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Objective: Changes in prescribing patterns of antiepileptic drugs (AEDs) in pregnant women with epilepsy would be expected to affect the risk of major congenital malformations (MCMs). To test this hypothesis, we analyzed data from an international pregnancy registry (EURAP)., Methods: EURAP is an observational prospective cohort study designed to determine the risk of MCMs after prenatal exposure to AEDs. The Cochrane-Armitage linear trend analysis was used to assess changes in AED treatment, prevalence of MCMs, and occurrence of generalized tonic-clonic seizures (GTCs) over 3 time periods: 2000-2005 (n = 4,760), 2006-2009 (n = 3,599), and 2010-2013 (n = 2,949)., Results: There were pronounced changes in the use of specific AEDs over time, with a decrease in the use of valproic acid and carbamazepine and an increase in the use of lamotrigine and levetiracetam. The prevalence of MCMs with monotherapy exposure decreased from 6.0% in 2000-2005 to 4.4% in 2010-2013. The change over time in MCM frequency after monotherapy exposure showed a significant linear trend in the crude analysis ( p = 0.0087), which was no longer present after adjustment for changes in AED treatment ( p = 0.9923). There was no indication of an increase over time in occurrence of GTCs during pregnancy., Conclusions: There have been major changes in AED prescription patterns over the years covered by the study. In parallel, we observed a significant 27% decrease in the prevalence of MCMs. The results of adjusting the trend analysis for MCMs for changes in AED treatment suggest that changes in prescription patterns played a major role in the reduction of teratogenic events., (© 2019 American Academy of Neurology.)

Objective: To assess the risk of major congenital malformations (MCMs) in association with maternal use of valproic acid (VPA) in monotherapy or adjunctive therapy, and its relationship with dose., Methods: The analysis was based on prospectively acquired data from EURAP, a registry enrolling women treated with antiepileptic drugs (AEDs) in early pregnancy, in which the primary outcome is presence of MCMs at 1 year after birth. Exposure was defined as type and dose of AEDs at time of conception. A comparison was made among 3 exposure types: (1) VPA monotherapy (n = 1,224); (2) VPA combined with lamotrigine (LTG) (n = 159); and (3) VPA combined with another AED but not LTG (n = 205)., Results: The frequency of MCMs at 1 year after birth was 10.0% for VPA monotherapy, 11.3% for exposures to VPA and LTG, and 11.7% for exposures to VPA + another (non-LTG) AED. Regardless of exposure group, the frequency of MCMs increased with dose of VPA, being highest at doses ≥1,500 mg/d (24.0% for monotherapy, 31.0% for VPA + LTG, and 19.2% for VPA + other AEDs), and was similar across treatment groups at the lowest VPA dose level of <700 mg/d (5.9% for monotherapy, 7.0% for VPA + LTG, and 5.4% for VPA + other AEDs)., Conclusions: The risk of MCMs associated with VPA exposure increases with increasing VPA dose, both in the presence and in the absence of one concomitant AED, and appears to be related primarily to the dose of VPA., (© 2015 American Academy of Neurology.)

Objective: To compare the risk of spontaneous abortions and stillbirth associated with maternal use of different antiepileptic drugs (AEDs)., Methods: The EURAP registry is an observational international cohort study primarily designed to determine the risk of major congenital malformations (MCMs) after prenatal AED exposure. Using EURAP data, we prospectively monitored pregnancies exposed to the 6 most common AED monotherapies and to polytherapy. Intrauterine death (spontaneous abortion and stillbirth combined) was the primary endpoint., Results: Of 7,055 pregnancies exposed to monotherapy with lamotrigine (n = 1,910), carbamazepine (n = 1,713), valproic acid (n = 1,171), levetiracetam (n = 324), oxcarbazepine (n = 262), or phenobarbital (n = 260), and to polytherapy (n = 1,415), 632 ended in intrauterine deaths (592 spontaneous abortions and 40 stillbirths). Rates of intrauterine death were similar across the different monotherapies (8.2%; 95% confidence interval [CI] 7.5%-8.9%), higher with polytherapy (12.1%; 95% CI 10.5%-13.9%), but showed no relationship with AED dose in monotherapy at conception. Multivariable analysis including 11 covariates in addition to the different AED exposures showed that the risk was greater with polytherapy vs monotherapy (risk ratio [RR] 1.38; 95% CI 1.14-1.66), parental history of MCMs (RR 1.92; 1.20-3.07), maternal age (RR 1.06; 1.04-1.07), and number of previous intrauterine deaths (RR 1.09; 1.00-1.19). The risk was greater with early enrollment and decreased with later gestational week at enrollment (RR 0.84; 0.82-0.86)., Conclusions: The most important risk factors for intrauterine death in pregnancies of women with epilepsy include maternal exposure to AED polytherapy and the presence of MCMs in at least one of the parents., (© 2015 American Academy of Neurology.)

Background: Atrial fibrillation is the most frequent arrhythmia, but few data are available on patients' characteristics and management in the context of Internal Medicine wards., Methods: Data were collected at the beginning of 2010 in 18 Internal Medicine units of the regions Liguria and Piemonte (Italy). Each centre reviewed the hospital charts of the last 50 patients discharged during the year 2009 in whom a diagnosis of atrial fibrillation had been made (patient's history or during the hospitalization)., Results: A total of 903 atrial fibrillation patients were evaluated. Prevalence of atrial fibrillation among patients hospitalized in Internal Medicine units was 18.2%. More than 85% of patients had at least two diseases other than atrial fibrillation, and 'lone' atrial fibrillation was rare (1.3%). During hospital stay, 80.5% of the patients received at least one treatment for atrial fibrillation: 55.5% received an antithrombotic and 61.8% a drug for arrhythmia, mostly aimed at rate control (47.2%). In-hospital all-cause mortality was 13.4%. At discharge, 70.2 and 68.9% of the patients received prescription of a drug for arrhythmia and for antithrombotic treatment, respectively. Prescription of oral anticoagulants was significantly associated with hypertension, while previous bleeding, age above 75 years, paroxysmal atrial fibrillation, male sex and a number of concomitant drugs of more than four were strong negative predictors., Conclusion: Data from our study confirm that atrial fibrillation is a common finding in patients hospitalized in Internal Medicine units, and this population is characterized by multiple comorbidities and severe prognosis. Discrepancies exist between recommendations by guidelines and real-world management, owing to the complexity of patients and limits of existing treatment strategies.

Background: Concerns about the long-term safety of drug-eluting stents (DES) in saphenous vein grafts has become an area of controversy and uncertainty., Methods and Results: In this retrospective registry, we compared the outcomes in 127 patients (143 lesions) treated with DES from April 2002 to June 2006 (DES group) with 131 patients (160 lesions) treated with bare-metal stents in the preceding 36 months (bare-metal stent group). End points analyzed were cumulative death, myocardial infarction, and target vessel revascularization at 2 years after stent implantation. The DES group was significantly (P<0.05) more complex with a greater frequency of diabetes (33.1%versus 15.3%), older grafts (11.6+/-5.3 years versus 9.6+/-5.2 years), restenotic lesions (23.8% versus 4.4%), total occlusions (7.7% versus 1.2%), and smaller grafts (3.16+/-0.66 mm versus 3.44+/-0.76 mm) treated with longer stents (34.1+/-25.1 mm versus 22.7+/-11.6 mm). At 2 years, there was no statistical difference in death (8.7% versus 7.8%), myocardial infarction (6.3% versus 9.4%), or target vessel revascularization (19.7% versus 24.2%) between DES and bare-metal stents, respectively. A propensity analysis to adjust for baseline differences suggested that there was no observed association between DES and increased mortality (hazard ratio, 0.72; 95% CI, 0.21 to 2.44; P=0.60) but possibly an association with a reduction in target vessel revascularization (hazard ratio, 0.31; 95% CI, 0.14 to 0.66; P=0.002)., Conclusions: Despite being implanted in patients and lesions more complex than the bare-metal stent group, there was no observed association between DES implantation in saphenous vein grafts and an increase in late mortality. DES may maintain their efficacy in reducing revascularization rates in diseased saphenous vein grafts over a 2-year follow-up period.

Summary Background Data: High rate of complications has been reported following revascularization for acute limb ischemia (ALI). No adjuvant pharmacologic treatment, apart from anticoagulation and standard perioperative care, has been shown clinically effective., Objective: Aim of this study was to evaluate the effects of the prostacyclin analog iloprost as adjuvant to surgery for ALI., Methods: A total of 300 patients were randomly assigned to receive perioperative iloprost (intra-arterial, intraoperative bolus of 3000 ng, plus intravenous infusion of 0.5-2.0 ng/kg/min for 6 hours/day for 4-7 days following surgery), or placebo. The primary endpoint was the combined incidence of death and amputation at 3-month follow-up. Secondary endpoints were the incidence of each single major complication, total event rate, symptomatology, and tolerability., Results: The combined incidence of death and amputation was 19.9% in the placebo and 14.1% in the iloprost group (relative risk, 1.56; 95% confidence interval, 0.89-2.75, P = 0.12, Cox regression analysis). A statistically significant lower mortality (4.7%) was reported in patients receiving iloprost, compared with controls (10.6%; relative risk, 2.61; 95% confidence interval, 1.07-6.37, P = 0.03). The overall incidence of fatal plus major cardiovascular events was 33.1% and 22.8% in placebo and iloprost groups, respectively (relative risk, 1.61; 95% confidence interval, 1.04-2.49, P = 0.03). No serious adverse reactions occurred after iloprost administration, nor differences in the incidence of bleeding or hypotension between treatment groups., Conclusions: Although at lower levels than previously reported, our results confirm the severity of ALI. Iloprost as adjuvant to surgery significantly reduced mortality and overall major event rate. Further data are needed to support this finding, and to face a still open medical issue.

Background In patients with non-ST elevation acute coronary syndrome (NST-ACS) that is treated invasively, glycoprotein (GP) IIb/IIIa inhibitors can be used either as upstream treatment in a coronary care unit or as downstream provisional treatment in selected patients who are undergoing percutaneous coronary intervention (PCI). The relative advantage of either strategy is unknown. The purpose of this study was to assess 30-day outcome of patients enrolled in a prospective NST-ACS registry and treated invasively with either of these two therapeutic strategies. Methods Patients treated invasively (coronary arteriography within 4 days of admission), in the prospective registry ROSAI-2, were divided into two groups according to the upstream use of GPIIb/IIIa inhibitors (n = 241), or not (n = 548). In the latter group, 76 (14%) patients received GPIIb/IIIa in association with a PCI procedure. Clinical and angiographic characteristics as well as in-hospital and 30-day outcome of these two groups of patients were compared. Results The two groups were similar with respect to age, sex, presence of hypertension, diabetes, number of PCI procedures. However, patients treated with upstream GPllb/llla blockers had more frequently ST-segment depression (P = 0.002), a high TIMI risk score (P = 0.01) and were more frequently admitted to centres with Cath Lab facilities (P = 0.001). At 30-day follow-up, the composite of death, acute myocardial infarction and stroke, as well as major bleeding, was not significantly different between the two groups, although it occurred more frequently in patients who received upstream GPIIb/IIIa blockers (9.5% versus 5.7% and 1.7% versus 0.2%, respectively). By multivariate analysis, diabetes [odds ratio (OR) = 2.22, 95% confidence interval (CI) = 1.2-4.09] and a diagnosis on admission of non-Q-wave myocardial infarction (OR = 2.0, 95% Cl = 1.10-3.6) were independently related to outcome. No additional risk or benefit was related to upstream GPIIb/IIIa inhibitor treatment (OR = 1.5, 95% Cl = 0.84-2.68). Conclusions Among invasively-treated patients with NST-ACS, upstream treatment with GPIIb/IIIa inhibitors was used in those with a higher clinical risk profile, whereas downstream treatment was reserved for a limited number of patients undergoing PCI. Thirty-day outcome was similar in the two groups, irrespective of the treatment strategy used.

Summary Background Data: The epidemiology of venous thromboembolism (VTE) after cancer surgery is based on clinical trials on VTE prophylaxis that used venography to screen deep vein thrombosis (DVT). However, the clinical relevance of asymptomatic venography-detected DVT is unclear, and the population of these clinical trials is not necessarily representative of the overall cancer surgery population., Objective: The aim of this study was to evaluate the incidence of clinically overt VTE in a wide spectrum of consecutive patients undergoing surgery for cancer and to identify risk factors for VTE., Methods: @RISTOS was a prospective observational study in patients undergoing general, urologic, or gynecologic surgery. Patients were assessed for clinically overt VTE occurring up to 30 +/- 5 days after surgery or more if the hospital stay was longer than 35 days. All outcome events were evaluated by an independent Adjudication Committee., Results: A total of 2373 patients were included in the study: 1238 (52%) undergoing general, 685 (29%) urologic, and 450 (19%) gynecologic surgery. In-hospital prophylaxis was given in 81.6% and postdischarge prophylaxis in 30.7% of the patients. Fifty patients (2.1%) were adjudicated as affected by clinically overt VTE (DVT, 0.42%; nonfatal pulmonary embolism, 0.88%; death 0.80%). The incidence of VTE was 2.83% in general surgery, 2.0% in gynecologic surgery, and 0.87% in urologic surgery. Forty percent of the events occurred later than 21 days from surgery. The overall death rate was 1.72%; in 46.3% of the cases, death was caused by VTE. In a multivariable analysis, 5 risk factors were identified: age above 60 years (2.63, 95% confidence interval, 1.21-5.71), previous VTE (5.98, 2.13-16.80), advanced cancer (2.68, 1.37-5.24), anesthesia lasting more than 2 hours (4.50, 1.06-19.04), and bed rest longer than 3 days (4.37, 2.45-7.78)., Conclusions: VTE remains a common complication of cancer surgery, with a remarkable proportion of events occurring late after surgery. In patients undergoing cancer surgery, VTE is the most common cause of death at 30 days after surgery.

Background: It is still unknown whether it is better to administer cyclosporine (CsA) once or twice a day to renal-transplant patients., Methods: Fifty-four patients were randomized to receive CsA once a day (OD group, 28 patients) or twice a day (BD group, 26 patients). Clinical parameters and pharmacokinetic studies were regularly monitored over the first year., Results: Two patients lost their grafts because of renal vascular thrombosis. A patient in the BD group died. The other 51 patients were alive with graft functioning after a minimum follow-up of 1 year. Five patients per group had reversible acute rejection. There was a not significant trend toward a lower mean serum creatinine in OD than in BD (1.38 +/- 0.38 and 1.7 +/- 0.80 mg/dL at 1 year posttransplant, respectively). In 47 patients, 319 pharmacokinetic studies were performed. We measured the area under the concentration-time curve during the first 4 hours (AUC0-4) and CsA blood levels at 0, 2, and 4 hours after dosing. C0 was significantly lower in OD than in BD (P=0.0011), whereas C2 (P<0.0001) and C4 (P<0.0001) were significantly higher in OD than in BD. In OD, the AUC was higher than in BD (P<0.0001). OD allows us to reach high levels of C2 and AUC for several hours after dosing, whereas BD showed persistently high levels throughout the whole day., Conclusion: No difference in survival and rejection rates were observed between OD and BD groups.