Archive for September, 2016

Evolution of Bad Science

September 29, 2016 1 comment

Smaldino and McElreath McElreath examine the dynamics of the quality of scientific literature. This is a very important, sobering (and timely) paper. This paper provides a clear (literate) exposition. The definitions, the models used and the parameter distributions provide a compelling case that high output is an important ( subconscious and unintentional driver of under-powered studies and increasing rate of false discovery.

The graphics from the paper follow. It is highly recommended that the full paper be carefully read.


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Statistical Rethinking.

September 27, 2016 2 comments

The movement to improve statistical rigor in biomedical science is increasing. The lecture series by Professor McElreath is very instructive (particularly lecture 10 comments re: p-value ”star-gazing”).  There is a logical progression and lectures are not independent.


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Systolic Blood Pressure Variability Vascular and Renal Outomes

September 22, 2016 Leave a comment

Gosmanova et al report a large cohort study of US 3285684 veterans. The authors determine and quantify the relationship between systolic blood pressure variability and mortality, coronary heart disease, stroke and end-stage renal disease.

The editorial is available here.



Intraindividual blood pressure (BP) fluctuates dynamically over time. Previous studies suggested an adverse link between greater visit-to-visit variability in systolic blood pressure (SBP) and various outcomes. However, these studies have significant limitations, such as a small size, inclusion of selected populations, and restricted outcomes.


This study investigated the association of increased visit-to-visit variability and all-cause mortality, cardiovascular events, and end-stage renal disease (ESRD) in a large cohort of U.S. veterans.


From among 3,285,684 U.S. veterans with and without hypertension and normal estimated glomerular filtration rates (eGFR) during 2005 and 2006, we identified 2,865,157 patients who had 8 or more outpatient BP measurements. Systolic blood pressure variability (SBPV) was measured using the SD of all SBP values (normally distributed) in 1 individual. Associations of SD quartiles (<10.3, 10.3 to 12.7, 12.7 to 15.6, and $15.6 mm Hg) with all-cause mortality, incident coronary heart disease (CHD), stroke, and ESRD was examined using Cox models adjusted for sociodemographic characteristics, baseline eGFR, comorbidities, body mass index, SBP, diastolic BP, and antihypertensive
medication use.


Several sociodemographic variables (older age, male sex, African-American race, divorced or widowed status) and clinical characteristics (lower baseline eGFR, higher SBP and diastolic BP), and comorbidities (presence of diabetes, hypertension, cardiovascular disease, and lung disease) were all associated with higher intraindividual SBPV. The multivariable adjusted hazard ratios and 95% confidence intervals for SD quartiles 2 through 4 (compared with the first quartile) associated with all-cause mortality, CHD, stroke, and ESRD were incrementally higher.


Higher SBPV in individuals with and without hypertension was associated with increased risks of all-cause mortality, CHD, stroke, and ESRD. Further studies are needed to determine interventions that can lower SBPV and their impact on adverse health outcomes.

bpv03The reader is urged to see the subgroup analysis in the paper.

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ICD in Non-ischemic Heart Failure Patients

September 20, 2016 Leave a comment

Køber et al reports for the DANISH Investigators a randomized clinical trial of ICD therapy in patients with non-ischemic cardiomyopathy. They found that there was no reduction in overall long-term mortality though sudden death was lower.

The editorial is available here.



The benefit of an implantable cardioverter–defibrillator (ICD) in patients with symptomatic systolic heart failure caused by coronary artery disease has been well documented. However, the evidence for a benefit of prophylactic ICDs in patients
with systolic heart failure that is not due to coronary artery disease has been based primarily on subgroup analyses. The management of heart failure has improved since the landmark ICD trials, and many patients now receive cardiac resynchronization therapy (CRT).


In a randomized, controlled trial, 556 patients with symptomatic systolic heart failure (left ventricular ejection fraction, ≤35%) not caused by coronary artery disease were assigned to receive an ICD, and 560 patients were assigned to receive usual clinical care (control group). In both groups, 58% of the patients received CRT. The primary outcome of the trial was death from any cause. The secondary outcomes were sudden cardiac death and cardiovascular death.


After a median follow-up period of 67.6 months, the primary outcome had occurred in 120 patients (21.6%) in the ICD group and in 131 patients (23.4%) in the control group (hazard ratio, 0.87; 95% confidence interval [CI], 0.68 to 1.12; P = 0.28). Sudden cardiac death occurred in 24 patients (4.3%) in the ICD group and in 46 patients (8.2%) in the control group (hazard ratio, 0.50; 95% CI, 0.31 to 0.82; P = 0.005). Device infection occurred in 27 patients (4.9%) in the ICD group and in 20 patients (3.6%) in the control group (P = 0.29).


In this trial, prophylactic ICD implantation in patients with symptomatic systolic heart failure not caused by coronary artery disease was not associated with a significantly lower long-term rate of death from any cause than was usual clinical care.


Semaglutide and Cardiovascular Events (SUSTAIN-6)

September 20, 2016 Leave a comment

Marso et al
report the cardiovascular safety data of the glucagon-like peptide (GLP-1) analogue in patients with type II diabetes mellitus (weekly injection 0.5 or 1 mg). A non-inferiority margin of  1.8 ( hazard ratio) for the 95% upper bound of the hazard ratio. Semaglutide was associated with lower rates of cardiovascular death and non-fatal myocardial infarction (approximately 2 years follow up). The hazard ratio was below the inferiority margin.



Regulatory guidance specifies the need to establish cardiovascular safety of new diabetes therapies in patients with type 2 diabetes in order to rule out excess cardiovascular risk. The cardiovascular effects of semaglutide, a glucagon-like peptide 1 analogue with an extended half-life of approximately 1 week, in type 2 diabetes are unknown.


We randomly assigned 3297 patients with type 2 diabetes who were on a standard care regimen to receive once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks. The primary composite outcome was the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. We hypothesized that semaglutide would be noninferior to placebo for the primary outcome. The noninferiority margin was 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio.


At baseline, 2735 of the patients (83.0%) had established cardiovascular disease, chronic kidney disease, or both. The primary outcome occurred in 108 of 1648 patients (6.6%) in the semaglutide group and in 146 of 1649 patients (8.9%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.58 to 0.95; P<0.001 for noninferiority).
Nonfatal myocardial infarction occurred in 2.9% of the patients receiving semaglutide and in 3.9% of those receiving placebo (hazard ratio, 0.74; 95% CI, 0.51 to 1.08; P = 0.12); nonfatal stroke occurred in 1.6% and 2.7%, respectively (hazard ratio, 0.61; 95% CI, 0.38 to 0.99; P = 0.04). Rates of death from cardiovascular causes weresimilar in the two groups. Rates of new or worsening nephropathy were lower in the semaglutide group, but rates of retinopathy complications (vitreous hemorrhage, blindness, or conditions requiring treatment with an intravitreal agent or photocoagulation)
were significantly higher (hazard ratio, 1.76; 95% CI, 1.11 to 2.78; P = 0.02). Fewer serious adverse events occurred in the semaglutide group, although more patients discontinued treatment because of adverse events, mainly gastrointestinal.


In patients with type 2 diabetes who were at high cardiovascular risk, the rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo, an outcome that confirmed the noninferiority of semaglutide.


Alcohol, Left Atrial Size and Atrial Fibrillation

September 15, 2016 Leave a comment

McManus et al report on the relationship between alcohol consumption (questionnaire-> dose in g/day), left atrial diameter and subsequent atrial fibrillation. The authors use the original Framingham Heart Study and the Offspring study with longitudinal assessment.

The authors found a positive relationship between alcohol consumption and left atrial diameter. This disappeared in models for covariates (see figure labelled table 3). Left atrial diameter was correlated with the incidence of atrial fibrillation with follow up.



Alcohol consumption has been associated with atrial fibrillation (AF) in several epidemiologic studies, but the underlying mechanisms remain unknown. We sought to test the hypothesis that an atrial myopathy, manifested by echocardiographic left atrial enlargement, explains the association between chronic alcohol use and AF.

Methods and Results

We evaluated the relationship between cumulative alcohol consumption and risk of incident AF in 5220
Offspring and Original Framingham Heart Study participants (mean age 56.3 years, 54% women) with echocardiographic left atrial size measurements. The incidence of AF was 8.4 per 1000 person-years, with 1088 incident AF cases occurring over a median 6.0 years (25th–75th percentiles 4.0–8.7 years) of follow-up. After multivariable adjustment for potential confounders, every additional 10 g of alcohol per day (just under 1 drink per day) was associated with a 0.16 mm (95% CI, 0.10–0.21 mm) larger left atrial dimension. Also in multivariable adjusted analysis, every 10 g per day of alcohol consumed was associated with a 5% higher risk of developing new-onset AF (hazard ratio, 1.05; 95% CI, 1.01–1.09). An estimated 24% (95% CI, 8–75) of the association between alcohol and AF risk was explained by left atrial enlargement.


Our study of a large, community-based sample identified alcohol consumption as a predictor of left atrial enlargement and subsequent incident AF. Left atrial enlargement may be an intermediate phenotype along the causal pathway linking long-term alcohol consumption to AF.



Review of Statin Safety and Efficacy

The Lancet has published an excellent review of statin efficacy and safety.




The following very instructive comments form <a href="; E. Topol tweet.