Blood Pressure Level in Late Adolescence and Risk for Cardiovascular Events: A Cohort Study: Annals of Internal Medicine: Vol 176, No 10

Background: Not enough is known about the association between blood pressure (BP) in adolescence and future cardiovascular events. Objective: To measure this association using the 2017 American College of Cardiology/American Heart Association guidelines for classifying BP elevation. Design: Cohort study. Setting: Sweden. Participants: Males in late adolescence who were conscripted into the military from 1969 to 1997. Measurements: Baseline BP was measured at conscription. The primary outcome was a composite of cardiovascular death or first hospitalization for myocardial infarction, heart failure, ischemic stroke, or intracerebral hemorrhage. Results: The study included 1 366 519 males with a mean age of 18.3 years. The baseline BP was classified as elevated (120 to 129/<80 mm Hg) for 28.8% of participants and hypertensive (≥130/80 mm Hg) for 53.7%. During a median follow-up of 35.9 years, 79 644 had a primary outcome. The adjusted hazard ratio was 1.10 for elevated BP (95% CI, 1.07 to 1.13), 1.15 for stage 1 isolated systolic hypertension (ISH) (CI, 1.11 to 1.18), 1.23 for stage 1 isolated diastolic hypertension (IDH) (CI, 1.18 to 1.28), 1.32 for stage 1 systolic–diastolic hypertension (SDH) (CI, 1.27 to 1.37), 1.31 for stage 2 ISH (CI, 1.28 to 1.35), 1.55 for stage 2 IDH (CI, 1.42 to 1.69), and 1.71 for stage 2 SDH (CI, 1.58 to 1.84). The cumulative risk for cardiovascular events also increased gradually across BP stages, ranging from 14.7% for normal BP to 24.3% for stage 2 SDH at age 68 years. Limitation: This was an observational study of Swedish men. Conclusion: Increasing BP levels in late adolescence are associated with gradually increasing risks for major cardiovascular events, beginning at a BP level of 120/80 mm Hg. Primary Funding Source: Västerbotten County Council, Swedish Society for Medical Research, and Heart Foundation of Northern Sweden.

Effects of Implementation of a Supervised Walking Program in Veterans Affairs Hospitals: A Stepped-Wedge, Cluster Randomized Trial: Annals of Internal Medicine: Vol 176, No 6

Background: In trials, hospital walking programs have been shown to improve functional ability after discharge, but little evidence exists about their effectiveness under routine practice conditions. Objective: To evaluate the effect of implementation of a supervised walking program known as STRIDE (AssiSTed EaRly MobIlity for HospitalizeD VEterans) on discharge to a skilled-nursing facility (SNF), length of stay (LOS), and inpatient falls. Design: Stepped-wedge, cluster randomized trial. (ClinicalTrials.gov: NCT03300336) Setting: 8 Veterans Affairs hospitals from 20 August 2017 to 19 August 2019. Patients: Analyses included hospitalizations involving patients aged 60 years or older who were community dwelling and admitted for 2 or more days to a participating medicine ward. Intervention: Hospitals were randomly assigned in 2 stratified blocks to a launch date for STRIDE. All hospitals received implementation support according to the Replicating Effective Programs framework. Measurements: The prespecified primary outcomes were discharge to a SNF and hospital LOS, and having 1 or more inpatient falls was exploratory. Generalized linear mixed models were fit to account for clustering of patients within hospitals and included patient-level covariates. Results: Patients in pre-STRIDE time periods (n = 6722) were similar to post-STRIDE time periods (n = 6141). The proportion of patients with any documented walk during a potentially eligible hospitalization ranged from 0.6% to 22.7% per hospital. The estimated rates of discharge to a SNF were 13% pre-STRIDE and 8% post-STRIDE. In adjusted models, odds of discharge to a SNF were lower among eligible patients hospitalized in post-STRIDE time periods (odds ratio [OR], 0.6 [95% CI, 0.5 to 0.8]) compared with pre-STRIDE. Findings were robust to sensitivity analyses. There were no differences in LOS (rate ratio, 1.0 [CI, 0.9 to 1.1]) or having an inpatient fall (OR, 0.8 [CI, 0.5 to 1.1]). Limitation: Direct program reach was low. Conclusion: Although the reach was limited and variable, hospitalizations occurring during the STRIDE hospital walking program implementation period had lower odds of discharge to a SNF, with no change in hospital LOS or inpatient falls. Primary Funding Source: U.S. Department of Veterans Affairs Quality Enhancement Research Initiative (Optimizing Function and Independence QUERI).

The War on Reproductive Health Care in the United States

Risk for Chronic Kidney Disease Progression After Acute Kidney Injury: Findings From the Chronic Renal Insufficiency Cohort Study

Background: Prior studies associating acute kidney injury (AKI) with more rapid subsequent loss of kidney function had methodological limitations, including inadequate control for differences between patients who had AKI and those who did not. Objective: To determine whether AKI is independently associated with subsequent kidney function trajectory among patients with chronic kidney disease (CKD). Design: Multicenter prospective cohort study. Setting: United States. Participants: Patients with CKD (n = 3150). Measurements: Hospitalized AKI was defined by a 50% or greater increase in inpatient serum creatinine (SCr) level from nadir to peak. Kidney function trajectory was assessed using estimated glomerular filtration rate (eGFR) based on SCr level (eGFRcr) or cystatin C level (eGFRcys) measured at annual study visits. Results: During a median follow-up of 3.9 years, 433 participants had at least 1 AKI episode. Most episodes (92%) had stage 1 or 2 severity. There were decreases in eGFRcr (−2.30 [95% CI, −3.70 to −0.86] mL/min/1.73 m2) and eGFRcys (−3.61 [CI, −6.39 to −0.82] mL/min/1.73 m2) after AKI. However, in fully adjusted models, the decreases were attenuated to −0.38 (CI, −1.35 to 0.59) mL/min/1.73 m2 for eGFRcr and −0.15 (CI, −2.16 to 1.86) mL/min/1.73 m2 for eGFRcys, and the CI bounds included the possibility of no effect. Estimates of changes in eGFR slope after AKI determined by either SCr level (0.04 [CI, −0.30 to 0.38] mL/min/1.73 m2 per year) or cystatin C level (−0.56 [CI, −1.28 to 0.17] mL/min/1.73 m2 per year) also had CI bounds that included the possibility of no effect. Limitations: Few cases of severe AKI, no adjudication of AKI cause, and lack of information about nephrotoxic exposures after hospital discharge. Conclusion: After pre-AKI eGFR, proteinuria, and other covariables were accounted for, the association between mild to moderate AKI and worsening subsequent kidney function in patients with CKD was small. Primary Funding Source: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.

Oral Fluvoxamine With Inhaled Budesonide for Treatment of Early-Onset COVID-19: A Randomized Platform Trial: Annals of Internal Medicine: Vol 176, No 5

Background: Previous trials have demonstrated the effects of fluvoxamine alone and inhaled budesonide alone for prevention of disease progression among outpatients with COVID-19. Objective: To determine whether the combination of fluvoxamine and inhaled budesonide would increase treatment effects in a highly vaccinated population. Design: Randomized, placebo-controlled, adaptive platform trial. (ClinicalTrials.gov: NCT04727424) Setting: 12 clinical sites in Brazil. Participants: Symptomatic adults with confirmed SARS-CoV-2 infection and a known risk factor for progression to severe disease. Intervention: Patients were randomly assigned to either fluvoxamine (100 mg twice daily for 10 days) plus inhaled budesonide (800 mcg twice daily for 10 days) or matching placebos. Measurements: The primary outcome was a composite of emergency setting retention for COVID-19 for more than 6 hours, hospitalization, and/or suspected complications due to clinical progression of COVID-19 within 28 days of randomization. Secondary outcomes included health care attendance (defined as hospitalization for any cause or emergency department visit lasting >6 hours), time to hospitalization, mortality, patient-reported outcomes, and adverse drug reactions. Results: Randomization occurred from 15 January to 6 July 2022. A total of 738 participants were allocated to oral fluvoxamine plus inhaled budesonide, and 738 received placebo. The proportion of patients observed in an emergency setting for COVID-19 for more than 6 hours or hospitalized due to COVID-19 was lower in the treatment group than the placebo group (1.8% [95% credible interval {CrI}, 1.1% to 3.0%] vs. 3.7% [95% CrI, 2.5% to 5.3%]; relative risk, 0.50 [95% CrI, 0.25 to 0.92]), with a probability of superiority of 98.7%. No relative effects were found between groups for any of the secondary outcomes. More adverse events occurred in the intervention group than the placebo group, but no important differences between the groups were detected. Limitation: Low event rate overall, consistent with contemporary trials in vaccinated populations. Conclusion: Treatment with oral fluvoxamine plus inhaled budesonide among high-risk outpatients with early COVID-19 reduced the incidence of severe disease requiring advanced care. Primary Funding Source: Latona Foundation, FastGrants, and Rainwater Charitable Foundation.

Risk for Bleeding-Related Hospitalizations During Use of Amiodarone With Apixaban or Rivaroxaban in Patients With Atrial Fibrillation: A Retrospective Cohort Study: Annals of Internal Medicine: Vol 176, No 6

Background: Amiodarone, the most effective antiarrhythmic drug in atrial fibrillation, inhibits apixaban and rivaroxaban elimination, thus possibly increasing anticoagulant-related risk for bleeding. Objective: For patients receiving apixaban or rivaroxaban, to compare risk for bleeding-related hospitalizations during treatment with amiodarone versus flecainide or sotalol, antiarrhythmic drugs that do not inhibit these anticoagulants’ elimination. Design: Retrospective cohort study. Setting: U.S. Medicare beneficiaries aged 65 years or older. Patients: Patients with atrial fibrillation began anticoagulant use between 1 January 2012 and 30 November 2018 and subsequently initiated treatment with study antiarrhythmic drugs. Measurements: Time to event for bleeding-related hospitalizations (primary outcome) and ischemic stroke, systemic embolism, and death with or without recent (past 30 days) evidence of bleeding (secondary outcomes), adjusted with propensity score overlap weighting. Results: There were 91 590 patients (mean age, 76.3 years; 52.5% female) initiating use of study anticoagulants and antiarrhythmic drugs, 54 977 with amiodarone and 36 613 with flecainide or sotalol. Risk for bleeding-related hospitalizations increased with amiodarone use (rate difference [RD], 17.5 events [95% CI, 12.0 to 23.0 events] per 1000 person-years; hazard ratio [HR], 1.44 [CI, 1.27 to 1.63]). Incidence of ischemic stroke or systemic embolism did not increase (RD, −2.1 events [CI, −4.7 to 0.4 events] per 1000 person-years; HR, 0.80 [CI, 0.62 to 1.03]). The risk for death with recent evidence of bleeding (RD, 9.1 events [CI, 5.8 to 12.3 events] per 1000 person-years; HR, 1.66 [CI, 1.35 to 2.03]) was greater than that for other deaths (RD, 5.6 events [CI, 0.5 to 10.6 events] per 1000 person-years; HR, 1.15 [CI, 1.00 to 1.31]) (HR comparison: P = 0.003). The increased incidence of bleeding-related hospitalizations for rivaroxaban (RD, 28.0 events [CI, 18.4 to 37.6 events] per 1000 person-years) was greater than that for apixaban (RD, 9.1 events [CI, 2.8 to 15.3 events] per 1000 person-years) (P = 0.001). Limitation: Possible residual confounding. Conclusion: In this retrospective cohort study, patients aged 65 years or older with atrial fibrillation treated with amiodarone during apixaban or rivaroxaban use had greater risk for bleeding-related hospitalizations than those treated with flecainide or sotalol. Primary Funding Source: National Heart, Lung, and Blood Institute.

Prioritizing Quality Measures in Acute Stroke Care: A Cost-Effectiveness Analysis: Annals of Internal Medicine: Vol 176, No 5

Background: The American Heart Association and American Stroke Association (AHA/ASA) endorsed 15 process measures for acute ischemic stroke (AIS) to improve the quality of care. Identifying the highest-value measures could reduce the administrative burden of quality measure adoption while retaining much of the value of quality improvement. Objective: To prioritize AHA/ASA-endorsed quality measures for AIS on the basis of health impact and cost-effectiveness. Design: Individual-based stroke simulation model. Data Sources: Published literature. Target Population: U.S. patients with incident AIS. Time Horizon: Lifetime. Perspective: Health care sector. Intervention: Current versus complete (100%) implementation at the population level of quality measures endorsed by the AHA/ASA with sufficient clinical evidence (10 of 15). Outcome Measures: Life-years, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios, and incremental net health benefits. Results of Base-Case Analysis: Discounted life-years gained from complete implementation would range from 472 (tobacco use counseling) to 34 688 (early carotid imaging) for an annual AIS patient cohort. All AIS quality measures were cost-saving or highly cost-effective by AHA standards (<$50 000 per QALY for high-value care). Early carotid imaging and intravenous tissue plasminogen activator contributed the largest fraction of the total potential value of quality improvement (measured as incremental net health benefit), accounting for 72% of the total value. The top 5 quality measures accounted for 92% of the total potential value. Results of Sensitivity Analysis: A web-based user interface allows for context-specific sensitivity and scenario analyses. Limitation: Correlations between quality measures were not incorporated. Conclusion: Substantial variation exists in the potential net benefit of quality improvement across AIS quality measures. Benefits were highly concentrated among 5 of 10 measures assessed. Our results can help providers and payers set priorities for quality improvement efforts and value-based payments in AIS care. Primary Funding Source: National Institute of Neurological Disorders and Stroke.

Effectiveness of Molnupiravir and Nirmatrelvir–Ritonavir in Hospitalized Patients With COVID-19: A Target Trial Emulation Study: Annals of Internal Medicine: Vol 176, No 4

Background: Whether hospitalized patients benefit from COVID-19 oral antivirals is uncertain. Objective: To examine the real-world effectiveness of molnupiravir and nirmatrelvir–ritonavir in hospitalized patients with COVID-19 during the Omicron outbreak. Design: Target trial emulation study. Setting: Electronic health databases in Hong Kong. Participants: The molnupiravir emulated trial included hospitalized patients with COVID-19 aged 18 years or older between 26 February and 18 July 2022 (n = 16 495). The nirmatrelvir–ritonavir emulated trial included hospitalized patients with COVID-19 aged 18 years or older between 16 March and 18 July 2022 (n = 7119). Intervention: Initiation of molnupiravir or nirmatrelvir–ritonavir within 5 days of hospitalization with COVID-19 versus no initiation of molnupiravir or nirmatrelvir–ritonavir. Measurements: Effectiveness against all-cause mortality, intensive care unit (ICU) admission, or use of ventilatory support within 28 days. Results: The use of oral antivirals in hospitalized patients with COVID-19 was associated with a lower risk for all-cause mortality (molnupiravir: hazard ratio [HR], 0.87 [95% CI, 0.81 to 0.93]; nirmatrelvir–ritonavir: HR, 0.77 [CI, 0.66 to 0.90]) but no significant risk reduction in terms of ICU admission (molnupiravir: HR, 1.02 [CI, 0.76 to 1.36]; nirmatrelvir–ritonavir: HR, 1.08 [CI, 0.58 to 2.02]) or the need for ventilatory support (molnupiravir: HR, 1.07 [CI, 0.89 to 1.30]; nirmatrelvir–ritonavir: HR, 1.03 [CI, 0.70 to 1.52]). There was no significant interaction between drug treatment and the number of COVID-19 vaccine doses received, thereby supporting the effectiveness of oral antivirals regardless of vaccination status. No significant interaction between nirmatrelvir–ritonavir treatment and age, sex, or Charlson Comorbidity Index was observed, whereas molnupiravir tended to be more effective in older people. Limitation: The outcome of ICU admission or need for ventilatory support may not capture all severe COVID-19 cases; unmeasured confounders, such as obesity and health behaviors, may exist. Conclusion: Molnupiravir and nirmatrelvir–ritonavir reduced all-cause mortality in both vaccinated and unvaccinated hospitalized patients. No significant reduction in ICU admission or the need for ventilatory support was observed. Primary Funding Source: Health and Medical Research Fund Research on COVID-19, Government of the Hong Kong Special Administrative Region; Research Grants Council, Collaborative Research Fund; and Health Bureau, Government of the Hong Kong Special Administrative Region.

Recommended and Prevalent Use of Glucagon-like Peptide-1 Receptor Agonists and Sodium–Glucose Cotransporter-2 Inhibitors in a National Population-Based Sample

How Would You Manage This Patient With Chronic Insomnia?: Grand Rounds Discussion From Beth Israel Deaconess Medical Center: Annals of Internal Medicine: Vol 175, No 12

Insomnia, which is characterized by persistent sleep difficulties in association with daytime dysfunction, is a common concern in clinical practice. Chronic insomnia disorder is defined as symptoms that occur at least 3 times per week and persist for at least 3 months. The American Academy of Sleep Medicine (AASM) published recent guidelines on behavioral and psychological treatment as well as pharmacologic therapy for chronic insomnia disorder. Regarding behavioral and psychological approaches, the only intervention strongly recommended was multicomponent cognitive behavioral therapy for insomnia. Regarding pharmacologic treatment, the AASM, based on weak evidence, suggested a limited number of medications that might be useful and others that probably are not. Here, 2 clinicians with expertise in sleep disorders—one a clinical psychologist and the other a physician—debate the management of a patient with chronic insomnia who has been treated with medications. They discuss the role of behavioral and psychological interventions and pharmacologic therapy for chronic insomnia and how the primary care practitioner should approach such a patient.