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Fibrinogen Predicts Mortality in High Risk Patients with Peripheral Artery Disease

      Abstract

      Objective: Fibrinogen plays a key role in the pathogenesis of atherosclerosis and complications of atherothrombotic disease. We investigated the prognostic impact of fibrinogen levels on mortality of high risk patients with peripheral artery disease (PAD).
      Methods: We studied 486 patients with PAD and several cardiovascular comorbidities. Atherosclerotic risk factors and fibrinogen levels were determined at initial presentation and patients were followed for median 7 years (IQR 6–10) for all-cause and cardiovascular mortality. Multivariate Cox regression analysis was applied to assess the predictive value of fibrinogen levels (in quartiles) on patients' outcome.
      Results: Cumulative survival rates at 1, 3, 5 and 10 years were 96, 91, 83 and 67%, respectively. Overall, 138 patients (28%) died, 70% of these patients died of cardiovascular complications (n=96). Patients with fibrinogen levels 10.2–12.2μmol/l (third quartile) and patients with fibrinogen levels above 12.2μmol/l (fourth quartile) had a significantly increased adjusted risk for all-cause mortality (hazard ratios [HR] 1.87 and 1.90, p=0.025 and p=0.020, respectively) compared to patients in the lowest quartile (fibrinogen below 8.6μmol/l). A consistent effect was observed for cardiovascular causes of death. Diabetes mellitus and critical limb ischemia were the only other independent predictor variables (HR 2.08, p<0.001 and 1.88, p=0.001, respectively).
      Conclusion: Elevated fibrinogen levels in high risk patients with PAD indicate an increased risk for poor outcome, particularly for fatal cardiovascular complications.

      Keywords

      Introduction

      Complications of atherosclerosis are the most common causes of death in Western societies.
      • Lusis AJ
      Atherosclerosis.
      Although atherosclerosis was formerly considered a bland lipid storage disease, substantial advances in basic and experimental science have illuminated the role of inflammation and the underlying cellular and molecular mechanisms that contribute to atherogenesis.
      • Lusis AJ
      Atherosclerosis.
      • Ross R
      Atherosclerosis: an inflammatory disease.
      Compelling evidence for the importance of inflammation and atherosclerosis at both the basic and clinical level has evolved in parallel. Accumulating data indicate that insights gained from the link between inflammation and atherosclerosis can yield predictive and prognostic information of considerable clinical utility.
      • Libby P
      • Ridker P
      • Maseri A
      Inflammation and atherosclerosis.
      In broad outline, atherosclerosis can be considered to be a form of chronic inflammation resulting from interaction between modified lipoproteins, monocyte-derived macrophages, T-cells, and the normal cellular elements of the arterial wall.
      • Glass CK
      • Witztum JL
      Atherosclerosis: the road ahead.
      This inflammatory process can ultimately lead to the development of complex lesions, or plaques, that protrude into the arterial lumen.
      • Lusis AJ
      Atherosclerosis.
      Plaque rupture and thrombosis may result in the clinical complications of stroke or myocardial infarction.
      • Glass CK
      • Witztum JL
      Atherosclerosis: the road ahead.
      Fibrinogen is essential for fibrin formation under the influence of thrombin, and forms the basic plug of plasmatic coagulation and platelet aggregation.
      • Mannucci PM
      Recent progress in the pathophysiology of fibrinogen.
      • Bombeli T
      • Schwartz BR
      • Harlan JM
      Adhesion of activated platelets to endothelial cells: evidence for a GPIIbIIIa-dependent bridging mechanism and novel roles for endothelial intercellular adhesion molecule 1 (ICAM-1), alphavbeta3, integrin, and GPIbalpha.
      Furthermore, fibrinogen synthesis is stimulated by cytokines from activated megacaryocytes thus acting as an acute phase reactant and a mediator of inflammatory processes. In particular, it is a ligand for cellular integrins and increases the binding of platelets, endothelial cells and leukocytes to each other which in turn causes activation of leukocytes and platelets, and release of mediators from these cells.
      • Marguerie G
      • Ginsberg MH
      • Plow EF
      • Dejana E
      • Languino LR
      Fibrinogen, therefore, can be considered as a key molecule in the cascades of inflammation and coagulation and supposedly is involved in the pathogenesis of atherosclerosis and occurrence of atherothrombotic complications.
      • Ernst E
      • Resch KL
      Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature.
      • Lee AJ
      • Mowbray PI
      • Lowe GD
      • et al.
      Blood viscosity and elevated intima-media thickness in men and women: the Edinburgh Artery Study.
      Recently, fibrinogen was described as a risk factor particularly for the development of peripheral artery disease (PAD)
      • Murabito JM
      • Evans JC
      • Nieto K
      • et al.
      Prevalence and clinical correlates of peripheral arterial disease in the Framingham Offspring Study.
      and was suggested to be associated with an increased risk of short-term mortality.
      • Acevedo M
      • Pearce GL
      • Kottke-Marchant K
      • et al.
      Elevated fibrinogen and homocysteine levels enhance the risk of mortality in patients from a high-risk preventive cardiology clinic.
      However, the predictive value of fibrinogen on the long-term outcome of high risk patients with PAD has not been assessed as yet.
      We hypothesized that elevated fibrinogen levels would be associated with an increased risk of long term mortality in patients with pre-existing, severe atherosclerosis. Therefore, the aim of the present study was to investigate the prognostic impact of fibrinogen on 10 year all-cause and cardiovascular mortality of high risk patients with PAD.

      Methods

       Study design, inclusion and exclusion criteria

      We analyzed the data of all inpatients with symptomatic PAD Fontaine stages IIa, IIb, III and IV who were admitted to the Angiology department of a tertiary care university hospital from January 1, 1990 to December 31, 1992. PAD was assessed by clinical evaluation, ankle brachial index measurements, duplex sonography and confirmed by lower limb angiography in all patients. Patients were identified using our registry database, which prospectively recorded these patients' data. Furthermore, data were completed by systematic chart review. The main outcome measure was mortality until December 31, 1999. The study complied with the Declaration of Helsinki.

       Definitions

      Diabetes mellitus was defined as fasting blood glucose levels above 110 mg/dl measured at three different occasions, pathologic oral glucose tolerance tests and glycated hemoglobin (HbA1c) >6.0%. Hyperlipidemia was defined as fasting total serum cholesterol >200 mg/dl, LDL cholesterol >130 mg/dl or serum triglycerides >180 mg/dl and was assumed to be present in all patients on lipid lowering medication. Arterial hypertension was defined as blood pressure values above 140/90 mmHg in repetitive measurements and was considered to be present in all patients with a history of hypertension taking anti-hypertensive medication.

       Patient data

      At admission patients medical history and data from physical examination were recorded using a standard questionnaire. Laboratory examination included complete blood count, global coagulation tests, HbA1c, total cholesterol, LDL cholesterol, HDL cholesterol, lipoprotein (a), and serum uric acid. Clinical history and physical examination were evaluated with special attention to cardiovascular risk factors and comorbidities: age, gender, hyperlipidemia, hypertension, diabetes mellitus, coronary artery disease, history of cerebrovascular events, current medication, and smoking habits at the time of admission in categories (non-smoker, 1–9 cigarettes daily, 10–19 cigarettes daily, 20 or more cigarettes daily).

       Laboratory investigations

      For measurement of fibrinogen Fibrinogen Clauss® (Stago, Roche) with a sensitivity of 0.6μmol/l, a normal range of 4.4–10.3μmol/l, and a coefficient of variation of 5.2% was used, since the automated Clauss assay has been established as the standard for measurement of fibrinogen.
      • Whitton CM
      • Sands D
      • Hubbard AR
      • et al.
      A ccolaborative study to establish the 2nd international standard for fibrinogen, plasma.

       Follow-up

      Patients were followed for case fatality until December 31, 1999. The Austrian Central Statistical Office provided data of patients who died within that period (day and cause of death, ICD 9).

       Statistical analysis

      Continuous data are presented as the median and the interquartile range (IQR, range from the 25th to the 75th percentile). Discrete data are given as counts and percentages. The Chi-square test was used to compare proportions and the Mann–Whitney U Test was applied for univariate comparison of continuous data. Mortality rates according to the fibrinogen level (in quartiles) are presented as a Kaplan–Meier curve and compared by means of the Log Rank test. Multivariate Cox regression analysis was applied to assess the independent effect of fibrinogen on all-cause and cardiovascular mortality, and to adjust for confounding effects of other atherosclerotic risk factors. Results of the Cox logistic regression model were presented as the hazard ratio (HR) and the 95% confidence interval (95% CI). Multiplicative interaction terms and log likelihood ratio Chi-square tests were used to test for interactions between predictor variables. A two sided p-value <0.05 was considered as statistically significant. All calculations were performed with SPSS for Windows (Version 10.0, SPSS Inc, Chicago, IL, USA).

      Results

      We included 486 patients with PAD in the present analysis. The median age was 72 years (IQR 64–79), and 296 patients were male (61%). Fibrinogen values at the time of initial presentation were median 10.2μmol/l (IQR 8.6–12.2). According to the reference values of our laboratory, 256 patients (53%) had a normal fibrinogen level (4.4–10.3μmol/l), 228 patients (47%) had an elevated fibrinogen level (>10.3μmol/l) and two patients (0.4%) had a lower than normal fibrinogen (<4.4μmol/l).

       Mortality

      The median follow-up period was 89 months (i.e. 7.3 years) (IQR 72–119 months). Cumulative survival rates at 1, 3, 5 and 10 years were 96, 91, 83 and 67%, respectively. During the follow-up period until December 31, 1999, overall 138 patients (28%) died. Median survival time in non-survivors was 67 months (i.e. 5.5 years) (IQR 39–93 months). We found predominately cardiovascular causes of death (myocardial infarction and stroke) in these patients (96 of 138, 70%). Twenty-three patients (17%) died because of carcinomas, the remaining 19 patients (14%) died following traumas, infectious diseases and respiratory insufficiency due to chronic obstructive pulmonary diseases and renal insufficiency. Demographic data and clinical characteristics of survivors and non-survivors are given in Table 1. Non-survivors were older, had more frequently diabetes mellitus, arterial hypertension and critical limb ischemia.
      Table 1Demographic data and clinical characteristics of 486 patients presenting with peripheral artery disease: comparing long-term survivors and non-survivors
      Survivors (n=348, 72%)Non-survivors (n=138, 28%)p-value
      Age (years)71 (61–79)74 (69–80)<0.001
      Male sex212 (61%)84 (61%)0.99
      Smoking at admission0.16
      Non-smoker140 (40%)70 (51%)
      1–9 cigarettes daily128 (37%)44 (32%)
      10–19 cigarettes daily46 (13%)16 (12%)
      20 or more cigarettes daily34 (10)8 (6%)
      Diabetes mellitus102 (29%)76 (55%)<0.001
      Arterial hypertension147 (42%)77 (56%)0.007
      Hyperlipidemia301 (87%)110 (80%)0.062
      Critical limb ischemia62 (18%)45 (33%)<0.001
      Coronary artery disease176 (51%)69 (50%)0.97
      History of myocardial infarction54 (16%)29 (21%)0.57
      History of stroke17 (5%)7 (5%)0.93
      Continuous data are given as median and interquartile range (range from the 25th to the 75th percentile).

       Fibrinogen and mortality

      Fibrinogen values were divided into quartiles to analyze its potential impact on patients' outcome. Compared to patients in the lowest quartile (n=122, fibrinogen <8.6μmol/l), patients in the second (n=121, fibrinogen 8.6–10.2μmol/l), third (n=122, fibrinogen 10.2–12.2μmol/l) and fourth quartile (n=121, fibrinogen >12.2μmol/l) had a cumulatively increasing risk for mortality (p=0.0014, Fig. 1).
      We then applied a multivariate Cox proportional hazard model to assess the independent effect of fibrinogen on all-cause mortality and adjust for the confounding effects of other baseline variables.
      Figure thumbnail gr1
      Fig. 1Cumulative mortality of 486 patients with peripheral artery disease according to the fibrinogen level at initial presentation.
      Patients in the third and fourth quartile of fibrinogen values had a significantly increased adjusted risk for mortality compared to patients in the lowest quartile (Table 2). The final model adjusted for age (in quartiles), sex, smoking (in categories), diabetes mellitus, hyperlipidemia, arterial hypertension and critical limb ischemia (vs. intermittent claudication). Although patients with diabetes mellitus showed significantly higher fibrinogen values compared to non-diabetic patients (p=0.001), we observed no significant interaction between fibrinogen and diabetes or any other baseline variable, indicating that fibrinogen is an independent predictor of mortality in these patients. In particular, we found no significant interaction between fibrinogen, smoking habits and death, and there were no significant differences of fibrinogen levels between non-smokers and smokers (in categories) (p=0.47). Diabetes mellitus and critical limb ischemia were the only other independent predictors of death in these patients.
      Table 2Cox proportional hazard model to assess the predictive value of fibrinogen on 10 year mortality of patients with peripheral artery disease adjusting for confounding factors
      Hazard ratio95% Confidence intervalp- value
      Fibrinogen
       First quartile (<8.6μmol/l)1.0
       Second quartile (8.6–10.2μmol/l)1.470.85–2.560.17
       Third quartile (10.2–12.2μmol/l)1.871.09–3.230.025
       Fourth quartile (>12.2μmol/l)1.901.11–3.410.020
      Male sex1.220.85–1.760.31
      Age (in quartiles)1.170.97–1.380.13
      Smoking (in categories)
       Non-smoking1.0
       1–9 cigarettes daily1.220.77–1.930.40
       10–19 cigarettes daily1.220.65–2.270.53
       20 or more cigarettes daily0.800.35–1.800.58
      Hyperlipidemia0.800.45–1.170.18
      Diabetes mellitus2.251.51–3.36<0.001
      Arterial hypertension1.300.89–1.900.17
      Critical limb ischemia1.881.30–2.740.001
      Assessing the risk for cardiovascular death according to patients' baseline fibrinogen level, we found that patients in the second (adjusted HR 1.99, 95% CI 1.07–4.08, p=0.031), third (adjusted HR 2.66, 95% CI 1.37–5.10, p=0.007) and fourth quartile (adjusted HR 2.68, 95% CI 1.39–5.16, p=0.003) had an increased risk for poor outcome compared to patients in the lowest quartile of fibrinogen levels, adjusting for age (in quartiles), sex, smoking (in categories), diabetes mellitus, hyperlipidemia, and arterial hypertension and critical limb ischemia.

      Discussion

      We found that higher fibrinogen levels were associated with a significantly increased risk for 10-year-mortality in patients with PAD. Particularly, fatal cardiovascular complications frequently occurred in these patients. This association was independent of any other atherothrombotic risk factor.
      Atherosclerosis has been demonstrated to be related to an inflammatory process in the vascular wall.
      • Ross R
      Atherosclerosis: an inflammatory disease.
      • Libby P
      • Ridker P
      • Maseri A
      Inflammation and atherosclerosis.
      • Blake GJ
      • Ridker PM
      Novel clinical markers of vascular wall inflammation.
      • Elkind MS
      • Cheng J
      • Boden-Albala B
      • Paik MC
      • Sacco RL
      Elevated white blood cell count and carotid plaque thickness: the northern Manhattan stroke study.
      The activity of the disease and the likelihood of its progression are influenced by the extent of the vascular inflammatory process.
      • Blake GJ
      • Ridker PM
      Novel clinical markers of vascular wall inflammation.
      • Elkind MS
      • Cheng J
      • Boden-Albala B
      • Paik MC
      • Sacco RL
      Elevated white blood cell count and carotid plaque thickness: the northern Manhattan stroke study.
      In this context, a close association between atherosclerosis and increased levels of fibrinogen have been described,
      • Danesh J
      • Collins R
      • Appleby P
      • Peto R
      Association of fibrinogen, C-reactive protein, albumin, or leukocyt count with coronary heart disease: meta analysis of prospective studies.
      • Ernst E
      Fibrinogen. An independent risk factor for cardiovascular disease.
      presumably indicating underlying vascular inflammation. Fibrinogen is a marker of acute phase response and provides an indirect measure of a cytokine dependent inflammatory process of the arterial wall. The molecule is a ligand for cellular integrins and increases the binding of platelets, endothelial cells and leukocytes to each other which in turn causes activation of leukocytes and platelets, and release of mediators from these cells.
      • Marguerie G
      • Ginsberg MH
      • Plow EF
      • Dejana E
      • Languino LR
      Furthermore, fibrinogen plays a key role in the coagulation cascade serving as a ligand for the platelet GPIIb/IIIa receptor. Such a pivotal role in platelet physiology and development of arterial thrombosis parallels the consistency of clinical studies, which showed an increased cardiovascular risk for elevated fibrinogen levels.
      • Ernst E
      • Resch KL
      Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature.
      • Lee AJ
      • Mowbray PI
      • Lowe GD
      • et al.
      Blood viscosity and elevated intima-media thickness in men and women: the Edinburgh Artery Study.
      • Acevedo M
      • Pearce GL
      • Kottke-Marchant K
      • et al.
      Elevated fibrinogen and homocysteine levels enhance the risk of mortality in patients from a high-risk preventive cardiology clinic.
      • Maresca G
      • Di Blasio A
      • Marchioli R
      • et al.
      Measuring plasma fibrinogen to predict stroke and myocardial infarction: an update.
      • Wilhelmsen L
      • Svardsudd K
      • Korsan-Bengtsen K
      • et al.
      Fibrinogen as a risk factor for stroke and myocardial infarction.
      • Folsom AR
      • Wu KK
      • Rosamond WD
      • et al.
      Prospective study of hemostatic factors and incidence of coronary heart disease: the Atherosclerosis Risk in the Communities (ARIC) Study.
      Another causal mechanism for fibrinogen involvement in atherosclerosis is the promotion of endothelial damage and diffuse intimal thickening early during the disease's course.
      • Lee AJ
      • Mowbray PI
      • Lowe GD
      • et al.
      Blood viscosity and elevated intima-media thickness in men and women: the Edinburgh Artery Study.
      Putting these findings together, it seems reasonable to speculate that fibrinogen levels potentially reflect the activity of the atherosclerotic process and are a surrogate marker for the individual's risk for poor outcome. Previously in cardiologic patients, elevated fibrinogen was reported to increase the risk of short term mortality.
      • Acevedo M
      • Pearce GL
      • Kottke-Marchant K
      • et al.
      Elevated fibrinogen and homocysteine levels enhance the risk of mortality in patients from a high-risk preventive cardiology clinic.
      Analysing mortality rates in the present study according to the baseline fibrinogen level (Fig. 1), it becomes obvious the Kaplan Meier curves markedly diverge after 3–5 years, indicating that elevated fibrinogen was mainly associated with increased long-term rather than early mortality in this groups of high risk patients with peripheral atherosclerosis.
      Considering the prognostic impact of fibrinogen for the occurrence of future cardiovascular or all-cause mortality, one has to recognise that the effect size in terms of the hazard ratios was rather small, suggesting that this measurement adds little to risk prediction of adverse events in clinical practice. However, patients with atherosclerosis and hyperfibrinogenaemia may be good candidates for treatment with fibrates, which in contrast to statins combine lipid-lowering with beneficial fibrinogen-lowering effects.
      • Maison P
      • Mennen L
      • Sapinho D
      • et al.
      A pharmacological assessment of the effect of statins and fibrates on fibrinogen concentration.
      Nevertheless, it has to be acknowledged that statins have a larger effect on the reduction of cardiovascular and all-cause mortality
      • Bucher HC
      • Griffith LE
      • Guyatt GH
      Systematic review on the risk and benefit of different cholesterol-lowering interventions.
      and, therefore, should be used preferentially or in controlled combination.
      Remarkably, in the present patient series, smokers and patients with hyperlipidemia exhibited reduced mortality rates in univariate analysis. This may be explained by an interaction with patients' age, since current smokers and hyperlipidemic patients were significantly younger. Indeed, we found no significant influence of these variables on outcome when adjusting for patients' age in the multivariate model. Patients with diabetes mellitus, in contrast, had an increased mortality during the follow up period. These patients also had significantly higher fibrinogen levels at initial presentation, presumably due to enhanced inflammatory activity. Nevertheless, no effect modification was observed testing for interaction between fibrinogen and diabetes and both variables independently predicted patients' mortality.

       Limitations

      We are aware of the limitations of a retrospective study design. In a non-randomised setting it is very difficult to account for the effects of changing medication during a study period of 10 years. Certainly, the increasing use of statins and ACE inhibitors during the recent years may influence mortality rates of these patients, but these data hardly can be acquired retrospectively. However, due to the careful and standardised patient evaluation with respect to cardiovascular risk factors and the complete follow-up data which were obtained via an independent institution, the interpretation of our findings seem valid.

      Conclusion

      Elevated fibrinogen levels in patients with PAD indicate an increased risk for poor outcome, particularly for fatal cardiovascular complications. Patients with hyperfibrinogenaemia, therefore, may be considered for close monitoring of cardiovascular comorbidities, aggressive treatment of concomitant risk factors and potentially for fibrinogen-lowering therapeutic approaches.

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