Arrhythmia monitoring and outcome after myocardial infarction (BIO|GUARD-MI): a randomized trial.

Objectives: Cardiac arrhythmias predict poor outcome after myocardial infarction (MI). We studied if arrhythmia monitoring with an insertable cardiac monitor (ICM) can improve treatment and outcome. Design: BIO|GUARD-MI was a randomized, international open-label study with blinded outcome assessment. Setting: Tertiary care facilities monitored the arrhythmias, while the follow-up remained with primary care physicians. Participants: Patients after ST-elevation (STEMI) or non-ST-elevation MI with an ejection fraction >35% and a CHA2DS2-VASc score ≥4 (men) or ≥5 (women). Interventions: Patients were randomly assigned to receive or not receive an ICM in addition to standard post-MI treatment. Device-detected arrhythmias triggered immediate guideline recommended therapy changes via remote monitoring. Main outcome measures: MACE, defined as a composite of cardiovascular death or acute unscheduled hospitalization for cardiovascular causes. Results: 790 patients (mean age 71 years, 72% male, 51% non-STEMI) of planned 1,400 pts were enrolled and followed for a median of 31.6 months. At 2 years, 39.4% of the device group and 6.7% of the control group had their therapy adapted for an arrhythmia [hazard ratio (HR) = 5.9, P < 0.0001]. Most frequent arrhythmias were atrial fibrillation, pauses and bradycardia. The use of an ICM did not improve outcome in the entire cohort (HR = 0.84, 95%-CI: 0.65-1.10; P = 0.21). In secondary analysis, a statistically significant interaction of the type of infarction suggests a benefit in the pre-specified non-STEMI subgroup. Risk factor analysis indicates that this may be connected to the higher incidence of MACE in patients with non-STEMI. Conclusions: The burden of asymptomatic but actionable arrhythmias is large in post-infarction patients. However, arrhythmia monitoring with an ICM did not improve outcome in the entire cohort. Post-hoc analysis suggests that it may be beneficial in non-STEMI patients or other high-risk subgroups. Clinical Trial Registration: [https://www.clinicaltrials.gov/ct2/show/NCT02341534], NCT02341534.

Anterior-Lateral Versus Anterior-Posterior Electrode Position for Cardioverting Atrial Fibrillation.

BACKGROUND: Smaller randomized studies have reported conflicting results regarding the optimal electrode position for cardioverting atrial fibrillation. However, anterior-posterior electrode positioning is widely used as a standard and believed to be superior to anterior-lateral electrode positioning. Therefore, we aimed to compare anterior-lateral and anterior-posterior electrode positioning for cardioverting atrial fibrillation in a multicenter randomized trial. METHODS: In this multicenter, investigator-initiated, open-label trial, we randomly assigned patients with atrial fibrillation scheduled for elective cardioversion to either anterior-lateral or anterior-posterior electrode positioning. The primary outcome was the proportion of patients in sinus rhythm after the first shock. The secondary outcome was the proportion of patients in sinus rhythm after up to 4 shocks escalating to maximum energy. Safety outcomes were any cases of arrhythmia during or after cardioversion, skin redness, and patient-reported periprocedural pain. RESULTS: We randomized 468 patients. The primary outcome occurred in 126 patients (54%) assigned to the anterior-lateral electrode position and in 77 patients (33%) assigned to the anterior-posterior electrode position (risk difference, 22 percentage points [95% CI, 13-30]; P<0.001). The number of patients in sinus rhythm after the final cardioversion shock was 216 (93%) assigned to anterior-lateral electrode positioning and 200 (85%) assigned to anterior-posterior electrode positioning (risk difference, 7 percentage points [95% CI, 2-12]). There were no significant differences between groups in any safety outcomes. CONCLUSIONS: Anterior-lateral electrode positioning was more effective than anterior-posterior electrode positioning for biphasic cardioversion of atrial fibrillation. There were no significant differences in any safety outcome. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03817372.

All-Cause and Cardiovascular Mortality Among Insulin-Naïve People With Type 2 Diabetes Treated With Insulin Detemir or Glargine: A Cohort Study in the UK.

INTRODUCTION: Uncontrolled type 2 diabetes (T2D) is associated with an increased risk of micro- and macrovascular complications and mortality. The impact of basal insulins on the risks of mortality and cardiovascular mortality in people with T2D has not been thoroughly investigated in real-world settings. The aim of the present real-word study was to investigate differences in mortality among insulin-naïve people with T2D who initiated insulin detemir (detemir) and insulin glargine (glargine). METHODS: We assessed all-cause and cardiovascular mortality in people with T2D, aged ≥ 40 years and insulin-naïve at treatment initiation. People were identified from the United Kingdom Clinical Practice Research Datalink GOLD national database (2004-2019). Database information included prescribed medications, demographic and clinical variables and mortality. Cause of death was obtained from the Office for National Statistics (ONS). For mortality, 24 clinically relevant confounders were considered and adjusted for using Cox regression analyses. RESULTS: The total cohort included 12,847 people with T2D, including 3031 who commenced detemir and 9816 who commenced glargine. Median age was 66.8 years and median diabetes duration was 7.6 years. From the total cohort, 3231 deaths occurred during follow-up and 6897 people were eligible for linkage to the ONS for cardiovascular mortality data (528 cardiovascular deaths). The adjusted hazard ratio (HR) (95% confidence interval [CI]) was 0.86 (0.79; 0.95) for all-cause mortality and 0.83 (0.67; 1.03) for cardiovascular mortality, in favour of detemir versus glargine. These associations were more pronounced among people with obesity (body mass index ≥ 30 kg/m2), with HRs (95% CI) of 0.79 (0.69; 0.91) and 0.69 (0.50; 0.96) for all-cause and cardiovascular mortality, respectively. CONCLUSION: In this real-world observational study, there was an association between all-cause mortality and basal insulin choice in insulin-naïve people with T2D; the mortality risk was lower with detemir versus glargine after adjustment for potential confounders.

Acute Lung Injury in Critically Ill Patients: Actin-Scavenger Gelsolin Signals Prolonged Respiratory Failure.

BACKGROUND: Gelsolin is an actin-scavenger controlling the tissue damage from actin in the blood. Gelsolin levels in circulation drops when tissue damage and corresponding actin release is pronounced due to catabolic conditions. The purpose of this study was to determine if low plasma gelsolin independently predicts a reduced chance of weaning from ventilator-demanding respiratory failure in critically ill patients within 28 days from admission. RESULTS: This cohort study included 746 critically ill patients with ventilator-demanding respiratory failure from the randomized clinical trial, "Procalcitonin And Survival Study (PASS)." Primary end point was successful weaning from mechanical ventilation within 28 days. We used multivariable Cox regression adjusted for age, sepsis, PaO2/FiO2 ratio and other known and suspected predictors of persistent respiratory failure. Follow-up was complete.For medical patients, baseline-gelsolin below the 25th percentile independently predicted a 40% lower chance of successful weaning within 28 days (HR 0.60, 95% CI 0.46-0.79, P = 0.0002); among surgical patients this end point was not predicted. Low gelsolin levels predicted chance of being "alive and out of intensive care at day 14" for both medical and surgical patients (HR 0.69, 95% CI 0.54-0.89, P = 0.004). Gelsolin levels did not predict 28 day mortality for surgical or medical patients. CONCLUSIONS: Low levels of serum gelsolin independently predict a decreased chance of successful weaning from ventilator within 28 days among medical intensive care patients. This finding has implications for identifying patients who need individualized intervention early in intensive care course to prevent unfavorable lung prognosis in acute respiratory failure. TRIAL REGISTRATION: This is a substudy to the PASS, Clinicaltrials.gov ID: NCT00271752, first registered January 1, 2006.

Predictive value of serum gelsolin and Gc globulin in sepsis - a pilot study.

BACKGROUND: Simultaneous determination of the two main actin scavenger proteins in sepsis has not been investigated until now. In our pilot study, we elucidated the predictive values of Gc globulin and gelsolin (GSN) in sepsis by comparing them to classic laboratory and clinical parameters. METHODS: A 5-day follow-up was performed, including 46 septic patients, 28 non-septic patients and 35 outpatients as controls. Serum Gc globulin and GSN levels were determined by automated immune turbidimetric assay on a Cobas 8000/c502 analyzer. Patients were retrospectively categorized according to the sepsis-3 definitions, and 14-day mortality was also investigated. RESULTS: First-day GSN also differentiated sepsis from non-sepsis (AUC: 0.88) similarly to C-reactive protein (AUC: 0.80) but was slightly inferior to procalcitonin (PCT) (AUC: 0.98) with a cutoff value of GSN at 22.29 mg/L (sensitivity: 83.3%; specificity: 86.2%). Only first-day SOFA scores (0.88) and GSN (0.71) distinguished septic survivors from non-survivors, whereas lactate (0.99), Gc globulin (0.76) and mean arterial pressure (MAP) (0.74) discriminated septic shock from sepsis. Logistic regression analyses revealed SOFA scores and GSN being significant factors regarding 14-day mortality. First-day GSN levels were higher (p<0.05) in septic survivors than in non-survivors. Gc globulin levels remained higher (p<0.01) in sepsis when compared with septic shock during the follow-up period. CONCLUSIONS: Both serum GSN and Gc globulin may have predictive values in sepsis. Considering the small sample size of our study, further measurements are needed to evaluate our results. Measurement of Gc globulin and GSN maybe useful in assessment of sepsis severity and in therapeutic decision-making.

Validation of an automated immune turbidimetric assay for serum gelsolin and its possible clinical utility in sepsis.

BACKGROUND: Studies showing the potential predictive value of the actin-binding protein gelsolin, in critically ill patients are scarce. Moreover, even up to now a rapid automated measurement of gelsolin has still remained a challenge. Therefore, we developed and validated an automated serum gelsolin immune turbidimetric assay for possible clinical use. METHODS: Validation of serum gelsolin assay was performed on a Cobas 8000/c502 analyzer (Roche) according to the second edition of Eurachem guidelines. Furthermore, we also studied the diagnostic value of serum gelsolin in sepsis when investigating sera of septic (n = 25), systemic inflammatory response syndrome (SIRS; n = 8) and control patients (n = 14). We compared our previously published Western blot data with those of the new turbidimetric assay. RESULTS: The sample volume was 7 µL and the assay time was 10 minutes. The detection limit was 0.72 mg/L, intra- and inter-assay imprecision remained in most cases less than 5% expressed as CV. Recovery was found to be 84.56%-93.52% and linearity study gave an appropriate correlation coefficient by linear regression analysis (r2  = .998). Septic patients exhibited lower (P = .015) first-day serum gelsolin levels than SIRS patients, which confirmed our previous Western blot results. The determined cut-off point for serum gelsolin was 14.05 mg/L (sensitivity: 75%; specificity: 60%) when investigating its diagnostic value in sepsis. CONCLUSION: Based on the results, our immune turbidimetric measurement offers a rapid and accurate quantitation of gelsolin in human serum samples. Serum gelsolin seems a promising additional diagnostic marker of sepsis which has to be further investigated.

Application of the WEAP model in strategic environmental assessment: Experiences from a case study in an arid/semi-arid area in China.

This article investigated how the use of a water resources assessment model contributed to one of the first strategic environmental assessments (SEA) conducted for arid/semi-arid regions in China. The study was based on the SEA of a coal industry development plan in Ordos, an arid/semi-arid region of northwest China, where a temporally and spatially simplified version of the WEAP (Water Evaluation And Planning System) model was applied for assessing the impact of the planned activities on local water resource system. Four scenarios were developed to simulate various alternatives using a diverse range of water utilisation measures such as irrigation efficiency, treatment and the reuse of water. The WEAP model itself was found to be a useful tool for efficient water resources assessment in SEA: 1) WEAP provides built-in simulation modules for water assessment, which improve the SEA's efficiency significantly; 2) WEAP temporally has the flexibility in both delivering information on a reasonably aggregated level by evaluating water resource on an annual time step, which fits most SEA cases, and being possible to take a finer time step analysis monthly, weekly even daily; 3) Spatially, WEAP has advantage in dealing with distributed demand sites in large spatial scale. However, although WEAP appears as a useful tool in providing support for decision-making, in this SEA case we experienced difficulty in building a feasible scenario to mitigate the impact of the proposed activities on the local water system, so that solution had to be found outside of the assessed scenarios - which led to the discussion on the fact that the proposed activities in SEA cases are rarely regarded as an uncertainty. Therefore future research on the scope of SEA scenarios could be valuable.

Indicators' role: How do they influence Strategic Environmental Assessment and Sustainable Planning - The Chinese experience.

As an information carrier and communication medium, indicators provide useful decision-making assistance in setting process goals and effectively reaching the goals. The main focus of this article is to investigate indicators' role in influencing planning through Strategic Environmental Assessment (SEA) especially related to Chinese experiences. From the perspective of planning and decision-making theory, the influence on planning is studied as influence of planning structure and influence of planning actors. Such a conceptual framework is applied in order to demonstrate how the use of indicators can influence planning through a SEA process. The study holds two empirical levels. On a general level, based on an online survey, this article investigates SEA practitioners' experiences in using indicators. On a case level, two urban plans are selected to provide more detailed experiences. The case level investigation is based on a documentary study and individual interviews with SEA practitioners/planners. By exploring how indicators influence planning through the structure of and the actors within SEA, this study tries to provide an overview of indicators' role in SEA. The results indicate that indicators are perceived as a useful tool in the Chinese SEA system. By improving and simplifying the procedures of SEA, the indicators exert more structural influence on SEA and on plan making. On the other hand, indicators are also shown to have more influence through political actors than found among technical actors.

Urinary orosomucoid: validation of an automated immune turbidimetric test and its possible clinical use.

INTRODUCTION: Besides routine serum markers of inflammatory diseases, the diagnostic potential of selected urinary proteins has not been fully exploited yet. Former studies revealed that urinary orosomucoid (u-ORM) might have complementary information in inflammatory disorders. Our aim was to develop and validate a fully automated method for u-ORM measurements and to evaluate its potential clinical impact on systemic inflammatory diseases. MATERIALS AND METHODS: A particle-enhanced immune turbidimetric assay was validated for a Cobas 8000/c502 analyzer to determine u-ORM levels. Spot urine samples from 72 healthy individuals, 28 patients with Crohn's disease and 30 septic patients were studied. RESULTS: Our assay time was 10 minutes and the detection limit of u-ORM was 0.02 mg/L. The intra- and inter-assay imprecision expressed as CV was less than 5%, and the recovery ranged between 95-103%. Within 10 to 60 years of age, a preliminary reference range for urinary orosomucoid/creatinine ratio (u-ORM/u-CREAT) was found to be 0.08 (0.01-0.24) mg/mmol [median (2.5-97.5 percentiles)]. Compared to controls, a five-fold increase of u-ORM/u-CREAT values in Crohn's disease and approximately a 240-fold increase in sepsis were observed. CONCLUSIONS: We set up a fast, sensitive and precise turbidimetric approach for automated u-ORM determination. Our highly sensitive assay is ideal for routine u-ORM measurements and might be a potential novel laboratory test in the management of systemic inflammatory processes.

Using design of experiments to optimize derivatization with methyl chloroformate for quantitative analysis of the aqueous phase from hydrothermal liquefaction of biomass.

Hydrothermal liquefaction is a promising technique for the production of bio-oil. The process produces an oil phase, a gas phase, a solid residue, and an aqueous phase. Gas chromatography coupled with mass spectrometry is used to analyze the complex aqueous phase. Especially small organic acids and nitrogen-containing compounds are of interest. The efficient derivatization reagent methyl chloroformate was used to make analysis of the complex aqueous phase from hydrothermal liquefaction of dried distillers grains with solubles possible. A circumscribed central composite design was used to optimize the responses of both derivatized and nonderivatized analytes, which included small organic acids, pyrazines, phenol, and cyclic ketones. Response surface methodology was used to visualize significant factors and identify optimized derivatization conditions (volumes of methyl chloroformate, NaOH solution, methanol, and pyridine). Twenty-nine analytes of small organic acids, pyrazines, phenol, and cyclic ketones were quantified. An additional three analytes were pseudoquantified with use of standards with similar mass spectra. Calibration curves with high correlation coefficients were obtained, in most cases R (2) > 0.991. Method validation was evaluated with repeatability, and spike recoveries of all 29 analytes were obtained. The 32 analytes were quantified in samples from the commissioning of a continuous flow reactor and in samples from recirculation experiments involving the aqueous phase. The results indicated when the steady-state condition of the flow reactor was obtained and the effects of recirculation. The validated method will be especially useful for investigations of the effect of small organic acids on the hydrothermal liquefaction process.

Analysis of organic gas phase compounds formed by hydrothermal liquefaction of Dried Distillers Grains with Solubles.

This work provides a comprehensive characterization of the gas phase from hydrothermal liquefaction of Dried Distillers Grains with Solubles (DDGS) collected during a 24-h continuous experiment. The gas consisted mainly of CO2, CO, H2, CH4 and C2H6 accounting for 96 v/v% while further analysis by gas chromatography coupled to mass spectrometry (GC-MS) showed additionally 62 compounds of which 54 were tentatively identified. These products included methanethiol, dimethyl sulfide, various olefins and several aromatic compounds. The composition provided clear indication of the steady state of the system. Apart from CO2, olefins were the most abundant compound class and could provide a source of revenue.

Generation of a new cystatin C-based estimating equation for glomerular filtration rate by use of 7 assays standardized to the international calibrator.

BACKGROUND: Many different cystatin C-based equations exist for estimating glomerular filtration rate. Major reasons for this are the previous lack of an international cystatin C calibrator and the nonequivalence of results from different cystatin C assays. METHODS: Use of the recently introduced certified reference material, ERM-DA471/IFCC, and further work to achieve high agreement and equivalence of 7 commercially available cystatin C assays allowed a substantial decrease of the CV of the assays, as defined by their performance in an external quality assessment for clinical laboratory investigations. By use of 2 of these assays and a population of 4690 subjects, with large subpopulations of children and Asian and Caucasian adults, with their GFR determined by either renal or plasma inulin clearance or plasma iohexol clearance, we attempted to produce a virtually assay-independent simple cystatin C-based equation for estimation of GFR. RESULTS: We developed a simple cystatin C-based equation for estimation of GFR comprising only 2 variables, cystatin C concentration and age. No terms for race and sex are required for optimal diagnostic performance. The equation, [Formula: see text] is also biologically oriented, with 1 term for the theoretical renal clearance of small molecules and 1 constant for extrarenal clearance of cystatin C. CONCLUSIONS: A virtually assay-independent simple cystatin C-based and biologically oriented equation for estimation of GFR, without terms for sex and race, was produced.

Serum and plasma neutrophil gelatinase associated lipocalin (NGAL) levels are not equivalent in patients admitted to intensive care.

BACKGROUND: Neutrophil gelatinase associated lipocalin (NGAL) is proposed as a biomarker of acute kidney injury (AKI). NGAL has been studied in a range of body fluids including serum and EDTA plasma. The aim of the present study was to establish relationship between serum NGAL concentrations and EDTA plasma NGAL concentrations in patients admitted to intensive care units (ICUs) and whether these determinations are directly comparable in this setting. METHODS: NGAL was measured in 40 paired samples of serum and EDTA plasma from 25 patients admitted to intensive care with a commercial particle-enhanced turbidimetric immunoassay (The NGAL Test™, BioPorto Diagnostics A/S, Gentofte, Denmark) on a Roche Hitachi 917 (Roche-Hitachi, Inc., Tokyo, Japan) analyzer. RESULTS: Serum NGAL concentrations ranged from 26.8 to 1,808 ng/ml (median 281 ng/ml, interquartile range (IQR) 453 ng/ml). EDTA plasma NGAL concentrations ranged from 25.7 to 1,752 ng/ml (median 225 ng/ml, IQR 352 ng/ml). The difference in NGAL concentrations in paired serum and EDTA plasma samples (serum- plasma) ranged from -13.8 to 321 ng/ml (median 79 ng/ml, IQR 116 ng/ml; difference from zero, P < 0.0001, Wilcoxon's signed rank test). Although serum and EDTA plasma values were correlated (Spearman's r = 0.95, P < 0.0001), Deming regression analysis showed a slope of 1.1 that was not significantly different from unity (95% confidence interval (CI) 1.0-1.1) and a highly significant intercept of 67.9 ng/ml with a wide confidence interval (95% CI 29.8-106). CONCLUSION: NGAL concentration values measured in serum and EDTA plasma cannot be directly compared and should not be used as equivalents in studies of patients admitted to intensive care.

A historical perspective of Global Warming Potential from Municipal Solid Waste Management.

The Municipal Solid Waste Management (MSWM) sector has developed considerably during the past century, paving the way for maximum resource (materials and energy) recovery and minimising environmental impacts such as global warming associated with it. The current study is assessing the historical development of MSWM in the municipality of Aalborg, Denmark throughout the period of 1970 to 2010, and its implications regarding Global Warming Potential (GWP(100)), using the Life Cycle Assessment (LCA) approach. Historical data regarding MSW composition, and different treatment technologies such as incineration, recycling and composting has been used in order to perform the analysis. The LCA results show a continuous improvement in environmental performance of MSWM from 1970 to 2010 mainly due to the changes in treatment options, improved efficiency of various treatment technologies and increasing focus on recycling, resulting in a shift from net emission of 618 kg CO(2)-eq.tonne(-1) to net saving of 670 kg CO(2)-eq.tonne(-1) of MSWM.

Stabilization, characterization, and selective removal of cystatin C amyloid oligomers.

The pathophysiological process in amyloid disorders usually involves the transformation of a functional monomeric protein via potentially toxic oligomers into amyloid fibrils. The structure and properties of the intermediary oligomers have been difficult to study due to their instability and dynamic equilibrium with smaller and larger species. In hereditary cystatin C amyloid angiopathy, a cystatin C variant is deposited in arterial walls and cause brain hemorrhage in young adults. In the present investigation, we use redox experiments of monomeric cystatin C, stabilized against domain swapping by an intramolecular disulfide bond, to generate stable oligomers (dimers, trimers, tetramers, decamers, and high molecular weight oligomers). These oligomers were characterized concerning size by gel filtration, polyacrylamide gel electrophoresis, and mass spectrometry, shape by electron and atomic force microscopy, and, function by assays of their capacity to inhibit proteases. The results showed the oligomers to be highly ordered, domain-swapped assemblies of cystatin C and that the oligomers could not build larger oligomers, or fibrils, without domain swapping. The stabilized oligomers were used to induce antibody formation in rabbits. After immunosorption, using immobilized monomeric cystatin C, and elution from columns with immobilized cystatin C oligomers, oligomer-specific antibodies were obtained. These could be used to selectively remove cystatin C dimers from biological fluids containing both dimers and monomers.

[Dizziness in patients with heart disease]. / Svimmelhed hos den kardiologiske patient.

In patients with heart disease, dizziness is primarily associated with syncope or pre-syncope and mandates further investigation to obtain a specific diagnosis, estimation of risk of sudden death and treatment options. After a focused history and physical examination, the cause of the problem may be determined in more than half of the patients. The reflex syncope is by far the most common form and may usually be handled by reassurance of the benign nature of the problem. Patients with syncope caused by brachy- or tachy-arrhythmia or structural or ischaemic heart disease should be referred to a cardiological department for specific diagnosis and treatment.

Critical factors for EIA implementation: literature review and research options.

After decades of development, the gap between expectations of Environment Impact Assessments (EIA) and their practical performance remains significant. Research has been done to identify the critical factors for an effective implementation of EIA. However, this research, to a large extent, has not been cumulated and analysed comprehensively according to the stages of the EIA process. This paper contributes to the critical review of the literature on EIA implementation and effectiveness by cumulating mainly empirical findings in an implementation theoretical perspective. It focuses on the links between different critical factors and how they relate to different stages in the EIA and thus influence the decision making process. After reviewing 33 refereed journal articles published between 1999 and 2011, we identified 203 notions of critical factors. Of these, 102 related to different stages defined in our comprehensive EIA implementation model, and 101 were identified as general factors related to the whole EIA system. The number of notions of stage factors and general factors is thus about equal. An overlap between stage factors and general factors was found, which demonstrates that critical factors function differently in different cases. The function of the critical factors is complex and it is difficult to determine contingencies and causations. In the sources we examined, there is evidently an imbalance between in-depth empirical research and general knowledge, and the paper offers some suggestions for future research.

Heart failure in patients with sick sinus syndrome treated with single lead atrial or dual-chamber pacing: no association with pacing mode or right ventricular pacing site.

AIMS: Previous studies indicate that ventricular pacing may precipitate heart failure (HF). We investigated occurrence of HF during long-term follow-up among patients with sick sinus syndrome (SSS) randomized to AAIR or DDDR pacing. Furthermore, we investigated effects of percentage of ventricular pacing (%VP) and pacing site in the ventricle. METHODS AND RESULTS: We analysed data from 1415 patients randomized to AAIR (n = 707) or DDDR pacing (n = 708). Ventricular pacing leads were recorded as located in either an apical or a non-apical position. The %VP and HF hospitalizations were recorded during follow-up. Patients were classified with new HF, if in New York Heart Association (NYHA) functional class IV or if presence of ≥2 of: oedema; dyspnoea; NYHA functional class III. Mean follow-up was 5.4 ± 2.4 years. Heart failure hospitalizations did not differ between groups. In the AAIR group, 170 of the 707 (26%) patients developed HF vs. 169 of the 708 (26%) patients in the DDDR group, hazard rate ratio (HR) 1.00, 95% confidence interval (CI) 0.79-1.22, P = 0.87. In DDDR patients, 146 of the 512 patients (29%) with ventricular leads in an apical position developed HF vs. 28 of the 161 patients (17%) with the leads in a non-apical position, HR 0.67, CI 0.45-1.00, P = 0.05. After adjustments this difference was non-significant. The incidence of HF was not associated with %VP (P = 0.57). CONCLUSION: In patients with SSS, HF was not associated with pacing mode, %VP, or ventricular lead localization. This suggests that DDDR pacing is safe in patients with SSS without precipitating HF.

A comprehensive approach to benefit-risk assessment in drug development.

Major regulatory agencies, for example, FDA and EMA, have started to request comprehensive benefit-risk analyses of pharmaceutical products prior to approval or labelling expansion. The purpose of this study is to develop a generally applicable and reliable data-driven benefit-risk assessment method, where two or more drugs/doses can be compared. Our aim is to formulate an approach that is simple to apply, allows direct comparison of different types of risks and benefits, and is tailored for application in different disease areas both during clinical development and in the marketing approval phase. The proposed benefit-risk assessment method involves eight successive steps: (1) establishment of the decision context, (2) identification of benefit and risk criteria, (3) weighting, (4) scoring, (5) evaluation of uncertainty, (6) calculation of weighted scores, (7) visualization, and (8) discussion and formulation of an overall conclusion. To reduce the impact of subjective judgements, scores are assigned to each criterion on the basis of objective information (data) wherever possible. The proposed benefit-risk evaluation approach offers comprehensive, data-driven assessments that can facilitate decision processes. It employs descriptive statistical methods to highlight the clinically significant differences between drugs in clinical trials. The approach can be used in single as well as in multiple trials and provides clear diagrams as the basis for presentation and discussion of the results.