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New Strategies to Prevent CV Events After Hospital Discharge New Strategies to Prevent CV Events After Hospital Discharge

New Strategies to Prevent CV Events After Hospital Discharge - PowerPoint Presentation

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New Strategies to Prevent CV Events After Hospital Discharge - PPT Presentation

Program Agenda Crisis and Unmet Needs in Medically Ill Hospitalized Patients Call to Action World Thrombosis Day Facts Absolute Risk of DVT in Hospitalized Patients Lack of Prophylaxis in Medical Patients ID: 724996

patients vte bleeding hospital vte patients hospital bleeding discharge hospitalized prophylaxis betrixaban primary medical efficacy trials reversal summary fda

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Slide1

New Strategies to Prevent CV Events After Hospital Discharge

CHAIR

Samuel Z.

Goldhaber

, MD

Professor of Medicine

Harvard Medical School

Interim Chief

Division of Cardiovascular Medicine

Section Head

Vascular Medicine

Brigham and Women's Hospital

Boston, MassachusettsSlide2

Program Agenda

Welcome and Introductions

Samuel Z.

Goldhaber

, MD

Crisis and Unmet Need in Medically Ill Hospitalized Patients

Steven B. Deitelzweig, MD

Prevention of VTE, Stroke, and Rehospitalization for Medically Ill Hospitalized Patients

Samuel Z.

Goldhaber

, MD

Management of Major Bleeding among Patients Taking DOACs: State-of-the-Art

Samuel A. Berkman, MD

Questions & Answers, Concluding Remarks

Samuel Z.

Goldhaber

, MDSlide3

Crisis and Unmet Needs in Medically Ill Hospitalized Patients

Steven B.

Deitelzweig

, MD

Professor of Medicine

University of Queensland

Regional Business Development

System Chair

Department of Hospital Medicine

Ochsner

Health System

New Orleans, LouisianaSlide4

Call to Action

100,000 to 180,000 PE-related deaths annually in the United States alone

PE is the most preventable cause of death among hospitalized patients

Office of the Surgeon General (US). The Surgeon General's Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism. 2008.

4Slide5

World Thrombosis Day Facts

Every year, there are approximately 10 million cases of VTE worldwide

Up to 60% of VTE cases are associated with a recent hospital stay, making it a leading preventable cause of hospital death

In the United States, diagnosis and treatment of VTE cost $15.5 billion per year

World Thrombosis Day website.

5Slide6

Absolute Risk of DVT in Hospitalized Patients

Reprinted from Chest, 133,

Geerts

WH, et al., Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)., 381S-453S, Copyright 2008, with permission from Elsevier.

6

Figure No Longer Available Slide7

Lack of Prophylaxis in Medical Patients

CURVE study

4124 patients in 29 Canadian hospitals

16% appropriate prophylaxis

IMPROVE study

15,156 patients, 52 hospitals, 12 countries

60% appropriate prophylaxis in the United States

ENDORSE study

68,183 patients, 358 hospitals, 32 countries

48% appropriate prophylaxis in the United States

Kahn SR, et al.

Thromb

Res

. 2007;119:145-155;

Tapson

VF, et al.

Chest.

2007;132:936-945; Cohen AT, et al.

Lancet

. 2008;371:387-394.

7Slide8

Cochrane Review of Interventions for Implementation of Hospital VTE

Thromboprophylaxis

Providing system-wide interventions, particularly alerts, to physicians and other healthcare professionals probably improves the use of

Thromboprophylaxis

or appropriate

thromboprophylaxis

Decreases the number of symptomatic blood clots (clots showing symptoms) at 3 months

However, the certainty of the evidence was rated as moderate or low; thus, more high-quality studies examining the effectiveness of system-wide interventions are needed to confirm the findings of this review

Kahn S, et al.

Cochrane Database

Syst

Rev

. 2018;4:CD008201.

8Slide9

Trials of VTE Prophylaxis in Hospitalized Medical Patients

a. Samama MM, et al.

N Engl J Med

. 1999;341:793-800.

b. Leizorovicz A, et al.

Circulation

. 2004;110:874-879.

c. Cohen AT, et al.

BMJ. 2006;332:325-329.

9

MEDENOX (enoxaparin 40 mg)

[a]

PREVENT

(dalteparin

5000 IU)

[b]

ARTEMIS (fondaparinux

2.5 mg)

[c]Slide10

3 Randomized Trials

Samama MM, et al.

N Engl J Med

. 1999;341:793-800.

Leizorovicz A, et al.

Circulation

. 2004;110:874-879.

Cohen AT, et al.

BMJ. 2006;332:325-329.

10

Once-daily injected low-dose anticoagulant prophylaxis, in these 3 placebo-controlled trials, reduced DVT/PE by > 50%, without increasing major bleeding.Slide11

VTE After Hospital Discharge

Despite in-hospital VTE prophylaxis, 75% of VTEs present out-of-hospital

About half occur within 5 to 6 weeks of discharge

37% have been hospitalized within the

3 months preceding the diagnosis of VTE

Spencer FA, et al.

Arch Intern Med.

2007;167:1471-1475.

11

Spencer FA, et al. Arch Intern Med. 2007;167:1471-1475. Copyright © 2007 American Medical Association. All rights reserved.

Figure No Longer Available Slide12

Risk of VTE Extends Post-Hospital Discharge

Observational study of > 11,000 hospitalized medical patients

> 50% of VTE Risk Within 35 days

Patients with

Cancer

CHF

Lung disease

Infection

Amin AN, et al.

J

Hosp

Med

. 2012;7:231-238. PMID: 22190427.

12

3.5%

Figure No Longer Available Slide13

More Than Half of VTE Occurs After 10 Days of Prophylaxis

a. Goldhaber SZ, et al.

N Engl J Med.

2011;365:2167-2177

.

b. Cohen AT, et al.

N Engl J Med

. 2013;368:513-523.

13

[a]

[b]Slide14

Extended VTE Prophylaxis: 3 Failed Trials

Medical Patients

a. Hull RD, et al.

Ann Intern Med

. 2010;153:8-18.

b. Cohen AT, et al.

N Engl J Med.

2013;368:513-523.

c.

Goldhaber SZ, et al. N Engl J Med. 2011;365:2167-2177.

14

Study

Study Conclusion

Net Clinical Benefit

EXCLAIM -- LMWH

(n = 5963)

[a]

VTE↓

Major

bleeding ↑

Marginal

MAGELLAN

--

Rivaroxaban

(n = 8101

)

[b]

VTE↓

Major

bleeding ↑

No

ADOPT

--

Apixaban

(n = 6528)

[c]

VTE↔

Major

bleeding ↑

NoSlide15

ADOPT and MAGELLAN

Lessons Learned

ADOPT: the rate of symptomatic VTE more than doubles over 21 days post-discharge

a. Goldhaber SZ, et al.

N Engl J Med

. 2011;365:2167-2177; b. Cohen AT, et al.

N Engl J Med

. 2013;368:513-523.

MAGELLAN: the risk of fatal VTE increases 5-fold

15

[a]

[b]

From N

Engl

J Med., Goldhaber SZ, et al., Apixaban versus Enoxaparin for Thromboprophylaxis in Medically Ill Patients, 365., 2167-2177. Copyright © 2011 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Figure No Longer Available

Figure No Longer Available Slide16

MARINER Trial

Rivaroxaban

Raskob

GE, et al.

Thromb

Haemostas

. 2016;115:1240-1248.

16

Screening phase

Day -10 to Day 1

30-day

follow-up

Day 45 to Day 75

Stratum 1

Subjects with

CrCl

≥30 to <50 ml/min

Placebo

Stratum 2

Subjects with

CrCl

≥ 50 ml/min

Rivaroxaban 7.5 mg daily

Placebo

Rivaroxaban 10 mg daily

R

R

1:1

R

1:1Slide17

Summary

Hospital-associated VTE remains a major healthcare concern

Multiple guidelines recommend all medical patients should have VTE risk assessment and use an externally validated risk assessment model

Most hospital-associated VTE occurs after discharge

17Slide18

Prevention of VTE, Stroke, and Rehospitalization for Medically Ill Hospitalized Patients

Samuel Z.

Goldhaber

, MD

Professor of Medicine

Harvard Medical School

Interim Chief

Division of Cardiovascular Medicine

Section Head

Vascular MedicineBrigham and Women's Hospital

Boston, MassachusettsSlide19

Fatal Saddle PE

Autopsy

19

Courtesy of Samuel Z.

Goldhaber

, MD.Slide20

Brigham and Women's Hospital

Readmission With NEW VTE Within 30 Days of Hospital Discharge

DEXUR website.

20Slide21

VTE After Hospital Discharge

Despite in-hospital VTE prophylaxis with UFH or LMWH, > 400,000 VTE events occur in this patient population annually

About half occur within 6 weeks of discharge

In 2017, the FDA approved a novel DOAC, betrixaban, for 35-42 days of extended-duration VTE prophylaxis

21

Courtesy of Samuel Z. Goldhaber, MD.Slide22

Prevention

22

An Ounce of Prevention Is Worth

a Pound of CureSlide23

Betrixaban

Factor

Xa

inhibitor

19- to 25-hour half-life

Low peak: trough ratio

11% to 18% renal clearance

Antidote (

andexanet

)BEVYXXA™ PI 2017.

23Slide24

Double blind, double dummy

APEX

Study Design

Cohen AT, et al.

N Engl J Med

. 2016;375:534-544.

24

Evaluation

Extended prophylaxis

35 to 42 days

Subjects enrolled

(N = 7513)

Follow-up safety visit

30 days after visit 3

(+5 days)

Standard prophylaxis

10 ± 4 days

Ultrasound and visit 3

Day 35

(+7 days)

Loading dose

160 mg

Betrixaban

80 mg

Enoxaparin

40 mg

Placebo

Betrixaban

80 mg

R

1:1Slide25

Study Design

Key Inclusion Criteria

Anticipated to be severely immobilized for ≥ 24 hours after randomization with anticipated length of hospitalization ≥ 3 days

Hospitalized for 1 of the following acute presentations:

Heart failure decompensation

Respiratory failure

Infection without septic shock

Rheumatic disorders

Ischemic stroke (with immobilization)

Cohen AT, et al.

N Engl J Med.

2016;375:534-544.

25Slide26

Baseline CharacteristicsPrimary Admission Diagnoses

Cohen AT, et al.

N

Engl

J Med.

2016;375:534-544.

26

Primary Admission Diagnosis, n (%)

Enoxaparin (n = 3754)

Betrixaban (n = 3759)

Heart Failure NYHA III-IV

44.5 (1672)

44.6

(1677)

Infection

28.2

(1058)

29.6

(1112)

Respiratory failure

12.6

(474)

11.9

(448)

Ischemic stroke with immobilization

11.5 (432)

10.9 (411)

Rheumatic disorders

3.1

(117)

2.9 (109)Slide27

Primary Efficacy Endpoint

Asymptomatic proximal DVT, symptomatic proximal/distal DVT, nonfatal PE, VTE-related death

RRR = 24.0%

Cohen AT, et al.

N

Engl

J Med.

2016;375:534-544.

27

P

=.006Slide28

Symptomatic VTE Events

RRR = 46%

Cohen AT, et al.

N Engl J Med

. 2016;375:534-544.

28

1.80%

0.99%

p=0.003

P

=.003Slide29

Primary Safety EndpointMajor Bleeding

Cohen AT, et al.

N

Engl

J Med

. 2016;375:534-544.

29

P

=.055

n = 21

n = 25Slide30

Percent Fatal Bleeding and ICHSafety Population

Safety population defined as patients who received at least one dose of active study drug. Analysis by actual treatment

Gibson CM, et al.

J Am Heart Assoc

. 2017;6.

30

P

=.18

n = 1

n = 1

n = 7

n = 2Slide31

FDA: Betrixaban Indication and Use

BEVYXXA™ PI 2017.

31

Betrixaban is a factor

Xa

(

FXa

) inhibitor indicated for the prophylaxis of venous thromboembolism (VTE) in adult patients hospitalized for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE.Slide32

Rate of Stroke or TIA

Gibson CM, et al.

Circulation.

2017;135:648-655.

32

Stroke Type

Enoxaparin

(n = 3716), No. (%)

Betrixaban

(n = 3716), No. (%)

RR

(95% CI)

P

V

alue

Any stroke

36 (0.97)

20 (0.54)

0.44 (0.04, 0.68)

.032

Ischemic

34 (0.91)

18 (0.48)

0.47 (0.06,

0.70)

.026

Hemorrhagic

1 (0.03)

1 (0.03)

---

-

Uncertain type

1 (0.03)

1 (0.03)

0.00 (-14.98, 0.94)

1.000

TIA

5 (0.13)

4 (0.11)

0.20 (-1.98, 0.79)

.739

Any stroke or TIA

41 (1.10)

24 (0.65)

0.41 (0.03,

0.65)

.034Slide33

VTE-Related Rehospitalization

Chi G, et al.

Circulation

. 2018;137:91-94.

33

Figure No Longer Available Slide34

Primary Efficacy Outcome by History of VTE

Yee MK, et al.

J

Thromb

Thrombolysis.

2018;45:1-8.

34

RR = 0.57 (0.38, 0.86)

P

=.006

NNT = 12

RR = 0.79 (0.64, 0.99)

P

=.042

NNT = 100

P

interaction = NSSlide35

Summary of Betrixaban

24% reduction in VTE (

P

=.006)

46% reduction in symptomatic VTE (

P

=.003)

56% reduction in stroke (

P

=.32)No increase in major or fatal bleeding

Cohen AT, et al.

N

Engl

J Med

. 2016;375:534-544.

35Slide36

Summary

Betrixaban

Substudies

56% reduction in VTE-related rehospitalization

42% reduction in VTE-related death

47% reduction in VTE-related rehospitalization and VTE-related death

Lower thrombus burden due to better "clean-out" of veins with

betrixban

explains "legacy effect"

Cohen AT, et al.

N

Engl

J Med

. 2016;375:534-544.

36Slide37

Management of Major Bleeding Among Patients Taking DOACs:

State-of-the-Art

Samuel A. Berkman, MD

Clinical Professor of Medicine

Division of Hematology/Oncology

The University of California, Los Angeles

Private Practice

Internal Medicine/Hematology

Cedars Sinai Medical Center

Los Angeles, CaliforniaSlide38

What Is Major Bleeding?

Critical organ bleeding

Bleeding into a closed cavity

Unstable vital signs

Significant drop in hemoglobin, transfusion requirement

Life- or limb-threatening bleeding

38Slide39

Measures to Treat Significant Bleeding Short of Reversal

Hold the DOAC

Compression

Surgical procedures

Volume

Blood products

39Slide40

Reversal Agents

Specific Agents

Idarucizumab

Andexanet

alfa

Ciraparantag

Nonspecific Agents

4-Factor Prothrombin Complex Concentrate

FEIBA

40Slide41

Idarucizumab Is BIG

AndexXa™ PI 2018

41

Idarucizumab

Thrombin

DabigatranSlide42

Idarucizumab Full Cohort

503 patients: 301 group A, 202 group B

100% reversal by ECT, DTT,

aPTT

Medium time bleeding cessation = 2.5 h

Med time initiate procedure = 1.6 h

Hemostasis

nl

93.4%

Thrombotic events 90 days: 6.3% group A, 7.4% group B

Pollack CV, et al.

N

Engl

J Med

. 2017;377:431-441.

42

New England Journal

of Medicine

Idarucizumab

for dabigatran reversal — full cohort analysis

Charles V. Pollack, Jr, MD, Paul A. Reilly, PhD, Joanne van

Ryn

, PhD, John W.

Eikelboom

, MB, BS, Stephan

Glund

, PhD, Richard A. Bernstein, MD, PhD, Robert

Dubiel

,

Pharm.D

., Menno V.

Huisman

, MD, PhD, Elaine M.

Hylek

, MD,

Chak-Wah

Kam

, MD, Pieter W.

Kamphuisen

, MD, PhD,

Jörg

Kreuzer

, MD, Jerrold H. Levy, MD, Gordon

Royle

, MD, Frank W.

Sellke

, MD, Joachim

Stangier

, PhD, Thorsten Steiner, MD, Peter

Verhamme

, MD,

Bushi

Wang, PhD, Laura Young, MD, and Jeffrey I.

Weitz

, MD Slide43

Novel Mechanism of Action Provides Rapid Reversal of Factor Xa

Inhibitor Activity Without

Prohemostatic

or Anticoagulant Effects

Engineered to remove any procoagulant or anticoagulant effects:

Prothrombotic effects are eliminated by modification of the catalytic domain

Anticoagulant effects are eliminated by deletion of GLA domain

a. Exerts its effect by binding to the ATIII complex.

AndexXa™ PI 2018.

43

Lacks

FXa

catalytic activity as a result of changing serine to alanine in active site

Native Factor

Xa

Prevents anticoagulant effect by removing GLA domain, which eliminates the ability of the protein to assemble into the

prothrombinase

complex

Andexanet

Factor

Xa

Decoy

Active site

Rapidly binds with high affinity

Binds to Factor

Xa

inhibitors

Rivaroxaban

Apixaban

Edoxaban

Enoxaparin

[a]Slide44

Andexanet

: FDA Approved

44

FDA Approved in May 2018 for Reversal of Rivaroxaban and ApixabanSlide45

Time Courses of Anti-Factor Xa

Activity Before and After the Administration of

Andexanet

in Healthy Volunteers: 2016

From N Engl J Med., Siegal DM et al., Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity, 373, 2413-2424. Copyright © 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

45

Figure No Longer Available Slide46

Bleeding Patients 2018:Clinical Hemostatic Efficacy

Stuart J, Connolly S. ACC 2018.

46

Subgroup

No. of Patients

Excellent or Good (95% CI)

25

50

75

100

Total Efficacy Patients

132

83 ( 76- 89 )

Drug

Rivaroxaban

54

83 ( 73- 93 )

Apixaban

68

82 ( 73- 91 )

Enoxaparin

10

80 ( 55-100 )

Sex

Male

67

81 ( 71- 90 )

Female

65

85 ( 76- 93 )

Site of bleeding

Gastrointestinal

43

86 ( 76- 96 )

Intracranial

74

81 ( 72- 90 )

Other

15

80 ( 60-100 )

Age

<65

yr

18

83 ( 66-100 )

65-75

yr

38

87 ( 76- 98 )

>75

yr

76

80 ( 71- 89 )

Andexanet

dose

Low

117

81 ( 74- 88 )

High

15

93 ( 81-100 )Slide47

30-Day Assessment in Clinical Trial of Patients who Bled

Thrombotic events occurred within 3 days of

Andexanet

in 6/227 patients (2.6%) and by 30 days in 24 (11%)

Anticoagulation restarted in 129 patients (57%) by 30 days

Therapeutic anticoagulation was restarted in 9 patients before a thrombotic event occurred

27 deaths occurred by 30 days (12%), of which 11 were CV

Stuart J, Connolly S. ACC 2018.

47Slide48

Summary

Reversal agents are very effective and rapid in reversing DOACs

Group of patients with high underlying mortality

No thrombotic or severe allergic events in healthy volunteers

Most thrombotic events remote from time of reversal

Potential for overuse needs to be supervised

48

Slide49

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