Peripheral arterial disease has a strong impact on cardiovascular outcome in patients with acute coronary syndromes: from the START Antiplatelet registry.

BACKGROUND: Peripheral arterial disease (PAD) was reported to increase the risk of new cardiovascular events in patients with acute coronary syndromes (ACS). However, most of the evidence comes from randomized clinical trials. We aimed to assess the impact of PAD on cardiovascular outcome and treatment decisions in ACS patients in a current real-life setting. METHODS: START-ANTIPLATELET is a multicenter registry enrolling ACS patient. Baseline clinical characteristics and treatment at discharge were recorded and follow-up was repeated at 6-months and 1-year. PAD was defined as intermittent claudication and/or previous revascularization. RESULTS: Among 1442 patients enrolled, 103 (7.1%) had PAD. PAD patients were older (71.8 ± 10.6vs66.2 ± 12.6 yrs., p < 0.0001), more frequently hypertensive (90.3vs68.6%, p< 0.0001), hypercholesterolemic (66vs52%, p= 0.037), diabetic (51.5vs24%, p= 0.0001), obese (28.2vs19.3%, p= 0.029) and with previous TIA (7.8vs2.8%, p= 0.005) or stroke (11.7vs3.1%, p< 0.0001). Clinical presentation and acute treatment were similar in non-PAD and PAD patients, but the latter were discharged significantly less frequently on dual antiplatelet therapy (DAPT) (68.9vs85%, p= 0.005). After a median follow-up time of 11.1 months, major cardio/cerebrovascular event-free survival [MACCE, including cardiovascular death, MI, TIA and stroke, target-vessel revascularization (TVR) and major arterial ischemic events] was significantly shorter (9.0vs11.2 months, p= 0.02; HR 3.2, 2.4-8.4) in PAD patients and net adverse cardiovascular events (NACE = MACCE plus major hemorrhages) were significantly more frequent (19.1%vs10.5%, p = 0.049). CONCLUSIONS: PAD identifies a subgroup of ACS patients at significantly increased cardiovascular risk, but these patients tend to be undertreated. Patients admitted for ACS should be screened for PAD and optimal medical therapy at discharge should be implemented.

The American College of Chest Physician score to assess the risk of bleeding during anticoagulation in patients with venous thromboembolism.

Essentials The risk of bleeding influences the duration of anticoagulation (AC) after venous thromboembolism. We assessed the ACCP bleeding risk score in an inception-cohort of patients receiving AC. 53% were categorized at high-risk, but their bleeding rate was low during long-term AC. ACCP score had low predictive value for bleeding. SUMMARY: Background The American College of Chest Physicians (ACCP) guideline proposes a score to decide on extended anticoagulation after an unprovoked venous thromboembolism (VTE). Methods We investigated the ACCP score to predict bleeding risk in an inception cohort of 2263 patients on long-term anticoagulation (1522 treated with vitamin K antagonists [VKAs] and the remaining with direct oral anticoagulants [DOACs]) belonging to the Italian START2 Register. Results More than half the patients were categorized as high risk; nevertheless, a higher proportion received anticoagulation for > 1 year compared with those in the low-risk category. For 3130 years (median 12 [interquartile range 6, 24] months), 48 bleeding outcomes occurred (1.53%/year) in the cohort (1.7%/year and 0.95%/year in high- and low-risk categories, respectively). The c-statistic of the ACCP score was 0.55 (0.48-0.63), 0.50 (0.42-0.58) and 0.56 (0.48-0.64) in low-, moderate- and high-risk categories, respectively. The bleeding incidence was higher during the first 90 days of treatment (3.0%/year) than afterwards (1.2%/year; relative risk (RR), 2.5 [1.3-4.7]), and similar among the three categories. The bleeding rate was not different during the initial 3 months of treatment in patients receiving VKAs or DOACs; it was, however, lower in the latter patients in the subsequent period (0.5%/year vs. 1.4%/year, respectively). Conclusion The bleeding rate during extended treatment was rather low in our patients. ACCP score had insufficiently predictive value for bleeding and cannot be used to guide decisions on extended treatment. New prediction tools for bleeding risk during anticoagulant treatments (including DOACs) are required.

Low drug levels and thrombotic complications in high-risk atrial fibrillation patients treated with direct oral anticoagulants.

Essentials Direct oral anticoagulants (DOACs) do not require laboratory monitoring currently. DOAC specific measurements were performed at trough in patients with atrial fibrillation. Patients who developed thromboembolic events showed lower DOAC plasma levels. This study supports the concept of measuring DOAC levels at steady state. SUMMARY: Background Direct oral anticoagulants (DOACs) are administered at fixed doses without the need for dose adjustment according to laboratory testing. High interindividual variability in drug blood levels has been shown with all DOACs. To evaluate a possible relationship between DOAC C-trough anticoagulant levels and thromboembolic events, 565 consecutive naive patients with atrial fibrillation (AF) were enrolled in this study performed within the START Laboratory Registry. Methods DOAC-specific measurements (diluted thrombin time or anti-activated factor II calibrated for dabigatran; anti-activated FX calibrated for rivaroxaban or apixaban) at C-trough were performed locally at steady state within 15-25 days after the start of treatment. For each DOAC, the interval of C-trough levels, from the limit of quantification to the highest value, was subdivided into four equal classes, and results were attributed to these classes; the median values of results were also calculated. Thromboembolic complications occurring during 1 year of follow-up were recorded. Results Thromboembolic events (1.8%) occurred in 10 patients who had baseline C-trough levels in the lowest class of drug levels. The incidence of thromboembolic events among patients with DOAC C-trough levels in the lowest level class was 2.4%, and that in the remaining groups was 0%. The patients with thrombotic complications also had a higher mean CHA2 DS2 -VASc score than that of the total patient population: 5.3 (95% confidence interval [CI] 4.3-6.3 versus 3.0 (95% CI 2.9-3.1). Conclusion In this study cohort, thrombotic complications occurred only in DOAC-treated AF patients who had very low C-trough levels, with a relatively high CHA2 DS2 -VASc score. Larger studies are warranted to confirm these preliminary observations.

External validation of the DASH prediction rule: a retrospective cohort study.

Essentials Predicting recurrences may guide therapy after unprovoked venous thromboembolism (VTE). We evaluated the DASH score in 827 patients with unprovoked VTE to verify prediction accuracy. A DASH score ≤ 1 had a cumulative recurrence risk at 1 year of 3.6%, as predicted by the model. The DASH score performed better in younger (< 65 years old) subjects. SUMMARY: Background The DASH prediction model has been proposed as a guide to identify patients at low risk of recurrence of venous thromboembolism (VTE), but has never been validated in an independent cohort. Aims To validate the calibration and discrimination of the DASH prediction model, and to evaluate the DASH score in a predefined patient subgroup aged > 65 years. Methods Patients with a proximal unprovoked deep vein thrombosis (DVT) or pulmonary embolism (PE) who received a full course of vitamin K antagonist or direct oral anticoagulant (> 3 months) and had D-dimer measured after treatment withdrawal were eligible. The DASH score was computed on the basis of the D-dimer level after therapy withdrawal and personal characteristics at the time of the event. Recurrent VTE events were symptomatic proximal or distal DVT/PE, and were analyzed with a time-dependent analysis. Observed 12-month and 24-month recurrence rates were compared with recurrence rates predicted by the DASH model. Results We analyzed a total of 827 patients, of whom 100 (12.1%) had an objectively documented recurrence. As compared with the original DASH cohort, there was a greater proportion of subjects with a 'low-risk' (≤ 1) DASH score (66.3% versus 51.6%, P < 0.001). The slope of the observed versus expected cumulative incidence at 2 years was 0.71 (95% confidence interval 0.51-1.45). The c-statistic was lower for subjects aged > 65 years (0.54) than for younger subjects (0.72). Conclusions These results confirm the validity of DASH prediction model, particularly in young subjects. The recurrence risk in elderly patients (> 65 years) was, however, > 5% even in those with the lowest DASH scores.

OC-15 - Risk factors for cancer development after idiopathic venous thromboembolism.

INTRODUCTION: Idiopathic venous thromboembolism (VTE) is associated with the risk of cancer but the risk factors for cancer development in such patients are still uncertain. AIM: To assess risk factors for the development of cancer after a standard course of anticoagulation in patients with first episode of idiopathic VTE. MATERIALS AND METHODS: Subjects were enrolled in the three large prospective multicentre studies: PROLONG (NEJM 2006) PROLONG II (Blood 2010) and DULCIS (Blood 2014). Women whose index event was hormone related were excluded from the analysis. The development of cancer was recorded during a 2-year follow-up. RESULTS: 1,805 patients were enrolled (M/F: 510/453), mean age: 62, median: 67; range:18-87 years). Cancer developed in 55 patients (3% ; 1.7% pt-years) of whom 15 (2.0%; 1.1% pt-years) had PE with or without DVT and 40 (3.8%; 2.1% pt-years) had DVT without PE (p=0.03). The development of cancer was associated with DVT without PE (HR:1.8; 95% CI: 1.1-3.3) and age >65 (HR: 2.5; 95%: 1.3-4.9). Among patients with DVT, with or without PE, the development of cancer was associated with the presence of residual vein obstruction>4mm (RVO) at compression ultrasound (HR: 1.8, 95% CI: 1.1-3.3) and age>65 (HR: 2.8; 95% CI: 1.3-6.2). CONCLUSIONS: Age>65 years, DVT without PE and the presence of RVO are significantly associated with the risk of developing cancer after a first episode of idiopathic VTE over a two-year follow-up.

Comparison between different D-Dimer cutoff values to assess the individual risk of recurrent venous thromboembolism: analysis of results obtained in the DULCIS study.

INTRODUCTION: D-dimer assay, generally evaluated according to cutoff points calibrated for VTE exclusion, is used to estimate the individual risk of recurrence after a first idiopathic event of venous thromboembolism (VTE). METHODS: Commercial D-dimer assays, evaluated according to predetermined cutoff levels for each assay, specific for age (lower in subjects <70 years) and gender (lower in males), were used in the recent DULCIS study. The present analysis compared the results obtained in the DULCIS with those that might have been had using the following different cutoff criteria: traditional cutoff for VTE exclusion, higher levels in subjects aged ≥60 years, or age multiplied by 10. RESULTS: In young subjects, the DULCIS low cutoff levels resulted in half the recurrent events that would have occurred using the other criteria. In elderly patients, the DULCIS results were similar to those calculated for the two age-adjusted criteria. The adoption of traditional VTE exclusion criteria would have led to positive results in the large majority of elderly subjects, without a significant reduction in the rate of recurrent event. CONCLUSION: The results confirm the usefulness of the cutoff levels used in DULCIS.

Glucocorticoid administration in sepsis and septic shock: time for a paradigm change?

The use of corticosteroids in patients with septic shock remains controversial. Questions remain regarding the more appropriate dose, the optimal timing to initiate therapy, the selection of patients who will benefit most from the treatment and the exact mechanisms involved in their effectiveness. Recent studies have highlighted that, in critically ill patients, corticosteroid metabolism was reduced and associated with high circulating cortisol levels. Hence the required doses of hydrocortisone may be lower than the currently recommended doses in septic shock (i.e. 200 mg/day). However, altered expression and/or function of corticosteroid receptors may still suggest that higher hydrocortisone doses are necessary to overcome this so-called "steroid-resistance". In this article, we summarized these recent concepts and discussed how they could influence the administration of corticosteroids in such patients.

The predictive ability of bleeding risk stratification models in very old patients on vitamin K antagonist treatment for venous thromboembolism: results of the prospective collaborative EPICA study.

BACKGROUND: The optimal duration of anticoagulant treatment after venous thromboembolism (VTE) should be evaluated in relation to bleeding risk. This assessment is particularly difficult with elderly patients, because of their increased risk of both recurrences and hemorrhages. Bleeding risk stratification models have been proposed, but their predictive ability in very elderly patients is unknown. We aimed to assess six bleeding stratification models in this setting, by using information available in our dataset. PATIENTS AND METHODS: Patients aged ≥ 80 years receiving vitamin K antagonists (VKAs) for the secondary prevention of VTE were eligible for this prospective cohort study. All patients were followed at Italian anticoagulation clinics for monitoring of VKA treatment. Risk factors for bleeding were collected, and major bleeding events and mortality were documented during follow-up. The association of bleeding events with the available risk factors was tested by means of Cox regression analysis; the c-statistic was used to quantify the predictive validity of the classification schemes. RESULTS: A total of 1078 patients (37.2% males; mean age, 84 years) were enrolled in the study, for a total observation period of 1981 patient-years. The rate of major bleeding was 2.4 per 100 patient-years (47 events; one was fatal). The mortality rate was 5.2 per 100 patient-years. None of the considered risk factors were significantly associated with bleeding events. The predictive validity of the risk stratification models was low, and the most accurate model was not specifically developed for VTE patients (HEMORR2 HAGES, c-statistic 0.60, 95% confidence interval 0.49-0.70). CONCLUSIONS: Bleeding risk stratification models appear to have little accuracy in very elderly VTE patients.

HERSCHEL/SCORE, imaging the solar corona in visible and EUV light: CCD camera characterization.

The HERSCHEL (helium resonant scattering in the corona and heliosphere) experiment is a rocket mission that was successfully launched last September from White Sands Missile Range, New Mexico, USA. HERSCHEL was conceived to investigate the solar corona in the extreme UV (EUV) and in the visible broadband polarized brightness and provided, for the first time, a global map of helium in the solar environment. The HERSCHEL payload consisted of a telescope, HERSCHEL EUV Imaging Telescope (HEIT), and two coronagraphs, HECOR (helium coronagraph) and SCORE (sounding coronagraph experiment). The SCORE instrument was designed and developed mainly by Italian research institutes and it is an imaging coronagraph to observe the solar corona from 1.4 to 4 solar radii. SCORE has two detectors for the EUV lines at 121.6 nm (HI) and 30.4 nm (HeII) and the visible broadband polarized brightness. The SCORE UV detector is an intensified CCD with a microchannel plate coupled to a CCD through a fiber-optic bundle. The SCORE visible light detector is a frame-transfer CCD coupled to a polarimeter based on a liquid crystal variable retarder plate. The SCORE coronagraph is described together with the performances of the cameras for imaging the solar corona.

The balance between pro- and anti-inflammatory cytokines is associated with platelet aggregability in acute coronary syndrome patients.

BACKGROUND: Residual platelet reactivity (RPR) on antiplatelet therapy in ischemic heart disease patients is associated with adverse events. Clinical, cellular and pharmacogenetic factors may account for the variable response to antiplatelet treatment. OBJECTIVE: We sought to explore the interplay of multiple pro-inflammatory and anti-inflammatory cytokines with platelet function in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) on dual antiplatelet therapy. METHODS: In 208 ACS patients undergoing PCI on dual antiplatelet therapy we measured platelet function by platelet aggregation with two agonists [1mM arachidonic acid (AA) and 10muM ADP]. IL-1beta, IL-1ra, IL-4, IL-6, IL-8, IL-10, IL-12, IP-10, IFN-gamma, MCP-1, MIP-1alpha, MIP-1beta, TNF-alpha, and VEGF levels were determined by using the Bio-Plex cytokine assay (Bio-Rad Laboratories Inc., Hercules, CA, USA). We defined patients with RPR those with platelet aggregation by AA >or=20% and/or ADP (10micromol) >or=70%. RESULTS: We documented a significant association between IP-10, IFN-gamma, IL-4 and RPR by both AA- and ADP-induced platelet aggregation after adjustment for age, sex, cardiovascular risk factors, ejection fraction, BMI, vWF and CRP. Patients with pro-inflammatory cytokines not compensated by anti-inflammatory cytokines had higher risk of RPR by both AA and ADP (AA: OR=3.85, 95% CI 1.52-9.74; ADP: OR=2.49, 95% CI 1.33-4.68) with respect to patients with balanced anti-/pro-inflammatory cytokines. Patients with anti-inflammatory response overwhelming pro-inflammatory response have lower risk of RPR (AA: OR=0.55, 95% CI 0.28-1.06; ADP: OR=0.47, 95% CI 0.26-0.87). CONCLUSION: Our study provides new insights into the interplay of anti-/pro-inflammatory cytokines with platelet hyper-reactivity in high-risk patients.

Different methodologies for evaluating the effect of clopidogrel on platelet function in high-risk coronary artery disease patients.

BACKGROUND: Two point-of-care (POC) systems have been recently proposed as rapid tools with which to evaluate residual platelet reactivity (RPR) in coronary artery disease (CAD) patients. OBJECTIVES AND METHODS: We compared Platelet Function Analyzer-100 (PFA-100) closure times (CTs) by collagen/adenosine 5'-diphosphate (ADP) (C/ADP CT) cartridge and the VerifyNow P2Y12 Assay (VerifyNow) with light transmission aggregation (LTA) induced by 2 and 10 micromol L(-1) ADP in 1267 CAD patients on dual antiplatelet therapy who underwent percutaneous coronary intervention. We also performed the vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay by cytofluorimetric analysis in a subgroup of 115 patients. RESULTS: Cut-off values for identifying RPR were: > or = 54% and > or = 66% for LTA induced by 2 and 10 micromol L(-1) ADP respectively, and > or = 264 P2Y12 Reaction Units (PRU) for VerifyNow. The cut-off for PFA-100 C/ADP CT was > or = 68 s. RPR was detected in 25.1% of patients by 2 mumol L(-1) ADP-induced LTA (ADP-LTA), in 23.2% by 10 micromol L(-1) ADP-LTA, in 24.4% by PFA-100, and in 24.7% by VerifyNow. PFA-100 results did not parallel those obtained with LTA. VerifyNow showed a significant correlation (rho = 0.62, P < 0.001) and significant agreement (k = 0.34, P < 0.001) with LTA induced by 2 micromol L(-1) ADP. The correlation was similar but the agreement was better between VerifyNow and 10 micromol L(-1) ADP-LTA (rho = 0.64, P < 0.0001; k = 0.43, P < 0.001). Significant relationships were found between VASP platelet reactivity index and both ADP-LTA and VerifyNow. PFA-100 C/ADP CT did not significantly correlate with any of the other assays. CONCLUSIONS: Our results show a significant correlation between LTA and VerifyNow but not the PFA-100 C/ADP assay. Clinical validation studies for POC systems are necessary.

[Sustained low-efficiency dialysis in acute renal failure]. / Terapie sostitutive renali intermittenti prolungate (SLED/EED) nell'insufficienza renale acuta in terapia intensiva.

Renal replacement therapies (RRT) are a key component of the therapeutic approach to acute renal failure (ARF) in the intensive care unit (ICU), and they are usually performed as classic Intermittent (intermittent hemodialysis) or continuous RRT (such as for example continuous venovenous hemofiltration, CVVH). No clear evidence exists on what the first-choice RRT option should be for ICU patients with ARF. Alternative strategies have been developed, under the form of intermittent prolonged RRT, with the aim of providing easy to perform, highly efficient, and less expensive RRT in the ICU. In this review we put forward the hypothesis that hybrid RRT, such as sustained low-efficiency dialysis ( sLED), could offer a valuable alternative to the currently available strategies in the critically ill with ARF.

[Antihaemostatic strategies or renal replacement therapies in acute renal failure]. / Trattamento anticoagulante per le terapie sostitutive della funzione renale (RRT) nell'insufficienza renale acuta.

Critically ill patients with acute renal failure, and especially those with sepsis, may have increased coagulation changes as well as a high incidence of hemorrhagic complications. Thus, in this clinical condition, the use of renal replacement therapies (RRT) can be frequently complicated both by high rates of extracorporeal circuit coagulation, resulting in a reduced treatment efficacy, and by increased incidence of bleeding. Heparin is the most commonly used RRT anticoagulant, even if several alternative options have been proposed, aiming at obtaining regional anticoagulation (i.e., limited to the extracorporeal circuit). This review analyses modern strategies for RRT anticoagulation and evaluates safety and efficacy parameters of each method. In this regard, no definite recommendations can be made based on the available evidence further randomised controlled trials are needed in this field, with a clear endpoint definition.

Renal transplant recipients are at high risk for both symptomatic and asymptomatic deep vein thrombosis.

BACKGROUND: Venous thromboembolism (VTE) is one of the thrombotic complications that can occur in patients receiving renal transplantation (RT). The prevalence of VTE in RT patients is, however, undefined. OBJECTIVES: To evaluate the rate of a first episode of VTE in a series of 538 consecutive RT recipients admitted to our institution, the timing of occurrence of the thromboembolic events after transplantation, and the rate of recurrence after thromboprophylaxis withdrawal. Risk factors for recurrence were also evaluated, particularly in relation to the type of the first event (symptomatic or asymptomatic). RESULTS: During follow-up, 47 of 518 patients (28 males, 19 females; 9.1%) developed a first episode of VTE at a median time of 17 months (range 1-165 months) after kidney transplantation. Cancer was associated with the occurrence of VTE (odds ratio 4.8). Seventeen of 43 patients (39.5%) with deep vein thrombosis were asymptomatic and the diagnosis was made during routine ultrasound examination. Twenty-two patients (46.8%) experienced a recurrence of VTE. A relevant rate of recurrence was documented amongst patients with a first episode of both symptomatic (53%) and asymptomatic (23.5%) VTE. CONCLUSION: This study confirms that RT patients are at high risk of symptomatic and asymptomatic VTE and that this risk persists even after several years. Patients who experience VTE are at high risk of recurrence after thromboprophylaxis withdrawal.

Venous thromboembolism in renal transplant recipients: high rate of recurrence.

Few data are available on the incidence of venous thromboembolism occurring in renal transplant recipients and optimal duration of oral anticoagulant therapy after thrombotic episode. Our study was performed to evaluate the risk of thrombosis recurrence in patients developing a first episode. Among 484 renal transplant patients 34 (7%) developed a first thromboembolism and were referred to the Thrombosis Centre: 28 patients (group 1) were prospectively studied, after stopping anticoagulants. Group 1 was compared with a group of 84 patients without an history of renal disease who had suffered from a first thrombotic episode and were matched for age, sex, and type of thrombotic event (group 2). During follow-up, 14/28 group 1 patients and 8/84 group 2 patients experienced thrombotic recurrence (P = .0001). Our data outline the high risk of recurrence in renal transplant recipients. Strategies for recurrence prevention are needed taking into account the high bleeding risk of anticoagulants in renal transplant patients.

Need of more frequent International Normalized Ratio monitoring in elderly patients on long-term anticoagulant therapy after influenza vaccination.

Previous findings suggest the safety of influenza vaccination for patients on oral anticoagulant therapy (OAT). However, some studies reported a moderate reduction or increase of the anticoagulation. We assessed the effect of influenza vaccination on anticoagulation levels. Seventy-three patients on stable long-term OAT were recruited. Patients were compared with a control group of 72 patients observed during the same period. No differences in the anticoagulation levels were found in patients and in controls during the 3 months before and after the vaccination. However, in patients older than 70 years we observed a reduction of anticoagulation intensity achieved in the month after the vaccination, with a prolonged time spent below the therapeutic range (10% before and 27% after, P = 0.001), and this behaviour was still observed 3 months after vaccination. Influenza vaccination is safe in patients on OAT, but it is associated with a slight reduction in warfarin effect in the elderly, suggesting the need of more frequent International Normalized Ratio monitoring after vaccination in these subjects.