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Introduction: Autonomic dysfunction is common in chronic obstructive pulmonary disease (COPD), and worse autonomic function may be a marker of risk for acute exacerbations of COPD (AECOPD). Heart rate variability (HRV) is a measure of autonomic function. Our objective was to test whether lower (worse) HRV is a risk factor for AECOPD. Methods: We measured standard deviation of normal RR intervals (SDNN) and root mean square of successive RR interval differences (RMSSD) on 10-second electrocardiograms (ECGs) performed at screening and day 42 in participants in the Beta Blockers for the Prevention of Acute Exacerbations of COPD trial ( BLOCK-COPD), a placebo-controlled trial of metoprolol for prevention of AECOPD. We used Cox-proportional hazards models to test if these HRV measures were associated with risk of any AECOPD, and separately, hospitalized AECOPD. We tested associations using baseline HRV measures and incorporating HRV measures from day 42 as a time-varying covariate. We also tested for interactions with metoprolol assignment. Results: Of 532 trial participants, 529 (forced expiratory volume in 1 second [FEV(1) ]41 ± 16.3 % predicted) were included in this analysis. We did not find a significant association between HRV measures and risk of AECOPD when all participants were analyzed together. There was a significant interaction between RMSSD and assignment to metoprolol on time to first hospitalized AECOPD; in the placebo group greater RMSSD was associated with a lower risk of hospitalized AECOPD (adjusted hazard ratio0.71, 95% confidence interval: 0.52 to 0.96, per 10 ms increase) but there was no association in the metoprolol group. Conclusions: Autonomic dysfunction as measured by HRV may be a risk factor for AECOPD. Future studies should analyze longer HRV recordings and their performance in broader samples of people with COPD, including those on beta-blockers.

RATIONALE: The chronotropic index quantifies the proportion of the expected heart rate increase that is attained during exercise. The relationship between the chronotropic index and acute exacerbations of chronic obstructive pulmonary disease (AECOPDs) has not been evaluated. OBJECTIVES: To determine whether a higher chronotropic index during a 6-minute walk (CI-6MW) is associated with lower risk of AECOPD and whether the CI-6MW is a marker of susceptibility to adverse effects of metoprolol in chronic obstructive pulmonary disease (COPD). METHODS: We analyzed data from the BLOCK COPD (Beta-Blockers for the Prevention of AECOPDs) trial. We used Cox proportional hazards models to investigate the relationship between the CI-6MW and the time to AECOPDs. We also tested for interactions between study group assignment (metoprolol vs. placebo) and the CI-6MW on the time to AECOPDs. RESULTS: Four hundred seventy-seven participants with exacerbation-prone COPD (mean forced expiratory volume in 1 second, 41% of predicted) were included in this analysis. A higher CI-6MW was independently associated with a decreased risk of AECOPDs of any severity (adjusted hazard ratio per 0.1 increase in CI-6MW of 0.88; 95% confidence interval, 0.80–0.96) but was not independently associated with AECOPDs requiring hospitalization (adjusted hazard ratio, 0.94; 95% confidence interval, 0.81–1.05). There was a significant interaction by treatment assignment, and in a stratified analysis, the protective effects of a higher CI-6MW on AECOPDs were negated by metoprolol use. CONCLUSIONS: A higher CI-6MW is associated with a decreased risk of AECOPDs and may be an indicator of susceptibility to the adverse effects of metoprolol.

BackgroundSARS-CoV-2 viral entry may disrupt angiotensin II (Ang II) homeostasis in part via ACE2 downregulation, potentially contributing to COVID-19 induced lung injury. Preclinical models of viral pneumonias that utilize ACE2 demonstrate Ang II type 1 receptor (AT1R) blockade mitigates lung injury, though observational COVID-19 data addressing the effect of AT1R blockade remain mixed.MethodsMulticenter, blinded, placebo-controlled randomized trial of losartan (50 mg PO twice daily for 10 days) versus placebo. Hospitalized patients with COVID-19 and a respiratory sequential organ failure assessment score of at least 1 and not already taking a renin-angiotensin-aldosterone system (RAAS) inhibitor were eligible. The primary outcome was the imputed partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) ratio at 7 days. Secondary outcomes included ordinal COVID-19 severity, oxygen, ventilator, and vasopressor-free days, and mortality. Losartan pharmacokinetics (PK) and RAAS components [Ang II, angiotensin-(1–7) (Ang-(1–7)), ACE, ACE2] were measured in a subgroup of participants.FindingsFrom April 2020 - February 2021, 205 participants were randomized, 101 to losartan and 104 to placebo. Compared to placebo, losartan did not significantly affect PaO2/FiO2 ratio at 7 days [difference of -24.8 (95% -55.6 to 6.1; p=0.12)]. Losartan did not improve any secondary clinical outcome, but worsened vasopressor-free days. PK data were consistent with appropriate steady-state concentrations, but we observed no significant effect of losartan on RAAS components.InterpretationInitiation of orally administered losartan to hospitalized patients with COVID-19 and acute lung injury does not improve PaO2 / FiO2 ratio at 7 days. These data may have implications for ongoing clinical trials.Trial RegistrationLosartan for Patients With COVID-19 Requiring Hospitalization (NCT04312009), https://clinicaltrials.gov/ct2/show/NCT04312009

Background The SARS-CoV-2 virus enters cells via Angiotensin-converting enzyme 2 (ACE2), disrupting the renin-angiotensin-aldosterone axis, potentially contributing to lung injury. Treatment with angiotensin receptor blockers (ARBs), such as losartan, may mitigate these effects, though induction of ACE2 could increase viral entry, replication, and worsen disease. Methods This study represents a placebo-controlled blinded randomized clinical trial (RCT) to test the efficacy of losartan on outpatients with COVID-19 across three hospital systems with numerous community sites in Minnesota, U.S. Participants included symptomatic outpatients with COVID-19 not already taking ACE-inhibitors or ARBs, enrolled within 7 days of symptom onset. Patients were randomized to 1:1 losartan (25 mg orally twice daily unless estimated glomerular filtration rate, eGFR, was reduced, when dosing was reduced to once daily) versus placebo for 10 days, and all patients and outcome assesors were blinded. The primary outcome was all-cause hospitalization within 15 days. Secondary outcomes included functional status, dyspnea, temperature, and viral load. (clinicatrials.gov, NCT04311177, closed to new participants) Findings From April to November 2020, 117 participants were randomized 58 to losartan and 59 to placebo, and all were analyzed under intent to treat principles. The primary outcome did not differ significantly between the two arms based on Barnard's test [losartan arm: 3 events (5.2% 95% CI 1.1, 14.4%) versus placebo arm: 1 event (1.7%; 95% CI 0.0, 9.1%)]; proportion difference -3.5% (95% CI -13.2, 4.8%); p = 0.32]. Viral loads were not statistically different between treatment groups at any time point. Adverse events per 10 patient days did not differ signifcantly [0.33 (95% CI 0.22–0.49) for losartan vs. 0.37 (95% CI 0.25–0.55) for placebo]. Due to a lower than expected hospitalization rate and low likelihood of a clinically important treatment effect, the trial was terminated early. Interpretation In this multicenter blinded RCT for outpatients with mild symptomatic COVID-19 disease, losartan did not reduce hospitalizations, though assessment was limited by low event rate. Importantly, viral load was not statistically affected by treatment. This study does not support initiation of losartan for low-risk outpatients. Funding This study was supported by Minnesota Partnership for Biotechnology and Medical Genomics (CON000000076883).

Background: The SARS-CoV-2 virus enters cells via the ACE2 receptor, disrupting the renin-angiotensin-aldosterone axis, potentially contributing to lung injury. Treatment with angiotensin receptor blockers(ARBs) may mitigate these effects, though induction of ACE2 expression could increase viral entry, replication, and worsen disease. Methods: This study represents a placebo-controlled blinded randomized clinical trial (RCT) to test the efficacy of losartan on outpatients with COVID-19 across three hospital systems in Minnesota, U.S. Participants included symptomatic outpatients with COVID-19 not already taking ACE-inhibitors or ARBs, enrolled within 7 days of symptom onset. Patients were randomized to losartan versus placebo for 10 days. The primary outcome was all-cause hospitalization within 15 days. Secondary outcomes included functional status, dyspnea, temperature, and viral load. Findings: From April-November 2020, 117 participants were randomized 58 to losartan and 59 to placebo. The primary outcome did not differ significantly between the two arms based on Barnard’s test [losartan arm: 3 events (5.2%; 95% CI 1.8-14.1%) versus placebo arm: 1 event (1.7% 95% CI 0.01-9.0%); proportion difference -3.5% (95% CI -12.7-4.5%); p=0.32]. Functional status, self-reported dyspnea, maximum daily temperatures, and viral load were not significantly different between treatment groups. Due to a lower than expected hospitalization rate and low likelihood of a clinically important treatment effect, the trial was terminated early. Interpretation: In this multicenter blinded RCT for outpatients with mild symptomatic COVID-19 disease, losartan did not significantly reduce hospitalizations, affect functional status or assessment of dyspnea. Viral load was not significantly affected by treatment. This study does not support initiation of losartan for low-risk outpatients. Trial Registration: The trial was conducted under the authority of the Food and Drug Administration (IND 148365), was registered on clinicaltrials.gov prior to study initialization (NCT04311177). Funding Statement: This study was supported by Minnesota Partnership for Biotechnology and Medical Genomics (CON000000076883) Declaration of Interests: The authors have no financial conflicts of interest to disclose. MAP, MHN, TWS, and CJT have received additional funding from the Bill and Melinda Gates Foundation to conduct a clinical trial of losartan in inpatients with COVID-19. Ethics Approval Statement: The protocol was approved by a central institutional review board and underwent local context review. The study was conducted following good clinical practice guidelines under the oversight of an independent data safety monitoring board (DSMB).

Rationale Acute exacerbations negatively impact quality of life in patients with chronic obstructive pulmonary disease (COPD), but the impact of hospitalized exacerbations on quality of life is not clear. We hypothesized that patients with hospitalized exacerbations would benefit from hospitalization and experience improvement in general and disease-specific quality of life (as measured by the St. George's respiratory questionnaire (SGRQ) and the medical outcomes study 36-item short form health survey (SF-36)) compared to those without exacerbations, or with non-hospitalized acute exacerbations. Methods 1219 COPD patients enrolled in either the simvastatin for the prevention of exacerbations in moderate-to severe COPD Trial (STATCOPE) or azithromycin for prevention of exacerbations of COPD trial (MACRO) were analyzed. Demographic information, spirometry, and symptom scores were noted at baseline. Exacerbation events and changes in quality of life scores were assessed over a mean of 538 days of follow-up. Results Of patients studied, 25.6% were hospitalized, 44.0% had at least one outpatient exacerbation, and 30.4% had no exacerbation. Baseline SGRQ and SF-36 scores were severely impaired in all groups studied. Over time, SF-36 scores did not change significantly between groups. SGRQ symptom domain scores improved in other groups but did not improve in those hospitalized for a COPD exacerbation. Conclusions At baseline, patients hospitalized for acute exacerbations of COPD had more impaired quality of life scores. Over time, SGRQ symptom domain scores improved in other groups but did not in those who were hospitalized. Other measurements of quality of life were not improved by hospitalization for COPD.

Background No evidence-based guidelines exist for preventive dental care before radiation therapy (RT) in patients with head and neck cancer (HNC). An ongoing multicenter, prospective cohort study, Clinical Registry of Dental Outcomes in Head and Neck Cancer Patients (OraRad), is addressing this knowledge gap. The authors evaluated the level of dental disease before RT in the OraRad cohort, factors associated with dental disease, and dental treatment recommendations made before RT. Methods As part of OraRad, the authors assessed caries, periodontal disease, dental recommendations, and dental interventions performed before RT. Results Baseline measures were reported for 356 participants (77% men) with mean (standard deviation) age of 59.9 (11.0) years. Measures included mean number of teeth (22.9), participants with at least 1 tooth with caries (37.2%), and participants with at least 1 tooth with probing depth 5 millimeters or greater (47.4%). Factors associated with less extensive dental disease before RT included having at least a high school diploma, having dental insurance, history of routine dental care, and a smaller tumor size (T1 or T2). Based on the dental examination before RT, 163 (49.5%) participants had dental treatment recommended before RT, with extractions recommended most frequently. Conclusion Many patients with HNC require dental treatment before RT; more than one-third require extractions. Practical Implications Most patients have some level of dental disease at the start of RT, indicating the importance of dental evaluation before RT. By observing dental outcomes after RT, OraRad has the potential to determine the best dental treatment recommendations for patients with HNC.

BackgroundObservational studies suggest that beta-blockers may reduce the risk of exacerbations and death in patients with moderate or severe chronic obstructive pulmonary disease (COPD), but these findings have not been confirmed in randomized trials.MethodsIn this prospective, randomized trial, we assigned patients between the ages of 40 and 85 years who had COPD to receive either a beta-blocker (extended-release metoprolol) or placebo. All the patients had a clinical history of COPD, along with moderate airflow limitation and an increased risk of exacerbations, as evidenced by a history of exacerbations during the previous year or the prescribed use of supplemental oxygen. We excluded patients who were already taking a beta-blocker or who had an established indication for the use of such drugs. The primary end point was the time until the first exacerbation of COPD during the treatment period, which ranged from 336 to 350 days, depending on the adjusted dose of metoprolol.ResultsA total of 532 patients underwent randomization. The mean (±SD) age of the patients was 65.0±7.8 years; the mean forced expiratory volume in 1 second (FEV1) was 41.1±16.3% of the predicted value. The trial was stopped early because of futility with respect to the primary end point and safety concerns. There was no significant between-group difference in the median time until the first exacerbation, which was 202 days in the metoprolol group and 222 days in the placebo group (hazard ratio for metoprolol vs. placebo, 1.05; 95% confidence interval [CI], 0.84 to 1.32; P = 0.66). Metoprolol was associated with a higher risk of exacerbation leading to hospitalization (hazard ratio, 1.91; 95% CI, 1.29 to 2.83). The frequency of side effects that were possibly related to metoprolol was similar in the two groups, as was the overall rate of nonrespiratory serious adverse events. During the treatment period, there were 11 deaths in the metoprolol group and 5 in the placebo group.ConclusionsAmong patients with moderate or severe COPD who did not have an established indication for beta-blocker use, the time until the first COPD exacerbation was similar in the metoprolol group and the placebo group. Hospitalization for exacerbation was more common among the patients treated with metoprolol. (Funded by the Department of Defense; BLOCK COPD ClinicalTrials.gov number, NCT02587351.).

Rationale: Colder temperatures have been shown to increase hospitalization and mortality rates in adults with chronic obstructive pulmonary disease (COPD) and cardiac disease. Seasonal influences on exacerbation rates in adults with severe COPD but without significant cardiovascular disease are unclear. In addition, regional variations in COPD exacerbations in North America have not yet been explored. Objectives: In this study, we sought to determine the seasonal and regional variability in exacerbation rates in those with COPD but without significant cardiovascular risk factors. Methods: We studied adults without cardiovascular risk factors from STATCOPE (Simvastatin in the Prevention of COPD Exacerbations) and placebo arm of MACRO (Azithromycin for the Prevention of Exacerbations of COPD) studies. Forty-five study sites were divided into climate regions in Canada and the United States; seasons were defined as winter, spring, summer, and fall. The primary outcome was the rate of COPD exacerbation. Secondary outcomes included time to first exacerbation, severity of exacerbations, all-cause mortality, and antibiotic and steroid use. Results: We analyzed 1,175 subjects with a mean age of 63.3 ± 8.6 years, forced expiratory volume in 1 second of 41.5 ± 17.1% predicted, and 53.6 ± 29.4 pack-years of smoking history. The COPD exacerbation rate was higher in winter (0.13 exacerbations/person-month) than in spring, summer, and fall (0.11, 0.079, and 0.10 exacerbations/person-month, respectively) (P

Patients with Chronic Obstructive Pulmonary Disease (COPD) frequently experience unplanned hospital readmissions leading to increased morbidity [1]. The European Union COPD audit found that 35% of patients admitted with acute exacerbation of COPD (AECOPD) were readmitted within 90 days [2]. In the United States, 22% of patients admitted with AECOPD experienced a 30-day readmission, motivating financial policies to incentivize readmission reduction [1]. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Krishnan reports grants from NHLBI/NIH, during the conduct of the study. Conflict of interest: Ms. Voelker has nothing to disclose. Conflict of interest: Dr. Connett has nothing to disclose. Conflict of interest: Dr. Niewoehner reports grants from National Institute of Health, during the conduct of the study; personal fees from Boehringer Ingelheim, personal fees from Astrazeneca, personal fees from GlaxoSmithKline, outside the submitted work. Conflict of interest: Dr. Albert has nothing to disclose. Conflict of interest: Dr. Scanlon reports grants from National Heart Lung and Blood Institute, during the conduct of the study; grants from Astra Zeneca, grants from Boehringer Ingelheim, grants from Forest Pharmaceuticals, grants from GlaxoSmithKline, grants from Novartis, grants from Pearl Therapeutics, other from Boehringer Ingelheim, other from GlaxoSmithKline, outside the submitted work. Conflict of interest: Dr. Dransfield reports grants from NHLBI, during the conduct of the study; grants from Department of Defense , personal fees and other from Boehringer Ingeheim, personal fees and other from GlaxoSmithKline, other from Novartis, personal fees and other from AstraZeneca, other from Yungjin, other from PneumRx/BTG, other from Pulmonx, personal fees from Genentech, personal fees and other from Boston Scientific , outside the submitted work. Conflict of interest: Dr. Han reports personal fees from BI, personal fees from GSK, personal fees from AZ, non-financial support from Novartis, non-financial support from Sunovion, outside the submitted work. Conflict of interest: Dr. Martinez reports non-financial support from GlaxoSmithKline, during the conduct of the study; personal fees from Continuing Education, personal fees from Forest Laboratories, other from Janssen, personal fees from GlaxoSmithKline, personal fees from Nycomed/Takeda, personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Bellerophon (formerly Ikaria), personal fees from Genentech, personal fees from Novartis, personal fees from Pearl, personal fees from Roche, personal fees from Sunovion, personal fees from Theravance, personal fees from CME Incite, personal fees from Annenberg Center for Health Sciences at Eisenhower, personal fees from Integritas, personal fees from InThought, personal fees from National Association for Continuing Education, personal fees from Paradigm Medical Communications, LLC, personal fees from PeerVoice, personal fees from UpToDate, personal fees from Haymarket Communications, personal fees from Western Society of Allergy and Immunology, from Proterixbio (formerly Bioscale), personal fees from Unity Biotechnology, personal fees from ConCert Pharmaceuticals, personal fees from Lucid, personal fees from Methodist Hospital, personal fees from Columbia University, personal fees from Prime Healthcare Ltd, personal fees from WebMD, personal fees from PeerView Network, personal fees from California Society of Allergy and Immunology, personal fees from Chiesi, personal fees from Puerto Rico Thoracic Society, outside the submitted work. Conflict of interest: Dr. Criner reports grants from Boehringer- Ingelheim, grants from Novartis, grants from Astra Zeneca, grants from Respironics, grants from MedImmune, grants from Actelion, grants from Forest, grants from Pearl , grants from Ikaria , grants from Aeris , grants from PneumRx, grants from Pulmonx , other from HGE Health Care Solutions, Inc, other from Amirall, other from Boehringer- Ingelheim, other from Holaira, outside the submitted work.

No evidence-based guidelines exist for preventive dental care before radiation therapy (RT) in patients with head and neck cancer (HNC). An ongoing multicenter, prospective cohort study, Clinical Registry of Dental Outcomes in Head and Neck Cancer Patients (OraRad), is addressing this knowledge gap. The authors evaluated the level of dental disease before RT in the OraRad cohort, factors associated with dental disease, and dental treatment recommendations made before RT.As part of OraRad, the authors assessed caries, periodontal disease, dental recommendations, and dental interventions performed before RT.Baseline measures were reported for 356 participants (77% men) with mean (standard deviation) age of 59.9 (11.0) years. Measures included mean number of teeth (22.9), participants with at least 1 tooth with caries (37.2%), and participants with at least 1 tooth with probing depth 5 millimeters or greater (47.4%). Factors associated with less extensive dental disease before RT included having at least a high school diploma, having dental insurance, history of routine dental care, and a smaller tumor size (T1 or T2). Based on the dental examination before RT, 163 (49.5%) participants had dental treatment recommended before RT, with extractions recommended most frequently.Many patients with HCN require dental treatment before RT; more than one-third require extractions.Most patients have some level of dental disease at the start of RT, indicating the importance of dental evaluation before RT. By observing dental outcomes after RT, OraRad has the potential to determine the best dental treatment recommendations for patients with HCN.

Introduction A substantial majority of chronic obstructive pulmonary disease (COPD)-related morbidity, mortality and healthcare costs are due to acute exacerbations, but existing medications have only a modest effect on reducing their frequency, even when used in combination. Observational studies suggest β-blockers may reduce the risk of COPD exacerbations; thus, we will conduct a randomised, placebo-controlled trial to definitively assess the impact of metoprolol succinate on the rate of COPD exacerbations. Methods and analyses This is a multicentre, placebo-controlled, double-blind, prospective randomised trial that will enrol 1028 patients with at least moderately severe COPD over a 3-year period. Participants with at least moderate COPD will be randomised in a 1:1 fashion to receive metoprolol or placebo; the cohort will be enriched for patients at high risk for exacerbations. Patients will be screened and then randomised over a 2-week period and will then undergo a dose titration period for the following 6 weeks. Thereafter, patients will be followed for 42 additional weeks on their target dose of metoprolol or placebo followed by a 4-week washout period. The primary end point is time to first occurrence of an acute exacerbation during the treatment period. Secondary end points include rates and severity of COPD exacerbations; rate of major cardiovascular events; all-cause mortality; lung function (forced expiratory volume in 1 s (FEV 1 )); dyspnoea; quality of life; exercise capacity; markers of cardiac stretch (pro-NT brain natriuretic peptide) and systemic inflammation (high-sensitivity C reactive protein and fibrinogen). Analyses will be performed on an intent-to-treat basis. Ethics and dissemination The study protocol has been approved by the Department of Defense Human Protection Research Office and will be approved by the institutional review board of all participating centres. Study findings will be disseminated through presentations at national and international conferences and publications in peer-reviewed journals. Trial registration number NCT02587351; Pre-results.