Congestive heart failure and thrombosis

Editors-in-Chief: C. Michael Gibson, M.S., M.D. Associate Editor-In-Chief: Ujjwal Rastogi, MBBS [1]

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## Contents

* 1 Overview
* 2 Historical Perspective
* 3 Pathophysiology
* 4 Epidemiology
* 5 Natural History, Complications & Prognosis
* 5.1 Cause of death in autopsied Heart failure patients: ATLAS Trial
* 5.2 Cause of death in Heart failure: SOLVD Trial
* 6 Treatment
* 6.1 Rationale for Antithrombotic therapy in Heart failure
* 6.2 Supportive Trial Data
* 6.3 Other Trials
* 6.4 Current Guidelines
* 6.4.1 European Society of Cardiology[11]
* 6.4.2 ACC/AHA[25]
* 7 See also
* 8 References

## Overview

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CHF results when heart is not able to meet the demands of circulation causing insufficient blood flow. These patients are at higher risk of arterial and venous thrombosis.

## Historical Perspective

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Throughout history many renowned researchers and health care professionals have contributed to the understanding, definition, and recognition of thrombosis in Heart Failure patients.[1] [2] [3]

Year | Event

|

1628  | William Harvey describes the circulation.
1785  | William Withering publishes an account of medical use of digitalis.
1920  | Organomercurial diuretics are first used.
1950s  | Prognosis appeared better in Anticoagulated patient.
1960s - 1970s  | Retrospective analysis and Autopsy findings showed thromboembolism as an etiology.
1980s - 1990s  | Better understanding of hypercoaugubilty in Heart failure patients. In 1987, the landmark CONSENSUS-I study showed the unequivocal survival benefits of enalapril in patients with severe heart failure.
2000-  | Role of Aspirin in heart failure patients is studied.

## Pathophysiology

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Stagnation of blood flow, disorder in vascular wall, and blood coagulation system are known factors that participate in the thrombosis formation, and its evident that Heart failure is often accompanied by hypercoaguble state[4] [5] [6].

| Thrombus formation

|
|
|
|

Abnormal blood flow (Blood Stasis)|

| Abnormal blood constituents|

| Abnormal blood vessel wall|

In Heart failure, several factors come into play,

* Firstly
* Akinetic ventricular segments
* Dilated ventricular chambers,
* Dilated atria

with stagnant flow may increase thrombus formation[7].

* Secondly endothelial dysfunction which occur in heart failure, may impair the antithrombotic function of the endothelium[8].

* Thirdly, elevated levels of
* d-dimer,
* Beta-thromboglobulin,
* von Willebrand factor have been observed[6].

The prothrombotic stage[9] is further enhanced by

* Activated renin-angiotensin-aldosterone system (RAAS)
* Sympathetic nervous system,
* Systemic inflammation.

## Epidemiology

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Heart failure is the most frequent cause of hospitalization in patient aged 65 and above.[10] Heart failure is one of the most important public health problems, affecting an approximate half million patients in United States, with more than 550,000 new cases each year, and many more worldwide[11][4].

The incidence is expected to increase further in the next two decade as more number of people are surviving after myocardial infarction[12].

## Natural History, Complications & Prognosis

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Death is the ultimate complication that can happen in heart failure patients having thrombosis. In the ATLAS (Assessment of Treatment with Lisinopril and Survival) trial[13], there were many Heart failure patients who underwent autopsy, providing an unique opportunity and answering many questions about the cause of death.

Various trials have been conducted to suggest surrogate markers of heart failure.

### Cause of death in autopsied Heart failure patients: ATLAS Trial

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[13]

Condition | Percentage (%)

|

No specific pathology (presumed arrhythmic death)  | 50.6
Myocardial infarction | 42.1
Other Cardiovascular cause  | 4.8
Non-cardiac  | 2.4

### Cause of death in Heart failure: SOLVD Trial

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[14]

Condition | Percentage (%)

|

Pump failure  | 49
Sudden death | 23
Myocardial infarction | 12
Non-cardiac  | 13
Fatal stroke or Pulmonary embolism |  3*

## Treatment

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### Rationale for Antithrombotic therapy in Heart failure

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* Prevention of Stroke[15],
* Prevention of Systemic or Pulmonary embolism,
* Prevention of coronary thrombosis,
* Retarding progression of Heart failure.
* Increase survival.

### Supportive Trial Data

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The following Table shows the comparative data from various studies, each showing the probability of a thromboembolic events in Heart Failure patients.

Study | Year | Patients (n) | Follow-up (y) | NYHA Class | LVEF (%) | CVA | MI | PE | TTE

|
|
|
|
|
|
|
|
|

V-Heft I[16] | 1993  | 642  | 2.3  | NR  | 30  | NR  | NR  | NR  | 2.7
V-Heft II  | 1993  | 804  | 2.6  | NR  | 29  | NR  | NR  | NR  | 2.1
SAVE[17] | 1997  | 2231  | 3.5  | NR  | 31  | 1.5  | NR  | NR  | NR
SOLVD[18] | 1997  | 6796  | 3.3  | I-III | ≤35  | 1.1  | NR  | NR  | 1.6
WASH[19] | 2004  | 254  | 2.3  | I-IV | ≤35  | 0.6  | 2.7  | NR  | 3.3
HELAS IHD[20] | 2006  | 116  | 1.6  | II-IV | 29  | 2.3  | 0.6  | 0  | 2.8
HELAS DCM[20] | 2006  | 82  | 1.7  | II-IV | 27  | 0.7  | 0.7  | 0  | 1.5
SCD-HeFT[21] | 2007  | 2114  | 3.8  | II-III | ≤35  | 0.8  | NR  | 0.1  | 1.7

Figures mentioned under CVA, MI, PE, TTE represents per 100 patient-years. Abbreviations Used: TTE, Total Thromboembolic event rate; NR, not reported; V-HeFT I and II Vasodilator-Heart Failure Trials; SAVE, Survival and Ventricular Enlargement; SOLVD, Studies of Left Ventricular Dysfunction; WASH, Warfarin/Aspirin Study of Heart Failure;HELAS,Heart Failure Long-Term Antithrombotic Study;IHD, Ischemic Heart Disease;DCM, Dilated Cardiomyopathy SCD-HeFT, Sudden Cardiac Death in Heart Failure Study.

### Other Trials

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* The Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH[22]) trial was the first modern RCT to study warfarin in patients with heart failure. The trial showed a reduction of nonfatal stroke events with warfarin over aspirin or clopidogrel.

* In the ARixtra for ThromboEMbolISm prevention in a medical indications study (ARTEMIS[23]) trial in acutely ill medical patients, fondaparinux signiﬁcantly reduced the risk of total venous thromboembolism, without increasing bleeding risk compared with placebo.

* In the Survival and Ventricular Enlargement (SAVE[24]) Trial,which enrolled patients with left ventricular dysfunction after MI, the VTE annual rate (fatal and nofatal stroke) was 1.5%.

* The Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) Trial is a randomized study evaluating the efficacy of warfarin versus aspirin in reducing the risk of death or stroke in patients with congestive heart failure and a left ventricular ejection fraction < 35%. Read more about WARCEF Trial by clicking here.

### Current Guidelines

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#### European Society of Cardiology[11]

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* Anticoagulants have shown to be more effective than antiplatelet agents in reducing the risk of stroke; thus they are preferred agents in
* patients with more than one risk factors, like
* Left ventricular ejection fraction ≤ 35%
* Age≥75
* Hypertension
* Diabetes mellitus
* In patients with Heart failure and Atrial fibrillation lacking any other additional risk factors., to prevent primary VTE event.

* With respect to Antiplatelet agents,
* They are found to be less efficacious than anticougulants, in preventing a VTE event in patients with Atrial fibrillation, .
* Hospitalization for heart failure was significantly greater in aspirin-treated patients than in warfarin-treated patients.

#### ACC/AHA[25]

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* Anticoagulants should be considered in
* Patients with heart failure having prior history of VTE.
* Patients having paroxysmal or persistant Atrial fibrillation.
* Patients with other co-morbidity, which increases the risk for VTE.
* Patients with familial dilated cardiomyopathy and a history of VTE in first-degree relatives.

* With respect to Antiplatelet agents, it should be used in:
* Myocardial infarction.
* Heart failure patients with known history of coronary artery disease.

* However, ACC/AHA has stated that
* Role of aspirin in heart failure is still not established.
* Aspirin may attenuate the hemodynamic and survival benefits of ACE inhibitors.

## See also

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* Coagulation
* Anticoagulants

## References

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1. ↑ WISHART JH, CHAPMAN CB (1948). "Dicumarol therapy in congestive heart failure". N Engl J Med. 239 (19): 701–4. doi:10.1056/NEJM194811042391902. PMID 18892580.
2. ↑ HARVEY WP, FINCH CA (1950). "Dicumarol prophylaxis of thromboembolic disease in congestive heart failure". N Engl J Med. 242 (6): 208–11. doi:10.1056/NEJM195002092420603. PMID 15403339.
3. ↑ GRIFFITH GC, STRAGNELL R, LEVINSON DC, MOORE FJ, WARE AG (1952). "A study of the beneficial effects of anticoagulant therapy in congestive heart failure". Ann Intern Med. 37 (5): 867–87. PMID 12986600.CS1 maint: Multiple names: authors list (link)
4. ↑ 4.0 4.1 Massie BM, Shah NB (1997). "Evolving trends in the epidemiologic factors of heart failure: rationale for preventive strategies and comprehensive disease management". Am Heart J. 133 (6): 703–12. PMID 9200399.
5. ↑ Yamamoto K, Ikeda U, Furuhashi K, Irokawa M, Nakayama T, Shimada K (1995). "The coagulation system is activated in idiopathic cardiomyopathy". J Am Coll Cardiol. 25 (7): 1634–40. PMID 7539015.CS1 maint: Multiple names: authors list (link)
6. ↑ 6.0 6.1 Sbarouni E, Bradshaw A, Andreotti F, Tuddenham E, Oakley CM, Cleland JG (1994). "Relationship between hemostatic abnormalities and neuroendocrine activity in heart failure". Am Heart J. 127 (3): 607–12. PMID 8122609.CS1 maint: Multiple names: authors list (link)
7. ↑ de Peuter OR, Kok WE, Torp-Pedersen C, Büller HR, Kamphuisen PW (2009). "Systolic heart failure: a prothrombotic state". Semin Thromb Hemost. 35 (5): 497–504. doi:10.1055/s-0029-1234145. PMID 19739040.CS1 maint: Multiple names: authors list (link)
8. ↑ Lip GY, Gibbs CR (1999). "Does heart failure confer a hypercoagulable state? Virchow's triad revisited". J Am Coll Cardiol. 33 (5): 1424–6. PMID 10193748.
9. ↑ Niebauer J, Volk HD, Kemp M, Dominguez M, Schumann RR, Rauchhaus M; et al. (1999). "Endotoxin and immune activation in chronic heart failure: a prospective cohort study". Lancet. 353 (9167): 1838–42. doi:10.1016/S0140-6736(98)09286-1. PMID 10359409.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
10. ↑ Rosamond W, Flegal K, Friday G, Furie K, Go A, Greenlund K; et al. (2007). "Heart disease and stroke statistics--2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee". Circulation. 115 (5): e69–171. doi:10.1161/CIRCULATIONAHA.106.179918. PMID 17194875.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
11. ↑ 11.0 11.1 Task Force for Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of European Society of Cardiology. Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P; et al. (2008). "ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM)". Eur Heart J. 29 (19): 2388–442. doi:10.1093/eurheartj/ehn309. PMID 18799522.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
12. ↑ Davis RC, Hobbs FD, Lip GY (2000). "ABC of heart failure. History and epidemiology". BMJ. 320 (7226): 39–42. PMC 1117316. PMID 10617530.CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
13. ↑ 13.0 13.1 Uretsky BF, Thygesen K, Armstrong PW, Cleland JG, Horowitz JD, Massie BM; et al. (2000). "Acute coronary findings at autopsy in heart failure patients with sudden death: results from the assessment of treatment with lisinopril and survival (ATLAS) trial". Circulation. 102 (6): 611–6. PMID 10931799.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
14. ↑ Dries DL, Exner DV, Gersh BJ, Domanski MJ, Waclawiw MA, Stevenson LW (1998). "Atrial fibrillation is associated with an increased risk for mortality and heart failure progression in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a retrospective analysis of the SOLVD trials. Studies of Left Ventricular Dysfunction". J Am Coll Cardiol. 32 (3): 695–703. PMID 9741514.CS1 maint: Multiple names: authors list (link)
15. ↑ Kannel WB, Wolf PA, Verter J (1983). "Manifestations of coronary disease predisposing to stroke. The Framingham study". JAMA. 250 (21): 2942–6. PMID 6227757.CS1 maint: Multiple names: authors list (link)
16. ↑ Dunkman WB, Johnson GR, Carson PE, Bhat G, Farrell L, Cohn JN (1993). "Incidence of thromboembolic events in congestive heart failure. The V-HeFT VA Cooperative Studies Group". Circulation. 87 (6 Suppl): VI94–101. PMID 8500246.CS1 maint: Multiple names: authors list (link)
17. ↑ Loh E, Sutton MS, Wun CC, Rouleau JL, Flaker GC, Gottlieb SS; et al. (1997). "Ventricular dysfunction and the risk of stroke after myocardial infarction". N Engl J Med. 336 (4): 251–7. doi:10.1056/NEJM199701233360403. PMID 8995087.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
18. ↑ Dries DL, Rosenberg YD, Waclawiw MA, Domanski MJ (1997). "Ejection fraction and risk of thromboembolic events in patients with systolic dysfunction and sinus rhythm: evidence for gender differences in the studies of left ventricular dysfunction trials". J Am Coll Cardiol. 29 (5): 1074–80. PMID 9120162.CS1 maint: Multiple names: authors list (link)
19. ↑ Cleland JG, Findlay I, Jafri S, Sutton G, Falk R, Bulpitt C; et al. (2004). "The Warfarin/Aspirin Study in Heart failure (WASH): a randomized trial comparing antithrombotic strategies for patients with heart failure". Am Heart J. 148 (1): 157–64. doi:10.1016/j.ahj.2004.03.010. PMID 15215806.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
20. ↑ 20.0 20.1 Cokkinos DV, Haralabopoulos GC, Kostis JB, Toutouzas PK, HELAS investigators (2006). "Efficacy of antithrombotic therapy in chronic heart failure: the HELAS study". Eur J Heart Fail. 8 (4): 428–32. doi:10.1016/j.ejheart.2006.02.012. PMID 16737850.CS1 maint: Multiple names: authors list (link)
21. ↑ Freudenberger RS, Hellkamp AS, Halperin JL, Poole J, Anderson J, Johnson G; et al. (2007). "Risk of thromboembolism in heart failure: an analysis from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)". Circulation. 115 (20): 2637–41. doi:10.1161/CIRCULATIONAHA.106.661397. PMID 17485579.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
22. ↑ Massie BM, Krol WF, Ammon SE, Armstrong PW, Cleland JG, Collins JF; et al. (2004). "The Warfarin and Antiplatelet Therapy in Heart Failure trial (WATCH): rationale, design, and baseline patient characteristics". J Card Fail. 10 (2): 101–12. PMID 15101020.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
23. ↑ Cohen AT, Davidson BL, Gallus AS, Lassen MR, Prins MH, Tomkowski W; et al. (2006). "Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial". BMJ. 332 (7537): 325–9. doi:10.1136/bmj.38733.466748.7C. PMC 1363908. PMID 16439370.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
24. ↑ St John Sutton M, Pfeffer MA, Moye L, Plappert T, Rouleau JL, Lamas G; et al. (1997). "Cardiovascular death and left ventricular remodeling two years after myocardial infarction: baseline predictors and impact of long-term use of captopril: information from the Survival and Ventricular Enlargement (SAVE) trial". Circulation. 96 (10): 3294–9. PMID 9396419.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
25. ↑ Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG; et al. (2009). "2009 Focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation". J Am Coll Cardiol. 53 (15): e1–e90. doi:10.1016/j.jacc.2008.11.013. PMID 19358937.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)

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