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1.  Variability in research ethics review of cluster randomized trials: a scenario-based survey in three countries 
Trials  2014;15:48.
Background
Cluster randomized trials (CRTs) present unique ethical challenges. In the absence of a uniform standard for their ethical design and conduct, problems such as variability in procedures and requirements by different research ethics committees will persist. We aimed to assess the need for ethics guidelines for CRTs among research ethics chairs internationally, investigate variability in procedures for research ethics review of CRTs within and among countries, and elicit research ethics chairs’ perspectives on specific ethical issues in CRTs, including the identification of research subjects. The proper identification of research subjects is a necessary requirement in the research ethics review process, to help ensure, on the one hand, that subjects are protected from harm and exploitation, and on the other, that reviews of CRTs are completed efficiently.
Methods
A web-based survey with closed- and open-ended questions was administered to research ethics chairs in Canada, the United States, and the United Kingdom. The survey presented three scenarios of CRTs involving cluster-level, professional-level, and individual-level interventions. For each scenario, a series of questions was posed with respect to the type of review required (full, expedited, or no review) and the identification of research subjects at cluster and individual levels.
Results
A total of 189 (35%) of 542 chairs responded. Overall, 144 (84%, 95% CI 79 to 90%) agreed or strongly agreed that there is a need for ethics guidelines for CRTs and 158 (92%, 95% CI 88 to 96%) agreed or strongly agreed that research ethics committees could be better informed about distinct ethical issues surrounding CRTs. There was considerable variability among research ethics chairs with respect to the type of review required, as well as the identification of research subjects. The cluster-cluster and professional-cluster scenarios produced the most disagreement.
Conclusions
Research ethics committees identified a clear need for ethics guidelines for CRTs and education about distinct ethical issues in CRTs. There is disagreement among committees, even within the same countries, with respect to key questions in the ethics review of CRTs. This disagreement reflects variability of opinion and practices pointing toward possible gaps in knowledge, and supports the need for explicit guidelines for the ethical conduct and review of CRTs.
doi:10.1186/1745-6215-15-48
PMCID: PMC3925119  PMID: 24495542
Cluster randomized trials; Informed consent; Research ethics guidelines; Research ethics review; Web-based survey
2.  Internet-Based Device-Assisted Remote Monitoring of Cardiovascular Implantable Electronic Devices 
Executive Summary
Objective
The objective of this Medical Advisory Secretariat (MAS) report was to conduct a systematic review of the available published evidence on the safety, effectiveness, and cost-effectiveness of Internet-based device-assisted remote monitoring systems (RMSs) for therapeutic cardiac implantable electronic devices (CIEDs) such as pacemakers (PMs), implantable cardioverter-defibrillators (ICDs), and cardiac resynchronization therapy (CRT) devices. The MAS evidence-based review was performed to support public financing decisions.
Clinical Need: Condition and Target Population
Sudden cardiac death (SCD) is a major cause of fatalities in developed countries. In the United States almost half a million people die of SCD annually, resulting in more deaths than stroke, lung cancer, breast cancer, and AIDS combined. In Canada each year more than 40,000 people die from a cardiovascular related cause; approximately half of these deaths are attributable to SCD.
Most cases of SCD occur in the general population typically in those without a known history of heart disease. Most SCDs are caused by cardiac arrhythmia, an abnormal heart rhythm caused by malfunctions of the heart’s electrical system. Up to half of patients with significant heart failure (HF) also have advanced conduction abnormalities.
Cardiac arrhythmias are managed by a variety of drugs, ablative procedures, and therapeutic CIEDs. The range of CIEDs includes pacemakers (PMs), implantable cardioverter-defibrillators (ICDs), and cardiac resynchronization therapy (CRT) devices. Bradycardia is the main indication for PMs and individuals at high risk for SCD are often treated by ICDs.
Heart failure (HF) is also a significant health problem and is the most frequent cause of hospitalization in those over 65 years of age. Patients with moderate to severe HF may also have cardiac arrhythmias, although the cause may be related more to heart pump or haemodynamic failure. The presence of HF, however, increases the risk of SCD five-fold, regardless of aetiology. Patients with HF who remain highly symptomatic despite optimal drug therapy are sometimes also treated with CRT devices.
With an increasing prevalence of age-related conditions such as chronic HF and the expanding indications for ICD therapy, the rate of ICD placement has been dramatically increasing. The appropriate indications for ICD placement, as well as the rate of ICD placement, are increasingly an issue. In the United States, after the introduction of expanded coverage of ICDs, a national ICD registry was created in 2005 to track these devices. A recent survey based on this national ICD registry reported that 22.5% (25,145) of patients had received a non-evidence based ICD and that these patients experienced significantly higher in-hospital mortality and post-procedural complications.
In addition to the increased ICD device placement and the upfront device costs, there is the need for lifelong follow-up or surveillance, placing a significant burden on patients and device clinics. In 2007, over 1.6 million CIEDs were implanted in Europe and the United States, which translates to over 5.5 million patient encounters per year if the recommended follow-up practices are considered. A safe and effective RMS could potentially improve the efficiency of long-term follow-up of patients and their CIEDs.
Technology
In addition to being therapeutic devices, CIEDs have extensive diagnostic abilities. All CIEDs can be interrogated and reprogrammed during an in-clinic visit using an inductive programming wand. Remote monitoring would allow patients to transmit information recorded in their devices from the comfort of their own homes. Currently most ICD devices also have the potential to be remotely monitored. Remote monitoring (RM) can be used to check system integrity, to alert on arrhythmic episodes, and to potentially replace in-clinic follow-ups and manage disease remotely. They do not currently have the capability of being reprogrammed remotely, although this feature is being tested in pilot settings.
Every RMS is specifically designed by a manufacturer for their cardiac implant devices. For Internet-based device-assisted RMSs, this customization includes details such as web application, multiplatform sensors, custom algorithms, programming information, and types and methods of alerting patients and/or physicians. The addition of peripherals for monitoring weight and pressure or communicating with patients through the onsite communicators also varies by manufacturer. Internet-based device-assisted RMSs for CIEDs are intended to function as a surveillance system rather than an emergency system.
Health care providers therefore need to learn each application, and as more than one application may be used at one site, multiple applications may need to be reviewed for alarms. All RMSs deliver system integrity alerting; however, some systems seem to be better geared to fast arrhythmic alerting, whereas other systems appear to be more intended for remote follow-up or supplemental remote disease management. The different RMSs may therefore have different impacts on workflow organization because of their varying frequency of interrogation and methods of alerts. The integration of these proprietary RM web-based registry systems with hospital-based electronic health record systems has so far not been commonly implemented.
Currently there are 2 general types of RMSs: those that transmit device diagnostic information automatically and without patient assistance to secure Internet-based registry systems, and those that require patient assistance to transmit information. Both systems employ the use of preprogrammed alerts that are either transmitted automatically or at regular scheduled intervals to patients and/or physicians.
The current web applications, programming, and registry systems differ greatly between the manufacturers of transmitting cardiac devices. In Canada there are currently 4 manufacturers—Medtronic Inc., Biotronik, Boston Scientific Corp., and St Jude Medical Inc.—which have regulatory approval for remote transmitting CIEDs. Remote monitoring systems are proprietary to the manufacturer of the implant device. An RMS for one device will not work with another device, and the RMS may not work with all versions of the manufacturer’s devices.
All Internet-based device-assisted RMSs have common components. The implanted device is equipped with a micro-antenna that communicates with a small external device (at bedside or wearable) commonly known as the transmitter. Transmitters are able to interrogate programmed parameters and diagnostic data stored in the patients’ implant device. The information transfer to the communicator can occur at preset time intervals with the participation of the patient (waving a wand over the device) or it can be sent automatically (wirelessly) without their participation. The encrypted data are then uploaded to an Internet-based database on a secure central server. The data processing facilities at the central database, depending on the clinical urgency, can trigger an alert for the physician(s) that can be sent via email, fax, text message, or phone. The details are also posted on the secure website for viewing by the physician (or their delegate) at their convenience.
Research Questions
The research directions and specific research questions for this evidence review were as follows:
To identify the Internet-based device-assisted RMSs available for follow-up of patients with therapeutic CIEDs such as PMs, ICDs, and CRT devices.
To identify the potential risks, operational issues, or organizational issues related to Internet-based device-assisted RM for CIEDs.
To evaluate the safety, acceptability, and effectiveness of Internet-based device-assisted RMSs for CIEDs such as PMs, ICDs, and CRT devices.
To evaluate the safety, effectiveness, and cost-effectiveness of Internet-based device-assisted RMSs for CIEDs compared to usual outpatient in-office monitoring strategies.
To evaluate the resource implications or budget impact of RMSs for CIEDs in Ontario, Canada.
Research Methods
Literature Search
The review included a systematic review of published scientific literature and consultations with experts and manufacturers of all 4 approved RMSs for CIEDs in Canada. Information on CIED cardiac implant clinics was also obtained from Provincial Programs, a division within the Ministry of Health and Long-Term Care with a mandate for cardiac implant specialty care. Various administrative databases and registries were used to outline the current clinical follow-up burden of CIEDs in Ontario. The provincial population-based ICD database developed and maintained by the Institute for Clinical Evaluative Sciences (ICES) was used to review the current follow-up practices with Ontario patients implanted with ICD devices.
Search Strategy
A literature search was performed on September 21, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from 1950 to September 2010. Search alerts were generated and reviewed for additional relevant literature until December 31, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search.
Inclusion Criteria
published between 1950 and September 2010;
English language full-reports and human studies;
original reports including clinical evaluations of Internet-based device-assisted RMSs for CIEDs in clinical settings;
reports including standardized measurements on outcome events such as technical success, safety, effectiveness, cost, measures of health care utilization, morbidity, mortality, quality of life or patient satisfaction;
randomized controlled trials (RCTs), systematic reviews and meta-analyses, cohort and controlled clinical studies.
Exclusion Criteria
non-systematic reviews, letters, comments and editorials;
reports not involving standardized outcome events;
clinical reports not involving Internet-based device assisted RM systems for CIEDs in clinical settings;
reports involving studies testing or validating algorithms without RM;
studies with small samples (<10 subjects).
Outcomes of Interest
The outcomes of interest included: technical outcomes, emergency department visits, complications, major adverse events, symptoms, hospital admissions, clinic visits (scheduled and/or unscheduled), survival, morbidity (disease progression, stroke, etc.), patient satisfaction, and quality of life.
Summary of Findings
The MAS evidence review was performed to review available evidence on Internet-based device-assisted RMSs for CIEDs published until September 2010. The search identified 6 systematic reviews, 7 randomized controlled trials, and 19 reports for 16 cohort studies—3 of these being registry-based and 4 being multi-centered. The evidence is summarized in the 3 sections that follow.
1. Effectiveness of Remote Monitoring Systems of CIEDs for Cardiac Arrhythmia and Device Functioning
In total, 15 reports on 13 cohort studies involving investigations with 4 different RMSs for CIEDs in cardiology implant clinic groups were identified in the review. The 4 RMSs were: Care Link Network® (Medtronic Inc,, Minneapolis, MN, USA); Home Monitoring® (Biotronic, Berlin, Germany); House Call 11® (St Jude Medical Inc., St Pauls, MN, USA); and a manufacturer-independent RMS. Eight of these reports were with the Home Monitoring® RMS (12,949 patients), 3 were with the Care Link® RMS (167 patients), 1 was with the House Call 11® RMS (124 patients), and 1 was with a manufacturer-independent RMS (44 patients). All of the studies, except for 2 in the United States, (1 with Home Monitoring® and 1 with House Call 11®), were performed in European countries.
The RMSs in the studies were evaluated with different cardiac implant device populations: ICDs only (6 studies), ICD and CRT devices (3 studies), PM and ICD and CRT devices (4 studies), and PMs only (2 studies). The patient populations were predominately male (range, 52%–87%) in all studies, with mean ages ranging from 58 to 76 years. One study population was unique in that RMSs were evaluated for ICDs implanted solely for primary prevention in young patients (mean age, 44 years) with Brugada syndrome, which carries an inherited increased genetic risk for sudden heart attack in young adults.
Most of the cohort studies reported on the feasibility of RMSs in clinical settings with limited follow-up. In the short follow-up periods of the studies, the majority of the events were related to detection of medical events rather than system configuration or device abnormalities. The results of the studies are summarized below:
The interrogation of devices on the web platform, both for continuous and scheduled transmissions, was significantly quicker with remote follow-up, both for nurses and physicians.
In a case-control study focusing on a Brugada population–based registry with patients followed-up remotely, there were significantly fewer outpatient visits and greater detection of inappropriate shocks. One death occurred in the control group not followed remotely and post-mortem analysis indicated early signs of lead failure prior to the event.
Two studies examined the role of RMSs in following ICD leads under regulatory advisory in a European clinical setting and noted:
– Fewer inappropriate shocks were administered in the RM group.
– Urgent in-office interrogations and surgical revisions were performed within 12 days of remote alerts.
– No signs of lead fracture were detected at in-office follow-up; all were detected at remote follow-up.
Only 1 study reported evaluating quality of life in patients followed up remotely at 3 and 6 months; no values were reported.
Patient satisfaction was evaluated in 5 cohort studies, all in short term follow-up: 1 for the Home Monitoring® RMS, 3 for the Care Link® RMS, and 1 for the House Call 11® RMS.
– Patients reported receiving a sense of security from the transmitter, a good relationship with nurses and physicians, positive implications for their health, and satisfaction with RM and organization of services.
– Although patients reported that the system was easy to implement and required less than 10 minutes to transmit information, a variable proportion of patients (range, 9% 39%) reported that they needed the assistance of a caregiver for their transmission.
– The majority of patients would recommend RM to other ICD patients.
– Patients with hearing or other physical or mental conditions hindering the use of the system were excluded from studies, but the frequency of this was not reported.
Physician satisfaction was evaluated in 3 studies, all with the Care Link® RMS:
– Physicians reported an ease of use and high satisfaction with a generally short-term use of the RMS.
– Physicians reported being able to address the problems in unscheduled patient transmissions or physician initiated transmissions remotely, and were able to handle the majority of the troubleshooting calls remotely.
– Both nurses and physicians reported a high level of satisfaction with the web registry system.
2. Effectiveness of Remote Monitoring Systems in Heart Failure Patients for Cardiac Arrhythmia and Heart Failure Episodes
Remote follow-up of HF patients implanted with ICD or CRT devices, generally managed in specialized HF clinics, was evaluated in 3 cohort studies: 1 involved the Home Monitoring® RMS and 2 involved the Care Link® RMS. In these RMSs, in addition to the standard diagnostic features, the cardiac devices continuously assess other variables such as patient activity, mean heart rate, and heart rate variability. Intra-thoracic impedance, a proxy measure for lung fluid overload, was also measured in the Care Link® studies. The overall diagnostic performance of these measures cannot be evaluated, as the information was not reported for patients who did not experience intra-thoracic impedance threshold crossings or did not undergo interventions. The trial results involved descriptive information on transmissions and alerts in patients experiencing high morbidity and hospitalization in the short study periods.
3. Comparative Effectiveness of Remote Monitoring Systems for CIEDs
Seven RCTs were identified evaluating RMSs for CIEDs: 2 were for PMs (1276 patients) and 5 were for ICD/CRT devices (3733 patients). Studies performed in the clinical setting in the United States involved both the Care Link® RMS and the Home Monitoring® RMS, whereas all studies performed in European countries involved only the Home Monitoring® RMS.
3A. Randomized Controlled Trials of Remote Monitoring Systems for Pacemakers
Two trials, both multicenter RCTs, were conducted in different countries with different RMSs and study objectives. The PREFER trial was a large trial (897 patients) performed in the United States examining the ability of Care Link®, an Internet-based remote PM interrogation system, to detect clinically actionable events (CAEs) sooner than the current in-office follow-up supplemented with transtelephonic monitoring transmissions, a limited form of remote device interrogation. The trial results are summarized below:
In the 375-day mean follow-up, 382 patients were identified with at least 1 CAE—111 patients in the control arm and 271 in the remote arm.
The event rate detected per patient for every type of CAE, except for loss of atrial capture, was higher in the remote arm than the control arm.
The median time to first detection of CAEs (4.9 vs. 6.3 months) was significantly shorter in the RMS group compared to the control group (P < 0.0001).
Additionally, only 2% (3/190) of the CAEs in the control arm were detected during a transtelephonic monitoring transmission (the rest were detected at in-office follow-ups), whereas 66% (446/676) of the CAEs were detected during remote interrogation.
The second study, the OEDIPE trial, was a smaller trial (379 patients) performed in France evaluating the ability of the Home Monitoring® RMS to shorten PM post-operative hospitalization while preserving the safety of conventional management of longer hospital stays.
Implementation and operationalization of the RMS was reported to be successful in 91% (346/379) of the patients and represented 8144 transmissions.
In the RM group 6.5% of patients failed to send messages (10 due to improper use of the transmitter, 2 with unmanageable stress). Of the 172 patients transmitting, 108 patients sent a total of 167 warnings during the trial, with a greater proportion of warnings being attributed to medical rather than technical causes.
Forty percent had no warning message transmission and among these, 6 patients experienced a major adverse event and 1 patient experienced a non-major adverse event. Of the 6 patients having a major adverse event, 5 contacted their physician.
The mean medical reaction time was faster in the RM group (6.5 ± 7.6 days vs. 11.4 ± 11.6 days).
The mean duration of hospitalization was significantly shorter (P < 0.001) for the RM group than the control group (3.2 ± 3.2 days vs. 4.8 ± 3.7 days).
Quality of life estimates by the SF-36 questionnaire were similar for the 2 groups at 1-month follow-up.
3B. Randomized Controlled Trials Evaluating Remote Monitoring Systems for ICD or CRT Devices
The 5 studies evaluating the impact of RMSs with ICD/CRT devices were conducted in the United States and in European countries and involved 2 RMSs—Care Link® and Home Monitoring ®. The objectives of the trials varied and 3 of the trials were smaller pilot investigations.
The first of the smaller studies (151 patients) evaluated patient satisfaction, achievement of patient outcomes, and the cost-effectiveness of the Care Link® RMS compared to quarterly in-office device interrogations with 1-year follow-up.
Individual outcomes such as hospitalizations, emergency department visits, and unscheduled clinic visits were not significantly different between the study groups.
Except for a significantly higher detection of atrial fibrillation in the RM group, data on ICD detection and therapy were similar in the study groups.
Health-related quality of life evaluated by the EuroQoL at 6-month or 12-month follow-up was not different between study groups.
Patients were more satisfied with their ICD care in the clinic follow-up group than in the remote follow-up group at 6-month follow-up, but were equally satisfied at 12- month follow-up.
The second small pilot trial (20 patients) examined the impact of RM follow-up with the House Call 11® system on work schedules and cost savings in patients randomized to 2 study arms varying in the degree of remote follow-up.
The total time including device interrogation, transmission time, data analysis, and physician time required was significantly shorter for the RM follow-up group.
The in-clinic waiting time was eliminated for patients in the RM follow-up group.
The physician talk time was significantly reduced in the RM follow-up group (P < 0.05).
The time for the actual device interrogation did not differ in the study groups.
The third small trial (115 patients) examined the impact of RM with the Home Monitoring® system compared to scheduled trimonthly in-clinic visits on the number of unplanned visits, total costs, health-related quality of life (SF-36), and overall mortality.
There was a 63.2% reduction in in-office visits in the RM group.
Hospitalizations or overall mortality (values not stated) were not significantly different between the study groups.
Patient-induced visits were higher in the RM group than the in-clinic follow-up group.
The TRUST Trial
The TRUST trial was a large multicenter RCT conducted at 102 centers in the United States involving the Home Monitoring® RMS for ICD devices for 1450 patients. The primary objectives of the trial were to determine if remote follow-up could be safely substituted for in-office clinic follow-up (3 in-office visits replaced) and still enable earlier physician detection of clinically actionable events.
Adherence to the protocol follow-up schedule was significantly higher in the RM group than the in-office follow-up group (93.5% vs. 88.7%, P < 0.001).
Actionability of trimonthly scheduled checks was low (6.6%) in both study groups. Overall, actionable causes were reprogramming (76.2%), medication changes (24.8%), and lead/system revisions (4%), and these were not different between the 2 study groups.
The overall mean number of in-clinic and hospital visits was significantly lower in the RM group than the in-office follow-up group (2.1 per patient-year vs. 3.8 per patient-year, P < 0.001), representing a 45% visit reduction at 12 months.
The median time from onset of first arrhythmia to physician evaluation was significantly shorter (P < 0.001) in the RM group than in the in-office follow-up group for all arrhythmias (1 day vs. 35.5 days).
The median time to detect clinically asymptomatic arrhythmia events—atrial fibrillation (AF), ventricular fibrillation (VF), ventricular tachycardia (VT), and supra-ventricular tachycardia (SVT)—was also significantly shorter (P < 0.001) in the RM group compared to the in-office follow-up group (1 day vs. 41.5 days) and was significantly quicker for each of the clinical arrhythmia events—AF (5.5 days vs. 40 days), VT (1 day vs. 28 days), VF (1 day vs. 36 days), and SVT (2 days vs. 39 days).
System-related problems occurred infrequently in both groups—in 1.5% of patients (14/908) in the RM group and in 0.7% of patients (3/432) in the in-office follow-up group.
The overall adverse event rate over 12 months was not significantly different between the 2 groups and individual adverse events were also not significantly different between the RM group and the in-office follow-up group: death (3.4% vs. 4.9%), stroke (0.3% vs. 1.2%), and surgical intervention (6.6% vs. 4.9%), respectively.
The 12-month cumulative survival was 96.4% (95% confidence interval [CI], 95.5%–97.6%) in the RM group and 94.2% (95% confidence interval [CI], 91.8%–96.6%) in the in-office follow-up group, and was not significantly different between the 2 groups (P = 0.174).
The CONNECT Trial
The CONNECT trial, another major multicenter RCT, involved the Care Link® RMS for ICD/CRT devices in a15-month follow-up study of 1,997 patients at 133 sites in the United States. The primary objective of the trial was to determine whether automatically transmitted physician alerts decreased the time from the occurrence of clinically relevant events to medical decisions. The trial results are summarized below:
Of the 575 clinical alerts sent in the study, 246 did not trigger an automatic physician alert. Transmission failures were related to technical issues such as the alert not being programmed or not being reset, and/or a variety of patient factors such as not being at home and the monitor not being plugged in or set up.
The overall mean time from the clinically relevant event to the clinical decision was significantly shorter (P < 0.001) by 17.4 days in the remote follow-up group (4.6 days for 172 patients) than the in-office follow-up group (22 days for 145 patients).
– The median time to a clinical decision was shorter in the remote follow-up group than in the in-office follow-up group for an AT/AF burden greater than or equal to 12 hours (3 days vs. 24 days) and a fast VF rate greater than or equal to 120 beats per minute (4 days vs. 23 days).
Although infrequent, similar low numbers of events involving low battery and VF detection/therapy turned off were noted in both groups. More alerts, however, were noted for out-of-range lead impedance in the RM group (18 vs. 6 patients), and the time to detect these critical events was significantly shorter in the RM group (same day vs. 17 days).
Total in-office clinic visits were reduced by 38% from 6.27 visits per patient-year in the in-office follow-up group to 3.29 visits per patient-year in the remote follow-up group.
Health care utilization visits (N = 6,227) that included cardiovascular-related hospitalization, emergency department visits, and unscheduled clinic visits were not significantly higher in the remote follow-up group.
The overall mean length of hospitalization was significantly shorter (P = 0.002) for those in the remote follow-up group (3.3 days vs. 4.0 days) and was shorter both for patients with ICD (3.0 days vs. 3.6 days) and CRT (3.8 days vs. 4.7 days) implants.
The mortality rate between the study arms was not significantly different between the follow-up groups for the ICDs (P = 0.31) or the CRT devices with defribillator (P = 0.46).
Conclusions
There is limited clinical trial information on the effectiveness of RMSs for PMs. However, for RMSs for ICD devices, multiple cohort studies and 2 large multicenter RCTs demonstrated feasibility and significant reductions in in-office clinic follow-ups with RMSs in the first year post implantation. The detection rates of clinically significant events (and asymptomatic events) were higher, and the time to a clinical decision for these events was significantly shorter, in the remote follow-up groups than in the in-office follow-up groups. The earlier detection of clinical events in the remote follow-up groups, however, was not associated with lower morbidity or mortality rates in the 1-year follow-up. The substitution of almost all the first year in-office clinic follow-ups with RM was also not associated with an increased health care utilization such as emergency department visits or hospitalizations.
The follow-up in the trials was generally short-term, up to 1 year, and was a more limited assessment of potential longer term device/lead integrity complications or issues. None of the studies compared the different RMSs, particularly the different RMSs involving patient-scheduled transmissions or automatic transmissions. Patients’ acceptance of and satisfaction with RM were reported to be high, but the impact of RM on patients’ health-related quality of life, particularly the psychological aspects, was not evaluated thoroughly. Patients who are not technologically competent, having hearing or other physical/mental impairments, were identified as potentially disadvantaged with remote surveillance. Cohort studies consistently identified subgroups of patients who preferred in-office follow-up. The evaluation of costs and workflow impact to the health care system were evaluated in European or American clinical settings, and only in a limited way.
Internet-based device-assisted RMSs involve a new approach to monitoring patients, their disease progression, and their CIEDs. Remote monitoring also has the potential to improve the current postmarket surveillance systems of evolving CIEDs and their ongoing hardware and software modifications. At this point, however, there is insufficient information to evaluate the overall impact to the health care system, although the time saving and convenience to patients and physicians associated with a substitution of in-office follow-up by RM is more certain. The broader issues surrounding infrastructure, impacts on existing clinical care systems, and regulatory concerns need to be considered for the implementation of Internet-based RMSs in jurisdictions involving different clinical practices.
PMCID: PMC3377571  PMID: 23074419
3.  Postoperative chemoradiotherapy vs. preoperative chemoradiotherapy for locally advanced (operable) gastric cancer: clarifying the role and technique of radiotherapy 
Background
Worldwide, almost one million new cases of stomach cancer were diagnosed in 2012, making it the fifth most common cancer, and the third leading cause of cancer deaths. The current tumor node metastasis (TNM) staging system represents a consensus between the East and the West, and will serve as a strong foundation upon which to build future evidence. In this review article, we first discuss the definition and optimal surgery for locally advanced gastric cancer, followed by the general principles when considering a pre vs. postoperative radiotherapy (RT) strategy. We then provide a synthesis of the existing randomized trial evidence in an attempt clarify the role of pre and postoperative RT in the management of locally advanced gastric cancer.
Methods
A Medline search 1966-Jun 2014 was undertaken. Randomized trials including patients with locally advanced gastric cancer (using established definitions), comparing RT [with or without chemotherapy (CT)], with surgery alone or other treatment modalities were included. Systematic reviews and evidence based practice guidelines that include this body of primary studies were preferentially discussed. Medline, Cochrane Library, Clinicaltrial.gov, Guidelines Clearinghouse were searched.
Results
Sixteen randomized trials, three systematic reviews and one practice guideline were included as the evidence base. In this group of studies, two reports compared postoperative chemoradiotherapy (CRT) with surgery alone. Driven predominantly by INT0116, they established the role of postoperative CRT to provide a survival benefit in a patient group that underwent surgery with predominantly D0-1 dissections. Preoperative RT (four studies) showed promise for survival benefit but the risks of bias in these trials were high. Postoperative CRT compared with CT alone (eight trials) showed no survival benefit with the addition of radiation although some evidence of activity can be observed with improved local regional control.
Conclusions and future directions
Technical expertise to enable the delivery of high quality RT to complex target volumes as is required in gastric cancer, and surgical standards to ensure the delivery of high quality surgery, have matured in recent years. Six trials with large sample sizes are currently ongoing to better define the role of preoperative CRT (two studies) and postoperative CRT (four studies), when used in conjunction with high quality surgery and RT, and contemporary CT regimens. The moderate likelihood of locoregional recurrences and the favorable therapeutic ratio with using RT preoperatively in other settings, provide optimism that preoperative CRT would have a pivotal role to play in locally advanced gastric cancer. Active accrual into ongoing trials is strongly encouraged.
doi:10.3978/j.issn.2078-6891.2014.089
PMCID: PMC4294828  PMID: 25642342
Gastric cancer; radiotherapy (RT); multimodality; locally advanced cancer
4.  Enhancing access to reports of randomized trials published world-wide – the contribution of EMBASE records to the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library 
Background
Randomized trials are essential in assessing the effects of healthcare interventions and are a key component in systematic reviews of effectiveness. Searching for reports of randomized trials in databases is problematic due to the absence of appropriate indexing terms until the 1990s and inconsistent application of these indexing terms thereafter.
Objectives
The objectives of this study are to devise a search strategy for identifying reports of randomized trials in EMBASE which are not already indexed as trials in MEDLINE and to make these reports easily accessible by including them in the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, with the permission of Elsevier, the publishers of EMBASE.
Methods
A highly sensitive search strategy was designed for EMBASE based on free-text and thesaurus terms which occurred frequently in the titles, abstracts, EMTREE terms (or some combination of these) of reports of trials indexed in EMBASE. This search strategy was run against EMBASE from 1980 to 2005 (1974 to 2005 for four of the terms) and records retrieved by the search, which were not already indexed as randomized trials in MEDLINE, were downloaded from EMBASE, printed and read. An analysis of the language of publication was conducted for the reports of trials published in 2005 (the most recent year completed at the time of this study).
Results
Twenty-two search terms were used (including nine which were later rejected due to poor cumulative precision). More than a third of a million records were downloaded and scanned and approximately 80,000 reports of trials were identified which were not already indexed as randomized trials in MEDLINE. These are now easily identifiable in CENTRAL, in The Cochrane Library. Cumulative sensitivity ranged from 0.1% to 60% and cumulative precision ranged from 8% to 61%. The truncated term 'random$' identified 60% of the total number of reports of trials but only 35% of the more than 130,000 records retrieved by this term were reports of trials. The language analysis for the sample year 2005 indicated that of the 18,427 reports indexed as randomized trials in MEDLINE, 959 (5%) were in languages other than English. The EMBASE search identified an additional 658 reports in languages other than English, of which the highest number were in Chinese (320).
Conclusion
The results of the search to date have greatly increased access to reports of trials in EMBASE, especially in some languages other than English. The search strategy used was subjectively derived from a small 'gold standard' set of test records and was not validated in an independent test set. We intend to design an objectively-derived validated search strategy using logistic regression based on the frequency of occurrence of terms in the approximately 80,000 reports of randomized trials identified compared with the frequency of these terms across the entire EMBASE database.
doi:10.1186/1742-7622-5-13
PMCID: PMC2586626  PMID: 18826567
5.  Researchers’ perceptions of ethical challenges in cluster randomized trials: a qualitative analysis 
Trials  2013;14:1.
Background
Cluster randomized trials (CRTs) pose ethical challenges for investigators and ethics committees. This study describes the views and experiences of CRT researchers with respect to: (1) ethical challenges in CRTs; (2) the ethics review process for CRTs; and (3) the need for comprehensive ethics guidelines for CRTs.
Methods
Descriptive qualitative analysis of interviews conducted with a purposive sample of 20 experienced CRT researchers.
Results
Informants expressed concern over the potential for bias that may result from requirements to obtain informed consent from research participants in CRTs. Informants suggested that the need for informed consent ought to be related to the type of intervention under study in a CRT. Informants rarely expressed concern regarding risks to research participants in CRTs, other than risks to privacy. Important issues identified in the research ethics literature, including fair subject selection and other justice issues, were not mentioned by informants. The ethics review process has had positive and negative impacts on CRT conduct. Informants stated that variability in ethics review between jurisdictions, and increasingly stringent ethics review in recent years, have hampered their ability to conduct CRTs. Many informants said that comprehensive ethics guidelines for CRTs would be helpful to researchers and research ethics committees.
Conclusions
Informants identified key ethical challenges in the conduct of CRTs, specifically relating to identifying subjects, seeking informed consent, and the use of gatekeepers. These data have since been used to identify topics for in-depth ethical analysis and to guide the development of comprehensive ethics guidelines for CRTs.
doi:10.1186/1745-6215-14-1
PMCID: PMC3561139  PMID: 23286245
Cluster randomized trials; Research ethics; Informed consent; Clinical trials; Bioethics; Knowledge translation; Quality improvement; Implementation research
6.  Effectiveness of cardiac resynchronization therapy in mild congestive heart failure: systematic review and meta-analysis of randomized trials 
European Journal of Heart Failure  2010;12(4):360-366.
Aims
Cardiac resynchronization therapy (CRT) improves echocardiographic parameters, symptoms, hospitalizations, and mortality in patients with New York Heart Association (NYHA) Class III or IV symptoms with left ventricular systolic dysfunction, sinus rhythm, and a prolonged QRS duration. The effectiveness of CRT in patients with mild heart failure symptoms has not been systematically reviewed.
Methods and results
Randomized controlled trials of CRT in patients with NYHA Class I or II heart failure were identified from MEDLINE and EMBASE. The effects of CRT on left ventricular remodelling at 1 year were systematically reviewed, and the effects of CRT on clinical outcomes at 1 year were meta-analysed. Two studies met the pre-specified search criteria, with a total of 2430 patients (REVERSE n = 610 and MADIT-CRT n = 1820). CRT was associated with a reduction in heart failure events in both trials [combined OR 0.57, 95% confidence interval (CI) 0.46–0.70], but not mortality (combined OR 0.96, 95% CI 0.67–1.36). The effect of CRT on the combined endpoint of heart failure events or death favoured CRT (OR 0.63, 95% CI 0.51–0.77). CRT was also associated with improvement in left ventricular remodelling parameters in both studies, including a greater increase in left ventricular ejection fraction in the CRT group than in the control group, at 1 year after randomization. Serious adverse events were rare with CRT.
Conclusion
CRT reduces heart failure events in patients with mild heart failure symptoms, left ventricular dysfunction, sinus rhythm, and prolonged QRS duration.
doi:10.1093/eurjhf/hfq029
PMCID: PMC2844759  PMID: 20335354
Artificial cardiac pacemaker; Artificial pacemaker; Heart failure; Mortality; Cardiac resynchronization therapy
7.  Who is the research subject in cluster randomized trials in health research? 
Trials  2011;12:183.
This article is part of a series of papers examining ethical issues in cluster randomized trials (CRTs) in health research. In the introductory paper in this series, we set out six areas of inquiry that must be addressed if the CRT is to be set on a firm ethical foundation. This paper addresses the first of the questions posed, namely, who is the research subject in a CRT in health research? The identification of human research subjects is logically prior to the application of protections as set out in research ethics and regulation. Aspects of CRT design, including the fact that in a single study the units of randomization, experimentation, and observation may differ, complicate the identification of human research subjects. But the proper identification of human research subjects is important if they are to be protected from harm and exploitation, and if research ethics committees are to review CRTs efficiently.
We examine the research ethics literature and international regulations to identify the core features of human research subjects, and then unify these features under a single, comprehensive definition of human research subject. We define a human research subject as any person whose interests may be compromised as a result of interventions in a research study. Individuals are only human research subjects in CRTs if: (1) they are directly intervened upon by investigators; (2) they interact with investigators; (3) they are deliberately intervened upon via a manipulation of their environment that may compromise their interests; or (4) their identifiable private information is used to generate data. Individuals who are indirectly affected by CRT study interventions, including patients of healthcare providers participating in knowledge translation CRTs, are not human research subjects unless at least one of these conditions is met.
doi:10.1186/1745-6215-12-183
PMCID: PMC3162904  PMID: 21791064
8.  Participant Informed Consent in Cluster Randomized Trials: Review 
PLoS ONE  2012;7(7):e40436.
Background
The Nuremberg code defines the general ethical framework of medical research with participant consent as its cornerstone. In cluster randomized trials (CRT), obtaining participant informed consent raises logistic and methodologic concerns. First, with randomization of large clusters such as geographical areas, obtaining individual informed consent may be impossible. Second, participants in randomized clusters cannot avoid certain interventions, which implies that participant informed consent refers only to data collection, not administration of an intervention. Third, complete participant information may be a source of selection bias, which then raises methodological concerns. We assessed whether participant informed consent was required in such trials, which type of consent was required, and whether the trial was at risk of selection bias because of the very nature of participant information.
Methods and Findings
We systematically reviewed all reports of CRT published in MEDLINE in 2008 and surveyed corresponding authors regarding the nature of the informed consent and the process of participant inclusion. We identified 173 reports and obtained an answer from 113 authors (65.3%). In total, 23.7% of the reports lacked information on ethics committee approval or participant consent, 53.1% of authors declared that participant consent was for data collection only and 58.5% that the group allocation was not specified for participants. The process of recruitment (chronology of participant recruitment with regard to cluster randomization) was rarely reported, and we estimated that only 56.6% of the trials were free of potential selection bias.
Conclusions
For CRTs, the reporting of ethics committee approval and participant informed consent is less than optimal. Reports should describe whether participants consented for administration of an intervention and/or data collection. Finally, the process of participant recruitment should be fully described (namely, whether participants were informed of the allocation group before being recruited) for a better appraisal of the risk of selection bias.
doi:10.1371/journal.pone.0040436
PMCID: PMC3391275  PMID: 22792319
9.  Comparison of population-averaged and cluster-specific models for the analysis of cluster randomized trials with missing binary outcomes: a simulation study 
Abstracts
Background
The objective of this simulation study is to compare the accuracy and efficiency of population-averaged (i.e. generalized estimating equations (GEE)) and cluster-specific (i.e. random-effects logistic regression (RELR)) models for analyzing data from cluster randomized trials (CRTs) with missing binary responses.
Methods
In this simulation study, clustered responses were generated from a beta-binomial distribution. The number of clusters per trial arm, the number of subjects per cluster, intra-cluster correlation coefficient, and the percentage of missing data were allowed to vary. Under the assumption of covariate dependent missingness, missing outcomes were handled by complete case analysis, standard multiple imputation (MI) and within-cluster MI strategies. Data were analyzed using GEE and RELR. Performance of the methods was assessed using standardized bias, empirical standard error, root mean squared error (RMSE), and coverage probability.
Results
GEE performs well on all four measures — provided the downward bias of the standard error (when the number of clusters per arm is small) is adjusted appropriately — under the following scenarios: complete case analysis for CRTs with a small amount of missing data; standard MI for CRTs with variance inflation factor (VIF) <3; within-cluster MI for CRTs with VIF≥3 and cluster size>50. RELR performs well only when a small amount of data was missing, and complete case analysis was applied.
Conclusion
GEE performs well as long as appropriate missing data strategies are adopted based on the design of CRTs and the percentage of missing data. In contrast, RELR does not perform well when either standard or within-cluster MI strategy is applied prior to the analysis.
doi:10.1186/1471-2288-13-9
PMCID: PMC3560270  PMID: 23343209
Marginal model; Population-averaged model; Cluster-specific model; Multiple imputation; Cluster randomized trial; Covariate dependent missingness; Generalized estimating equations; Random-effects logistic regression
10.  A systematic review of cognitive remediation therapy for anorexia nervosa – development, current state and implications for future research and clinical practice 
Objective
To systematically review studies of cognitive remediation therapy (CRT) for anorexia nervosa (AN), and to discuss findings with references to clinical practice and future research.
Method
The literature was reviewed using the PubMed, Web of Science and PsycINFO search terms “cognitive remediation therapy” AND “anorexia nervosa”. Papers published online between 2005 and 2013 were selected on the basis of three inclusion criteria: 1) studies of any design focusing on CRT for AN, 2) papers that were written in English or had an available published English translation, and 3) papers published in peer reviewed journals.
Results
A total of 45 papers were identified of which 21 were recognized as being relevant for the review. Relevant papers were divided into three different categories 1) single case reports, 2) case series and 3) randomised controlled trials (RCTs). Single case studies and case series yielded strong evidence of feasibility and acceptability of CRT for AN despite great variety in sample compositions. Four RCTs demonstrate that CRT has the potential of enhancing the effectiveness of current treatments, reduce attrition, increase cognitive set-shifting abilities and quality of life, as well as reduce eating disorder psychopathology.
Discussion
The number of CRT studies published is growing rapidly, in particular RCTs. Further research is needed to define the primary aim of delivering CRT to patients with eating disorders, and to establish how to best measure the effect of the intervention. Moreover, researchers and clinicians should focus on identifying and assessing specific versus non-specific CRT contributions, and explore long-term effects of the intervention. It is imperative that adolescent RCTs are conducted to evaluate how CRT may be effective as a treatment for this young patient group.
doi:10.1186/s40337-014-0026-y
PMCID: PMC4173002  PMID: 25254110
Cognitive remediation therapy; Anorexia nervosa; Review; Treatment; Neuropsychology; Eating disorders; Metacognition
11.  Does clinical equipoise apply to cluster randomized trials in health research? 
Trials  2011;12:118.
This article is part of a series of papers examining ethical issues in cluster randomized trials (CRTs) in health research. In the introductory paper in this series, Weijer and colleagues set out six areas of inquiry that must be addressed if the cluster trial is to be set on a firm ethical foundation. This paper addresses the third of the questions posed, namely, does clinical equipoise apply to CRTs in health research? The ethical principle of beneficence is the moral obligation not to harm needlessly and, when possible, to promote the welfare of research subjects. Two related ethical problems have been discussed in the CRT literature. First, are control groups that receive only usual care unduly disadvantaged? Second, when accumulating data suggests the superiority of one intervention in a trial, is there an ethical obligation to act?
In individually randomized trials involving patients, similar questions are addressed by the concept of clinical equipoise, that is, the ethical requirement that, at the start of a trial, there be a state of honest, professional disagreement in the community of expert practitioners as to the preferred treatment. Since CRTs may not involve physician-researchers and patient-subjects, the applicability of clinical equipoise to CRTs is uncertain. Here we argue that clinical equipoise may be usefully grounded in a trust relationship between the state and research subjects, and, as a result, clinical equipoise is applicable to CRTs. Clinical equipoise is used to argue that control groups receiving only usual care are not disadvantaged so long as the evidence supporting the experimental and control interventions is such that experts would disagree as to which is preferred. Further, while data accumulating during the course of a CRT may favor one intervention over another, clinical equipoise supports continuing the trial until the results are likely to be broadly convincing, often coinciding with the planned completion of the trial. Finally, clinical equipoise provides research ethics committees with formal and procedural guidelines that form an important part of the assessment of the benefits and harms of CRTs in health research.
doi:10.1186/1745-6215-12-118
PMCID: PMC3113987  PMID: 21569349
12.  Impact of Etiology on the Outcomes in Heart Failure Patients Treated with Cardiac Resynchronization Therapy: A Meta-Analysis 
PLoS ONE  2014;9(4):e94614.
Background
Cardiac resynchronization therapy (CRT) has been extensively demonstrated to benefit heart failure patients, but the role of underlying heart failure etiology in the outcomes was not consistently proven. This meta-analysis aimed to determine whether efficacy and effectiveness of CRT is affected by underlying heart failure etiology.
Methods and Results
Searches of MEDLINE, EMBASE and Cochrane databases were conducted to identify RCTs and observational studies that reported clinical and functional outcomes of CRT in ischemic cardiomyopathy (ICM) and non-ischemic cardiomyopathy (NICM) patients. Efficacy of CRT was assessed in 7 randomized controlled trials (RCTs) with 7072 patients and effectiveness of CRT was evaluated in 14 observational studies with 3463 patients In the pooled analysis of RCTs, we found that CRT decreased mortality or heart failure hospitalization by 29% in ICM patients (95% confidence interval [CI], 21% to 35%), and by 28% (95% CI, 18% to 37%) in NICM patients. No significant difference was observed between the 2 etiology groups (P = 0.55). In the pooled analysis of observational studies, however, we found that ICM patients had a 54% greater risk for mortality or HF hospitalization than NICM patients (relative risk: 1.54; 95% CI: 1.30–1.83; P<0.001). Both RCTs and observational studies demonstrated that NICM patients had greater echocardiographic improvements in the left ventricular ejection fraction and end-systolic volume, as compared with ICM patients (both P<0.001).
Conclusion
CRT might reduce mortality or heart failure hospitalization in both ICM and NICM patients similarly. The improvement of the left ventricular function and remodeling is greater in NICM patients.
doi:10.1371/journal.pone.0094614
PMCID: PMC3986107  PMID: 24732141
13.  In-service training for health professionals to improve care of the seriously ill newborn or child in low and middle-income countries (Review) 
Background
A variety of emergency care training courses based on developed country models are being promoted as a strategy to improve the quality of care of the seriously ill newborn or child in developing countries. Clear evidence of their effectiveness is lacking.
Objectives
To investigate the effectiveness of in-service training of health professionals on their management and care of the seriously ill newborn or child in low and middle-income settings.
Search strategy
We searched The Cochrane Register of Controlled Trials (CENTRAL), the Specialised Register of the Cochrane EPOC group (both up to May 2009), MEDLINE (1950 to May 2009), EMBASE (1980 to May 2009), CINAHL (1982 to March 2008), ERIC / LILACS / WHOLIS (all up to October 2008), and ISI Science Citation Index Expanded and ISI Social Sciences Citation Index (both from 1975 to March 2009). We checked references of retrieved articles and reviews and contacted authors to identify additional studies.
Selection criteria
Randomised controlled trials (RCTs), cluster-randomised trials (CRTs), controlled clinical trials (CCTs), controlled before-after studies (CBAs) and interrupted time series studies (ITSs) that reported objectively measured professional practice, patient outcomes, health resource /services utilization, or training costs in healthcare settings (not restricted to studies in low-income settings).
Data collection and analysis
We independently selected studies for inclusion, abstracted data using a standardised form, and assessed study quality. Meta-analysis was not appropriate. Study results were summarised and appraised.
Main results
Two studies of varied designs were included. In one RCT of moderate quality, Newborn Resuscitation Training (NRT) was associated with a significant improvement in performance of adequate initial resuscitation steps (risk ratio 2.45, 95% confidence interval (CI) 1.75 to 3.42, P < 0.001, adjusted for clustering) and a reduction in the frequency of inappropriate and potentially harmful practices (mean difference 0.40, 95% CI 0.13 to 0.66, P = 0.004). In the second RCT, available limited data suggested that there was improvement in assessment of breathing and newborn care practices in the delivery room following implementation of Essential Newborn Care (ENC) training.
Authors' conclusions
There is limited evidence that in-service neonatal emergency care courses improve health-workers' practices when caring for a seriously ill newborn although there is some evidence of benefit. Rigorous trials evaluating the impact of refresher emergency care training on long-term professional practices are needed. To optimise appropriate policy decisions, studies should aim to collect data on resource use and costs of training implementation.
doi:10.1002/14651858.CD007071.pub2
PMCID: PMC2868967  PMID: 20393956
14.  Strategies for Increasing Recruitment to Randomised Controlled Trials: Systematic Review 
PLoS Medicine  2010;7(11):e1000368.
Patrina Caldwell and colleagues performed a systematic review of randomized studies that compared methods of recruiting individual study participants into trials, and found that strategies that focus on increasing potential participants' awareness of the specific health problem, and that engaged them, appeared to increase recruitment.
Background
Recruitment of participants into randomised controlled trials (RCTs) is critical for successful trial conduct. Although there have been two previous systematic reviews on related topics, the results (which identified specific interventions) were inconclusive and not generalizable. The aim of our study was to evaluate the relative effectiveness of recruitment strategies for participation in RCTs.
Methods and Findings
A systematic review, using the PRISMA guideline for reporting of systematic reviews, that compared methods of recruiting individual study participants into an actual or mock RCT were included. We searched MEDLINE, Embase, The Cochrane Library, and reference lists of relevant studies. From over 16,000 titles or abstracts reviewed, 396 papers were retrieved and 37 studies were included, in which 18,812 of at least 59,354 people approached agreed to participate in a clinical RCT. Recruitment strategies were broadly divided into four groups: novel trial designs (eight studies), recruiter differences (eight studies), incentives (two studies), and provision of trial information (19 studies). Strategies that increased people's awareness of the health problem being studied (e.g., an interactive computer program [relative risk (RR) 1.48, 95% confidence interval (CI) 1.00–2.18], attendance at an education session [RR 1.14, 95% CI 1.01–1.28], addition of a health questionnaire [RR 1.37, 95% CI 1.14–1.66]), or a video about the health condition (RR 1.75, 95% CI 1.11–2.74), and also monetary incentives (RR1.39, 95% CI 1.13–1.64 to RR 1.53, 95% CI 1.28–1.84) improved recruitment. Increasing patients' understanding of the trial process, recruiter differences, and various methods of randomisation and consent design did not show a difference in recruitment. Consent rates were also higher for nonblinded trial design, but differential loss to follow up between groups may jeopardise the study findings. The study's main limitation was the necessity of modifying the search strategy with subsequent search updates because of changes in MEDLINE definitions. The abstracts of previous versions of this systematic review were published in 2002 and 2007.
Conclusion
Recruitment strategies that focus on increasing potential participants' awareness of the health problem being studied, its potential impact on their health, and their engagement in the learning process appeared to increase recruitment to clinical studies. Further trials of recruitment strategies that target engaging participants to increase their awareness of the health problems being studied and the potential impact on their health may confirm this hypothesis.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Before any health care intervention—a treatment for a disease or a measure such as vaccination that is designed to prevent an illness—is adopted by the medical community, it undergoes exhaustive laboratory-based and clinical research. In the laboratory, scientists investigate the causes of diseases, identify potential new treatments or preventive methods, and test these interventions in animals. New interventions that look hopeful are then investigated in clinical trials—studies that test these interventions in people by following a strict trial protocol or action plan. Phase I trials test interventions in a few healthy volunteers or patients to evaluate their safety and to identify possible side effects. In phase II trials, a larger group of patients receives an intervention to evaluate its safety further and to get an initial idea of its effectiveness. In phase III trials, very large groups of patients (sometimes in excess of a thousand people) are randomly assigned to receive the new intervention or an established intervention or placebo (dummy intervention). These “randomized controlled trials” or “RCTs” provide the most reliable information about the effectiveness and safety of health care interventions.
Why Was This Study Done?
Patients who participate in clinical trials must fulfill the inclusion criteria laid down in the trial protocol and must be given information about the trial, its risks, and potential benefits before agreeing to participate (informed consent). Unfortunately, many RCTs struggle to enroll the number of patients specified in their trial protocol, which can reduce a trial's ability to measure the effect of a new intervention. Inadequate recruitment can also increase costs and, in the worst cases, prevent trial completion. Several strategies have been developed to improve recruitment but it is not clear which strategy works best. In this study, the researchers undertake a systematic review (a study that uses predefined criteria to identify all the research on a given topic) of “recruitment trials”—studies that have randomly divided potential RCT participants into groups, applied different strategies for recruitment to each group, and compared recruitment rates in the groups.
What Did the Researchers Do and Find?
The researchers identified 37 randomized trials of recruitment strategies into real and mock RCTs (where no actual trial occurred). In all, 18,812 people agreed to participate in an RCT in these recruitment trials out of at least 59,354 people approached. Some of these trials investigated novel strategies for recruitment, such as changes in how patients are randomized. Others looked at the effect of recruiter differences (for example, increased contact between the health care professionals doing the recruiting and the trial investigators), the effect of offering monetary incentives to participants, and the effect of giving more information about the trial to potential participants. Recruitment strategies that improved people's awareness of the health problem being studied—provision of an interactive computer program or a video about the health condition, attendance at an educational session, or inclusion of a health questionnaire in the recruitment process—improved recruitment rates, as did monetary incentives. Increasing patients' understanding about the trial process itself, recruiter differences, and alterations in consent design and randomization generally had no effect on recruitment rates although consent rates were higher when patients knew the treatment to which they had been randomly allocated before consenting. However, differential losses among the patients in different treatment groups in such nonblinded trials may jeopardize study findings.
What Do These Findings Mean?
These findings suggest that trial recruitment strategies that focus on increasing the awareness of potential participants of the health problem being studied and its possible effects on their health, and that engage potential participants in the trial process are likely to increase recruitment to RCTs. The accuracy of these findings depends on whether the researchers identified all the published research on recruitment strategies and on whether other research on recruitment strategies has been undertaken and not published that could alter these findings. Furthermore, because about half of the recruitment trials identified by the researchers were undertaken in the US, the successful strategies identified here might not be generalizable to other countries. Nevertheless, these recruitment strategies should now be investigated further to ensure that the future evaluation of new health care interventions is not hampered by poor recruitment into RCTs.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000368.
The ClinicalTrials.gov Web site is a searchable register of federally and privately supported clinical trials in the US and around the world, providing information about all aspects of clinical trials
The US National Institutes of Health provides information about clinical trials
The UK National Health Service Choices Web site has information for patients about clinical trials and medical research
The UK Medical Research Council Clinical Trials Units also provides information for patients about clinical trials and links to information on clinical trials provided by other organizations
MedlinePlus has links to further resources on clinical trials (in English and Spanish)
The Australian Government's National Health and Medical Research Council has information about clinical trials
WHO International Clinical Trials Registry Platform aims to ensure that all trials are publicly accessible to those making health care decisions
The Star Child Health International Forum of Standards for Research is a resource center for pediatric clinical trial design, conduct, and reporting
doi:10.1371/journal.pmed.1000368
PMCID: PMC2976724  PMID: 21085696
15.  Imputation strategies for missing binary outcomes in cluster randomized trials 
Background
Attrition, which leads to missing data, is a common problem in cluster randomized trials (CRTs), where groups of patients rather than individuals are randomized. Standard multiple imputation (MI) strategies may not be appropriate to impute missing data from CRTs since they assume independent data. In this paper, under the assumption of missing completely at random and covariate dependent missing, we compared six MI strategies which account for the intra-cluster correlation for missing binary outcomes in CRTs with the standard imputation strategies and complete case analysis approach using a simulation study.
Method
We considered three within-cluster and three across-cluster MI strategies for missing binary outcomes in CRTs. The three within-cluster MI strategies are logistic regression method, propensity score method, and Markov chain Monte Carlo (MCMC) method, which apply standard MI strategies within each cluster. The three across-cluster MI strategies are propensity score method, random-effects (RE) logistic regression approach, and logistic regression with cluster as a fixed effect. Based on the community hypertension assessment trial (CHAT) which has complete data, we designed a simulation study to investigate the performance of above MI strategies.
Results
The estimated treatment effect and its 95% confidence interval (CI) from generalized estimating equations (GEE) model based on the CHAT complete dataset are 1.14 (0.76 1.70). When 30% of binary outcome are missing completely at random, a simulation study shows that the estimated treatment effects and the corresponding 95% CIs from GEE model are 1.15 (0.76 1.75) if complete case analysis is used, 1.12 (0.72 1.73) if within-cluster MCMC method is used, 1.21 (0.80 1.81) if across-cluster RE logistic regression is used, and 1.16 (0.82 1.64) if standard logistic regression which does not account for clustering is used.
Conclusion
When the percentage of missing data is low or intra-cluster correlation coefficient is small, different approaches for handling missing binary outcome data generate quite similar results. When the percentage of missing data is large, standard MI strategies, which do not take into account the intra-cluster correlation, underestimate the variance of the treatment effect. Within-cluster and across-cluster MI strategies (except for random-effects logistic regression MI strategy), which take the intra-cluster correlation into account, seem to be more appropriate to handle the missing outcome from CRTs. Under the same imputation strategy and percentage of missingness, the estimates of the treatment effect from GEE and RE logistic regression models are similar.
doi:10.1186/1471-2288-11-18
PMCID: PMC3055218  PMID: 21324148
16.  Is Immediate Imaging Important in Managing Low Back Pain? 
Journal of Athletic Training  2011;46(1):99-102.
Abstract
Reference:
Chou R, Fu R, Carrino JA, Deyo RA. Imaging strategies for low-back pain: systematic review and meta-analysis. Lancet. 2009;373(9662):463–472.
Clinical Questions:
In patients with low back pain (LBP) who do not have indications of a serious underlying condition, does routine, immediate lumbar imaging result in improved patient outcomes when compared with clinical care without immediate imaging?
Data Sources:
Studies were identified by searching MEDLINE (1966 through first week of August 2008) and the Cochrane Central Register of Controlled Trials (third quarter of 2008). The reference lists of identified studies were manually reviewed for additional citations. The search terms spine, low-back pain, diagnostic imaging, and randomized controlled trials were used in both databases. The complete search strategy was made available as an online supplement.
Study Selection:
The search criteria were applied to the articles obtained from the electronic searches and the subsequent manual searches with no language restrictions. This systematic review and meta-analysis included randomized, controlled trials that compared immediate, routine lumbar imaging (or routine provision of imaging findings) with usual clinical care without immediate lumbar imaging (or not routinely providing results of imaging) for LBP without indications of serious underlying conditions.
Data Extraction:
Data extraction and assessment of study quality were well described. The trials assessed one or more of the following outcomes: pain, function, mental health, quality of life, patient satisfaction, and overall patient-reported improvement. Two reviewers independently appraised citations considered potentially relevant, with disagreements between reviewers resolved by consensus. Two independent reviewers abstracted data from the trials and assessed quality with modified Cochrane Back Review Group criteria. The criterion for blinding of patients and providers was excluded because of lack of applicability to imaging studies. In addition, the criterion of co-intervention similarity was excluded because a potential effect of different imaging strategies is to alter subsequent treatment decisions. As a result of excluding these criteria, quality ratings were based on the remaining 8 criteria. The authors resolved disagreements about quality ratings through discussion and consensus. Trials that met 4 or more of the 8 criteria were classified as higher quality, whereas those that met 3 or fewer of the 8 criteria were classified as lower quality. In addition, the authors categorized duration of symptoms as acute (<4 weeks), subacute (4–12 weeks), or chronic (>12 weeks). The investigators also contacted the study authors for additional data if included outcomes were not published or if median (rather than mean) outcomes were reported. Statistical analysis was conducted on the primary outcomes of improvement in pain or function. Secondary outcomes of improvement in mental health, quality of life, patient satisfaction, and overall improvement were also analyzed. Outcomes were categorized as short term (≤3 months), long term (>6 months to ≤1 year), or extended (>1 year). For continuous outcomes, standardized mean differences (SMDs) of interventions for change between baseline and follow-up measurements were calculated. In studies reporting the same pain (visual analog scale [VAS] or Short Form-36 bodily pain score) or function (Roland-Morris Disability Questionnaire [RDQ]) outcomes, weighted mean differences (WMDs) were calculated. In all analyses, lower pain and function scores indicated better outcomes. For quality-of-life and mental health outcomes, higher scores indicated improved outcomes. All statistical analyses were performed with Stata 10.0. For outcomes in which SMDs were calculated, values of 0.2 to 0.5 were considered small, 0.5 to 0.8 were considered moderate, and values greater than 0.8 were considered large. For WMDs, mean improvements of 5 to 10 points on a 100-point scale (or equivalent) were considered small, 10-point to 20-point changes were considered moderate, and changes greater than 20 points were considered large. For the RDQ, mean improvements of 1 to 2 points were termed small, and improvements of 2 to 5 points were termed moderate.
Main Results:
The total number of citations identified using the search criteria was 479 articles and abstracts. Of these, 466 were excluded because either they were not randomized trials or they did not use imaging strategies for LBP. At this step, 13 articles were retrieved for further analysis. This analysis resulted in 3 additional articles being excluded (1 was not a randomized trial and the other 2 compared 2 imaging techniques rather than immediate imaging versus no imaging). The final step resulted in the inclusion of 6 trials reported in 10 publications for the meta-analysis. In the studies meeting the inclusion criteria, 4 assessed lumbar radiography and 2 assessed magnetic resonance imaging (MRI) or computed tomography (CT) scans. In these 6 trials, 1804 patients were randomly assigned to the intervention group. The duration of patient follow-up ranged from 3 weeks to 2 years. In addition, 1 trial excluded patients with sciatica or other radiculopathy symptoms, whereas another did not report the proportion of patients with these symptoms. In the other 4 studies, the proportion of patients with sciatica or radiculopathy ranged from 24% to 44%. Of the included trials, 3 compared immediate lumbar radiography with usual clinical care without immediate radiography, and a fourth study compared immediate lumbar radiography and a brief educational intervention with lumbar radiography if no improvement was seen by 3 weeks. The final 2 studies assessed advanced imaging modalities. Specifically, one group compared immediate MRI or CT with usual clinical care without advanced imaging in patients with primarily chronic LBP (82% with LBP for >3 months) who were referred to a surgeon. In the other advanced imaging study, all patients with LBP for <3 weeks underwent MRI and were then randomized to routine notification of results or to notification of results only if clinically indicated. With respect to study quality, 5 trials met at least 4 of the 8 predetermined quality criteria, leading to a classification of higher quality. In addition, 5 trials were included in the primary meta-analysis on pain or function improvement at 1 or more follow-up periods. With regard to short-term and long-term improvements in pain, no differences were noted between routine, immediate lumbar imaging and usual clinical care without immediate imaging (Table 1). In studies using the VAS pain score, the WMD (0.62, 95% confidence interval [CI]  =  0.03, 1.21) at short-term follow-up slightly favored no immediate imaging. No differences in outcome were seen in studies using the Short Form-36 bodily pain score. No improvements in function at short-term or long-term follow-up were noted between imaging strategies. Specifically, short-term function measured with the RDQ in 3 studies showed a WMD of 0.48 points (95% CI  =  −1.39, 2.35) between imaging strategies, whereas long-term function in 3 studies, also measured with the RDQ, showed a WMD of 0.33 points (95% CI  =  −0.65, 1.32). One included trial reported pain outcomes at extended (2-year) follow-up and found no differences between imaging strategies for pain (Short Form-36 bodily pain or Aberdeen pain score), with SMDs of −2.7 (95% CI  =  −6.17, 0.79) and −1.6 (−4.04, 0.84), respectively. The outcomes between immediate imaging and usual clinical care without immediate imaging did not differ for short-term follow-up in those studies reporting quality of life (SMD  =  −0.10, 95% CI  =  −0.53, 0.34), mental health (SMD  =  0.12, 95% CI  =  −0.37, 0.62), or overall improvement (mean risk ratio  =  0.83, 95% CI  =  0.65, 1.06). In those studies reporting long-term follow-up periods, similar results can be seen for quality of life (SMD  =  −0.15, 95% CI  =  −0.33, 0.04) and mental health (SMD  =  0.01, 95% CI  =  −0.32, 0.34). In the study reporting extended follow-up, immediate imaging was not better in terms of improving quality of life (SMD  =  0.02, 95% CI  =  −0.02, 0.07) or mental health (SMD  =  −1.50, 95% CI  =  −4.09, 1.09) when compared with usual clinical care without immediate imaging. In the included studies, no cases of cancer, infection, cauda equina syndrome, or other serious diagnoses were reported in patients randomly assigned to either imaging strategy.
Conclusions:
Available evidence indicates that immediate, routine lumbar spine imaging in patients with LBP and without features indicating a serious underlying condition did not improve outcomes compared with usual clinical care without immediate imaging. Clinical care without immediate imaging seems to result in no increased odds of failure in identifying serious underlying conditions in patients without risk factors for these conditions. In addition to lacking clinical benefit, routine lumbar imaging is associated with radiation exposure (radiography and CT) and increased direct expenses for patients and may lead to unnecessary procedures. This evidence confirms that clinicians should refrain from routine, immediate lumbar imaging in primary care patients with nonspecific, acute or subacute LBP and no indications of underlying serious conditions. Specific consideration of patient expectations about the value of imaging was not addressed here; however, this aspect must be considered to avoid unnecessary imaging while also meeting patient expectations and increasing patient satisfaction.
doi:10.4085/1062-6050-46.1.99
PMCID: PMC3017496  PMID: 21214357
spine; assessment; outcomes
17.  What is the role and authority of gatekeepers in cluster randomized trials in health research? 
Trials  2012;13:116.
This article is part of a series of papers examining ethical issues in cluster randomized trials (CRTs) in health research. In the introductory paper in this series, we set out six areas of inquiry that must be addressed if the CRT is to be set on a firm ethical foundation. This paper addresses the sixth of the questions posed, namely, what is the role and authority of gatekeepers in CRTs in health research? ‘Gatekeepers’ are individuals or bodies that represent the interests of cluster members, clusters, or organizations. The need for gatekeepers arose in response to the difficulties in obtaining informed consent because of cluster randomization, cluster-level interventions, and cluster size. In this paper, we call for a more restrictive understanding of the role and authority of gatekeepers.
Previous papers in this series have provided solutions to the challenges posed by informed consent in CRTs without the need to invoke gatekeepers. We considered that consent to randomization is not required when cluster members are approached for consent at the earliest opportunity and before any study interventions or data-collection procedures have started. Further, when cluster-level interventions or cluster size means that obtaining informed consent is not possible, a waiver of consent may be appropriate. In this paper, we suggest that the role of gatekeepers in protecting individual interests in CRTs should be limited. Generally, gatekeepers do not have the authority to provide proxy consent for cluster members. When a municipality or other community has a legitimate political authority that is empowered to make such decisions, cluster permission may be appropriate; however, gatekeepers may usefully protect cluster interests in other ways. Cluster consultation may ensure that the CRT addresses local health needs, and is conducted in accord with local values and customs. Gatekeepers may also play an important role in protecting the interests of organizations, such as hospitals, nursing homes, general practices, and schools. In these settings, permission to access the organization relies on resource implications and adherence to institutional policies.
doi:10.1186/1745-6215-13-116
PMCID: PMC3443001  PMID: 22834691
18.  Overexpression of miR-21-5p as a predictive marker for complete tumor regression to neoadjuvant chemoradiotherapy in rectal cancer patients 
BMC Medical Genomics  2014;7(1):68.
Background
Neoadjuvant chemoradiotherapy (nCRT) followed by radical surgery is the preferred treatment strategy for locally advanced rectal cancer. However, complete tumor regression is observed in a significant proportion of patients after nCRT, making them ideal candidates for alternative treatment strategies to this considerably morbid procedure. Identification of such patients based on clinical findings (complete clinical response - cCR) is difficult mainly because it relies on subjective clinical and imaging studies. Our goal was to identify biomarkers capable of predicting complete response to nCRT.
Methods
We analyzed miRNA expression profile using deep sequencing in rectal tumor biopsies prior to nCRT. Differential expression was investigated by EdgeR for a training (n = 27) and a validation (n = 16) set of patients to identify miRNAs associated with treatment response (complete vs. incomplete). In vitro experiments with two cancer cell lines were also performed in order to evaluate the possible role of miRNAs on response to nCRT.
Results
We found 4 miRNAs differentially expressed between complete and incomplete responders to nCRT. In addition, validation was performed using an independent group of patients and miR-21-5p was confirmed as being overexpressed in complete responders. Overall sensitivity and specificity of miR-21-5p expression in predicting complete response to nCRT was 78% and 86% respectively. Interestingly, in a subset of patients with cCR followed by early local recurrence, the expression level of miR-21-5p was considerably low, similarly to incomplete responders. We also found SATB1, a miR-21-5p target gene and known multidrug resistance gene, whose expression was inversely correlated with miR-21-5p expression. Finally, we performed functional experiments and showed that miR-21-5p and SATB1 may be directly involved with poor response to nCRT in rectal cancer patients.
Conclusions
This study suggests miR-21-5p as a promising predictive biomarker, which should aid in the selection of patients with cCR to nCRT that potentially could be spared from radical surgery.
Electronic supplementary material
The online version of this article (doi:10.1186/s12920-014-0068-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12920-014-0068-7
PMCID: PMC4279677  PMID: 25496125
miRNA; Predictive biomarker; Rectal cancer; miR-21-5p; SATB1; Chemoradiotherapy
19.  When is informed consent required in cluster randomized trials in health research? 
Trials  2011;12:202.
This article is part of a series of papers examining ethical issues in cluster randomized trials (CRTs) in health research. In the introductory paper in this series, we set out six areas of inquiry that must be addressed if the cluster trial is to be set on a firm ethical foundation. This paper addresses the second of the questions posed, namely, from whom, when, and how must informed consent be obtained in CRTs in health research? The ethical principle of respect for persons implies that researchers are generally obligated to obtain the informed consent of research subjects. Aspects of CRT design, including cluster randomization, cluster level interventions, and cluster size, present challenges to obtaining informed consent. Here we address five questions related to consent and CRTs: How can a study proceed if informed consent is not possible? Is consent to randomization always required? What information must be disclosed to potential subjects if their cluster has already been randomized? Is passive consent a valid substitute for informed consent? Do health professionals have a moral obligation to participate as subjects in CRTs designed to improve professional practice?
We set out a framework based on the moral foundations of informed consent and international regulatory provisions to address each of these questions. First, when informed consent is not possible, a study may proceed if a research ethics committee is satisfied that conditions for a waiver of consent are satisfied. Second, informed consent to randomization may not be required if it is not possible to approach subjects at the time of randomization. Third, when potential subjects are approached after cluster randomization, they must be provided with a detailed description of the interventions in the trial arm to which their cluster has been randomized; detailed information on interventions in other trial arms need not be provided. Fourth, while passive consent may serve a variety of practical ends, it is not a substitute for valid informed consent. Fifth, while health professionals may have a moral obligation to participate as subjects in research, this does not diminish the necessity of informed consent to study participation.
doi:10.1186/1745-6215-12-202
PMCID: PMC3184061  PMID: 21906277
20.  Effect of QRS morphology on clinical event reduction with cardiac resynchronization therapy: Meta-analysis of randomized controlled trials 
American heart journal  2012;163(2):260-7.e3.
Background
Cardiac resynchronization therapy (CRT) is effective in reducing clinical events in systolic heart failure patients with a wide QRS. Previous retrospective studies suggest only patients with QRS prolongation due to a left bundle-branch block (LBBB) benefit from CRT. Our objective was to examine this by performing a meta-analysis of all randomized controlled trials of CRT.
Methods
Systematic searches of MEDLINE and the Food and Drug Administration official website were conducted for randomized controlled CRT trials. Trials reporting adverse clinical events (eg, all-cause mortality, heart failure hospitalizations) according to QRS morphology were included in the meta-analysis.
Results
Four randomized trials totaling 5,356 patients met the inclusion criteria. In patients with LBBB at baseline, there was a highly significant reduction in composite adverse clinical events with CRT (RR = 0.64 [95% CI (0.52–0.77)], P = .00001). However no such benefit was observed for patients with non-LBBB conduction abnormalities (RR = 0.97 [95% CI (0.82–1.15)], P = .75). When examined separately, there was no benefit in patients with right-bundle branch block (RR = 0.91 [95% CI (0.69–1.20)], P = .49) or non-specific intraventricular conduction delay (RR = 1.19 [95% CI (0.87–1.63)], P = .28). There was no heterogeneity among the clinical trials with regards to the lack of benefit in non-LBBB patients (I2 = 0%). When directly compared, the difference in effect of CRT between LBBB versus non-LBBB patients was highly statistically significant (P = .0001 by heterogeneity analysis).
Conclusions
While CRT was very effective in reducing clinical events in patients with LBBB, it did not reduce such events in patients with wide QRS due to other conduction abnormalities.
doi:10.1016/j.ahj.2011.11.014
PMCID: PMC4113034  PMID: 22305845
21.  Medical interventions for traumatic hyphema 
Background
Traumatic hyphema is the entry of blood into the anterior chamber (the space between the cornea and iris) subsequent to a blow or a projectile striking the eye. Hyphema uncommonly causes permanent loss of vision. Associated trauma (e.g., corneal staining, traumatic cataract, angle recession glaucoma, optic atrophy, etc.) may seriously affect vision. Such complications may lead to permanent impairment of vision. Patients with sickle cell trait/disease may be particularly susceptible to increases of elevated intraocular pressure. If rebleeding occurs, the rates and severity of complications increase.
Objectives
The objective of this review was to assess the effectiveness of various medical interventions in the management of traumatic hyphema.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2010, Issue 6), MEDLINE (January 1950 to June 2010), EMBASE (January 1980 to June 2010), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) and ClinicalTrials.gov (http://clinicaltrials.gov). We searched the reference lists of identified trial reports to find additional trials. We also searched the ISI Web of Science Social Sciences Citation Index (SSCI) to find studies that cited the identified trials. There were no language or date restrictions in the search for trials. The electronic databases were last searched on 25 June 2010.
Selection criteria
Two authors independently assessed the titles and abstracts of all reports identified by the electronic and manual searches. In this review, we included randomized and quasi-randomized trials that compared various medical interventions to other medical interventions or control groups for the treatment of traumatic hyphema following closed globe trauma. There were no restrictions regarding age, gender, severity of the closed globe trauma or level of visual acuity at the time of enrollment.
Data collection and analysis
Two authors independently extracted the data for the primary and secondary outcomes. We entered and analyzed data using Review Manager (RevMan) 5. We performed meta-analyses using a fixed-effect model and reported dichotomous outcomes as odds ratios and continuous outcomes as mean differences.
Main results
Nineteen randomized and seven quasi-randomized studies with 2,560 participants were included in this review. Interventions included antifibrinolytic agents (oral and systemic aminocaproic acid, tranexamic acid, and aminomethylbenzoic acid), corticosteroids (systemic and topical), cycloplegics, miotics, aspirin, conjugated estrogens, monocular versus bilateral patching, elevation of the head, and bed rest. No intervention had a significant effect on visual acuity whether measured at two weeks or less after the trauma or at longer time periods. The number of days for the primary hyphema to resolve appeared to be longer with the use of aminocaproic acid compared to no use, but was not altered by any other intervention.
Systemic aminocaproic acid reduced the rate of recurrent hemorrhage (odds ratio (OR) 0.25, 95% confidence interval (CI) 0.11 to 0.5), but a sensitivity analysis omitting studies not using an intention-to-treat (ITT) analysis reduced the strength of the evidence (OR 0.41, 95% CI 0.16 to 1.09). We obtained similar results for topical aminocaproic acid (OR 0.42, 95% CI 0.16 to 1.10). We found tranexamic acid had a significant effect in reducing the rate of secondary hemorrhage (OR 0.25, 95% CI 0.13 to 0.49), as did aminomethylbenzoic acid as reported in a single study (OR 0.07, 95% CI 0.01 to 0.32). The evidence to support an associated reduction in the risk of complications from secondary hemorrhage (i.e., corneal blood staining, peripheral anterior synechiae, elevated intraocular pressure, and development of optic atrophy) by antifibrinolytics was limited by the small number of these events. Use of aminocaproic acid was associated with increased nausea, vomiting, and other adverse events compares with placebo. We found no difference in the number of adverse events with the use of systemic versus topical aminocaproic acid or with standard versus lower drug dose.
The available evidence on usage of corticosteroids, cycloplegics or aspirin in traumatic hyphema was limited due to the small numbers of participants and events in the trials.
We found no difference in effect between a single versus binocular patch nor ambulation versus complete bed rest on the risk of secondary hemorrhage or time to rebleed.
Authors’ conclusions
Traumatic hyphema in the absence of other intraocular injuries, uncommonly leads to permanent loss of vision. Complications resulting from secondary hemorrhage could lead to permanent impairment of vision, especially in patients with sickle cell trait/disease. We found no evidence to show an effect on visual acuity by any of the interventions evaluated in this review. Although evidence is limited, it appears that patients with traumatic hyphema who receive aminocaproic acid or tranexamic acid are less likely to experience secondary hemorrhaging. However, hyphema in patients on aminocaproic acid take longer to clear.
Other than the possible benefits of antifibrinolytic usage to reduce the rate of secondary hemorrhage, the decision to use corticosteroids, cycloplegics, or non-drug interventions (such as binocular patching, bed rest, or head elevation) should remain individualized because no solid scientific evidence supports a benefit. As these multiple interventions are rarely used in isolation, further research to assess the additive effect of these interventions might be of value.
doi:10.1002/14651858.CD005431.pub2
PMCID: PMC3437611  PMID: 21249670
22.  Incomplete evidence: the inadequacy of databases in tracing published adverse drug reactions in clinical trials 
Background
We would expect information on adverse drug reactions in randomised clinical trials to be easily retrievable from specific searches of electronic databases. However, complete retrieval of such information may not be straightforward, for two reasons. First, not all clinical drug trials provide data on the frequency of adverse effects. Secondly, not all electronic records of trials include terms in the abstract or indexing fields that enable us to select those with adverse effects data. We have determined how often automated search methods, using indexing terms and/or textwords in the title or abstract, would fail to retrieve trials with adverse effects data.
Methods
We used a sample set of 107 trials known to report frequencies of adverse drug effects, and measured the proportion that (i) were not assigned the appropriate adverse effects indexing terms in the electronic databases, and (ii) did not contain identifiable adverse effects textwords in the title or abstract.
Results
Of the 81 trials with records on both MEDLINE and EMBASE, 25 were not indexed for adverse effects in either database. Twenty-six trials were indexed in one database but not the other. Only 66 of the 107 trials reporting adverse effects data mentioned this in the abstract or title of the paper. Simultaneous use of textword and indexing terms retrieved only 82/107 (77%) papers.
Conclusions
Specific search strategies based on adverse effects textwords and indexing terms will fail to identify nearly a quarter of trials that report on the rate of drug adverse effects.
doi:10.1186/1471-2288-1-7
PMCID: PMC57741  PMID: 11591220
23.  Identifying Diagnostic Studies in MEDLINE: Reducing the Number Needed to Read 
Objectives. The search filters in PubMed have become a cornerstone in information retrieval in evidence-based practice. However, the filter for diagnostic studies is not fully satisfactory, because sensitive searches have low precision. The objective of this study was to construct and validate better search strategies to identify diagnostic articles recorded on MEDLINE with special emphasis on precision.
Design. A comparative, retrospective analysis was conducted. Four medical journals were hand-searched for diagnostic studies published in 1989 and 1994. Four other journals were hand-searched for 1999. The three sets of studies identified were used as gold standards. A new search strategy was constructed and tested using the 1989-subset of studies and validated in both the 1994 and 1999 subsets. We identified candidate text words for search strategies using a word frequency analysis of the abstracts. According to the frequency of identified terms, searches were run for each term independently. The sensitivity, precision, and number needed to read (1/precision) of every candidate term were calculated. Terms with the highest sensitivity × precision product were used as free text terms in combination with the MeSH term “SENSITIVITY AND SPECIFICITY” using the Boolean operator OR. In the 1994 and 1999 subsets, we performed head-to-head comparisons of the currently available PubMed filter with the one we developed.
Measurements. The sensitivity, precision and the number needed to read (1/precision) were measured for different search filters.
Results. The most frequently occurring three truncated terms (diagnos*; predict* and accura*) in combination with the MeSH term “SENSITIVITY AND SPECIFICITY” produced a sensitivity of 98.1 percent (95% confidence interval: 89.9–99.9%) and a number needed to read of 8.3 (95% confidence interval: 6.7–11.3%). In direct comparisons of the new filter with the currently available one in PubMed using the 1994 and 1999 subsets, the new filter achieved better precision (12.0% versus 8.2% in 1994 and 5.0% versus 4.3% in 1999. The 95% confidence intervals for the differences range from 0.05% to 7.5% (p = 0.041) and –1.0% to 2.3% (p = 0.45), respectively). The new filter achieved slightly better sensitivities than the currently available one in both subsets, namely 98.1 and 96.1% (p = 0.32) versus 95.1 and 88.8% (p = 0.125).
Conclusions. The quoted performance of the currently available filter for diagnostic studies in PubMed may be overstated. It appears that even single external validation may lead to over optimistic views of a filter’s performance. Precision appears to be more unstable than sensitivity. In terms of sensitivity, our filter for diagnostic studies performed slightly better than the currently available one and it performed better with regards to precision in the 1994 subset. Additional research is required to determine whether these improvements are beneficial to searches in practice.
doi:10.1197/jamia.M1124
PMCID: PMC349381  PMID: 12386115
24.  Medical interventions for traumatic hyphema 
Background
Traumatic hyphema is the entry of blood into the anterior chamber (the space between the cornea and iris) subsequent to a blow or a projectile striking the eye. Hyphema uncommonly causes permanent loss of vision. Associated trauma (e.g. corneal staining, traumatic cataract, angle recession glaucoma, optic atrophy, etc.) may seriously affect vision. Such complications may lead to permanent impairment of vision. Patients with sickle cell trait/disease may be particularly susceptible to increases of elevated intraocular pressure. If rebleeding occurs, the rates and severity of complications increase.
Objectives
To assess the effectiveness of various medical interventions in the management of traumatic hyphema.
Search methods
We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2013, Issue 8), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMED-LINE (January 1946 to August 2013), EMBASE (January 1980 to August 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 30 August 2013.
Selection criteria
Two authors independently assessed the titles and abstracts of all reports identified by the electronic and manual searches. In this review, we included randomized and quasi-randomized trials that compared various medical interventions versus other medical interventions or control groups for the treatment of traumatic hyphema following closed globe trauma. We applied no restrictions regarding age, gender, severity of the closed globe trauma, or level of visual acuity at the time of enrolment.
Data collection and analysis
Two authors independently extracted the data for the primary and secondary outcomes. We entered and analyzed data using Review Manager 5. We performed meta-analyses using a fixed-effect model and reported dichotomous outcomes as odds ratios and continuous outcomes as mean differences.
Main results
We included 20 randomized and seven quasi-randomized studies with 2643 participants in this review. Interventions included antifibrinolytic agents (oral and systemic aminocaproic acid, tranexamic acid, and aminomethylbenzoic acid), corticosteroids (systemic and topical), cycloplegics, miotics, aspirin, conjugated estrogens, traditional Chinese medicine, monocular versus bilateral patching, elevation of the head, and bed rest. No intervention had a significant effect on visual acuity whether measured at two weeks or less after the trauma or at longer time periods. The number of days for the primary hyphema to resolve appeared to be longer with the use of aminocaproic acid compared with no use, but was not altered by any other intervention.
Systemic aminocaproic acid reduced the rate of recurrent hemorrhage (odds ratio (OR) 0.25, 95% confidence interval (CI) 0.11 to 0.57), but a sensitivity analysis omitting studies not using an intention-to-treat (ITT) analysis reduced the strength of the evidence (OR 0.41, 95% CI 0.16 to 1.09). We obtained similar results for topical aminocaproic acid (OR 0.42, 95% CI 0.16 to 1.10). We found tranexamic acid had a significant effect in reducing the rate of secondary hemorrhage (OR 0.25, 95% CI 0.13 to 0.49), as did aminomethylbenzoic acid as reported in one study (OR 0.07, 95% CI 0.01 to 0.32). The evidence to support an associated reduction in the risk of complications from secondary hemorrhage (i.e. corneal blood staining, peripheral anterior synechiae, elevated intraocular pressure, and development of optic atrophy) by antifibrinolytics was limited by the small number of these events. Use of aminocaproic acid was associated with increased nausea, vomiting, and other adverse events compared with placebo. We found no difference in the number of adverse events with the use of systemic versus topical aminocaproic acid or with standard versus lower drug dose.
The available evidence on usage of corticosteroids, cycloplegics, or aspirin in traumatic hyphema was limited due to the small numbers of participants and events in the trials.
We found no difference in effect between a single versus binocular patch or ambulation versus complete bed rest on the risk of secondary hemorrhage or time to rebleed.
Authors’ conclusions
Traumatic hyphema in the absence of other intraocular injuries uncommonly leads to permanent loss of vision. Complications resulting from secondary hemorrhage could lead to permanent impairment of vision, especially in patients with sickle cell trait/disease. We found no evidence to show an effect on visual acuity by any of the interventions evaluated in this review. Although evidence was limited, it appears that patients with traumatic hyphema who receive aminocaproic acid or tranexamic acid are less likely to experience secondary hemorrhaging. However, hyphema in patients treated with aminocaproic acid take longer to clear.
Other than the possible benefits of antifibrinolytic usage to reduce the rate of secondary hemorrhage, the decision to use corticosteroids, cycloplegics, or nondrug interventions (such as binocular patching, bed rest, or head elevation) should remain individualized because no solid scientific evidence supports a benefit. As these multiple interventions are rarely used in isolation, further research to assess the additive effect of these interventions might be of value.
doi:10.1002/14651858.CD005431.pub3
PMCID: PMC4268787  PMID: 24302299
6-Aminocaproic Acid [therapeutic use]; Adrenal Cortex Hormones [therapeutic use]; Antifibrinolytic Agents [therapeutic use]; Aspirin [therapeutic use]; Bandages; Bed Rest; Estrogens, Conjugated (USP) [therapeutic use]; Hyphema [etiology, *therapy]; Mydriatics [therapeutic use]; Patient Positioning [methods]; Platelet Aggregation Inhibitors [therapeutic use]; Randomized Controlled Trials as Topic; Wounds, Nonpenetrating [*complications]; Humans
25.  Developing Appropriate Methods for Cost-Effectiveness Analysis of Cluster Randomized Trials 
Medical Decision Making  2012;32(2):350-361.
Aim. Cost-effectiveness analyses (CEAs) may use data from cluster randomized trials (CRTs), where the unit of randomization is the cluster, not the individual. However, most studies use analytical methods that ignore clustering. This article compares alternative statistical methods for accommodating clustering in CEAs of CRTs. Methods. Our simulation study compared the performance of statistical methods for CEAs of CRTs with 2 treatment arms. The study considered a method that ignored clustering—seemingly unrelated regression (SUR) without a robust standard error (SE)—and 4 methods that recognized clustering—SUR and generalized estimating equations (GEEs), both with robust SE, a “2-stage” nonparametric bootstrap (TSB) with shrinkage correction, and a multilevel model (MLM). The base case assumed CRTs with moderate numbers of balanced clusters (20 per arm) and normally distributed costs. Other scenarios included CRTs with few clusters, imbalanced cluster sizes, and skewed costs. Performance was reported as bias, root mean squared error (rMSE), and confidence interval (CI) coverage for estimating incremental net benefits (INBs). We also compared the methods in a case study. Results. Each method reported low levels of bias. Without the robust SE, SUR gave poor CI coverage (base case: 0.89 v. nominal level: 0.95). The MLM and TSB performed well in each scenario (CI coverage, 0.92–0.95). With few clusters, the GEE and SUR (with robust SE) had coverage below 0.90. In the case study, the mean INBs were similar across all methods, but ignoring clustering underestimated statistical uncertainty and the value of further research. Conclusions. MLMs and the TSB are appropriate analytical methods for CEAs of CRTs with the characteristics described. SUR and GEE are not recommended for studies with few clusters.
doi:10.1177/0272989X11418372
PMCID: PMC3757919  PMID: 22016450
randomized trial methodology; statistical methods; cost-effectiveness analysis

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