Implantable cardioverter defibrillators for the treatment of arrhythmias and cardiac resynchronisation therapy for the treatment of heart failure: systematic review and economic evaluation

Background This assessment updates and expands on two previous technology assessments that evaluated implantable cardioverter defibrillators (ICDs) for arrhythmias and cardiac resynchronisation therapy (CRT) for heart failure (HF). Objectives To assess the clinical effectiveness and cost-effectiveness of ICDs in addition to optimal pharmacological therapy (OPT) for people at increased risk of sudden cardiac death (SCD) as a result of ventricular arrhythmias despite receiving OPT; to assess CRT with or without a defibrillator (CRT-D or CRT-P) in addition to OPT for people with HF as a result of left ventricular systolic dysfunction (LVSD) and cardiac dyssynchrony despite receiving OPT; and to assess CRT-D in addition to OPT for people with both conditions. Data sources Electronic resources including MEDLINE, EMBASE and The Cochrane Library were searched from inception to November 2012. Additional studies were sought from reference lists, clinical experts and manufacturers’ submissions to the National Institute for Health and Care Excellence. Review methods Inclusion criteria were applied by two reviewers independently. Data extraction and quality assessment were undertaken by one reviewer and checked by a second. Data were synthesised through narrative review and meta-analyses. For the three populations above, randomised controlled trials (RCTs) comparing (1) ICD with standard therapy, (2) CRT-P or CRT-D with each other or with OPT and (3) CRT-D with OPT, CRT-P or ICD were eligible. Outcomes included mortality, adverse events and quality of life. A previously developed Markov model was adapted to estimate the cost-effectiveness of OPT, ICDs, CRT-P and CRT-D in the three populations by simulating disease progression calculated at 4-weekly cycles over a lifetime horizon. Results A total of 4556 references were identified, of which 26 RCTs were included in the review: 13 compared ICD with medical therapy, four compared CRT-P/CRT-D with OPT and nine compared CRT-D with ICD. ICDs reduced all-cause mortality in people at increased risk of SCD, defined in trials as those with previous ventricular arrhythmias/cardiac arrest, myocardial infarction (MI) > 3 weeks previously, non-ischaemic cardiomyopathy (depending on data included) or ischaemic/non-ischaemic HF and left ventricular ejection fraction ≤ 35%. There was no benefit in people scheduled for coronary artery bypass graft. A reduction in SCD but not all-cause mortality was found in people with recent MI. Incremental cost-effectiveness ratios (ICERs) ranged from £14,231 per quality-adjusted life-year (QALY) to £29,756 per QALY for the scenarios modelled. CRT-P and CRT-D reduced mortality and HF hospitalisations, and improved other outcomes, in people with HF as a result of LVSD and cardiac dyssynchrony when compared with OPT. The rate of SCD was lower with CRT-D than with CRT-P but other outcomes were similar. CRT-P and CRT-D compared with OPT produced ICERs of £27,584 per QALY and £27,899 per QALY respectively. The ICER for CRT-D compared with CRT-P was £28,420 per QALY. In people with both conditions, CRT-D reduced the risk of all-cause mortality and HF hospitalisation, and improved other outcomes, compared with ICDs. Complications were more common with CRT-D. Initial management with OPT alone was most cost-effective (ICER £2824 per QALY compared with ICD) when health-related quality of life was kept constant over time. Costs and QALYs for CRT-D and CRT-P were similar. The ICER for CRT-D compared with ICD was £27,195 per QALY and that for CRT-D compared with OPT was £35,193 per QALY. Limitations Limitations of the model include the structural assumptions made about disease progression and treatment provision, the extrapolation of trial survival estimates over time and the assumptions made around parameter values when evidence was not available for specific patient groups. Conclusions In people at risk of SCD as a result of ventricular arrhythmias and in those with HF as a result of LVSD and cardiac dyssynchrony, the interventions modelled produced ICERs of < £30,000 per QALY gained. In people with both conditions, the ICER for CRT-D compared with ICD, but not CRT-D compared with OPT, was < £30,000 per QALY, and the costs and QALYs for CRT-D and CRT-P were similar. A RCT comparing CRT-D and CRT-P in people with HF as a result of LVSD and cardiac dyssynchrony is required, for both those with and those without an ICD indication. A RCT is also needed into the benefits of ICD in non-ischaemic cardiomyopathy in the absence of dyssynchrony. Study registration This study is registered as PROSPERO number CRD42012002062. Funding The National Institute for Health Research Health Technology Assessment programme

The cubicle warrior: the marionette of the digitalized warfare

In the last decade we have entered the era of remote controlled military technology. The excitement about this new technology should not mask the ethical questions that it raises. A fundamental ethical question is who may be held responsible for civilian deaths. In this paper we will discuss the role of the human operator or so-called ‘cubicle warrior’, who remotely controls the military robots behind visual interfaces. We will argue that the socio-technical system conditions the cubicle warrior to dehumanize the enemy. As a result the cubicle warrior is morally disengaged from his destructive and lethal actions. This challenges what he should know to make responsible decisions (the so-called knowledge condition). Nowadays and in the near future, three factors will influence and may increase the moral disengagement even further due to the decrease of locus of control orientation: (1) photo shopping the war; (2) the moralization of technology; (3) the speed of decision-making. As a result, cubicle warriors cannot be held reasonably responsible anymore for the decisions they make

Norwegian Physicians' Knowledge of and Opinions about Evidence-Based Medicine: Cross-Sectional Study

Objective: To answer five research questions: Do Norwegian physicians know about the three important aspects of EBM? Do they use EBM methods in their clinical practice? What are their attitudes towards EBM? Has EBM in their opinion changed medical practice during the last 10 years? Do they use EBM based information sources? Design: Cross sectional survey in 2006. Setting: Norway. Participants: 966 doctors who responded to a questionnaire (70% response rate). Results: In total 87% of the physicians mentioned the use of randomised clinical trials as a key aspect of EBM, while 53% of them mentioned use of clinical expertise and only 19% patients' values. 40% of the respondents reported that their practice had always been evidence-based. Many respondents experienced difficulties in using EBM principles in their clinical practice because of lack of time and difficulties in searching EBM based literature. 80% agreed that EBM helps physicians towards better practice and 52% that it improves patients' health. As reasons for changes in medical practice 86% of respondents mentioned medical progress, but only 39% EBM. Conclusions: The results of the study indicate that Norwegian physicians have a limited knowledge of the key aspects of EBM but a positive attitude towards the concept. They had limited experience in the practice of EBM and were rather indifferent to the impact of EBM on medical practice. For solving a patient problem, physicians would rather consult a colleague than searching evidence based resources such as the Cochrane Library

Neutralization, effector function and immune imprinting of Omicron variants

Currently circulating SARS-CoV-2 variants have acquired convergent mutations at hot spots in the receptor-binding domain$^{1}$ (RBD) of the spike protein. The effects of these mutations on viral infection and transmission and the efficacy of vaccines and therapies remains poorly understood. Here we demonstrate that recently emerged BQ.1.1 and XBB.1.5 variants bind host ACE2 with high affinity and promote membrane fusion more efficiently than earlier Omicron variants. Structures of the BQ.1.1, XBB.1 and BN.1 RBDs bound to the fragment antigen-binding region of the S309 antibody (the parent antibody for sotrovimab) and human ACE2 explain the preservation of antibody binding through conformational selection, altered ACE2 recognition and immune evasion. We show that sotrovimab binds avidly to all Omicron variants, promotes Fc-dependent effector functions and protects mice challenged with BQ.1.1 and hamsters challenged with XBB.1.5. Vaccine-elicited human plasma antibodies cross-react with and trigger effector functions against current Omicron variants, despite a reduced neutralizing activity, suggesting a mechanism of protection against disease, exemplified by S309. Cross-reactive RBD-directed human memory B cells remained dominant even after two exposures to Omicron spikes, underscoring the role of persistent immune imprinting

How Does Reasoning (Fail to) Contribute to Moral Judgment? Dumbfounding and Disengagement

Recent experiments in moral psychology have been taken to imply that moral reasoning only serves to reaffirm prior moral intuitions. More specifically, Jonathan Haidt concludes from his moral dumbfounding experiments, in which people condemn other people’s behavior, that moral reasoning is biased and ineffective, as it rarely makes people change their mind. I present complementary evidence pertaining to self-directed reasoning about what to do. More specifically, Albert Bandura’s experiments concerning moral disengagement reveal that moral reasoning often does contribute effectively to the formation of moral judgments. And such reasoning need not be biased. Once this evidence is taken into account, it becomes clear that both cognition and affect can play a destructive as well as a constructive role in the formation of moral judgments

Implementing evidence-based medicine in general practice: a focus group based study

BACKGROUND: Over the past years concerns are rising about the use of Evidence-Based Medicine (EBM) in health care. The calls for an increase in the practice of EBM, seem to be obstructed by many barriers preventing the implementation of evidence-based thinking and acting in general practice. This study aims to explore the barriers of Flemish GPs (General Practitioners) to the implementation of EBM in routine clinical work and to identify possible strategies for integrating EBM in daily work. METHODS: We used a qualitative research strategy to gather and analyse data. We organised focus groups between September 2002 and April 2003. The focus group data were analysed using a combined strategy of 'between-case' analysis and 'grounded theory approach'. Thirty-one general practitioners participated in four focus groups. Purposeful sampling was used to recruit participants. RESULTS: A basic classification model documents the influencing factors and actors on a micro-, meso- as well as macro-level. Patients, colleagues, competences, logistics and time were identified on the micro-level (the GPs' individual practice), commercial and consumer organisations on the meso-level (institutions, organisations) and health care policy, media and specific characteristics of evidence on the macro-level (policy level and international scientific community). Existing barriers and possible strategies to overcome these barriers were described. CONCLUSION: In order to implement EBM in routine general practice, an integrated approach on different levels needs to be developed