European Journal of Heart Failure 3 2001.

265 269

Thromboembolism in heart failure, old ideas and new challenges

Richard IsnardU , Michel Komajda
Cardiology Department, Hopital Pitie-Salpetriere, 47 Boule ard de lHopital, 75651 Paris Cedex 13, France ` Received 2 August 2000; received in revised form 22 December 2000; accepted 12 February 2001

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Abstract Until now, the administration of antithrombotic therapy in patients with congestive heart failure has not been well codied. The incidence of thromboembolic complication, such as stroke, peripheral or pulmonary embolism, is regarded as too low to justify the use of anticoagulation in non-selected patients. However, other thrombotic complications may occur especially in patients with ischemic heart failure and represent potential targets for antithrombotic therapy. The objective of this paper is to review the available evidence in the absence of the results of large ongoing trials. 2001 European Society of Cardiology. All rights reserved.
Keywords: Congestive heart failure; Anticoagulation; Antithrombotic therapy

1. Introduction It is well recognized that patients with heart failure HF. have an increased risk of thromboembolic complications. For prevention purposes, some patients receive warfarin, others receive antiplatelet agents or no antithrombotic therapy. Anticoagulation with warfarin is mandatory in patients with heart failure and atrial brillation in the absence of contraindications. However, the decision whether to give antithrombotic therapy to patients with heart failure in sinus rhythm, essentially depends on the physicians experience and his own evaluation of the thromboembolic risk of each patient. Unfortunately, until now neither randomized nor controlled studies have been available to guide the physicians prescription. The objective of

this paper is to review the available evidence in the absence of the results of large ongoing trials.

2. Thromboembolism in heart failure: old ideas When considering thromboembolism in heart failure, the rst idea which occurs is the risk of thrombus formation in the cardiac chambers and the risk of thrombus migration in the systemic or pulmonary circulation. Intra-cardiac thrombi were rst demonstrated by autopsy studies, then during cardiac surgery and nally by cardiac imaging, especially echocardiography. The risk of thromboembolism in HF is multifactorial: low cardiac output through dilated cavities of poor contractility; regional wall motion abnormalities; and atrial brillation are the main factors. Abnormal endocardial surface after myocardial infarction or in inammatory or inltrative cardiomyopathy may also favour the formation of clots. It has also been suggested recently that patients with HF

Corresponding author. IFR 14 Muscles, cur, vaisseaux. Tel.: q33-142176727; fax: q33-142176719. E-mail address: richard.isnard@psl.ap-hop-paris.fr R. Isnard..

1388-9842r01r$20.00 2001 European Society of Cardiology. All rights reserved. PII: S 1 3 8 8 - 9 8 4 2 0 1 . 0 0 1 4 0 - 4

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R. Isnard, M. Komajda r European Journal of Heart Failure 3 (2001) 265 269

Table 1 Incidence and type of TE events in small studies ) 100 patients. a N Fuster a w5x Katz w7x Natterson w6x Ciof w4x Mean age 49 62 50 Follow-up months. 72 24 10 AF %. 30 na 12 LVEF %. TE events n type. 23 6 strokes 3 TIA 3 strokes 1 TIA 2 periph E 7 strokes 1 TIA 3 periph E. TE events incidence%ry. 3.5 1.7 2.2

103 264 224

27 20

406

54

16

10

24

Retrospective; AF, atrial brillation; LVEF, left ventricular ejection fraction; TIA, transient ischemic attacks; periph. E, peripheral emboli.

may be in a hypercoagulable state w1,2x. Furthermore, venous stasis due to circulatory slowing and reduced activity may result in pulmonary embolism. Therefore, thromboembolism in HF has usually been dened as the occurrence of stroke, peripheral embolism or pulmonary embolism. In autopsy studies, the incidence is very high; Roberts reported a frequency of 37% in 152 patients with dilated cardiomyopathy w3x. However, it is difcult to extrapolate from these studies if death is related to a thromboembolic complication or if the presence of thrombus in the cardiovascular system is only a marker of end-stage heart failure. On the opposite, several small clinical studies w4 7x have reported a relatively low incidence of clinical thromboembolic complications, ranging from 1.7 to 3.5% a year Table 1.. A metaanalysis reported an incidence of stroke and peripheral arterial embolism of 1.9% in patients not receiving anticoagulant therapy w8x. Large scale therapeutic trials provided the opportunity to follow for several years large cohorts of patients with heart failure or asymptomatic left ventricular systolic dysfunction following or not myocardial inTable 2 Incidence and type of TE events in large scale therapeutic trials Etudes CONSENSUS w9x Ve-HeFT I w10x Ve-HeFTII w10x SOLVD ttt q prev. w11x SAVE w12x N Mean Age years. 70 58 Follow-up months. 6 28

farction w9 12x: even if there were some slight differences in the methodology some studies reported only strokes or fatal strokes, others reported all the events including pulmonary events. it is noteworthy that the incidence is very close to the previous values approx. 2% a year. Table 2.. This incidence is not signicantly different according to whether patients received warfarin, which does not mean that warfarin is not efcient, as we can guess that patients receiving warfarin have the higher risk of thromboembolism. Information about the proportion of the different types of thromboembolic events is available from VHeF-T and SOLVD trials w10,11x: stroke represents 60 80% of these events whereas peripheral and pulmonary embolism only 10 20% each. Therefore, the annual incidence of stroke is less than 2% and not all of the cases are related to cardioembolic events, especially in patients with ischemic heart disease in whom associated cerebrovascular atherosclerosis may sometimes be the cause of the events. To summarize, there is agreement in all the published studies for the expected incidence of clinical TE events to be approximately 2% a year. However,

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AF %. 50 16

LVEF %.

TE events n type. 3 fatal stroke 26 strokes 5 Periph E 5 Pulm E 38 strokes 2 Periph E 6 Pulm E 226 strokes 59 Periph E 55 Pulm E 103 strokes

TE events incidence %ryear. 2.3a 2.7

253 642

30

804

61

31

15

29

2.1

6378 b 5457 men 921 women 2231

69

39

- 35 - 40

1.8 men. 2.4 women. 1.5a

59

42

10

a Retrospective; AF, atrial brillation; LVEF, left ventricular ejection fraction; TIA, transient ischemic attacks; periph. E, peripheral emboli. a, only strokes. b Only patients in sinus rhythm.

R. Isnard, M. Komajda r European Journal of Heart Failure 3 (2001) 265 269

267

the annual incidence of major haemorrhages during anticoagulant therapy reported in recent studies ranges from 2.3 in the randomized controlled study in which patients are highly selected, to 5.3% in population-based studies and 6.8% in elderly patients w13 16x. Therefore, given the low incidence of thromboembolic events in unselected patients and the risk of major bleedings with the anticoagulant, it is generally admitted that anticoagulation must be reserved for patients with HF with a very high risk of thromboembolism. In this setting, atrial brillation, mobile thrombus in the cardiac chambers and previous cardioembolic events are factors that predispose to TE events. The incidence of atrial brillation in HF grows with the stage of the disease and the age of the patient, ranging from 10% in the SOLVD study mild to moderate HF, mean age 60. w17x, to 30% in the ELITE II study mild to moderate heart failure, mean age 73. w18x, and to 50% in the CONSENSUS study severe HF, mean age 70. w9x. Other risk factors, such as low left ventricular ejection fraction or low peak oxygen consumption, have also been identied, suggesting that patients with severe left ventricular systolic dysfunction or heart failure, are considered as being at high risk for thromboembolism, but there is no clear cut-off values for identifying high-risk subgroups.

3. Thromboembolism in heart failure: new challenges As a matter of fact, we must be very cautious with a too simplistic interpretation of the previous results. Firstly, some thromboembolic events may have been underestimated or misdiagnosed. This is probably the case for pulmonary embolism, as this diagnosis is often difcult in clinical practice. This is particularly true in patients with heart failure, in whom episodes of acute heart failure may be triggered by pulmonary embolism and sudden death may result from massive pulmonary embolism. This is borne out by the necropsic data from Roberts showing that unlike the ndings from clinical studies, pulmonary embolism is more frequent than systemic embolism w3x. The same might be true for stroke as it has been shown using brain nuclear imaging that clinically silent strokes are more frequent in patients with dilated cardiomyopathy than in controls w19x. Secondly, the relevant target for antithrombotic therapy might be not limited to the previously dened thromboembolic events. To date, ischemic heart disease is still the leading cause of HF. In these patients, acute coronary events such as unstable angina or myocardial infarction may occur and represent a common and severe thrombotic complication w20x. Conversely, some sudden deaths whether arrhythmic or

not, are related to coronary thrombosis or to massive pulmonary embolism. This has been clearly shown in patients who experienced a cardiac arrest without previous known cardiovascular disease, in whom signicant coronary artery disease is found in 40 60% with a high proportion of coronary thrombosis w21,22x. As regards mechanisms of sudden death in heart failure, data are scarce: Stevenson reported 29 cardiac arrests in hospitalized but stable patients with HF: myocardial ischemia is reported as the trigger in approximately 20% of the cases w23x. Recently, Urestsky et al. reported a 33% prevalence of acute coronary ndings at autopsy in 171 patients from the ATLAS study. This prevalence was 54% in patients with ischemic heart failure who died suddenly w24x. These observations raise an interesting hypothesis: if we assume that thrombosis is involved not only in acute coronary events but also in sudden deaths in patients with ischemic heart disease, the challenge of antithrombotic therapy in heart failure is therefore not limited to classical thromboembolic complications. In the WARIS study, warfarin anticoagulation when started within 4 weeks after acute myocardial infarction reduces mortality, fatal and non-fatal coronary events, pulmonary embolism and stroke w25x. Other studies also demonstrated a reduction of recurrent myocardial infarction achieved with anticoagulant given after acute myocardial infarction. Recent cohort post-hoc analysis from SOLVD suggested that warfarin prescription at baseline was associated with a decrease in sudden death, fatal myocardial, and hospital admissions for non-fatal MI w26x. Similar results were observed with aspirin w27x. What is the incidence of acute coronary events and sudden death in heart failure? In the SOLVD trial, in which almost 75% of patients had ischemic heart disease, the annual incidence of unstable angina and

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Table 3 Estimated incidence of all thromboembolic events in patients with ischemic heart failure Events Incidence %ryear. 2

Stroke, peripheral embolism, pulmonary embolism w8x Unstable angina w20x Fatal and non-fatal MI w20x Sudden death related to coronary thrombosis w23,24x Total

4.5 2.5 0.6 3

f 9.6 12

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R. Isnard, M. Komajda r European Journal of Heart Failure 3 (2001) 265 269 w8x Baker DW, Wright RF. Management of heart failure. IV. Anticoagulation for patients with heart failure due to left ventricular systolic dysfunction. J Am Med Assoc 1994;272:1614 18. w9x The CONSENSUS Trial Study Group. Effect of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study CONSENSUS.. N Engl J Med 1987;316:1429 35. w10x Dunkman WB, Johnson GR, Carson PE, Bhat G, Farrell L, Cohn JN. Incidence of thromboembolic events in congestive heart failure. The V-HeFT VA Cooperative Studies Group. Circulation 1993;876 Suppl..:94 101. w11x Dries DL, Rosenberg YD, Waclawiw MA, Domanski MJ. 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 1997;29:1074 80. w12x Loh E, St. John Sutton M, Wun CC et al. Ventricular dysfunction and the risk of stroke after myocardial infarction. N Engl J Med 1997;336:251 7. w13x Warfarin versus aspirin for prevention of thromboembolism in atrial brillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet. 1994;343:687 91. w14x van der Meer FJ, Rosendaal FR, Vandenbroucke JP, Briet E. Bleeding complications in oral anticoagulant therapy. An analysis of risk factors. Arch Intern Med 1993;153:1557 62. w15x Gitter MJ, Jaeger TM, Petterson TM, Gersh BJ, Silverstein MD. Bleeding and thromboembolism during anticoagulant therapy: a population-based study in Rochester, Minnesota. Mayo Clin Proc 1995;70:725 33. w16x Fihn SD, Callahan CM, Martin DC, McDonell MB, Henikoff JG, White RH. The risk for and severity of bleeding complications in elderly patients treated with warfarin. The National Consortium of Anticoagulation Clinics. Ann Intern Med 1996;124:970 9. w17x Investigators S. Effect of enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Engl J Med 1991;325:293 302. w18x Pitt B, Poole-Wilson PA, Segal R et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial the Losartan Heart Failure Survival Study ELITE II. Lancet 2000;355:1582 7. w19x Schmidt R, Fazekas F, Offenbacher H, Dusleag J, Lechner H. Brain magnetic resonance imaging and neuropsychologic evaluation of patients with idiopathic dilated cardiomyopathy. Stroke 1991;22:195 9. w20x Yusuf S, Pepine CJ, Garces C et al. Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fractions. Lancet. 1992;340:1173 78. w21x Loire R, Tabib A. Unexpected sudden cardiac death. An evaluation of 1000 autopsies. Arch Mal Coeur Vaiss 1996;89:13 18. w22x Spaulding CM, Joly LM, Rosenberg A et al. Immediate coronary angiography in survivors of out-of-hospital cardiac arrest. N Engl J Med 1997;336:1629 33. w23x Stevenson WG, Stevenson LW, Middlekauff HR, Saxon LA. Sudden death prevention in patients with advanced ventricular dysfunction. Circulation 1993;88:2953 61. w24x Uretsky BF, Thygesen K, Armstrong PW et al. Acute coronary ndings at autopsy in heart failure patients with sudden death. Results from the Assessment of Treatment with Lisinopril and Survival ATLAS. Trial. Circulation 2000;102: 611 16. w25x Smith P, Arnesen H, Holme I. The effect of warfarin on mortality and reinfarction after myocardial infarction. N Engl J Med 1990;323:147 52.

total myocardial infarction was approximately 5 and 3%, respectively, including 1% of fatal myocardial infarction w20x. Comparable rates of fatal myocardial infarction 0.8 1.3% a year. have been reported in other recent heart failure studies w18,28,29x. The incidence of sudden death ranges between 3 and 6% a year in CHF in the same recent studies including those with betablockers w18,28,29x. If we assume that 20 50% of these sudden deaths are triggered by a thrombotic event, 0.6 3% of sudden death per year could be prevented by antithrombic therapy. Thus, when adding the incidence of classical thromboembolic events to the incidence of coronary events and sudden death presumably related to coronary thrombosis, the estimated incidence of thromboembolic events could reach 12% a year Table 3., a quite high incidence that represents a real challenge for antithrombotic therapy. Which antithrombotic therapy should we prefer in this perspective? Antiplatelet agents have the advantage of being efcient in coronary and cerebrovascular disease and do not increase the risk of bleeding complications too much. However, they are less efcient than warfarin for preventing thrombus formation in the cardiac chambers and a potential negative interaction between aspirin and angiotensin converting enzyme inhibitors has been shown, even if its real clinical relevance in terms of morbidity and mortality remains unknown. We hope that results of the on going WATCH trial will provide denitive answers to all these questions. References
w1x Yamamoto K, Ikeda U, Furuhashi K, Irokawa M, Nakayama T, Shimada K. The coagulation system is activated in idiopathic cardiomyopathy. J Am Coll Cardiol 1995;25:1634 40. w2x Sbarouni E, Bradshaw A, Andreotti F, Tuddenham E, Oakley CM, Cleland JG. Relationship between hemostatic abnormalities and neuroendocrine activity in heart failure. Am Heart J 1994;127:607 12. w3x Roberts WC, Siegel RJ, McManus BM. Idiopathic dilated cardiomyopathy: analysis of 152 necropsy patients. Am J Cardiol 1987;60:1340 55. w4x Ciof G, Pozzoli M, Forni G et al. Systemic thromboembolism in chronic heart failure. A prospective study in 406 patients. Eur Heart J 1996;17:1381 9. w5x Fuster V, Gersh BJ, Giuliani ER, Tajik AJ, Brandenburg RO, Frye RL. The natural history of idiopathic dilated cardiomyopathy. Am J Cardiol 1981;47:525 31. w6x Natterson PD, Stevenson WG, Saxon LA, Middlekauff HR, Stevenson LW. Risk of arterial embolization in 224 patients awaiting cardiac transplantation. Am Heart J 1995;129: 564 70. w7x Katz SD, Marantz PR, Biasucci L et al. Low incidence of stroke in ambulatory patients with heart failure: a prospective study. Am Heart J 1993;126:141 6.

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R. Isnard, M. Komajda r European Journal of Heart Failure 3 (2001) 265 269 w26x Al-Khadra AS, Salem DN, Rand WM, Udelson JE, Smith JJ, Konstam MA. Warfarin anticoagulation and survival: a cohort analysis from the studies of left ventricular dysfunction. J Am Coll Cardiol 1998;31:749 53. w27x Al-Khadra AS, Salem DN, Rand WM, Udelson JE, Smith JJ, Konstam MA. Antiplatelet agents and survival: a cohort analysis from the studies of left ventricular dysfunction SOLVD. trial. J Am Coll Cardiol 1998;31:419 25.

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w28x Effect of metoprolol CRrXL in chronic heart failure: Metoprolol CRrXL Randomised Intervention Trial in Congestive Heart Failure MERIT-HF.. Lancet 1999;353:2001 7. w29x The Cardiac Insufciency Bisoprolol Study II CIBIS-II.: a randomised trial. Lancet 1999;353:9 13.

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