Long-term safety outcomes of prekallikrein (Fletcher factor) deficiency: A systematic literature review of case reports.

Background: Hereditary prekallikrein (Fletcher factor) deficiency is a rare condition characterized by a prolonged activated partial thromboplastin time. Inhibitors of plasma kallikrein have recently been approved for prophylaxis of hereditary angioedema and are under investigation for use in other indications. Objective: We attempted to conservatively assess the impact of long-term inhibition of this pathway by reviewing reported comorbidities in patients with hereditary prekallikrein deficiency. Methods: We searched several medical literature databases for publications that reported data from patients with hereditary prekallikrein deficiency (<10% of normal and/or shortening of activated partial thromboplastin time on increased incubation time). Data reporting of cardiovascular, bleeding, and autoimmune-related diseases were extracted. Results: Of 1966 publications screened, 45 publications (which represented 53 patients with prekallikrein deficiency) were included. Among 53 identified patients with prekallikrein deficiency, 25 were explicitly defined as asymptomatic, with no comorbidities mentioned in another three cases. Another 16 of the 53 patients were described as having undergone surgery or dental extractions with no complications. Cardiovascular comorbidities were reported in 19 patients, mainly hypertension (9 patients) and cerebrovascular ischemia or stroke (5 patients). Excessive bleeding episodes after surgery were reported in four patients. Autoimmune-related diseases were reported for three patients (two with Graves disease and one with systemic lupus erythematosus). Conclusion: This review identified patients with hereditary prekallikrein deficiency who reported a spectrum of health outcomes from asymptomatic to infrequent reports of cardiovascular, bleeding, and autoimmune comorbidities. The majority of the reports did not indicate any association between prekallikrein deficiency and comorbidities; however, additional observation is required to confirm the long-term safety of plasma kallikrein inhibition.

Efficacy, pharmacokinetics, and safety of icatibant for the treatment of Japanese patients with an acute attack of hereditary angioedema: A phase 3 open-label study.

BACKGROUND: Hereditary angioedema (HAE) is a genetic disease characterized by recurrent swelling episodes affecting the skin, gastrointestinal mucosa, and upper respiratory tract. METHODS: A phase 3, single-arm, open-label study was performed to evaluate a selective bradykinin B2 receptor antagonist, icatibant, for the treatment of acute attacks in Japanese patients with HAE Type I or II. After the onset of an acute attack, icatibant 30 mg was administered by the patient or a healthcare professional via subcutaneous injection in the abdomen. RESULTS: Eight patients who had an attack affecting the skin (n = 4), abdomen (n = 3), or larynx (n = 1) were treated with icatibant (3 of the injections were self-administered). The median time to onset of symptom relief was 1.75 h (95% confidence interval, 1.00-2.50), and all patients had symptom relief within 5 h after administration. The time to maximum plasma concentration of icatibant was 1.79 h, and the maximum plasma concentration was 405 ng/ml. Seven patients experienced an injection site reaction, and 3 patients had adverse events (2 patients had a worsening or repeat HAE attack 29.0 and 18.3 h after icatibant administration, respectively, and 1 had headache). CONCLUSIONS: Although the number of patients is small, the efficacy and tolerability of icatibant for acute attacks were demonstrated in Japanese patients with HAE, regardless of self-administration or administration by healthcare professional.

[EFFICACY, PHARMACOKINETICS, PHARMACODYNAMICS, AND SAFETY OF INTRAVENOUS C1 INHIBITOR FOR LONG-TERM PROPHYLAXIS AND TREATMENT OF BREAKTHROUGH ATTACKS IN JAPANESE SUBJECTS WITH HEREDITARY ANGIOEDEMA: A PHASE 3 OPEN-LABEL STUDY].

BACKGROUND: Hereditary angioedema (HAE) is associated with recurrent, painful, and potentially lifethreatening attacks characterized by swelling of subcutaneous or submucosal tissues. PURPOSE: To investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of repeat-use C1 inhibitor (C1-INH) replacement therapy for long-term prophylaxis and treatment of breakthrough attacks in the management of Japanese patients with HAE type I or II. METHODS: An open-label, single-arm, Phase 3 study was conducted in Japanese patients with HAE (NCT02865720). For patients 6 years of age or older, 1000U were administered biweekly (by a healthcare professional or self-administered) via intravenous infusion. RESULTS: In 8 enrolled patients, the mean number of attacks normalized per month was lower during C1-INH treatment than during the 3 months prior (1.826 vs. 3.375). Clinically meaningful mean change from baseline in the angioedema-quality of life (AE-QoL) total score was shown during treatment with C1-INH. Pharmacokinetic data showed markedly higher and enduring post-baseline plasma levels of C1-INH functional activity and C1-INH antigen concentration, starting from 0.5h after first dose of C1-INH and lasting up to 72 hours. C1-INH was well tolerated with no new safety signals identified in this population of Japanese patients with HAE. CONCLUSION: C1-INH was effective for long-term prophylaxis and treatment of breakthrough attacks with favourable safety profile in Japanese patients with HAE.

A randomized trial of human C1 inhibitor prophylaxis in children with hereditary angioedema.

BACKGROUND: Patients with hereditary angioedema with C1 inhibitor deficiency or dysfunction have burdensome recurrent angioedema attacks. The safety, efficacy, and health-related quality of life (HRQoL) outcomes of C1 inhibitor (C1-INH) prophylaxis (intravenously administered) in patients aged 6-11 years were investigated. METHODS: Eligible patients were enrolled in a randomized, single-blind, crossover, phase 3 trial. After a 12-week baseline observation period (BOP), patients received 500 or 1000 U C1-INH, twice weekly, for 12 weeks before crossing over to the alternate dose for 12 weeks. The primary efficacy end-point was the monthly normalized number of angioedema attacks (NNA). HRQoL was assessed using the EuroQoL 5-dimensional descriptive system youth version and visual analog scale (EQ-VAS). RESULTS: Twelve randomized patients had a median (range) age of 10.0 (7-11) years. Mean (SD) percentage reduction in monthly NNA from BOP was 71.1% (27.1%) with 500 U and 84.5% (20.0%) with 1000 U C1-INH. Mean (SD) within-patient difference (-0.4 [0.58]) for monthly NNA with both doses was significant (P = 0.035 [90% CI, -0.706 to -0.102]). Cumulative attack severity, cumulative daily severity, and number of acute attacks treated were reduced. No serious adverse events or discontinuations occurred. Mean EQ-VAS change from BOP to week 9 of treatment (500 U C1-INH, 10.4; 1000 U C1-INH, 21.6) was greater than the minimal important difference, indicating a meaningful HRQoL change. CONCLUSIONS: C1-INH prophylaxis was effective, safe, and well tolerated in children aged 6-11 years experiencing recurrent angioedema attacks. A post hoc analysis indicated a meaningful improvement in HRQoL with C1-INH. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02052141.

Long-term safety outcomes of prekillikrein (Fletcher factor) deficiency: A systematic literature review of case reports.

BACKGROUND: Hereditary prekallikrein (Fletcher factor) deficiency is a rare condition characterized by a prolonged activated partial thromboplastin time. Inhibitors of plasma kallikrein have recently been approved for prophylaxis of hereditary angioedema and are under investigation for use in other indications. OBJECTIVE: We attempted to conservatively assess the impact of long-term inhibition of this pathway by reviewing reportedcomorbidities in patients with hereditary prekallikrein deficiency. METHODS: We searched several medical literature databases for publications that reported data from patients with hereditaryprekallikrein deficiency (<10% of normal and/or shortening of activated partial thromboplastin time on increased incubationtime). Data reporting of cardiovascular, bleeding, and autoimmune-related diseases were extracted. RESULTS: Of 1966 publications screened, 45 publications (which represented 53 patients with prekallikrein deficiency) wereincluded. Among 53 identified patients with prekallikrein deficiency, 25 were explicitly defined as asymptomatic, with no comorbidities mentioned in another three cases. Another 16 of the 53 patients were described as having undergone surgery or dental extractions with no complications. Cardiovascular comorbidities were reported in 19 patients, mainly hypertension (9 patients) and cerebrovascular ischemia or stroke (5 patients). Excessive bleeding episodes after surgery were reported in four patients. Autoimmune-related diseases were reported for three patients (two with Graves disease and onewith systemic lupus erythematosus). CONCLUSION: This review identified patients with hereditary prekallikrein deficiency who reported a spectrum of health outcomes from asymptomatic to infrequent reports of cardiovascular, bleeding, and autoimmune comorbidities. The majority of the reports did not indicate any association between prekallikrein deficiency and comorbidities; however, additional observation is required to confirm the long-term safety of plasma kallikrein inhibition.

[EFFICACY, PHARMACOKINETICS, AND SAFETY OF ICATIBANT FOR THE TREATMENT OF JAPANESE PATIENTS WITH AN ACUTE ATTACK OF HEREDITARY ANGIOEDEMA: A PHASE 3 OPEN-LABEL STUDY].

BACKGROUND: Hereditary angioedema (HAE) is characterized by paroxysmal edema of the skin, gastrointestinal mucosa, and upper respiratory tract. PURPOSE: This study investigated icatibant, a selective bradykinin B2 receptor antagonist, as treatment for Japanese patients with an acute HAE attack. METHODS: This was an open-label, single-arm, Phase 3 study of Japanese adults with HAE type I or II. Icatibant (30 mg) was administered (by a healthcare professional [HCP] or self-administered) as a subcutaneous injection in the abdomen. RESULTS: Eight patients (4 cutaneous, 3 abdominal, 1 laryngeal) were treated with icatibant (all single injection; 3 self-administered, 5 HCP-administered). The median time to onset of symptom relief was 1.75 hours (95% confidence interval, 1.00 to 2.50); all patients had onset of relief within 5 hours. The estimated time to maximum icatibant concentration in the circulation was 1.79 hours and the maximum concentration was 405 ng/mL. There were 3 patients who experienced 3 adverse events (2 HAE attacks and 1 headache); 7 patients experienced an injection site reaction. CONCLUSION: Although our study was limited by the small number of patients, we found that icatibant was an effective and well-tolerated treatment for Japanese patients with acute HAE attacks, regardless of whether it was administered by a HCP or self-administered.

Hemoglobin levels and blood transfusion in patients with sepsis in Internal Medicine Departments.

BACKGROUND: Acute reduction in hemoglobin levels is frequently seen during sepsis. Previous studies have focused on the management of anemia in patients with septic shock admitted to intensive care units (ICU's), including aggressive blood transfusion aiming to enhance tissue oxygenation. AIM: To study the changes in hemoglobin concentrations during the first week of sepsis in the setting of Internal Medicine (IM) units, and their correlation to survival. DESIGN: Observational prospective study. METHODS: We recorded hemoglobin values upon admission and throughout the first week of hospital stay in a consecutive cohort of septic patients admitted to IM units at a community hospital, the patients were enrolled into a prospective registry. Data on blood transfusions was also collected, we examined the correlation between hemoglobin concentrations during the first week of sepsis and survival, the effect of blood transfusion was also assessed. RESULTS: Eight hundred and fifteen patients (815) with sepsis were enrolled between February 2008 to January 2009. More than 20 % of them had hemoglobin levels less than 10g/dL on admission, a rate that was doubled during the first week of sepsis. Overall, 68 (8.3 %) received blood transfusions, 14 of them (20.6 %) due to bleeding. Typically, blood transfusion was given to older patients with a higher rate of malignancy and lower hemoglobin levels. While hemoglobin concentration on admission had strong correlation with in-hospital mortality (O.R-0.83 [95 % C.I. 0.74-0.92], blood transfusion was not found to be an independent predicting factor for mortality. CONCLUSION: Anemia is very common in sepsis. While hemoglobin level on admission exhibit independent correlation with survival, blood transfusion do not.

Safety and efficacy metrics for primary nitinol stenting in femoropopliteal occlusive disease: a meta-analysis and critical examination of current methodologies.

BACKGROUND: The efficacy and safety of primary stenting for superficial femoral artery (SFA) disease have been benchmarked against historically derived performance goals. However, contemporary evidence evaluating SFA stenting is accumulating. The objective of this systematic review and meta-analysis was to quantitatively assess outcomes after primary SFA stenting with nitinol stents in contemporary practice, to compare these rates with commonly used efficacy and safety goals, and to discuss the clinical and regulatory implications of these findings. METHODS AND RESULTS: We searched MEDLINE, the US Food and Drug Administration (FDA) website, reference lists of qualifying articles, and conference proceedings until October 2012. Studies prospectively assessing primary nitinol stenting for diseased SFA were sought. Data from 11 prospective clinical trials were included. The twelve-month primary patency (PP) rate was reported in five trials. The meta-analytic 12-month PP rate was 71.6% (95% confidence interval [CI] 66.4-76.7%). The meta-analytic rate of 30-day freedom from a composite of death, target limb amputation, and reintervention was 99.9% (95% CI 100.0-90.0%). CONCLUSION: Contemporary nitinol-based bare-metal stents performed well in controlled settings. Occurrence of the 1-month composite safety endpoint was extremely uncommon.

Ising model partition-function computation as a weighted counting problem.

While the Ising model is most often used to understand physical phenomena, its natural connection to combinatorial reasoning also makes it one of the best models to probe complex systems in science and engineering. We bring a computational lens to the study of Ising models, where our computer-science perspective is twofold: On the one hand, we show that partition function computation (#Ising) can be reduced to weighted model counting (WMC). This enables us to take off-the-shelf model counters and apply them to #Ising. We show that one model counter (TensorOrder) outperforms state-of-the-art tools for #Ising on midsize and topologically unstructured instances, suggesting the tool would be a useful addition to a portfolio of partition function solvers. On the other hand, we consider the computational complexity of #Ising and relate it to the logic-based counting of constraint-satisfaction problems or #CSP. We show that known dichotomy results for #CSP give an easy proof of the hardness of #Ising and provide intuition on where the difficulty of #Ising comes from.

Vitamin E in the prevention of cardiovascular disease: the importance of proper patient selection.

Vitamin E is a naturally occurring fat-soluble antioxidant which has been proposed as a treatment for both primary and secondary protection against cardiovascular (CV) events. Promising data from observational epidemiological studies associating higher vitamin E dietary intake with lower risk of CV events have not been validated in randomized controlled clinical trials assessing the effect of vitamin E on CV outcomes. While the pendulum of medical opinion has swung to suggest that high dose vitamin E supplements have no place in the treatment and prevention of CV disease, new data is emerging that allows identification of a specific target population for this treatment, namely patients with diabetes mellitus and the haptoglobin genotype 2-2. This review details the scientific basis and clinical evidence related to the effect of vitamin E on CV outcomes, and the importance of proper patient selection in gaining therapeutic benefit from this intervention.

Long-term efficacy and safety of Zotarolimus-eluting stent in patients with diabetes mellitus: pooled 5-year results from the ENDEAVOR III and IV trials.

OBJECTIVE: To assess long-term outcomes of Endeavor Zotarolimus-eluting stent (E-ZES) implantation in patients with diabetes mellitus (DM). BACKGROUND: Patients with DM and coronary artery disease have lower restenosis with drug-eluting stent (DES) compared with bare-metal stents. Recent data suggest that the E-ZES is inferior to other DES in this population. METHODS: Patient-level data for 601 patients with DM from the ENDEAVOR III and ENDEAVOR IV trials were pooled, of which 337 were treated with E-ZES and 264 were treated with other DES. The primary outcome was target vessel failure (TVF) in the course of 5 years. Outcomes are reported as rates using Kaplan-Meier (KM) survival method and differences between E-ZES and other stent types (sirolimus-eluting stent or paclitaxel-eluting stent) were compared using the log-rank statistic. The independent effect of stent type on TVF was assessed using Cox proportional hazards regression. RESULTS: Baseline characteristics were similar between the groups. Five-year TVF KM rate estimate was numerically lower for E-ZES, but the difference did not reach statistical significance (20.2 vs. 26.9%, P = 0.065). The 5-year KM rate estimates of major adverse cardiac events (17.7 vs. 26.6%, P = 0.012), death (7.6 vs. 15.0%, P = 0.004), and myocardial infarction (1.3 vs. 5.1%, P = 0.011) were also lower for E-ZES versus other DES. CONCLUSIONS: Patients with DM implanted with E-ZES have favorable long-term outcomes compared to first-generation DES. Long-term performance of DES should be assessed routinely and may differ from initial performance.

An enzyme linked immunosorbent assay (ELISA) for the determination of the human haptoglobin phenotype.

BACKGROUND: Haptoglobin (Hp) is an abundant serum protein which binds extracorpuscular hemoglobin (Hb). Two alleles exist in humans for the Hp gene, denoted 1 and 2. Diabetic individuals with the Hp 2-2 genotype are at increased risk of developing vascular complications including heart attack, stroke, and kidney disease. Recent evidence shows that treatment with vitamin E can reduce the risk of diabetic vascular complications by as much as 50% in Hp 2-2 individuals. We sought to develop a rapid and accurate test for Hp phenotype (which is 100% concordant with the three major Hp genotypes) to facilitate widespread diagnostic testing as well as prospective clinical trials. METHODS: A monoclonal antibody raised against human Hp was shown to distinguish between the three Hp phenotypes in an enzyme linked immunosorbent assay (ELISA). Hp phenotypes obtained in over 8000 patient samples using this ELISA method were compared with those obtained by polyacrylamide gel electrophoresis or the TaqMan PCR method. RESULTS: Our analysis showed that the sensitivity and specificity of the ELISA test for Hp 2-2 phenotype is 99.0% and 98.1%, respectively. The positive predictive value and the negative predictive value for Hp 2-2 phenotype is 97.5% and 99.3%, respectively. Similar results were obtained for Hp 2-1 and Hp 1-1 phenotypes. In addition, the ELISA was determined to be more sensitive and specific than the TaqMan method. CONCLUSIONS: The Hp ELISA represents a user-friendly, rapid and highly accurate diagnostic tool for determining Hp phenotypes. This test will greatly facilitate the typing of thousands of samples in ongoing clinical studies.

Is it time to screen for the haptoglobin genotype to assess the cardiovascular risk profile and vitamin E therapy responsiveness in patients with diabetes?

Diabetes mellitus (DM) carries an increased risk for cardiovascular complications. Haptoglobin (Hp) is an abundant plasma protein with an antioxidant function by virtue of its ability to block the oxidative activity of extracorpuscular hemoglobin. There exist two common functional alleles at the Hp genetic locus, denoted 1 and 2, with three Hp genotypes (Hp 1-1, 2-1, and 2-2). The Hp protein expressed in Hp 2-2 individuals is markedly inferior in protecting against hemoglobin-induced oxidative stress. Hp 2-2 DM individuals have been shown to be at increased risk for the development of diabetes complications, particularly diabetic cardiovascular disease (CVD). We review the biological mechanisms underlying the interaction between the Hp genotype and DM on CVD and the accumulating evidence in favor of Hp genotyping all individuals with DM and providing antioxidant vitamin E supplementation specifically to Hp 2-2 DM individuals to reduce their CVD morbidity and mortality.

Benefits versus risks of pharmacological prophylaxis to prevent symptomatic venous thromboembolism in unselected medical patients revisited. Meta-analysis of the medical literature.

A significant proportion of the outcomes reported in trials assessing venous thromboembolism (VTE) prophylaxis in medical patients are related to asymptomatic events found on routine imaging studies. The implications of these events are controversial. Moreover, such trials did not always reflect the patient mix in today's internal medicine departments. We summarized the evidence assessing the rate of symptomatic VTE events and the benefit of pharmacological prophylaxis in unselected medical patients, and formally evaluated the benefit versus risk of this intervention. We searched MEDLINE, EMBASE and CENTRAL until June 2011 for studies that prospectively followed cohorts of medical patients and assessed the rates of VTE, and randomized controlled trials reporting the effect of prophylaxis on these events, at 3 weeks and 3 months. Eight trials were included. The rates of symptomatic VTE were 0.69 and 3.7 % for short term and long term follow-up periods, respectively. In the interventional meta-analysis, the odds ratio (OR) for overall mortality and for symptomatic VTE at 3 weeks were 0.93 and 0.59, favouring intervention. The OR for major bleeding at 3 weeks was 2.0, favouring no intervention. None of these results were statistically significant. The number needed to treat to prevent one overt VTE event was 292, while the number needed to treat for an additional major bleeding was 336. In unselected medical patients, the rate of symptomatic VTE is lower than the reported overall VTE rate, and the benefit to risk ratio of pharmacological intervention for alleviating this condition in at-risk medical inpatient is questionable. Further specifying the population at risk for an overt VTE, and the clinical significance of asymptomatic events, is warranted.

Clinical characteristics and outcomes of patients with clinically unsuspected pulmonary embolism versus patients with clinically suspected pulmonary embolism.

BACKGROUND: The routine use of multidetector computed tomography has led to increased detection of unsuspected pulmonary embolism (UPE), with questionable benefit for diagnosis and treatment. OBJECTIVE: The purpose of this work was to compare the clinical characteristics and prognosis of patients with UPE to patients with suspected PE (SPE). METHODS: We retrospectively reviewed the charts of patients diagnosed with PE in a community-based university hospital between the years 2002 and 2007. UPE was defined as PE detected on CT scans performed for indications other than suspicion of PE. We compared patients with UPE to patients with SPE for differences in clinical features, electrocardiogram, imaging and echocardiographic findings. We also assessed the long-term outcomes using electronic patient records. RESULTS: Of 500 patients with PE, 408 had SPE and 92 had UPE. Patients with UPE were similar to patients with SPE regarding age and sex distribution. Malignancy was more prevalent in UPE patients (39 vs. 23%, p < 0.0068). UPE patients had significantly less tachypnea (37 vs. 57%, p = 0.0005), dyspnea (47 vs. 87%, p < 0.0001), chest pain (19 vs. 42%, p < 0.0001) and hypoxemia (36 vs. 55%, p = 0.0011). Mortality was higher in UPE patients (70.3 vs. 53%, p = 0.0029). The hazard ratio after adjustment for confounders including age, sex and malignancy was 1.546 (95% CI: 1.139-2.099, p = 0.0052). CONCLUSIONS: We suggest that UPE is more prevalent in patients with a malignancy and is associated with higher mortality despite a less severe clinical presentation. UPE may be a marker of poor prognosis.

Risk factors for urinary tract infection caused by Enterobacteriaceae with extended-spectrum beta-lactamase resistance in patients admitted to internal medicine departments.

BACKGROUND: Extended-spectrum beta-lactamase (ESBL) resistance is a growing concern in and outside hospitals. Physicians often face a true clinical dilemma when initiating empirical antibiotic treatment in patients admitted to internal medicine departments. OBJECTIVES: To determine the prevalence of risk factors for ESBL resistance in patients with urinary tract infection (UTI) admitted to internal medicine departments. METHODS: We conducted a retrospective analysis of the medical records of patients with UTI admitted to an internal medicine division in a community-based academic hospital over a 1 year period. We collected clinical, laboratory and imaging data that were available to the treating physician at admission. Outcome measures included ESBL resistance and death. RESULTS: Of the 6754 admissions 366 patients were included in the study. Hospitalization during the previous 3 months (odds ratio 3.4, P < 0.0001), residency in a long-term-care facility (OR 2.4, P = 0.004), and the presence of a permanent urinary catheter (OR 2.2, P = 0.015) were correlated to ESBL resistance with statistical significance. These risk factors were extremely prevalent in our patient cohort. CONCLUSIONS: ESBL resistance is becoming prevalent outside hospital settings, and patients admitted to an internal medicine department with UTI frequently carry risk factors for harboring resistant bacteria. In such patients a high index of suspicion and early targeted antibiotic treatment for ESBL-producing Enterobacteriaceae may be justified.

Assessment of disease-severity scoring systems for patients with sepsis in general internal medicine departments.

INTRODUCTION: Due to the increasing burden on hospital systems, most elderly patients with non-surgical sepsis are admitted to general internal medicine departments. Disease-severity scoring systems are used for stratification of patients for utilization management, performance assessment, and clinical research. Some widely used scoring systems for septic patients are inappropriate when rating non-surgical patients in a non-intensive care unit (ICU) environment mainly because their calculations require types of data that are frequently unavailable. This study aimed to assess the fitness of four scoring systems for septic patients hospitalized in general internal medicine departments: modified early warning score (MEWS), simple clinical score (SCS), mortality in emergency department sepsis (MEDS) score, and rapid emergency medicine score (REMS). METHODS: We prospectively collected computerized data of septic patients admitted to general internal medicine departments in our community-based university hospital. We followed 28-day in-hospital mortality, overall in-hospital mortality, and 30- and 60-day mortality. Using a logistic regression procedure we calculated the area under ROC curve (AUC) for every scoring system. RESULTS: Between February 1st, 2008 and April 30th, 2009 we gathered data of 1,072 patients meeting sepsis criteria on admission to general internal medicine departments. The 28-day mortality was 19.4%. The AUC for the MEWS was 0.65-0.70, for the SCS 0.76-0.79, for the MEDS 0.73-0.75, and for the REMS, 0.74-0.79. Using Hosmer-Lemeshow statistics, a lack of fit was found for the MEDS model. All scoring systems performed better than calculations based on sepsis severity. CONCLUSIONS: The SCS and REMS are the most appropriate clinical scores to predict the mortality of patients with sepsis in general internal medicine departments.

Subcutaneous unfractionated heparin for the initial treatment of venous thromboembolism.

BACKGROUND: Venous thromboembolism is a prevalent condition with potentially dire consequences. Its medical treatment requires anticoagulation, which is usually achieved with either unfractionated or low molecular weight heparin (LMWH). Unfractionated heparin (UFH) is usually administered intravenously, but can be applied subcutaneously as well. OBJECTIVES: To explore the effectiveness of subcutaneous UFH for the initial treatment of venous thromboembolism compared with other treatment modalities. SEARCH STRATEGY: The Cochrane Peripheral Vascular Diseases Group searched their Specialised Register (last searched 14 July 2009) and the Cochrane Central Register of Controlled Trials (CENTRAL) (last searched The Cochrane Library 2009, Issue 3). We searched MEDLINE and EMBASE (last searched February 2009). SELECTION CRITERIA: Randomised controlled trials, in which treatment with subcutaneous UFH was compared to control, such as subcutaneous LMWH continuous intravenous UFH in patients with acute venous thromboembolism. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality. MAIN RESULTS: Fifteen randomised controlled trials were included with a total of 3054 participants (1475 patients in the intervention group and 1579 patients in the control group). The results for all the major outcomes were statistically non-significant. The odds ratio (OR) for recurrent deep vein thrombosis (DVT) or pulmonary embolism (PE) during three months follow up were 1.68 (95% confidence interval (CI) 0.92 to 3.04) and 1.18. (95% CI 0.54 to 2.56), favouring the control arm. The odds ratio for developing PE during heparin treatment also favoured the control group (OR 1.10, 95% CI 0.46 to 2.62). The ORs for major bleeding during heparin treatment and throughout three months follow up were non significant (1.07, 95% CI 0.64 to 1.79, and 0.66, 95% CI 0.33 to 1.32, respectively). Disease or treatment related deaths as well as total mortality during heparin treatment and at three months follow up did not differ between study groups. AUTHORS' CONCLUSIONS: Subcutaneous unfractionated heparin for the treatment of venous thromboembolism cannot be considered non-inferior to other treatment modalities in terms of recurrent DVT and PE at three months, but seems as safe and effective with regards to rates of major bleeding and death.

Fixed-Dose Subcutaneous C1-Inhibitor Liquid for Prophylactic Treatment of C1-INH-HAE: SAHARA Randomized Study.

BACKGROUND: Hereditary angioedema (HAE) with C1 inhibitor deficiency (C1-INH) is characterized by swelling of subcutaneous and/or submucosal tissues. OBJECTIVE: To evaluate efficacy/safety of fixed-dose subcutaneous plasma-derived C1-INH (pdC1-INH) liquid for HAE attack prevention (NCT02584959). METHODS: Eligible patients were ≥12 years with ≥2 monthly attacks prescreening or pre-long-term prophylaxis. In a partial crossover design, 80% of patients were randomized to placebo or pdC1-INH liquid for 14 weeks and crossed over from active to placebo or vice versa for another 14 weeks. The remainder were randomized to pdC1-INH liquid for 28 weeks. The primary efficacy endpoint was normalized number of attacks (NNA) versus placebo. Key additional endpoints were the proportion of patients achieving NNA reduction ≥50%, attack severity, number of attack-free days, and safety. RESULTS: Seventy-five patients were randomized and 58 (77%) completed the study. Mean age 41 years; 88% HAE type I. Least-squares means of NNA were reduced from 3.9 with placebo to 1.6 with pdC1-INH (from day 1; P < .0001). Most patients had ≥50% NNA reduction with pdC1-INH (from day 1, 78%). A total of 8.8% of placebo-treated patients were attack-free and 5.3%, 22.8%, and 63.2% had mild, moderate, and severe attacks, respectively; 37.5% of pdC1-INH-treated patients were attack-free and 8.9%, 26.8%, and 26.8% had mild, moderate, and severe attacks, respectively. Treatment-emergent adverse event rates were similar between groups (52% vs 56% for pdC1-INH crossover vs placebo, respectively). CONCLUSIONS: Fixed-dose subcutaneous pdC1-INH liquid was superior to placebo in preventing HAE attacks and demonstrated a favorable safety profile.