Showing papers on "Randomized controlled trial published in 2011"

Standardized Bleeding Definitions for Cardiovascular Clinical Trials A Consensus Report From the Bleeding Academic Research Consortium

Abstract: Advances in antithrombotic therapy, along with an early invasive strategy, have reduced the incidence of recurrent ischemic events and death in patients with acute coronary syndromes (ACS; unstable angina, non–ST-segment–elevation myocardial infarction [MI], and ST-segment–elevation MI).1,–,4 However, the combination of multiple pharmacotherapies, including aspirin, platelet P2Y12 inhibitors, heparin plus glycoprotein IIb/IIIa inhibitors, direct thrombin inhibitors, and the increasing use of invasive procedures, has also been associated with an increased risk of bleeding. Editorial see p 2664 Bleeding complications have been associated with an increased risk of subsequent adverse outcomes, including MI, stroke, stent thrombosis, and death, in patients with ACS and in those undergoing percutaneous coronary intervention (PCI),5,–,10 as well as in the long-term antithrombotic setting.11,12 Thus, balancing the anti-ischemic benefits against the bleeding risk of antithrombotic agents and interventions is of paramount importance in assessing new therapies and in managing patients. Prior randomized trials comparing antithrombotic agents suggest that a reduction in bleeding events is associated with improved survival.13,14 Because prevention of major bleeding may represent an important step in improving outcomes by balancing safety and efficacy in the contemporary treatment of ACS, bleeding events have been systematically identified as a crucial end point for the assessment of the safety of drugs during the course of randomized clinical trials, and are an important aspect of the evaluation of new devices and interventional therapies.15 Unlike ischemic clinical events (eg, cardiac death, MI, stent thrombosis), for which there is now general consensus on end-point definitions,16,17 there is substantial heterogeneity among the many bleeding definitions currently in use. Lack of standardization makes it difficult to optimally organize key clinical trial processes such as adjudication, and even more difficult to interpret relative …

Intention-to-treat concept: A review.

Abstract: Randomized controlled trials often suffer from two major complications, ie, noncompliance and missing outcomes One potential solution to this problem is a statistical concept called intention-to-treat (ITT) analysis ITT analysis includes every subject who is randomized according to randomized treatment assignment It ignores noncompliance, protocol deviations, withdrawal, and anything that happens after randomization ITT analysis maintains prognostic balance generated from the original random treatment allocation In ITT analysis, estimate of treatment effect is generally conservative A better application of the ITT approach is possible if complete outcome data are available for all randomized subjects Per-protocol population is defined as a subset of the ITT population who completed the study without any major protocol violations

Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial.

Abstract: Context Screening for ovarian cancer with cancer antigen 125 (CA-125) and transvaginal ultrasound has an unknown effect on mortality. Objective To evaluate the effect of screening for ovarian cancer on mortality in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Design, Setting, and Participants Randomized controlled trial of 78 216 women aged 55 to 74 years assigned to undergo either annual screening (n = 39 105) or usual care (n = 39 111) at 10 screening centers across the United States between November 1993 and July 2001. Intervention The intervention group was offered annual screening with CA-125 for 6 years and transvaginal ultrasound for 4 years. Participants and their health care practitioners received the screening test results and managed evaluation of abnormal results. The usual care group was not offered annual screening with CA-125 for 6 years or transvaginal ultrasound but received their usual medical care. Participants were followed up for a maximum of 13 years (median [range], 12.4 years [10.9-13.0 years]) for cancer diagnoses and death until February 28, 2010. Main Outcome Measures Mortality from ovarian cancer, including primary peritoneal and fallopian tube cancers. Secondary outcomes included ovarian cancer incidence and complications associated with screening examinations and diagnostic procedures. Results Ovarian cancer was diagnosed in 212 women (5.7 per 10 000 person-years) in the intervention group and 176 (4.7 per 10 000 person-years) in the usual care group (rate ratio [RR], 1.21; 95% confidence interval [CI], 0.99-1.48). There were 118 deaths caused by ovarian cancer (3.1 per 10 000 person-years) in the intervention group and 100 deaths (2.6 per 10 000 person-years) in the usual care group (mortality RR, 1.18; 95% CI, 0.82-1.71). Of 3285 women with false-positive results, 1080 underwent surgical follow-up; of whom, 163 women experienced at least 1 serious complication (15%). There were 2924 deaths due to other causes (excluding ovarian, colorectal, and lung cancer) (76.6 per 10 000 person-years) in the intervention group and 2914 deaths (76.2 per 10 000 person-years) in the usual care group (RR, 1.01; 95% CI, 0.96-1.06). Conclusions Among women in the general US population, simultaneous screening with CA-125 and transvaginal ultrasound compared with usual care did not reduce ovarian cancer mortality. Diagnostic evaluation following a false-positive screening test result was associated with complications. Trial Registration clinicaltrials.gov Identifier: NCT00002540

The national lung screening trial: Overview and study design

Abstract: The National Lung Screening Trial (NLST) is a randomized multicenter study comparing low-dose helical computed tomography (CT) with chest radiography in the screening of older current and former heavy smokers for early detection of lung cancer, which is the leading cause of cancer-related death in the United States Five-year survival rates approach 70% with surgical resection of stage IA disease; however, more than 75% of individuals have incurable locally advanced or metastatic disease, the latter having a 5-year survival of less than 5% It is plausible that treatment should be more effective and the likelihood of death decreased if asymptomatic lung cancer is detected through screening early enough in its preclinical phase For these reasons, there is intense interest and intuitive appeal in lung cancer screening with low-dose CT The use of survival as the determinant of screening effectiveness is, however, confounded by the well-described biases of lead time, length, and overdiagnosis Despite previous attempts, no test has been shown to reduce lung cancer mortality, an endpoint that circumvents screening biases and provides a definitive measure of benefit when assessed in a randomized controlled trial that enables comparison of mortality rates between screened individuals and a control group that does not undergo the screening intervention of interest The NLST is such a trial The rationale for and design of the NLST are presented

Retraining Automatic Action Tendencies Changes Alcoholic Patients’ Approach Bias for Alcohol and Improves Treatment Outcome

Abstract: This study tested the effects of a new cognitive-bias modification (CBM) intervention that targeted an approach bias for alcohol in 214 alcoholic inpatients. Patients were assigned to one of two experimental conditions, in which they were explicitly or implicitly trained to make avoidance movements (pushing a joystick) in response to alcohol pictures, or to one of two control conditions, in which they received no training or sham training. Four brief sessions of experimental CBM preceded regular inpatient treatment. In the experimental conditions only, patients’ approach bias changed into an avoidance bias for alcohol. This effect generalized to untrained pictures in the task used in the CBM and to an Implicit Association Test, in which alcohol and soft-drink words were categorized with approach and avoidance words. Patients in the experimental conditions showed better treatment outcomes a year later. These findings indicate that a short intervention can change alcoholics’ automatic approach bias for alcohol and may improve treatment outcome.

Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial

Abstract: Summary Background Hemiplegia and hemiparesis are the most common deficits caused by stroke. A few small clinical trials suggest that fluoxetine enhances motor recovery but its clinical efficacy is unknown. We therefore aimed to investigate whether fluoxetine would enhance motor recovery if given soon after an ischaemic stroke to patients who have motor deficits. Methods In this double-blind, placebo-controlled trial, patients from nine stroke centres in France who had ischaemic stroke and hemiplegia or hemiparesis, had Fugl-Meyer motor scale (FMMS) scores of 55 or less, and were aged between 18 years and 85 years were eligible for inclusion. Patients were randomly assigned, using a computer random-number generator, in a 1:1 ratio to fluoxetine (20 mg once per day, orally) or placebo for 3 months starting 5–10 days after the onset of stroke. All patients had physiotherapy. The primary outcome measure was the change on the FMMS between day 0 and day 90 after the start of the study drug. Participants, carers, and physicians assessing the outcome were masked to group assignment. Analysis was of all patients for whom data were available (full analysis set). This trial is registered with ClinicalTrials.gov, number NCT00657163. Findings 118 patients were randomly assigned to fluoxetine (n=59) or placebo (n=59), and 113 were included in the analysis (57 in the fluoxetine group and 56 in the placebo group). Two patients died before day 90 and three withdrew from the study. FMMS improvement at day 90 was significantly greater in the fluoxetine group (adjusted mean 34·0 points [95% CI 29·7–38·4]) than in the placebo group (24·3 points [19·9–28·7]; p=0·003). The main adverse events in the fluoxetine and placebo groups were hyponatraemia (two [4%] vs two [4%]), transient digestive disorders including nausea, diarrhoea, and abdominal pain (14 [25%] vs six [11%]), hepatic enzyme disorders (five [9%] vs ten [18%]), psychiatric disorders (three [5%] vs four [7%]), insomnia (19 [33%] vs 20 [36%]), and partial seizure (one [ vs 0). Interpretation In patients with ischaemic stroke and moderate to severe motor deficit, the early prescription of fluoxetine with physiotherapy enhanced motor recovery after 3 months. Modulation of spontaneous brain plasticity by drugs is a promising pathway for treatment of patients with ischaemic stroke and moderate to severe motor deficit. Funding Public French National Programme for Clinical Research.

A Systematic Review and Meta-Analysis on the Use of Preemptive Hemodynamic Intervention to Improve Postoperative Outcomes in Moderate and High-Risk Surgical Patients

Abstract: BACKGROUND: Complications from major surgery are undesirable, common, and potentially avoidable. The long-term consequences of short-term surgical complications have recently been recognized to have a profound influence on longevity and quality of life in survivors. In the past 30 years, there have been a number of studies conducted attempting to reduce surgical mortality and morbidity by deliberately and preemptively manipulating perioperative hemodynamics. Early studies had a high control-group mortality rate and were criticized for this as being unrepresentative of current practice and raised opposition to its implementation as routine care. We performed this review to update this body of literature and to examine the effect of changes in current practice and quality of care to see whether the conclusions from previous quantitative analyses of this field remain valid. METHODS: Randomized clinical trials evaluating the use of preemptive hemodynamic intervention to improve surgical outcome were identified using multiple methods. Electronic databases (MEDLINE, EMBASE, and the Cochrane Controlled Clinical Trials register) were screened for potential trials, reference lists of identified trials were examined, and additional sources were sought from experts and industry representatives. Identified studies that fulfilled the entry criteria were examined in full and subjected to quantifiable analysis, subgroup analysis, and sensitivity analysis where possible. RESULTS: There were 29 studies identified, 23 of which reported surgical complications. In total, the 29 trials involved 4805 patients with an overall mortality of 7.6%. The use of preemptive hemodynamic intervention significantly reduced mortality (pooled odds ratio [95% confidence interval] of 0.48 [0.33-0.78]; P = 0.0002) and surgical complications (odds ratio 0.43 [0.34-0.53]; P < 0.0001). Subgroup analysis showed significant reductions in mortality for studies using a pulmonary artery catheter, supranormal resuscitation targets, studies using cardiac index or oxygen delivery as goals, and the use of fluids and inotropes as opposed to fluids alone. By contrast, there was a significant reduction in morbidity for each of the 4 subgroups analyzed. CONCLUSION: The use of a preemptive strategy of hemodynamic monitoring and coupled therapy reduces surgical mortality and morbidity.

Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial

Abstract: Objective The aim of this study was to assess the efficacy and safety of adalimumab (ADA), a recombinant human monoclonal antibody against tumour necrosis factor a (TNF), for the induction of clinical remission in anti-TNF nao¨ve patients with moderately to severely active ulcerative colitis. Methods This 8-week, multicentre, randomised, doubleblind, placebo-controlled study (NCT00385736), conducted at 94 centres in North America and Europe, enrolled ambulatory adult patients with Mayo score of $6 points and endoscopic subscore of $2 points despite treatment with corticosteroids and/or immunosuppressants. Under the original study protocol, 186 patients were randomised (1:1) to subcutaneous treatment with ADA160/80 (160 mg at week 0, 80 mg at week 2, 40 mg at weeks 4 and 6) or placebo. Subsequently, at the request of European regulatory authorities, the protocol was amended to include a second induction group (ADA80/40: 80 mg at week 0, 40 mg at weeks 2, 4 and 6). The primary efficacy endpoint was clinical remission (Mayo score #2 with no individual subscore >1) at week 8, assessed in 390 patients randomised (1:1:1) to ADA160/80, ADA80/40, or placebo. Safety was assessed in all enrolled patients. Patients, study site personnel, investigators, and the sponsor were blinded to treatment assignment. Results At week 8, 18.5% of patients in the ADA160/80 group (p¼0.031 vs placebo) and 10.0% in the ADA80/40 group (p¼0.833 vs placebo) were in remission, compared with 9.2% in the placebo group. Serious adverse events occurred in 7.6%, 3.8% and 4.0% of patients in the placebo, ADA80/40, and ADA160/80 groups, respectively. There were two malignancies in the placebo group, none in the ADA groups. There were no cases of tuberculosis and no deaths. Conclusions ADA160/80 was safe and effective for induction of clinical remission in patients with moderately to severely active ulcerative colitis failing treatment with corticosteroids and/or immunosuppressants. Clinical trial NCT00385736.

Reduction in the Incidence of Type 2-Diabetes with the Mediterranean Diet: Results of the PREDIMED-Reus Nutrition Intervention Randomized Trial

Abstract: Objective - To test the effects of two Mediterranean-diet interventions versus a low-fat diet on incidence of diabetes. Research Design and Methods - Three-arm randomized trial in 418 nondiabetic subjects aged 55-80 years recruited in one center (PREDIMED-Reus, North-Eastern Spain) of the PREDIMED study, a large nutrition-intervention trial for primary cardiovascular prevention in persons at high cardiovascular risk. Participants were randomized to education on a low-fat diet (control group) or one of two Mediterranean diets, supplemented with either free virgin olive oil (1 liter/week) or nuts (30 g/day). Diets were ad libitum and no advice on physical activity was given. The main outcome was diabetes incidence diagnosed by the 2009 American Diabetes Association criteria. Results - After a median follow-up of 4.0 years, diabetes incidence was 10.1% (95% confidence interval [CI], 5.1-15.1), 11.0% (5.9-16.1), and 17.9% (11.4-24.4) in the Mediterranean-diet with olive oil group, the Mediterranean-diet with nuts group, and the control group, respectively. Multivariable-adjusted hazard ratios of diabetes were 0.49 (0.25-0.97) and 0.48 (0.24-0.96) in the Mediterranean-diet groups supplemented with olive oil and nuts, respectively, compared to the control group. When pooling the two Mediterranean-diet groups compared to the control group, diabetes incidence was reduced by 52% (27-86). In all study arms, increased adherence to the Mediterranean-diet was inversely associated with diabetes incidence. Diabetes risk reduction occurred in the absence of significant changes in body weight or physical activity. Conclusion - Mediterranean diets without calorie restriction appear to be effective in the prevention of diabetes in subjects at high cardiovascular risk. Trial Registration: [www.controlled-trials.com][1] Identifier: ISRCTN35739639 [1]: http://www.controlled-trials.com

International Phase III Trial Assessing Neoadjuvant Cisplatin, Methotrexate, and Vinblastine Chemotherapy for Muscle-Invasive Bladder Cancer: Long-Term Results of the BA06 30894 Trial

Abstract: Purpose This article presents the long-term results of the international multicenter randomized trial that investigated the use of neoadjuvant cisplatin, methotrexate, and vinblastine (CMV) chemotherapy in patients with muscle-invasive urothelial cancer of the bladder treated by cystectomy and/or radiotherapy. Nine hundred seventy-six patients were recruited between 1989 and 1995, and median follow-up is now 8.0 years. Patients and Methods This was a randomized phase III trial of either no neoadjuvant chemotherapy or three cycles of CMV. Results The previously reported possible survival advantage of CMV is now statistically significant at the 5% level. Results show a statistically significant 16% reduction in the risk of death (hazard ratio, 0.84; 95% CI, 0.72 to 0.99; P = .037, corresponding to an increase in 10-year survival from 30% to 36%) after CMV. Conclusion We conclude that CMV chemotherapy improves outcome as first-line adjunctive treatment for invasive bladder cancer. Two large randomized trials...

Comparative Effectiveness of Weight-Loss Interventions in Clinical Practice

Abstract: BackgroundObesity and its cardiovascular complications are extremely common medical problems, but evidence on how to accomplish weight loss in clinical practice is sparse. MethodsWe conducted a randomized, controlled trial to examine the effects of two behavioral weight-loss interventions in 415 obese patients with at least one cardiovascular risk factor. Participants were recruited from six primary care practices; 63.6% were women, 41.0% were black, and the mean age was 54.0 years. One intervention provided patients with weight-loss support remotely — through the telephone, a study-specific Web site, and e-mail. The other intervention provided in-person support during group and individual sessions, along with the three remote means of support. There was also a control group in which weight loss was self-directed. Outcomes were compared between each intervention group and the control group and between the two intervention groups. For both interventions, primary care providers reinforced participation at r...

Mindfulness-Based Stress Reduction and Mindfulness-Based Cognitive Therapy – a systematic review of randomized controlled trials

Abstract: Fjorback LO, Arendt M, Ornbol E, Fink P, Walach H. Mindfulness-Based Stress Reduction and Mindfulness-Based Cognitive Therapy – a systematic review of randomized controlled trials. Objective: To systematically review the evidence for MBSR and MBCT. Method: Systematic searches of Medline, PsycInfo and Embase were performed in October 2010. MBSR, MBCT and Mindfulness Meditation were key words. Only randomized controlled trials (RCT) using the standard MBSR/MBCT programme with a minimum of 33 participants were included. Results: The search produced 72 articles, of which 21 were included. MBSR improved mental health in 11 studies compared to wait list control or treatment as usual (TAU) and was as efficacious as active control group in three studies. MBCT reduced the risk of depressive relapse in two studies compared to TAU and was equally efficacious to TAU or an active control group in two studies. Overall, studies showed medium effect sizes. Among other limitations are lack of active control group and long-term follow-up in several studies. Conclusion: Evidence supports that MBSR improves mental health and MBCT prevents depressive relapse. Future RCTs should apply optimal design including active treatment for comparison, properly trained instructors and at least one-year follow-up. Future research should primarily tackle the question of whether mindfulness itself is a decisive ingredient by controlling against other active control conditions or true treatments.

A Systematic Review of Early Intensive Intervention for Autism Spectrum Disorders

Abstract: CONTEXT: Early intensive behavioral and developmental interventions for young children with autism spectrum disorders (ASDs) may enhance developmental outcomes. OBJECTIVE: To systematically review evidence regarding such interventions for children aged 12 and younger with ASDs. METHODS: We searched Medline, PsycINFO, and ERIC (Education Resources Information Center) from 2000 to May 2010. Two reviewers independently assessed studies against predetermined inclusion/exclusion criteria. Two reviewers independently extracted data regarding participant and intervention characteristics, assessment techniques, and outcomes and assigned overall quality and strength-of-evidence ratings using predetermined criteria. RESULTS: Thirty-four unique studies met inclusion criteria. Seventeen studies were case series; 2 were randomized controlled trials. We rated 1 study as good quality, 10 as fair quality, and 23 as poor quality. The strength of the evidence overall ranged from insufficient to low. Studies of University of California Los Angeles/Lovaas–based interventions and variants reported clinically significant gains in language and cognitive skills in some children, as did 1 randomized controlled trial of an early intensive developmental intervention approach (the Early Start Denver Model). Specific parent-training approaches yielded gains in short-term language function and some challenging behaviors. Data suggest that subgroups of children displayed more prominent gains across studies, but participant characteristics associated with greater gains are not well understood. CONCLUSIONS: Studies of Lovaas-based approaches and early intensive behavioral intervention variants and the Early Start Denver Model resulted in some improvements in cognitive performance, language skills, and adaptive behavior skills in some young children with ASDs, although the literature is limited by methodologic concerns.

Strategy for intention to treat analysis in randomised trials with missing outcome data

Abstract: Loss to follow-up is often hard to avoid in randomised trials. This article suggests a framework for intention to treat analysis that depends on making plausible assumptions about the missing data and including all participants in sensitivity analyses

A systematic review on the effectiveness of physical and rehabilitation interventions for chronic non-specific low back pain

Abstract: Low back pain (LBP) is a common and disabling disorder in western society. The management of LBP comprises a range of different intervention strategies including surgery, drug therapy, and non-medical interventions. The objective of the present study is to determine the effectiveness of physical and rehabilitation interventions (i.e. exercise therapy, back school, transcutaneous electrical nerve stimulation (TENS), low level laser therapy, education, massage, behavioural treatment, traction, multidisciplinary treatment, lumbar supports, and heat/cold therapy) for chronic LBP. The primary search was conducted in MEDLINE, EMBASE, CINAHL, CENTRAL, and PEDro up to 22 December 2008. Existing Cochrane reviews for the individual interventions were screened for studies fulfilling the inclusion criteria. The search strategy outlined by the Cochrane Back Review Groups (CBRG) was followed. The following were included for selection criteria: (1) randomized controlled trials, (2) adult (≥18 years) population with chronic (≥12 weeks) non-specific LBP, and (3) evaluation of at least one of the main clinically relevant outcome measures (pain, functional status, perceived recovery, or return to work). Two reviewers independently selected studies and extracted data on study characteristics, risk of bias, and outcomes at short, intermediate, and long-term follow-up. The GRADE approach was used to determine the quality of evidence. In total 83 randomized controlled trials met the inclusion criteria: exercise therapy (n = 37), back school (n = 5), TENS (n = 6), low level laser therapy (n = 3), behavioural treatment (n = 21), patient education (n = 1), traction (n = 1), and multidisciplinary treatment (n = 6). Compared to usual care, exercise therapy improved post-treatment pain intensity and disability, and long-term function. Behavioural treatment was found to be effective in reducing pain intensity at short-term follow-up compared to no treatment/waiting list controls. Finally, multidisciplinary treatment was found to reduce pain intensity and disability at short-term follow-up compared to no treatment/waiting list controls. Overall, the level of evidence was low. Evidence from randomized controlled trials demonstrates that there is low quality evidence for the effectiveness of exercise therapy compared to usual care, there is low evidence for the effectiveness of behavioural therapy compared to no treatment and there is moderate evidence for the effectiveness of a multidisciplinary treatment compared to no treatment and other active treatments at reducing pain at short-term in the treatment of chronic low back pain. Based on the heterogeneity of the populations, interventions, and comparison groups, we conclude that there are insufficient data to draw firm conclusion on the clinical effect of back schools, low-level laser therapy, patient education, massage, traction, superficial heat/cold, and lumbar supports for chronic LBP.

Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial

Abstract: Summary Background Treatment with adjuvant trastuzumab for 1 year improves disease-free survival and overall survival in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. We aimed to assess disease-free survival and overall survival after a median follow-up of 4 years for patients enrolled on the Herceptin Adjuvant (HERA) trial. Methods The HERA trial is an international, multicentre, randomised, open-label, phase 3 trial comparing treatment with trastuzumab for 1 and 2 years with observation after standard neoadjuvant, adjuvant chemotherapy, or both in patients with HER2-positive early breast cancer. The primary endpoint was disease-free survival. After a positive first interim analysis at a median follow-up of 1 year for the comparison of treatment with trastuzumab for 1 year with observation, event-free patients in the observation group were allowed to cross over to receive trastuzumab. We report trial outcomes for the 1-year trastuzumab and observation groups at a median follow-up of 48·4 months (IQR 42·0–56·5) and assess the effect of the extensive crossover to trastuzumab. Our analysis was by intention-to-treat. The HERA trial is registered with the European Clinical Trials Database, number 2005-002385-11. Findings The HERA trial population comprised 1698 patients randomly assigned to the observation group and 1703 to the 1-year trastuzumab group. Intention-to-treat analysis of disease-free survival showed a significant benefit in favour of patients in the 1-year trastuzumab group (4-year disease-free survival 78·6%) compared with the observation group (4-year disease-free survival 72·2%; hazard ratio [HR] 0·76; 95% CI 0·66–0·87; p vs 87·7%, respectively; HR 0·85; 95% CI 0·70–1·04; p=0·11). Overall, 885 patients (52%) of the 1698 patients in the observation group crossed over to receive trastuzumab, and began treatment at median 22·8 months (range 4·5–52·7) from randomisation. In a non-randomised comparison, patients in the selective-crossover cohort had fewer disease-free survival events than patients remaining in the observation group (adjusted HR 0·68; 95% CI 0·51–0·90; p=0·0077). Higher incidences of grade 3–4 and fatal adverse events were noted on 1-year trastuzumab than in the observation group. The most common grade 3 or 4 adverse events, each in less than 1% of patients, were congestive cardiac failure, hypertension, arthralgia, back pain, central-line infection, hot flush, headache, and diarrhoea. Interpretation Treatment with adjuvant trastuzumab for 1 year after chemotherapy is associated with significant clinical benefit at 4-year median follow-up. The substantial selective crossover of patients in the observation group to trastuzumab was associated with improved outcomes for this cohort. Funding F Hoffmann-La Roche, Michelangelo Foundation.

Extracranial-intracranial bypass surgery for stroke prevention in hemodynamic cerebral ischemia: the Carotid Occlusion Surgery Study randomized trial.

Abstract: Context Patients with symptomatic atherosclerotic internal carotid artery occlusion (AICAO) and hemodynamic cerebral ischemia are at high risk for subsequent stroke when treated medically. Objective To test the hypothesis that extracranial-intracranial (EC-IC) bypass surgery, added to best medical therapy, reduces subsequent ipsilateral ischemic stroke in patients with recently symptomatic AICAO and hemodynamic cerebral ischemia. Design Parallel-group, randomized, open-label, blinded-adjudication clinical treatment trial conducted from 2002 to 2010. Setting Forty-nine clinical centers and 18 positron emission tomography (PET) centers in the United States and Canada. The majority were academic medical centers. Participants Patients with arteriographically confirmed AICAO causing hemispheric symptoms within 120 days and hemodynamic cerebral ischemia identified by ipsilateral increased oxygen extraction fraction measured by PET. Of 195 patients who were randomized, 97 were randomized to receive surgery and 98 to no surgery. Follow-up for the primary end point until occurrence, 2 years, or termination of trial was 99% complete. No participant withdrew because of adverse events. Interventions Anastomosis of superficial temporal artery branch to a middle cerebral artery cortical branch for the surgical group. Antithrombotic therapy and risk factor intervention were recommended for all participants. Main Outcome Measure For all participants who were assigned to surgery and received surgery, the combination of (1) all stroke and death from surgery through 30 days after surgery and (2) ipsilateral ischemic stroke within 2 years of randomization. For the nonsurgical group and participants assigned to surgery who did not receive surgery, the combination of (1) all stroke and death from randomization to randomization plus 30 days and (2) ipsilateral ischemic stroke within 2 years of randomization. Results The trial was terminated early for futility. Two-year rates for the primary end point were 21.0% (95% CI, 12.8% to 29.2%; 20 events) for the surgical group and 22.7% (95% CI, 13.9% to 31.6%; 20 events) for the nonsurgical group (P = .78, Z test), a difference of 1.7% (95% CI, −10.4% to 13.8%). Thirty-day rates for ipsilateral ischemic stroke were 14.4% (14/97) in the surgical group and 2.0% (2/98) in the nonsurgical group, a difference of 12.4% (95% CI, 4.9% to 19.9%). Conclusion Among participants with recently symptomatic AICAO and hemodynamic cerebral ischemia, EC-IC bypass surgery plus medical therapy compared with medical therapy alone did not reduce the risk of recurrent ipsilateral ischemic stroke at 2 years. Trial Registration clinicaltrials.gov Identifier: NCT00029146

Once-Only Sigmoidoscopy in Colorectal Cancer Screening: Follow-up Findings of the Italian Randomized Controlled Trial—SCORE

Abstract: Background A single flexible sigmoidoscopy at around the age of 60 years has been proposed as an effective strategy for colorectal cancer (CRC) screening. Methods We conducted a randomized controlled trial to evaluate the effect of flexible sigmoidoscopy screening on CRC incidence and mortality. A questionnaire to assess the eligibility and interest in screening was mailed to 236,568 men and women, aged 55-64 years, who were randomly selected from six trial centers in Italy. Of the 56,532 respondents, interested and eligible subjects were randomly assigned to the intervention group (invitation for flexible sigmoidoscopy; n = 17,148) or the control group (no further contact; n = 17,144), between June 14, 1995, and May 10, 1999. Flexible sigmoidoscopy was performed on 9911 subjects. Intention-to-treat and per-protocol analyses were performed to compare the CRC incidence and mortality rates in the intervention and control groups. Per-protocol analysis was adjusted for noncompliance. Results A total of 34,272 subjects (17,136 in each group) were included in the follow-up analysis. The median follow-up period was 10.5 years for incidence and 11.4 years for mortality; 251 subjects were diagnosed with CRC in the intervention group and 306 in the control group. Overall incidence rates in the intervention and control groups were 144.11 and 176.43, respectively, per 100,000 person-years. CRC-related death was noted in 65 subjects in the intervention group and 83 subjects in the control group. Mortality rates in the intervention and control groups were 34.66 and 44.45, respectively, per 100,000 person-years. In the intention-to-treat analysis, the rate of CRC incidence was statistically significantly reduced in the intervention group by 18% (rate ratio [RR] = 0.82, 95% confidence interval [CI] = 0.69 to 0.96), and the mortality rate was non-statistically significantly reduced by 22% (RR = 0.78; 95% CI = 0.56 to 1.08) compared with the control group. In the per-protocol analysis, both CRC incidence and mortality rates were statistically significantly reduced among the screened subjects; CRC incidence was reduced by 31% (RR = 0.69; 95% CI = 0.56 to 0.86) and mortality was reduced by 38% (RR = 0.62; 95% CI = 0.40 to 0.96) compared with the control group. Conclusion A single flexible sigmoidoscopy screening between ages 55 and 64 years was associated with a substantial reduction of CRC incidence and mortality.

Screening by Chest Radiograph and Lung Cancer Mortality: The Prostate, Lung, Colorectal, and Ovarian (PLCO) Randomized Trial

Abstract: Context The effect on mortality of screening for lung cancer with modern chest radiographs is unknown Objective To evaluate the effect on mortality of screening for lung cancer using radiographs in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial Design, Setting, and Participants Randomized controlled trial that involved 154 901 participants aged 55 through 74 years, 77 445 of whom were assigned to annual screenings and 77 456 to usual care at 1 of 10 screening centers across the United States between November 1993 and July 2001 The data from a subset of eligible participants for the National Lung Screening Trial (NLST), which compared chest radiograph with spiral computed tomographic (CT) screening, were analyzed Intervention Participants in the intervention group were offered annual posteroanterior view chest radiograph for 4 years Diagnostic follow-up of positive screening results was determined by participants and their health care practitioners Participants in the usual care group were offered no interventions and received their usual medical care All diagnosed cancers, deaths, and causes of death were ascertained through the earlier of 13 years of follow-up or until December 31, 2009 Main Outcome Measures Mortality from lung cancer Secondary outcomes included lung cancer incidence, complications associated with diagnostic procedures, and all-cause mortality Results Screening adherence was 866% at baseline and 79% to 84% at years 1 through 3; the rate of screening use in the usual care group was 11% Cumulative lung cancer incidence rates through 13 years of follow-up were 201 per 10 000 person-years in the intervention group and 192 per 10 000 person-years in the usual care group (rate ratio [RR]; 105, 95% CI, 098-112) A total of 1213 lung cancer deaths were observed in the intervention group compared with 1230 in usual care group through 13 years (mortality RR, 099; 95% CI, 087-122) Stage and histology were similar between the 2 groups The RR of mortality for the subset of participants eligible for the NLST, over the same 6-year follow-up period, was 094 (95% CI, 081-110) Conclusion Annual screening with chest radiograph did not reduce lung cancer mortality compared with usual care Trial Registration clinicaltrialsgov Identifier: NCT00002540

Randomized double-blind placebo-controlled trial of bevacizumab therapy for radiation necrosis of the central nervous system

Abstract: Purpose: To conduct a controlled trial of bevacizumab for the treatment of symptomatic radiation necrosis of the brain. Methods and Materials: A total of 14 patients were entered into a placebo-controlled randomized double-blind study of bevacizumab for the treatment of central nervous system radiation necrosis. All patients were required to have radiographic or biopsy proof of central nervous system radiation necrosis and progressive neurologic symptoms or signs. Eligible patients had undergone irradiation for head-and-neck carcinoma, meningioma, or low- to mid-grade glioma. Patients were randomized to receive intravenous saline or bevacizumab at 3-week intervals. The magnetic resonance imaging findings 3 weeks after the second treatment and clinical signs and symptoms defined the response or progression. Results: The volumes of necrosis estimated on T2-weighted fluid-attenuated inversion recovery and T1-weighted gadolinium-enhanced magnetic resonance imaging scans demonstrated that although no patient receiving placebo responded (0 of 7), all bevacizumab-treated patients did so (5 of 5 randomized and 7 of 7 crossover) with decreases in T2-weighted fluid-attenuated inversion recovery and T1-weighted gadolinium-enhanced volumes and a decrease in endothelial transfer constant. All bevacizumab-treated patients - and none of the placebo-treated patients - showed improvement in neurologic symptoms or signs. At a median of 10 months after the last dose of bevacizumab in patients receiving all four study doses, only 2 patients had experienced a recurrence of magnetic resonance imaging changes consistent with progressive radiation necrosis; one patient received a single additional dose of bevacizumab and the other patient received two doses. Conclusion: The Class I evidence of bevacizumab efficacy from the present study in the treatment of central nervous system radiation necrosis justifies consideration of this treatment option for people with radiation necrosis secondary to the treatment of head-and-neck cancer and brain cancer. © 2011 Elsevier Inc.

Association between time to initiation of adjuvant chemotherapy and survival in colorectal cancer: a systematic review and meta-analysis.

Abstract: Context Adjuvant chemotherapy (AC) improves survival among patients with resected colorectal cancer. However, the optimal timing from surgery to initiation of AC is unknown. Objective To determine the relationship between time to AC and survival outcomes via a systematic review and meta-analysis. Data Sources MEDLINE (1975 through January 2011), EMBASE, the Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials were searched to identify studies that described the relationship between time to AC and survival. Study Selection Studies were only included if the relevant prognostic factors were adequately described and either comparative groups were balanced or results adjusted for these prognostic factors. Data Extraction Hazard ratios (HRs) for overall survival and disease-free survival from each study were converted to a regression coefficient (β) and standard error corresponding to a continuous representation per 4 weeks of time to AC. The adjusted β from individual studies were combined using a fixed-effects model. Inverse variance (1/SE 2 ) was used to weight individual studies. Publication bias was investigated using the trim and fill approach. Results We identified 10 eligible studies involving 15 410 patients (7 published articles, 3 abstracts). Nine of the studies were cohort or population based and 1 was a secondary analysis from a randomized trial of chemotherapy. Six studies reported time to AC as a binary variable and 4 as 3 or more categories. Meta-analysis demonstrated that a 4-week increase in time to AC was associated with a significant decrease in both overall survival (HR, 1.14; 95% confidence interval [CI], 1.10-1.17) and disease-free survival (HR, 1.14; 95% CI, 1.10-1.18). There was no significant heterogeneity among included studies. Results remained significant after adjustment for potential publication bias and when the analysis was repeated to exclude studies of largest weight. Conclusion In a meta-analysis of the available literature on time to AC, longer time to AC was associated with worse survival among patients with resected colorectal cancer.

Use of twice-daily exenatide in Basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial.

Abstract: This randomized trial tested whether twice-daily exenatide reduces hemoglobin A1c levels more than placebo in people with type 2 diabetes who are receiving insulin glargine. After 30 weeks, exenati...