Carotid Intima-Media Thickness Progression as Surrogate Marker for Cardiovascular Risk: Meta-Analysis of 119 Clinical Trials Involving 100 667 Patients.

BACKGROUND: To quantify the association between effects of interventions on carotid intima-media thickness (cIMT) progression and their effects on cardiovascular disease (CVD) risk. METHODS: We systematically collated data from randomized, controlled trials. cIMT was assessed as the mean value at the common-carotid-artery; if unavailable, the maximum value at the common-carotid-artery or other cIMT measures were used. The primary outcome was a combined CVD end point defined as myocardial infarction, stroke, revascularization procedures, or fatal CVD. We estimated intervention effects on cIMT progression and incident CVD for each trial, before relating the 2 using a Bayesian meta-regression approach. RESULTS: We analyzed data of 119 randomized, controlled trials involving 100 667 patients (mean age 62 years, 42% female). Over an average follow-up of 3.7 years, 12 038 patients developed the combined CVD end point. Across all interventions, each 10 µm/y reduction of cIMT progression resulted in a relative risk for CVD of 0.91 (95% Credible Interval, 0.87-0.94), with an additional relative risk for CVD of 0.92 (0.87-0.97) being achieved independent of cIMT progression. Taken together, we estimated that interventions reducing cIMT progression by 10, 20, 30, or 40 µm/y would yield relative risks of 0.84 (0.75-0.93), 0.76 (0.67-0.85), 0.69 (0.59-0.79), or 0.63 (0.52-0.74), respectively. Results were similar when grouping trials by type of intervention, time of conduct, time to ultrasound follow-up, availability of individual-participant data, primary versus secondary prevention trials, type of cIMT measurement, and proportion of female patients. CONCLUSIONS: The extent of intervention effects on cIMT progression predicted the degree of CVD risk reduction. This provides a missing link supporting the usefulness of cIMT progression as a surrogate marker for CVD risk in clinical trials.

Walking-induced endothelial dysfunction predicts ischemic cardiovascular events in patients with intermittent claudication.

Endothelial dysfunction, evaluated by flow-mediated dilatation (FMD), predicts adverse cardiovascular events in patients with intermittent claudication (IC). IC is an example of repeated ischemia/reperfusion injury that may contribute to the progression of vascular disease by worsening endothelial function, a trigger for acute cardiovascular events. The predictive value of effort-induced endothelial dysfunction for cardiovascular events in patients with IC has not been studied previously. The objective of this study was to assess whether exercise-induced endothelial dysfunction is predictive of adverse cardiovascular outcome in IC. In 44 patients with IC, we measured brachial artery FMD by B-mode ultrasonography at rest and 10 minutes after a maximal treadmill exercise. Treadmill exercise halved the FMD (from 3.5 ± 0.6% to 1.45 ± 0.46%, p < 0.05). After a follow-up period of 85 (72-98) months, a total of 20 major cardiovascular events occurred. In a multivariate analysis, a post-exercise reduction of brachial FMD > 1.3% was predictive for cardiovascular events. Maximal exercise-induced endothelial dysfunction is predictive of cardiovascular events in patients with IC.

Simplified PESI score and sex difference in prognosis of acute pulmonary embolism: a brief report from a real life study.

Prognostic stratification of acute pulmonary embolism (PE) remains a challenge in clinical practice. Simplified PESI (sPESI) score is a practical validated score aimed to stratify 30-day mortality risk in acute PE. Whether prognostic value of sPESI score differs according to sex has not been previously investigated. Therefore the aim of our study was to provide information about it. Data records of 452 patients, 180 males (39.8 %) and 272 females (60.2 %) discharged for acute PE from Internal Medicine wards of Tuscany (Italy) were analysed. sPESI was retrospectively calculated. Variables enclosed in sPESI score, all cause in-hospital mortality and overall bleedings were compared between sexes. Moreover, predictive ability of sPESI score as prognosticator of all cause in-hospital mortality was tested and compared between sexes. sPESI score 0 (low risk) was found in 17.7 % of males and 13.6 % of females (p = 0.2323). We didn't find significant difference in sPESI scoring distribution. Age ≥80 years (51.4 vs. 33.8 %, p = 0.0003) and heart rate ≥110 bpm (23.5 vs. 14.4 %, p = 0.0219) were found significantly more prevalent in females, whereas active cancer (23.8 vs. 39.4 %, p = 0.0004) and cardio-respiratory diseases (19.8 vs. 27.7 %, p = 0.0416) were in males. All cause in-hospital mortality was 0 % in both genders for sPESI score 0, whereas it was 5.4 % in females and 13.6 % in males with sPESI score 1-2 (p = 0.0208) and 22 % in females and 19.3 % in males with sPESI score ≥3 (p = 0.7776). Overall bleedings were significantly more frequent in females compared with males (4.77 vs. 0.55 %, p = 0.0189). In females overall bleedings ranged from 2.7 % in sPESI score 0 to 6 % in sPESI score ≥3. Predictive ability of sPESI score as prognosticator of all cause in-hospital mortality was higher in females compared to males (AUC 0.72 vs. 0.67, respectively). In real life different co-morbidity burdens in females compared to males. Females seems to be at lower risk of all cause in-hospital mortality for sPESI score ≤2 but at higher risk of bleeding, irrespective from sPESI scoring. Predictive ability of sPESI score seems better in females.

Effect on walking distance and atherosclerosis progression of a nitric oxide-donating agent in intermittent claudication.

BACKGROUND: Peripheral arterial disease (PAD) is almost invariably associated with a generalized atherosclerotic involvement of the arterial tree and endothelial dysfunction. Previous short-term studies showed improvement of vascular reactivity and walking capacity in PAD patients by measures aimed at restoring nitric oxide (NO) production. NO is also known to prevent the progression of atherosclerosis. We wished to assess whether the prolonged administration of an NO-donating agent (NCX 4016) improves the functional capacity of PAD patients and affects the progression of atherosclerosis as assessed by carotid intima-media thickness (IMT). METHODS: This prospective, double-blind, placebo-controlled study enrolled 442 patients with stable intermittent claudication who were randomized to NCX 4016 (800 mg, twice daily) or its placebo for 6 months. The primary study outcome was the absolute claudication distance on a constant treadmill test (10% incline, 3 km/h). The main secondary end point was the change of the mean far-wall right common carotid artery IMT. RESULTS: The increase of absolute claudication distance at 6 months compared with baseline was 126±140 meters in the placebo-treated group and 117±137 meters in the NCX 4016-treated group, with no significant differences. Carotid IMT increased in the placebo-treated group (+0.01±0.01 mm; P=.55) and decreased in the NCX 4016-treated group (-0.03±0.01 mm; P=.0306). Other secondary end points did not differ between the two treatments. CONCLUSIONS: Long-term NO donation does not improve the claudication distance but does reduce progression of atherosclerosis in patients with PAD. Further studies aimed at assessing whether long-term NO donation may prevent ischemic cardiovascular events are warranted.

Guideline on carotid surgery for stroke prevention: updates from the Italian Society of Vascular and Endovascular Surgery. A trend towards personalized medicine.

BACKGROUND: This guideline (GL) on carotid surgery as updating of "Stroke: Italian guidelines for Prevention and Treatment" of the ISO-SPREAD Italian Stroke Organization-Group, has recently been published in the National Guideline System and shared with the Italian Society of Vascular and Endovascular Surgery (SICVE) and other Scientific Societies and Patient's Association. METHODS: GRADE-SIGN version, AGREE quality of reporting checklist. Clinical questions formulated according to the PICO model. Recommendations developed based on clinical questions by a multidisciplinary experts' panel and patients' representatives. Systematic reviews performed for each PICO question. Considered judgements filled by assessing the evidence level, direction, and strength of the recommendations. RESULTS: The panel provided indications and recommendations for appropriate, comprehensive, and individualized management of patients with carotid stenosis. Diagnostic and therapeutic processes of the best medical therapy, carotid endarterectomy (CEA), carotid stenting (CAS) according to the evidences and the judged opinions were included. Symptomatic carotid stenosis in elective and emergency, asymptomatic carotid stenosis, association with ischemic heart disease, preoperative diagnostics, types of anesthesia, monitoring in case of CEA, CEA techniques, comparison between CEA and CAS, post-surgical carotid restenosis, and medical therapy are the main topics, even with analysis of uncertainty areas for risk-benefit assessments in the individual patient (personalized medicine [PM]). CONCLUSIONS: This GL updates on the main recommendations for the most appropriate diagnostic and medical-surgical management of patients with atherosclerotic carotid artery stenosis to prevent ischemic stroke. This GL also provides useful elements for the application of PM in good clinical practice.

Anesthetic management of carotid endarterectomy: an update from Italian guidelines.

BACKGROUND AND AIMS: In order to systematically review the latest evidence on anesthesia, intraoperative neurologic monitoring, postoperative heparin reversal, and postoperative blood pressure management for carotid endarterectomy. The present review is based on a single chapter of the Italian Health Institute Guidelines for diagnosis and treatment of extracranial carotid stenosis and stroke prevention. METHODS AND RESULTS: A systematic article review focused on the previously cited topics published between January 2016 and October 2020 has been performed; we looked for both primary and secondary studies in the extensive archive of Medline/PubMed and Cochrane library databases. We selected 14 systematic reviews and meta-analyses, 13 randomized controlled trials, 8 observational studies, and 1 narrative review. Based on this analysis, syntheses of the available evidence were shared and recommendations were indicated complying with the GRADE-SIGN version methodology. CONCLUSIONS: From this up-to-date analysis, it has emerged that any type of anesthesia and neurological monitoring method is related to a better outcome after carotid endarterectomy. In addition, insufficient evidence was found to justify reversal or no-reversal of heparin at the end of surgery. Furthermore, despite a low evidence level, a suggestion for blood pressure monitoring in the postoperative period was formulated.

Antithrombotic treatment of asymptomatic carotid atherosclerosis: a medical dilemma.

Carotid artery atherosclerosis (CAAS) is a common finding in asymptomatic subjects evaluated for cardiovascular (CV)-risk stratification. Besides the careful control of CV-risk factors, antithrombotic agents, and in particular aspirin, may be considered for primary prevention in patients at CV-risk. However, there is strong controversy on the use of aspirin in primary prevention. Even if several studies confirmed the association between CAAS and CV-events, CAAS is not universally recognized as an independent risk factor and the choice to use aspirin as primary prevention in these patients remains a medical dilemma. Here we review the available evidence on the prognostic value of asymptomatic CAAS for major CV-events and on the utility of antithrombotic agents in this population. We conclude that the detection of asymptomatic CAAS can not be considered as a direct indication to carry out primary prophylaxis with antithrombotic drugs, and the choice to use aspirin should be made only after the careful estimate of the individual's CV-and hemorrhagic risk.

Ankle-brachial index measured by palpation for the diagnosis of peripheral arterial disease.

BACKGROUND: The ankle-brachial index (ABI), i.e. the ratio of the ankle to brachial systolic blood pressure, is the golden standard for the diagnosis of peripheral arterial disease (PAD) and is a highly specific method for the assessment of vascular risk in otherwise asymptomatic patients. OBJECTIVE: To assess the diagnostic accuracy of the ABI measured by palpation in patients at increased cardiovascular risk in a primary care setting. METHODS: Twenty-four GPs enrolled 10 consecutive patients each, at intermediate cardiovascular risk, based on age >55 and <65 years and one or two associated major cardiovascular risk factors or age >65 and <80 years without associated cardiovascular risk factor. Clinical data recording and measurements of the ABI were performed. The design of the study was a prospective, blind comparison between the ABI measured by palpation by the GP and simultaneously by Doppler ultrasound by an angiologist (reference test). RESULTS: Out of 240 enrolled patients, 205 completed the study (35 lost to follow-up); in 9, ABI by palpation was not measurable. Out of the remaining 196 assessable patients, 8 (4.08%) had PAD. Sensitivity of the palpation method was 88% (95% confidence intervals: 65-100), specificity 82% (77-88), positive predictive value 18% (6-29), negative predictive value 99% (98-100), positive likelihood ratio = 4.98 (3.32-7.48) and negative likelihood ratio = 0.15 (0.02-0.95). CONCLUSIONS: The measurement of ABI by palpation in the setting of primary care, in patients at intermediate cardiovascular risk, is a sufficiently sensitive method to consider its use as a screening test for the exclusion of PAD.

Prevention by NCX 4016, a nitric oxide-donating aspirin, but not by aspirin, of the acute endothelial dysfunction induced by exercise in patients with intermittent claudication.

Ischemia/reperfusion damage evokes systemic inflammation and endothelial dysfunction in patients with intermittent claudication. We compared the effects of aspirin with those of a nitric oxide-donating aspirin in preventing the acute, systemic endothelial dysfunction provoked by exercise-induced ischemia of the lower limbs in patients with intermittent claudication. In a prospective, randomized, single-blind, parallel-groups trial among 44 patients with intermittent claudication we compared four weeks of aspirin (100 mg o.d.) with NCX 4016 (800 mg b.i.d.). Primary end point was the exercise-induced changes in brachial flow-mediated vasodilation (FMD) at day 28; secondary end points were effort-induced changes of markers of neutrophil (plasma elastase) and endothelial (soluble VCAM-1) activation. Baseline FMD was comparable in the two groups, both on day 1 (pre-treatment: aspirin = 3.1 +/- 0.5%, nitroaspirin = 3.9 +/- 0.7%, p = NS), and on day 28 (aspirin = 3.4 +/- 0.7%, NCX 4016 = 3.2 +/- 0.6%, p = NS). Maximal treadmill exercise induced an acute worsening of FMD in both groups at baseline (aspirin = -1.15%, nitroaspirin = -1.76%); after four weeks treatment, the impairment of FMD induced by exercise was still present in the aspirintreated group (-1.46%) while it was abolished in the NCX 4016-treated group (+0.79%, p = 0.038 vs. aspirin). Similarly, exercise induced an increase of plasma elastase and of sVCAM-1 which were not affected by aspirin while they were suppressed by NCX 4016. Maximal treadmill exercise induces a systemic arterial endothelial dysfunction in patients with intermittent claudication. A nitric oxide-donating aspirin, but not aspirin, prevents effort-induced endothelial dysfunction.

Endothelial dysfunction in patients with spontaneous venous thromboembolism.

BACKGROUND AND OBJECTIVES: A high incidence of atherosclerotic lesions and cardiovascular events has been reported in patients with spontaneous venous thromboembolism. Endothelial dysfunction is an early marker of atherosclerosis and has predictive value for ischemic events. We have evaluated endothelial function in patients with a history of spontaneous venous thromboembolism. DESIGN AND METHODS: Patients with a history of symptomatic, objectively confirmed, spontaneous venous thromboembolism were included in a case-control study. Exclusion criteria were any known risk factors for cardiovascular diseases, other conditions associated with endothelial dysfunction, estro-progestinic therapy or pregnancy. Controls were age- (+/-5 years) and sex-matched subjects with the same exclusion criteria but without previous venous thromboembolism. Endothelial function was evaluated by the non-invasive measurement of flow-mediated vasodilation of the brachial artery and of plasma markers of endothelium activation; platelet activation parameters were also measured. RESULTS: Twenty-eight cases (8 females; mean age 59+/-15 years) and 28 controls (8 females; mean age 58+/-15) were studied. Flow-mediated vasodilation was 3.5+/-0.6% in cases (95% CIs: 2.2 to 4.8) and 5.7+/-0.6% (4.2 to 6.8) in controls (p=0.015). Brachial artery blood flow and hyperemic blood flow did not differ between the two groups. Plasma von Willebrand factor and soluble P-selectin levels were significantly higher in patients with venous thromboembolism, while plasma soluble CD40 ligand and urinary 11-dehydro-TxB2 levels were similar in cases and controls. INTERPRETATION AND CONCLUSIONS: Patients with spontaneous venous thromboembolism have endothelial dysfunction, unlike age- and sex- matched controls. This finding suggests that spontaneous venous thromboembolism may be a condition associated with an enhanced risk of atherosclerosis.

Endothelial dysfunction in patients with kidney failure and vascular risk factors: acute effects of hemodialysis.

BACKGROUND: Patients with kidney failure present endothelial dysfunction, which was shown to be partly corrected by hemodialysis. No data exist on the effects of hemodialysis on endothelial dysfunction in kidney failure patients with associated vascular risk factors. The aim of this study was to evaluate the acute effects of hemodialysis on endothelial dysfunction in patients with kidney failure and associated vascular risk factors and to assess the role of endothelium-toxic substances. METHODS: We assessed endothelial dysfunction in 13 patients with chronic renal failure and other vascular risk factors before and after hemodialysis and in 13 healthy controls and simultaneously measured nitric oxide (NO) synthesis and activity. Endothelial dysfunction was studied using an echographic method as flow-mediated dilation (FMD) of the brachial artery; plasma NO2- and NO3-, cyclic guanosine-5-monophosphate (cGMP), plasma homocysteine levels and low molecular mass-advanced glycation end-products (LMM-AGEs) were simultaneously measured. RESULTS: As compared with healthy controls, patients with renal failure showed a reduced FMD (2.89 +/- 1.43 vs. 7.81 +/- 1.54%, p < 0.01) which was not corrected by dialysis (after dialysis 2.40 +/- 1.65%, p = NS vs. pre). Plasma NO2- and NO3- were normal or slightly increased and remained unchanged after dialysis. Plasma cGMP levels were reduced and remained unchanged after dialysis. Homocysteine and LMM-AGE plasma levels were raised and, although significantly reduced by dialysis, remained higher than in controls. CONCLUSIONS: Patients with kidney failure and associated vascular risk factors show an endothelial dysfunction related to defective NO activity, which is not corrected by hemodialysis despite the reduction, though not to normal, in homocysteine and LMM-AGE levels. Endothelial dysfunction may contribute to the progression of atherosclerosis in patients with kidney failure and vascular risk factors.

Endothelium, venous thromboembolism and ischaemic cardiovascular events.

The association between venous thromboembolism and arterial thrombosis has emerged as consistent clinical observation in the last few years. While several experimental, epidemiological and pharmacologic studies support this association, the initial pathophysiological mechanism linking these two clinical conditions remains to be established. This review discusses the pathophysiological bases and a number of experimental and clinical observations suggesting that the common link between venous thromboembolism and arterial thrombosis is represented by a dysfunctional endothelium.