Allan J. Hsiao

Atrial fibrillation and risks of cardiovascular disease, renal disease, and death: systematic review and meta-analysis

Objective To quantify the association between atrial fibrillation and cardiovascular disease, renal disease, and death. Design Systematic review and meta-analysis. Data sources Medline and Embase. Eligibility criteria Cohort studies examining the association between atrial fibrillation and cardiovascular disease, renal disease, and death. Two reviewers independently extracted study characteristics and the relative risk of outcomes associated with atrial fibrillation: specifically, all cause mortality, cardiovascular mortality, major cardiovascular events, any stroke, ischaemic stroke, haemorrhagic stroke, ischaemic heart disease, sudden cardiac death, congestive heart failure, chronic kidney disease, and peripheral arterial disease. Estimates were pooled with inverse variance weighted random effects meta-analysis. Results 104 eligible cohort studies involving 9 686 513 participants (587 867 with atrial fibrillation) were identified. Atrial fibrillation was associated with an increased risk of all cause mortality (relative risk 1.46, 95% confidence interval 1.39 to 1.54), cardiovascular mortality (2.03, 1.79 to 2.30), major cardiovascular events (1.96, 1.53 to 2.51), stroke (2.42, 2.17 to 2.71), ischaemic stroke (2.33, 1.84 to 2.94), ischaemic heart disease (1.61, 1.38 to 1.87), sudden cardiac death (1.88, 1.36 to 2.60), heart failure (4.99, 3.04 to 8.22), chronic kidney disease (1.64, 1.41 to 1.91), and peripheral arterial disease (1.31, 1.19 to 1.45) but not haemorrhagic stroke (2.00, 0.67 to 5.96). Among the outcomes examined, the highest absolute risk increase was for heart failure. Associations between atrial fibrillation and included outcomes were broadly consistent across subgroups and in sensitivity analyses. Conclusions Atrial fibrillation is associated with an increased risk of death and an increased risk of cardiovascular and renal disease. Interventions aimed at reducing outcomes beyond stroke are warranted in patients with atrial fibrillation.

Atrial fibrillation as risk factor for cardiovascular disease and death in women compared with men: systematic review and meta-analysis of cohort studies

Objective To determine whether atrial fibrillation is a stronger risk factor for cardiovascular disease and death in women compared with men. Design Meta-analysis of cohort studies. Data sources Studies published between January 1966 and March 2015, identified through a systematic search of Medline and Embase and review of references. Eligibility for selecting studies Cohort studies with a minimum of 50 participants with and 50 without atrial fibrillation that reported sex specific associations between atrial fibrillation and all cause mortality, cardiovascular mortality, stroke, cardiac events (cardiac death and non-fatal myocardial infarction), and heart failure. Data extraction Two independent reviewers extracted study characteristics and maximally adjusted sex specific relative risks. Inverse variance weighted random effects meta-analysis was used to pool sex specific relative risks and their ratio. Results 30 studies with 4 371 714 participants were identified. Atrial fibrillation was associated with a higher risk of all cause mortality in women (ratio of relative risks for women compared with men 1.12, 95% confidence interval 1.07 to 1.17) and a significantly stronger risk of stroke (1.99, 1.46 to 2.71), cardiovascular mortality (1.93, 1.44 to 2.60), cardiac events (1.55, 1.15 to 2.08), and heart failure (1.16, 1.07 to 1.27). Results were broadly consistent in sensitivity analyses. Conclusion Atrial fibrillation is a stronger risk factor for cardiovascular disease and death in women compared with men, though further research would be needed to determine any causality.

Genetic Association of Waist-to-Hip Ratio With Cardiometabolic Traits, Type 2 Diabetes, and Coronary Heart Disease

Importance In observational studies, abdominal adiposity has been associated with type 2 diabetes and coronary heart disease (CHD). Whether these associations represent causal relationships remains uncertain. Objective To test the association of a polygenic risk score for waist-to-hip ratio (WHR) adjusted for body mass index (BMI), a measure of abdominal adiposity, with type 2 diabetes and CHD through the potential intermediates of blood lipids, blood pressure, and glycemic phenotypes. Design, Setting, and Participants A polygenic risk score for WHR adjusted for BMI, a measure of genetic predisposition to abdominal adiposity, was constructed with 48 single-nucleotide polymorphisms. The association of this score with cardiometabolic traits, type 2 diabetes, and CHD was tested in a mendelian randomization analysis that combined case-control and cross-sectional data sets. Estimates for cardiometabolic traits were based on a combined data set consisting of summary results from 4 genome-wide association studies conducted from 2007 to 2015, including up to 322 154 participants, as well as individual-level, cross-sectional data from the UK Biobank collected from 2007-2011, including 111 986 individuals. Estimates for type 2 diabetes and CHD were derived from summary statistics of 2 separate genome-wide association studies conducted from 2007 to 2015 and including 149 821 individuals and 184 305 individuals, respectively, combined with individual-level data from the UK Biobank. Exposures Genetic predisposition to increased WHR adjusted for BMI. Main Outcomes and Measures Type 2 diabetes and CHD. Results Among 111 986 individuals in the UK Biobank, the mean age was 57 (SD, 8) years, 58 845 participants (52.5%) were women, and mean WHR was 0.875. Analysis of summary-level genome-wide association study results and individual-level UK Biobank data demonstrated that a 1-SD increase in WHR adjusted for BMI mediated by the polygenic risk score was associated with 27-mg/dL higher triglyceride levels, 4.1-mg/dL higher 2-hour glucose levels, and 2.1–mm Hg higher systolic blood pressure (each P < .001). A 1-SD genetic increase in WHR adjusted for BMI was also associated with a higher risk of type 2 diabetes (odds ratio, 1.77 [95% CI, 1.57-2.00]; absolute risk increase per 1000 participant-years, 6.0 [95% CI, CI, 4.4-7.8]; number of participants with type 2 diabetes outcome, 40 530) and CHD (odds ratio, 1.46 [95% CI, 1.32-1.62]; absolute risk increase per 1000 participant-years, 1.8 [95% CI, 1.3-2.4]; number of participants with CHD outcome, 66 440). Conclusions and Relevance A genetic predisposition to higher waist-to-hip ratio adjusted for body mass index was associated with increased risk of type 2 diabetes and coronary heart disease. These results provide evidence supportive of a causal association between abdominal adiposity and these outcomes.

Meta-Analysis of Anxiety as a Risk Factor for Cardiovascular Disease.

Whether anxiety is a risk factor for a range of cardiovascular diseases is unclear. We aimed to determine the association between anxiety and a range of cardiovascular diseases. MEDLINE and EMBASE were searched for cohort studies that included participants with and without anxiety, including subjects with anxiety, worry, posttraumatic stress disorder, phobic anxiety, and panic disorder. We examined the association of anxiety with cardiovascular mortality, major cardiovascular events (defined as the composite of cardiovascular death, stroke, coronary heart disease, and heart failure), stroke, coronary heart disease, heart failure, and atrial fibrillation. We identified 46 cohort studies containing 2,017,276 participants and 222,253 subjects with anxiety. Anxiety was associated with a significantly elevated risk of cardiovascular mortality (relative risk [RR] 1.41, CI 1.13 to 1.76), coronary heart disease (RR 1.41, CI 1.23 to 1.61), stroke (RR 1.71, CI 1.18 to 2.50), and heart failure (RR 1.35, CI 1.11 to 1.64). Anxiety was not significantly associated with major cardiovascular events or atrial fibrillation although CIs were wide. Phobic anxiety was associated with a higher risk of coronary heart disease than other anxiety disorders, and posttraumatic stress disorder was associated with a higher risk of stroke. Results were broadly consistent in sensitivity analyses. Anxiety disorders are associated with an elevated risk of a range of different cardiovascular events, including stroke, coronary heart disease, heart failure, and cardiovascular death. Whether these associations are causal is unclear.

Association between randomised trial evidence and global burden of disease: cross sectional study (Epidemiological Study of Randomized Trials—ESORT)

Objectives To determine whether an association exists between the number of published randomised controlled trials and the global burden of disease, whether certain diseases are under-investigated relative to their burden, and whether the relation between the output of randomised trials and global burden of disease can be explained by the relative disease burden in high and low income regions. Design Cross sectional investigation. Study sample All primary reports of randomised trials published in December 2012 and indexed in PubMed by 17 November 2013. Main outcome measures Number of trials conducted and number of participants randomised for each of 239 different diseases or injuries; variation in each outcome explainable by total disability adjusted life years (a measure of the overall burden of each disease) and the ratio of disability adjusted life years in low income to high income regions (a measure of whether a disease is more likely to affect people living in high income regions) quantified using multivariable regression. Results 4190 abstracts were reviewed and 1351 primary randomised trials identified, of which 1097 could be classified using the global burden of disease taxonomy. Total disability adjusted life years was poorly associated with number of randomised trials and number of participants randomised in univariable analysis (Spearman’s r=0.35 and 0.33, respectively), although it was a significant predictor in the univariable and multivariable models (P<0.001). Diseases for which the burden was predominantly located in low income regions had sevenfold fewer trials per million disability adjusted life years than diseases predominantly located in high income regions. However, only 26% of the variation in number of trials among diseases could be explained by total disability adjusted life years and the ratio of disability adjusted life years in low income regions to high income regions. Many high income type diseases (for example, neck pain, glomerulonephritis) have proportionally fewer randomised trials compared with low income type diseases (for example, vitamin A deficiency). Conclusions Overall, a weak association existed between global burden of disease and number of published randomised trials. A global observatory for research is needed to monitor and reduce the discordance between the output of randomised trials and global burden of disease.

Reporting of a Publicly Accessible Protocol and Its Association With Positive Study Findings in Cardiovascular Trials (from the Epidemiological Study of Randomized Trials [ESORT]).

Selective outcome reporting is common among published randomized trials and is often associated with the reporting of positive study findings. We investigated whether publication of study protocols in publicly accessible formats is associated with the reporting of positive findings. An extended version of the Cochrane highly sensitive search strategy was used to identify reports of randomized trials on cardiovascular disease that were published in December 2012 and indexed in PubMed by November 2013. Study characteristics and methodologic characteristics were extracted in duplicate. The Fishers exact test and multivariable logistic regression were used to compare characteristics between trials that reported a publicly accessible protocol and those that did not. One hundred ninety-one reports of cardiovascular randomized trials were identified, 23 (12%) of which reported an accessible protocol. Trials reporting an accessible protocol were significantly larger and more likely to report strong trial methods, including reporting a power calculation, attrition, and the use of an intention-to-treat analysis. Despite greater statistical power, trials reporting an accessible protocol were less likely to report positive findings after controlling for known confounders (odds ratio 0.35, 95% confidence interval 0.13 to 0.94). Reporting of an accessible protocol is associated with a reduced likelihood of reporting positive findings. Further investigation is needed to determine if this association is causal.

Association between trial registration and positive study findings: cross sectional study (Epidemiological Study of Randomized Trials-ESORT).

Abstract Objective To assess whether randomised controlled trials (RCTs) that were registered were less likely to report positive study findings compared with RCTs that were not registered and whether the association varied by funding source. Design Cross sectional study. Study sample All primary RCTs published in December 2012 and indexed in PubMed by November 2013. Trial registration was determined based on the report of a trial registration number in published RCTs or the identification of the trial in a search of trial registries. Trials were separated into prospectively and retrospectively registered studies. Main outcome measure Association between trial registration and positive study findings. Results 1122 eligible RCTs were identified, of which 593 (52.9%) were registered and 529 (47.1%) were not registered. Overall, registration was marginally associated with positive study findings (adjusted risk ratio 0.87, 95% confidence interval 0.78 to 0.98), even with stratification as prospectively and retrospectively registered trials (0.87, 0.74 to 1.03 and 0.88, 0.78 to 1.00, respectively). The interaction term between overall registration and funding source was marginally statistically significant and relative risk estimates were imprecise (0.75, 0.63 to 0.89 for non-industry funded and 1.03, 0.79 to 1.36 for industry funded, P interaction=0.046). Furthermore, a statistically significant interaction was not maintained in sensitivity analyses. Within each stratum of funding source, relative risk estimates were also imprecise for the association between positive study findings and prospective and retrospective registration. Conclusion Among published RCTs, there was little evidence of a difference in positive study findings between registered and non-registered clinical trials, even with stratification by timing of registration. Relative risk estimates were imprecise in subgroups of non-industry and industry funded trials.

Blood pressure targets and absolute cardiovascular risk.

In the Eighth Joint National Committee guideline on hypertension, the threshold for the initiation of blood pressure–lowering treatment for elderly adults (≥60 years) without chronic kidney disease or diabetes mellitus was raised from 140/90 mm Hg to 150/90 mm Hg. However, the committee was not unanimous in this decision, particularly because a large proportion of adults ≥60 years may be at high cardiovascular risk. On the basis of Eighth Joint National Committee guideline, we sought to determine the absolute 10-year risk of cardiovascular disease among these adults through analyzing the National Health and Nutrition Examination Survey (2005–2012). The primary outcome measure was the proportion of adults who were at ≥20% predicted absolute cardiovascular risk and above goals for the Seventh Joint National Committee guideline but reclassified as at target under the Eighth Joint National Committee guideline (reclassified). The Framingham General Cardiovascular Disease Risk Score was used. From 2005 to 2012, the surveys included 12 963 adults aged 30 to 74 years with blood pressure measurements, of which 914 were reclassified based on the guideline. Among individuals reclassified as not in need of additional treatment, the proportion of adults 60 to 74 years without chronic kidney disease or diabetes mellitus at ≥20% absolute risk was 44.8%. This corresponds to 0.8 million adults. The proportion at high cardiovascular risk remained sizable among adults who were not receiving blood pressure–lowering treatment. Taken together, a sizable proportion of reclassified adults 60 to 74 years without chronic kidney disease or diabetes mellitus was at ≥20% absolute cardiovascular risk.

Referral for Specialist Follow-up and Its Association With Post-discharge Mortality Among Patients With Systolic Heart Failure (from the National Heart Failure Audit for England and Wales).

For patients admitted with worsening heart failure (HF), early follow-up after discharge is recommended. Whether outcomes can be improved when follow-up is done by cardiologists is uncertain. We aimed to determine the association between cardiology follow-up and risk of death for patients with HF discharged from hospital. Using data from the National Heart Failure Audit (England and Wales), we investigated the effect of referral to cardiology follow-up on 30-day and 1-year mortality in 68,772 patients with HF and a reduced left ventricular ejection fraction discharged from 185 hospitals from 2007 to 2013. The primary analyses used instrumental variable analysis complemented by hierarchical logistic and propensity-matched models. At the hospital level, rates of referral to cardiologists varied from 6% to 96%. The median odds ratio (OR) for referral to cardiologist was 2.3 (95% confidence interval [CI] 2.1 to 2.5), suggesting that, on average, the odds of a patient being referred for cardiologist follow-up after discharge differed ∼2.3 times from one randomly selected hospital to another one. Based on the proportion of patients (per region) referred for cardiology follow-up, referral for cardiology follow-up was associated with lower 30-day (OR 0.70; 95% CI 0.55 to 0.89) and 1-year mortality (OR 0.81; 95% CI 0.68 to 0.95) compared with no plans for cardiology follow-up (i.e., standard follow-up done by family doctors). Results from hierarchical logistic models and propensity-matched models were consistent (30-day mortality OR 0.66; 95% CI 0.61 to 0.72 and 0.66; 95% CI 0.58 to 0.76 for hierarchical and propensity matched models, respectively). For patients with HF and a reduced left ventricular ejection fraction admitted to hospital with worsening symptoms, referral to cardiology services for follow-up after discharge is strongly associated with reduced mortality, both early and late.

The association between development assistance for health and malaria, HIV and tuberculosis mortality: A cross-national analysis

Development assistance for health (DAH) and foreign aid have been criticized for being poorly associated with health and economic outcomes on a national level. This study is an attempt to examine whether DAH targeted specifically to malaria, HIV and tuberculosis (TB) is associated with changes in malaria, HIV and TB mortality, respectively. A dataset of DAH targeted to malaria, HIV and TB and corresponding malaria-, HIV- and TB-specific mortality was compiled for 120 low- and middle-income countries. Regression analysis was performed using country and time-period fixed effects and control variables. While malaria and HIV DAH were associated with reductions in malaria and HIV mortality, respectively, TB DAH was not significantly associated with reductions in TB mortality. Estimates were consistent in various sensitivity analyses, including generalized method of moments estimation, addition of extra controls and analysis of a multiply imputed dataset. In conclusion, targeted DAH is associated with reduction of HIV and malaria mortality on a national level.