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

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.

49/527

68/415

14/527

47/415

Confounded by AF, VHD,

activity limitation

0

5

10

15

20

Deaths Embolic Events

Even

t R

ate

(%

)

Anticoagulation Control

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.

Lip GYH, Gibbs CR et al. J Am Coll Cardiol. 1999;33:1424-6.

Heart Failure is a Pro-Thrombotic State Heart failure is a prothrombotic milieu

(Virchow’s 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

Virchow’s Triad Predisposing Conditions for Thromboembolism

Hypercoagulable state

Venous stasis

Increased markers of endothelial damage and inflammation

Endothelial damage/

dysfunction

Abnormal blood flow

Immobility

Low cardiac output

Increased procoagulant factors

VTE

Virchow’s Triad • Abnormal blood flow

• Vessel wall abnormalities

• Abnormalities in blood

constituents

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 F1•2, d-dimers)

Increased platelet aggregability (ß-thromboglobulin, PF IV)

Factors Contributing to

Hypercoagulability in HF

Platelet function

Increased platelet aggregation and elevated beta thromboglobulin, P–selectin, PECAM–1 (platelet/endothelial cell adhesion molecule–1; CD–31), osteonectin

Increased coagulability

Elevated TNF, thrombin–antithrombin complexes (TAT), D-dimer, prothrombin fragment F1 + 2 (even greater increase in AF), fibrinopeptide A, IL–6 (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.

Fatal Stroke or PE 3%

Pump Failure 49%

Sudden Death 23%

Myocardial Infarction

12%

Noncardiac

13%

Cause of Death in Heart Failure

Dries et al, JACC 1998;32:695

ATLAS Effect of Autopsy on Classification of Death

0

5

10

15

20

25

30

35

40

45

50

Sudden Cardiac

Death

CHF MI

Perc

en

t

No Autopsy Autopsy

171 patients (12.4%) had autopsy

.

Can these outcomes be prevented with antiplatelet

agents or anticoagulation?

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

Kalaria et al, Am Heart J 1998;135:215

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.

Evidence for Embolism in Cardiomyopathy

Chaudhry et al, Circulation 1998;97:412

Relationship Between Mural Thrombus and Systemic Emboli

Data confounded by post-hoc nature of analyses and use of anticoagulation.

Mobile and protruding thrombi

may be more likely to embolize.

Risk Increased Risk Not Increased

Katz (n = 264) Cioffi (n = 406) Stratton (n = 83) Natterson (n = 224) Falk (n = 25) Ciaccheri (n = 126) Gottdiener (n = 123) Blondheim (n = 91) Kyrle (n = 38)

Interaction

P = 0.0005

13% ↓ 10% ↑ 20% ↓

13% ↓ 10% ↑ 20% ↓

0

0.2

0.4

0.6

0.8

1

1.2

Ad

jus

ted

Ha

za

rd R

ati

os

En

ala

pri

l vs

. P

lac

eb

o

All Patients APA Users APA Non-users

SOLVD Interaction Between Antiplatelet Tx and Enalapril Effect

All-cause Mortality

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.

Angiotensinogen

Angiotensin I

Angiotensin II

Angiotensin II Receptors

Renin Bradykinin

ACE

(Kininase II) Inactive

fragments

ACE-I

PGE2

PGI2

ACE-I

NO

NOS

COX-1

ASA

-

-

-

Pathways Affected by ACE-Inhibitors

0

10

20

30

40

50

60

70

0 3 6 9 12 15 18 21 24 27 30 33 36

Months

Perc

en

t

Control 48 (48%) Warfarin 42 (47%) Aspirin 58 (64%)

P = 0.05

WASH Study All-cause Hospitalization

Cleland JGF. Presented ESC 1999.

Excess driven by higher rate

of heart failure hospitalizations

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

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

Clopidogrel 75 mg/d

(double-blind)

1,500 patients

Aspirin 162 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 α = 0.017 with annual event rates of 14 – 18%

WATCH Study Design

Death and Non-fatal MI or Stroke

W vs A: HR 0.99, CI 0.88 – 1.11 C vs A: HR 1.10, CI 0.88 – 1.30

Even

t R

ate

0.0 –

0.1 –

0.2 –

0.3 –

0.4 –

0.5 –

0.6 –

Year of Follow-up

| | | | |

0 1 2 3 4

Aspirin (n = 523)

Clopidogrel (n = 524)

Warfarin (n = 540)

Massie B. Circulation 2009;119;1616-1624

Aspirin vs Warfarin

Aspirin (523) Warfarin (540) p

N % N %

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 4 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

Patients Hospitalized No. of Hospitalizations/

100 patient-years

Aspirin Clopidogrel Warfarin

27% , P = 0.01 31% , P < 0.001

P = 0.17 P = 0.12

0

5

10

15

20

25

A C W 0

5

10

15

20

25

A C W

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.