text:
Ivabradine for coronary artery disease and/or heart failure—a protocol for a systematic review of randomised clinical trials with meta-analysis and Trial Sequential Analysis
M. Maagaard ORCID: orcid.org/0000-0002-9037-72951,
E. E. Nielsen1,3,
C. Gluud1,2 &
J. C. Jakobsen1,2,3
Systematic Reviews volume 8, Article number: 39 (2019) Cite this article
Coronary artery disease and heart failure are both highly prevalent diseases with a global prevalence of 93 million and 40 million. These patients are at increased risk of morbidity and mortality. The management of these patients involves medical therapy, and both diseases can be treated using the heart rate-lowering drug ivabradine. However, the evidence regarding the use of ivabradine in the treatment of coronary artery disease and/or heart failure is unclear. Our objective is to assess the beneficial and harmful effects of ivabradine in the treatment of coronary artery disease and/or heart failure.
This protocol for a systematic review was undertaken using the recommendations of The Cochrane Collaboration, the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P), and the eight-step assessment procedure suggested by Jakobsen and colleagues. We plan to include all relevant randomised clinical trials assessing the use of ivabradine in the treatment of coronary artery disease and/or heart failure. We will search the Cochrane Central Register of Controlled Trials (CENTRAL), Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (EMBASE), Latin American and Caribbean Health Sciences Literature (LILACS), Science Citation Index Expanded on Web of Science, Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Science Journal Database (VIP), and BIOSIS in order to identify relevant trials. We will begin the searches in February 2019. All included trials will be assessed and classified at low risk of bias or at high risk of bias. Our primary conclusions will be based on the results from the primary outcomes at low risk of bias. Extracted data will be analysed using Review Manager 5.3 and Trial Sequential Analysis 0.9.5.10. We will create a 'Summary of Findings' table in which we will present our primary and secondary outcomes, and we will assess the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE).
The systematic review will have the potential to aid clinicians in decision-making regarding ivabradine and to benefit patients with coronary artery disease and/or heart failure.
Systematic review registration
PROSPERO CRD42018112082
Description of the conditions
Coronary artery disease is thought to be the most common risk factor and underlying disease of angina pectoris and heart failure [1, 2]. Coronary artery disease can lead to angina pectoris through a decrease in myocardial oxygen supply and to heart failure through acute myocardial infarction, pathological cardiac remodelling, and chronic myocardial dysfunction mediated by myocardial hypoperfusion [3].
Coronary artery disease and angina pectoris
Cardiovascular diseases account for 30% of all deaths worldwide with ischaemic heart disease (e.g. coronary artery disease) accounting for almost half of all cardiovascular deaths [4, 5]. The prevalence of coronary artery disease increased by 65% between 1990 and 2013, leading to an estimated global prevalence of approximately 93 million in 2013 [6] and a prevalence in the USA of more than 16.5 million [7]. The prevalence is higher in males [7]. Important risk factors for developing coronary artery disease and thereby angina pectoris are smoking, dyslipidaemia, age, hypertension, hyperglycaemia, physical inactivity, obesity, and diet [8,9,10]. Coronary artery disease is an economic burden with an estimated cost of $ 200 billion in the USA in 2015, whereas the total expenditure for cardiovascular diseases is estimated to be close to $ 550 billion in the USA in 2015 [7].
Coronary artery disease is characterised by recurrent, reproducible episodes of a mismatch between myocardial oxygen supply and myocardial oxygen demand resulting in myocardial ischaemia [11]. The most common manifestation of coronary artery disease is exercise or stress-induced chest discomfort known as stable angina pectoris, and often the diagnosis of angina is based solely on the symptoms as presented by the patient [11,12,13,14].
Coronary artery disease is a continuum of clinical presentations most commonly with symptoms of stable angina pectoris or with angina equivalent symptoms (e.g. dyspnoea). The clinical presentation differs due to the underlying pathophysiological mechanisms [11, 15]. There are three mechanisms thought to be the main mediators of angina pectoris: atherosclerotic disease (obstructive coronary artery disease), vasospastic disease (coronary artery spasm), and microvascular dysfunction [16,17,18]. The three mechanisms all lead to ischaemia, and thereby angina pectoris, by a decreased coronary blood flow due to narrowing of the lumen in the coronary arteries in atherosclerotic and vasospastic disease [16, 18] and in the pre-arterioles and arterioles in microvascular dysfunction [17].
Diagnosis and prognosis
The severity of coronary artery disease can be assessed by either of two validated questionnaires—the Rose Questionnaire for Angina Pectoris and the Seattle Angina Questionnaire [19, 20]. Guidelines recommend diagnostic workup to consist of an initial non-invasive test (coronary computed tomography, stress test with exercise electrocardiography, or stress imaging with myocardial perfusion scintigraphy) [11]. The non-invasive tests are not diagnostic but are indicative of coronary artery disease warranting invasive testing [21,22,23]. However, invasive testing with coronary arteriography should be reserved for patients that are unable to undergo stress testing and where the result will influence patient management (e.g. they are eligible for revascularisation) [11, 24]. In people with coronary artery disease, the annual risk of death appears to be similar to the general population with non-cardiovascular causes being responsible for most fatalities [25]. A review summarising results of non-randomised studies on the prognosis of angina pectoris in primary care estimated the yearly all-cause mortality rate to be 2.8 to 6.6% [26].
Heart failure is a prevalent disease with an estimated global prevalence of up to 37.7 million people [27, 28]. The lifetime risk for developing heart failure is approximately 20% [29]. The prevalence of heart failure is increasing, presumably caused by an increase in life-expectancy, improved treatment of acute cardiovascular events, and due to risk factors being more prevalent in the populations [27, 28, 30,31,32,33]. Risk factors for developing heart failure are hypertension, coronary artery disease, diabetes mellitus, and metabolic syndrome [29]. Heart failure is a costly disease with the USA spending $ 30.8 billion in 2012 and with estimated worldwide costs of $ 108 billion in 2012 [29, 34].
Definition and classification
Heart failure is a syndrome characterised by symptoms such as peripheral oedema, fluid retention, breathlessness, and dyspnoea [29]. Heart failure can occur due to functional cardiac disease (e.g. decrease in myocardial function) or structural cardiac disease (e.g. cardiac valve pathology), which may lead to either of or a combination of forward and backward failures [29, 35]. Forward heart failure of the left ventricle is defined as a decrease in cardiac output by means of impaired ejection or filling. Symptoms of forward failure are fatigue, dizziness, confusion, and asthenia (weakness) [36, 37]. Backward failure of the left ventricle is defined as pressure backing up from the left ventricle to the lungs, resulting in increased pulmonary blood pressure and retention of fluid in the lungs leading to dyspnoea and pulmonary oedema. Right ventricular failure might occur due to left ventricular failure, increased pulmonary blood pressure, or myocardial infarction. The symptoms of right ventricular failure are hepatomegaly, elevated jugular venous pressure, and peripheral oedema [38]. Decompensated (congestive) heart failure is the clinical syndrome of heart failure in relation to fluid and salt retention [29].
Heart failure can be classified according to left ventricular ejection fraction and is grouped into heart failure with preserved ejection fraction (ejection fraction ≥ 50%), heart failure with borderline/mid-range ejection fraction (ejection fraction 40 to 49%), and heart failure with reduced ejection fraction (ejection fraction < 40%) [29, 35]. The method most commonly used in staging heart failure is the New York Heart Association (NYHA) classification that stages heart failure according to the physical capabilities of an individual with heart failure [29, 35, 39].
Heart failure is the end stage of several diseases affecting the heart [40]. Heart failure is initiated by an index event that happens either abruptly (e.g. acute myocardial infarction) or gradually (e.g. genetic cardiomyopathies, ischaemic heart disease, or valve pathology) [41]. Following the index event, compensatory mechanisms attempt to maintain haemodynamic stability by means of maintaining an adequate cardiac output [41]. The main compensatory mechanism is the activation of the sympathetic nervous system led by the renin-angiotensin-aldosterone system [41, 42]. Prolonged activation of compensatory mechanisms might lead to the development of cardiac fibrosis, endothelial dysfunction, atherosclerosis, cardiomyopathy, cardiac remodelling, left ventricular hypertrophy, and aortic stiffening [42]. In pathological cardiac remodelling, the ventricles alter their function, shape, and size leading to increased afterload, subendocardial hypoperfusion, increased myocardial oxygen demand, and myocardial desynchronization [40, 43].
The diagnosis of heart failure is based on a thorough clinical examination of patients [29]. Paraclinical tests should include, but are not limited to, a 12-lead electrocardiogram and blood sampling [29]. Echocardiography is a low-cost, easy to apply modality for assessing the structure (e.g. size of chambers) and function of the heart (e.g. valve function and systolic and diastolic function). Traditionally, left ventricular ejection fraction measured by transthoracic echocardiography is the mainstay in the diagnosis and management of heart failure [44]. An observational study on the survival following a hospitalisation for incident heart failure found the all-cause mortality at 1, 2, and 5 years to be 37.3%, 52.9%, and 78.5% [45]. From the Framingham Heart Study, the 30-day mortality was 11% in men and 10% in women and the 5-year mortality was 59% in men and 45% in women [46]. Studies on the temporal trends of mortality related to heart failure have shown a decrease in mortality over time [46, 47]. The decrease in mortality is thought to be due to improved treatment of acute and chronic heart failure, early diagnosis, and partly due to a decrease in the prevalence of risk factors such as smoking [28].
Description of the intervention
The purpose of the treatment of coronary artery disease is well established across different guidelines: prevent premature death, prevent acute myocardial infarction and heart failure, minimise or eliminate symptoms of ischaemia, and restore or maintain physical activity and life quality [11, 24]. The treatment of coronary artery disease is focused on preventing attacks of angina and treating attacks when they occur [48]. These 'anti-anginal drugs' exert their effect in preventing and treating angina pectoris by decreasing myocardial oxygen consumption by means of decreasing heart rate, blood pressure, and myocardial contractility or by increasing the myocardial oxygen supply, mainly by means of increasing the coronary blood flow [48]. The 2013 European Society of Cardiology and the 2012 American College of Cardiology/American Heart Association guidelines recommend the following interventions for preventing and treating angina pectoris in coronary artery disease:
First line of treatment: beta-blocker or calcium channel blocker alone or in combination [11, 24]
Second line of treatment: switching to or adding either long-acting nitrates, ivabradine, nicorandil, ranolazine, or trimetazidine [11, 24]
Treatment of heart failure
The purpose of the treatment of heart failure is to improve clinical status, functional capabilities, and quality of life; prevent hospitalisation; and reduce mortality [29, 35]. Guidelines recommend the main treatment of heart failure with reduced ejection fraction to be a beta-blocker in addition to an angiotensin-converting enzyme inhibitor. For patients with heart failure with reduced ejection fraction who remain symptomatic despite treatment with an angiotensin-converting enzyme inhibitor and a beta-blocker, the addition of a mineralocorticoid-receptor antagonist is recommended [29, 35]. In addition, diuretics are used in patients with volume overload and in patients with decompensated heart failure as well as being the main component in the treatment of patients with heart failure with preserved ejection fraction [29, 35].
Ivabradine is used in the treatment of coronary artery disease and heart failure [11, 29, 35, 49]. Ivabradine is administered in tablet form from 2.5 to 7.5 mg twice daily in both coronary artery disease and heart failure [11, 35].
In the normal heart, the sinoatrial node is the dominant site of pacemaker activity through the If-channel that spontaneously generates action potentials when the cell becomes hyperpolarised. Thereby, the sinoatrial node is responsible for the heart rate [50]. Ivabradine selectively inhibits the If-channel, resulting in a decrease in action potentials and thereby a decrease in heart rate [50]. Ivabradine selectively decreases the heart rate, but unlike beta-blockers, ivabradine does not inhibit the inner conduction system of the heart [50]. Unlike beta-blockers and heart rate-lowering calcium channel antagonists, ivabradine does not exert a negative inotropic effect (the force of muscular contraction of the heart) [50].
Ivabradine is recommended in the European Society of Cardiology guidelines on acute and chronic heart failure for stable, symptomatic patients with left ventricular ejection fraction below or equal to 35% in sinus rhythm with a resting heart rate above or equal to 70 beats per minute despite therapy with beta-blocker, angiotensin-converting enzyme inhibitor (or angiotensin receptor blocker), or a mineralocorticoid receptor antagonist, or for people in whom beta-blocker therapy is contraindicated [35]. Ivabradine is also recommended as the second-line therapy for angina relief in the European Society of Cardiology guidelines on stable coronary artery disease [11]. Ivabradine was not included as a recommendation in the 2012 American College of Cardiology Foundation/American Heart Association guidelines on ischaemic heart disease, since the drug was first approved by the Food and Drug Administration in the USA in 2015 [24, 51].
In both heart failure and coronary artery disease, ivabradine might be beneficial due to its ability to selectively decrease heart rate, thereby decreasing myocardial oxygen demand. Theoretically, ivabradine also increases myocardial oxygen supply by prolonging diastole, thereby increasing the coronary artery perfusion without inhibiting the force of muscular contraction of the heart [50, 52, 53].
CYP3A4 inhibitors (e.g. clarithromycin, atazanavir, ketoconazole) may increase the plasma concentration of ivabradine, and adverse events associated with ivabradine are bradycardia, hypertension, atrial fibrillation, and phosphenes [54].
Why is it important to do this review?
Several reviews of randomised clinical trials have assessed the effect of ivabradine [55,56,57,58]. A review of randomised trials on ivabradine in the treatment of systolic heart failure found that treatment with ivabradine did not improve isolated cardiovascular death, isolated heart failure hospitalisation, or all-cause mortality [55]. A recent review of randomised trials on ivabradine for heart failure or coronary artery disease found that mortality in ivabradine-treated groups might not differ from groups treated with placebo [56]. Another review of randomised trials on the effectiveness of ivabradine in treating stable angina pectoris found that ivabradine significantly increased exercise duration and time to onset of angina [57]. Yet another review of randomised trials on ivabradine for coronary artery disease with or without left ventricular dysfunction found that ivabradine did not seem to affect the risk of all-cause mortality, cardiovascular death, or hospitalisation for new onset or worsening heart failure [58]. A review on ivabradine for stable angina also found that ivabradine does not seem to affect the risk of all-cause mortality, cardiovascular mortality and morbidity, or hospitalisation for worsening heart failure [59]. However, none of the above-mentioned reviews were systematic reviews, none adhered to the Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) guidelines, none of them published a protocol, none of them used Trial Sequential Analysis to minimise the risk of random errors, and only the 2016 review by Ye et al. and the 2017 review by Mengesha et al. assessed the risk of bias in individual trials according to The Cochrane Collaboration risk of bias in individual trial tool [57, 60,61,62,63,64,65]. There is a need for an updated systematic review assessing the harms and benefits of ivabradine for coronary artery disease and/or heart failure, adhering to the PRISMA statement, searching all relevant databases, assessing risk of bias in individual trials, minimising the risk of random error by means of Trial Sequential Analysis, and assessing the certainty of the evidence with GRADE [60, 61, 66,67,68].
The question sought to be answered is:
In patients with coronary artery disease and/or heart failure, does ivabradine compared with placebo benefit any clinical outcomes or induce any harms?
This protocol for a systematic review has been developed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) guidelines for reporting systematic reviews evaluating interventions in healthcare [66, 69] and the Cochrane Handbook [60].
Criteria for considering studies for this review
Types of studies
We will include randomised clinical trials irrespective of trial design, setting, publication status, publication year, and language for assessment of benefits and harms. We will include cluster-randomised studies. We will not include quasi-randomised studies or observational studies for the assessments of benefits. However, such non-randomised studies identified during our searches for trials will be included in the review for the assessments of adverse events. We are aware that by not searching for all observational studies on harms, we run the risk of putting more weight on potential benefits than on potential harms and we are likely to overlook rare adverse events and late adverse events [70].
Types of participants
We will include participants with coronary artery disease and/or heart failure. We will include participants irrespective of age, sex, and comorbidities.
Types of interventions
Experiment intervention: ivabradine in any form or dose
Control intervention: placebo or no intervention
We will accept any co-intervention, if the co-intervention is intended to be delivered similarly to the intervention and control groups.
Types of outcomes
For all outcomes, we will use the trial results reported at maximum follow-up. However, if the trialists report results at multiple time points, we will use the results reported at maximum follow-up.
Primary outcomes
Proportion of participants with one or more serious adverse events. We will define a serious adverse event as any untoward medical occurrence that resulted in death, was life-threatening, required hospitalisation or prolongation of existing hospitalisation, and resulted in persistent or significant disability or jeopardised the patient [71] (dichotomous outcome)
Quality of life measured on any valid scale (continuous outcome)
Cardiovascular mortality
Myocardial infarction (dichotomous outcome)
Proportion of participants with one or more adverse events not considered serious (please see above)
Exploratory outcomes
Resting heart rate (continuous outcome)
Ejection fraction (continuous outcome)
Six-minute walking distance (continuous outcome)
Angina measured on any valid scale (continuous outcome)
New York Heart Association (NYHA) classification of heart failure (dichotomous outcome)
Hospitalisation during follow-up (dichotomous outcome)
Individual serious adverse events
Individual adverse events not considered serious
Search methods
Electronic searches
We will search the Cochrane Central Register of Controlled Trials (CENTRAL), Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (EMBASE), Latin American and Caribbean Health Sciences Literature (LILACS), Science Citation Index Expanded on Web of Science, Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Science Journal Database (VIP), and BIOSIS in order to identify relevant trials. The preliminary search strategy for MEDLINE (Ovid) is given in Additional file 1. We will search all databases from their inception to the present. We will begin the search in February 2019.
Searching other resources
The reference lists of relevant publications will be checked for any unidentified randomised trials. We will contact authors of included studies and major pharmaceutical companies involved in the production or sales of ivabradine by email asking for unpublished randomised trials. Further, we will search for ongoing trials on:
ClinicalTrials.gov (www.clinicaltrials.gov)
Google Scholar (https://scholar.google.dk/)
The Turning Research into Practice (TRIP) Database (https://www.tripdatabase.com)
European Medicines Agency (EMA) (https://www.ema.europa.eu/ema/)
US Food and Drug Administration (FDA) (www.fda.gov)
China Food and Drug Administration (CFDA) (http://eng.sfda.gov.cn/WS03/CL0755/)
Medicines and Healthcare products Regulatory Agency (https://www.gov.uk/government/organisations/medicines-and-healthcare-products-regulatory-agency)
The World Health Organization (WHO) International Clinical trials Registry Platform (ICTRP) search portal (http://apps.who.int/trialsearch)
Additionally, we will by hand search conference abstracts from cardiology conferences for relevant trials. We will also consider unpublished and grey literature trials relevant to the review, if we identify such trials.
We will perform the review following the recommendations of The Cochrane Collaboration [60]. The analyses will be performed using Review Manager [72] and Trial Sequential Analysis [73]. In case of Review Manager statistical software not being sufficient, we will use STATA 15 [74].
Selection of studies
Two review authors (MM and EEN) will independently screen titles and abstracts. We will retrieve all relevant full-text study reports and publications. Two review authors (MM and EE) will independently screen the full text and identify and record reasons for exclusion of the ineligible studies. We will resolve any disagreement through discussion or, if required, we will consult a third author (JCJ). Trial selection will be displayed in an adapted flow diagram as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [61].
Data extraction and management
Two authors (MM and EEN) will extract data independently from included trials. Disagreements will be resolved by discussion with a third author (JCJ). We will assess duplicate publications and companion papers of a trial together to evaluate all available data simultaneously (maximise data extraction, correct bias assessment). We will contact the trial authors by email to specify any additional data, which may not have been reported sufficiently or at all in the publication.
Trial characteristics
Bias risk components (as defined below), trial design (parallel, cluster, factorial, or crossover), number of intervention arms, length of follow-up, estimation of sample size, and inclusion and exclusion criteria.
Participant characteristics and diagnosis
Number of randomised participants; number of analysed participants; number of participants lost to follow-up/withdrawals/crossover; compliance with medication; age range (mean or median) and sex ratio; type of arrhythmia (atrial fibrillation or atrial flutter); baseline numbers of cardiovascular risk factors (i.e. diabetes mellitus, hypertension, hyperlipidaemia, or smoking); baseline NYHA class; baseline number of participants with heart failure; baseline number of participants with valvular heart disease; baseline number of participants with previous myocardial infarction; baseline number of participants with previous revascularisation; and baseline number of participants with previous angina. We will additionally report the proportion of participants in the compared groups who receive beta-blockers, calcium channel blockers, long or short acting nitrates, angiotensin converting enzyme inhibitors, angiotensin II-receptor antagonists, angiotensin II-neprilysin inhibitors, and/or mineralocorticoid receptor antagonists.
Ivabradine strategy characteristics
Dose of intervention, mode of administration, and duration of administration
Co-intervention characteristics
Type of co-intervention, dose of co-intervention, duration of co-intervention, and mode of administration
Individual patient data
We will ask those responsible for the included trials to supply individual patient data.
Funding of the trial and notable conflicts of interest of trial authors will be extracted, if available. We will note in the 'Characteristics of included studies' table if outcome data were not reported in a usable way. Two review authors (MM and EEN) will independently transfer data into the Review Manager file. Disagreements will be resolved through discussion, or if required, we will consult with a third author (JCJ).
Assessment of risk of bias in included studies
We will use the instructions given in the Cochrane Handbook for Systematic Reviews of Interventions in our evaluation of the methodology and hence the risk of bias of the included trials. We will evaluate the methodology in respect of:
Random sequence generation
Blinding of participants and treatment providers
Blinding of outcome assessment
Incomplete outcome data
Selective outcome reporting
For profit bias
Other risks of bias
Overall risk of bias
These components enable classification of randomised trials with low risk of bias and high risk of bias. The latter trials tend to overestimate positive intervention effects and underestimate negative effects [75,76,77,78,79,80,81]. We will classify a trial as being at overall 'low risk of bias', only if all bias domains are classified as 'low risk of bias'. We will classify a trial as being at overall 'high risk of bias', if any of the bias domains are classified as 'unclear' or 'high risk of bias'. We will also assess for profit bias (see the 'Appendix' section for a list of criteria that we will classify the trials according to).
We will assess the domains 'blinding of outcome assessment', 'incomplete outcome data', and 'selective outcome reporting' for each outcome result. Thus, we can assess the bias risk for each outcome assessed in addition to each trial. Our primary conclusions will be based on the results of our primary outcomes at overall low risk of bias.
Differences between the protocol and the review
We will conduct the review according to this published protocol and report any deviations from it in the 'Differences between the protocol and the review' section of the systematic review.
Measures of treatment effect
Dichotomous outcomes
We will calculate risk ratios (RRs) with 95% confidence interval (CI) for dichotomous outcomes, as well as the Trial Sequential Analysis-adjusted CIs (see below).
Continuous outcomes
We will calculate the mean differences (MDs) with 95% CI for continuous outcomes, as well as the Trial Sequential Analysis-adjusted CIs (see below).
We will, as first option, contact all trial authors to obtain any relevant missing data (i.e. for data extraction and for assessment of risk of bias, as specified above).
We will not impute missing values for any outcomes in our primary analysis. In two of our sensitivity analyses (see paragraph below), we will impute data.
We will primarily analyse scores assessed at single time points. If only changes from baseline scores are reported, we will analyse the results together with follow-up scores. If standard deviations (SDs) are not reported, we will calculate the SDs using trial data, if possible. We will not use intention-to-treat data if the original report did not contain such data. We will not impute missing values for any outcomes in our primary analysis. In our sensitivity analysis (see paragraph below) for continuous outcomes, we will impute data.
Assessment of heterogeneity
We will primarily investigate forest plots to visually assess any sign of heterogeneity. We will secondly assess the presence of statistical heterogeneity by chi-square test (threshold P < 0.10) and measure the quantities of heterogeneity by the I2 statistics [82, 83].
We will investigate possible heterogeneity through subgroup analyses. Ultimately, we may decide that a meta-analysis should be avoided [60].
Assessment of reporting biases
We will use a funnel plot to assess reporting bias if ten or more trials are included. We will visually inspect funnel plots to assess the risk of bias. We are aware of the limitations of a funnel plot (i.e. a funnel plot assesses bias due to small sample size). From this information, we assess possible reporting bias. For dichotomous outcomes, we will test asymmetry with the Harbord test [84] if τ2 is less than 0.1 and with the Rücker test if τ2 is greater than 0.1. For continuous outcomes, we will use the regression asymmetry test [85] and the adjusted rank correlation test [86].
Unit of analysis issues
We will only include randomised clinical trials. For trials using crossover design, only data from the first period will be included [60, 87]. We will also include cluster-randomised trials after adjusting the original sample size of the trial to the effective sample size using the intracluster correlation coefficient from the 'design effect' [60]. Therefore, there will not be any unit of analysis issues.
We will undertake this meta-analysis according to the recommendations stated in the Cochrane Handbook for Systematic Reviews of Interventions [60], Keus et al. [88], and the eight-step assessment suggested by Jakobsen et al. [89]. We will use the statistical software Review Manager 5.3 provided by Cochrane to analyse data [72]. We will assess our intervention effects with both random effects meta-analyses [90] and fixed effects meta-analyses [91]. We will use the more conservative point estimate of the two [89]. The more conservative point estimate is the estimate closest to zero effect. If the two estimates are similar, we will use the estimate with the highest P value. We use three primary outcomes, and therefore, we will consider a P value of 0.025 as the threshold for statistical significance [89]. For secondary and exploratory outcomes, we will consider a P value of 0.05 as the threshold for statistical significance. We will investigate possible heterogeneity through subgroup analyses. Ultimately, we may decide that a meta-analysis should be avoided because of unexpected high heterogeneity [60]. We will use the eight-step procedure to assess if the thresholds for significance are crossed [89]. Our primary conclusion will be based on the results from the primary outcomes at low risk of bias [89]. Where multiple trial groups are reported in a single trial, we will include only the relevant groups. If two comparisons are combined in the same meta-analysis, we will have the control group to avoid double-counting [60]. Trials with a factorial design will be included.
Trial Sequential Analysis
Traditional meta-analysis runs the risk of random errors due to sparse data and repetitive testing of accumulating data when updating reviews. We wish to control the risks of type I errors and type II errors. We will, therefore, perform Trial Sequential Analysis on the outcomes, in order to calculate the required information size (that is the number of participants needed in a meta-analysis to detect or reject a certain intervention effect) and the cumulative Z-curve's breach of relevant trial sequential monitoring boundaries [62,63,64,65, 73, 92,93,94,95,96]. A more detailed description of Trial Sequential Analysis can be found in the Trial Sequential Analysis manual and at http://www.ctu.dk/tsa/ [94]. For dichotomous outcomes, we will estimate the required information size based on the observed proportion of patients with an outcome in the control group (the cumulative proportion of patients with an event in the control groups relative to all patients in the control groups), a relative risk reduction of 15%, an alpha of 2.5% for primary outcomes, an alpha of 5% for secondary and exploratory outcomes, a beta of 10%, and diversity as suggested by the trials in the meta-analysis. For continuous outcomes, we will in the Trial Sequential Analysis use the observed SD, a mean difference of the observed SD/2, an alpha of 2.5% for primary outcomes, an alpha of 5% for secondary and exploratory outcomes, and a beta of 10%.
Subgroup analysis and investigation of heterogeneity
Subgroup analysis
We will perform the following subgroup analysis when analysing the primary outcomes (all-cause mortality, serious adverse event, and quality of life):
Trials at high risk of bias compared to trials at low risk of bias
Angina pectoris trials compared to heart failure trials
Men compared to women
Participants with a resting heart rate at or above 70 compared to participants with a resting heart rate below 70.
Trials administering at or above median daily doses of ivabradine compared to trials administering ivabradine below median daily doses.
Trials administering at or above median duration (days) of ivabradine compared to trials administering ivabradine below median duration.
We will use the formal test for subgroup interactions in Review Manager [97].
To assess the potential impact of the missing data for dichotomous outcomes, we will perform the two following sensitivity analyses on both the primary and secondary outcomes:
'Best-worst-case' scenario: we will assume that all participants lost to follow-up in the ivabradine group have survived, had no serious adverse events, had a higher quality of life (see paragraph below), and had no myocardial infarction. We will assume the opposite for all participants lost to follow-up in the control group.
'Worst-base-case' scenario: we will assume that all participants lost to follow-up in the ivabradine group have not survived, had serious adverse events, had a lower quality of life (see paragraph below), and had myocardial infarction. We will assume the opposite for all participants lost to follow-up in the control group.
We will present results of both scenarios in our review. When analysing quality of life or ejection fraction, a 'beneficial outcome' will be the group mean plus two standard deviations (SDs) of the group mean and a 'harmful outcome' will be the group mean minus two SDs of the group mean [89].
We will present results of this scenario in our review. Other post hoc sensitivity analyses might be warranted if unexpected clinical or statistical heterogeneity is identified during the analysis of the review results [89].
'Summary of Findings' table
We will create a 'Summary of Findings' table using each of the prespecified outcomes (all-cause mortality, serious adverse event, quality of life, cardiovascular death, myocardial infarction, adverse events not considered to be serious). We will use the five GRADE considerations (bias risk of the trials, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of a body of evidence as it relates to the studies which contribute data to the meta-analyses for the prespecified outcomes [89, 98,99,100]. We will use methods and recommendations described in Chapter 8 (Section 8.5) and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions using GRADEpro software [60]. We will justify all decisions to downgrade the quality of studies using footnotes, and we will make comments to aid the reader's understanding of the review where necessary. First, we will present our results in the 'Summary of Findings' table based on the results from the trials with low risk of bias. Secondly, we will present the results based on all trials.
We will compare our GRADE assessment of imprecision based on a fixed effects model calculation of the optimal information size with that obtained with Trial Sequential Analysis based on a random effects model and heterogeneity correction of the required information size [101].
This systematic review protocol has several strengths. We have based the protocol on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) checklist [66, 69]. We have pre-defined our methodology based on the Cochrane Handbook for Systematic Reviews of Interventions [60], Keus et al. [88], the eight-step assessment as suggested by Jakobsen et al. [89], Trial Sequential Analysis [73], and the GRADE assessment [99, 102]. Through our pre-defined methodology, we consider the risk of random errors and systematic errors.
The systematic review will also have limitations. We will pool data from all trials regarding the treatment of coronary artery disease and heart failure using ivabradine, thereby potentially giving rise to clinical and statistical heterogeneity. However, we believe that there is significant overlap between patients with coronary artery disease and heart failure and the effects of ivabradine might therefore be similar in these different patient groups. Furthermore, we will estimate statistical heterogeneity and ultimately decide if a meta-analysis of all trials should be avoided. Moreover, we have pre-defined several subgroup and sensitivity analysis in order to assess whether or not the intervention effect differs between conditions and trials. We may conduct further subgroup analyses and sensitivity analyses to explain unexplained heterogeneity. By not searching for all non-randomised studies, we will likely overlook harms [70]. If the present review finds solid evidence for benefits, then a more thorough investigation of potential harms seems warranted. With this systematic review, we seek to provide the clinicians and decision-makers on clinical practice with a reliable evidence adjusted for bias, sparse data, and multiple testing regarding the treatment of coronary artery disease and heart failure using ivabradine.
Gheorghiade M, Sopko G, De Luca L, Velazquez EJ, Parker JD, Binkley PF, et al. Navigating the crossroads of coronary artery disease and heart failure. Circulation. 2006;114(11):1202–13.
Lala A, Desai AS. The role of coronary artery disease in heart failure. Heart Fail Clin. 2014;10(2):353–65.
Velagaleti R, Vasan RS. Heart failure in the 21st century: is it a coronary artery disease problem or hypertension problem? Cardiology Clinics. 2007;25(4):487 -v.
Wang H, Naghavi M, Allen C, Barber RM, Bhutta ZA, Carter A, et al. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015. The Lancet. 2016;388(10053):1459–544.
Nichols M, Townsend N, Scarborough P, Rayner M. Cardiovascular disease in Europe 2014: epidemiological update. Eur Heart J. 2014;35(42):2950–9.
Vos T, Barber RM, Bell B, Bertozzi-Villa A, Biryukov S, Bolliger I, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386(9995):743–800.
Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, et al. Heart disease and stroke statistics-2018 update: a report from the American Heart Association. Circulation. 2018;137(12):e67–e492.
Aykan AC, Gul I, Kalaycioglu E, Gokdeniz T, Hatem E, Mentese U, et al. Is metabolic syndrome related with coronary artery disease severity and complexity: an observational study about IDF and AHA/NHLBI metabolic syndrome definitions. Cardiol J. 2014;21(3):245–51.
Hung MJ, Hu P, Hung MY. Coronary artery spasm: review and update. Int J Med Sci. 2014;11(11):1161–71.
Jespersen L, Abildstrom SZ, Hvelplund A, Madsen JK, Galatius S, Pedersen F, et al. Burden of hospital admission and repeat angiography in angina pectoris patients with and without coronary artery disease: a registry-based cohort study. PLoS One. 2014;9(4):e93170.
Task Force M, Montalescot G, Sechtem U, Achenbach S, Andreotti F, Arden C, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J. 2013;34(38):2949–3003.
Pakhomov S, Hemingway H, Weston SA, Jacobsen SJ, Rodeheffer R, Roger VL. Epidemiology of angina pectoris: role of natural language processing of the medical record. Am Heart J. 2007;153:666–73.
Daly C, Clemens F, Lopez Sendon JL, Tavazzi L, Boersma E, Danchin N, et al. Gender differences in the management and clinical outcome of stable angina. Circulation. 2006;113(4):490–8.
Mozaffarian D, Bryson CL, Spertus JA, McDonell MB, Fihn SD. Anginal symptoms consistently predict total mortality among outpatients with coronary artery disease. Am Heart J. 2003;146(6):1015–22.
Valgimigli M, Biscaglia S. Stable angina pectoris. Curr Atheroscler Rep. 2014;16(7):422.
Arbab-Zadeh A, Nakano M, Virmani R, Fuster V. Acute coronary events. Circulation. 2012;125(9):1147–56.
Crea F, Camici PG, Bairey Merz CN. Coronary microvascular dysfunction: an update. Eur Heart J. 2014;35(17):1101–11.
Yilmaz A, Sechtem U. Angina pectoris in patients with normal coronary angiograms: current pathophysiological concepts and therapeutic options. Heart. 2012;98(13):1020–9.
Spertus JA, Winder JA, Dewhurst TA, Deyo RA, Prodzinski J, McDonnell M, et al. Development and evaluation of the Seattle Angina Questionnaire: a new functional status measure for coronary artery disease. J Am Coll Cardiol. 1995;25(2):333–41.
Sorlie PD, Cooper L, Schreiner PJ, Rosamond W, Szklo M. Repeatability and validity of the Rose questionnaire for angina pectoris in the Atherosclerosis Risk in Communities Study. J Clin Epidemiol. 1996;49:719–25.
Mahmoodzadeh S, Moazenzaddeh M, Rashidinejad H, Shekihvatan M. Diagnostic performance of ECG in the assessment of significant coronary artery disease. J Res Med Sci. 2011;16(6):750–5.
Banerjee A, Newman DR, Van den Bruel A, Heneghan C. Diagnostic accuracy of exercise stress testing for coronary artery disease: a systematic review and meta-analysis of prospective studies. Int J Clin Pract. 2012;66(5):477–92.
Zaya M, Mehta PK, Merz CN. Provocative testing for coronary reactivity and spasm. J Am Coll Cardiol. 2014;63(2):103–9.
Fihn SD, Gardin JM, Abrams J, Berra K, Blankenship JC, Dallas AP, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2012;60(24):e44–e164.
Bauters C, Deneve M, Tricot O, Meurice T, Lamblin N, Investigators C. Prognosis of patients with stable coronary artery disease (from the CORONOR study). Am J Cardiol. 2014;113(7):1142–5.
Jones M, Rait G, Falconer J, Feder G. Systematic review: prognosis of angina in primary care. Fam Pract. 2006;23(5):520–8.
Bui AL, Horwich TB, Fonarow GC. Epidemiology and risk profile of heart failure. Nat Rev Cardiol. 2011;8(1):30–41.
Ziaeian B, Fonarow GC. Epidemiology and aetiology of heart failure. Nat Rev Cardiol. 2016;13(6):368–78.
Writing Committee M, Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128(16):e240–327.
Vos T, Abajobir AA, Abate KH, Abbafati C, Abbas KM, Abd-Allah F, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390(10100):1211–59.
Sakata Y, Shimokawa H. Epidemiology of heart failure in Asia. Circ J. 2013;77(9):2209–17.
Maggioni AP. Epidemiology of heart failure in Europe. Heart Fail Clin. 2015;11(4):625–35.
McMurray JJ, Stewart S. Epidemiology, aetiology and prognosis of heart failure. Heart. 2000;83(5):596–602.
Cook C, Cole G, Asaria P, Jabbour R, Francis DP. The annual global economic burden of heart failure. Int J Cardiol. 2014;171(3):368–76.
Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016;18(8):891–975.
Carlsson M, Andersson R, Bloch KM, Steding-Ehrenborg K, Mosen H, Stahlberg F, et al. Cardiac output and cardiac index measured with cardiovascular magnetic resonance in healthy subjects, elite athletes and patients with congestive heart failure. J Cardiovasc Magn Reson. 2012;14:51.
Inamdar AA, Inamdar AC. Heart failure: diagnosis, management and utilization. J Clin Med. 2015;5(7):1–28.
Voelkel NF, Quaife RA, Leinwand LA, Barst RJ, McGoon MD, Meldrum DR, et al. Right ventricular function and failure: report of a National Heart, Lung, and Blood Institute working group on cellular and molecular mechanisms of right heart failure. Circulation. 2006;114(17):1883–91.
Dolgin M. Nomenclature and criteria for diagnosis of diseases of the heart and great vessels. Boston: Little Brown; 1994.
Jessup M, Brozena S. Heart failure. N Engl J Med. 2003;348:2007–18.
Mazurek JA, Jessup M. Understanding heart failure. Card Electrophysiol Clin. 2015;7(4):557–75.
Ferrario CM, Strawn WB. Role of the renin-angiotensin-aldosterone system and proinflammatory mediators in cardiovascular disease. Am J Cardiol. 2006;98(1):121–8.
Mann DL, Bristow MR. Mechanisms and models in heart failure: the biomechanical model and beyond. Circulation. 2005;111(21):2837–49.
Marwick TH. The role of echocardiography in heart failure. J Nucl Med. 2015;56(Suppl 4):31S–8S.
Goldberg RJ, Ciampa J, Lessard D, Meyer TE, Spencer FA. Long-term survival after heart failure: a contemporary population-based perspective. Arch Intern Med. 2007;167:490–6.
Levy D, Kenchaiah S, Larson MG, Benjamin EJ, Kupka MJ, Ho KK, et al. Long-term trends in the incidence of and survival with heart failure. N Engl J Med. 2002;347:1397–402.
Krumholz HM, Normand SL, Wang Y. Trends in hospitalizations and outcomes for acute cardiovascular disease and stroke, 1999-2011. Circulation. 2014;130(12):966–75.
Henderson RA, O'Flynn N, Guideline Development G. Management of stable angina: summary of NICE guidance. Heart. 2012;98(6):500–7.
Fihn SD, Blankenship JC, Alexander KP, Bittl JA, Byrne JG, Fletcher BJ, et al. 2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2014;64(18):1929–49.
Sulfi S, Timmis AD. Ivabradine the first selective sinus node I f channel inhibitor in the treatment of stable angina. Int J Clin Pract. 2006;60(2):222–8.
Thomas AM. Corlanor (ivabradine) Summary Review. In: FDA, editor. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206143Orig1s000SumR.pdf: Food and Drug Administration; 2015.
Lopez-Bescos L, Filipova S, Martos R. Long-term safety and efficacy of ivabradine in patients with chronic stable angina. Cardiology. 2007;108(4):387–96.
Weeda ER, Nguyen E, White CM. Role of Ivabradine in the treatment of patients with cardiovascular disease. Ann Pharmacother. 2016;50(6):475–85.
Tse S, Mazzola N. Ivabradine (Corlanor) for heart failure: the first selective and specific I f inhibitor. Pharm Ther. 2015;40(12):810–4.
Anantha Narayanan M, Reddy YN, Baskaran J, Deshmukh A, Benditt DG, Raveendran G. Ivabradine in the treatment of systolic heart failure - a systematic review and meta-analysis. World J Cardiol. 2017;9(2):182–90.
Kang S, Li CJ, Zhang XM. Ivabradine has a neutral effect on mortality in randomized controlled trials. Medicine (Baltimore). 2017;96(40):e8067.
Ye L, Ke D, Chen Q, Li G, Deng W, Wu Z. Effectiveness of ivabradine in treating stable angina pectoris. Medicine (Baltimore). 2016;95(14):e3245.
Cammarano C, Silva M, Comee M, Donovan JL, Malloy MJ. Meta-analysis of ivabradine in patients with stable coronary artery disease with and without left ventricular dysfunction. Clin Ther. 2016;38(2):387–95.
Mengesha HG, Weldearegawi B, Petrucka P, Bekele T, Otieno MG, Hailu A. Effect of ivabradine on cardiovascular outcomes in patients with stable angina: meta-analysis of randomized clinical trials. BMC Cardiovasc Disord. 2017;17(1):105.
Higgins JP, Green S. Cochrane Handbook for Systematic Reviews of Interventions. Available from http://handbook-5-1.cochrane.org/. The Cochrane Collaboration; 2011.
Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535.
Brok J, Thorlund K, Gluud C, Wetterslev J. Trial sequential analysis reveals insufficient information size and potentially false positive results in many meta-analyses. J Clin Epidemiol. 2008;61:763–9.
Wetterslev J, Thorlund K, Brok J, Gluud C. Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. J Clin Epidemiol. 2008;61:64–75.
Brok J, Thorlund K, Wetterslev J, Gluud C. Apparently conclusive meta-analyses may be inconclusive - trial sequential analysis adjustment of random error risk due to repetitive testing of accumulating data in apparently conclusive neonatal meta-analyses. Int J Epidemiol. 2009;38:287–98.
Thorlund K, Devereaux PJ, Wetterslev J. Can trial sequential monitoring boundaries reduce spurious inferences from meta-analyses? Int J Epidemiol. 2009;38:276–86.
Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4:1.
Schünemann H, Brożek J, Guyatt GH, Oxman A, editors. GRADE handbook for grading quality of evidence and strength of recommendations. The GRADE Working Group. 2013.
Wetterslev J, Jakobsen JC, Gluud C. Trial Sequential Analysis in systematic reviews with meta-analysis. BMC Med Res Methodol. 2017;17(1):39.
Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015;350:g7647.
Storebo OJ, Pedersen N, Ramstad E, Kielsholm ML, Nielsen SS, Krogh HB, et al. Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents - assessment of adverse events in non-randomised studies. Cochrane Database Syst Rev. 2018;5:CD012069.
International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use (ICH) adopts consolidated guideline on good clinical practice in the conduct of clinical trials on medicinal products for human use. Int Dig Health Legis. 1997;48(2):231–4. https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_Guideline.pdf.
The Cochrane Collaboration. Review Manager. 5.3 ed 2014.
Copenhagen Trial Unit. Trial Sequential Analysis. http://www.ctu.dk/tsa/.
StataCorp. Stata: Release 14. Statistical software. http://www.stata.com: StataCorp LP; 2014.
Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? Lancet. 1998;352:609–13.
Kjaergaard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Ann Intern Med. 2001;135:982–9.
Wood L, Egger M, Gluud LL, Schulz KF, Juni P, Altman DG, et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study. BMJ. 2008;336(7644):601–5.
Lundh A, Lexchin J, Mintzes B, Schroll JB, Bero L. Industry sponsorship and research outcome. Cochrane Database Syst Rev. 2017;2:MR000033.
Savovic J, Jones HE, Altman DG, Harris RJ, Juni P, Pildal J, et al. Influence of reported study design characteristics on intervention effect estimates from randomised controlled trials combined analysis of meta epidemiological studies. Health Technol Assess. 2012;16.
Schulz KF, Chalmers I, Hayes RJ, et al. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA. 1995;275:408–4012.
Gluud LL. Bias in clinical intervention research. Am J Epidemiol. 2006;163(6):493–501.
Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539–58.
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. Br Med J. 2003;327:557–60.
Harbord RM, Egger M, Sterne JA. A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints. Stat Med. 2006;25(20):3443–57.
Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. Br Med J. 1997;315:629–34.
Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088–101.
Elbourne DR, Altman DG, Higgins JP, Curtin F, Worthington HV, Vail A. Meta-analyses involving cross-over trials: methodological issues. Int J Epidemiol. 2002;31:140–9.
Keus F, Wetterslev J, Gluud C, van Laarhoven CJ. Evidence at a glance: error matrix approach for overviewing available evidence. BMC Med Res Methodol. 2010;10:90.
Jakobsen JC, Wetterslev J, Winkel P, Lange T, Gluud C. Thresholds for statistical and clinical significance in systematic reviews with meta-analytic methods. BMC Med Res Methodol. 2014;14:120.
DerSimonian R, Laird N. Meta-analysis in clinical trials revisited. Contemp Clin Trials. 2015;45(Pt A):139–45.
Demets DL. Methods for combining randomized clinical trial: strengths and limitations. Stat Med. 1986;6:341–50.
Wetterslev J, Thorlund K, Brok J, Gluud C. Estimating required information size by quantifying diversity in random-effects model meta-analyses. BMC Med Res Methodol. 2009;9:86.
Thorlund K, Anema A, Mills E. Interpreting meta-analysis according to the adequacy of sample size. An example using isoniazid chemoprophylaxis for tuberculosis in purified protein derivative negative HIV-infected individuals. Clin Epidemiol. 2010;2:57–66.
Thorlund K, Wetterslev J, Brok J, Imberger G, Gluud C. User manual for trial sequential analysis (TSA) http://www.ctu.dk/tsa/files/TSA_manual.pdf2011.
Imberger G, Gluud C, Boylan J, Wetterslev J. Systematic reviews of anesthesiologic interventions reported as statistically significant: problems with power, precision, and type 1 error protection. Anesth Analg. 2015;121:1611–22.
Imberger G, Thorlund K, Gluud C, Wetterslev J. False-positive findings in Cochrane meta-analyses with and without application of trial sequential analysis: an empirical review. BMJ Open. 2016;6(8):e011890.
Review Manager (RevMan). 5.3 ed: Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration; 2014.
Schünemann HJ, Best D, Vist G, Oxman AD. Letters, numbers, symbols and words: how to communicate grades of evidence and recommendations. Canadian Medical Assosiations Journal. 2003;169:677–80.
Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. Br Med J. 2008;336:924–6.
Guyatt GH, Oxman AD, Schüneman HJ, Tugwell P, Knottnerus A. GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology. J Clin Epidemiol. 2011;64:380–2.
Castellini G, Bruschettini M, Gianola S, Gluud C, Moja L. Assessing imprecision in Cochrane systematic reviews: a comparison of GRADE and Trial Sequential Analysis. Syst Rev. 2018;7(1):110.
Gartlehner G, Nussbaumer-Streit B, Wagner G, Patel S, Swinson-Evans T, Dobrescu A, et al. Increased risks for random errors are common in outcomes graded as high certainty of evidence. J Clin Epidemiol. 2019;106:50–9.
No funding has been received.
This protocol was written with the support from Copenhagen Trial Unit, Dept. 7812, Centre for Clinical Intervention Research, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100, Copenhagen Ø, Denmark
M. Maagaard, E. E. Nielsen, C. Gluud & J. C. Jakobsen
Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
C. Gluud & J. C. Jakobsen
Department of Cardiology, Holbaek Hospital, Holbaek, Denmark
E. E. Nielsen & J. C. Jakobsen
M. Maagaard
E. E. Nielsen
C. Gluud
J. C. Jakobsen
MM drafted the protocol. JCJ supervised and aided in the drafting of the protocol. EEN and CG amended the protocol. All authors read and approved of the final manuscript.
Correspondence to M. Maagaard.
Additional file 1
Preliminary search strategy for MEDLINE (OvidSP; 1946 to October 2018) (DOCX 14 kb)
Detailed explanation of each bias domain
Low risk: If sequence generation was achieved using computer random number generator or a random number table. Drawing lots, tossing a coin, shuffling cards, and throwing dice were also considered adequate if performed by an independent adjudicator.
Unclear risk: If the method of randomisation was not specified, but the trial was still presented as being randomised.
High risk: If the allocation sequence is not randomised or only quasi-randomised. These trials will be excluded.
Low risk: If the allocation of patients was performed by a central independent unit, on-site locked computer, identical-looking numbered sealed envelopes, drug bottles, or containers prepared by an independent pharmacist or investigator.
Uncertain risk: If the trial was classified as randomised but the allocation concealment process was not described.
High risk: If the allocation sequence was familiar to the investigators who assigned participants.
Low risk: If the participants and the treatment providers were blinded to intervention allocation and this was described.
Uncertain risk: If the procedure of blinding was insufficiently described.
High risk: If blinding of participants and the treatment providers was not performed.
Low risk of bias: If it was mentioned that outcome assessors were blinded, and this was described.
Uncertain risk of bias: If it was not mentioned if the outcome assessors in the trial were blinded or the extent of blinding was insufficiently described.
High risk of bias: If no blinding or incomplete blinding of outcome assessors was performed.
Low risk of bias: If missing data were unlikely to make treatment effects depart from plausible values. This could be either (1) there were no drop-outs or withdrawals for all outcomes or (2) the numbers and reasons for the withdrawals and drop-outs for all outcomes were clearly stated and could be described as being similar to both groups. Generally, the trial is judged as at a low risk of bias due to incomplete outcome data if drop-outs are less than 5%. However, the 5% cut-off is not definitive.
Uncertain risk of bias: If there was insufficient information to assess whether missing data were likely to induce bias on the results.
High risk of bias: If the results were likely to be biased due to missing data either because the pattern of drop-outs could be described as being different in the two intervention groups or the trial used improper methods in dealing with the missing data (e.g. last observation carried forward).
Low risk of bias: If a protocol was published before or at the time the trial was begun, and the outcomes specified in the protocol were reported on. If there is no protocol or the protocol was published after the trial has begun, reporting of all-cause mortality and all serious adverse events will grant the trial a grade of low risk of bias.
Uncertain risk of bias: If no protocol was published and the outcome all-cause mortality and serious adverse events were not reported on.
High risk of bias: If the outcomes in the protocol were not reported on.
Low risk of bias: If the trial is not financed by a company that might have an interest in a given result.
Uncertain risk of bias: If there is no description of how the trial is financed.
High risk of bias: If the trial is financed by a company that might have an interest in a given result.
Low risk of bias: If the trial appears to be free of other components (for example, academic bias or for profit bias) that could put it at risk of bias.
Unclear risk of bias: If the trial may or may not be free of other components that could put it at risk of bias.
High risk of bias: If there are other factors in the trial that could put it at risk of bias (for example, authors conducted trials on the same topic and for profit bias).
Low risk of bias: The trial will be classified as overall 'low risk of bias' only if all of the bias domains described in the above paragraphs are classified as 'low risk of bias'.
High risk of bias: The trial will be classified as 'high risk of bias' if any of the bias risk domains described in the above are classified as 'unclear' or 'high risk of bias'.
Maagaard, M., Nielsen, E.E., Gluud, C. et al. Ivabradine for coronary artery disease and/or heart failure—a protocol for a systematic review of randomised clinical trials with meta-analysis and Trial Sequential Analysis. Syst Rev 8, 39 (2019). https://doi.org/10.1186/s13643-019-0957-0
Accepted: 22 January 2019


text:
Q: CloudFoundry manifest.yml with objects as env variables so I am building a SpringBootApplication and I currently have the following settings in the yml:
my:
   caller:
      - id: someId
        url: someUrl
        context: someContext
      - id: someId2
        url: someUrl2
        context: someContext2

So basically it's a list of objects (I've created a POJO which has the 3 fields). Those objects are represented as a List in another class which is a @Component and has a @ConfigurationProperties(prefix = "my") and the List of POJOs is with @NestedConfigurationproperty.
So far everything works perfectly, Spring constructs the objects from the application.yml and fills the List just fine, however I can't simulate this configuration in CloudFoundry. I'm using a different manifest.yml for cloudfoundry, and I'm trying to place this structure in the env part of the manifest but it's not working (Cloudfoundry ignores it).
It looks something like this:
env:
   my:
   caller:
      - id: someId
        url: someUrl
        context: someContext
      - id: someId2
        url: someUrl2
        context: someContext2

I know with simple lines it works (for example ev_my_caller_id) but that way I can construct only 1 object, not a whole list and I haven't found anything in the CloudFoundry doc on how to construct multiple objects from the manifest.
If anyone has any ideas I would be really grateful!

A: The env block of the Cloud Foundry cli's manifest.yml file has a specific format.  You cannot use an arbitrary structure and expect it to work.
The format is:

env:
  var_name_1: val_1
  var_name_2: val_2

See docs for more details -> https://docs.cloudfoundry.org/devguide/deploy-apps/manifest.html#env-block
If you set the env variable with the correct name, you can use that to override certain values in Spring.  Thanks to Spring Boot's external configuration support.  Maybe that would be an option for you here.
https://docs.spring.io/spring-boot/docs/current/reference/html/boot-features-external-config.html
Ex: MY_PROPERTY=1234 would override my.property in application.properties.

A: You could use the SPRING_APPLICATION_JSON environment variable mentioned in the Spring Boot external config link that Daniel provided.
In your case, that would like something like this:
env:
  SPRING_APPLICATION_JSON: '{ "my": { "caller": [{ "id": "someId", "url": "someUrl", "context": "someContext" }, { "id": "someId2", "url": "someUrl2", "context": "someContext2" }]}}'

A: Not sure what you are trying to do, but you can try something like this:
env:
  test: '{ whatever complex object/variables }'

e.g.
env:
  test: '{ variable = value, variable2 = value2 }'

redpajama_set_name: RedPajamaStackExchange


We exterminate ten pests in one treatment when we spray your home for spiders.
As a business ourselves, we understand it's "your" needs that matter most.
At Canberra Pest Control, our primary concern is your primary concern, whether it be your customers, your staff, your clients, your students, your patrons, or your patients. For a discreet, effective pest control service that you can rely on not only in an emergency, but year after year for all your pest problems, contact Canberra Pest Control today.
Why are Canberra Pest Control's methods so effective?
Pest Control is a process, not a one time event. We believe that pest control should be proactive. Every one of our technicians are qualified & licensed to carry out pest control in accordance with Integrated Pest Management. Our Integrated Pest Management approach means that we try to address pest problems before they start, minimising the need for reactive treatments, so we're always one step ahead.
After a thorough assessment of your premises and pest problem, we will tailor a specific Integrated Pest Management strategy to suit your business. In addition to chemical pest control, we also focus on ongoing control measures and monitoring, depending on the pest species and life cycle.
By choosing a Canberra Pest Control Integrated Pest Management strategy, you are assured of a pest control plan suited specifically to your needs. We eliminate pest problems before they become an issue, so you can get back to focusing on your business – leave the pests to us.
Our tailored approach means we service a wide variety of businesses.
Canberra Pest Control offers pest control services to customers in various fields, from cafe's to restaurants, warehouses to retail furniture stores, manufacturing operations, tyre outlets and many others. We tailor our programs to fit the countless different environments we face every day and we hold as standard a $20,000,000 Liability & Indemnity Insurance Policy. When you choose Canberra Pest Control, you choose a program that addresses your specific needs and uses proven systems & products for the fast and effective control of your pests.
In the hospitality business, maintaining a pristine reputation can be what makes you. One Zomato review claiming to have seen a cockroach in your restaurant, can also break you. We understand that restaurants, bars, pubs and other food service businesses carry enormous pressures regarding health and safety, which means all our Technicians are fully trained in order to provide you with a pest control plan that adheres to the strictest government regulations, whilst remaining discreet.
Nobody knows your business like you do. That's why your Canberra Pest Control Technician will start with a comprehensive inspection of your property to understand the unique pest pressures your establishment faces. Then, based on their findings, we'll work with you to build a tailor made protection plan for your restaurant or food service business.
A pest problem in the office can be a major disturbance. Not only can pests cause panic, discomfort and even sickness amongst your staff and visitors, but certain pests like rodents can seriously damage your fittings and expensive electronic equipment.
We offer pest control services to customers in a wide variety of government & non-government offices & buildings. In order to provide you with a tailored Integrated Pest Management strategy, we preempt treatments with a comprehensive inspection of your building, so we can fully understand the unique pest pressures your office faces and offer the best solution to keep you and your employees safe.
Many pests are drawn to healthcare facilities due to their warmth and abundant food sources, yet there is no other place where pests can pose such a significant risk. Canberra Pest Control understands the importance of preventing cross-contamination and secondary infections due to an infestation and we are committed to maintaining impeccable standards of health and hygiene.
Just like patients, we understand that no two healthcare facilities are alike. That's why your Canberra Pest Control Technician will start with a comprehensive inspection to understand the unique pest pressures your facility faces. Then, based on their findings, we'll work with you to build an Integrated Pest Management strategy that is tailored to your facility, utilising our proven systems & products to better protect your patients and staff.
With an abundant supply of food, water and shelter, schools are an ideal habitat for pests. We service many schools throughout Canberra & surrounds, so we understand the unique pest control challenges facing education environments, from childcare centres & kindergartens through to university campuses.
In November 2009 the ACT Department of Education enacted a policy that requires any contractor that is to complete work on any Government School site to complete a Safe Work Methods Statement (SWMS). This is to ensure that any works carried out will be done in the safest possible way. The SWMS must be emailed, faxed or given to the School Business Officer (SBO), so they can go over the SWMS with the technician before the commencement of work.
From the factory to the warehouse to the shop floor, pests can pose a serious threat to your business. Canberra Pest Control has over 45 years of pest control experience and we understand the health and safety issues that business owners and management must encounter in the face of an infestation.
We offer pest control services to a wide variety of industrial and retail premises, tailoring Integrated Pest Management strategies to combat each site's specific pest problems. Canberra Pest control will work with you to ensure that your stock, equipment and staff remain safe from pests in the workplace. Whatever your business, we make it our business to protect it.


text:
Best Review Guide / Articles / Services / Vehicle service contracts/Extended Car Warranties / Toco Vehicle Warranty Service Review
Toco Vehicle Warranty Service Review
By: Kurtis | Last updated December 22, 2020
Has good coverage inclusion even for the most affordable plans
Has a good website where users can get a free quote and read their FAQ
Easy contract processing
Only has a few options for car coverages
Extended car warranties are the solution for owners whose original car manufacturer warranties are ending. It is not technically a warranty because it can be acquired at any time after the purchase of a car and because it can be bought from a third-party. Buying one can give users the peace of mind that they will be reimbursed for the repair of parts damaged during a mechanical breakdown.
Toco Warranty
Toco is an extended car warranty notable for its easy customer sign-up and flexible contracts.
To inquire and purchase a contract from them, users simply need to visit their website. Here, their zip code and information will be asked. An instant quote can be made online which makes it more convenient because of the lack of forceful dealers that has been a staple of most extended car warranty services.
Users should take note that Toco is currently not available for all states. Their available states are written in their website.
Available coverages
Currently, Toco offers three plans namely the Blue Plan, Yellow Plan, and the Orange Plan which may be not the most diverse set of options when compared to other services.
The Blue Plan is for cars aged from 2000 or later and have travelled 100,000 to 175,000 miles. Included in the coverage are Engine, Drive Axle, Transmission, Transfer Case, Electrical, Cooling System, Air Conditioning, Fuel System, and Turbo and Supercharger. This plan is best for those who own older vehicles.
The Yellow Plan is for cars aged from 2011 or later and have travelled 60,000 to 100,000 miles. Included in the coverage are those in the Blue Plan along with Brakes, Steering, Suspension, Electronic High-Tech package, Technology Package, and Modern Features package. The full list of those included in the packages is written in their website.
The Orange Plan is for cars aged from 2016 or newer and have travelled 0 to 60,000 miles. The coverage included are also those in the Yellow Plan.
Their plans are friendlier for those who own newer vehicles mainly because it has less risks of suffering from a mechanical breakdown which makes it good for those whose original manufacturer warranties are just ending.
The customer support for Toco Warranty is one of the best among extended car warranty service providers. For starters, they have a FAQ available on their website for questions regarding technical terms and the process of getting a contract. They also offer a free quote online.
Their customer representatives are also attentive and easy to communicate with. This is especially important to settle disputes and inquiries about the contracts.
Toco Warranty is an extended service warranty with straightforward coverages that can accommodate cars of different ages and mileage. Their customer service is top-notch because of their knowledgeable customer representatives and their online FAQ section. The only downside is their lack of diversity in terms of contracts (they only offer three).

redpajama_set_name: RedPajamaCommonCrawl


text:
Q: Android custom circular ProgressBar direction I have a custom Circular Progressbar. This is the drawable I have for it to be determinate:
<?xml version="1.0" encoding="utf-8"?>
<layer-list xmlns:android="http://schemas.android.com/apk/res/android">
  <item android:id="@android:id/secondaryProgress">
    <shape
        android:innerRadiusRatio="6"
        android:shape="ring"
        android:thicknessRatio="20.0"
        android:useLevel="true">
     <gradient
          android:centerColor="#999999"
          android:endColor="#999999"
          android:startColor="#999999"
          android:type="sweep" />
    </shape>
  </item>
  <item android:id="@android:id/progress">
   <rotate
      android:fromDegrees="270"
      android:pivotX="50%"
      android:pivotY="50%"
      android:toDegrees="270">

  <shape
      android:innerRadiusRatio="6"
      android:shape="ring"
      android:thicknessRatio="20.0"
      android:useLevel="true">

    <rotate
        android:fromDegrees="360"
        android:pivotX="50%"
        android:pivotY="50%"
        android:toDegrees="0" />

    <gradient
        android:centerColor="?attr/colorAccent"
        android:endColor="?attr/colorAccent"
        android:startColor="?attr/colorAccent"
        android:type="sweep" />

      </shape>
    </rotate>
  </item>
</layer-list>

I want it to show the progress in a clockwise direction, but now it's showing counterclockwise.
How do I change it?

A: I guess you're using an rtl language? You can force the progress bar to an ltr or clockwise direction by setting the layoutDirection property on your ProgressBar.
<ProgressBar
    ...
    android:layoutDirection="ltr" />

A: By using latest versions of material design library, you can achieve this:

*

*in the layout with this attribute
app:indicatorDirectionCircular

*or programmatically with this method
setIndicatorDirection()

Refer here for more info.

A: Change this
<rotate
    android:fromDegrees="360"
    android:pivotX="50%"
    android:pivotY="50%"
    android:toDegrees="0" />

to
<rotate
    android:fromDegrees="0"
    android:pivotX="50%"
    android:pivotY="50%"
    android:toDegrees="360" />

A: I'm not sure if it will work, but just try to set android:toDegrees="-360" like this :
<rotate
    android:fromDegrees="0"
    android:pivotX="50%"
    android:pivotY="50%"
    android:toDegrees="-360" />

A: you can change rotation on Y axis by 180 degrees
android:rotationY="180"


text:
Lance Becker: Back From the Dead
A Penn doctor is reviving patients like Chris Brooks — a 23-year-old who was clinically dead for 35 minutes — through a radical new procedure for victims of sudden cardiac arrest. But his work also raises a bold question: When are we really dead?
By Vicki Glembocki·	 11/24/2009, 2:21 a.m.
He calmly talked the ER doc through Penn's protocol for cooling — reducing the body's temp to 91 degrees for 24 hours. The hospital didn't have the high-tech "cooling suit" Penn wraps around a patient's torso and limbs, so the nurses packed Mike's body in Ziploc baggies filled with ice. Just like at Penn, they gave him a sedative, and a drug so he wouldn't shiver. They pumped chilled saline through his veins. And then they waited.
And Lynn waited, staring at her husband as he lay on his hospital bed in a coma, encased in ice, with tubes poking out of his body. After 24 hours, the nurses started to warm him slowly, taking away the ice, decreasing the drugs, carefully prodding him to wake up. No one knew if Mike was even still in there, if his brain would actually work. Finally, his eyes opened.
"Do you know who I am?" Lynn asked him.
"Yes," he said. "This is the strangest hotel room I've ever been in."
A joke. That was all Lynn needed to know that Mike was still there. She started to cry.
Lance Becker, though, is frustrated by this story. Yes, it has a happy ending. Yes, that ending is a direct result of the work at the Center for Resuscitation Science at Penn, which he runs. But here's Becker's problem:
Mike Rossman was lucky.
He was lucky that he collapsed in a roomful of people instead of in his house, alone. Lucky that among those people, there were doctors and nurses who gave him good CPR. Lucky that one of those doctors was his sister-in-law, who had just read about cooling, that some of the ER doctors at the hospital had heard about it, that they were willing to try a procedure they'd never done. Lucky that his wife not only knew the single most knowledgeable physician in the field of therapeutic hypothermia, but had his phone number.
"If she hadn't called, he'd be dead," Becker says. "We have to get to a point where cooling is standard." In all ambulances. In all emergency rooms. In all hospitals. But it's not. Yet.
And that's why Becker can't sleep at night, why he stays in his office on South 31st Street sometimes until 2:30 in the morning. He's certain that because of him, because he isn't working fast enough, people who shouldn't be are dying.
IT'S NOT AN easy job, changing what death means.
Well, that's not exactly true. The hard part isn't pushing the boundary between life and death. Becker's already doing that. That standard four-minute time limit during which you can be dead and still be brought back? Becker thinks it's now more like 15 minutes, maybe even 30.
The Best Events of Philly Beer Week 2019
Where to Eat Filipino Food in Philadelphia
It's Peak Spritz Season in Philly


Thomas (Tommy) Foster, Stillbrook, Mountrath, Co.Laois. Died 9th February 2019, (unexpectedly). Predeceased by his wife Sheila, deeply regretted by his son Martin, daughter-in-law Angela, sisters Katie and Molly, nieces, nephews, close family friends, extended family, relatives, neighbours and friends.
Reposing at his home on Monday evening from 7pm, with Rosary at 9pm. Removal on Tuesday morning to St. Fintan's Church Mountrath, for Requiem Mass at 11am, followed by burial in St. Fintan's Cemetery, Mountrath.
House private on Tuesday morning please.


The 2017 KTM 450 SX-F is still one of the best looking production machines on the dealer floors. . The air fuel mixture on both maps (1 and 2) seems to be really clean through the middle part of the KTM 450 SX-F's power. If you like to rev your machine the KTM 450 SX-F is the only.
How's the latest big-bore four-stroke from KTM? Check out our thoughts on the 2017 KTM 450 SX-F after.
For this FIRST RIDE we take a look at the all new 2017 KTM 450SXF featuring new triple clamps, new map.
Last but by no means least we give the big 2017 KTM 450 SX-F a Toofast Test. Big thanks to Buttercup Farm.
KTM 450 SX-F 2017 TEST. Markus Enok 371. Loading. Unsubscribe from Markus Enok 371? Cancel.
Check out this breakdown of the 2017 model with KTM's David O'Connor and TWMX test pilot Rich Taylor.
Take a KTM 450SX, swap to an 18ʺ rear wheel, larger capacity fuel tank, change to slightly more plush suspension compared to the full-motocross bike, add a .
Show #6 – Living long term with the 2017 KTM 450 SXF. 10 Jul 2017 · Rocky Mountain ATV/MC Keefer Tested. Presented by Rocky Mountain ATV/MC, Kris .


text:
Q: Shell script for checking if array is empty and restarting program if so I want to make a shell script that keeps running to check if my two light weight web servers are still running, and restart them if one is not.
I can use the the command pgrep -f thin to get an array (?) of pids of my server called thin.
When this returned array has a count of zero I want to run a command which starts both servers:
cd [path_to_app] && bundle exec thin -C app_config.yml start

pgrep -f thin returns all the pids of the servers that are running. For example:

2354223425

I am new to shell scripting and don't know how to store the results of pgrep-f thin in an array. E.g.,
#!/bin/sh
while true
do

    arr=$(pgrep -f thin) # /edited and now THIS WORKS!

    #Then I want to check the length of the array and when it is empty run the above
    #command, e.g.,

    if [ ${#arr[@]} == 0 ]; then
        cd [path_to_app] && bundle exec thin -C app_config.yml start
    fi

    #wait a bit before checking again
    sleep 30
done

The first problem I have is that I cannot store the pgrep values in an array, and I am not sure if I can check against zero values. After that I am not sure if there are problems with the other code. I hope someone can help me!

A: You forgot to execute the command:
arr=($(pgrep -f thin))

[...] when it is empty

If you only check for emptyness, you can directly use the exit status of grep.

-q, --quiet, --silent
     Quiet;  do  not write anything to standard output.
     Exit immediately with zero status
     if any match is  found,  even  if  an  error  was  detected.


The conception of the Energy Union, presented in spring 2014 by then Polish prime minister, Donald Tusk, met with varied reception. Its adoption by the new European Commission as one of the leading themes for the coming years is an indication that at the same time this project will be an important area around which negotiations will take place in the coming months.
As usual in such cases, various interested circles in the Member States have taken positions on this project, and have also assessed the potential stances of other countries in the EU – sometimes guided by conjecture, stereotypes, or on the basis of fragmented, incomplete information. In order to get a broader picture of the real views of entities influencing energy policy in given countries and to show the similarities and differences that exist in this field between Member States of the EU, the Institute of Public Affairs from Poland together with the Genshagen Stiftung from Germany, and in consultation with experts from France and Great Britain, implemented a research project presenting the opinions of members of political, economic/business and scientific elites from France, Germany, Poland, and Great Britain on the subject of the Energy Union and the potential for cooperation between countries of the EU in this field.
The research of the Institute of Public Affairs indicates that connected problems with energy are building active interest in Europe. Polish respondents place the greatest importance on the issue of energy dependence from abroad. They hope that the realization of the current energy project from the European Union will bring solutions that strengthen Member States in negotiations with gas deliveries, mostly with Russia, and streamline procedures on sudden incidences in deliveries. The development of connections between gas networks of the EU Member States has to ease the transnational transportation of gas and at the same time increase energy security and boost competition on the market. The Polish idea of creating mechanisms for the mutual purchase of gas for all of the EU, however, will not obtain approval from all of Eastern Europe. This proposition is perceived as a departure from free market principles.
In France, Germany and Great Britain, the main issue is a functioning internal energy market. Respondents in these countries wish to fully implement the Third Energy Package, which contains guidelines to ease the dealing of energy. It also brings attention to the need for a large coordinated strategy from individual members to make sure that operations undertaken in one country will cause no disturbances in their neighbors' energy market. The proposed synchronization of countries that have subsidized energy production systems for renewable energy, and also common regulations touching on the assistance of producers of conventional energy, whose task is the assurance of the consistent delivery of energy in a moment – taking into account weather conditions –may not produce renewable energy. Representatives from mid-sized economies claim that high energy prices in the European Union and exact environmental standards will assure that the industry will move to other parts of the world, which can seriously damage the economic conditions of the Union.
In Western Europe emphasis is on the close connections between energy and climate politics. France, Germany, and Great Britain are leading the need to continue efforts in reducing CO2 emissions. Therefore, they are planning the development of renewable energy sources as well as – for example, in France and Great Britain – nuclear energy. Emphasis is also placed on the importance of gas, as fossil fuels generate less greenhouse gas emissions than coal. In turn, coal is generally referred to as a raw material whose participation in the energy mix must be reduced. Polish conversation partners emphasize the high costs of an ambitious climate policy, particularly in countries such as Poland that are dependent on coal and do not have a large potential for the development of renewable resources. They also mention that accepted climate commitments from the European Union should be relative to the actions of other world powers.
During the debate organized with the Representation of the European Commission in Poland, the research results were presented and thought was given on to what extent the differences in energy policies divide Europe between East and West. Some voiced the opinion that divisions, if analyzed in some aspects, are formed between "Poland and the rest". However, taking into account many dimensions, exactly how climate energy policies are covered speaks many lines of division. The representatives of Polish administrations, Adrain Kondaszewski from the EU Economics Deparment in the Ministry of Foreign Affairs and Elżbieta Wróblewska from the Energy Department in the Ministry of Economy emphasized how many Polish demands from the primary concepts of the Energy Union, contrary to earlier fears, have been fulfilled.
The invited experts from the other three countries surveyed - Severin Fischer from SWP in Berlin, Jonathan Gaventa from E3G in London, and Carole Mathieu from IFR in Paris - brought up concerns about the different levels where discussion about the Energy Union is conducted. Political aspects are engaged pragmatically, whereby solutions that have the nature of being purely organizational can also take a long time to be implemented. Hence, for example, the possible regulation of industries that further integrate the Energy Union on a European scale, although technically possible and often desirable, will be the subject of further discussion.
The publication and the event in Warsaw was implemented under the project: "The Energy Union – the Perspectives of France, Germany, Poland, and Great Britain" produced in cooperation with the Genshagen Foundation and the Representation of the European Commission in Poland and the financial support of the Foundation for Polish-German Reconciliation and PKN Orlen.


text:
Newsmakers : IFAC Offers Lifeline for Beleaguered Accountants
Author: Anita Hawser
IFAC president Graham Ward
Executives who are still bogged down in Sarbanes-Oxley and IFRS compliance are probably thinking the regulators and the world of accountancy professionals have said all they need to say on transparency and accountability of financial reporting. But they would be wrong. At its recent board meeting in New York, the International Federation of Accountants (IFAC) announced that it would look at further measures for enhancing the "financial reporting supply chain" and that age-old bugbear, corporate management and governance.
The more skeptical may be thinking, 'Uh, oh! Not more regulatory compliance,' but IFAC president Graham Ward says it is too early to conclude that its work would lead to further regulation. Instead, he says, the initial focus would be on providing practical help to people within the financial reporting supply chain to ensure they "do the right thing" when it comes to preparing company financial statements. "We are not starting from a pre-judged position that more regulation is needed, " says Ward. "It has more to do with professional accountants within companies saying to us, 'Can you give us some help in a practical sense?' They want more recognition for the role they play in the production of audited financial statements."
Ward says the renewed focus on the quality of financial accounting and reporting stemmed from a "credibility report" it issued two years ago entitled "Rebuilding Public Confidence in Financial Reporting." And while company CFOs, CEOs and auditors have been in the firing line recently for inaccurate or dishonest financial reporting, IFAC's aim is that everybody involved in the production of financial statements from the initial stages should focus on quality. That includes lawyers and banks. Ward says there was evidence to suggest that they earned fees based on the measure of success they had in convincing auditors that financial statements that weren't fair were really fair. IFAC's study will also look at whether measures such as the independence and rotation of auditors has made any difference in the quality of financial reporting.
Anita Hawser
This article appeared in issue September 2005


A vulnerability assessment is the process of identifying, quantifying, and prioritizing (or ranking) the vulnerabilities in a system. Examples of systems for which vulnerability assessments are performed include, but are not limited to, information technology systems, energy supply systems, water supply systems, transportation systems, and communication systems. Such assessments may be conducted on behalf of a range of different organizations, from small businesses up to large regional infrastructures. Vulnerability from the perspective of disaster management means assessing the threats from potential hazards to the population and to infrastructure. It may be conducted in the political, social, economic or environmental fields.


I am using zsh. However, my zsh has default Emacs bindings as well.
> because it does better terminal emulation.
OK, this confirms my point of view. Thank you.
> Snapshots are generally not very reliable.
guess. Have to look for a different source of Debian packages.
>> Which Debian Wheezy packages from which source do you recommend?
> I don't know about Debian.  Others have posted about that.
> drag along).  Perhaps something similar is available under Debian.
the underlying methods are the same.
massively terrorizing the freedom of us and the next generations.
Next by Date: Buffer created but why movement command of function ignored?


text:
Clumsy flirting is not an offense
This is funny. Feminists are in hysterics about this:
Paris (CNN)A collective of 100 French women including film star Catherine Deneuve have signed an open letter defending men's "freedom to pester" women, sparking an angry response from a group of feminist activists.
The open letter, which criticized the #MeToo movement and warned about a new "puritanism" sparked by recent sexual harassment allegations, was published Tuesday in French newspaper Le Monde.
The group of writers, performers, academics and businesswomen denounced a "hatred of men and sexuality" and the recent wave of "denunciations." Men's "freedom to pester" is "indispensable to sexual freedom," they wrote.
"Rape is a crime, but insistent or clumsy flirting is not an offense, nor is gallantry macho aggression." ...
Deneuve and others argue that while the Harvey Weinstein scandal had led to a "legitimate wake-up call to the sexual violence exercised against women," the "fever" of publicly denouncing abusers "really only serves the enemies of sexual freedom."
Cycle of shame: Harassed in the street, then again on social media
To make matters worse, they wrote, "the movement chains women to the status of the eternal victim" by framing them as "poor little things who are dominated by demon phallocrats."
Not only that, but the movement has spawned a wave of hatred toward the accused, they said, who are mentioned in the same breath as sexual aggressors without being given the chance to defend themselves.
This new type of "swift justice" has already claimed its victims, they wrote, citing men forced to resign "when all they did wrong was touch a knee."
This comment is a clear reference to the resignation of former UK Defense Secretary Michael Fallon, who stepped down in November after admitting to touching journalist Julia Hartley-Brewer's knee in 2002.
Even the NY Times published a MeTooism criticism:
But privately, I suspect, many of us, including many longstanding feminists, will be rolling our eyes, having had it with the reflexive and unnuanced sense of outrage that has accompanied this cause from its inception, turning a bona fide moment of moral accountability into a series of ad hoc and sometimes unproven accusations.
I am beginning to think that no one expects women to make any sense on this subject.
When those women wore black at the Golden Globes, were they trying to make a statement that they too had traded sexual favors to get movie roles? And when women complain about sexual harassment, how many of them are just trying to brag that they are pretty enough to attract male attention. Most of these complainers appear to be seriously mentally disturbed.
Labels: feminism
Why Hollywood is liberal
New fossils from ex-Africans
Lost without Indian engineers
Most people are irresponsible for their actions
Brooks on the power of touch
ADL targets whites for blame
No discernible empathy for Trayvon
You guys are all the same
Increasingly Dangerous To Be A Christian
Pinker swallowed the red pill
The mental inference fallacy
Pinker explains the Alt Right
Skeptic article says Sandusky is innocent
Google Stifles Conservatives
Likes Trump policies, hates the man
Bonobos prefer socially dominant jerks
Who controls what you see