Prothrombotic Factors in Heart Failure: Virchow’s Triad Revisited

Various abnormalities seen in patients with severe left ventricular (LV) systolic dysfunction, including endothelial damage and dysfunction, abnormal blood stasis, and a hypercoagulable state, provide a milieu contributing to thrombogenesis and thromboembolism. These 3 components are representative of Virchow’s triad of thrombogenesis, originally proposed >150 years ago.

Indeed, endothelial damage and dysfunction are a hallmark of HF, and their presence adversely affects prognosis in this condition. Endothelial dysfunction is accompanied by the imbalance of pro- and anticoagulant systems, with clear shift toward a prothrombotic direction. Plasma markers of endothelial damage and dysfunction, such as von Willebrand factor, soluble thrombomodulin, and soluble E-selectin, are significantly increased in patients with acute and chronic HF. A dysfunctional endothelium also actively produces inflammatory cytokines (e.g., tumor necrosis factor–α and interleukin-1), which are significantly upregulated in HF and further promote thrombogenesis.

In addition, the presence of dilated and/or dysfunctional cardiac chambers creates areas of blood stasis, particularly in patients with dilated cardiomyopathy, large anterior myocardial infarctions, and LV aneurysms. Stasis accelerates the activation of the coagulation system and fibrin formation. Also, abnormal blood constituents leading to a prothrombotic or hypercoagulable state have been reported in HF patients, as reflected by high circulating biomarker levels, including fibrinogen, antithrombin III, fibrinopeptide A, and fibrin d -dimer. Activation of the neuroendocrine system, especially upregulation of angiotensin and endothelin production, further enhances the prothrombotic state in HF.

Thrombosis in Chronic Heart Failure

Evidence of an increased risk for thromboembolic events (stroke, pulmonary and peripheral thromboembolism) in patients with chronic HF free of AF in large prospective cohorts is relatively limited, although retrospective analyses of HF treatment trials and data from some epidemiologic cohort studies are available. Many older cohort studies have included proportions of patients with AF, which may well be asymptomatic and/or paroxysmal in nature, which is itself a strong independent risk factor for thromboembolism. Without associated AF, the risk for thromboembolism may be small; for example, 1 analysis of patients with HF in New York Heart Association class II and III without AF found only a 1% annual risk for thromboembolism. However, almost half of sudden cardiac deaths in HF have been shown to be due to acute myocardial infarction or coronary thrombosis, and 27% of deaths in HF originally classified as progressive congestive HF are actually caused by coronary thrombosis. Given that sudden cardiac death is a major contributor to mortality in HF populations, it is probable that the impact of thromboembolism in HF might be underestimated.

The risk for thromboembolism may be particularly high in patients with severely depressed cardiac contractility. In the Survival and Ventricular Enlargement (SAVE) trial, for example, the risk for stroke was twofold higher in patients with ejection fractions (EFs) <28% compared to those with EFs ≥28%, and every 5% reduction in the EF was associated with an 18% increase in stroke risk. In the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), from which patients with AF were excluded, the 4-year rate of thromboembolic events was 3.5% in those with EFs of 30% to 35%, 3.6% in those with EFs of 20% to 30%, and 4.6% in those with EFs <20%, equivalent to annual rates of 0.9%, 0.9%, and 1.2%, respectively.

Thrombosis in Chronic Heart Failure

Evidence of an increased risk for thromboembolic events (stroke, pulmonary and peripheral thromboembolism) in patients with chronic HF free of AF in large prospective cohorts is relatively limited, although retrospective analyses of HF treatment trials and data from some epidemiologic cohort studies are available. Many older cohort studies have included proportions of patients with AF, which may well be asymptomatic and/or paroxysmal in nature, which is itself a strong independent risk factor for thromboembolism. Without associated AF, the risk for thromboembolism may be small; for example, 1 analysis of patients with HF in New York Heart Association class II and III without AF found only a 1% annual risk for thromboembolism. However, almost half of sudden cardiac deaths in HF have been shown to be due to acute myocardial infarction or coronary thrombosis, and 27% of deaths in HF originally classified as progressive congestive HF are actually caused by coronary thrombosis. Given that sudden cardiac death is a major contributor to mortality in HF populations, it is probable that the impact of thromboembolism in HF might be underestimated.

The risk for thromboembolism may be particularly high in patients with severely depressed cardiac contractility. In the Survival and Ventricular Enlargement (SAVE) trial, for example, the risk for stroke was twofold higher in patients with ejection fractions (EFs) <28% compared to those with EFs ≥28%, and every 5% reduction in the EF was associated with an 18% increase in stroke risk. In the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), from which patients with AF were excluded, the 4-year rate of thromboembolic events was 3.5% in those with EFs of 30% to 35%, 3.6% in those with EFs of 20% to 30%, and 4.6% in those with EFs <20%, equivalent to annual rates of 0.9%, 0.9%, and 1.2%, respectively.

Oral Anticoagulation in Heart Failure

Retrospective analyses of large HF trials have produced controversial results on the role of oral anticoagulation. For example, the analyses from the Studies of Left Ventricular Dysfunction (SOLVD) and SAVE trials found that warfarin seemed to be beneficial in patients with HF, being associated with a significant 24% relative risk reduction in all-cause mortality as well as a lower risk for HF hospitalization, but not with a reduction of thromboembolic events. However, no benefits from warfarin for thromboembolism prevention were evident in the Veterans Affairs Vasodilator–Heart Failure Trial (V-HeFT) and SCD-HeFT.

Recent controlled clinical trials of oral anticoagulation for HF have had poor recruitment and small numbers and were underpowered. The largest published study was the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial, which randomized patients with HF with EFs <30% to receive warfarin or aspirin or clopidogrel, but the study was terminated early because of poor recruitment. Despite being underpowered, the WATCH study did show a strong trend favoring warfarin over aspirin for the reduction of nonfatal stroke (0.7% vs 2.1%), as well as fewer hospitalizations in the warfarin group (16.1%) compared to aspirin (22.2%) and clopidogrel (18.3%). However, the grim side of warfarin therapy was a significant increase in the bleeding rate (5.5%) compared to aspirin (3.6%) and clopidogrel (2.5%).

In this issue of The American Journal of Cardiology , Mujib et al provide further evidence that the universal administration of oral anticoagulation in patients with HF may not be beneficial. The study has the advantage of studying >1,600 patients with severe LV dysfunction, and the investigators conclude that despite therapeutic international normalized ratios in those receiving warfarin, its use had no significant effect on mortality and hospitalization. However, the study represents a post hoc analysis of a previously published randomized clinical trial, and administration of anticoagulants was at the discretion of the treating physician and not randomized. Second, only 471 patients received warfarin, with a median international normalized ratio of 2.0, which perhaps suggests that about half the patients treated with warfarin received suboptimal anticoagulation. Indeed, good anticoagulation control (expressed as time in therapeutic range) is crucial for the best outcomes when warfarin is used. Third, detailed data on stroke and thromboembolism incidence were not recorded. Indeed, given the very high mortality of patients with HF (30% in this study), relatively small changes in thromboembolism-related mortality could pass unnoticed.

Given that the secondary end point of stroke was significantly reduced in WATCH, attention to this outcome in future analyses would be needed in any future clinical trials, rather than the focus on overall mortality, which may not be significantly affected. Although Mujib et al tried to exclude patients with AF from their study, many patients with HF could develop AF in paroxysms and asymptomatically; thus, it is essentially how hard one looks to exclude underlying AF from being a major confounder.