Trastuzumab-containing regimens for metastatic breast cancer.

BACKGROUND: Patients with breast cancer are classified as having cells that over-express the human epidermal growth factor receptor 2 (known as HER2-positive) or not (HER2-negative). Typically, patients with HER2-positive disease have a worse prognosis. Trastuzumab is a selective treatment that targets the HER2 pathway. The available evidence supporting trastuzumab regimens mostly relies upon surrogate endpoints and, although the efficacy results seem to support its use, other uncertainties have been raised about its net benefit in relation to transient cardiac toxicity and a long-term increased risk of metastasis to the central nervous system. OBJECTIVES: To assess the evidence on the efficacy and safety of therapy with trastuzumab (overall) and in relation to the type of co-administered regimen and the line of treatment, i.e. first-line or beyond progression, in women with HER2-positive metastatic breast cancer. SEARCH METHODS: We searched the Cochrane Breast Cancer Group's (CBCG) Specialised Register and used the search strategy developed by the CBCG to search for randomised controlled trials (RCTs) in CENTRAL (2013, Issue 1), MEDLINE, EMBASE, BIOSIS, the WHO International Clinical Trials Registry Platform (ICTRP) search portal and ClinicalTrials.gov (up to 17 January 2013). SELECTION CRITERIA: RCTs comparing the efficacy and safety of trastuzumab alone or in combination with chemotherapy, hormonal therapy or targeted agents in women with HER2-positive metastatic breast cancer. DATA COLLECTION AND ANALYSIS: We collected data from published trials. We used hazard ratios (HRs) for time-to-event outcomes and risk ratio (RRs) for binary outcomes. Subgroup analyses included type of regimen (taxane-containing, anthracycline-containing, aromatase inhibitor-containing or other) and treatment line (first-line, beyond progression). MAIN RESULTS: The review found seven trials, involving 1497 patients, which met the criteria to be included. The trials were generally of moderate methodological quality; two studies have not published their results on overall survival so the presence of selective outcome reporting bias cannot be ruled out. None of the studies used blinding to treatment allocation, though this is unlikely to have biased the results for overall survival. Studies varied in terms of co-administered regimen and in terms of treatment line. In four studies, trastuzumab was administered with a chemotherapy, such as a taxane-containing, anthracycline-containing or capecitabine-containing regimen. Two studies considered postmenopausal women and administered trastuzumab with hormone-blocking medications, such as an aromatase inhibitor. One study administered trastuzumab in addition to lapatinib. Five studies out of seven included women treated with trastuzumab administered until progression as first-line treatment and two studies considered trastuzumab beyond progression. The combined HRs for overall survival and progression-free survival favoured the trastuzumab-containing regimens (HR 0.82, 95% confidence interval (CI) 0.71 to 0.94, P = 0.004; and HR 0.61, 95% CI 0.54 to 0.70, P < 0.00001, respectively; moderate-quality evidence). Trastuzumab increased the risk of congestive heart failure (RR 3.49, 90% CI 1.88 to 6.47, P = 0.0009; moderate-quality evidence) and left ventricular ejection fraction (LVEF) decline (RR 2.65, 90% CI 1.48 to 4.74, P = 0.006). For haematological toxicities, such as neutropenic fever and anaemia, there was no clear evidence that risks differed between groups, while trastuzumab seemed to raise the risk of neutropenia. The overall survival improvement was maintained when considering patients treated as first-line or patients receiving taxane-based regimens. The progression-free survival improvement was maintained when considering patients receiving taxane-based regimens, and patients treated as first-line or subsequent lines. Few data were collected on central nervous system progression. Similarly, few studies reported on quality of life and treatment-related deaths. AUTHORS' CONCLUSIONS: Trastuzumab improved overall survival and progression-free survival in HER2-positive women with metastatic breast cancer, but it also increased the risk of cardiac toxicities, such as congestive heart failure and LVEF decline. The available subgroup analyses are limited by the small number of studies. Studies that administered trastuzumab as first-line treatment, or along with a taxane-based regimen, improved mortality outcomes. The evidence to support the use of trastuzumab beyond progression is limited. The recruitment in three out of seven studies was stopped early and in three trials more than 50% of patients in the control groups were permitted to switch to the trastuzumab arms at progression, making it more difficult to understand the real net benefit of trastuzumab.Trastuzumab is generally used for women with HER2-positive early breast cancer in clinical practice, while women enrolled in most of the trials in the metastatic setting were naive to trastuzumab. The effectiveness of trastuzumab for women relapsing after adjuvant trastuzumab is therefore still an open issue, although it is likely that the majority are being offered it again.

Remote magnetic with open-irrigated catheter vs. manual navigation for ablation of atrial fibrillation: a systematic review and meta-analysis.

The aim of this study was to determine the efficacy and safety of remote magnetic navigation (RMN) with open-irrigated catheter vs. manual catheter navigation (MCN) in performing atrial fibrillation (AF) ablation. We searched in PubMed (1948-2013) and EMBASE (1974-2013) studies comparing RMN with MCN. Outcomes considered were AF recurrence (primary outcome), pulmonary vein isolation (PVI), procedural complications, and data on procedure's performance. Odds ratios (OR) and mean difference (MD) were extracted and pooled using a random-effect model. Confidence in the estimates of the obtained effects (quality of evidence) was assessed using the Grading of Recommendations Assessment, Development and Evaluation approach. We identified seven controlled trials, six non-randomized and one randomized, including a total of 941 patients. Studies were at high risk of bias. No difference was observed between RMN and MCN on AF recurrence [OR 1.18, 95% confidence interval (CI) 0.85 to 1.65, P = 0.32] or PVI (OR 0.41, 95% CI 0.11-1.47, P = 0.17). Remote magnetic navigation was associated with less peri-procedural complications (Peto OR 0.41, 95% CI 0.19-0.88, P = 0.02). Mean fluoroscopy time was reduced in RMN group (-22.22 min; 95% CI -42.48 to -1.96, P = 0.03), although the overall duration of the procedure was longer (60.91 min; 95% CI 31.17 to 90.65, P < 0.0001). In conclusion, RMN is not superior to MCN in achieving freedom from recurrent AF at mid-term follow-up or PVI. The procedure implies less peri-procedural complications, requires a shorter fluoroscopy time but a longer total procedural time. For the low quality of the available evidence, a proper designed randomized controlled trial could turn the direction and the effect of the dimensions explored.

Damage control surgery for abdominal trauma.

BACKGROUND: Trauma is one of the leading causes of death in any age group. The 'lethal triad' of acidosis, hypothermia, and coagulopathy has been recognized as a significant cause of death in patients with traumatic injuries. In order to prevent the lethal triad two factors are essential, early control of bleeding and prevention of further heat loss. In patients with major abdominal trauma, damage control surgery (DCS) avoids extensive procedures on unstable patients, stabilizes potentially fatal problems at initial operation, and applies staged surgery after successful initial resuscitation. It is not currently known whether DCS is superior to immediate surgery for patients with major abdominal trauma. OBJECTIVES: To assess the effects of damage control surgery compared to traditional immediate definitive surgical treatment for patients with major abdominal trauma. SEARCH METHODS: We searched the Cochrane Injuries Group Specialised Register, CENTRAL (The Cochrane Library 2012, Issue 12 of 12), MEDLINE, EMBASE, Web of Science: Science Citation Index & ISI Proceedings, Current Controlled Trials MetaRegister, Clinicaltrials.gov, Zetoc, and CINAHL for all published and unpublished randomised controlled trials. We did not restrict the searches by language, date, or publication status. The search was through December 2012. SELECTION CRITERIA: Randomised controlled trials of damage control surgery versus immediate traditional surgical repair were included in this review. We included patients with major abdominal trauma (Abbreviated Injury Scale > 3) who were undergoing surgery. Patient selection was crucial as patients with relatively simple abdominal injuries should not undergo unnecessary procedures. DATA COLLECTION AND ANALYSIS: Two authors independently evaluated the search results. MAIN RESULTS: A total of 2551 studies were identified by our search. No randomised controlled trials comparing DCS with immediate and definitive repair in patients with major abdominal trauma were found. A total of 2551 studies were excluded because they were not relevant to the review topic and two studies were excluded with reasons after examining the full-text. AUTHORS' CONCLUSIONS: Evidence that supports the efficacy of damage control surgery with respect to traditional laparotomy in patients with major abdominal trauma is limited.

Trastuzumab containing regimens for early breast cancer.

BACKGROUND: Approximately one-fifth of women who develop early breast cancer have HER2-positive tumours, which if untreated, have a worse prognosis than HER2-negative tumours. Trastuzumab is a selective treatment targeting the HER2 pathway. Although the results on efficacy seem to support its use, there are potential cardiac toxicities which need to be considered, especially for women at lower risk of recurrence, or those at increased cardiovascular risk. OBJECTIVES: To assess the evidence on the efficacy and safety of therapy with trastuzumab, overall and in relation to its duration, concurrent or sequential administration with the standard chemotherapy regimen in patients with HER2-positive early breast cancer. SEARCH METHODS: We searched the Cochrane Breast Cancer Group's (CBCGs) Specialised Trials Register, and used the search strategy developed by the CBCG to search for randomised controlled trials (RCTs) in CENTRAL, MEDLINE, EMBASE, BIOSIS, TOXNET, and the WHO ICTRP search portal (up to February 2010). SELECTION CRITERIA: RCTs comparing the efficacy and safety of trastuzumab alone, or in combination with chemotherapy, or no treatment, or standard chemotherapy alone, in women with HER2-positive early breast cancer including women with locally advanced breast cancer. DATA COLLECTION AND ANALYSIS: We collected data from published and unpublished trials. We used hazard ratios (HRs) for time-to-event outcomes and risk ratio (RRs) for binary outcomes. Subgroup analyses included duration (less or greater than six months) and concurrent or sequential trastuzumab administration. MAIN RESULTS: We included eight studies involving 11,991 patients. The combined HRs for overall survival (OS) and disease-free survival (DFS) significantly favoured the trastuzumab-containing regimens (HR 0.66; 95% confidence interval (CI) 0.57 to 0.77, P < 0.00001; and HR 0.60; 95% CI 0.50 to 0.71, P < 0.00001, respectively). Trastuzumab significantly increased the risk of congestive heart failure (CHF: RR 5.11; 90% CI 3.00 to 8.72, P < 0.00001); and left ventricular ejection fraction decline (LVEF: RR 1.83; 90% CI 1.36 to 2.47, P = 0.0008). For haematological toxicities, risks did not differ. The two small trials that administered trastuzumab for less than six months did not differ in efficacy from longer studies, but found fewer cardiac toxicities. Studies with concurrent administration gave similar efficacy and toxicity results to sequential studies. AUTHORS' CONCLUSIONS: Trastuzumab significantly improves OS and DFS in HER2-positive women with early and locally advanced breast cancer, although it also significantly increases the risk of CHF and LVEF decline. The available subgroup analyses are limited by the small number of studies. Studies that administered trastuzumab concurrently or sequentially did not differ significantly in efficacy. Shorter duration of therapy may reduce cardiotoxicity and maintain efficacy, however there is insufficient evidence at present to conclude this due to small numbers of patients in these trials.

Damage control surgery for abdominal trauma.

BACKGROUND: Trauma is one of the leading causes of death in any age group. The 'lethal triad' of acidosis, hypothermia, and coagulopathy has been recognized as a significant cause of death in patients with traumatic injuries. In order to prevent the lethal triad two factors are essential, early control of bleeding and prevention of further heat loss. In patients with major abdominal trauma, damage control surgery (DCS) avoids extensive procedures on unstable patients, stabilizes potentially fatal problems at initial operation, and applies staged surgery after successful initial resuscitation. It is not currently known whether DCS is superior to immediate surgery for patients with major abdominal trauma. OBJECTIVES: To assess the effectiveness of DCS compared to traditional immediate definitive surgical treatment for patients with major abdominal trauma. SEARCH STRATEGY: We searched the Cochrane Injuries Group Specialised Register, CENTRAL (The Cochrane Library 2008, Issue 3), MEDLINE, EMBASE, Web of Science: Science Citation Index & ISI Proceedings, Current Controlled Trials MetaRegister, Clinicaltrials.gov, Zetoc, and CINAHL for all published and unpublished randomised controlled trials. We did not restrict the searches by language, date, or publication status. Searches were conducted in August 2008. SELECTION CRITERIA: Randomised controlled trials of DCS versus immediate traditional surgical repair were included in this review. We included patients with major abdominal trauma (Abbreviated Injury Scale > 3) who were undergoing surgery. Patient selection was crucial as patients with relatively simple abdominal injuries should not undergo unnecessary procedures. DATA COLLECTION AND ANALYSIS: Two authors independently evaluated the search results. MAIN RESULTS: A total of 1523 studies were identified by our search. No randomised controlled trials comparing DCS with immediate and definitive repair in patients with major abdominal trauma were found. A total of 1521 studies were excluded because they were not relevant to the review topic and two studies were excluded because they were case-control studies. AUTHORS' CONCLUSIONS: Evidence that supports the efficacy of DCS with respect to traditional laparotomy in patients with major abdominal trauma is limited.

A review of online evidence-based practice point-of-care information summary providers.

BACKGROUND: Busy clinicians need easy access to evidence-based information to inform their clinical practice. Publishers and organizations have designed specific tools to meet doctors' needs at the point of care. OBJECTIVE: The aim of this study was to describe online point-of-care summaries and evaluate their breadth, content development, and editorial policy against their claims of being "evidence-based." METHODS: We searched Medline, Google, librarian association websites, and information conference proceedings from January to December 2008. We included English Web-based point-of-care summaries designed to deliver predigested, rapidly accessible, comprehensive, periodically updated, evidence-based information to clinicians. Two investigators independently extracted data on the general characteristics and content presentation of summaries. We assessed and ranked point-of-care products according to: (1) coverage (volume) of medical conditions, (2) editorial quality, and (3) evidence-based methodology. We explored how these factors were associated. RESULTS: We retrieved 30 eligible summaries. Of these products, 18 met our inclusion criteria and were qualitatively described, and 16 provided sufficient data for quantitative evaluation. The median volume of medical conditions covered was 80.6% (interquartile range, 68.9%-84.2%) and varied for the different products. Similarly, differences emerged for editorial policy (median 8.0, interquartile range 5.8-10.3) and evidence-based methodology scores (median 10.0, interquartile range 1.0-12.8) on a 15-point scale. None of these dimensions turned out to be significantly associated with the other dimensions (editorial quality and volume, Spearman rank correlation r = -0.001, P = .99; evidence-based methodology and volume, r = -0.19, P = .48; editorial and evidence-based methodology, r = 0.43, P =.09). CONCLUSIONS: Publishers are moving to develop point-of-care summary products. Some of these have better profiles than others, and there is room for improved reporting of the strengths and weaknesses of these products.

Addressing the management of atrial fibrillation - a systematic review of the role of dronedarone.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia. It occurs in 1%-2% of the general population and its prevalence increases with age. Dronedarone, a noniodinated benzofuran similar to amiodarone, was developed as an antiarrhythmic agent for patients with atrial fibrillation. The aim of our systematic review was to critically evaluate randomized controlled trials that compared treatment with dronedarone versus placebo or amiodarone in patients with atrial fibrillation. METHODS: Electronic databases (MEDLINE, Embase, and Central) were searched up to November 2011 with no language restrictions. We included randomized controlled trials in which dronedarone was compared to placebo or other drugs in patients with AF. Internal and external validity was assessed. RESULTS: We identified seven papers corresponding to eight randomized controlled trials. The DAFNE, EURIDIS/ADONIS, and ATHENA trials demonstrated a reduction of AF recurrence with dronedarone as compared to placebo in patients with nonpermanent AF. The DIONYSOS study showed that dronedarone is less effective for the prevention of recurrent AF but improved tolerability as compared to amiodarone. Considering patients with permanent AF, the ERATO trial showed that dronedarone had rate-control effects while the PALLAS study was stopped early since stroke, myocardial infarction, systemic embolism, or death from cardiovascular causes were significantly more frequent in subjects treated with dronedarone as compared to placebo. The ANDROMEDA trial included patients with recent hospitalization for heart failure and was terminated early because of excess of deaths in the dronedarone group. CONCLUSION: Like most antiarrhythmic drugs, dronedarone reduces the recurrence of AF in patients with paroxysmal or persistent AF as compared to placebo. However, relapse rates in the first year of therapy are high. Moreover, dronedarone showed to be less effective than amiodarone. Finally, dronedarone should be avoided in patients with permanent AF and a high risk for cardiovascular events or severe congestive heart failure.

Speed of updating online evidence based point of care summaries: prospective cohort analysis.

OBJECTIVE: To evaluate the ability of international point of care information summaries to update evidence relevant to medical practice. DESIGN: Prospective cohort bibliometric analysis. SETTING: Top five point of care information summaries (Clinical Evidence, EBMGuidelines, eMedicine, Dynamed, UpToDate) ranked for coverage of medical conditions, editorial quality, and evidence based methodology. MAIN OUTCOME MEASURES: From June 2009 to May 2010 we measured the incidence of research findings relating to potentially eligible newsworthy evidence. As samples, we chose systematic reviews rated as relevant by international research networks (such as, Evidence-Based Medicine, ACP Journal Club, and the Cochrane Collaboration). Every month we assessed whether each sampled review was cited in at least one chapter of the five summaries. The cumulative updating rate was analysed with Kaplan-Meier curves. Results From April to December 2009, 128 reviews were retrieved; 53% (68) from the literature surveillance journals and 47% (60) from the Cochrane Library. At nine months, Dynamed had cited 87% of the sampled reviews, while the other summaries had cited less than 50%. The updating speed of Dynamed clearly led the others. For instance, the hazard ratios for citations in EBM Guidelines and Clinical Evidence versus the top performer were 0.22 (95% confidence interval 0.17 to 0.29) and 0.03 (0.01 to 0.05). Conclusions Point of care information summaries include evidence relevant to practice at different speeds. A qualitative analysis of updating mechanisms is needed to determine whether greater speed corresponds to more appropriate incorporation of new information.