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1.
Effects of tibolone on fibrinogen and antithrombin III: A systematic review and meta-analysis of controlled trials.
Bała, M, Sahebkar, A, Ursoniu, S, Serban, MC, Undas, A, Mikhailidis, DP, Lip, GYH, Rysz, J, Banach, M, ,
Pharmacological research. 2017;:64-73
Abstract
Tibolone is a synthetic steroid with estrogenic, androgenic and progestogenic activity, but the evidence regarding its effects on fibrinogen and antithrombin III (ATIII) has not been conclusive. We assessed the impact of tibolone on fibrinogen and ATIII through a systematic review and meta-analysis of available randomized controlled trials (RCTs). The search included PUBMED, Web of Science, Scopus, and Google Scholar (up to January 31st, 2016) to identify controlled clinical studies investigating the effects of oral tibolone treatment on fibrinogen and ATIII. Overall, the impact of tibolone on plasma fibrinogen concentrations was reported in 10 trials comprising 11 treatment arms. Meta-analysis did not suggest a significant reduction of fibrinogen levels following treatment with tibolone (WMD: -5.38%, 95% CI: -11.92, +1.16, p=0.107). This result was robust in the sensitivity analysis and not influenced after omitting each of the included studies from meta-analysis. When the studies were categorized according to the duration of treatment, there was no effect in the subsets of trials lasting either <12months (WMD: -7.64%, 95% CI: -16.58, +1.29, p=0.094) or ≥12months (WMD: -0.62%, 95% CI: -8.40, +7.17, p=0.876). With regard to ATIII, there was no change following treatment with tibolone (WMD: +0.74%, 95% CI: -1.44, +2.93, p=0.505) and this effect was robust in sensitivity analysis. There was no differential effect of tibolone on plasma ATIII concentrations in trials with either <12months (WMD: +2.26%, 95% CI: -3.14, +7.66, p=0.411) or≥12months (WMD: +0.06%, 95% CI: -1.16, +1.28, p=0.926) duration. Consistent with the results of subgroup analysis, meta-regression did not suggest any significant association between the changes in plasma concentrations of fibrinogen (slope: +0.40; 95% CI: -0.39, +1.19; p=0.317) and ATIII (slope: -0.17; 95% CI: -0.54, +0.20; p=0.374) with duration of treatment. In conclusion, meta-analysis did not suggest a significant reduction of fibrinogen and ATIII levels following treatment with tibolone.
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Inflammatory markers and extent and progression of early atherosclerosis: Meta-analysis of individual-participant-data from 20 prospective studies of the PROG-IMT collaboration.
Willeit, P, Thompson, SG, Agewall, S, Bergström, G, Bickel, H, Catapano, AL, Chien, KL, de Groot, E, Empana, JP, Etgen, T, et al
European journal of preventive cardiology. 2016;(2):194-205
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Abstract
BACKGROUND Large-scale epidemiological evidence on the role of inflammation in early atherosclerosis, assessed by carotid ultrasound, is lacking. We aimed to quantify cross-sectional and longitudinal associations of inflammatory markers with common-carotid-artery intima-media thickness (CCA-IMT) in the general population. METHODS Information on high-sensitivity C-reactive protein, fibrinogen, leucocyte count and CCA-IMT was available in 20 prospective cohort studies of the PROG-IMT collaboration involving 49,097 participants free of pre-existing cardiovascular disease. Estimates of associations were calculated within each study and then combined using random-effects meta-analyses. RESULTS Mean baseline CCA-IMT amounted to 0.74 mm (SD = 0.18) and mean CCA-IMT progression over a mean of 3.9 years to 0.011 mm/year (SD = 0.039). Cross-sectional analyses showed positive linear associations between inflammatory markers and baseline CCA-IMT. After adjustment for traditional cardiovascular risk factors, mean differences in baseline CCA-IMT per one-SD higher inflammatory marker were: 0.0082 mm for high-sensitivity C-reactive protein (p < 0.001); 0.0072 mm for fibrinogen (p < 0.001); and 0.0025 mm for leucocyte count (p = 0.033). 'Inflammatory load', defined as the number of elevated inflammatory markers (i.e. in upper two quintiles), showed a positive linear association with baseline CCA-IMT (p < 0.001). Longitudinal associations of baseline inflammatory markers and changes therein with CCA-IMT progression were null or at most weak. Participants with the highest 'inflammatory load' had a greater CCA-IMT progression (p = 0.015). CONCLUSION Inflammation was independently associated with CCA-IMT cross-sectionally. The lack of clear associations with CCA-IMT progression may be explained by imprecision in its assessment within a limited time period. Our findings for 'inflammatory load' suggest important combined effects of the three inflammatory markers on early atherosclerosis.
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Baseline and long-term fibrinogen levels and risk of sudden cardiac death: A new prospective study and meta-analysis.
Kunutsor, SK, Kurl, S, Zaccardi, F, Laukkanen, JA
Atherosclerosis. 2016;:171-80
Abstract
BACKGROUND Inflammatory markers such as C-reactive protein (CRP) and interleukin-6 have been linked with an increased risk of sudden cardiac death (SCD), but the relationship between fibrinogen and SCD is uncertain. We aimed to assess the association between fibrinogen and SCD. METHODS Plasma fibrinogen was measured at baseline in a prospective cohort of 1773 men aged 42-61 years free of heart failure or cardiac arrhythmias, that recorded 131 SCDs during 22 years follow-up. Correction for within-person fibrinogen variability was made using data from repeat measurements taken several years apart. RESULTS Fibrinogen was strongly correlated with CRP, weakly correlated with several cardiovascular risk markers, and was log-linearly associated with SCD risk. In analyses adjusted for conventional risk factors, the hazard ratio (HR) (95% CIs) for SCD per 1 standard deviation (SD) higher baseline loge fibrinogen was 1.32 (1.11-1.57). The results remained consistent on further adjustment for alcohol consumption, resting heart rate, and circulating lipids 1.30 (1.09-1.56). The corresponding HRs were 1.80 (1.25-2.58) and 1.74 (1.20-2.52) after correction for within-person variability. HRs remained unchanged on further adjustment for CRP and accounting for incident coronary events. In a meta-analysis of three cohort studies, the fully-adjusted relative risks for SCD per 1 SD higher baseline and long-term fibrinogen levels were 1.42 (1.25-1.61) and 2.07 (1.59-2.69) respectively. The associations were similar for non-SCDs in both cohort analysis and the meta-analysis. Addition of plasma fibrinogen to a SCD risk prediction model containing established risk factors did not significantly improve risk discrimination, but improved the net reclassification. CONCLUSIONS Available data suggest fibrinogen is positively, log-linearly, and independently associated with risk of SCD. Further research is needed to assess the potential relevance of plasma fibrinogen concentrations in SCD prevention.
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No evidence for genome-wide interactions on plasma fibrinogen by smoking, alcohol consumption and body mass index: results from meta-analyses of 80,607 subjects.
Baumert, J, Huang, J, McKnight, B, Sabater-Lleal, M, Steri, M, Chu, AY, Trompet, S, Lopez, LM, Fornage, M, Teumer, A, et al
PloS one. 2014;(12):e111156
Abstract
Plasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI). Genome-wide association studies (GWAS) have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation. Therefore, we conducted large-scale meta-analyses of genome-wide interaction studies to identify possible interactions of genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentration. The present study included 80,607 subjects of European ancestry from 22 studies. Genome-wide interaction analyses were performed separately in each study for about 2.6 million single nucleotide polymorphisms (SNPs) across the 22 autosomal chromosomes. For each SNP and risk factor, we performed a linear regression under an additive genetic model including an interaction term between SNP and risk factor. Interaction estimates were meta-analysed using a fixed-effects model. No genome-wide significant interaction with smoking status, alcohol consumption or BMI was observed in the meta-analyses. The most suggestive interaction was found for smoking and rs10519203, located in the LOC123688 region on chromosome 15, with a p value of 6.2 × 10(-8). This large genome-wide interaction study including 80,607 participants found no strong evidence of interaction between genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. Further studies are needed to yield deeper insight in the interplay between environmental factors and gene variants on the regulation of fibrinogen concentrations.
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Exercise intervention and inflammatory markers in coronary artery disease: a meta-analysis.
Swardfager, W, Herrmann, N, Cornish, S, Mazereeuw, G, Marzolini, S, Sham, L, Lanctôt, KL
American heart journal. 2012;(4):666-76.e1-3
Abstract
BACKGROUND Inflammatory activity plays a role in the development and progression of coronary artery disease (CAD), and exercise confers survival benefit. We performed a meta-analysis of changes in inflammatory biomarkers over the course of exercise interventions in patients with CAD. METHODS We searched MEDLINE, Embase, the Cochrane Collaboration, AMED, and CINAHL for studies reporting peripheral inflammatory biomarker concentrations before and after exercise interventions of ≥ 2 weeks in patients with CAD. Data were summarized using standard mean differences (SMD) and 95% CIs. RESULTS Twenty-three studies were included. Concentrations of C-reactive protein (CRP; SMD -0.345, 95% CI -0.444 to -0.246, n = 1,466, P < .001), interleukin 6 (SMD -0.546, 95% CI -0.739 to -0.353, n = 280, P < .001), fibrinogen (SMD -0.638, 95% CI -0.953 to -0.323, n = 247, P < .001), and vascular cell adhesion molecule 1 (SMD -0.413, 95% CI -0.778 to -0.048, n = 187, P = .027) were lower postintervention. Higher total cholesterol (B = -0.328, 95% CI -0.612 to -0.043, P = .026) and higher total/high-density lipoprotein cholesterol ratios (B = -0.250, 95% CI -0.425 to -0.076, P = .008) at baseline were associated with greater reductions in CRP. In controlled studies, follow-up concentrations of CRP (SMD -0.500, 95% CI -0.844 to -0.157, n(exercise/control) = 485/284, P = .004), and fibrinogen (SMD -0.544, 95% CI -1.058 to -0.030, n(exercise/control) = 148/100, P = .038) were lower in subjects who exercised compared with controls. CONCLUSION Exercise training is associated with reduced inflammatory activity in patients with CAD. C-reactive protein and fibrinogen have provided the strongest evidence. Higher baseline CRP and adverse baseline lipid profiles predicted greater reductions in CRP.
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Associations of plasma fibrinogen levels with established cardiovascular disease risk factors, inflammatory markers, and other characteristics: individual participant meta-analysis of 154,211 adults in 31 prospective studies: the fibrinogen studies collaboration.
, , Kaptoge, S, White, IR, Thompson, SG, Wood, AM, Lewington, S, Lowe, GD, Danesh, J
American journal of epidemiology. 2007;(8):867-79
Abstract
Long-term increases in plasma fibrinogen levels of 1 g/liter are associated with an approximate doubling of risk of major cardiovascular disease outcomes, but causality remains uncertain. To quantify cross-sectional associations of fibrinogen levels with established risk factors and other characteristics, the investigators combined individual data on 154,211 apparently healthy adults from 31 prospective studies conducted between 1967 and 2003, using a linear mixed model that included random effects at the cohort level. Fibrinogen levels increased with age and showed continuous, approximately linear relations with several risk markers and slightly curvilinear associations with log triglycerides, albumin, and tobacco and alcohol consumption. Female sex, Black ethnicity, lower socioeconomic status, and alcohol abstinence were each associated with modestly higher fibrinogen levels. Approximately one third of the variation in fibrinogen levels was explained by cohort, age, and sex. An additional 7% was explained by established risk factors (notably, positive associations with smoking and body mass index and an inverse association with high density lipoprotein cholesterol), and a further 10% was explained by inflammatory markers (notably, a positive association with C-reactive protein). The association with body mass index was twice as strong in women as in men, whereas the association with smoking was much stronger in men. These findings substantially advance understanding of the correlates and possible determinants of fibrinogen levels.
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Effect of dialysis modality on plasma fibrinogen concentration: a meta-analysis.
Goldwasser, P, Feldman, JG, Emiru, M, Barth, RH
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2004;(6):941-9
Abstract
BACKGROUND Concentrations of plasma fibrinogen, a vascular risk factor, tend to be greater in patients on peritoneal dialysis (PD) than hemodialysis (HD) therapy, like concentrations of serum cholesterol, lipoprotein(a), and transthyretin, despite the substantial loss of protein during PD. Worse vascular outcome has been noted in PD patients compared with HD patients in several studies. METHODS In this study, the mean difference in plasma fibrinogen levels (PD-HD) was quantified by means of meta-analysis of mean differences found in 12 cohorts with both PD and HD patients (set 1; N = 630) by using a fixed-effects model and meta-analysis of mean fibrinogen values reported in 30 cohorts of patients on a single dialysis modality (set 2; 8 PD cohorts, 22 HD cohorts; N = 2,096) by using a mixed model. RESULTS On meta-analysis, the weighted mean difference (PD-HD) was 105 mg/dL (95% confidence interval [CI], 86 to 124 [3.1 micromol/L; 95% CI, 2.5 to 3.6]) in set 1 and 103 mg/dL (95% CI, 53 to 153 [3.0 micromol/L; 95% CI, 1.6 to 4.5) in set 2. CONCLUSION Like other vascular risk factors, such as cholesterol and lipoprotein(a), plasma fibrinogen level is markedly greater in PD than HD patients, with an approximate difference of 100 mg/dL [2.9 mumol/L]. Different plasma reference ranges for fibrinogen need to be defined for PD and HD patients. The mechanism for the difference and the possible role of hyperfibrinogenemia in worsening vascular disease in PD patients deserve study.