Safety and Effectiveness of two treatment regimes with tranexamic acid to minimize inflammatory response in elective cardiopulmonary bypass patients: a randomized double-blind, dose-dependent, phase IV clinical trial

Background. In cardiopulmonary bypass (CPB) patients, fibrinolysis may enhance postoperative inflammatory response. We aimed to determine whether an additional postoperative dose of antifibrinolytic tranexamic acid (TA) reduced CPB-mediated inflammatory response (IR). Methods. We performed a randomized, double-blind, dose-dependent, parallel-groups study of elective CPB patients receiving TA. Patients were randomly assigned to either the single-dose group (40 mg/Kg TA before CPB and placebo after CPB) or the double-dose group (40 mg/Kg TA before and after CPB). Results. 160 patients were included, 80 in each group. The incident rate of IR was significantly lower in the double-dose-group TA2 (7.5% vs. 18.8% in the single-dose group TA1; P = 0.030). After adjusting for hypertension, total protamine dose and temperature after CPB, TA2 showed a lower risk of IR compared with TA1 [OR: 0.29 (95% CI: 0.10-0.83), (P = 0.013)]. Relative risk for IR was 2.5 for TA1 (95% CI: 1.02 to 6.12). The double-dose group had significantly lower chest tube bleeding at 24 hours [671 (95% CI 549-793 vs. 826 (95% CI 704-949) mL; P = 0.01 corrected-P significant] and lower D-dimer levels at 24 hours [489 (95% CI 437-540) vs. 621(95% CI: 563-679) ng/mL; P = 0.01 corrected-P significant]. TA2 required lower levels of norepinephrine at 24 h [0.06 (95% CI: 0.03-0.09) vs. 0.20(95 CI: 0.05-0.35) after adjusting for dobutamine [F = 6.6; P = 0.014 corrected-P significant]. We found a significant direct relationship between IL-6 and temperature (rho = 0.26; P < 0.01), D-dimer (rho = 0.24; P < 0.01), norepinephrine (rho = 0.33; P < 0.01), troponin I (rho = 0.37; P < 0.01), Creatine-Kinase (rho = 0.37; P < 0.01), Creatine Kinase-MB (rho = 0.33; P < 0.01) and lactic acid (rho = 0.46; P < 0.01) at ICU arrival. Two patients (1.3%) had seizure, 3 patients (1.9%) had stroke, 14 (8.8%) had acute kidney failure, 7 (4.4%) needed dialysis, 3 (1.9%) suffered myocardial infarction and 9 (5.6%) patients died. We found no significant differences between groups regarding these events. Conclusions. Prolonged inhibition of fibrinolysis, using an additional postoperative dose of tranexamic acid reduces inflammatory response and postoperative bleeding (but not transfusion requirements) in CPB patients. A question which remains unanswered is whether the dose used was ideal in terms of safety, but not in terms of effectiveness.

Long-term efficacy and tolerability of flutamide combined with oral contraception in moderate to severe hirsutism: A 12-month, double-blind, parallel clinical trial

OBJECTIVE Our objective was to test the efficacy and tolerability of three doses of flutamide (125, 250, and 375 mg) combined with a triphasic oral contraceptive (ethynylestradiol/levonorgestrel) during 12 months to treat moderate to severe hirsutism in patients with polycystic ovary syndrome or idiopathic hirsutism. DESIGN We conducted a randomized, double-blind, placebo-controlled, parallel clinical trial. PATIENTS A total of 131 premenopausal women, suffering from moderate to severe hirsutism, were randomized to placebo or 125, 250, or 375 mg flutamide daily associated with a triphasic oral contraceptive pill. Hirsutism (Ferriman-Gallwey), acne and seborrhea (Cremoncini), and hormone serum levels were monitored at baseline and at 3 (except hormone serum levels), 6, and 12 months. Side effects and biochemical, hematological, and hepatic parameters were assessed. METHODS We used three-way ANOVA (subject, dose, and visit) with Scheffé adjustment for multiple comparisons or nonparametrical Friedman test and least-squares mean (paired data) and Kruskall-Wallis test for unpaired data analyses. We used chi(2) or Fisher's test for categorical data. RESULTS A total of 119 patients were included in the intention-to-treat analysis. All flutamide doses induced a significant decrease in hirsutism, acne, and seborrhea scores after 12 months compared with placebo without differences among dose levels. Similar related side effects were observed with placebo and 125 mg flutamide (12.5%), and slightly higher with 250 mg (17.3%) and 375 mg (21.2%). No statistically significant differences were observed either among doses or compared with placebo. CONCLUSIONS Flutamide at 125 mg daily during 12 months was the minimum effective dose to diminish hirsutism in patients with polycystic ovary syndrome or with idiopathic hirsutism.

Treatment rationale and study design for a phase III, double-blind, placebo-controlled study of maintenance pemetrexed plus best supportive care versus best supportive care immediately following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer.

BACKGROUND: To improve the efficacy of first-line therapy for advanced non-small cell lung cancer (NSCLC), additional maintenance chemotherapy may be given after initial induction chemotherapy in patients who did not progress during the initial treatment, rather than waiting for disease progression to administer second-line treatment. Maintenance therapy may consist of an agent that either was or was not present in the induction regimen. The antifolate pemetrexed is efficacious in combination with cisplatin for first-line treatment of advanced NSCLC and has shown efficacy as a maintenance agent in studies in which it was not included in the induction regimen. We designed a phase III study to determine if pemetrexed maintenance therapy improves progression-free survival (PFS) and overall survival (OS) after cisplatin/pemetrexed induction therapy in patients with advanced nonsquamous NSCLC. Furthermore, since evidence suggests expression levels of thymidylate synthase, the primary target of pemetrexed, may be associated with responsiveness to pemetrexed, translational research will address whether thymidylate synthase expression correlates with efficacy outcomes of pemetrexed. METHODS/DESIGN: Approximately 900 patients will receive four cycles of induction chemotherapy consisting of pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) on day 1 of a 21-day cycle. Patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 who have not progressed during induction therapy will randomly receive (in a 2:1 ratio) one of two double-blind maintenance regimens: pemetrexed (500 mg/m2 on day 1 of a 21-day cycle) plus best supportive care (BSC) or placebo plus BSC. The primary objective is to compare PFS between treatment arms. Secondary objectives include a fully powered analysis of OS, objective tumor response rate, patient-reported outcomes, resource utilization, and toxicity. Tumor specimens for translational research will be obtained from consenting patients before induction treatment, with a second biopsy performed in eligible patients following the induction phase. DISCUSSION: Although using a drug as maintenance therapy that was not used in the induction regimen exposes patients to an agent with a different mechanism of action, evidence suggests that continued use of an agent present in the induction regimen as maintenance therapy enables the identification of patients most likely to benefit from maintenance treatment.

Alveolar overdistension as a cause of lung injury: differences among three animal species.

This study analyses characteristics of lung injuries produced by alveolar overdistension in three animal species. Mechanical ventilation at normal tidal volume (10 mL/Kg) and high tidal volume (50 mL/Kg) was applied for 30 min in each species. Data were gathered on wet/dry weight ratio, histological score, and area of alveolar collapse. Five out of six rabbits with high tidal volume developed tension pneumothorax, and the rabbit results were therefore not included in the histological analysis. Lungs from the pigs and rats showed minimal histological lesions. Pigs ventilated with high tidal volume had significantly greater oedema, higher neutrophil infiltration, and higher percentage area of alveolar collapse than rats ventilated with high tidal volume. We conclude that rabbits are not an appropriate species for in vivo studies of alveolar overdistension due to their fragility. Although some histological lesions are observed in pigs and rats, the lesions do not appear to be relevant.

Differences in osteogenic and apoptotic genes between osteoporotic and osteoarthritic patients.

BACKGROUND Osteoporosis is a metabolic disorder characterized by a reduction in bone mass and deterioration in the microarchitectural structure of the bone, leading to a higher risk for spontaneous and fragility fractures.The main aim was to study the differences between human bone from osteoporotic and osteoarthritic patients about gene expression (osteogenesis and apoptosis), bone mineral density, microstructural and biomechanic parameters. METHODS We analyzed data from 12 subjects: 6 with osteoporotic hip fracture (OP) and 6 with hip osteoarthritis (OA), as the control group. All subjects underwent medical history, analytical determinations, densitometry, histomorphometric and biochemical study. The expression of 86 genes of osteogenesis and 86 genes of apoptosis was studied in pool of bone samples from patients with OP and OA by PCR array. RESULTS We observed that most of the genes of apoptosis and osteogenesis show a decrease in gene expression in the osteoporotic group in comparison with the osteoarthritic group. The histomorphometric study shows a lower bone quality in the group of patients with hip fractures compared to the osteoarthritic group. CONCLUSIONS The bone tissue of osteoporotic fracture patients is more fragile than the bone of OA patients. Our results showed an osteoporotic bone with a lower capacities for differentiation and osteoblastic activity as well as a lower rate of apoptosis than osteoarthritic bone. These results are related with structural and biochemical parameters.

Nevirapine vs efavirenz in virologically supressed patients: Differences in lipoprotein subclasses and inflammatory biomarkers.

Background: The interaction between lipid disturbances and inflammatory markers is not well known in patients on antiretroviral therapy (ART). As nevirapine (NVP) is associated with a better lipid profile than efavirenz (EFV), we investigated the relationships between lipid profiles, lipoprotein subclasses and inflammatory biomarkers in patients with prolonged viral suppression with either NVP or EFV and no obvious clinical inflammation. Methods: 122 clinically stable HIV-infected patients with HIV-1 RNA <20 copies longer than 6 months on NNRTI therapy were studied. 72 (59%) were on EFV and 50 (41%) on NVP. Any potentially inflammatory co-morbid diseases (concurrent viral hepatitis, diabetes, hypertension, chronic liver or renal diseases), or statin treatment, were exclusion criteria. Inflammatory biomarkers included hsCRP, LpPLA2, sCD40L, IL-6, IL-8, t-PA, MCP-1, p-selectin and VCAM-1. Lipoprotein subclass measures (VLDL, LDL, IDL and HDL particle number and size) were obtained by the use of proton nuclear magnetic resonance spectroscopy. Results: 82% were male; median age 45 years. Median CD4 count 550/μL (IQR 324). Median time since HIV diagnosis 96 months (IQR 102) and accumulated time on ART 50 months (IQR 101). Patients on NVP had higher time since HIV diagnosis (126.9 [66.7] vs 91.3 [6.6] months, p=0.008) a prolonged time on ART (89.6 [54.6] vs 62.3 [52.2] months, p=0.01) and were older (47.7 vs 40.7 years, p=0.001) than those on EFV. NVP-treated patients presented increased HDL-c (55.8 [16] vs 48.8 [10.7] mg/dL, p=0.007) and apoA1 levels (153.4 [31.9] vs 141.5 [20.5] mg/dL, p=0.02), and reduced apoB/apoA1 ratio (0.68 [0.1] vs 0.61 [0.1], p=0.003) than EFV-treated patients. No differences in inflammatory markers or lipoprotein subclasses were found between NVP and EFV. In patients with extreme lipid values (less favorable: 75th percentiles of LDL, small/dense LDLp and small HDLp, or more favorable: HDL p75 and apoB/apoA1 ratio p25), no consistent differences in inflammatory biomarkers were found. Conclusions: Patients with prolonged viral suppression on NVP present significantly higher HDL and apoA1 levels and reduced apoB/apoA1 ratios than those on EFV, but no differences were found in lipoprotein particles nor inflammatory biomarkers. Relationships between lipid parameters and inflammatory biomarkers in NNRTItreated patients are complex and do not show a linear relationship in this study.

Gender differences in cardiovascular risk factors in HIV infected patients on antiretroviral therapy: Data from the Spanish Coronator study.

Purpose: HIV-infected patients present an increased cardiovascular risk (CVR) of multifactorial origin, usually lower in women than in men. Information by gender about prevalence of modifiable risk factors is scarce. Methods: Coronator is a cross-sectional survey of a representative sample of HIV-infected patients on ART within 10 hospitals across Spain in 2011. Variables include sociodemographics, CVR factors and 10-year CV disease risk estimation (Regicor: Framingham score adapted to the Spanish population). Results: We included 860 patients (76.3% male) with no history of CVD. Median age 45.6 years; 84.1% were Spaniards; 29.9% women were IDUs. Median time since HIV diagnosis for men and women was 10 and 13 years (p=0.001), 28% had an AIDS diagnosis. Median CD4 cell count was 596 cells/mm3, 88% had undetectable viral load. Median time on ART was 91 and 108 months (p=0.017). There was a family history of early CVD in 113 men (17.9%) and 41 women (20.6%). Classical CVR factors are described in the table. Median (IQR) Regicor Score was 3% (2-5) for men and 2% (1-3) for women (p=0.000), and the proportion of subjects with mid-high risk (>5%) was 26.1% for men and 9.4% for women (p=0.000). Conclusions: In this population of HIV-infected patients, women have lower cardiovascular risk than men, partly due to higher levels of HDL cholesterol. Of note is the high frequency of smoking, abdominal obesity and sedentary lifestyle in our population. (Table Presented).

Rationale and design of a randomized, double-blind, placebo controlled multicenter trial to study efficacy, security, and long term effects of intermittent repeated levosimendan administration in patients with advanced heart failure: LAICA study.

BACKGROUND Advanced heart failure (HF) is associated with high morbidity and mortality; it represents a major burden for the health system. Episodes of acute decompensation requiring frequent and prolonged hospitalizations account for most HF-related expenditure. Inotropic drugs are frequently used during hospitalization, but rarely in out-patients. The LAICA clinical trial aims to evaluate the effectiveness and safety of monthly levosimendan infusion in patients with advanced HF to reduce the incidence of hospital admissions for acute HF decompensation. METHODS The LAICA study is a multicenter, prospective, randomized, double-blind, placebo-controlled, parallel group trial. It aims to recruit 213 out-patients, randomized to receive either a 24-h infusion of levosimendan at 0.1 μg/kg/min dose, without a loading dose, every 30 days, or placebo. RESULTS The main objective is to assess the incidence of admission for acute HF worsening during 12 months. Secondarily, the trial will assess the effect of intermittent levosimendan on other variables, including the time in days from randomization to first admission for acute HF worsening, mortality and serious adverse events. CONCLUSIONS The LAICA trial results could allow confirmation of the usefulness of intermittent levosimendan infusion in reducing the rate of hospitalization for HF worsening in advanced HF outpatients.

Relevant gender differences in epidemiological profile, exposure to first antiretroviral regimen and survival in the Spanish AIDS Research Network Cohort.

BACKGROUND The possible differences in the disease spectrum and prognosis of HIV infection in women and men is a major point of concern. Women are under-represented in randomized clinical trials and in some cohorts. Discordant results have often been obtained depending on the setting. METHODS We assessed gender differences in clinical and epidemiological features, antiretroviral treatment (ART) exposure and survival in two multicentre cohorts of HIV-positive subjects in Spain: CoRIS-MD and CoRIS. Competing risk regression models were used to assess gender effect on time to start ART and time to first ART change, and a Cox regression model to estimate gender effect on time to death. RESULTS Between January 1996 and December 2008, 1,953 women and 6,072 men naive to ART at study entry were included. The trend analysis over time showed the percentage of women in the younger (<20 years) and older (>50 years) strata increased significantly (P<0.001) from 0.5% and 1.8% in 1996 to 4.9% and 4.2% in 2008, respectively. By competing risk analysis women started ART earlier than men (adjusted subhazard ratio [ASHR] 1.21, 95% CI 1.11, 1.31) in CoRIS cohort, while in CoRIS-MD none of these differences were observed. In both cohorts women showed a shorter time to the first ART change (ASHR 1.10, 95% CI 1.01, 1.19). Pregnancy and patient's/physician's decisions as reasons for changing were more frequent in women than in men in CoRIS. In the Cox regression model, gender was not associated with differences in survival. CONCLUSIONS In two large cohorts in Spain, we observed relevant gender differences in epidemiological characteristics and antiretroviral exposure outcomes, while survival differences were not attributable to gender.

Role of double-balloon enteroscopy in malignant small bowel tumors.

AIMTo assess the double-balloon enteroscopy (DBE) role in malignant small bowel tumors (MSBT). METHODS This is a retrospective descriptive study performed in a single center. All consecutive patients who underwent a DBE with final diagnosis of a malignant neoplasm from 2004 to 2014 in our referral center were included. Patient demographic and clinical pathological characteristics were recorded and reviewed. MSBT diagnosis was achieved either by DBE directed biopsy with multiple tissue sampling, endoscopic findings or histological analysis of surgical specimen. We have analyzed double-balloon enteroscopy impact in outcome and clinical course of these patients. RESULTS Of 627 patients, 28 (4.5%) (mean age = 60 ± 17.3 years) underwent 30 procedures (25 anterograde, 5 retrograde) and were diagnosed of a malignant tumor. Patients presented with obscure gastrointestinal bleeding (n = 19, 67.9%), occlusion syndrome (n = 7, 25%) and diarrhea (n = 1, 3.6%). They were diagnosed by DBE biopsy (n = 18, 64.3%), histological analysis of surgical specimen (n = 7, 25%) and unequivocal endoscopic findings (n = 2, 7.1%). Gastrointestinal stromal tumor (n = 8, 28.6%), adenocarcinoma (n = 7, 25%), lymphoma (n = 4, 14.3%), neuroendocrine tumor (n = 4, 14.3%), metastatic (n = 3, 10.7%) and Kaposi sarcoma (n = 1, 3.6%) were identified. DBE modified outcome in 7 cases (25%), delaying or avoiding emergency surgery (n = 3), modifying surgery approach (n = 2) and indicating emergency SB partial resection instead of elective approach (n = 2). CONCLUSION DBE may be critical in the management of MSBT providing additional information that may be decisive in the clinical course of these patients.