Von Willebrand factor antigen levels predict major adverse cardiovascular events in patients with carotid stenosis of the ICARAS study.

BACKGROUND AND AIMS: Von Willebrand factor (VWF) plays an important role in thrombogenesis and mediates platelet adhesion particularly under high shear stress. Such conditions are generally found in stenotic arteries and can eventually cause myocardial infarction or stroke. We aimed to study whether levels of VWF antigen (VWF:Ag) predict future major adverse cardiovascular events (MACE) in patients suffering from carotid artery stenosis. METHODS: Patients with atherosclerotic carotid artery disease defined by the presence of nonstenotic plaques or any degree of carotid stenosis were prospectively enrolled. Concentrations of VWF were measured by enzyme immunoassay. RESULTS: VWF:Ag levels were more stable after 4 freeze-thaw cycles, when compared to VWF activity, and we showed similar concentrations of VWF in citrated plasma and serum (±4%). Levels of VWF:Ag predicted future cardiovascular events in 811 patients with carotid stenosis independent of known cardiovascular risk factors. Patients with VWF:Ag concentrations in the 4th quartile had a 44% event rate after an average 3-year follow up and a hazard ratio of 2.15 (95% confidence interval 1.46-3.16; p < 0.001). CONCLUSIONS: High concentrations of VWF:Ag predict major cardiovascular events in patients with carotid stenosis, and given their high event rate may be useful for risk stratification of such patients.

Carotid ultrasound investigation as a prognostic tool for patients with diabetes mellitus.

BACKGROUND: Experimental and clinical data indicate a major influence of diabetes on atherogenesis. We aimed to assess whether the effect of diabetes on long-term mortality in asymptomatic patient with carotid stenosis is contingent upon the degree of the carotid atherosclerotic burden. METHODS: 1065 patients with neurological asymptomatic carotid atherosclerosis as evaluated by duplex sonography were prospectively followed for cause-specific mortality. RESULTS: During a median of 11.8 years, a total of 549 deaths, including 362 cardiovascular deaths, were recorded. Diabetes and glycohemoglobin A1c (Hba1c) levels were significantly associated with mortality. Diabetes displayed an independent risk for all-cause (adjusted HR 1.62; 95% CI 1.35-1.94) and cardiovascular death (adjusted HR 1.75, 95% CI 1.40-2.19). The adjusted hazard ratio per increase of 1% of Hba1c levels was 1.21 (P < 0.01) for all-cause and 1.31 (P < 0.01) for cardiovascular mortality, respectively. Patients with diabetes mellitus and a higher degree of carotid stenosis and were at great risk of adverse outcome. Only 21% of the asymptomatic diabetic patients with carotid narrowing over 50% survived, whereas 62% of the patients without diabetes and with carotid atherosclerosis below 50% were still alive after 12-years of follow-up. The high risk for all-cause and cardiovascular death of these patients remained significant after adjustment for various established cardiovascular risk factors in multivariable regression analysis (adjusted hazard ratio 2.4, P < 0.001; compared to patients without diabetes and < 50% carotid atherosclerosis). CONCLUSION: Diabetic patients with carotid stenosis ≥ 50% are at exceptional high risk for all-cause and cardiovascular death. Thus, routinely ultrasound investigation of the carotid arteries might be a valuable prognostic tool for patients with diabetes mellitus.

The prognostic value of serum amyloid A for long-term mortality among patients with subclinical carotid atherosclerosis.

BACKGROUND AND PURPOSE: Despite extensive research in the last decade, the role of serum amyloid A (SAA) in atherogenesis remains highly controversial. The aim of this study was therefore to assess whether SAA is associated with long-term mortality in patients with subclinical carotid artery disease. METHODS: One thousand sixty-five patients with neurological asymptomatic carotid atherosclerosis as evaluated by duplex sonography were prospectively followed for cause-specific mortality. RESULTS: During a median of 11.8 years, a total of 549 deaths, including 362 cardiovascular deaths, were recorded. Patients who died within the follow-up period had significantly higher baseline SAA serum levels compared to those who survived (12.9 vs 9.5 mg/dL; P < 0.001). In univariable Cox regression analysis, the risk of all-cause and cardiovascular mortality significantly increased in patients with elevated serum levels of SAA (crude hazard ratio for cardiovascular mortality per increase of 1 SD of SAA levels was 1.14, 95% CI 1.08-1.22], P < 0.0001). However, SAA lost its significance after adjusting for high-sensitivity C-reactive protein (hsCRP), suggesting that SAA might not be directly associated with atherogenesis, but rather be a mere reflection of the individual patient's inflammatory status. CONCLUSIONS: Serum amyloid A is not independently associated with (cardiovascular) mortality in patients with subclinical carotid atherosclerosis.

Edoxaban Plus Aspirin vs Dual Antiplatelet Therapy in Endovascular Treatment of Patients With Peripheral Artery Disease: Results of the ePAD Trial.

PURPOSE: To report a randomized study that investigated the safety (risk of major bleeds) and potential efficacy of edoxaban, an oral anticoagulant that targets the major components of arterial thrombi, to prevent loss of patency following endovascular treatment (EVT). METHODS: Between February 2012 and June 2014, 203 patients who underwent femoropopliteal EVT were randomized to receive aspirin plus edoxaban or aspirin plus clopidogrel for 3 months in the Edoxaban in Peripheral Arterial Disease (ePAD) study ( ClinicalTrials.gov identifier NCT01802775). Randomization assigned 101 patients (mean age 68.0±10.4 years; 67 men) to the edoxaban group and 102 patients (mean age 66.7±8.6 years; 78 men) to the clopidogrel group. The primary safety endpoint was bleeding as classified by the TIMI (Thrombolysis in Myocardial Infarction) criteria and ISTH (International Society of Thrombosis and Hemostasis) criteria; the efficacy endpoint was the rate of restenosis/reocclusion. RESULTS: There were no major or life-threatening bleeding events in the edoxaban group, while there were 2 major and 2 life-threatening bleeding events in the clopidogrel group by the TIMI criteria. By the ISTH classification, there was 1 major and 1 life-threatening bleeding event vs 5 major and 2 life-threatening bleeding events, respectively [relative risk (RR) 0.20, 95% confidence interval (CI) 0.02 to 1.70]. The bleeding risk was not statistically different with either treatment when assessed by TIMI or ISTH. Following 6 months of observation, there was a lower incidence of restenosis/reocclusion with edoxaban compared with clopidogrel (30.9% vs 34.7%; RR 0.89, 95% CI 0.59 to 1.34, p=0.643). CONCLUSION: These results suggest that patients who have undergone EVT have similar risks for major and life-threatening bleeding events with edoxaban and aspirin compared with clopidogrel and aspirin. The incidence of restenosis/reocclusion events, while not statistically different, was lower with edoxaban and aspirin, but an adequately sized trial will be needed to confirm these findings.

Stent-induced flow disturbances in the ipsilateral external carotid artery following internal carotid artery stenting: a temporary cause of jaw claudication.

BACKGROUND: We hypothesize that stenting of the internal carotid artery can immediately impede blood flow to the external carotid artery by either plaque shift or stent coverage of the ostium, and thereby cause ischemic symptoms like ipsilateral jaw claudication. METHODS: Thirty-three patients with high-grade asymptomatic stenosis of the internal carotid artery who underwent endovascular treatment were examined by ultrasound of the external carotid artery and performed an exercise test by chewing chewing gum synchronously to an electronic metronome for 3 min. Tests were performed before, the day after, and 1 week after the stenting procedure. Claudication time was defined as the timespan until occurrence of pain of the masseter muscle and/or chewing dyssynchrony to the metronome for more than 15 s. Ten patients with an isolated, atherosclerotic stenosis of the external carotid artery served as controls. RESULTS: A significantly reduced claudication time (in seconds) was recorded in patients who underwent carotid artery stenting compared to baseline values; median 89 (interquartile range, IQR, 57 to 124) vs. median 180 (IQR 153 to 180; p < 0.001). By categorization of the flow velocity at the external carotid artery into faster or slower as 200 cm/sec, the effect was even accentuated. Stenting values showed improvement 1 week after but did not return to baseline levels. No respective changes were found in controls. CONCLUSION: Stenting of the internal carotid artery lead to ipsilateral flow deterioration at the external carotid artery resulting in temporary jaw claudication. This impairment attenuated over the time and was significantly reduced after 1 week.

Combined Effects of Inflammatory Status and Carotid Atherosclerosis: A 12-Year Follow-Up Study.

BACKGROUND AND PURPOSE: Inflammatory responses play a key role in atherogenesis. The aim of this study was to assess the prognostic value of hsCRP (high-sensitivity C-reactive protein) and to evaluate whether degree of carotid stenosis and serum levels of hsCRP jointly predict long-term mortality in asymptomatic patients with carotid atherosclerosis. METHODS: One thousand sixty-five patients with neurological asymptomatic carotid atherosclerosis as evaluated by duplex sonography were prospectively followed for cause-specific mortality. RESULTS: During a median of 11.81 years, a total of 549 deaths, including 362 cardiovascular deaths, were recorded. The risk of all-cause and cardiovascular mortality significantly increased in patients with elevated serum levels of hsCRP (the adjusted hazard ratio for cardiovascular mortality per increase of 1 mg/dL of hsCRP levels was 1.47; P<0.001). Patients with a high degree of carotid stenosis and increased hsCRP levels were particularly at risk of adverse outcome. Patients with carotid narrowing over 50% and hsCRP levels >0.29 mg/dL (=median) had nearly twice as high a risk of cardiovascular mortality compared with patients with carotid stenosis of <50% and hsCRP levels <0.29 mg/dL (adjusted hazard ratio 1.89; P<0.001). Improvement in risk stratification with combined assessment of carotid stenosis and hsCRP was confirmed by an improvement of the continuous net reclassification improvement with 18% for all-cause mortality and 15% for cardiovascular mortality compared with the degree of carotid stenosis alone (P<0.01). CONCLUSIONS: Measurement of hsCRP in combination with ultrasound investigations of the carotid arteries at a single time point provides additional prognostic information for patients with asymptomatic carotid atherosclerosis.

Percutaneous instillation of physiological saline solution for the treatment of femoral pseudoaneuryms.

OBJECTIVE: To investigate the efficacy of para-aneurysmal saline injection for closure of postcatheterization pseudo-aneurysm (PA) at the vascular access site. METHODS: Fifty-one consecutive patients with postcatheterization PA at the vascular access site were included to undergo percutaneous para-aneurysmal saline injection. In case of technical failure the day after, PA were treated by bovine thrombin injection. Anatomical properties of the PA were recorded as were details to injection. RESULTS: Initially all patients exhibited success which was reduced to 43 % at day one. A saline volume of median 7 ml (interquartile range 6-8 ml) has been injected. The amount of injected saline was not different in patients with and without treatment success at day one (P = 0.6). Several anatomical properties of the PA exhibited marked differences in patients with or without success. The length (10.3 mm (7.8-12.0) vs. 12.5 mm (10.3-15.0); P = 0.009) and the angulation (110° (100-118) vs. 140° (129-146); P < 0.001) of the fistula/vessel axis was statistically different between groups. The peak systolic velocity failed to show significance with a tendency to higher values in the ineffective study group (P = 0.07). No peripheral complications occurred. CONCLUSION: Para-aneurysmal saline injection may be a therapeutic alternative to percutaneous thrombin injection in patients exhibiting favorable anatomical properties.

Red cell distribution width and mortality in carotid atherosclerosis.

BACKGROUND: Red cell distribution width (RDW) is associated with morbidity and mortality in chronic cardiac disease. The aim of the present study was to investigate the role of RDW as a predictor of adverse outcome in patients with carotid atherosclerosis. MATERIALS AND METHODS: We prospectively studied 1065 of 1286 consecutive patients with neurological asymptomatic carotid artery stenosis as assessed by duplex Doppler sonography. The study end points were all-cause mortality and cardiovascular mortality respectively. RESULTS: During a median follow-up time of 6·2 years (interquartile range 5·9-6·6), corresponding to 5551 overall person-years, 275 patients (25·8%) died. Of them, 182 patients (66·2%) died due to cardiovascular causes. RDW was significantly associated with adverse outcome. In a continuous multivariate Cox regression analysis, the adjusted hazard ratio for each per cent increase in RDW was 1·39 (95% CI 1·27-1·53; P < 0·001) for all-cause and 1·43 (95% CI 1·28-1·60; P < 0·001) for cardiovascular mortality respectively. Kaplan-Meier estimates showed a gradual relationship between increasing quartiles of RDW and death (log rank P < 0·001). Adjusted hazard ratios for all-cause death ranged from 0·89 to 1·94 for the highest vs. the lowest quartile (P < 0·001 for trend) and for cardiovascular death from 1·08 to 2·34 for the highest vs. the lowest quartile (P < 0·001 for trend) respectively. CONCLUSIONS: Red cell distribution width was significantly and independently associated with all-cause and cardiovascular death in patients with asymptomatic carotid atherosclerosis.

The impact of selectins on mortality in stable carotid atherosclerosis.

Cellular adhesion molecules also known as selectins promote recruitment of inflammatory cells into the arterial wall where they interact with lipid particles leading subsequently to plaque formation. The intercellular adhesion molecule-1 (ICAM-1), the vascular cell adhesion molecule-1 (VCAM-1) and the endothelial-leukocyte adhesion molecule 1 (ELAM-1) also known as E-selectin mediate the attachment of leukocytes and have been implicated in the destabilisation of atherosclerotic plaques. Therefore, we hypothesised that plasma selectin levels are associated with adverse clinical outcome. We prospectively studied 855 patients with sonographically confirmed carotid atherosclerosis. During a median follow-up of 6.2 years, corresponding to 5,551 overall person-years, 275 patients (26 %) died. We detected a significant association between cardiovascular mortality and ICAM-1 (adjusted hazard ratio [HR]: 3.43, 95 % confidence interval [CI] 2.00-5.88, p< 0.001) as well as VCAM-1 (adjusted HR: 2.51, 95 %CI 1.45-4.34, p=0.001) when comparing the fourth with the first quartile. Comparable results were obtained for all-cause mortality. In contrast, we could not detect a significant association between E-selectin and all-cause or cardiovascular mortality. We identified the selectins ICAM-1 and VCAM-1 as strong and independent predictors of all-cause and cardiovascular mortality in patients with stable carotid atherosclerosis. These molecules are elevated in states of endothelial activation and might assist to monitor anti-atherosclerotic therapy and select those patients with carotid atherosclerosis, who are at higher risk for cardiovascular events.

A review of antithrombotic therapy and the rationale and design of the randomized edoxaban in patients with peripheral artery disease (ePAD) trial adding edoxaban or clopidogrel to aspirin after femoropopliteal endovascular intervention.

Compared with the coronary setting, knowledge about antithrombotic therapies after endovascular treatment (EVT) is inadequate in patients with peripheral artery disease (PAD). Based on a review of trials and guidelines, which is summarized in this article, there is scant evidence that antithrombotic drugs improve outcome after peripheral EVT. To address this knowledge gap, the randomized, open-label, multinational edoxaban in patients with Peripheral Artery Disease (ePAD) study (ClinicalTrials.gov identifier NCT01802775) was designed to explore the safety and efficacy of a combined regimen of antiplatelet therapy with clopidogrel and anticoagulation with edoxaban, a selective and direct factor Xa inhibitor, both combined with aspirin. As of July 2014, 203 patients (144 men; mean age 67 years) from 7 countries have been enrolled. These patients have been allocated to once-daily edoxaban [60 mg for 3 months (or 30 mg in the presence of factors associated with increased exposure)] or clopidogrel (75 mg/d for 3 months). All patients received aspirin (100 mg/d) for the 6-month duration of the study. The primary safety endpoint is major or clinically relevant nonmajor bleeding; the primary efficacy endpoint is restenosis or reocclusion at the treated segment(s) measured at 1, 3, and 6 months using duplex ultrasound scanning. All outcomes will be assessed and adjudicated centrally in a masked fashion. The ePAD study is the first of its kind to investigate a combined regimen of antiplatelet therapy and anticoagulation through factor Xa inhibition with edoxaban.

Integrative therapy in patients with intermittent claudication.

The generally accepted first-line treatment in patients with intermittent claudication is risk factor modification, medical treatment and exercise training. In an era of reduced resources, the benefit of any further invasive intervention must be weighted against best conservative therapy for patients with claudication. According to some recent trials an integrative therapeutic concept combining best conservative treatment - including (supervised) exercise therapy - with endovascular therapy gives the best midterm results concerning walking distance and health-related quality of life. The improved mid- and long-term patency rate with use of modern technology further supports this concept. The conservative and interventional treatment strategy are more complimentary than competitive. The current main challenge is to overcome the economic barriers concerning the availability of exercise programmes.

The impact of uric acid on long-term mortality in patients with asymptomatic carotid atherosclerotic disease.

BACKGROUND: Serum uric acid (SUA) has been discussed to be related to cardiovascular (CV) disease and outcome. We investigated whether levels of SUA predict long-term mortality in neurologically asymptomatic patients with carotid atherosclerotic disease. METHODS: We prospectively studied 959 consecutive patients with carotid atherosclerosis as evaluated by duplex Doppler sonography for all-cause and CV death, respectively. RESULTS: During a median follow-up time of 6.3 years (interquartile range [IQR], 5.4-7.1 years), 246 deaths (25.7%), including 160 CV deaths (16.7%), were recorded. Median baseline SUA levels were 5.9 mg/dL (IQR, 5.0-7.0 mg/dL). SUA was significantly associated with all-cause death and CV death. Adjusted hazard ratios (HRs) for an increase of 1 mg/dL of SUA levels were 1.12 (95% confidence interval [CI], 1.04-1.21; P = .003) and 1.20 (95% CI, 1.11-1.30; P < .001) for all-cause and CV death, respectively. Quartiles of SUA levels showed a significant association with CV mortality (log-rank P = .002). For CV death, adjusted HRs for quartiles of increasing SUA levels were 1.45 (95% CI, .87-2.43), 1.44 (95% CI, .85-2.46), and 2.26 (95% CI, 1.36-3.76; P < .01), compared with the lowest quartile, respectively. Patients with baseline carotid stenosis of more than 50% and/or increased levels of SUA (≥median) had an approximately 2-fold increase in risk of (CV) death, compared with patients with carotid narrowing of less than 50% and/or SUA levels less than the median (P < .001). CONCLUSIONS: Levels of SUA represent independent predictors for CV mortality in a cohort of patients with asymptomatic carotid atherosclerosis.

Mean platelet volume predicts outcome in patients with asymptomatic carotid artery disease.

BACKGROUND AND OBJECTIVE: Platelets play a pivotal role in atherothrombosis and are potentially involved in the pathogenesis of atherosclerosis. We investigated whether mean platelet volume (MPV) predicts clinical outcome and progression of atherosclerosis in patients with asymptomatic carotid artery disease. METHODS: We studied 1006 of 1268 prospectively collected consecutive patients with asymptomatic carotid atherosclerosis who were evaluated by duplex sonography. Patients were followed up clinically for the occurrence of a major adverse cardiovascular event (MACE), a composite of myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft, stroke and death. RESULTS: During a median follow-up of 3.1 years (interquartile range, 2.5-3.5), a total of 316 (31.5%) MACEs were recorded. Increased levels of MPV were significantly associated with increased risk of the occurrence of MACEs (adjusted hazard ratio [HR] for an increase in one standard deviation [SD] of MPV 1.22, confidence interval [CI] 1.05-1.35, P < 0.01). Patients with MPV levels above 11.8 femtolitre (= fifth quintile) had a significantly higher event rate (41.3% vs. 29.3%, P < 0.001) with an adjusted HR for MACEs of 1.65 (95% CI 1.26-2.16, P < 0.001) compared with patients with MPV levels in the first to fourth quintile. No significant association was found between baseline MPV levels with either baseline degree or progression during a 6-month follow-up of carotid stenosis. CONCLUSION: Mean platelet volume was independently and significantly associated with adverse cardiovascular outcome in patients with asymptomatic carotid atherosclerosis.

Prognostic value of neutrophils in patients with asymptomatic carotid artery disease.

BACKGROUND: Inflammation is associated with atherosclerotic disease. In this context, it has been shown that an increased neutrophil count is a risk factor for cardiovascular events in patients with coronary and peripheral artery disease. However, the impact of neutrophils on long-term mortality in patients with carotid atherosclerosis is not yet fully understood. METHODS: We prospectively studied 853 of 1268 consecutive patients with neurologically asymptomatic carotid stenosis for all-cause and cardiovascular death, respectively. RESULTS: During a median follow-up time of 6.3 years (IQR 5.8-6.7 years) a total of 203 deaths (23.8%), including 134 cardiovascular deaths (15.7%), were recorded. An increase of 1 G/L of neutrophil count indicated an increased risk for all-cause mortality of 1.20 (CI [95%] 1.10-1.31, P < 0.001) and of cardiovascular death of 1.30 (CI 1.17-1.45, P < 0.001), respectively. For the second to the fourth quartile of the neutrophil count, adjusted hazard ratios for all-cause mortality were 1.12 (CI, 0.71-1.75), 1.46 (CI, 0.96-2.21), and 1.76 (CI, 1.15-2.69; P = 0.03 for trend); and 1.41 (CI, 0.80-2.49), 1.53 (CI, 0.88-2.68), and 2.54 (CI, 1.49-4.33; P < 0.01 for trend) for cardiovascular mortality, compared to the lowest quartile, respectively. Patients with baseline carotid stenosis of more than 50% and/or increased neutrophil count (≥median), had a 1.9-2.4 fold increase in risk of (CV-) death, compared to patients with carotid narrowing of less than 50% and/or neutrophil count less than the median (P < 0.001). After adjusting for cardiovascular risk factors, only neutrophils, but not eosinophils, basophils, monocytes, lymphocytes, or the total leukocyte count showed a significant association with long-term mortality. No significant association was found between white blood cell subtypes with either baseline degree or progression during a 6 month follow-up of carotid stenosis. CONCLUSION: The baseline neutrophil count was an independent predictor for all-cause and cardiovascular mortality in neurologically asymptomatic patients with carotid stenosis. Thus, the measurement of neutrophils could provide prognostic information on outcome in patients at risk.

Assessment of self-expanding nitinol stent deformation after chronic implantation into the femoropopliteal arteries.

AIMS: The purpose of this prospective clinical investigation was to quantify the degree and range of compressive and bending deformations sustained by self-expanding nitinol stents when implanted into the femoropopliteal arteries of patients with symptomatic peripheral vascular disease (PVD). METHODS AND RESULTS: Twenty-three nitinol self-expanding stents (Absolute; Abbott Vascular, Santa Clara, CA, USA) with diameters ranging from 5-10 mm and lengths ranging from 40-100 mm were implanted in 19 lesions in 18 extremities of 17 patients. Two days following implantation, in vivo stent compression and bending were assessed by measurement of stent length and deflection angle via lateral view radiographs. The results showed that leg flexion was associated with significant stent bending; popliteal stents bent almost 90° while SFA stents bent only minimally. Leg flexion was also associated with stent shortening (compression), the greatest amount being observed for stents implanted into the popliteal artery (popliteal 8.5% ± 3.2%; SFA/prox pop 5.3% ± 0.5%; SFA 3.1% ± 1.8%). After a mean follow-up of 7.1 ± 1.3 months, the degree of stent deformation during leg flexion was essentially unchanged as compared to immediate post-procedure levels. CONCLUSIONS: Indwelling nitinol stents are routinely bent and compressed during leg flexion, with most bending observed in stents implanted near the popliteal artery. The degree of deformation observed immediately after implantation appears to be predictive of the chronic state, as repeat measurements obtained after a mean of seven months were essentially unchanged from baseline.

A validated risk score to predict outcomes after carotid stenting.

BACKGROUND: Periprocedural outcome has been extensively investigated in patients undergoing carotid artery stenting. However, risk factors contributing to long-term mortality have not been comprehensively assessed. We aimed to establish a validated clinical risk score for long-term mortality in patients after carotid artery stenting. METHODS AND RESULTS: Two independent cohorts after successful carotid artery stenting (602 and 552 patients) were prospectively investigated. Multivariable Cox regression and bootstrap variable selection were used to select the best-fitting multivariable model. The mortality rate was 35% in the derivation and 39% in the validation cohort during a median follow-up of 6.5 and 7.4 years, respectively. The following variables were identified as most robust risk factors in the derivation cohort: age, heart failure, diabetes mellitus, relative lymphocyte count, prothrombin time, peripheral artery disease, and contralateral carotid occlusion. A weighted multimarker risk score yielded an area under the receiver operating characteristic curve of 0.79 in the derivation (P<0.001) and of 0.69 (P<0.001) in the validation cohort. In comparison, the best area under the receiver operating characteristic curves for single risk factors were 0.67 and 0.63, respectively. For optimal clinical use, a simplified risk score was also developed, which discriminated very well from very low to very high risk. The risk of all-cause mortality ranged from 8% for a score of 1 to 93% for a score of 7 (P<0.001) in the derivation and from 11% to 100% in the validation cohort (P<0.001). CONCLUSIONS: A multimarker risk score outperformed the prognostic value of single risk factors for the prediction of long-term mortality.

Usefulness of hemoglobin level to predict long-term mortality in patients with asymptomatic carotid narrowing by ultrasonography.

Anemia is associated with the cardiovascular outcome in healthy subjects but its impact on outcome in patients with cardiovascular disease has not yet been fully understood. Therefore, we assessed the long-term influence of hemoglobin on all-cause and cardiovascular mortality in patients with atherosclerotic disease. We prospectively studied 1,065 of 1,286 consecutive patients with asymptomatic carotid narrowing. During a median follow-up of 6.2 years, corresponding to 5,551 overall person-years, 275 patients (25.8%) died. Continuous measures of hemoglobin displayed a significant inverse effect on all-cause mortality and cardiovascular mortality (adjusted hazard ratio [HR] for increase of 1 SD of hemoglobin 0.73, 95% confidence interval [CI] 0.64 to 0.83; p <0.001) and adjusted HR 0.76, 95% CI 0.64 to 0.89; p = 0.001, respectively). The cumulative 6-year survival rate was 61%, 79%, 80%, and 81% in the first, second, third, and fourth quartile of hemoglobin (log-rank p <0.001). Patients within the first quartile (<12.9 g/dl) had a significantly increased risk of all-cause mortality (adjusted HR 1.93, 95% CI 1.46 to 2.54, p <0.001) and cardiovascular mortality (adjusted HR 1.68, 95% CI 1.19 to 2.36, p = 0.003) compared to patients with greater levels. In conclusion, our study has demonstrated a significant association with hemoglobin levels and all-cause and cardiovascular mortality in patients with carotid narrowing. Nevertheless, additional research, in terms of randomized controlled trials, is needed to warrant these findings and to evaluate potential therapeutic interventions.