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
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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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