Showing papers on "Randomized controlled trial published in 2014"

2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults: Report From the Panel Members Appointed to the Eighth Joint National Committee (JNC 8)

Abstract: Hypertension is the most common condition seen in primary care and leads to myocardial infarction, stroke, renal failure, and death if not detected early and treated appropriately. Patients want to be assured that blood pressure (BP) treatment will reduce their disease burden, while clinicians want guidance on hypertension management using the best scientific evidence. This report takes a rigorous, evidence-based approach to recommend treatment thresholds, goals, and medications in the management of hypertension in adults. Evidence was drawn from randomized controlled trials, which represent the gold standard for determining efficacy and effectiveness. Evidence quality and recommendations were graded based on their effect on important outcomes. There is strong evidence to support treating hypertensive persons aged 60 years or older to a BP goal of less than 150/90 mm Hg and hypertensive persons 30 through 59 years of age to a diastolic goal of less than 90 mm Hg; however, there is insufficient evidence in hypertensive persons younger than 60 years for a systolic goal, or in those younger than 30 years for a diastolic goal, so the panel recommends a BP of less than 140/90 mm Hg for those groups based on expert opinion. The same thresholds and goals are recommended for hypertensive adults with diabetes or nondiabetic chronic kidney disease (CKD) as for the general hypertensive population younger than 60 years. There is moderate evidence to support initiating drug treatment with an angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel blocker, or thiazide-type diuretic in the nonblack hypertensive population, including those with diabetes. In the black hypertensive population, including those with diabetes, a calcium channel blocker or thiazide-type diuretic is recommended as initial therapy. There is moderate evidence to support initial or add-on antihypertensive therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in persons with CKD to improve kidney outcomes. Although this guideline provides evidence-based recommendations for the management of high BP and should meet the clinical needs of most patients, these recommendations are not a substitute for clinical judgment, and decisions about care must carefully consider and incorporate the clinical characteristics and circumstances of each individual patient.

A Randomized Trial of Protocol-Based Care for Early Septic Shock

Abstract: In 31 emergency departments in the United States, we randomly assigned patients with septic shock to one of three groups for 6 hours of resuscitation: protocol-based EGDT; protocol-based standard therapy that did not require the placement of a central venous catheter, administration of inotropes, or blood transfusions; or usual care. The primary end point was 60-day in-hospital mortality. We tested sequentially whether protocol-based care (EGDT and standard-therapy groups combined) was superior to usual care and whether protocol-based EGDT was superior to protocol-based standard therapy. Secondary outcomes included longer-term mortality and the need for organ support. Results We enrolled 1341 patients, of whom 439 were randomly assigned to protocol-based EGDT, 446 to protocol-based standard therapy, and 456 to usual care. Resuscitation strategies differed significantly with respect to the monitoring of central venous pressure and oxygen and the use of intravenous fluids, vasopressors, inotropes, and blood transfusions. By 60 days, there were 92 deaths in the protocol-based EGDT group (21.0%), 81 in the protocol-based standard-therapy group (18.2%), and 86 in the usual-care group (18.9%) (relative risk with protocol-based therapy vs. usual care, 1.04; 95% confidence interval [CI], 0.82 to 1.31; P = 0.83; relative risk with protocol-based EGDT vs. protocol-based standard therapy, 1.15; 95% CI, 0.88 to 1.51; P = 0.31). There were no significant differences in 90-day mortality, 1-year mortality, or the need for organ support. Conclusions In a multicenter trial conducted in the tertiary care setting, protocol-based resuscitation of patients in whom septic shock was diagnosed in the emergency department did not improve outcomes. (Funded by the National Institute of General Medical Sciences; ProCESS ClinicalTrials.gov number, NCT00510835.)

SYRCLE’s risk of bias tool for animal studies

Abstract: Systematic Reviews (SRs) of experimental animal studies are not yet common practice, but awareness of the merits of conducting such SRs is steadily increasing. As animal intervention studies differ from randomized clinical trials (RCT) in many aspects, the methodology for SRs of clinical trials needs to be adapted and optimized for animal intervention studies. The Cochrane Collaboration developed a Risk of Bias (RoB) tool to establish consistency and avoid discrepancies in assessing the methodological quality of RCTs. A similar initiative is warranted in the field of animal experimentation. We provide an RoB tool for animal intervention studies (SYRCLE’s RoB tool). This tool is based on the Cochrane RoB tool and has been adjusted for aspects of bias that play a specific role in animal intervention studies. To enhance transparency and applicability, we formulated signalling questions to facilitate judgment. The resulting RoB tool for animal studies contains 10 entries. These entries are related to selection bias, performance bias, detection bias, attrition bias, reporting bias and other biases. Half these items are in agreement with the items in the Cochrane RoB tool. Most of the variations between the two tools are due to differences in design between RCTs and animal studies. Shortcomings in, or unfamiliarity with, specific aspects of experimental design of animal studies compared to clinical studies also play a role. SYRCLE’s RoB tool is an adapted version of the Cochrane RoB tool. Widespread adoption and implementation of this tool will facilitate and improve critical appraisal of evidence from animal studies. This may subsequently enhance the efficiency of translating animal research into clinical practice and increase awareness of the necessity of improving the methodological quality of animal studies.

Mepolizumab Treatment in Patients with Severe Eosinophilic Asthma

Abstract: BACKGROUND: Some patients with severe asthma have frequent exacerbations associated with persistent eosinophilic inflammation despite continuous treatment with high-dose inhaled glucocorticoids with or without oral glucocorticoids. METHODS: In this randomized, double-blind, double-dummy study, we assigned 576 patients with recurrent asthma exacerbations and evidence of eosinophilic inflammation despite high doses of inhaled glucocorticoids to one of three study groups. Patients were assigned to receive mepolizumab, a humanized monoclonal antibody against interleukin-5, which was administered as either a 75-mg intravenous dose or a 100-mg subcutaneous dose, or placebo every 4 weeks for 32 weeks. The primary outcome was the rate of exacerbations. Other outcomes included the forced expiratory volume in 1 second (FEV1) and scores on the St. George's Respiratory Questionnaire (SGRQ) and the 5-item Asthma Control Questionnaire (ACQ-5). Safety was also assessed. RESULTS: The rate of exacerbations was reduced by 47% (95% confidence interval [CI], 29 to 61) among patients receiving intravenous mepolizumab and by 53% (95% CI, 37 to 65) among those receiving subcutaneous mepolizumab, as compared with those receiving placebo (P<0.001 for both comparisons). Exacerbations necessitating an emergency department visit or hospitalization were reduced by 32% in the group receiving intravenous mepolizumab and by 61% in the group receiving subcutaneous mepolizumab. At week 32, the mean increase from baseline in FEV1 was 100 ml greater in patients receiving intravenous mepolizumab than in those receiving placebo (P=0.02) and 98 ml greater in patients receiving subcutaneous mepolizumab than in those receiving placebo (P=0.03). The improvement from baseline in the SGRQ score was 6.4 points and 7.0 points greater in the intravenous and subcutaneous mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 4 points), and the improvement in the ACQ-5 score was 0.42 points and 0.44 points greater in the two mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 0.5 points) (P<0.001 for all comparisons). The safety profile of mepolizumab was similar to that of placebo. CONCLUSIONS: Mepolizumab administered either intravenously or subcutaneously significantly reduced asthma exacerbations and was associated with improvements in markers of asthma control. (Funded by GlaxoSmithKline; MENSA ClinicalTrials.gov number, NCT01691521.).

Meditation Programs for Psychological Stress and Well-being: A Systematic Review and Meta-analysis

Abstract: Importance Many people meditate to reduce psychological stress and stress-related health problems. To counsel people appropriately, clinicians need to know what the evidence says about the health benefits of meditation. Objective To determine the efficacy of meditation programs in improving stress-related outcomes (anxiety, depression, stress/distress, positive mood, mental health–related quality of life, attention, substance use, eating habits, sleep, pain, and weight) in diverse adult clinical populations. Evidence Review We identified randomized clinical trials with active controls for placebo effects through November 2012 from MEDLINE, PsycINFO, EMBASE, PsycArticles, Scopus, CINAHL, AMED, the Cochrane Library, and hand searches. Two independent reviewers screened citations and extracted data. We graded the strength of evidence using 4 domains (risk of bias, precision, directness, and consistency) and determined the magnitude and direction of effect by calculating the relative difference between groups in change from baseline. When possible, we conducted meta-analyses using standardized mean differences to obtain aggregate estimates of effect size with 95% confidence intervals. Findings After reviewing 18 753 citations, we included 47 trials with 3515 participants. Mindfulness meditation programs had moderate evidence of improved anxiety (effect size, 0.38 [95% CI, 0.12-0.64] at 8 weeks and 0.22 [0.02-0.43] at 3-6 months), depression (0.30 [0.00-0.59] at 8 weeks and 0.23 [0.05-0.42] at 3-6 months), and pain (0.33 [0.03- 0.62]) and low evidence of improved stress/distress and mental health–related quality of life. We found low evidence of no effect or insufficient evidence of any effect of meditation programs on positive mood, attention, substance use, eating habits, sleep, and weight. We found no evidence that meditation programs were better than any active treatment (ie, drugs, exercise, and other behavioral therapies). Conclusions and Relevance Clinicians should be aware that meditation programs can result in small to moderate reductions of multiple negative dimensions of psychological stress. Thus, clinicians should be prepared to talk with their patients about the role that a meditation program could have in addressing psychological stress. Stronger study designs are needed to determine the effects of meditation programs in improving the positive dimensions of mental health and stress-related behavior.

Surgery for weight loss in adults

Abstract: Background: bariatric (weight loss) surgery for obesity is considered when other treatments have failed. The effects of the available bariatric procedures compared with medical management and with each other are uncertain. This is an update of a Cochrane review first published in 2003 and most recently updated in 2009. Objectives: to assess the effects of bariatric surgery for overweight and obesity, including the control of comorbidities. Search methods: studies were obtained from searches of numerous databases, supplemented with searches of reference lists and consultation with experts in obesity research. Date of last search was November 2013. Selection criteria: randomised controlled trials (RCTs) comparing surgical interventions with non-surgical management of obesity or overweight or comparing different surgical procedures. Data collection and analysis: data were extracted by one review author and checked by a second review author. Two review authors independently assessed risk of bias and evaluated overall study quality utilising the GRADE instrument. Main results: twenty-two trials with 1798 participants were included; sample sizes ranged from 15 to 250. Most studies followed participants for 12, 24 or 36 months; the longest follow-up was 10 years. The risk of bias across all domains of most trials was uncertain; just one was judged to have adequate allocation concealment. All seven RCTs comparing surgery with non-surgical interventions found benefits of surgery on measures of weight change at one to two years follow-up. Improvements for some aspects of health-related quality of life (QoL) (two RCTs) and diabetes (five RCTs) were also found. The overall quality of the evidence was moderate. Five studies reported data on mortality, no deaths occurred. Serious adverse events (SAEs) were reported in four studies and ranged from 0% to 37% in the surgery groups and 0% to 25% in the no surgery groups. Between 2% and 13% of participants required reoperations in the five studies that reported these data. Three RCTs found that laparoscopic Roux-en-Y gastric bypass (L)(RYGB) achieved significantly greater weight loss and body mass index (BMI) reduction up to five years after surgery compared with laparoscopic adjustable gastric banding (LAGB). Mean end-of-study BMI was lower following LRYGB compared with LAGB: mean difference (MD) -5.2 kg/m² (95% confidence interval (CI) -6.4 to -4.0; P Open RYGB, LRYGB and laparoscopic sleeve gastrectomy (LSG) led to losses of weight and/or BMI but there was no consistent picture as to which procedure was better or worse in the seven included trials. MD was -0.2 kg/m² (95% CI -1.8 to 1.3); 353 participants; 6 trials; low quality evidence) in favour of LRYGB. No statistically significant differences in QoL were found (one RCT). Six RCTs reported mortality; one death occurred following LRYGB. SAEs were reported by one RCT and were higher in the LRYGB group (4.5%) than the LSG group (0.9%). Reoperations ranged from 6.7% to 24% in the LRYGB group and 3.3% to 34% in the LSG group. Effects on comorbidities, complications and additional surgical procedures were neutral, except gastro-oesophageal reflux disease improved following LRYGB (one RCT). One RCT of people with a BMI 25 to 35 and type 2 diabetes found laparoscopic mini-gastric bypass resulted in greater weight loss and improvement of diabetes compared with LSG, and had similar levels of complications. Two RCTs found that biliopancreatic diversion with duodenal switch (BDDS) resulted in greater weight loss than RYGB in morbidly obese patients. End-of-study mean BMI loss was greater following BDDS: MD -7.3 kg/m² (95% CI -9.3 to -5.4); P One RCT comparing laparoscopic duodenojejunal bypass with sleeve gastrectomy versus LRYGB found BMI, excess weight loss, and rates of remission of diabetes and hypertension were similar at 12 months follow-up (very low quality evidence). QoL, SAEs and reoperation rates were not reported. No deaths occurred in either group. One RCT comparing laparoscopic isolated sleeve gastrectomy (LISG) versus LAGB found greater improvement in weight-loss outcomes following LISG at three years follow-up (very low quality evidence). QoL, mortality and SAEs were not reported. Reoperations occurred in 20% of the LAGB group and in 10% of the LISG group. One RCT (unpublished) comparing laparoscopic gastric imbrication with LSG found no statistically significant difference in weight loss between groups (very low quality evidence). QoL and comorbidities were not reported. No deaths occurred. Two participants in the gastric imbrication group required reoperation. Authors' conclusions: surgery results in greater improvement in weight loss outcomes and weight associated comorbidities compared with non-surgical interventions, regardless of the type of procedures used. When compared with each other, certain procedures resulted in greater weight loss and improvements in comorbidities than others. Outcomes were similar between RYGB and sleeve gastrectomy, and both of these procedures had better outcomes than adjustable gastric banding. For people with very high BMI, biliopancreatic diversion with duodenal switch resulted in greater weight loss than RYGB. Duodenojejunal bypass with sleeve gastrectomy and laparoscopic RYGB had similar outcomes, however this is based on one small trial. Isolated sleeve gastrectomy led to better weight-loss outcomes than adjustable gastric banding after three years follow-up. This was based on one trial only. Weight-related outcomes were similar between laparoscopic gastric imbrication and laparoscopic sleeve gastrectomy in one trial. Across all studies adverse event rates and reoperation rates were generally poorly reported. Most trials followed participants for only one or two years, therefore the long-term effects of surgery remain unclear.

Management of Sickle Cell Disease: Summary of the 2014 Evidence-Based Report by Expert Panel Members

Abstract: Importance Sickle cell disease (SCD) is a life-threatening genetic disorder affecting nearly 100 000 individuals in the United States and is associated with many acute and chronic complications requiring immediate medical attention. Two disease-modifying therapies, hydroxyurea and long-term blood transfusions, are available but underused. Objective To support and expand the number of health professionals able and willing to provide care for persons with SCD. Evidence Review Databases of MEDLINE (including in-process and other nonindexed citations), EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, CINAHL, TOXLINE, and Scopus were searched using prespecified search terms and keywords to identify randomized clinical trials, nonrandomized intervention studies, and observational studies. Literature searches of English-language publications from 1980 with updates through April 1, 2014, addressed key questions developed by the expert panel members and methodologists. Findings Strong recommendations for preventive services include daily oral prophylactic penicillin up to the age of 5 years, annual transcranial Doppler examinations from the ages of 2 to 16 years in those with sickle cell anemia, and long-term transfusion therapy to prevent stroke in those children with abnormal transcranial Doppler velocity (≥200 cm/s). Strong recommendations addressing acute complications include rapid initiation of opioids for treatment of severe pain associated with a vasoocclusive crisis, and use of incentive spirometry in patients hospitalized for a vasoocclusive crisis. Strong recommendations for chronic complications include use of analgesics and physical therapy for treatment of avascular necrosis, and use of angiotensin-converting enzyme inhibitor therapy for microalbuminuria in adults with SCD. Strong recommendations for children and adults with proliferative sickle cell retinopathy include referral to expert specialists for consideration of laser photocoagulation and for echocardiography to evaluate signs of pulmonary hypertension. Hydroxyurea therapy is strongly recommended for adults with 3 or more severe vasoocclusive crises during any 12-month period, with SCD pain or chronic anemia interfering with daily activities, or with severe or recurrent episodes of acute chest syndrome. A recommendation of moderate strength suggests offering treatment with hydroxyurea without regard to the presence of symptoms for infants, children, and adolescents. In persons with sickle cell anemia, preoperative transfusion therapy to increase hemoglobin levels to 10 g/dL is strongly recommended with a moderate strength recommendation to maintain sickle hemoglobin levels of less than 30% prior to the next transfusion during long-term transfusion therapy. A strong recommendation to assess iron overload is accompanied by a moderate strength recommendation to begin iron chelation therapy when indicated. Conclusions and Relevance Hydroxyurea and transfusion therapy are strongly recommended for many individuals with SCD. Many other recommendations are based on quality of evidence that is less than high due to the paucity of clinical trials regarding screening, management, and monitoring for individuals with SCD.

Fibrinolysis for Patients with Intermediate- Risk Pulmonary Embolism

Abstract: BACKGROUND: The role of fibrinolytic therapy in patients with intermediate-risk pulmonary embolism is controversial. METHODS: In a randomized, double-blind trial, we compared tenecteplase plus heparin with placebo plus heparin in normotensive patients with intermediate-risk pulmonary embolism. Eligible patients had right ventricular dysfunction on echocardiography or computed tomography, as well as myocardial injury as indicated by a positive test for cardiac troponin I or troponin T. The primary outcome was death or hemodynamic decompensation (or collapse) within 7 days after randomization. The main safety outcomes were major extracranial bleeding and ischemic or hemorrhagic stroke within 7 days after randomization. RESULTS: Of 1006 patients who underwent randomization, 1005 were included in the intention-to-treat analysis. Death or hemodynamic decompensation occurred in 13 of 506 patients (2.6%) in the tenecteplase group as compared with 28 of 499 (5.6%) in the placebo group (odds ratio, 0.44; 95% confidence interval, 0.23 to 0.87; P=0.02). Between randomization and day 7, a total of 6 patients (1.2%) in the tenecteplase group and 9 (1.8%) in the placebo group died (P=0.42). Extracranial bleeding occurred in 32 patients (6.3%) in the tenecteplase group and 6 patients (1.2%) in the placebo group (P<0.001). Stroke occurred in 12 patients (2.4%) in the tenecteplase group and was hemorrhagic in 10 patients; 1 patient (0.2%) in the placebo group had a stroke, which was hemorrhagic (P=0.003). By day 30, a total of 12 patients (2.4%) in the tenecteplase group and 16 patients (3.2%) in the placebo group had died (P=0.42). CONCLUSIONS: In patients with intermediate-risk pulmonary embolism, fibrinolytic therapy prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke. (Funded by the Programme Hospitalier de Recherche Clinique in France and others; PEITHO EudraCT number, 2006-005328-18; ClinicalTrials.gov number, NCT00639743.).

Effect of Structured Physical Activity on Prevention of Major Mobility Disability in Older Adults: The LIFE Study Randomized Clinical Trial

Abstract: Importance In older adults reduced mobility is common and is an independent risk factor for morbidity, hospitalization, disability, and mortality. Limited evidence suggests that physical activity may help prevent mobility disability; however, there are no definitive clinical trials examining whether physical activity prevents or delays mobility disability. Objective To test the hypothesis that a long-term structured physical activity program is more effective than a health education program (also referred to as a successful aging program) in reducing the risk of major mobility disability. Design, Setting, and Participants The Lifestyle Interventions and Independence for Elders (LIFE) study was a multicenter, randomized trial that enrolled participants between February 2010 and December 2011, who participated for an average of 2.6 years. Follow-up ended in December 2013. Outcome assessors were blinded to the intervention assignment. Participants were recruited from urban, suburban, and rural communities at 8 centers throughout the United States. We randomized a volunteer sample of 1635 sedentary men and women aged 70 to 89 years who had physical limitations, defined as a score on the Short Physical Performance Battery of 9 or below, but were able to walk 400 m. Interventions Participants were randomized to a structured, moderate-intensity physical activity program (n = 818) conducted in a center (twice/wk) and at home (3-4 times/wk) that included aerobic, resistance, and flexibility training activities or to a health education program (n = 817) consisting of workshops on topics relevant to older adults and upper extremity stretching exercises. Main Outcomes and Measures The primary outcome was major mobility disability objectively defined by loss of ability to walk 400 m. Results Incident major mobility disability occurred in 30.1% (246 participants) of the physical activity group and 35.5% (290 participants) of the health education group (hazard ratio [HR], 0.82 [95% CI, 0.69-0.98], P = .03). Persistent mobility disability was experienced by 120 participants (14.7%) in the physical activity group and 162 participants (19.8%) in the health education group (HR, 0.72 [95% CI, 0.57-0.91]; P = .006). Serious adverse events were reported by 404 participants (49.4%) in the physical activity group and 373 participants (45.7%) in the health education group (risk ratio, 1.08 [95% CI, 0.98-1.20]). Conclusions and Relevance A structured, moderate-intensity physical activity program compared with a health education program reduced major mobility disability over 2.6 years among older adults at risk for disability. These findings suggest mobility benefit from such a program in vulnerable older adults. Trial Registration clinicaltrials.gov Identifier:NCT01072500

The use of propensity score methods with survival or time-to-event outcomes: reporting measures of effect similar to those used in randomized experiments

Abstract: Propensity score methods are increasingly being used to estimate causal treatment effects in observational studies. In medical and epidemiological studies, outcomes are frequently time-to-event in nature. Propensity-score methods are often applied incorrectly when estimating the effect of treatment on time-to-event outcomes. This article describes how two different propensity score methods (matching and inverse probability of treatment weighting) can be used to estimate the measures of effect that are frequently reported in randomized controlled trials: (i) marginal survival curves, which describe survival in the population if all subjects were treated or if all subjects were untreated; and (ii) marginal hazard ratios. The use of these propensity score methods allows one to replicate the measures of effect that are commonly reported in randomized controlled trials with time-to-event outcomes: both absolute and relative reductions in the probability of an event occurring can be determined. We also provide guidance on variable selection for the propensity score model, highlight methods for assessing the balance of baseline covariates between treated and untreated subjects, and describe the implementation of a sensitivity analysis to assess the effect of unmeasured confounding variables on the estimated treatment effect when outcomes are time-to-event in nature. The methods in the paper are illustrated by estimating the effect of discharge statin prescribing on the risk of death in a sample of patients hospitalized with acute myocardial infarction. In this tutorial article, we describe and illustrate all the steps necessary to conduct a comprehensive analysis of the effect of treatment on time-to-event outcomes. © 2013 The authors. Statistics in Medicine published by John Wiley & Sons, Ltd.

Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline

Abstract: Purpose To provide evidence-based guidance on the optimum prevention and treatment approaches in the management of chemotherapy-induced peripheral neuropathies (CIPN) in adult cancer survivors. Methods A systematic literature search identified relevant, randomized controlled trials (RCTs) for the treatment of CIPN. Primary outcomes included incidence and severity of neuropathy as measured by neurophysiologic changes, patient-reported outcomes, and quality of life. Results A total of 48 RCTs met eligibility criteria and comprise the evidentiary basis for the recommendations. Trials tended to be small and heterogeneous, many with insufficient sample sizes to detect clinically important differences in outcomes. Primary outcomes varied across the trials, and in most cases, studies were not directly comparable because of different outcomes, measurements, and instruments used at different time points. The strength of the recommendations is based on the quality, amount, and consistency of the evidence and the ba...

Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes.

Abstract: Look AHEAD (Action for Health in Diabetes) was a randomized controlled trial that examined the impact of long-term participation in an intensive weight loss intervention on cardiovascular disease (CVD) morbidity and mortality in people with type 2 diabetes (T2D). The results from this trial suggest that intensive lifestyle interventions are effective in helping patients to achieve management of cardiovascular risk factors and reducing the need to initiate medication usage to manage these conditions, though the benefits in terms of the prevention of CVD morbidity and mortality beyond those achieved through aggressive medical management of hypertension and dyslipidemia is not clear. Additional benefits of participation in an intensive lifestyle intervention such as lowered chronic kidney disease risk, blood pressure, medication usage, improved sleep apnea, and partial remission of diabetes are discussed.

Guidelines of care for the management of atopic dermatitis: Section 2. Management and treatment of atopic dermatitis with topical therapies

Abstract: Atopic dermatitis is a common and chronic, pruritic inflammatory skin condition that can affect all age groups. This evidence-based guideline addresses important clinical questions that arise in its management. In this second of 4 sections, treatment of atopic dermatitis with nonpharmacologic interventions and pharmacologic topical therapies are reviewed. Where possible, suggestions on dosing and monitoring are given based on available evidence.

Vaccines for preventing influenza in healthy adults

Abstract: Background Different types of influenza vaccines are currently produced worldwide. Healthy adults are presently targeted mainly in North America. Objectives Identify, retrieve and assess all studies evaluating the effects of vaccines against influenza in healthy adults. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2010, issue 2), MEDLINE (January 1966 to June 2010) and EMBASE (1990 to June 2010). Selection criteria Randomised controlled trials (RCTs) or quasi-RCTs comparing influenza vaccines with placebo or no intervention in naturally-occurring influenza in healthy individuals aged 16 to 65 years. We also included comparative studies assessing serious and rare harms. Data collection and analysis Two review authors independently assessed trial quality and extracted data. Main results We included 50 reports. Forty (59 sub-studies) were clinical trials of over 70,000 people. Eight were comparative non-RCTs and assessed serious harms. Two were reports of harms which could not be introduced in the data analysis. In the relatively uncommon circumstance of vaccine matching the viral circulating strain and high circulation, 4% of unvaccinated people versus 1% of vaccinated people developed influenza symptoms (risk difference (RD) 3%, 95% confidence interval (CI) 2% to 5%). The corresponding figures for poor vaccine matching were 2% and 1% (RD 1, 95% CI 0% to 3%). These differences were not likely to be due to chance. Vaccination had a modest effect on time off work and had no effect on hospital admissions or complication rates. Inactivated vaccines caused local harms and an estimated 1.6 additional cases of Guillain-Barre Syndrome per million vaccinations. The harms evidence base is limited. Authors' conclusions Influenza vaccines have a modest effect in reducing influenza symptoms and working days lost. There is no evidence that they affect complications, such as pneumonia, or transmission. WARNING: This review includes 15 out of 36 trials funded by industry (four had no funding declaration). An earlier systematic review of 274 influenza vaccine studies published up to 2007 found industry funded studies were published in more prestigious journals and cited more than other studies independently from methodological quality and size. Studies funded from public sources were significantly less likely to report conclusions favorable to the vaccines. The review showed that reliable evidence on influenza vaccines is thin but there is evidence of widespread manipulation of conclusions and spurious notoriety of the studies. The content and conclusions of this review should be interpreted in light of this finding.

Randomized, Controlled Trial of Ultrasound-Assisted Catheter-Directed Thrombolysis for Acute Intermediate-Risk Pulmonary Embolism

Abstract: Background—In patients with acute pulmonary embolism, systemic thrombolysis improves right ventricular (RV) dilatation, is associated with major bleeding, and is withheld in many patients at risk. This multicenter randomized, controlled trial investigated whether ultrasound-assisted catheter-directed thrombolysis (USAT) is superior to anticoagulation alone in the reversal of RV dilatation in intermediate-risk patients. Methods and Results—Fifty-nine patients (63±14 years) with acute main or lower lobe pulmonary embolism and echocardiographic RV to left ventricular dimension (RV/LV) ratio ≥1.0 were randomized to receive unfractionated heparin and an USAT regimen of 10 to 20 mg recombinant tissue plasminogen activator over 15 hours (n=30; USAT group) or unfractionated heparin alone (n=29; heparin group). Primary outcome was the difference in the RV/LV ratio from baseline to 24 hours. Safety outcomes included death, major and minor bleeding, and recurrent venous thromboembolism at 90 days. In the USAT group,...

Aspirin in Patients Undergoing Noncardiac Surgery

Abstract: The primary outcome occurred in 351 of 4998 patients (7.0%) in the aspirin group and in 355 of 5012 patients (7.1%) in the placebo group (hazard ratio in the aspirin group, 0.99; 95% confidence interval [CI], 0.86 to 1.15; P = 0.92). Major bleeding was more common in the aspirin group than in the placebo group (230 patients [4.6%] vs. 188 patients [3.8%]; hazard ratio, 1.23; 95% CI, 1.01, to 1.49; P = 0.04). The primary and secondary outcome results were similar in the two aspirin strata. Conclusions Administration of aspirin before surgery and throughout the early postsurgical period had no significant effect on the rate of a composite of death or nonfatal myocardial infarction but increased the risk of major bleeding. (Funded by the Canadian Institutes of Health Research and others; POISE-2 ClinicalTrials.gov number, NCT01082874.)

Effect of a Perioperative, Cardiac Output–Guided Hemodynamic Therapy Algorithm on Outcomes Following Major Gastrointestinal Surgery: A Randomized Clinical Trial and Systematic Review

Abstract: Importance: small trials suggest that postoperative outcomes may be improved by the use of cardiac output monitoring to guide administration of intravenous fluid and inotropic drugs as part of a hemodynamic therapy algorithm. Objective: to evaluate the clinical effectiveness of a perioperative, cardiac output–guided hemodynamic therapy algorithm. Design, setting, and participants: OPTIMISE was a pragmatic, multicenter, randomized, observer-blinded trial of 734 high-risk patients aged 50 years or older undergoing major gastrointestinal surgery at 17 acute care hospitals in the United Kingdom. An updated systematic review and meta-analysis were also conducted including randomized trials published from 1966 to February 2014. Interventions: patients were randomly assigned to a cardiac output–guided hemodynamic therapy algorithm for intravenous fluid and inotrope (dopexamine) infusion during and 6 hours following surgery (n=368) or to usual care (n=366). Main outcomes and measures: the primary outcome was a composite of predefined 30-day moderate or major complications and mortality. Secondary outcomes were morbidity on day 7; infection, critical care–free days, and all-cause mortality at 30 days; all-cause mortality at 180 days; and length of hospital stay. Results: baseline patient characteristics, clinical care, and volumes of intravenous fluid were similar between groups. Care was nonadherent to the allocated treatment for less than 10% of patients in each group. The primary outcome occurred in 36.6% of intervention and 43.4% of usual care participants (relative risk [RR], 0.84 [95% CI, 0.71-1.01]; absolute risk reduction, 6.8% [95% CI, ?0.3% to 13.9%]; P?=?.07). There was no significant difference between groups for any secondary outcomes. Five intervention patients (1.4%) experienced cardiovascular serious adverse events within 24 hours compared with none in the usual care group. Findings of the meta-analysis of 38 trials, including data from this study, suggest that the intervention is associated with fewer complications (intervention, 488/1548 [31.5%] vs control, 614/1476 [41.6%]; RR, 0.77 [95% CI, 0.71-0.83]) and a nonsignificant reduction in hospital, 28-day, or 30-day mortality (intervention, 159/3215 deaths [4.9%] vs control, 206/3160 deaths [6.5%]; RR, 0.82 [95% CI, 0.67-1.01]) and mortality at longest follow-up (intervention, 267/3215 deaths [8.3%] vs control, 327/3160 deaths [10.3%]; RR, 0.86 [95% CI, 0.74-1.00]). Conclusions and relevance: in a randomized trial of high-risk patients undergoing major gastrointestinal surgery, use of a cardiac output–guided hemodynamic therapy algorithm compared with usual care did not reduce a composite outcome of complications and 30-day mortality. However, inclusion of these data in an updated meta-analysis indicates that the intervention was associated with a reduction in complication rates

Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials.

Abstract: with depression (SMD, −0.54; 95% CI, −1.08 to −0.01; I 2 = 68%) and depressive symptoms (SMD, −0.27; 95% CI, −0.53 to −0.01; I 2 = 68%). The heterogeneity of the studies was not explained by differences in inclusion of clinical depression vs depressive symptoms or use of NSAIDs vs cytokine inhibitors. Subanalyses emphasized the antidepressant properties of the selective cyclooxygenase 2 inhibitor celecoxib (SMD, −0.29; 95% CI, −0.49 to −0.08; I 2 =7 3%) on remission (OR, 7.89; 95% CI, 2.94 to 21.17; I 2 = 0%) and response (OR, 6.59; 95% CI, 2.24 to 19.42; I 2 = 0%). Among the 6 studies reporting on adverse effects, we found no evidence of an increased number of gastrointestinal or cardiovascular events after 6 weeks or infections after 12 weeks of anti-inflammatory treatment compared with placebo. All trials were associated with a high risk of bias owing to potentially compromised internal validity.

Evaluation and Treatment of Functional Constipation in Infants and Children: Evidence-Based Recommendations From ESPGHAN and NASPGHAN

Abstract: Background: Constipation is a pediatric problem commonly encountered by many health care workers in primary, secondary, and tertiary care. To assist medical care providers in the evaluation and management of children with functional constipation, the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition were charged with the task of developing a uniform document of evidence-based guidelines. Methods: Nine clinical questions addressing diagnostic, therapeutic, and prognostic topics were formulated. A systematic literature search was performed from inception to October 2011 using Embase, MEDLINE, the Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials, and PsychInfo databases. The approach of the Grading of Recommendations Assessment, Development and Evaluation was applied to evaluate outcomes. For therapeutic questions, quality of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation system. Grading the quality of evidence for the other questions was performed according to the classification system of the Oxford Centre for Evidence-Based Medicine. During 3 consensus meetings, all recommendations were discussed and finalized. The group members voted on each recommendation, using the nominal voting technique. Expert opinion was used where no randomized controlled trials were available to support the recommendation. Results: This evidence-based guideline provides recommendations for the evaluation and treatment of children with functional constipation to standardize and improve their quality of care. In addition, 2 algorithms were developed, one for the infants <6 months of age and the other for older infants and children. Conclusions: This document is intended to be used in daily practice and as a basis for further clinical research. Large well-designed clinical trials are necessary with regard to diagnostic evaluation and treatment.

Enhanced Recovery Program in Colorectal Surgery: A Meta-analysis of Randomized Controlled Trials

Abstract: Meta-analyses in the literature show that enhanced recovery after surgery (ERAS) is associated with lower morbidity rate and shorter hospital stay after elective colorectal surgery. However, a recent Cochrane review did not indicate the ERAS pathway as being the new standard of care due to the limited number of published trials, together with their poor quality. We conducted a meta-analysis of randomized controlled trials (RCTs) to assess the impact of the ERAS pathway on overall morbidity, single postoperative complications, length of hospital stay, and readmission rate following colorectal surgery. We searched BioMedCentral, PubMed, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL) for RCTs comparing the ERAS pathway to conventional perioperative care. No language restrictions were considered. A quality score was calculated for each trial included. A total of 2,376 patients in 16 RCTs were included in the analysis. The ERAS pathway was associated with a reduction of overall morbidity [relative ratio (RR) = 0.60, (95 % CI 0.46–0.76)], particularly with respect to nonsurgical complications [RR = 0.40, (95 % CI 0.27–0.61)]. The reduction of surgical complications was not significant [RR = 0.76, (95 % CI 0.54–1.08)]. The ERAS pathway shortened hospital stay (WMD = −2.28 days [95 % CI –3.09 to –1.47]), without increasing readmission rate. The ERAS pathway reduced overall morbidity rates and shortened the length of hospital stay, without increasing readmission rates. A significant reduction in nonsurgical complications was evident, while no significant reduction was found for surgical complications.

Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial.

Abstract: Summary Background Fingolimod has shown reductions in clinical and MRI disease activity in patients with relapsing-remitting multiple sclerosis. We further assessed the efficacy and safety of fingolimod in such patients. Methods We did this placebo-controlled, double-blind phase 3 study predominantly in the USA (101 of 117 centres). Using a computer-generated sequence, we randomly allocated eligible patients—those aged 18–55 years with relapsing-remitting multiple sclerosis—to receive fingolimod 0·5 mg, fingolimod 1·25 mg, or placebo orally once daily (1:1:1; stratified by study centre). On Nov 12, 2009, all patients assigned to fingolimod 1·25 mg were switched to the 0·5 mg dose in a blinded manner after a review of data from other phase 3 trials and recommendation from the data and safety monitoring board, but were analysed as being in the 1·25 mg group in the primary outcome analysis. Our primary endpoint was annualised relapse rate at month 24, analysed by intention to treat. Secondary endpoints included percentage brain volume change (PBVC) from baseline and time-to-disability-progression confirmed at 3 months. This trial is registered with ClinicalTrilals.gov, number NCT00355134. Findings Between June 30, 2006, and March 4, 2009, we enrolled and randomly allocated 1083 patients: 370 to fingolimod 1·25 mg, 358 to fingolimod 0·5 mg, and 355 to placebo. Mean annualised relapse rate was 0·40 (95% CI 0·34–0·48) in patients given placebo and 0·21 (0·17–0·25) in patients given fingolimod 0·5 mg: rate ratio 0·52 (95% CI 0·40–0·66; p vs placebo; 95% CI 0·61–1·12; p=0·227). Fingolimod 0·5 mg caused more of the following adverse events versus placebo: lymphopenia (27 [8%] patients vs 0 patients), increased alanine aminotransferase (29 [8%] vs six [2%]), herpes zoster infection (nine [3%] vs three [1%]), hypertension (32 [9%] vs 11 [3%]), first-dose bradycardia (five [1%] vs one [ vs seven [2%]). 53 (15%) of 358 patients given fingolimod 0·5 mg and 45 (13%) of 355 patients given placebo had serious adverse events over 24 months, which included basal-cell carcinoma (ten [3%] patients vs two [1%] patients), macular oedema (three [1%] vs two [1%]), infections (11 [3%] vs four [1%]), and neoplasms (13 [4%] vs eight [2%]). Interpretation Our findings expand knowledge of the safety profile of fingolimod and strengthen evidence for its beneficial effects on relapse rates in patients with relapsing-remitting multiple sclerosis. We saw no effect of fingolimod on disability progression. Our findings substantiate the beneficial profile of fingolimod as a disease-modifying agent in the management of patients with relapsing-remitting multiple sclerosis. Funding Novartis Pharma AG.

Adjuvant Endocrine Therapy for Women With Hormone Receptor–Positive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Focused Update

Abstract: Purpose To update the ASCO clinical practice guideline on adjuvant endocrine therapy on the basis of emerging data on the optimal duration of treatment, particularly adjuvant tamoxifen. Methods ASCO convened the Update Committee and conducted a systematic review of randomized clinical trials from January 2009 to June 2013 and analyzed three historical trials. Guideline recommendations were based on the Update Committee’s review of the evidence. Outcomes of interest included survival, disease recurrence, and adverse events. Results This guideline update reflects emerging data on duration of tamoxifen treatment. There have been five studies of tamoxifen treatment beyond 5 years of therapy. The two largest studies with longest reported follow-up show a breast cancer survival advantage with 10-year durations of tamoxifen use. In addition to modest gains in survival, extended therapy with tamoxifen for 10 years compared with 5 years was associated with lower risks of breast cancer recurrence and contralateral breast cancer.

Computerized cognitive training in cognitively healthy older adults: a systematic review and meta-analysis of effect modifiers.

Abstract: Background New effective interventions to attenuate age-related cognitive decline are a global priority. Computerized cognitive training (CCT) is believed to be safe and can be inexpensive, but neither its efficacy in enhancing cognitive performance in healthy older adults nor the impact of design factors on such efficacy has been systematically analyzed. Our aim therefore was to quantitatively assess whether CCT programs can enhance cognition in healthy older adults, discriminate responsive from nonresponsive cognitive domains, and identify the most salient design factors. Methods and Findings We systematically searched Medline, Embase, and PsycINFO for relevant studies from the databases' inception to 9 July 2014. Eligible studies were randomized controlled trials investigating the effects of ≥4 h of CCT on performance in neuropsychological tests in older adults without dementia or other cognitive impairment. Fifty-two studies encompassing 4,885 participants were eligible. Intervention designs varied considerably, but after removal of one outlier, heterogeneity across studies was small (I2 = 29.92%). There was no systematic evidence of publication bias. The overall effect size (Hedges' g, random effects model) for CCT versus control was small and statistically significant, g = 0.22 (95% CI 0.15 to 0.29). Small to moderate effect sizes were found for nonverbal memory, g = 0.24 (95% CI 0.09 to 0.38); verbal memory, g = 0.08 (95% CI 0.01 to 0.15); working memory (WM), g = 0.22 (95% CI 0.09 to 0.35); processing speed, g = 0.31 (95% CI 0.11 to 0.50); and visuospatial skills, g = 0.30 (95% CI 0.07 to 0.54). No significant effects were found for executive functions and attention. Moderator analyses revealed that home-based administration was ineffective compared to group-based training, and that more than three training sessions per week was ineffective versus three or fewer. There was no evidence for the effectiveness of WM training, and only weak evidence for sessions less than 30 min. These results are limited to healthy older adults, and do not address the durability of training effects. Conclusions CCT is modestly effective at improving cognitive performance in healthy older adults, but efficacy varies across cognitive domains and is largely determined by design choices. Unsupervised at-home training and training more than three times per week are specifically ineffective. Further research is required to enhance efficacy of the intervention. Please see later in the article for the Editors' Summary

Preventing 30-day hospital readmissions: a systematic review and meta-analysis of randomized trials.

Abstract: Importance Reducing early ( Objective To synthesize the evidence of the efficacy of interventions to reduce early hospital readmissions and identify intervention features—including their impact on treatment burden and on patients’ capacity to enact postdischarge self-care—that might explain their varying effects. Data Sources We searched PubMed, Ovid MEDLINE, Ovid EMBASE, EBSCO CINAHL, and Scopus (1990 until April 1, 2013), contacted experts, and reviewed bibliographies. Study Selection Randomized trials that assessed the effect of interventions on all-cause or unplanned readmissions within 30 days of discharge in adult patients hospitalized for a medical or surgical cause for more than 24 hours and discharged to home. Data Extraction and Synthesis Reviewer pairs extracted trial characteristics and used an activity-based coding strategy to characterize the interventions; fidelity was confirmed with authors. Blinded to trial outcomes, reviewers noted the extent to which interventions placed additional work on patients after discharge or supported their capacity for self-care in accordance with the cumulative complexity model. Main Outcomes and Measures Relative risk of all-cause or unplanned readmission with or without out-of-hospital deaths at 30 days postdischarge. Results In 42 trials, the tested interventions prevented early readmissions (pooled random-effects relative risk, 0.82 [95% CI, 0.73-0.91]; P I 2 = 31%), a finding that was consistent across patient subgroups. Trials published before 2002 reported interventions that were 1.6 times more effective than those tested later (interaction P = .01). In exploratory subgroup analyses, interventions with many components (interaction P = .001), involving more individuals in care delivery (interaction P = .05), and supporting patient capacity for self-care (interaction P = .04) were 1.4, 1.3, and 1.3 times more effective than other interventions, respectively. A post hoc regression model showed incremental value in providing comprehensive, postdischarge support to patients and caregivers. Conclusions and Relevance Tested interventions are effective at reducing readmissions, but more effective interventions are complex and support patient capacity for self-care. Interventions tested more recently are less effective.