Relationship between sex, body size, and cardiac resynchronization therapy benefit: A patient-level meta-analysis of randomized controlled trials.

BACKGROUND: Women might benefit more than men from cardiac resynchronization therapy (CRT) and do so at shorter QRS durations. OBJECTIVE: This meta-analysis was performed to determine whether sex-based differences in CRT effects are better accounted for by height, body surface area (BSA), or left ventricular end-diastolic dimension (LVEDD). METHODS: We analyzed patient-level data from CRT trials (MIRACLE, MIRACLE ICD, MIRACLE ICD II, REVERSE, RAFT, COMPANION, and MADIT-CRT) using bayesian hierarchical Weibull regression models. Relationships between QRS duration and CRT effects were examined overall and in sex-stratified cohorts; additional analyses indexed QRS duration by height, BSA, or LVEDD. End points were heart failure hospitalization (HFH) or death and all-cause mortality. RESULTS: Compared with men (n = 5628), women (n = 1439) were shorter (1.62 [interquartile range, 1.57-1.65] m vs 1.75 [1.70-1.80] m; P < .001), with smaller BSAs (1.76 [1.62-1.90] m2 vs 2.02 [1.89-2.16] m2; P < .001). In adjusted sex-stratified analyses, the reduction in HFH or death was greater for women (hazard ratio, 0.54; credible interval, 0.42-0.70) than for men (hazard ratio, 0.77; credible interval, 0.66-0.89; Pinteraction = .009); results were similar for all-cause mortality even after adjustment for height, BSA, and LVEDD. Sex-specific differences were observed only in nonischemic cardiomyopathy. The effect of CRT on HFH or death was observed at a shorter QRS duration for women (126 ms) than for men (145 ms). Indexing QRS duration by height, BSA, or LVEDD attenuated sex-specific QRS duration thresholds for the effects of CRT on HFH or death but not on mortality. CONCLUSION: Although body size partially explains sex-specific QRS duration thresholds for CRT benefit, it is not associated with the magnitude of CRT benefit. Indexing QRS duration for body size might improve selection of patients for CRT, particularly with a "borderline" QRS duration. GOV REGISTRATION: NCT00271154, NCT00251251, NCT00267098, NCT00180271.

Benefit of cardiac resynchronization therapy among older patients: A patient-level meta-analysis.

BACKGROUND: Cardiac resynchronization therapy (CRT) reduces heart failure hospitalizations (HFH) and mortality for guideline-indicated patients with heart failure (HF). Most patients with HF are aged ≥70 years but such patients are often under-represented in randomized trials. METHODS: Patient-level data were combined from 8 randomized trials published 2002-2013 comparing CRT to no CRT (n = 6,369). The effect of CRT was estimated using an adjusted Bayesian survival model. Using age as a categorical (<70 vs ≥70 years) or continuous variable, the interaction between age and CRT on the composite end point of HFH or all-cause mortality or all-cause mortality alone was assessed. RESULTS: The median age was 67 years with 2436 (38%) being 70+; 1,554 (24%) were women; 2,586 (41%) had nonischemic cardiomyopathy and median QRS duration was 160 ms. Overall, CRT was associated with a delay in time to the composite end point (adjusted hazard ratio [aHR] 0.75, 95% credible interval [CI] 0.66-0.85, P = .002) and all-cause mortality alone (aHR of 0.80, 95% CI 0.69-0.96, P = .017). When age was treated as a categorical variable, there was no interaction between age and the effect of CRT for either end point (P > .1). When age was treated as a continuous variable, older patients appeared to obtain greater benefit with CRT for the composite end point (P for interaction = .027) with a similar but nonsignificant trend for mortality (P for interaction = .35). CONCLUSION: Reductions in HFH and mortality with CRT are as great or greater in appropriately indicated older patients. Age should not be a limiting factor for the provision of CRT.

Comorbidities and clinical response to cardiac resynchronization therapy: patient-level meta-analysis from eight clinical trials.

AIMS: Patients with heart failure usually have several other medical conditions that might alter the effects of interventions. We investigated whether the burden of comorbidity modified the clinical response to cardiac resynchronization therapy (CRT). METHODS AND RESULTS: Original patient-level data from eight randomized trials exploring the effects of CRT versus no CRT were pooled (BLOCK-HF, MIRACLE, MIRACLE-ICD, MIRACLE-ICD II, RAFT, COMPANION, MADIT-CRT and REVERSE). A prior history of the following comorbidities was considered: episodic or persistent atrial fibrillation (n = 920), coronary artery disease (n = 3732), diabetes (n = 2171), and hypertension (n = 3353). Patients were classified into three groups based on the number of comorbidities: 0, 1-2, or ≥3. The outcomes of interest were time to all-cause mortality and time to the composite outcome of heart failure hospitalization (HFH) or all-cause mortality. Outcomes were evaluated within each comorbidity group using a Bayesian hierarchical Weibull survival regression model. Of 6324 patients, 970 (15%) had no comorbidities, 4052 (64%) had 1-2 and 1302 (21%) had ≥3 comorbidities. The adjusted hazard ratio (aHR) for CRT versus no CRT for all-cause mortality in the overall cohort was 0.79 (95% credible interval [CI] 0.68-0.93) (p = 0.010); for no comorbidities the aHR was 0.54 (95% CI 0.34-0.86), for 1-2 comorbidities was 0.81 (95% CI 0.67-0.97) and for ≥3 comorbidities was 0.83 (95% CI 0.64-1.07) (no significant interaction between CRT and comorbidity burden: p = 0.13). For the endpoint of HFH or all-cause mortality, the aHR for the overall cohort was 0.74 (95% CI 0.65-0.84) (p = 0.001), for no comorbidities was 0.69 (95% CI 0.50-0.94), for 1-2 comorbidities was 0.77 (95% CI 0.66-0.90) and for ≥3 comorbidities was 0.68 (95% CI 0.55-0.82) (no significant interaction between CRT and comorbidity burden: p = 0.081). CONCLUSION: In a meta-analysis of patient-level data from eight major trials, the totality of evidence suggests that CRT reduces HFH and/or all-cause mortality even when several comorbid diseases are present. CLINICAL TRIAL REGISTRATION: NCT00271154, NCT00251251, NCT00267098, NCT00180271.

Cardiac resynchronization therapy in patients with a prior history of atrial fibrillation: Insights from four major clinical trials.

AIMS: To investigate the association of cardiac resynchronization therapy (CRT) on outcomes among participants with and without a history of atrial fibrillation (AF). METHODS: Individual-patient-data from four randomized trials investigating CRT-Defibrillators (COMPANION, MADIT-CRT, REVERSE) or CRT-Pacemakers (COMPANION, MIRACLE) were analyzed. Outcomes were time to a composite of heart failure hospitalization or all-cause mortality or to all-cause mortality alone. The association of CRT on outcomes for patients with and without a history of AF was assessed using a Bayesian-Weibull survival regression model adjusting for baseline characteristics. RESULTS: Of 3964 patients included, 586 (14.8%) had a history of AF; 2245 (66%) were randomized to CRT. Overall, CRT reduced the risk of the primary composite endpoint (hazard ratio [HR]: 0.69, 95% credible interval [CI]: 0.56-0.81). The effect was similar (posterior probability of no interaction = 0.26) in patients with (HR: 0.78, 95% CI: 0.55-1.10) and without a history of AF (HR: 0.67, 95% CI: 0.55-0.80). In these four trials, CRT did not reduce mortality overall (HR: 0.82, 95% CI: 0.66-1.01) without evidence of interaction (posterior probability of no interaction = 0.14) for patients with (HR: 1.09, 95% CI: 0.70-1.74) or without a history of AF (HR: 0.70, 95% CI: 0.60-0.97). CONCLUSION: The association of CRT on the composite endpoint or mortality was not statistically different for patients with or without a history of AF, but this could reflect inadequate power. Our results call for trials to confirm the benefit of CRT recipients with a history of AF.

Outcomes of Cardiac Resynchronization Therapy by New York Heart Association Class: A Patient-Level Meta-Analysis.

Data on the benefits of cardiac resynchronization therapy (CRT) in patients with severe heart failure (HF) symptoms are limited. We investigated the relative effects of CRT in patients with ambulatory NYHA IV vs. III functional class at the time of device implantation. In this meta-analysis, we pooled patient-level data from the MIRACLE, MIRACLE-ICD, and COMPANION trials. Outcomes evaluated were time to the composite endpoint of first HF hospitalization (HFH) or all-cause mortality and time to all-cause mortality alone. The association between CRT and outcomes was evaluated using a Bayesian Hierarchical Weibull survival regression model. We assessed if this association differs between NYHA III and IV groups by adding an interaction term between CRT and NYHA class as a random effect. A sensitivity analysis was performed by including data from the RAFT trial. Our pooled analysis included 2309 patients. Overall, CRT was associated with a longer time to HFH or all-cause mortality (adjusted hazard ratio [aHR] 0.79, 95%CI 0.64 - 0.99, p = 0.044), with a similar association with time to all-cause mortality (aHR 0.78, 95% CI 0.59 - 1.03, p = 0.083). Associations of CRT with outcomes were not significantly different for those in NYHA III and IV classes (ratio of aHR 0.72, 95% CI 0.30 - 1.27, p = 0.23 for HFH/mortality; ratio of aHR 0.70, 95% CI 0.35 - 1.34, p = 0.27 for all-cause mortality alone). The sensitivity analysis, including RAFT data, did not show a significant relative CRT benefit between NYHA III and IV classes. Overall, there was no significant difference in the association of CRT with either outcome for patients in NYHA functional class III compared with functional class IV.

Cardiac Resynchronization Therapy Improves Outcomes in Patients With Intraventricular Conduction Delay But Not Right Bundle Branch Block: A Patient-Level Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Benefit from cardiac resynchronization therapy (CRT) varies by QRS characteristics; individual randomized trials are underpowered to assess benefit for relatively small subgroups. METHODS: The authors analyzed patient-level data from pivotal CRT trials (MIRACLE [Multicenter InSync Randomized Clinical Evaluation], MIRACLE-ICD [Multicenter InSync ICD Randomized Clinical Evaluation], MIRACLE-ICD II [Multicenter InSync ICD Randomized Clinical Evaluation II], REVERSE [Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction], RAFT [Resynchronization-Defibrillation for Ambulatory Heart Failure], BLOCK-HF [Biventricular Versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block], COMPANION [Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure], and MADIT-CRT [Multicenter Automatic Defibrillator Implantation Trial - Cardiac Resynchronization Therapy]) using Bayesian Hierarchical Weibull survival regression models to assess CRT benefit by QRS morphology (left bundle branch block [LBBB], n=4549; right bundle branch block [RBBB], n=691; and intraventricular conduction delay [IVCD], n=1024) and duration (with 150-ms partition). The continuous relationship between QRS duration and CRT benefit was also examined within subgroups defined by QRS morphology. The primary end point was time to heart failure hospitalization (HFH) or death; a secondary end point was time to all-cause death. RESULTS: Of 6264 patients included, 25% were women, the median age was 66 [interquartile range, 58 to 73] years, and 61% received CRT (with or without an implantable cardioverter defibrillator). CRT was associated with an overall lower risk of HFH or death (hazard ratio [HR], 0.73 [credible interval (CrI), 0.65 to 0.84]), and in subgroups of patients with QRS ≥150 ms and either LBBB (HR, 0.56 [CrI, 0.48 to 0.66]) or IVCD (HR, 0.59 [CrI, 0.39 to 0.89]), but not RBBB (HR 0.97 [CrI, 0.68 to 1.34]; Pinteraction <0.001). No significant association for CRT with HFH or death was observed when QRS was <150 ms (regardless of QRS morphology) or in the presence of RBBB. Similar relationships were observed for all-cause death. CONCLUSIONS: CRT is associated with reduced HFH or death in patients with QRS ≥150 ms and LBBB or IVCD, but not for those with RBBB. Aggregating RBBB and IVCD into a single "non-LBBB" category when selecting patients for CRT should be reconsidered. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifiers: NCT00271154, NCT00251251, NCT00267098, and NCT00180271.

Developing the Next Generation of Leaders in Health Policy and Management: Lessons From an Undergraduate Student-Led Organization.

As health care continues to evolve, training the next generation of healthcare leaders is more important than ever. However, many university undergraduate students are not directly exposed to topics such as health policy and management within their coursework or co-curricular engagements. At Duke University, we developed the Student Collaborative on Health Policy (SCOHP) as an inter-disciplinary health policy hub that offers opportunities for learning, engagement, and leadership in the healthcare-related fields for students of all academic backgrounds. We see opportunity for similar student-led groups to be established by student leaders at other institutions, increasing interaction with experts, mentorship and the accessibility of experiential education, service, and leadership in the health care sector.

Evidence gaps in economic analyses of hearing healthcare: A systematic review.

BACKGROUND: Hearing loss is a common and costly medical condition. This systematic review sought to identify evidence gaps in published model-based economic analyses addressing hearing loss to inform model development for an ongoing Lancet Commission. METHODS: We searched the published literature through 14 June 2020 and our inclusion criteria included decision model-based cost-effectiveness analyses that addressed diagnosis, treatment, or prevention of hearing loss. Two investigators screened articles for inclusion at the title, abstract, and full-text levels. Data were abstracted and the studies were assessed for the qualities of model structure, data assumptions, and reporting using a previously published quality scale. FINDINGS: Of 1437 articles identified by our search, 117 unique studies met the inclusion criteria. Most of these model-based analyses were set in high-income countries (n = 96, 82%). The evaluated interventions were hearing screening (n = 35, 30%), cochlear implantation (n = 34, 29%), hearing aid use (n = 28, 24%), vaccination (n = 22, 19%), and other interventions (n = 29, 25%); some studies included multiple interventions. Eighty-six studies reported the main outcome in quality-adjusted or disability-adjusted life-years, 24 of which derived their own utility values. The majority of the studies used decision tree (n = 72, 62%) or Markov (n = 41, 35%) models. Forty-one studies (35%) incorporated indirect economic effects. The median quality rating was 92/100 (IQR:72-100). INTERPRETATION: The review identified a large body of literature exploring the economic efficiency of hearing healthcare interventions. However, gaps in evidence remain in evaluation of hearing healthcare in low- and middle-income countries, as well as in investigating interventions across the lifespan. Additionally, considerable uncertainty remains around productivity benefits of hearing healthcare interventions as well as utility values for hearing-assisted health states. Future economic evaluations could address these limitations. FUNDING: NCATS 3UL1-TR002553-03S3.

Right ventricular lead location and outcomes among patients with cardiac resynchronization therapy: A meta-analysis.

BACKGROUND: Cardiac resynchronization therapy (CRT) has been demonstrated to improve heart failure (HF) symptoms, reverse LV remodeling, and reduce mortality and HF hospitalization (HFH) in patients with a reduced left ventricular (LV) ejection fraction (LVEF). Prior studies examining outcomes based on right ventricular (RV) lead position among CRT patients have provided mixed results. We performed a systematic review and meta-analysis of randomized controlled trials and prospective observational studies comparing RV apical (RVA) and non-apical (RVNA) lead position in CRT. METHODS: Our meta-analysis was constructed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic reviews and meta-analyses. We searched EMBASE and MEDLINE. Eligible studies reported on at least one of the following outcomes of interest: all-cause mortality, the composite endpoint of death and first HFH hospitalization, change in LVEF, New York Heart Association (NYHA) class improvement, and change in LV end systolic volume (LVESV). We performed meta-analysis summaries using a DerSimonian-Laird random-effects model and conservatively used the Knapp-Hartung approach to adjust the standard errors of the estimated model coefficients. RESULTS: We included nine studies representing a total of 1832 patients. Of those, 1318 (72%) patients had RVA lead placement and 514 (28%) had RVNA lead placement. The mean age of patients was 65.5 ± 4.4 years, and they were predominantly men (69%-97%). There was no statistically significant difference in all-cause mortality by RVA vs. RVNA (OR = 0.77, 95% CI 0.32-1.89; I2 = 16.7%, p = 0.31), or in the combined endpoint of all-cause mortality and first HFH (OR 0.88, 95% CI 0.62-1.25; I2 = 0%, p = 0.84). Also, there was no difference between RVA and RVNA for NYHA class improvement (OR = 1.03, 95% CI 0.9-1.17; I2 = 0%, p = 0.99), change in LVEF (mean difference (MD) = 1.33, 95% CI -1.45 to 4.10; I2 = 47%; p = 0.093), and change in LVESV (MD = -1.11, 95% CI -3.34 to 1.12; I2 = 0%; p = 0.92). CONCLUSION: This meta-analysis shows that in CRT pacing, RV lead position does not appear to be associated with clinical outcomes or LV reverse remodeling. Further studies should focus on the relationship of RV lead vis-à-vis LV lead location, and its clinical importance.

Future research prioritization in cardiac resynchronization therapy.

BACKGROUND: Although cardiac resynchronization therapy (CRT) is effective for some patients with heart failure and a reduced left ventricular ejection fraction (HFrEF), evidence gaps remain for key clinical and policy areas. The objective of the study was to review the data on the effects of CRT for patients with HFrEF receiving pharmacological therapy alone or pharmacological therapy and an implantable cardioverter-defibrillator (ICD) and then, informed by a diverse group of stakeholders, to identify evidence gaps, prioritize them, and develop a research plan. METHODS: Relevant studies were identified using PubMed and EMBASE and ongoing trials using clinicaltrials.gov. Forced-ranking prioritization method was applied by stakeholders to reach a consensus on the most important questions. Twenty-six stakeholders contributed to the expanded list of evidence gaps, including key investigators from existing randomized controlled trials and others representing different perspectives, including patients, the public, device manufacturers, and policymakers. RESULTS: Of the 18 top-tier evidence gaps, 8 were related to specific populations or subgroups of interest. Seven were related to the comparative effectiveness and safety of CRT interventions or comparators, and 3 were related to the association of CRT treatment with specific outcomes. The association of comorbidities with CRT effectiveness ranked highest, followed by questions about the effectiveness of CRT among patients with atrial fibrillation and the relationship between gender, QRS morphology and duration, and outcomes for patients either with CRT plus ICD or with ICD. CONCLUSIONS: Evidence gaps presented in this article highlight numerous, important clinical and policy questions for which there is inconclusive evidence on the role of CRT and provide a framework for future collaborative research.

Assessing heterogeneity of treatment effect analyses in health-related cluster randomized trials: A systematic review.

BACKGROUND: Cluster-randomized trials (CRTs) are being increasingly used to test a range of interventions, including medical interventions commonly used in clinical practice. Policies created by the NIH and the Food and Drug Administration (FDA) require the reporting of demographics and the examination of demographic heterogeneity of treatment effect (HTE) for individually randomized trials. Little is known about how frequent demographics are reported and HTE analyses are conducted in CRTs. OBJECTIVES: We sought to understand the prevalence of HTE analyses and the statistical methods used to conduct them in CRTs focused on treating cardiovascular disease, cancer, and chronic lower respiratory diseases. Additionally, we also report on the proportion of CRTs that reported on baseline demographics of its populations and conducted demographic HTE analyses. DATA SOURCES: We searched PubMed and Embase for CRTs published between 1/1/2010 and 3/29/2016 that focused on treating the top 3 Center for Disease Control causes of death (cardiovascular disease, chronic lower respiratory disease, and cancer). Evidence Screening And Review: Of 1,682 unique titles, 117 abstracts were screened. After excluding 53 articles, we included 64 CRT publications and abstracted information on study characteristics and demographic information, statistical analysis, HTE analysis, and study quality. RESULTS: Age and sex were reported in greater than 95.3% of CRTs, while race and ethnicity were reported in only 20.3% of CRTs. HTE analyses were conducted in 28.1% (n = 18) of included CRTs and 77.8% (n = 12) were prespecified analyses. Four CRTs conducted a demographic subgroup analysis. Only 6/18 CRTs used interaction testing to determine whether HTE existed. CONCLUSIONS: Baseline demographic reporting was high for age and sex in CRTs, but was uncommon for race and ethnicity. HTE analyses were uncommon and was rare for demographic subgroups, which limits the ability to examine the extent of benefits or risks for treatments tested with CRT designs.

Rheumatologists' knowledge of contraception, teratogens, and pregnancy risks.

INTRODUCTION: Rheumatologists are essential partners in planning and managing pregnancies in women with lupus. Whether they know the essentials of contraceptive and medical treatment in pregnancy, however, is unknown. METHOD: Anonymous in-lecture surveys were completed by 270 rheumatologists to assess knowledge of contraceptive effectiveness, emergency contraception, medication teratogenicity, and lupus pregnancy risk assessment. RESULTS: Rheumatologists knew the high effectiveness of the intrauterine device, but over-estimated the effectiveness of injectable medroxyprogesterone and condoms. Almost all identified methotrexate as a teratogen, but only 69% identified cyclophosphamide and 37% mycophenolate. Most rheumatologists knew that lupus activity in pregnancy is the main predictor of pregnancy outcomes, but underestimated the risks of hypertension and race. CONCLUSION: To improve lupus pregnancy planning and management, rheumatologists would benefit from improved knowledge about contraceptive effectiveness, teratogens, and the risks from non-lupus factors for pregnancy complications.

Interventions for Preventing Thromboembolic Events in Patients With Atrial Fibrillation: A Systematic Review.

Background: The comparative safety and effectiveness of treatments to prevent thromboembolic complications in atrial fibrillation (AF) remain uncertain. Purpose: To compare the effectiveness of medical and procedural therapies in preventing thromboembolic events and bleeding complications in adults with nonvalvular AF. Data Sources: English-language studies in several databases from 1 January 2000 to 14 February 2018. Study Selection: Two reviewers independently screened citations to identify comparative studies of treatments to prevent stroke in adults with nonvalvular AF who reported thromboembolic or bleeding complications. Data Extraction: Two reviewers independently abstracted data, assessed study quality and applicability, and rated strength of evidence. Data Synthesis: Data from 220 articles were included. Dabigatran and apixaban were superior and rivaroxaban and edoxaban were similar to warfarin in preventing stroke or systemic embolism. Apixaban and edoxaban were superior and rivaroxaban and dabigatran were similar to warfarin in reducing the risk for major bleeding. Treatment effects with dabigatran were similar in patients with renal dysfunction (interaction P > 0.05), and patients younger than 75 years had lower bleeding rates with dabigatran (interaction P < 0.001). The benefit of treatment with apixaban was consistent in many subgroups, including those with renal impairment, diabetes, and prior stroke (interaction P > 0.05 for all). The greatest bleeding risk reduction was observed in patients with a glomerular filtration rate less than 50 mL/min/1.73 m2 (P = 0.003). Similar treatment effects were observed for rivaroxaban and edoxaban in patients with prior stroke, diabetes, or heart failure (interaction P > 0.05 for all). Limitation: Heterogeneous study populations, interventions, and outcomes. Conclusion: The available direct-acting oral anticoagulants (DOACs) are at least as effective and safe as warfarin for patients with nonvalvular AF. The DOACs had similar benefits across several patient subgroups and seemed safe and efficacious for a wide range of patients with nonvalvular AF. Primary Funding Source: Patient-Centered Outcomes Research Institute. (PROSPERO: CRD42017069999).

Predicting Thromboembolic and Bleeding Event Risk in Patients with Non-Valvular Atrial Fibrillation: A Systematic Review.

BACKGROUND: Atrial fibrillation (AF) is a common cardiac arrhythmia that increases the risk of stroke. Medical therapy for decreasing stroke risk involves anticoagulation, which may increase bleeding risk for certain patients. In determining the optimal therapy for stroke prevention for patients with AF, clinicians use tools with various clinical, imaging and patient characteristics to weigh stroke risk against therapy-associated bleeding risk. AIM: This article reviews published literature and summarizes available risk stratification tools for stroke and bleeding prediction in patients with AF. METHODS: We searched for English-language studies in PubMed, Embase and the Cochrane Database of Systematic Reviews published between 1 January 2000 and 14 February 2018. Two reviewers screened citations for studies that examined tools for predicting thromboembolic and bleeding risks in patients with AF. Data regarding study design, patient characteristics, interventions, outcomes, quality, and applicability were extracted. RESULTS: Sixty-one studies were relevant to predicting thromboembolic risk and 38 to predicting bleeding risk. Data suggest that CHADS2, CHA2DS2-VASc and the age, biomarkers, and clinical history (ABC) risk scores have the best evidence for predicting thromboembolic risk (moderate strength of evidence for limited prediction ability of each score) and that HAS-BLED has the best evidence for predicting bleeding risk (moderate strength of evidence). LIMITATIONS: Studies were heterogeneous in methodology and populations of interest, setting, interventions and outcomes analysed. CONCLUSION: CHADS2, CHA2DS2-VASc and ABC scores have the best prediction for stroke events, and HAS-BLED provides the best prediction for bleeding risk. Future studies should define the role of imaging tools and biomarkers in enhancing the accuracy of risk prediction tools. PRIMARY FUNDING SOURCE: Patient-Centered Outcomes Research Institute (PROSPERO #CRD42017069999).

Future Directions for Cost-effectiveness Analyses in Health and Medicine.

OBJECTIVES: In 2016, the Second Panel on Cost-effectiveness in Health and Medicine updated the seminal work of the original panel from 2 decades earlier. The Second Panel had an opportunity to reflect on the evolution of cost-effectiveness analysis (CEA) and to provide guidance for the next generation of practitioners and consumers. In this article, we present key topics for future research and policy. METHODS: During the course of its deliberations, the Second Panel discussed numerous topics for advancing methods and for improving the use of CEA in decision making. We identify and consider 7 areas for which the panel believes that future research would be particularly fruitful. In each of these areas, we highlight outstanding research needs. The list is not intended as an exhaustive inventory but rather a set of key items that surfaced repeatedly in the panel's discussions. In the online Appendix , we also list and expound briefly on 8 other important topics. RESULTS: We highlight 7 key areas: CEA and perspectives (determining, valuing, and summarizing elements for the analysis), modeling (comparative modeling and model transparency), health outcomes (valuing temporary health and path states, as well as health effects on caregivers), costing (a cost catalogue, valuing household production, and productivity effects), evidence synthesis (developing theory on learning across studies and combining data from clinical trials and observational studies), estimating and using cost-effectiveness thresholds (empirically representing 2 broad concepts: opportunity costs and public willingness to pay), and reporting and communicating CEAs (written protocols and a quality scoring system). CONCLUSIONS: Cost-effectiveness analysis remains a flourishing and evolving field with many opportunities for research. More work is needed on many fronts to understand how best to incorporate CEA into policy and practice.

Single vs. dual chamber implantable cardioverter-defibrillators or programming of implantable cardioverter-defibrillators in patients without a bradycardia pacing indication: systematic review and meta-analysis.

Aims: Implantable cardioverter-defibrillators (ICDs) are key in the prevention of sudden cardiac death, but outcomes may vary by type of device or programming [single chamber (SC) vs. dual chamber (DC)] in patients without a bradycardia pacing indication. We sought to meta-analyse patient outcomes of randomized trials of SC vs. DC devices or programming. Methods and results: We searched PubMed, Embase, Scopus, Web of Science, and Cochrane trials databases for relevant studies excluding those published before 2000, involving children, or not available in English. Endpoints included mortality, inappropriate ICD therapies, and implant complications. Endpoints with at least three reporting studies were meta-analysed. We identified eight studies meeting inclusion criteria representing 2087 patients with 16.1 months mean follow-up. Mean age was 62.7 years (SD 1.92); in six studies reporting sex, most patients were male (85%). Comparing patients with a SC or DC ICD or programming, we found similar rates of mortality [odds ratio (OR) 0.95, 95% confidence interval (CI) 0.54-1.68; P = 0.86] and inappropriate therapies (OR 1.46, 95% CI 0.97-2.19; P = 0.07) in five and six studies, respectively. In three studies of SC vs. DC ICDs (but not programming) rates of pneumothorax and lead dislodgement were not different (OR 2.12, 95% CI 0.18-24.72; P = 0.55 and OR 0.87, 95% CI 0.32-2.47; P = 0.83, respectively). Conclusion: In this meta-analysis of randomized controlled trials comparing SC vs. DC ICD device or programming, there was no significant difference in inappropriate therapies, mortality, pneumothorax, or lead dislodgement. Future studies should compare these devices over longer follow-up and in specific patient populations.

Nonpharmacologic Treatments for Attention-Deficit/Hyperactivity Disorder: A Systematic Review.

CONTEXT: Nonpharmacologic treatments for attention-deficit/hyperactivity disorder (ADHD) encompass a range of care approaches from structured behavioral interventions to complementary medicines. OBJECTIVES: To assess the comparative effectiveness of nonpharmacologic treatments for ADHD among individuals 17 years of age and younger. DATA SOURCES: PubMed, Embase, PsycINFO, and Cochrane Database of Systematic Reviews for relevant English-language studies published from January 1, 2009 through November 7, 2016. STUDY SELECTION: We included studies that compared any ADHD nonpharmacologic treatment strategy with placebo, pharmacologic, or another nonpharmacologic treatment. DATA EXTRACTION: Study design, patient characteristics, intervention approaches, follow-up times, and outcomes were abstracted. For comparisons with at least 3 similar studies, random-effects meta-analysis was used to generate pooled estimates. RESULTS: We identified 54 studies of nonpharmacologic treatments, including neurofeedback, cognitive training, cognitive behavioral therapy, child or parent training, dietary omega fatty acid supplementation, and herbal and/or dietary approaches. No new guidance was identified regarding the comparative effectiveness of nonpharmacologic treatments. Pooled results for omega fatty acids found no significant effects for parent rating of ADHD total symptoms (n = 411; standardized mean difference -0.32; 95% confidence interval -0.80 to 0.15; I2 = 52.4%; P = .10) or teacher-rated total ADHD symptoms (n = 287; standardized mean difference -0.08; 95% confidence interval -0.47 to 0.32; I2 = 0.0%; P = .56). LIMITATIONS: Studies often did not reflect the primary care setting and had short follow-up periods, small sample sizes, variations in outcomes, and inconsistent reporting of comparative statistical analyses. CONCLUSIONS: Despite wide use, there are significant gaps in knowledge regarding the effectiveness of ADHD nonpharmacologic treatments.

Implantable cardioverter-defibrillators in heart failure patients with reduced ejection fraction and diabetes.

AIM: There is limited information on the outcomes after primary prevention implantable cardioverter-defibrillator (ICD) implantation in patients with heart failure (HF) and diabetes. This analysis evaluates the effectiveness of a strategy of ICD plus medical therapy vs. medical therapy alone among patients with HF and diabetes. METHODS AND RESULTS: A patient-level combined-analysis was conducted from a combined dataset that included four primary prevention ICD trials of patients with HF or severely reduced ejection fractions: Multicenter Automatic Defibrillator Implantation Trial I (MADIT I), MADIT II, Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE), and Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). In total, 3359 patients were included in the analysis. The primary outcome of interest was all-cause death. Compared with patients without diabetes (n = 2363), patients with diabetes (n = 996) were older and had a higher burden of cardiovascular risk factors. During a median follow-up of 2.6 years, 437 patients without diabetes died (178 with ICD vs. 259 without) and 280 patients with diabetes died (128 with ICD vs. 152 without). ICDs were associated with a reduced risk of all-cause mortality among patients without diabetes [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.46-0.67] but not among patients with diabetes (HR 0.88, 95% CI 0.7-1.12; interaction P = 0.015). CONCLUSION: Among patients with HF and diabetes, primary prevention ICD in combination with medical therapy vs. medical therapy alone was not significantly associated with a reduced risk of all-cause death. Further studies are needed to evaluate the effectiveness of ICDs among patients with diabetes.

When Is It Safe Not to Reimplant an Implantable Cardioverter Defibrillator at the Time of Battery Depletion?

The implantable cardioverter defibrillator (ICD) is a life-saving therapy in various patient populations. Although data on the outcomes of initial ICD implants are abundant, data on ICD replacements, especially in patients with improved left ventricular (LV) function, are scarce. Therefore, it is not known when it is safe to not replace an ICD that has reached the end of battery life. This article reviews data on patients with primary prevention ICDs who have improvement in left ventricular ejection fraction during follow-up and provides some guidance, based on the available evidence, related to circumstances when replacement of an ICD may be forgone.