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AbstractObjectivesTo use the estimates from the Global Burden of Disease Study 2016 to describe patterns of suicide mortality globally, regionally, and for 195 countries and territories by age, sex, and Socio-demographic index, and to describe temporal trends between 1990 and 2016.DesignSystematic analysis.Main outcome measuresCrude and age standardised rates from suicide mortality and years of life lost were compared across regions and countries, and by age, sex, and Socio-demographic index (a composite measure of fertility, income, and education).ResultsThe total number of deaths from suicide increased by 6.7% (95% uncertainty interval 0.4% to 15.6%) globally over the 27 year study period to 817 000 (762 000 to 884 000) deaths in 2016. However, the age standardised mortality rate for suicide decreased by 32.7% (27.2% to 36.6%) worldwide between 1990 and 2016, similar to the decline in the global age standardised mortality rate of 30.6%. Suicide was the leading cause of age standardised years of life lost in the Global Burden of Disease region of high income Asia Pacific and was among the top 10 leading causes in eastern Europe, central Europe, western Europe, central Asia, Australasia, southern Latin America, and high income North America. Rates for men were higher than for women across regions, countries, and age groups, except for the 15 to 19 age group. There was variation in the female to male ratio, with higher ratios at lower levels of Socio-demographic index. Women experienced greater decreases in mortality rates (49.0%, 95% uncertainty interval 42.6% to 54.6%) than men (23.8%, 15.6% to 32.7%).ConclusionsAge standardised mortality rates for suicide have greatly reduced since 1990, but suicide remains an important contributor to mortality worldwide. Suicide mortality was variable across locations, between sexes, and between age groups. Suicide prevention strategies can be targeted towards vulnerable populations if they are informed by variations in mortality rates.

As mortality rates decline, life expectancy increases, and populations age, non-fatal outcomes of diseases and injuries are becoming a larger component of the global burden of disease. The Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) provides a comprehensive assessment of prevalence, incidence, and years lived with disability (YLDs) for 328 causes in 195 countries and territories from 1990 to 2016. We estimated prevalence and incidence for 328 diseases and injuries and 2982 sequelae, their non-fatal consequences. We used DisMod-MR 2.1, a Bayesian meta-regression tool, as the main method of estimation, ensuring consistency between incidence, prevalence, remission, and cause of death rates for each condition. For some causes, we used alternative modelling strategies if incidence or prevalence needed to be derived from other data. YLDs were estimated as the product of prevalence and a disability weight for all mutually exclusive sequelae, corrected for comorbidity and aggregated to cause level. We updated the Socio-demographic Index (SDI), a summary indicator of income per capita, years of schooling, and total fertility rate. GBD 2016 complies with the Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER). Globally, low back pain, migraine, age-related and other hearing loss, iron-deficiency anaemia, and major depressive disorder were the five leading causes of YLDs in 2016, contributing 57·6 million (95% uncertainty interval [UI] 40·8–75·9 million [7·2%, 6·0–8·3]), 45·1 million (29·0–62·8 million [5·6%, 4·0–7·2]), 36·3 million (25·3–50·9 million [4·5%, 3·8–5·3]), 34·7 million (23·0–49·6 million [4·3%, 3·5–5·2]), and 34·1 million (23·5–46·0 million [4·2%, 3·2–5·3]) of total YLDs, respectively. Age-standardised rates of YLDs for all causes combined decreased between 1990 and 2016 by 2·7% (95% UI 2·3–3·1). Despite mostly stagnant age-standardised rates, the absolute number of YLDs from non-communicable diseases has been growing rapidly across all SDI quintiles, partly because of population growth, but also the ageing of populations. The largest absolute increases in total numbers of YLDs globally were between the ages of 40 and 69 years. Age-standardised YLD rates for all conditions combined were 10·4% (95% UI 9·0–11·8) higher in women than in men. Iron-deficiency anaemia, migraine, Alzheimer's disease and other dementias, major depressive disorder, anxiety, and all musculoskeletal disorders apart from gout were the main conditions contributing to higher YLD rates in women. Men had higher age-standardised rates of substance use disorders, diabetes, cardiovascular diseases, cancers, and all injuries apart from sexual violence. Globally, we noted much less geographical variation in disability than has been documented for premature mortality. In 2016, there was a less than two times difference in age-standardised YLD rates for all causes between the location with the lowest rate (China, 9201 YLDs per 100 000, 95% UI 6862–11943) and highest rate (Yemen, 14 774 YLDs per 100 000, 11 018–19 228). The decrease in death rates since 1990 for most causes has not been matched by a similar decline in age-standardised YLD rates. For many large causes, YLD rates have either been stagnant or have increased for some causes, such as diabetes. As populations are ageing, and the prevalence of disabling disease generally increases steeply with age, health systems will face increasing demand for services that are generally costlier than the interventions that have led to declines in mortality in childhood or for the major causes of mortality in adults. Up-to-date information about the trends of disease and how this varies between countries is essential to plan for an adequate health-system response. Bill & Melinda Gates Foundation, and the National Institute on Aging and the National Institute of Mental Health of the National Institutes of Health.

Transcatheter aortic valve replacement (TAVR) is the preferred treatment option for older patients with symptomatic severe aortic stenosis. Differences in the properties of available TAVR systems can affect clinical outcomes. Among patients undergoing TAVR, we compared the self-expanding ACURATE neo TAVR system with the balloon-expandable SAPIEN 3 TAVR system with regard to early safety and efficacy. In this randomised non-inferiority trial, patients (aged ≥75 years) undergoing transfemoral TAVR for treatment of symptomatic severe aortic stenosis, and who were deemed to be at increased surgical risk, were recruited at 20 tertiary heart valve centres in Germany, the Netherlands, Switzerland, and the UK. Participants were randomly assigned (1:1) to receive treatment with the ACURATE neo or the SAPIEN 3 with a computer-based randomly permuted block scheme, stratified by study centre and Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) category. The primary composite safety and efficacy endpoint comprised all-cause death, any stroke, life-threatening or disabling bleeding, major vascular complications, coronary artery obstruction requiring intervention, acute kidney injury (stage 2 or 3), rehospitalisation for valve-related symptoms or congestive heart failure, valve-related dysfunction requiring repeat procedure, moderate or severe prosthetic valve regurgitation, or prosthetic valve stenosis within 30 days of the procedure. Endpoint assessors were masked to treatment allocation. Non-inferiority of ACURATE neo compared with SAPIEN 3 was assessed in the intention-to-treat population on the basis of a risk-difference margin of 7·7% for the primary composite endpoint, with a one-sided α of 0·05. This trial is registered with ClinicalTrials.gov (number NCT03011346) and is ongoing but not recruiting. Between Feb 8, 2017, and Feb 2, 2019, up to 5132 patients were screened and 739 (mean age 82·8 years [SD 4·1]; median STS-PROM score 3·5% [IQR 2·6–5·0]) were enrolled. 30-day follow-up was available for 367 (99%) of 372 patients allocated to the ACURATE neo group, and 364 (99%) of 367 allocated to the SAPIEN 3 group. Within 30 days, the primary endpoint occurred in 87 (24%) patients in the ACURATE neo and in 60 (16%) in the SAPIEN 3 group; thus, non-inferiority of the ACURATE neo was not met (absolute risk difference 7·1% [upper 95% confidence limit 12·0%], p=0·42). Secondary analysis of the primary endpoint suggested superiority of the SAPIEN 3 device over the ACURATE neo device (95% CI for risk difference −1·3 to −12·9, p=0·0156). The ACURATE neo and SAPIEN 3 groups did not differ in incidence of all-cause death (nine patients [2%] vs three [1%]) and stroke (seven [2%] vs 11 [3%]); whereas acute kidney injury (11 [3%] vs three [1%]) and moderate or severe prosthetic aortic regurgitation (34 [9%] vs ten [3%]) were more common in the ACURATE neo group. TAVR with the self-expanding ACURATE neo did not meet non-inferiority compared to the balloon-expandable SAPIEN 3 device in terms of early safety and clinical efficacy outcomes. An early composite safety and efficacy endpoint was useful in discriminating the performance of different TAVR systems. Boston Scientific (USA).

Reliable and timely information on the leading causes of death in populations, and how these are changing, is a crucial input into health policy debates. In the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010), we aimed to estimate annual deaths for the world and 21 regions between 1980 and 2010 for 235 causes, with uncertainty intervals (UIs), separately by age and sex. We attempted to identify all available data on causes of death for 187 countries from 1980 to 2010 from vital registration, verbal autopsy, mortality surveillance, censuses, surveys, hospitals, police records, and mortuaries. We assessed data quality for completeness, diagnostic accuracy, missing data, stochastic variations, and probable causes of death. We applied six different modelling strategies to estimate cause-specific mortality trends depending on the strength of the data. For 133 causes and three special aggregates we used the Cause of Death Ensemble model (CODEm) approach, which uses four families of statistical models testing a large set of different models using different permutations of covariates. Model ensembles were developed from these component models. We assessed model performance with rigorous out-of-sample testing of prediction error and the validity of 95% UIs. For 13 causes with low observed numbers of deaths, we developed negative binomial models with plausible covariates. For 27 causes for which death is rare, we modelled the higher level cause in the cause hierarchy of the GBD 2010 and then allocated deaths across component causes proportionately, estimated from all available data in the database. For selected causes (African trypanosomiasis, congenital syphilis, whooping cough, measles, typhoid and parathyroid, leishmaniasis, acute hepatitis E, and HIV/AIDS), we used natural history models based on information on incidence, prevalence, and case-fatality. We separately estimated cause fractions by aetiology for diarrhoea, lower respiratory infections, and meningitis, as well as disaggregations by subcause for chronic kidney disease, maternal disorders, cirrhosis, and liver cancer. For deaths due to collective violence and natural disasters, we used mortality shock regressions. For every cause, we estimated 95% UIs that captured both parameter estimation uncertainty and uncertainty due to model specification where CODEm was used. We constrained cause-specific fractions within every age-sex group to sum to total mortality based on draws from the uncertainty distributions. In 2010, there were 52·8 million deaths globally. At the most aggregate level, communicable, maternal, neonatal, and nutritional causes were 24·9% of deaths worldwide in 2010, down from 15·9 million (34·1%) of 46·5 million in 1990. This decrease was largely due to decreases in mortality from diarrhoeal disease (from 2·5 to 1·4 million), lower respiratory infections (from 3·4 to 2·8 million), neonatal disorders (from 3·1 to 2·2 million), measles (from 0·63 to 0·13 million), and tetanus (from 0·27 to 0·06 million). Deaths from HIV/AIDS increased from 0·30 million in 1990 to 1·5 million in 2010, reaching a peak of 1·7 million in 2006. Malaria mortality also rose by an estimated 19·9% since 1990 to 1·17 million deaths in 2010. Tuberculosis killed 1·2 million people in 2010. Deaths from non-communicable diseases rose by just under 8 million between 1990 and 2010, accounting for two of every three deaths (34·5 million) worldwide by 2010. 8 million people died from cancer in 2010, 38% more than two decades ago; of these, 1·5 million (19%) were from trachea, bronchus, and lung cancer. Ischaemic heart disease and stroke collectively killed 12·9 million people in 2010, or one in four deaths worldwide, compared with one in five in 1990; 1·3 million deaths were due to diabetes, twice as many as in 1990. The fraction of global deaths due to injuries (5·1 million deaths) was marginally higher in 2010 (9·6%) compared with two decades earlier (8·8%). This was driven by a 46% rise in deaths worldwide due to road traffic accidents (1·3 million in 2010) and a rise in deaths from falls. Ischaemic heart disease, stroke, chronic obstructive pulmonary disease (COPD), lower respiratory infections, lung cancer, and HIV/AIDS were the leading causes of death in 2010. Ischaemic heart disease, lower respiratory infections, stroke, diarrhoeal disease, malaria, and HIV/AIDS were the leading causes of years of life lost due to premature mortality (YLLs) in 2010, similar to what was estimated for 1990, except for HIV/AIDS and preterm birth complications. YLLs from lower respiratory infections and diarrhoea decreased by 45–54% since 1990; ischaemic heart disease and stroke YLLs increased by 17–28%. Regional variations in leading causes of death were substantial. Communicable, maternal, neonatal, and nutritional causes still accounted for 76% of premature mortality in sub-Saharan Africa in 2010. Age standardised death rates from some key disorders rose (HIV/AIDS, Alzheimer's disease, diabetes mellitus, and chronic kidney disease in particular), but for most diseases, death rates fell in the past two decades; including major vascular diseases, COPD, most forms of cancer, liver cirrhosis, and maternal disorders. For other conditions, notably malaria, prostate cancer, and injuries, little change was noted. Population growth, increased average age of the world's population, and largely decreasing age-specific, sex-specific, and cause-specific death rates combine to drive a broad shift from communicable, maternal, neonatal, and nutritional causes towards non-communicable diseases. Nevertheless, communicable, maternal, neonatal, and nutritional causes remain the dominant causes of YLLs in sub-Saharan Africa. Overlaid on this general pattern of the epidemiological transition, marked regional variation exists in many causes, such as interpersonal violence, suicide, liver cancer, diabetes, cirrhosis, Chagas disease, African trypanosomiasis, melanoma, and others. Regional heterogeneity highlights the importance of sound epidemiological assessments of the causes of death on a regular basis. Bill & Melinda Gates Foundation.

Patients with frailty are often perceived to have a less favorable risk/benefit profile for pharmacological and device-based therapies. We examined the long-term effects of a primary prevention implantable cardioverter-defibrillator (ICD), compared with usual care, according to frailty status in an extended follow-up study of the Danish Study to Assess the Efficacy of ICDs in Patients with nonischemic Systolic Heart failure on Mortality (DANISH) trial. The DANISH trial randomized 1,116 patients with nonischemic heart failure with reduced ejection fraction (HFrEF) to ICD implantation or usual care. Frailty was measured using the Rockwood cumulative deficit approach. The primary outcome was all-cause death, and secondary outcomes were cardiovascular death and sudden cardiovascular death. A frailty index (FI) was calculable in 1,109 patients. In total, 618 (55.7%) patients were in frailty class 1 (FI <0.210, i.e., not frail), 361 (32.6%) in frailty class 2 (FI 0.211 to 0.310, i.e., more frail), and 130 (11.7%) in frailty class 3 (FI >0.311, i.e., most frail). Compared with patients in FI class 1, those in FI class 2 and 3 had a higher rate of all outcomes. The effect of ICD implantation on all-cause death did not vary significantly by frailty class (class 1, HR 0.92 [95% CI, 0.68 to 1.24]; class 2 to 3, 0.93 [0.73 to 1.19]; Pinteraction = 0.99). Consistent effects were observed for cardiovascular death (Pinteraction = 0.94), but not for sudden cardiovascular death (Pinteraction = 0.03); the beneficial effect of ICD implantation on this outcome appeared to be greater in patients who were more frail. However, when the FI was analyzed as a continuous variable, frailty no longer significantly modified the effects of ICD implantation on any outcome. In conclusion, in patients with nonischemic HFrEF, frailty did not significantly modify the effects of ICD implantation compared with usual care. However, the need for a primary prevention ICD in frail patients with HFrEF receiving contemporary guideline-directed medical therapy remains uncertain. Clinical Trial Registration Number: NCT00542945.

Objective To examine whether elevated resting heart rate (RHR) is an independent risk factor for mortality or a mere marker of physical fitness (VO2Max). Methods This was a prospective cohort study: the Copenhagen Male Study, a longitudinal study of healthy middle-aged employed men. Subjects with sinus rhythm and without known cardiovascular disease or diabetes were included. RHR was assessed from a resting ECG at study visit in 1985–1986. VO2Max was determined by the Åstrand bicycle ergometer test in 1970–1971. Subjects were classified into categories according to level of RHR. Associations with mortality were studied in multivariate Cox models adjusted for physical fitness, leisure-time physical activity and conventional cardiovascular risk factors. Results 2798 subjects were followed for 16 years. 1082 deaths occurred. RHR was inversely related to physical fitness (p<0.001). Overall, increasing RHR was highly associated with mortality in a graded manner after adjusting for physical fitness, leisure-time physical activity and other cardiovascular risk factors. Compared to men with RHR ≤50, those with RHR >90 had an HR (95% CI) of 3.06 (1.97 to 4.75). With RHR as a continuous variable, risk of mortality increased with 16% (10–22) per 10 beats per minute (bpm). There was a borderline interaction with smoking (p=0.07); risk per 10 bpm increase in RHR was 20% (12–27) in smokers, and 14% (4–24) in non-smokers. Conclusions Elevated RHR is a risk factor for mortality independent of physical fitness, leisure-time physical activity and other major cardiovascular risk factors.

While there are several completed clinical trials that address treatment strategies in patients with symptomatic and recurrent atrial fibrillation (AF), there are no randomized clinical trials that address first-line rhythm control of new-onset AF. Recent data suggest that early initiation of rhythm control within 1 year can improve outcomes. In this open-label pragmatic clinical trial nested within the Get with The Guidelines Atrial Fibrillation registry, approximately 3,000 patients with first-detected AF will be enrolled at approximately 200 sites. Participants will be randomized (1:1) to treatment with dronedarone in addition to usual care versus usual care alone. The primary endpoint will be time to first cardiovascular (CV) hospitalization or death from any cause through 12 months from randomization. Secondary endpoints will include a WIN ratio (all-cause death, ischemic stroke or systemic embolism, heart failure hospitalization, acute coronary hospitalization), CV hospitalization, and all-cause mortality. Patient reported outcomes will be analyzed based on change in Atrial Fibrillation Effect on Quality of Life (AFEQT) and change in Mayo AF-Specific Symptom Inventory (MAFSI) from baseline to 12 months. CHANGE AFIB will determine if treatment with dronedarone in addition to usual care is superior to usual care alone for the prevention of CV hospitalization or death from any cause in patients with first-detected AF. The trial will also determine whether initiation of rhythm control at the time of first-detected AF affects CV events or improves patient reported outcomes. - NCT05130268

Rate control plays a fundamental role in the management of atrial fibrillation (AF), but the optimal target of resting heart rate (RHR) for reducing mortality remains uncertain. This study used longitudinal follow-up RHR data to evaluate the relation between RHR and all-cause mortality. Data from the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study were retrospectively analyzed. The association between RHR and mortality was longitudinally analyzed using mean RHR (mRHR) and trajectory patterns, where the Cox proportional hazards model and group-based trajectory model were used. A total of 3,921 patients (mean age, 69.47 ± 8.09 years) with AF were included in our study. A total of 578 deaths were recorded during a median follow-up of 3.4 years. Cox regression analyses showed an mRHR ≥80 bpm was associated with an increased risk of mortality (adjusted hazard ratio: 2.01, 95% confidence interval 1.59 to 2.55). Consistent association was found in the subgroup analyses. The Kaplan-Meier analysis showed notably reduced survival probabilities for patients with mRHR ≥80 bpm. Patients were classified into 4 stable trajectories based on RHR during follow-up, with the classes >70 bpm associated with an elevated risk of mortality. In conclusion, longitudinally measured RHR ≥80 bpm was associated with an increased risk of mortality in patients with AF.

Risk stratification tools used in patients with severe aortic stenosis have been mostly derived from surgical series. Although specific predictors of early mortality with transcatheter aortic valve replacement (TAVR) have been identified, the prognostic impact of their combination is unexplored. We sought to develop a simple score, using preprocedural variables, for prediction of 30-day mortality after TAVR. A total of 1,878 patients from a national multicenter registry who underwent TAVR were randomly assigned in a 2:1 manner to development and validation data sets. Baseline characteristics of the 1,256 patients in the development data set were considered as candidate univariate predictors of 30-day mortality. A bootstrap multivariate logistic regression process was used to select correlates of 30-day mortality that were subsequently weighted and integrated into a scoring system. Seven variables were weighted proportionally to their respective odds ratios for 30-day mortality (glomerular filtration rate <45 ml/min [6 points], critical preoperative state [5 points], New York Heart Association class IV [4 points], pulmonary hypertension [4 points], diabetes mellitus [4 points], previous balloon aortic valvuloplasty [3 points], and left ventricular ejection fraction <40% [3 points]). The model showed good discrimination in both the development and validation data sets (C statistics 0.73 and 0.71, respectively). Compared with the logistic European System for Cardiac Operative Risk Evaluation in the validation data set, the model showed better discrimination (C statistic 0.71 vs 0.66), goodness of fit (Hosmer-Lemeshow p value 0.81 vs 0.00), and global accuracy (Brier score 0.054 vs 0.073). In conclusion, the risk of 30-day mortality after TAVR may be estimated by combining 7 baseline clinical variables into a simple risk scoring system.