Electronic Health Records: An Unfulfilled Promise and a Call to Action

Detecting Heterogeneous Treatment Effects to Guide Personalized Blood Pressure Treatment: A Modeling Study of Randomized Clinical Trials: Annals of Internal Medicine: Vol 166, No 5

Background: Two recent randomized trials produced discordant results when testing the benefits and harms of treatment to reduce blood pressure (BP) in patients with cardiovascular disease (CVD). Objective: To perform a theoretical modeling study to identify whether large, clinically important differences in benefit and harm among patients (heterogeneous treatment effects [HTEs]) can be hidden in, and explain discordant results between, treat-to-target BP trials. Design: Microsimulation. Data Sources: Results of 2 trials comparing standard (systolic BP target <140 mm Hg) with intensive (systolic BP target <120 mm Hg) BP treatment and data from the National Health and Nutrition Examination Survey (2013 to 2014). Target Population: U.S. adults. Time Horizon: 5 years. Perspective: Societal. Intervention: BP treatment. Outcome Measures: CVD events and mortality. Results of Base-Case Analysis: Clinically important HTEs could explain differences in outcomes between 2 trials of intensive BP treatment, particularly diminishing benefit with each additional BP agent (for example, adding a second agent reduces CVD risk [hazard ratio, 0.61], but adding a fourth agent to a third has no benefit) and increasing harm at low diastolic BP. Results of Sensitivity Analysis: Conventional treat-to-target trial designs had poor (<5%) statistical power to detect the HTEs, despite large samples (n > 20 000), and produced biased effect estimates. In contrast, a trial with sequential randomization to more intensive therapy achieved greater than 80% power and unbiased HTE estimates, despite small samples (n = 3500). Limitations: The HTEs as a function of the number of BP agents only were explored. Simulated aggregate data from the trials were used as model inputs because individual-participant data were not available. Conclusion: Clinically important heterogeneity in intensive BP treatment effects remains undetectable in conventional trial designs but can be detected in sequential randomization trial designs. Primary Funding Source: National Institutes of Health and U.S. Department of Veterans Affairs.

Lack of Evidence Linking Calcium With or Without Vitamin D Supplementation to Cardiovascular Disease in Generally Healthy Adults: A Clinical Guideline From the National Osteoporosis Foundation and the American Society for Preventive Cardiology

Description: Calcium is the dominant mineral present in bone and a shortfall nutrient in the American diet. Supplements have been recommended for persons who do not consume adequate calcium from their diet as a standard strategy for the prevention of osteoporosis and related fractures. Whether calcium with or without vitamin D supplementation is beneficial or detrimental to vascular health is not known. Methods: The National Osteoporosis Foundation and American Society for Preventive Cardiology convened an expert panel to evaluate the effects of dietary and supplemental calcium on cardiovascular disease based on the existing peer-reviewed scientific literature. The panel considered the findings of the accompanying updated evidence report provided by an independent evidence review team at Tufts University. Recommendation: The National Osteoporosis Foundation and American Society for Preventive Cardiology adopt the position that there is moderate-quality evidence (B level) that calcium with or without vitamin D intake from food or supplements has no relationship (beneficial or harmful) to the risk for cardiovascular and cerebrovascular disease, mortality, or all-cause mortality in generally healthy adults at this time. In light of the evidence available to date, calcium intake from food and supplements that does not exceed the tolerable upper level of intake (defined by the National Academy of Medicine as 2000 to 2500 mg/d) should be considered safe from a cardiovascular standpoint.

Calibration of the Pooled Cohort Equations for Atherosclerotic Cardiovascular Disease: An Update: Annals of Internal Medicine: Vol 165, No 11

The latest guidelines from the American College of Cardiology and American Heart Association, released in fall 2013, provide a long-anticipated update to the recommendations of the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). The guidelines incorporate a new risk score for atherosclerotic cardiovascular disease that includes stroke as well as coronary heart disease. After publication, the new pooled cohort equations (PCEs) were evaluated in 15 studies from the United States and Europe, most of which used cohorts that were more contemporary than those used in developing the guidelines. In almost all of these external validation cohorts, the PCEs overestimated the observed risk. This narrative review provides an update of the published reports, an overview of the strengths and weaknesses of these validation efforts, and a discussion of possible reasons for the discrepancies. These issues may be useful in a recalibration process designed to better match predicted and observed risks relevant for current clinical practice.

Can Knowledge About Heterogeneity in Treatment Effects Help Us Choose Wisely?

Decreasing Prevalence of Chronic Kidney Disease in the United States: A Cause for Optimism

Firearm Acquisition Without Background Checks: Results of a National Survey: Annals of Internal Medicine: Vol 166, No 4

Background: In 1994, 40% of U.S. gun owners who had recently acquired a firearm did so without a background check. No contemporary estimates exist. Objective: To estimate the proportion of current U.S. gun owners who acquired their most recent firearm without a background check, by time since and manner of acquisition, for the nation as a whole and separately in states with and without legislation regulating private sales. Design: Probability-based online survey. Setting: United States, 2015. Participants: 1613 adult gun owners. Measurements: Current gun owners were asked where and when they acquired their last firearm; if they purchased the firearm; and whether, as part of that acquisition, they had a background check (or were asked to show a firearm license or permit). Results: 22% (95% CI, 16% to 27%) of gun owners who reported obtaining their most recent firearm within the previous 2 years reported doing so without a background check. For firearms purchased privately within the previous 2 years (that is, other than from a store or pawnshop, including sales between individuals in person, online, or at gun shows), 50% (CI, 35% to 65%) were obtained without a background check. This percentage was 26% (CI, 5% to 47%) for owners residing in states regulating private firearm sales and 57% (CI, 40% to 75%) for those living in states without regulations on private firearm sales. Limitation: Potential inaccuracies due to recall and social desirability bias. Conclusion: 22% of current U.S. gun owners who acquired a firearm within the past 2 years did so without a background check. Although this represents a smaller proportion of gun owners obtaining firearms without background checks than in the past, millions of U.S. adults continue to acquire guns without background checks, especially in states that do not regulate private firearm sales. Primary Funding Source: Fund for a Safer Future and the Joyce Foundation.

The Philadelphia Story: Attacking Behavioral and Social Determinants of Health

Extracranial Carotid Disease and Effect of Intra-arterial Treatment in Patients With Proximal Anterior Circulation Stroke in MR CLEAN

Background: The presence of extracranial carotid disease (ECD) is associated with less favorable clinical outcomes in patients with acute ischemic stroke caused by intracranial proximal occlusion. Acute intra-arterial treatment (IAT) in the setting of extracranial and intracranial lesions is considered challenging, and whether it yields improved outcomes remains uncertain. Objective: To examine whether the presence of ECD modified the effect of IAT for intracranial proximal anterior circulation occlusion. Design: Prespecified subgroup analysis of a randomized clinical trial of endovascular treatment for acute ischemic stroke in the Netherlands. (Trial registrations: NTR1804 [Netherlands Trial Register] and ISRCTN10888758) Setting: 16 hospitals in the Netherlands. Patients: Acute ischemic stroke caused by proximal intracranial arterial occlusion of the anterior circulation. Extracranial carotid disease was defined as cervical internal carotid artery stenosis (>50%) or occlusion. Intervention: IAT treatment versus no IAT. Measurements: The primary outcome was functional outcome, as measured by the modified Rankin Scale at 90 days and reported as adjusted common odds ratio (acOR) for a shift in direction of a better outcome. Multivariable ordinal logistic regression analysis with an interaction term was used to estimate treatment effect modification by ECD. Results: The overall acOR was 1.67 (95% CI, 1.21 to 2.30) in favor of the intervention. The acOR was 3.1 (CI, 1.7 to 5.8) in the prespecified subgroup of patients with ECD versus 1.3 (CI, 0.9 to 1.9) in patients presenting without ECD. Both acORs are in favor of the intervention (P for interaction = 0.07). Limitation: The study was not powered for subgroup analysis. Conclusion: Intra-arterial treatment may be at least as effective in patients with ECD as in those without ECD, and it should not be withheld in these complex patients with acute ischemic stroke. Primary Funding Source: Dutch Heart Foundation, AngioCare BV, Medtronic/Covidien/EV3, MEDAC Gmbh/LAMEPRO, Penumbra, Stryker, and Top Medical/Concentric.

Brain-Type Natriuretic Peptide and Amino-Terminal Pro–Brain-Type Natriuretic Peptide Discharge Thresholds for Acute Decompensated Heart Failure: A Systematic Review: Annals of Internal Medicine: Vol 166, No 3

Background: Acute decompensated heart failure (ADHF) requiring hospitalization is associated with high postdischarge mortality and readmission rates. Purpose: To examine the association between achieving predischarge natriuretic peptide (NP) thresholds and mortality and readmission rates in adults hospitalized for ADHF. Data Sources: Multiple databases from 1947 to October 2016 (English-language studies only). Study Selection: Trials and observational studies that compared mortality and readmission outcomes between patients with ADHF achieving a specific predischarge NP goal and those not achieving the goal. Data Extraction: Two investigators independently extracted study characteristics and assessed study risk of bias. One author graded the overall strength of evidence, with review by a second author. Data Synthesis: One randomized trial, 3 quasi-experimental studies, and 40 observational studies were identified. The most commonly used thresholds were a brain-type NP (BNP) level of 250 pg/mL or less or an amino-terminal pro–brain-type NP (NT-proBNP) decrease of at least 30%. Achievement of absolute BNP thresholds reduced postdischarge all-cause mortality (7 of 8 studies) and the composite outcome of mortality and readmission (12 of 14 studies). Achievement of percentage-change BNP thresholds reduced the composite outcome (5 of 6 studies), and achievement of percentage-change NT-proBNP thresholds reduced all-cause and cardiovascular mortality (2 of 4 studies) and the composite outcome (9 of 9 studies). All findings were low-strength. The randomized trial, assessed as having high risk of bias, suggested that a predischarge decrease in NT-proBNP level was associated with lower risk for the composite outcome. Two quasi-experimental studies and 5 observational studies had low risk of bias. Low-risk-of-bias studies had outcome estimates similar in magnitude and direction to estimates from high-risk-of-bias studies. Limitation: Most studies failed to adjust for critical confounders and had inadequate definition or assessment of exposures and outcomes. Conclusion: Low-strength evidence suggests an association between achieving NP predischarge thresholds and reduced ADHF mortality and readmission. Primary Funding Source: None.