagulation Reversal

•Provide greatest reduction in bleeding complications without increasing risk of thromboembolism

• Ideally reversal would be directed by institution specific guidelines

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21

Characteristics Dabigatran Rivaroxaban Apixaban Edoxaban Betrixaban

Drug target IIa Xa Xa Xa Xa

Peak effect (hr)

2 2‐4 1‐3 1‐2 3 – 4

Half‐life (hr) 12‐14 5‐9 Elderly 11‐13

8‐15 10‐14 19 ‐ 27

Renal Clearance (%)

80 36 27 50 11‐17.8

Proteinbinding (%)

35 92‐95 87 40‐59 60

Dialyzable Yes No No No unknown

Nutescu EA et al. Am J Health‐Syst Pharm. 2013;70:1914‐29.Chan NC et al. Vascuarlar Health and risk management 2015;11:343‐51.

Savaysa (edoxaban) Prescribing information. 2016 Parsippany, NJ: Daiichi Sankyo, Inc.

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Approaches to Reversal• Assess situation• Reversal indication and anticoagulant indication

• Status of patient

• Hold anticoagulant and determine level of anticoagulation • Time of last dose

• Laboratory assessment

• Administer supportive treatments and attempt local hemostasis • Volume replacement, blood transfusion

• Bleeding site control via mechanical compression or surgical intervention

• Administer reversal agents if indicated• Specific reversal agents are preferred (if available)

Shih et al. Hematology Am Soc Hematol Educ Program. 2016(1):612‐619.

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Level of Anticoagulation

• Time of last dose and regimen

• Patient specific factors affecting exposure

• Renal/hepatic function

• Age

• Interacting drugs

Property Dabigatran Rivaroxaban Apixaban Edoxaban

Renal clearance,%

80 36 27 50

Half‐life, hr• Young• Elderly

12‐14 5‐9 Elderly 11‐13

8‐15 10‐14

Half‐life, hr• Clcr> 80• Clcr 50‐79• Clcr 30‐49• Clcr < 30

14171928

89910

15151817

8‐9unknown9‐1017

Drug Interactions

P‐gP P‐gP,CYP3A4

P‐gp, CYP3A4

P‐gp

Nutescu EA et al. Am J Health‐Syst Pharm. 2013;70:1914‐29.Burnett AE et al. J Thromb Thrombolysis. 2016;41:206‐232.

Savaysa (edoxaban) Prescribing information. 2016 Parsippany, NJ: Daiichi Sankyo, Inc.

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22

Lab Monitoring Below on‐therapy

range On‐therapy range Above on‐therapy

range

Dabigatran

IIIIIIIIIIIIIIIIIIIII TT

Horizontal bars – Correspond to approximate range of detectability (sensitivity) Vertical hatching – Correspond to approximate range of linearity APTT = activated partial, thromboplastin time, PT = prothrombin time , TT = thrombin time

Ranges may vary on the based on reagent

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

Dilute TT

APTT

PT

Cuker A et al. J Am Coll Cardiol. 2014;64:1128‐39.

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Lab Monitoring Below on‐therapy

range On‐therapy range Above on‐therapy

range

Rivaroxaban, Edoxaban

Apixaban

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

Anti‐Xa Activity

PT

PT

Anti‐Xa Activity

APTT

APTT

Horizontal bars – Correspond to approximate range of detectability (sensitivity) Vertical hatching – Correspond to approximate range of linearity

Ranges may vary on the based on reagent Cuker A et al. J Am Coll Cardiol. 2014;64:1128‐39

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Lab Monitoring – Bottom LineDrug Lab Effect

Dabigatran APTT • Prolonged aPTT indicates an anticoagulant effect of dabigatran • Normal aPTT does not rule out dabigatran presence but indicates lower drug levels

TT • Normal TT indicates absence of dabigatran

Dilute TT • Quantifies dabigatran drug levels

Factor Xainhibitors(FXa)

APTT • Insensitive to FXa inhibitors, not recommended for monitoring

PT • Prolonged PT may indicate anticoagulant effect of FXa inhibitors (rivaroxaban, edoxaban >>> apixaban)

• Normal PT likely excludes excess levels of rivaroxaban

Chromogenicanti‐Xa

• Quantifies rivaroxaban, apixaban and edoxaban

Reversal should not be delayed in urgent situations for laboratory tests. Delayed turnaround times will diminish usefulness in urgent situations.

Levy JH et al. J Thromb Haemost 2016;14:6 23‐7.Cuker A et al. J Am Coll Cardiol. 2014;64:1128‐39.Samuelson BT et al. Blood Reviews 2017;31:77‐84.

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Reversal Strategies

Non specific reversal strategies

• Activated charcoal

• Hemodialysis

• 4‐Factor prothrombincomplex concentrate (4‐PCC)

• Activated PCC (aPCC)

• Recombinant Factor VIIa

Specific reversal strategies

• Idarucizumab (dabigatran only)

• Andexanet alfa (in development)

• Ciraparantag (in development)

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Non Specific Reversal ‐ Removal

Activated charcoal

• Recent ingestion within 2 hours

Hemodialysis

•Dabigatran only

• Eliminates ~65% of circulating dabigatribanafter 2‐4 hours

Wang et al. Am J Cardiovasc Drugs. 2014;14(2):147‐154.Stangier et al. Clin Pharmacokinet. 2010;49(4):259‐68.

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Non Specific Reversal – Bypassing 4 ‐PCC(Kcentra)

aPCC(FEIBA)

rVIIa(Novoseven)

Product composition

Factors II, VII, IX & X Protein C, S Heparin

Factors II, VII (activated) , IX & X Protein C, S

Factor VIIa(activated)

Literature –animal models, ex‐vivo studies, case series

Generally corrected coagulation and thrombin generation parameters

Corrected coagulation and thrombin generation parameters

Variable ability to correct coagulation and thrombin generation parameters

Disadvantage Increased risk of thrombotic complications;Heparin allergy

Increased risk of thrombotic complications

Meta‐analysis suggests thrombosisrisk >> PCCs

XSiegel et al. Drug Discov Today. 2014;19(9):1465‐1470.

Burnett AE et al. J Thromb Thrombolysis. 2016;41:206‐232.Dager W et al. Am J Health‐Syst Pharm 2016;73(suppl 2):S14‐26.

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Non Specific Reversal – Bypassing 4 ‐PCC(Kcentra)

aPCC(FEIBA)

rVIIa(Novoseven)

Product composition

Factors II, VII, IX & X Protein C, S Heparin

Factors II, VII (activated) , IX & X Protein C, S

Factor VIIa(activated)

Literature –animal models, ex‐vivo studies, case series

Generally corrected coagulation and thrombin generation parameters

Corrected coagulation and thrombin generation parameters

Variable ability to correct coagulation and thrombin generation parameters

Disadvantage Increased risk of thrombotic complications;Heparin allergy

Increased risk of thrombotic complications

Meta‐analysis suggests thrombosisrisk >> PCCs

XFor patients that require emergent reversal of FXa inhibitors for severe or life‐threatening bleeding consider: • 4‐PCCs (Kcentra) ~50 units/kg • aPCC (FEIBA) ~50 units/kg

Siegel et al. Drug Discov Today. 2014;19(9):1465‐70.Burnett AE et al. J Thromb Thrombolysis. 2016;41:206‐232.

Dager W et al. Am J Health‐Syst Pharm 2016;73(suppl 2):S14‐26.Rossaint et al. Critical Care (2016) 20:100.

Frontera JA et al. Neurocrit Care 2016;24:6‐46.

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Idarucizumab (Praxbind®)

•Humanized monoclonal antibody fragment

•Binds to dabigatran and its metabolites

•Onset: < 5 minutes

• T1/2: 47 min (terminal ~10.3 h)

•Dose: 5g (2.5 g x 2 doses)

• Elimination: Renal

Praxbind® [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2015.Pollack CV Jr et al. Thromb Haemost. 2015 Jul;114(1):198‐205.

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Idarucizumab for Dabigatran Reversal AKA “RE‐VERSE AD”

Prospective, single arm, multicenter phase III clinical trial

Inclusion• Overt, uncontrollable, or life‐threatening bleeding with dabigatran

(Group A) • Surgery or procedure could not be delayed for ≥ 8 hours (Group B)

Study Drug Idarucizumab 5 g IV once (2 x 2.5 g doses administered within 15 minutes)

Primary Endpoint

Percent reversal of anticoagulation up to 4 hours after idarucizumab measured by dilute thrombin time(dTT) and ecarin clotting time(ECT)

Secondary Endpoints

• Duration of reversal up to 24 hours after idarucizumab administration as measured by dabigatran levels

• Hemostasis following idarucizumab administration for serious bleeding• Intraoperative hemostasis as classified by physician• Thrombotic events • Mortality

Pollack CV et al. N Engl J Med 2017; 377:431‐441.

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RE‐VERSE AD‐Group A Results

• Source GI > ICH > Trauma

• Last dose ~15 hrs

Bleeding patients (N=301)

• N=276 with abnormal dTTor ECT included

• Median max reversal 100% based (based on dTT or ECT)

Reversal within 4 hours

• All confirmed cessation within 24 hrs

• Median time to hemostasis was 2.5 hrs

Bleeding cessation

confirmation (N=134)

Pollack CV et al. N Engl J Med 2017; 377:431‐441.

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RE‐VERSE AD‐Group B Results

• Last dose ~18 hrs

• Median time from first infusion to procedure initiation: 1.6 hrs

Surgical patients (N=202)

• N=185 with abnormal dTT or ECT included

• Median max reversal 100% based (based on dTT or ECT)

Reversal within 4 hrs

• Normal in 184 pts (93%)

• Mildly abnormal in 10 pts(5%)

• Moderately abnormal in 3 pts(2%)

Peri‐procedural hemostasis (N=197)

Pollack CV et al. N Engl J Med 2017; 377:431‐441

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RE‐VERSE AD Safety Group A (N=301)

Group B(N=202)

Mortality30 d, %90 d, %

13.5%18.8%

12.6%18.9%

Thrombotic Events* 30 d, N (%)90 d, N (%)

14 (4.7%)19 (6.3%)

10 (4.9%)15 (7.4%)

ImmunogenicityAnti‐idarucizumab antibodies

28/501 (5.6%)

No detectable effect on idarucizumab activity

*Three patients in group A and 5 patients in group B received anticoagulation (treatment or prophylaxis) prior to event

Pollack CV et al. N Engl J Med 2017; 377:431‐441

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26

RE‐VERSE AD Safety

Recurrence of elevated dabigatran levels (>20 ng/ml) Recurrence of elevated dabigatran levels (>20 ng/ml)

• Observed at 12 hrs in 23% (144/497) and at 24 hrs in 13% (67/497) of patients

• Associated with recurrent bleeding in 10 patients

Repeat dosing required in 8 patientsRepeat dosing required in 8 patients

• Due to recurrent bleeding or requiring second procedure

Consider a second 5g dose of idarucizumab if• Clinically significant bleeding along with elevated coagulation parameters recurs

• Additional procedure required in patient with elevated coagulation parameters

Pollack CV et al. N Engl J Med 2017; 377:431‐441Praxbind® [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2015.

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Idarucizumab Considerations and Remaining Questions

Are clinical outcomes improved in bleeding patients? Are clinical outcomes improved in bleeding patients?

Significance of increased dabigatran levels? Significance of increased dabigatran levels?

Is 5gm sufficient for patients with acute renal failure or in the case of an overdose?Is 5gm sufficient for patients with acute renal failure or in the case of an overdose?

Can we administer idarucizumab to allow for thrombolytic administration in ischemic stroke patients? Can we administer idarucizumab to allow for thrombolytic administration in ischemic stroke patients?

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Andexanet Alfa

•Decoy FXa molecule that binds FXa inhibitors restoring function of endogenous Fxa

•Also reverses UFH, LMWH and fondaparinux

•Onset < 2 minutes

•Half‐life 1 hour

• Investigational

Burnet A et al. BMJ 2017;357:j2216.Milling TJ et al. Am J Med. 2016, 129:S80‐S88.

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27

Andexanet Alfa in Healthy Subjects

Rapidly reduced unbound FXainhibitor concentrations leading to restored FXa activity and thrombin generation

Rapidly reduced unbound FXainhibitor concentrations leading to restored FXa activity and thrombin generation

Two hours following andexanet alfa infusion, unbound drug concentrations returned back to placebo associated levels

Two hours following andexanet alfa infusion, unbound drug concentrations returned back to placebo associated levels

Transient elevations in D‐dimer and Prothrombin fragments 1 and 2

Transient elevations in D‐dimer and Prothrombin fragments 1 and 2

Siegal DM et al. N Engl J Med 2015;373:2413‐24.

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Andexanet Alfa for FXa Inhibitor Associated

Major Bleeding AKA “ANNEXA‐4”Prospective, single arm, ongiong multicenter phase III clinical trial

Inclusion• Acute major bleeding within 18 hours of FXa inhibitor (apixaban,

rivaroxaban, edoxaban or enoxaparin) administration

Study Drug

Andexanet alfa bolus and infusion: • Apixaban or Rivaroxaban (>7 hours ago): 400mg bolus followed by

480mg infusion over 2 hours• Rivaroxaban (≤ 7 hours ago), enoxaparin or edoxaban: 800 mg bolus

followed by 960 mg infusion over 2 hrs

Primary Endpoints

• Percent change in the anti–factor Xa activity (chromogenic FXa assay)• Rate of excellent or good hemostatic efficacy 12 hours after infusion • Efficacy analysis included

• Anti‐Xa level ≥ 75 ng/ml or ≥ 0.5 U/ml for enoxaparin

Patient population

• 67 patients with acute major bleeding • GI bleed 33 (49%)• ICH 28 (42%)

• Mean time to andexanet bolus was 4.8 +/‐ 1.9 hrsConnolly SJ et al. N Engl J Med 2016;375:1131‐41.

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ANNEXA‐4 Results

Efficacy analysis:

• Anti‐FXa activity and change from baseline

• N=47

↓89%

↓93%

↓39%

↓30%

Connolly SJ et al. N Engl J Med 2016;375:1131‐41.

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ANNEXA‐4 Hemostatic Efficacy

79% (37/47) of patients experienced good or excellent hemostatic response*

• Excellent – 66% (31) of patients

• Good – 13% (6) of patients

19% (9/47) of patients experienced poor/no hemostatic response*

• Rivaroxaban – 5 patients

• Apixaban – 4 patients

*One patient not evaluatedConnolly SJ et al. N Engl J Med 2016;375:1131‐41.

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ANNEXA‐4 Safety N=67

30 d Mortality, N (%)

Cardiovascular causes

Non‐cardiovascular causes

10 (15%)

6 (9%)

4 (6%)

30 d Thrombotic Events, N‐patients (%)*

Deep vein thrombosis

Pulmonary Embolism

Stroke

Myocardial infarction

12 (18%)

7

1

5

1

*Several patients had more than one thrombotic event

Two patients received anticoagulation prior to thrombotic event

Connolly SJ et al. N Engl J Med 2016;375:1131‐41.

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Andexanet Alfa Considerations and Remaining Questions

Are clinical outcomes improved in bleeding patients? Are clinical outcomes improved in bleeding patients?

Does extending infusion improve efficacy?Does extending infusion improve efficacy?

Dosing in patients requiring emergent surgery?Dosing in patients requiring emergent surgery?

When can anticoagulation be restarted? When can anticoagulation be restarted?

Limited data with enoxaparin, edoxaban and betrixabanLimited data with enoxaparin, edoxaban and betrixaban

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Andexanet Alfa Moving Forward

Aug 2016 – FDA complete response letter required more data:

• Manufacturing process

• Edoxaban, enoxaparin

Portola resubmit Biologics License Application in Aug

2017

FDA response expected in Feb 2018

http://investors.portola.com

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Ciraparantag

• Synthetic molecule

• Binds to anticoagulants via non‐covalent hydrogen binding blocking target sites of FXa and FIIa

• Binds to DOACs, heparins, and fondaparinux

• Onset 5‐10 minutes

• Duration of action ~24 hours

• Reversal measured with whole‐blood clotting time(WBCT)

Burnet A et al. BMJ 2017;357:j2216.Milling TJ et al. Am J Med. 2016, 129:S80‐S88.

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Ciraparantag in Healthy Subjects

• Fast, sustained reversal of edoxaban based on WBCT

• No measurable thrombotic effects

Ciraparantag

Ansell et al. Thromb Haemost 2017;117:238‐245.

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Ciraparantag –Moving Forward

Received fast‐tracked status in April 2015

Currently in Phase II studies

http://perosphere.com/content

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When to Use Antidotes? In Favor

Life‐threatening bleeding: Intracranial hemorrhage or uncontrollable hemorrhage

Bleeding in a closed space or critical organ

Persistent major bleeding despite local hemostatic measures or risk of recurrent bleeding due to delayed DOAC clearance or overdose

Need for urgent intervention with high risk of bleeding that cannot be delayed

Emergency surgery or intervention in patients at high risk for procedural bleeding

Potential

Need for urgent surgery or intervention in patients with acute renal failure

Levy JH et al. J Thromb Haemost 2016;14:6 23‐7.

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When Not to Use Antidotes? Against use

Gastrointestinal bleeds that respond to supportive measures

Elective surgery

Need for surgery or intervention that can be delayed long enough to

permit DOAC clearance

High drug levels or excessive anticoagulation without associated bleeding

Levy JH et al. J Thromb Haemost 2016;14:6 23‐7.

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Reversal Summary

•DOAC reversal will vary based on the pharmacokinetics of the agent involved, urgency of the situation and the time of last dose

•Certain lab parameters may be helpful in identifying and quantifying anticoagulation activity

•Use of PCCs/aPCCs may be effective and should be considered after weighing the risks of thrombosis if emergent reversal is indicated

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Reversal Summary

• Idarucizumab effectively reverses dabigatran in patients with life threatening bleeds or undergoing urgent procedures

• Investigational agents, andexanet alfa and ciraparantag, are promising antidotes, and there is much to be known about their use

•Guidance for when to use specific reversal agents is available from the ISTH

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Updates in Oral Anticoagulation: An Evidence‐Based Review

Mona A. Ali, Pharm.D., BCPS

Jenna M. Holzhausen, Pharm.D., BCPS

updates in oral anticoagulation: an€¦ · updates in oral anticoagulation: an evidence ‐based...

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