Prognostic value of interleukin-6, plasma viscosity, fibrinogen, von Willebrand factor, tissue factor and vascular endothelial growth factor levels in congestive heart failure.

BACKGROUND: Congestive heart failure (CHF) carries a poor prognosis with a high mortality rate, frequent hospitalizations and increased risk of thrombotic complications such as stroke. Cytokines may contribute to the progression and prothrombotic state of CHF, including the pro-inflammatory interleukin-6 (IL-6) and the pro-angiogenic vascular endothelial growth factor (VEGF), both of which are raised in CHF. The procoagulant properties of both cytokines may be mediated via tissue factor (TF), a potent clotting activator. We hypothesized that plasma levels of these markers, as well as levels of plasma viscosity, fibrinogen, soluble P-selectin and von Willebrand factor (markers of abnormal rheology, clotting, platelet activation, and endothelial damage, respectively) will be useful in predicting morbidity and mortality in chronic stable CHF. METHODS AND RESULTS: One hundred and twenty consecutive out-patients with chronic stable CHF (92 males; mean [SD] age 64 [11] years, mean [SD] left ventricular ejection fraction of 29 [6]%) were recruited and followed for 2 years during which 42 patients reached a clinical end-point of all-cause mortality and cardiovascular hospitalizations, including stroke and myocardial infarction. Plasma IL-6 (P=0.003) and TF (P=0.013) levels, but not other research indices, were higher in those who suffered events compared with those without events. Predictors of end-points were high (> or =median) TF (P=0.011), and IL-6 (P=0.023) levels, as well as the lowest quartile of a left ventricular ejection fraction (P=0.007). A strong correlation was present between TF and IL-6 levels (r=0.59; P<0.0001) and with VEGF levels (r=0.43; P<0.0001). CONCLUSION: IL-6 and TF are predictors of poor prognosis in chronic CHF, raising the hypothesis that IL-6 may contribute to the progression and thrombotic complications of CHF via its actions on TF expression. Although VEGF did not independently predict outcome in chronic CHF, the possibility arises that it may act with IL-6 to induce TF expression.

Anticoagulation for heart failure in sinus rhythm: a Cochrane systematic review.

BACKGROUND: Patients with chronic heart failure (heart failure) are at risk of thromboembolic events, and coronary ischaemic events also contribute to the progression of heart failure. Long-term oral anticoagulation is established in certain groups, including patients with heart failure and atrial fibrillation, but there is wide variation in the use of oral anticoagulation in the broader heart failure population. OBJECTIVE: To determine whether long-term oral anticoagulation reduces total deaths and/or major thromboembolic events in patients with heart failure. DESIGN: Systematic review. DATA SOURCES: Reference lists of papers resulting from this search, electronic database searching (MEDLINE, EMBASE, DARE), and abstracts from national and international cardiovascular meetings were studied to identify unpublished studies. Relevant authors of these studies were contacted to obtain further data. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing oral anticoagulants with control or placebo. Non-randomized studies were included, as they may help in assessing side-effects. Other inclusion criteria included duration of treatment > or =1 month, and adults with heart failure due to any underlying cause. Inclusion decisions were duplicated, and disagreement resolved by discussion or a third party. RESULTS: One recent pilot RCT compared warfarin, aspirin and no antithrombotic therapy, but no definitive data have yet been published. Three small prospective studies of warfarin in heart failure were also identified, but were over 50 years old, with methods considered unreliable today: in these, anticoagulation was more efficacious than control in reducing all-cause death (OR 0.64; 95%CI 0.45-0.90) and cardiovascular events (OR 0.26; 95%CI 0.16-0.43). Four retrospective non-randomized cohort analyses and three small observational studies of oral anticoagulation in heart failure included differing populations of heart failure patients, and reported contradictory results. CONCLUSIONS: Limited evidence from randomized trials and observational studies found a reduction in mortality and cardiovascular events with anticoagulants compared to controls. This evidence should be interpreted with caution. Although oral anticoagulation is indicated in certain groups of patients with heart failure (e.g. atrial fibrillation), the available data do not support its routine use in heart failure patients who remain in sinus rhythm.

Antiplatelet agents versus control or anticoagulation for heart failure in sinus rhythm: a Cochrane systematic review.

BACKGROUND: Heart failure predisposes to stroke and thromboembolism, which in turn contribute to the high mortality and morbidity in heart failure. OBJECTIVES: To determine the effect of antiplatelet agents, compared to placebo or anticoagulant therapy, on death and/or major thromboembolic events in adults with heart failure who are in sinus rhythm. DESIGN: Systematic review of randomized parallel group placebo or controlled trials comparing oral antiplatelet therapy with control or anticoagulation therapy in adults with chronic heart failure in sinus rhythm. DATA SOURCES: Reference lists of papers resulting from this search, electronic database searching (MEDLINE, EMBASE, DARE), and abstracts from national and international cardiovascular meetings were studied to identify unpublished studies. Relevant authors of these studies were contacted to obtain further data. SELECTION CRITERIA: These included duration of treatment of at least 1 month, and adults with heart failure due to any underlying cause. To assess any adverse effects, cohort study and non-randomized controlled studies were assessed. Inclusion decisions were duplicated, disagreement resolved by discussion or a third party. No meta-analyses were performed, as no data were available from randomized comparisons. RESULTS: One randomized controlled trial of warfarin vs. aspirin vs. no antithrombotic therapy was found, but no definitive data have yet been published. Three retrospective, non-randomized cohort studies from large trials examining the role of ACE inhibitors have examined the role of aspirin therapy with and without anticoagulant therapy in patients with heart failure and/or left ventricular systolic dysfunction were identified, but the results from these trials were conflicting. A possible interaction with ACE inhibitors may reduce the efficacy of aspirin, although this evidence is from retrospective analyses of trial cohorts. CONCLUSIONS: At present there is no evidence from long term RCTs to recommend use of aspirin to prevent thromboembolism in patients with heart failure in sinus rhythm. There is also no evidence to indicate superior effects from oral anticoagulation, when compared to aspirin, in patients with heart failure in sinus rhythm.

Antiplatelet agents versus control or anticoagulation for heart failure in sinus rhythm.

BACKGROUND: Morbidity and mortality in patients with symptomatic chronic heart failure is high, it predisposes to stroke and thromboembolism which in turn contribute to high mortality in heart failure. OBJECTIVES: To determine effect of antiplatelet agents when compared to placebo or anticoagulant therapy on death and/or major thromboembolic events in adults with heart failure who are in sinus rhythm. SEARCH STRATEGY: Systematic search of electronic databases (MEDLINE, EMBASE, DARE). Abstracts from cardiology meetings and reference lists of relevant papers were searched. Authors of studies were contacted for further information. SELECTION CRITERIA: Randomised parallel group placebo or controlled trials comparing antiplatelet therapy with control or anticoagulation in adults with chronic heart failure in sinus rhythm. Treatment for at least 1 month. To assess any adverse effects cohort study & non-randomised controlled studies were assessed. Orally administered antiplatelet agents e.g. non-steroidal anti-inflammatory agents, TICLOPIDINE, CLOPIDOGREL, DIPYRIDAMOLE, ASPIRIN compared with anticoagulant agents e.g. COUMARINS, WARFARIN or placebo. DATA COLLECTION AND ANALYSIS: Data were extracted by two reviewers independently. No meta-analyses were performed as no data were available from randomised comparisons. The data extracted included data relating to the complexities of the topic area, such as patient characteristics and concomitant treatments, as well as data relating to study eligibility, quality, and outcomes. Non-randomised studies were used to identify side-effects caused by anticoagulants. MAIN RESULTS: One RCT of warfarin, aspirin versus no antithrombotic therapy was found but no definitive data have yet been published. Three retrospective, non-randomised cohort studies from the V-HeFT, SOLVD and SAVE trials examining the role of ACE inhibitors have examined the role of aspirin therapy +/- anticoagulant therapy in patients with heart failure and/or left ventricular systolic dysfunction. The results from these trials were conflicting. REVIEWER'S CONCLUSIONS: At present there is no evidence from long term RCTs to recommend use of aspirin to prevent thromboembolism in patients with heart failure in sinus rhythm. A possible interaction with ACE inhibitors may reduce the efficacy of aspirin, although this evidence is from retrospective analyses of trial cohorts. There is also no evidence to indicate superior effects from oral anticoagulation, when compared to aspirin, in patients with heart failure in sinus rhythm.

Anticoagulation for heart failure in sinus rhythm.

BACKGROUND: Patients with chronic heart failure (heart failure) are at risk of thromboembolic events, including stroke, pulmonary embolism and peripheral arterial embolism, whilst coronary ischaemic events also contribute to the progression of heart failure. Long-term oral anticoagulation is established in certain groups, including patients with heart failure and atrial fibrillation but there is wide variation in the indications and use of oral anticoagulation in the broader heart failure population. OBJECTIVES: To determine whether long-term oral anticoagulation reduces total deaths and/or major thromboembolic events in patients with heart failure, when compared to placebo. SEARCH STRATEGY: Reference lists of papers resulting from this search, electronic database searching (MEDLINE, EMBASE, DARE), and abstracts from national and international cardiovascular meetings were studied to identify unpublished studies. Relevant authors of these studies were contacted to obtain further data. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing oral anticoagulants with control or placebo. Non-randomised studies were included as they may help in assessing side-effects. Duration of treatment at least 1 month, adults with heart failure due to any underlying cause. Inclusion decisions were duplicated, disagreement resolved by discussion or a third party. DATA COLLECTION AND ANALYSIS: Data were collected by two reviewers independently and where appropriate data from RCTs were meta-analysed. MAIN RESULTS: One recent pilot RCT compared warfarin, aspirin and no antithrombotic therapy, but no definitive data have yet been published. Three small prospective studies of warfarin in heart failure were also identified, but were over 50 years old with methods not considered reliable by modern standards. Anticoagulation was more efficacious than control for the reduction of all cause death (odds ratio 0.64 95% CI 0.45,0.90) and the reduction of cardiovascular events (0.26 95% CI 0.16, 0.43). Four retrospective non-randomised cohort analyses and three small observational studies of oral anticoagulation in heart failure included differing populations of heart failure patients and reported contradictory results. REVIEWER'S CONCLUSIONS: Evidence from the RCTs and observational studies found a reduction in mortality and cardiovascular events with anticoagulants compared to control. This evidence needs to be interpreted with caution. Although oral anticoagulation is indicated in certain groups of patients with heart failure (eg atrial fibrillation), the data available does not support its routine use in heart failure patients who remain in sinus rhythm. A large randomised trial of warfarin in heart failure patients in sinus rhythm is currently in progress data from which will be useful addition to this story.

Effects of acute exercise on hemorheological, endothelial, and platelet markers in patients with chronic heart failure in sinus rhythm.

BACKGROUND: Chronic heart failure (CHF) is associated with an increased risk of thrombosis and thromboembolic events, including stroke and venous thromboembolism. which may be related to a prothrombotic or hypercoagulable state. Acute vigorous exercise has been associated with activation of hemostasis, and this risk may well be particularly increased in patients with CHF. HYPOTHESIS: The study was undertaken to determine whether acute exercise would adversely affect abnormalities of hemorheological (fibrinogen, plasma viscosity, hematocrit), endothelial (von Willebrand factor), and platelet markers (soluble P selectin) in patients with CHF. METHODS: We studied 22 ambulant outpatients (17 men; mean age 65+/-9 years) with stable CHF (New York Heart Association class II-III and a left ventricular ejection fraction of < or =40%) who were exercised to exhaustion on a treadmill. Results were compared with 20 hospital controls (patients with vascular disease, but free of CHF) and 20 healthy controls. RESULTS: Baseline von Willebrand factor (p = 0.01) and soluble P-selectin (p = 0.006) levels were significantly elevated in patients with CHF when compared with controls. In the patients with CHF who were exercised, plasma viscosity, fibrinogen, and hematocrit levels increased significantly, both immediately post exercise and at 20 min into the recovery period (repeated measures analysis of variance, all p<0.05). There was a positive correlation between exercise workload and the maximal changes in plasma viscosity in the patients with CHF (Spearman r = 0.5, p = 0.02). Plasma viscosity levels increased with exercise in the hospital control group, although no other exercise-induced changes were noted in this group. CONCLUSION: The present study indicates that the hemorheological indices. fibrinogen, and hematocrit specifically increase during acute exercise in patients with CHF. Although moderate exercise should be encouraged in patients with CHF, vigorous exercise should probably be avoided in view of its potential prothrombotic effects in this high-risk group of patients.

Effect of acute exercise on the raised plasma fibrinogen, soluble P-selectin and von Willebrand factor levels in chronic atrial fibrillation.

BACKGROUND: There is increasing evidence that chronic atrial fibrillation (AF) is associated with a prothrombotic or hypercoagulable state. HYPOTHESIS: This study was undertaken to determine whether short-term exercise in patients with chronic AF would shift the overall hemostatic balance toward a more prothrombotic state with a reduction in fibrinolytic potential. METHODS: We recruited 20 patients (13 men; mean age 65 years +/- 11 standard deviation [SD]) with chronic AF who were not treated with antithrombotic therapy and exercised them to exhaustion using a multistage treadmill exercise (standard Bruce) protocol. Blood samples were taken pre exercise, immediately after cessation of exercise, and at 20 min post exercise. The prothrombotic state was quantified by fibrinogen (an index of hemorheology and a coagulation factor), soluble P-selectin (sP-sel, marking platelet activation), von Willebrand factor (vWF, an index of endothelial dysfunction), and plasminogen activator inhibitor-1 (PAI-1, a regulator of fibrinolytic activity) levels. There were two groups of age- and gender-matched controls in sinus rhythm: (1) healthy controls, and (2) "hospital controls" who were patients with vascular disease. RESULTS: Baseline levels of vWf (p = 0.034) and fibrinogen (p < 0.0001), but not sP-sel (p = 0.075) were significantly elevated in patients with AF compared with both control groups in sinus rhythm. The PAI-1 levels were highest in the hospital control patients, but not in chronic AF (p = 0.041). Following treadmill exercise, achieving a mean metabolic equivalent of 4.9 METS (+/- 1.75 SD) and total exercise duration of 4.9 min (+/- 2 SD), there was a significant rise in plasma fibrinogen (repeated measures analysis of variance [ANOVA] p = 0.047) and a reduction in PAI-1 levels (p = 0.025) in patients with AF. There were no significant changes seen in vWf (p = 0.308) or sP-sel (p = 0.071) levels. No significant changes in these indices were seen in hospital controls (all p = not significant), despite a much longer duration of exercise with greater workload. CONCLUSION: Patients with chronic AF have increased vWf and fibrinogen levels compared with sinus rhythm. Exercise to exhaustion influences the hypercoagulable state in chronic AF, with a rise in plasma fibrinogen and possible increase in fibrinolytic activity. Nevertheless, acute exercise does not appear to have a significant influence on endothelial dysfunction or platelet activation in patients with AF.

Abnormalities of hemorheological, endothelial, and platelet function in patients with chronic heart failure in sinus rhythm: effects of angiotensin-converting enzyme inhibitor and beta-blocker therapy.

BACKGROUND: To investigate the hypothesis that abnormalities of hemorheological (fibrinogen, plasma viscosity), endothelial (von Willebrand factor [vWF]), and platelet (soluble P-selectin) function would exist in patients with chronic heart failure (CHF) who are in sinus rhythm, we conducted a cross-sectional study of 120 patients with stable CHF (median ejection fraction 30%). We also hypothesized that ACE inhibitors and beta-blockers would beneficially affect the measured indices. METHODS AND RESULTS: In the cross-sectional analysis, plasma viscosity (P=0.001), fibrinogen (P=0.02), vWF (P<0.0001), and soluble P-selectin (P<0.001) levels were elevated in patients with CHF compared with healthy controls. Women demonstrated greater abnormalities of hemorheological indices and vWF than males (all P<0.05). Plasma viscosity (P=0.009) and fibrinogen (P=0.0014) levels were higher in patients with more severe symptoms (New York Heart Association [NYHA] class III-IV), but there was no relationship with left ventricular ejection fraction. When ACE inhibitors were introduced, there was a reduction in fibrinogen (repeated-measures ANOVA, P=0.016) and vWF (P=0.006) levels compared with baseline. There were no significant changes in hemorheological, endothelial, or platelet markers after the introduction of beta-blocker therapy, apart from a rise in mean platelet count (P<0.001). CONCLUSIONS: Abnormal levels of soluble P-selectin, vWF, and hemorheological indices may contribute to a hypercoagulable state in CHF, especially in female patients and in those with more severe NYHA class. Treatment with ACE inhibitors improved the prothrombotic state in CHF, whereas the addition of beta-blockers did not. These positive effects of ACE inhibitors may offer an explanation for the observed reduction in ischemic events in clinical trials.

Management of pericardial effusion by drainage: a survey of 10 years' experience in a city centre general hospital serving a multiracial population.

The aim of the study was to determine the aetiology of large and symptomatic pericardial effusions and to review the management and subsequent outcome. A survey was done on a consecutive cases of patients who had undergone percutaneous pericardiocentesis over a 10 year period in a city centre general hospital serving a multiethnic catchment population. In all, 46 patients (24 male, 22 female; age range 16 to 90 years, mean 54 years) underwent a total of 51 pericardial drainage procedures (or attempted pericardiocentesis) between 1989 and 1998. Malignancy (44%), tuberculosis (26%), idiopathic (11%), and post-cardiac surgery (9%) were the most common causes of pericardial effusion. The most common presenting symptoms were breathlessness (90%), chest pain (74%), cough (70%), abdominal pain (61%) (presumed to be related to hepatic congestion), and unexplained fever (28%). In the 12 cases of tuberculous pericarditis, nine occurred in patients of Indo-Asian origin, and three in patients of Afro-Caribbean origin. Fever, night sweats, and weight loss were common among these patients, occurring in over 80% of cases of tuberculous pericarditis. Pulsus paradoxus was the most specific sign (100%) for the presence of echocardiographic features of tamponade, with strongest positive predictive value (100%). Although malignancy remains the most common cause in developed countries, tuberculous disease should be considered in patients from areas where tuberculosis is endemic. Percutaneous pericardiocentesis remains an effective measure for the immediate relief of symptoms in patients with cardiac tamponade, although its diagnostic yield in tuberculous pericarditis is relatively low.