Abnormal ankle-brachial index (ABI) predicts primary and secondary cardiovascular risk and cancer mortality.

BACKGROUND: An abnormal ankle-brachial pressure index (ABI) is a marker of the risk for increased total and cardiovascular (CV) mortality. However, it is not clear whether it is associated with an even worse prognosis in patients with previous CV events or with cancer mortality. MATERIALS AND METHODS: Consecutive subjects undergoing ABI assessment for suspected peripheral artery disease or for stratification of CV risk in ten centers in the Veneto Region (northeast Italy), between 2011 and 2014 were enrolled. The ABI was expressed as normal ≥0.9 to ≤1.3, and abnormal <0.9 or >1.3. All-cause mortality and CV or cancer mortality and hospitalizations for CV disease were collected from administrative databases up to December 2018. RESULTS: The study enrolled 1,177 patients. ABI was abnormal in 57.2%. Median follow-up was 61.6 months (53.4-70.1). All-cause, CV and cancer mortality were higher in patients with abnormal than normal ABI, with hazard ratios (HR) respectively 2.0 (95% CI 1.48-2.69), 1.98 (95% CI 1.24-3.17) and 1.85 (95% CI 1.09-3.15). Among subjects with abnormal ABI, the risk of overall mortality, HR 1.57 (95% CI 1.17-2.12), and CV mortality, HR 2.39 (95% CI 1.43-3.99), was higher in those with previous CV events. These latter also had a higher risk of hospitalization for myocardial infarction and stroke: HR 1.85 (95% CI 1.023.37) and 2.17 (95% CI 1.10-4.28). CONCLUSIONS: The co-existence of abnormal ABI and a history of CV events identifies subjects at higher risk, who call for a more aggressive approach. Abnormal ABI is also a predictor of cancer mortality.

The influence of interoceptive awareness on functional connectivity in patients with irritable bowel syndrome.

Irritable bowel syndrome (IBS) is characterized by visceral hypersensitivity likely related to altered processing of sensory stimuli along the brain-gut axis. Previous neuroimaging studies demonstrated structural and functional alteration of several brain areas involved in bodily representation, e.g. the insula, in patients with IBS. By means of resting-state functional magnetic resonance imaging (rs-fMRI) we searched for alteration of functional connectivity within the network involved in self-bodily consciousness. We found significant inverse correlation between hypochondriasis assessed through a clinical questionnaire and connectivity between posterior cingulate cortex and left supramarginal gyrus, extending into the adjacent superior temporal gyrus. Moreover, we observed a significant and positive correlation between a clinical questionnaire assessing interoception and connectivity between left anterior ventral insula and two clusters located in supramarginal gyrus bilaterally.Our findings highlight an "abnormal network synchrony" reflecting functional alteration, in the absence of structural and micro-structural changes, which might represent a possible therapeutic target for Irritable Bowel Syndrome.

Biosimilars of low-molecular-weight heparin products: fostering competition or reducing 'biodiversity'?

The term 'biosimilars' is used to qualify products developed to be similar to an original biological drug. Biosimilars are much more complicated to develop than a generic version of small-molecule drugs and this is especially true for low-molecular-weight heparins (LMWHs). Evidence on the antithrombotic management of acute coronary syndromes (ACS) showed that the introduction into the market of biosimilars approved on the basis of simple biological criteria, without robust data from comparative clinical trials, may be hazardous. Moreover, the mixtures of LMWH polysaccharide chains, some immunoallergic properties and potential contamination during the extraction process raise safety concerns. As was the case for the biosimilar erythropoietin, there is the risk that only copies of the most commercially successful LMWHs will be marketed, thus jeopardizing the 'biodiversity' now ensured by the presence of several LMWHs, each with unique features that support the use of an individual LMWH as first-choice therapy in certain categories of patients.

KRAS mutation detection by high-resolution melting analysis significantly predicts clinical benefit of cetuximab in metastatic colorectal cancer.

BACKGROUND: Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies are restricted to KRAS wild-type (WT) metastatic colorectal cancers (mCRCs), usually identified by direct sequencing, that may yield false negative results because of genetic heterogeneity within the tumour. We evaluated the efficiency of high-resolution melting analysis (HRMA) in identifying KRAS-mutant (MUT) tumours. METHODS: We considered 50 mCRC patients scored as KRAS-WT by direct sequencing and treated with cetuximab-containing chemotherapy, and tested the correlations between HRMA findings and response rate (RR), progression-free (PFS) and overall survival (OS). RESULTS: Aberrant melting curves were detected in four (8%) cases; gene cloning confirmed these mutations. Response rate (RR) of HRMA KRAS-WT patients was 28.3%. There was no response in HRMA KRAS-MUT patients. Disease control rate (responsive plus stable disease) was 58.7% in HRMA KRAS-WT patients and 25% in HRMA KRAS-MUT patients. There was no correlation between HRMA KRAS status and RR (P=0.287) or disease control (P=0.219). Median PFS (4.8 vs 2.3 months; hazard ratio (HR)=0.29, P=0.02) and OS (11.0 vs 2.7 months; HR=0.11, P=0.03) were significantly longer for the HRMA KRAS-WT than for HRMA KRAS-MUT patients. CONCLUSIONS: High-resolution melting analysis identified 8% more KRAS-MUT patients not responding to cetuximab-containing regimens, suggesting that HRMA may be more effective than direct sequencing in selecting patients for anti-EGFR antibodies.

Effects of elastic compression on hypomobility edema and fibrinolysis activation in multiple sclerosis.

AIM: In multiple sclerosis (MS) patients, loss of mobility leads to edema of the legs and raises their risk of thrombosis. They cannot use pharmacological prophylaxis over the long course of the disease. Elastic compression stockings are indicated to prevent venous thrombosis for hypomobile patients, and might therefore also limit edema. The aim of the study was to assess the feasibility of elastic compression with ATE stockings in severely disabled MS patients, and to make a preliminary assessment of their efficacy and safety. METHODS: We checked 201 MS patients, in a rehabilitation unit, by ultrasound for residues of thrombosis and recorded the duration of the MS, residual autonomy, and leg edema. Ninety-nine patients served as controls, and 102 were prescribed antithromboembolic stockings, to be worn 24h/day. RESULTS: The intervention group had higher baseline d-Dimer (471 ± 590 vs. 271 ± 183 mg/dL) and more had lower leg edema (80% vs. 40%). In all treated patients the edema disappeared. There were no cases of symptomatic deep venous thrombosis. D-Dimers dropped significantly in both groups, though more in the intervention group (to 363 ± 420 mg/dL, P=0.0001 and to 254 ± 180 mg/dL for controls, P=0.01). CONCLUSION: Antithromboembolic stockings can help eliminate edema of the legs in MS patients, and may also reduce the thrombotic risk: the lower d-Dimer values suggest an effect on the activation of inflammation and coagulation resulting from stasis-induced endothelial damage.

Risk factors for catheter-related thrombosis (CRT) in cancer patients: a patient-level data (IPD) meta-analysis of clinical trials and prospective studies.

BACKGROUND: Knowledge of independent, baseline risk factors for catheter-related thrombosis (CRT) may help select adult cancer patients who are at high risk to receive thromboprophylaxis. OBJECTIVES: We conducted a meta-analysis of individual patient-level data to identify these baseline risk factors. PATIENTS/METHODS: MEDLINE, EMBASE, CINAHL, CENTRAL, DARE and the Grey literature databases were searched in all languages from 1995 to 2008. Prospective studies and randomized controlled trials (RCTs) were eligible. Studies were included if original patient-level data were provided by the investigators and if CRT was objectively confirmed with valid imaging. Multivariate logistic regression analysis of 17 prespecified baseline characteristics was conducted. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. RESULTS: A total sample of 5636 subjects from five RCTs and seven prospective studies was included in the analysis. Among these subjects, 425 CRT events were observed. In multivariate logistic regression, the use of implanted ports as compared with peripherally implanted central venous catheters (PICCs), decreased CRT risk (OR, 0.43; 95% CI, 0.23-0.80), whereas past history of deep vein thrombosis (DVT) (OR, 2.03; 95% CI, 1.05-3.92), subclavian venipuncture insertion technique (OR, 2.16; 95% CI, 1.07-4.34) and improper catheter tip location (OR, 1.92; 95% CI, 1.22-3.02), increased CRT risk. CONCLUSIONS: CRT risk is increased with use of PICCs, previous history of DVT, subclavian venipuncture insertion technique and improper positioning of the catheter tip. These factors may be useful for risk stratifying patients to select those for thromboprophylaxis. Prospective studies are needed to validate these findings.

Risk of deep venous thrombosis (DVT) in bedridden or wheelchair-bound multiple sclerosis patients: a prospective study.

BACKGROUND: Multiple sclerosis (MS) often causes progressive loss of mobility, leading to limb paralysis. Venous and lymphatic stasis is a risk condition for venous thromboembolism (VTE). There is, however, no data on the frequency of VTE complicating the progression of MS. The aim of this study was to assess the frequency of deep vein thrombosis (DVT) in patients with late-stage MS attending a neurology center for rehabilitation. PATIENTS AND METHODS: A total of 132 patients with MS were enrolled, 87 women and 45 men, mean age 58+/-11 years. The disease had started on average 18.7 years before; patients reported 9.6 hours bedridden per day or 14.3 hours wheelchair-bound. Only 25 patients reported a residual ability to walk alone or with help. Lower limb edema was present in 113 patients, bilateral in 41 cases. At admission all patients underwent extended compression ultrasonography. Their plasma D-dimer levels were measured. No antithrombotic prophylaxis was given. RESULTS: DVT was found in 58 patients (43.9%); 32 had a history of VTE. Forty of these patients (69%) had chronic lower limb edema, in 19 cases bilateral. D-dimer levels in the DVT patients were significantly higher than in patients without DVT (553+/-678 vs. 261+/-152 ng/mL, p=0.0112, Mann-Whitney Test). Nearly half the DVT patients (26, 45%) had high D-dimer levels (701+/-684 ng/mL). Of the 74 patients without DVT, 48 had normal D-dimer (193.37+/-67.28 ng/mL) and 26 high (387.61+/-187.42 ng/mL). CONCLUSIONS: The frequency of DVT in late-stage MS may be over 40%. The long history of the disease means the onset of each episode cannot be established with certainty. A number of patients with positive CUS findings had negative D-dimer values, suggesting a VTE event in the past. However, the level of DVT risk in this series should lead physicians to consider the systematic application of long-term preventive measures.

Thrombosis-related complications and mortality in cancer patients with central venous devices: an observational study on the effect of antithrombotic prophylaxis.

BACKGROUND: Recent guidelines do not recommend antithrombotic prophylaxis (AP) to prevent catheter-related thrombosis in cancer patients with a central line. PATIENTS AND METHODS: This study assessed the management of central lines in cancer patients, current attitude towards AP, catheter-related and systemic venous thromboses, and survival. RESULTS: Of 1410 patients enrolled, 1390 were seen at least once in the 6-month median follow-up. Continuous AP, mainly low-dose warfarin, was given to 451 (32.4%); they were older, with a more frequent history of venous thromboembolism (VTE), and more advanced cancer. There was no difference in catheter-related thrombosis in patients given AP or not (2.8% and 2.2%, odds ratio 1.29, 95% confidence interval 0.64-2.6). The median time to first catheter-related complication was 120 days. Systemic VTE including deep and superficial thromboses and pulmonary embolism, were less frequent with AP (4% versus 8.2%, P = 0.005). Mortality was also lower (25% versus 44%, P = 0.0001). Multiple logistic regression analysis found only advanced cancer and no AP significantly associated with mortality. No major bleeding was recorded with AP. CONCLUSIONS: Current AP schedules do not appear to prevent catheter-related thrombosis. Systemic VTE and mortality, however, appeared lower after prophylaxis.

Low ankle-brachial index predicts an adverse 1-year outcome after acute coronary and cerebrovascular events.

BACKGROUND: Low ankle-brachial Index (ABI) identifies patients with symptomatic and asymptomatic peripheral arterial disease. The aim of this study was to correlate ABI value (normal or low) with 1-year clinical outcome in patients hospitalized for acute coronary syndromes or cerebrovascular diseases (CVD). METHODS: ABI was measured in consecutive patients hospitalized because of acute myocardial infarction, unstable angina, stroke or transient ischemic attack (TIA). An ABI lower than or equal to 0.90 was considered abnormal. The primary outcome of the study was the composite of non-fatal acute myocardial infarction, non-fatal ischemic stroke, and death from any cause during the year following the index event. RESULTS: An abnormal ABI was found in 27.2% of 1003 patients with acute coronary syndromes, and in 33.5% of 755 patients with acute CVD. After a median follow-up of 372 days, the frequency of the primary outcome was 10.8% (57/526) in patients with abnormal ABI and 5.9% (73/1232) in patients with normal ABI [odds ratio (OR) 1.96; 95% CI 1.36-2.81]. Death was more common in patients with abnormal ABI (OR 2.05; 95% CI 1.31-3.22). Cardiovascular mortality accounted for 81.7% of overall mortality. ABI was predictive of adverse outcome after adjustment for vascular risk factors in the logistic regression analysis (OR 1.93; 95% CI 1.24-3.01). The predictive value of ABI was mainly accounted for by patients hospitalized for acute coronary syndromes (adverse outcome: 12.8% in patients with abnormal ABI and 5.9% in patients with normal ABI, OR 2.35; 95% CI 1.47-3.76). CONCLUSIONS: An abnormal ABI can be found in one-third of patients hospitalized for acute coronary or cerebrovascular events and is a predictor of an adverse 1-year outcome.

The Stroke in Italy and Related Impact on Outcome (SIRIO) study: design and baseline data.

The SIRIO study collected detailed information on the stroke care of patients treated in neurological departments in Italy. This report refers to the baseline profile of patients. Each centre recorded the incident cases of ischaemic and haemorrhagic stroke, excluding SAH, for 1-4 months. Baseline data include demographics, risk factors, comorbidities, pre-event medications, social conditions, NIHSS and Rankin scale on entry, Barthel Index pre-event, diagnostic tests and treatments applied on entry. Overall, 3018 patients (56.7% men; mean age 72.1+/-12.2 years) with ischaemic (85.3%) or haemorrhagic stroke were hospitalised in 103 centres; 51% arrived by ambulance. Median time to hospital was 140 min (RIQ: 60-615). TOAST classification of the 2573 ischaemic strokes was: 29.4% large-artery atherosclerosis, 24.6% cardioembolic, 26.2% small vessels occlusion, 6.5% other determined causes and 13.3% undetermined. CT and/or MR were performed in all patients. Total Greenfield's comorbidity score was 5.4+/-3.5. Mean Barthel Index pre-event was 93+/-17; Rankin score on entry was 4-5 in 48% of the patients and 0-1 in 25%. Mean NIHSS on entry was 7.1+/-5.4; 52% of the patients had a NHISS <6 and 1% >22. SIRIO began giving the expected insights on the in-hospital management of stroke in Italy. Further information will be provided by the longitudinal phase of the study, which is in progress. Pre-event patient management and mode of reporting call for additional educational actions.

PAD. Epidemiology and pathophysiology.

The real prevalence of Peripheral Arterial Disease (PAD) is considerably underestimated if only symptomatic patients (i.e those with Intermittent Claudication) are taken into account instead of subjects with instrumental abnormalities such as a low Ankle-Branchial Index (ABI). The risk of both-fatal and non-fatal-cardiovascular events is particularly high in these patients either presenting with symptoms or asymptomatic. On the contrary the tendency to local worsening (need of revascularization or amputation of leg) is reduced. PAD is markedly prevailing in elderly, with a peak of incidence after the fifth decade of life. Owing to this, the prevalence is not significantly different in men compared to women. The risk factors related to PAD are the same as those observed in the other locations of atherosclerosis but cigarette smoking and diabetes seem to be more often associated to PAD than the remaining factors.

Ticlopidine versus aspirin after myocardial infarction (STAMI) trial.

OBJECTIVES: We sought to compare the efficacy of aspirin and ticlopidine in survivors of acute myocardial infarction (AMI) treated with thrombolysis. BACKGROUND: The role of ticlopidine in secondary prevention after AMI has not yet been explored. METHODS: Of 4,696 patients with AMI treated with thrombolysis who were screened, 261 died in the hospital (5.6%) and 1,470 were enrolled in this randomized, double-blind, multicenter trial and allocated to treatment with either aspirin (160 mg/day) or ticlopidine (500 mg/day). The most frequent reasons for exclusion were refusal to give informed consent, planned myocardial revascularization, risk of noncompliance with study procedures, need for anticoagulant therapy and contraindications to the study treatments. The primary end point was the first occurrence of any of the following events during the six-month follow-up: fatal and nonfatal AMI, fatal and nonfatal stroke, angina with objective evidence of myocardial ischemia, vascular death or death due to any other cause. RESULTS: The primary end point was recorded in 59 (8.0%) of the 736 aspirin-treated and 59 (8.0%) of the 734 ticlopidine-treated patients (p = 0.966). Vascular death was the first event in five patients taking aspirin and in six patients taking ticlopidine (0.7% vs. 0.8%; p = NS); nonfatal AMI in 18 and 8 (2.4% vs. 1.1%; p = 0.049); nonfatal stroke in 3 and 4 (0.4% vs. 0.5%; p = NS); and angina in 33 and 40 (4.5% vs. 5.4%; p = NS), respectively. The frequency of adverse reactions was not significantly different between the two groups. CONCLUSIONS: No difference was found between the ticlopidine and aspirin groups in the rate of the primary combined end point of death, recurrent AMI, stroke and angina.

Effects of gemfibrozil on insulin sensitivity and on haemostatic variables in hypertriglyceridemic patients.

In order to assess the efficacy of gemfibrozil on lipid and haemostatic parameters in patients with plurimetabolic syndrome, a multicenter double-blind placebo controlled, parallel study was carried out in 56 patients with primary hypertriglyceridemia and glucose intolerance. These patients had elevated PAI activity and antigen and t-PA antigen levels at rest and after venous occlusion. Gemfibrozil reduced plasma triglyceride levels (P<0.001), whereas it increased free fatty acids (P<0.05) and high density lipoprotein cholesterol levels (P<0.05). In those patients reaching normalization of plasma triglyceride levels (triglyceride reduction > or =50%) (n=15), insulin levels (P<0.05) as well as the insulin resistance index were reduced by gemfibrozil treatment, suggesting an improvement of the insulin resistance index in this patient subgroup. Gemfibrozil treatment did not affect plasma fibrinolysis or fibrinogen levels, despite marked reduction of plasma triglycerides and improvement of the insulin sensitivity associated with triglyceride normalization.

[State of the art: low-molecular-weight heparin and beyond]. / Stato dell'arte: eparine a basso peso molecolare ed oltre.

Approximately 20 years ago a new family of antithrombotic compounds started to be investigated: the low-molecular weight heparins (LMWH). The rationale for their use was based on the evidence that the inhibition of the Factor Xa of blood coagulation was less marked than that of Factor IIa when using the LMWHs as compared to unfractioned heparin (HF). This particular mechanism of action was considered to be of advantage regarding the safety profile (the pro-haemorrhagic effect) compared to HF. Today we know that the real advantage of LMWHs is due to their high bioavailability which makes safe and reliable their subcutaneous administration without laboratory monitoring. The LMWHs are equally effective than HF for the treatment of acute Deep Vein Thrombosis. For the prophylaxis of Venous Thromboembolism, LMWHs are indicated as first choice in high-risk patients such as those undergoing major orthopaedic surgery. The future development of this family of drugs encompasses the launch of the pentasaccharide which is a pure anti-/Xa inhibitor.