A Rush to Judgment? Rapid Reporting and Dissemination of Results and Its Consequences Regarding the Use of Hydroxychloroquine for COVID-19

Should You Recommend Inhaled Corticosteroids for This Patient With Chronic Obstructive Pulmonary Disease?: Grand Rounds Discussion From Beth Israel Deaconess Medical Center: Annals of Internal Medicine: Vol 172, No 11

Approximately 12 million adults in the United States receive a diagnosis of chronic obstructive pulmonary disease (COPD) each year, and it is the fourth leading cause of death. Chronic obstructive pulmonary disease refers to a group of diseases that cause airflow obstruction and a constellation of symptoms, including cough, sputum production, and shortness of breath. The main risk factor for COPD is tobacco smoke, but other environmental exposures also may contribute. The GOLD (Global Initiative for Chronic Obstructive Lung Disease) 2020 Report aims to provide a nonbiased review of the current evidence for the assessment, diagnosis, and treatment of patients with COPD. To date, no conclusive evidence exists that any existing medications for COPD modify mortality. The mainstay of treatment for COPD is inhaled bronchodilators, whereas the role of inhaled corticosteroids is less clear. Inhaled corticosteroids have substantial risks, including an increased risk for pneumonia. Here, 2 experts, both pulmonologists, reflect on the care of a woman with severe COPD, a 50–pack-year smoking history, frequent COPD exacerbations, and recurrent pneumonia. They consider the indications for inhaled corticosteroids in COPD, when inhaled corticosteroids should be withdrawn, and what other treatments are available.

Chekhov on Epic

Finding the Pathway: Mediation Analyses in Randomized Controlled Trials

Delayed Denosumab Injections and Fracture Risk Among Patients With Osteoporosis: A Population-Based Cohort Study: Annals of Internal Medicine: Vol 173, No 7

Background: Denosumab is effective for osteoporosis, but discontinuation leads to rapid reversal of its therapeutic effect. Objective: To estimate the risk for fracture among users of denosumab who delayed subsequent doses compared with users who received doses on time. Design: Population-based cohort study. Setting: The Health Improvement Network U.K. primary care database, 2010 to 2019. Patients: Persons aged 45 years or older who initiated denosumab therapy for osteoporosis. Measurements: Observational data were used to emulate an analysis of a hypothetical trial with 3 dosing intervals: subsequent denosumab injection given within 4 weeks after the recommended date (“on time”), delay by 4 to 16 weeks (“short delay”), and delay by more than 16 weeks (“long delay”). The primary outcome was a composite of all fracture types at 6 months after the recommended date. Secondary outcomes were major osteoporotic fracture, vertebral fracture, hip fracture, and nonvertebral fracture. Results: Investigators identified 2594 patients initiating denosumab therapy. The risk for composite fracture over 6 months was 27.3 in 1000 for on-time dosing, 32.2 in 1000 for short delay, and 42.4 in 1000 for long delay. Compared with on-time injections, short delay had a hazard ratio (HR) for composite fracture of 1.03 (95% CI, 0.63 to 1.69) and long delay an HR of 1.44 (CI, 0.96 to 2.17) (P for trend = 0.093). For vertebral fractures, short delay had an HR of 1.48 (CI, 0.58 to 3.79) and long delay an HR of 3.91 (CI, 1.62 to 9.45). Limitation: Dosing schedules were not randomly assigned. Conclusion: Although delayed administration of subsequent denosumab doses by more than 16 weeks is associated with increased risk for vertebral fracture compared with on-time dosing, evidence is insufficient to conclude that fracture risk is increased at other anatomical sites with long delay. Primary Funding Source: National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation.

Developing Primary Care–Based Recommendations for Social Determinants of Health: Methods of the U.S. Preventive Services Task Force

The purpose of the U.S. Preventive Services Task Force (USPSTF) is to provide evidence-based recommendations on primary care screening, behavioral counseling, and preventive medications. A person's health is strongly influenced by social determinants of health, such as economic and social conditions; therefore, preventive recommendations that address these determinants would be ideal. However, differing social determinants have been proposed by a wide range of agencies and organizations, little prevention evidence is available, and responsible parties are in competition, all of which make the creation of evidence-based prevention recommendations for social determinants of health challenging. This article highlights social determinants already included in USPSTF recommendations and proposes a process by which others may be considered for primary care preventive recommendations. In many ways, incorporating social determinants of health into evidence-based recommendations is an evolving area. By reviewing the evidence on the effects of screening and interventions on social determinants relevant to primary care, the USPSTF will continue to provide recommendations on clinical preventive services to improve the health of all Americans.

A Call to Systematically Monitor for Adverse Events in Users of Low-Dose Methotrexate Therapy

Participation of African American Persons in Clinical Trials Supporting U.S. Food and Drug Administration Approval of Cancer Drugs

Associations Between Dietary Patterns and Subclinical Cardiac Injury: An Observational Analysis From the DASH Trial: Annals of Internal Medicine: Vol 172, No 12

Background: The DASH diet has been found to lower blood pressure (BP) and low-density lipoprotein cholesterol levels. Objective: To compare diets rich in fruits and vegetables with a typical American diet in their effects on cardiovascular injury in middle-aged adults without known preexisting cardiovascular disease (CVD). Design: Observational study based on a 3-group, parallel-design, randomized trial conducted in the United States from 1994 to 1996. (ClinicalTrials.gov: NCT00000544) Setting: 3 of the 4 original clinical trial centers. Participants: 326 of the original 459 trial participants with available stored specimens. Intervention: Participants were randomly assigned to 8 weeks of monitored feeding with a control diet typical of what many Americans eat; a diet rich in fruits and vegetables but otherwise similar to the control diet; or the DASH diet, which is rich in fruits, vegetables, low-fat dairy, and fiber and has low levels of saturated fat and cholesterol. Weight was kept constant throughout feeding. Measurements: Biomarkers collected at baseline and 8 weeks: high-sensitivity cardiac troponin I (hs-cTnI), N-terminal pro–B-type natriuretic peptide (NT-proBNP), and high-sensitivity C-reactive protein (hs-CRP). Results: The mean age of participants was 45.2 years, 48% were women, 49% were black, and mean baseline BP was 131/85 mm Hg. Compared with the control diet, the fruit-and-vegetable diet reduced hs-cTnI levels by 0.5 ng/L (95% CI, −0.9 to −0.2 ng/L) and NT-proBNP levels by 0.3 pg/mL (CI, −0.5 to −0.1 pg/mL). Compared with the control diet, the DASH diet reduced hs-cTnI levels by 0.5 ng/L (CI, −0.9 to −0.1 ng/L) and NT-proBNP levels by 0.3 pg/mL (CI, −0.5 to −0.04 pg/mL). Levels of hs-CRP did not differ among diets. None of the markers differed between the fruit-and-vegetable and DASH diets. Limitation: Short duration, missing specimens, and an inability to isolate the effects of specific foods or micronutrients. Conclusion: Diets rich in fruits and vegetables given over 8 weeks were associated with lower levels of markers for subclinical cardiac damage and strain in adults without preexisting CVD. Primary Funding Source: National Institutes of Health, National Heart, Lung, and Blood Institute.

Key Evidence Supporting Prescription Opioids Approved by the U.S. Food and Drug Administration, 1997 to 2018

Background: Little is known about the evidence required by the U.S. Food and Drug Administration (FDA) for new approvals of opioid analgesics. Objective: To characterize the quality of safety and efficacy data in new drug applications (NDAs) for opioid analgesics approved by the FDA between 1997 and 2018. Design: Cross-sectional analysis. Setting: Data from ClinicalTrials.gov, FDA reviews, and peer-reviewed publications. Participants: Patients with pain who participated in phase 3 pivotal trials. Intervention: FDA-approved opioid analgesics. Measurements: Key characteristics of each NDA, including the number, size, and duration of pivotal trials; trial control groups; the use of enriched trial populations; and systematically measured safety outcomes. Results: Most of the 48 NDAs evaluated were for new dosage forms (n = 25 [52.1%]) or new formulations (n = 9 [18.8%]); only 1 (2.1%) was for a new molecular entity. Of 39 NDAs approved for treating chronic pain, only 21 products were supported by at least 1 pivotal trial; these trials (n = 28) had a median duration of 84 days (interquartile range [IQR], 25 to 84 days) and enrolled a median of 299 patients (IQR, 174 to 525 patients). Seventeen (81%) of these products were approved on the basis of designs that excluded patients who could not tolerate the drugs, had early adverse effects, or reported few immediate benefits. Among NDAs for chronic pain, 8 (20.5%) included pooled safety reviews that reported systematic assessment of diversion, 7 (17.9%) reported systematic measurement of nonmedical use, and 15 (38.5%) assessed development of tolerance. Eight of 9 products for acute pain were supported by at least 1 pivotal trial; the pivotal trials (n = 19) had a median duration of 1 day (IQR, 1 to 2 days) and enrolled a median of 329 patients (IQR, 199 to 456 patients). Although all but 1 of the 48 approved NDAs were for previously approved moieties, analysis of available NDAs for referent products yielded similar findings. Limitations: The analysis was limited to approved opioids. Animal studies and nonpivotal trials were excluded. Evidence for safety in NDAs was presented for chronic pain only. Conclusion: Between 1997 and 2018, the FDA approved opioids on the basis of pivotal trials of short or intermediate duration, often in narrowly defined pain populations of patients who could tolerate the drug. Systematic collation of certain important safety outcomes was rare. Primary Funding Source: None.