Pathophysiology of Thrombosis in

Heart Failure
Barry M. Massie, M.D.
Professor of Medicine
University of California, San Francisco

Disclosures
I received consulting fees from Boehringer
Ingelheim, Portola and Takeda concerning
potential trials of antithrombotic agents in heart
failure patients.

Pathophysiology of Thrombosis in
Heart Failure
Points of Discussion
Historical perspective
Prothrombotic pathophysiological mechanisms
Completed and ongoing modern era trials
What heart failure setting and which patients?
Does routine antithrombotic therapy make
sense?

Historical Perspectives of Thromboemboli in HF

1950s: Outcomes appeared better in anticoagulated
patients (DCM patients treated with prolonged bed rest,
high rates of rheumatic valve disease & AF)
1960s-1970s: Patients anticoagulated based on
retrospective analyses & findings of thrombi and
thromboembolism on autopsy
1980s-90s: Better understanding of hypercoagulability in
HF, role of silent MI, systemic and pulmonary emboli in
heart failure outcomes
2000-: Concern about aspirin in HF patients

Pooled Results of 3 Early Trials of

Anticoagulants in HF
Event Rate (%)

20
68/415

Confounded by AF, VHD,

activity limitation

15
10

47/415

49/527
14/527

5
0
Deaths
Anticoagulation

Embolic Events
Control

Harvey WP, Finch CA. N Engl J Med. 1950;242:208-11.

Anderson GM, et al. Am Heart J. 1950;697-72.
Griffith GC, et al. Ann Intern Med. 1952;37:867-87.

Occult Thromboembolism in HF
Autopsy data
50% incidence of thromboembolism in HF.1

104 IDC patients with 18% vs. 0% thromboemboli without

vs. with anticoagulation.2
37% incidence in IDC.3

IDC and no cardiac thrombus: 20% incidence of

unrecognized cerebral damage associated with cognitive
defects.4

1Spodick

DH, Littmann D. Am J Cardiol 1958;1:610-623.

2Fuster V, et al. Am J Cardiol 1981;47:525-531.
3Roberts WC, et al. Am J Cardiol. 1987;60:1340-1355.
4Schmidt R, Stroke. 1991;22:195-199.

Heart Failure is a Pro-Thrombotic

State
Heart failure is a prothrombotic milieu
(Virchows Triad)
Embolic rate is 1-3 per 100 patient-years
(mostly stroke)

Contribution of thrombosis to outcomes

(sudden death, progressive heart failure, occult
pulmonary embolus) under-appreciated
Post-hoc analyses suggest efficacy of
antithrombotic Rx
Lip GYH, Gibbs CR et al. J Am Coll Cardiol. 1999;33:1424-6.

Virchows Triad

Predisposing Conditions for Thromboembolism

Increased procoagulant factors

Virchows Triad
Abnormal blood flow
Vessel wall abnormalities
Abnormalities in blood
constituents

Hypercoagulable state

VTE

Increased
markers of
endothelial
damage and
inflammation

Endothelial
damage/
dysfunction

Abnormal
blood flow
Venous
stasis

Immobility
Low cardiac
output

Factors Increasing Thrombotic Risk in CHF

Stasis
Low CO, atrial fibrillation, blood viscosity
Neurohormonal activation
catecholamines, A-II, inflammation, cytokines
Endothelial dysfunction
Reduced endothelial responses in CHF and atherosclerosis
Elevated markers (endothelin and von Willebrand factor)
Hypercoagulable state
Activated pro-thrombotic factors (thrombin-antithrombin III
complexes, fibrinopeptide A, plasminogen activator
inhibitor-1)
Increased fibrinolysis (prothrombin F12, d-dimers)
Increased platelet aggregability (-thromboglobulin, PF IV)

Factors Contributing to
Hypercoagulability in HF
Platelet function
Increased platelet aggregation and elevated beta
thromboglobulin, Pselectin, PECAM1
(platelet/endothelial cell adhesion molecule1;
CD31), osteonectin

Increased coagulability
Elevated TNF, thrombinantithrombin complexes
(TAT), D-dimer, prothrombin fragment F1 + 2 (even
greater increase in AF), fibrinopeptide A, IL6
(also increased in AF)

Garg RK, et al. Prog Cardiovasc Dis. 1998;41:225-236.

Davis CJ, et al. Int J Cardiol. 2000;75:15-21.

Rationale for Antithrombotic Therapy

in Chronic HF
Prevention of stroke
Prevention of systemic & pulmonary
embolism

Prevention of coronary thrombosis

Retarding progression of HF
Prevention of venous thromboembolism
Prolongation of survival

Risk of Stroke in SAVE

Low LVEF: For each 5%, risk of stroke RR 18%
Older age: For each 5 yr , RR 18%
Atrial fibrillation
Risk of stroke doubled in men and tripled in women
(Framingham)
Etiology of heart failure
Recent large MI (usually anteroapical)
No clear excess risk for DCM, but perhaps for peripartum
cardiomyopathy and acute myocarditis
Anticoagulation during follow-up: RR 0.19
Aspirin use during follow-up: RR 0.44
Loh, et al. NEJM 1997;336:251

Relative Risk of Thromboembolic Events

by Gender in SOLVD

Dries et al JACC; 1997;29:1074

Embolic Rates in CHF and AF

Rates per 100 patient-years
Trial

All Emboli Stroke

Death

V-HeFT*

2.3

1.8

14%

SOLVD*

1.9

1.3

12%

AF trials (all pts)

5.0

4.5

5%

AF trials (high-risk)

6 17%/y

* Includes AF patients (some anticoagulated)

Dunkman WB, et al. Circulation. 1993;87 (6 Suppl):VI94-101.
Dries DL, et al. J Am Coll Cardiol. 1997;29:1074-1080.
No authors listed. Arch Intern Med. 1994;154:1449-1457.

Cause of Death in Heart Failure

Fatal Stroke
Noncardiac
or PE
13%
3%
Myocardial
Infarction
12%
Pump Failure
49%
Sudden Death
23%
Dries et al, JACC 1998;32:695

ATLAS

Effect of Autopsy on Classification of Death

Percent

171 patients (12.4%) had autopsy

50
45
40
35
30
25
20
15
10
5
0
Sudden Cardiac
Death
No Autopsy

CHF

MI
Autopsy

Can these outcomes be prevented with antiplatelet

agents or anticoagulation?
.

Uretsky BF, et al. Circulation. 2000;102:611-616.

Evidence for Embolism in

Cardiomyopathy
Increased LV end-diastolic volume
and diminished contractility cause
stasis and thrombus formation.
Peripheral embolism in patients with
dilated LV is well-documented

12% of patients with cardiomyopathy

have LV thrombus (may be selection
bias).
Low EF is the main risk factor.
Chaudhry et al, Circulation 1998;97:412
Kalaria et al, Am Heart J 1998;135:215

Relationship Between Mural Thrombus and

Systemic Emboli
Risk Increased

Risk Not Increased

Katz (n = 264)
Stratton (n = 83)
Falk (n = 25)

Cioffi (n = 406)
Natterson (n = 224)
Ciaccheri (n = 126)
Gottdiener (n = 123)
Blondheim (n = 91)
Kyrle (n = 38)

Data confounded by posthoc nature of analyses and

use of anticoagulation.

Mobile and protruding thrombi

may be more likely to embolize.

SOLVD

Interaction Between Antiplatelet Tx and Enalapril Effect

All-cause Mortality
Adjusted Hazard Ratios
Enalapril vs. Placebo

1.2

Interaction
P = 0.0005

1
0.8
0.6
0.4
0.2

13%

10%

20%

13%

10%

20%

0
All Patients

APA Users

APA Non-users

Al-Khadra AS, et al. J Am Coll Cardiol. 1998;31:419-425.

Al-Khadra AS, et al. J Am Coll Cardiol. 1998;31:749-753.

Pathways Affected by ACE-Inhibitors

ASA
Angiotensinogen

PGE2
PGI2

COX-1

Renin
Bradykinin

Angiotensin I
ACE-I

NOS

ACE
(Kininase II)

Angiotensin II

Angiotensin II Receptors

Inactive
fragments

ACE-I

NO

WASH Study

All-cause Hospitalization
Excess driven by higher rate
of heart failure hospitalizations

70

Percent

60
50
40
30
20

P = 0.05

10
0
0

12

15

18

21

24

27

30

33

36

Months
Control 48 (48%)

Warfarin 42 (47%)

Aspirin 58 (64%)
Cleland JGF. Presented ESC 1999.

WATCH: Warfarin and Antiplatelet Trial in CHF

Objective: To determine the optimal anti-thrombotic agent
for heart failure patients, with regard to clinical outcomes,
safety, and cost.
Hypotheses:
Anticoagulation with warfarin is superior to antiplatelet
therapy with aspirin in preventing vascular events in
chronic heart failure patients.

Comparison of warfarin vs aspirin

Aspirin may have an adverse effect in chronic heart

failure patients, possibly due to interference with the

action of ACE inhibitors.

Comparison of clopidogrel vs aspirin

WATCH Study Design

Recruitment x 3 years
142 sites in US (VA & non-VA), Canada, and UK

Warfarin (INR 2.5 3.0)

(open-label)
1,500 patients

Aspirin 162 mg/d

(double-blind)
1,500 patients

Clopidogrel 75 mg/d
(double-blind)
1,500 patients

Intent-to-treat follow-up for up to 5 y (minimum 2 y) 3-mo. visits;

6 week contacts/INR checks 80 90% power to detect 20%
intergroup differences at = 0.017 with annual event rates of
14 18%

Death and Non-fatal MI or Stroke

0.6
Aspirin (n = 523)
Clopidogrel (n = 524)
Warfarin (n = 540)

Event Rate

0.5
0.4
0.3
0.2

W vs A: HR 0.99, CI 0.88 1.11

0.1
0.0

C vs A: HR 1.10, CI 0.88 1.30

|

Year of Follow-up
Massie B. Circulation 2009;119;1616-1624

Aspirin vs Warfarin
Aspirin (523) Warfarin (540)

Death, MI, stroke

107

20.5

107

19.8

0.20

Death

94

18.0

92

17.0

0.58

Non-fatal MI

14

2.7

22

4.1

0.15

Non-fatal stroke

11

2.1

0.7

0.06

Heart failure
hospitalization

116

22.2

87

16.1

0.01

There were no significant differences between aspirin and clopidogrel

Heart Failure Hospitalizations

No. of Hospitalizations/
100 patient-years

Patients Hospitalized
27% , P = 0.01

25

P = 0.12

20

25

31% , P < 0.001

20

P = 0.17

15

15

10

10

0
A

Aspirin

A
Clopidogrel

C
Warfarin

Warfarin vs Aspirin in Reduced

Cardiac EF (WARCEF)
Ongoing NINDS funded trial of warfarin vs aspirin in
HF patients at high risk of stroke.
Primary endpoint of death and stroke.

Results anticipated early 2012

Prespecified combined analyses with WATCH are
included.

Together, these studies should provide definitive

conclusions to the questions unresolved by WATCH

2008 US Guidelines for Antithrombotic Therapy in

Chronic HF (AHA/ACC & ACCP)
Anticoagulation recommended for heart failure patients:
With chronic or paroxysmal AF or flutter (IA, warfarin)
With prior systemic or pulmonary embolic events (IIA, warfarin)
With recent large anterior MI or LV thrombi (IIA, short term warfarin)
At risk for venous thromboembolism in hospitalized patients with
risk factors (IA, LMWH or UFH)
Anticoagulation possibly beneficial (but unproven)
In other patients with ventricular thrombi (IIB)
Anticoagulation not recommended
In other patients with non-ischemic CM (IB)
Aspirin for prevention of vascular events
Recommended at 75 162 mg QD in CAD patients (IC)
Warfarin and clopidogrel possible alternatives, IIB)
Not recommended in non-ischemic CM (IB)

Mechanisms of Current and Investigational

Antithrombotic Agents

Hirsh J, et al. Circulation 2007;116:551

Does a trial of antithrombotic therapy in heart

failure patients make sense: WATCH experience?
Major sources of arterial thromboembolism (large AMI, LV
aneurysm, severe LV dysfunction) have become uncommon.

Event rates likely to be impacted by an antithrombotic agent

are low (3/100 pt-yrs for stroke + MI; 12/100 pt-years for
stroke + MI + death) and do not differ between warfarin and
aspirin (but strokes less frequent on warfarin, ? AF patients).
HF hospitalizations exceed the combined primary endpoint
events and were significantly more frequent in the aspirin
group, probably reflecting an interaction with ACE inhibitors.
Placebo controlled trials that include AF patients would be
unethical and an active anticoagulant comparator would be
required.