β-Blocker Use and Incidence of Chronic Obstructive Pulmonary Disease Exacerbations

Chronic Obstructive Pulmonary Disease (COPD) exacerbations are associated with increased mortality and cardiovascular events. However, there is limited evidence on the relationship between COPD exacerbations and mortality and cardiovascular outcomes in China. This retrospective cohort study included Chinese patients with COPD aged ≥ 40 years from the Yinzhou regional electronic health records database. Patients were screened for eligibility between 1 Jan 2014 and 1 Mar 2022, with the index date being the first identified COPD diagnosis within this timeframe. Patient characteristics and frequency and severity of COPD exacerbations were collected during the 24-month baseline period prior to the index date. Outcomes included all-cause mortality and severe cardiovascular events. The incidence of death and first severe cardiovascular event was reported overall, and by baseline exacerbation history. Cox proportional hazards models were employed to identify the association between baseline COPD exacerbation history and all-cause death. A total of 14,713 patients with COPD were included, with a median follow-up duration of 41.3 months. During the follow-up period, 20.1% of patients died, with a crude incidence rate of 5.17 (95% CI: 4.98, 5.36) per 100 person-years. Additionally, 20.1% of patients experienced severe cardiovascular events. The incidence of severe cardiovascular events numerically increased with higher frequency and severity of baseline COPD exacerbations. Patients with history of severe COPD exacerbations exhibited an increased risk (adjusted HR: 1.26, 95%CI: 1.14, 1.38) of all-cause death compared with patients with no exacerbations. This study found that severe COPD exacerbations significantly increased mortality risk in Chinese patients with COPD. Patients with a history of severe exacerbations also reported a higher incidence rate of severe cardiovascular events. These findings emphasize the need for improved exacerbation prevention strategies in COPD management.

We appreciate the interest of Drs. Kempen, Basler and Daniel, Leslie, and Devereaux in our Editorial View published in the January issue of Anesthesiology.β-blockers have shown to reduce morbidity and mortality in nonsurgical patients with coronary artery disease, including myocardial ischemia and reduced left ventricular function.1–3Thirty percent of patients undergoing noncardiac surgery each year in the United States are at risk for or are known to have coronary artery disease.4In two randomized controlled trials β-blockers have been shown to reduce perioperative mortality.5,6Oddly enough, β-blocker prescription in the perioperative setting is considered as a different indication.Dr. Kempen is concerned about the issue of why primary care physicians should not be routinely prescribing β-blockers to high-risk patients. He is also concerned that anesthesiologists be considered to be “enabling” inferior care by assuming responsibility to initiate perioperative β-blocker therapy at a less opportune time of induction. We would be delighted if primary care physicians would prescribe β-blockers, but as reported by Nass et al., 7only 30% of patients with a history of coronary artery disease or those at risk referred to high-risk surgery are prescribed β-blockers. From our own experience (written communication, Don Poldermans, M.D. Ph.D., Professor, Department of Anesthesiology, Erasmus MC, Rotterdam, the Netherlands; April, 2004), only 25% of patients referred to high-risk surgery are chronic β-blocker users. The ability to initiate β-blocker use for a defined period before surgery represents the ideal situation, but often patients will present shortly before surgery without receiving β-blocker therapy. Realizing this important concern, Fleisher et al. 8conducted a cost-effectiveness analysis of different perioperative β-blocker strategies in high-risk patients. Their findings reveal that perioperative β-blocker use is both cost effective and efficacious from a short-term provider perspective. Furthermore, the results showed that if a β-blocker has not been started before the day of surgery, then the use of a short-acting intravenous or longer-acting oral medication would be cost-effective in high-risk surgery. Given these findings we feel that anesthesiologists could be enablers of appropriate care by initiating perioperative β-blocker use in high-risk patients.Drs. Basler and Daniel touch on issues related to efficacy and effectiveness of perioperative β-blocker use. In this context, they feel that the Editorial View failed to identify the lack of effectiveness studies as a stumbling block to the introduction of perioperative β-blocker use into clinical practice. They are also urging for larger-scale trials to be able to state clearly which patients will benefit for perioperative β-blocker use. We acknowledge that large-scale clinical trials should provide the ultimate solution to the issue of perioperative β-blocker use in patients of different risk categories, but we disagree that lack of effectiveness studies prevent integrating evidence into clinical practice. In that respect we would like to refer to the studies of Boersma et al. 9and Fleisher et al. 8showing effectiveness and cost-effectiveness of perioperative β-blocker use in patients with known coronary artery disease or those at risk undergoing high-risk surgery. In our opinion refraining of perioperative β-blocker use in high-risk patients just because there are no larger-scale studies would potentially subject these patients to the same level of risk of perioperative cardiac complications as before the introduction of perioperative β-blocker use.Finally, Drs. Leslie and Devereaux would like to see more definitive evidence from large-scale randomized clinical trials before embarking on strong recommendations. They fear that current evidence is limited and does not justify routine use of perioperative β-blocker use. To overcome these concerns they propose to wait until their own trial would provide more solid evidence about the effectiveness of perioperative β-blocker use. We agree that information with regard to the protective effect of perioperative β-blocker use in patients with moderate risk for cardiac complications is limited. However, we feel that there is scientific evidence that perioperative β-blocker use in high-risk patients proved to be effective for the reduction of perioperative cardiac complications.5,9Given these findings the practice guidelines of the American College of Cardiology/American Heart Association and the American College of Physicians recommend perioperative β-blocker therapy with one or more risk factors correlated with higher risk of cardiac complications.In summary, perioperative β-blocker use should be considered inherent to the patient at risk and not the type of surgical procedure to be performed. Evidence from the available studies can already be used to plan an effective approach for perioperative β-blocker use in high-risk patients while ongoing clinical trials will provide further evidence for recommendations using β-blockers in patients at low-to-intermediate risk for perioperative cardiac complications.* Erasmus Medical Center, Rotterdam, The Netherlands. d.poldermans@erasmusmc.nl

No More Equivalence Trials for Antibiotics in Exacerbations of COPD, Please

Antibiotics for treatment and prevention of exacerbations of chronic obstructive pulmonary disease

N-acetylcysteine for COPD: the evidence remains inconclusive – Authors' reply

Objective: To review the rate of exacerbations relative to β-blocker use in patients with chronic obstructive pulmonary disease (COPD). Data Sources: A MEDLINE search (1953 to May 2019) was performed using the search terms beta-blockers, chronic obstructive pulmonary disease, and exacerbations. An EMBASE search was also performed using the search terms chronic obstructive lung disease and beta adrenergic receptor blocking agents (1970 to May 2019). References from the review of literature citations were also identified. Study Selection and Data Extraction: English-language studies assessing COPD exacerbations in patients prescribed a β-blocker were included. Any article not addressing exacerbations was excluded. Data Synthesis: A total of 15 articles were included; 7 articles showed no change, 1 provided mixed results, and 7 indicated a significant decrease in COPD exacerbations in a variety of exacerbation severities. Two of the studies differentiated between cardioselective and noncardioselective β-blockers. Relevance to Patient Care and Clinical Practice: This work represents an initial assessment of the use of β-blockers to reduce COPD exacerbations. The findings raise the question if β-blockers should be used more frequently in patients with COPD. Conclusions: Based on the limited number of studies that address β-blocker use in COPD, it appears that exacerbations are not increased and may be decreased. A randomized, placebo-controlled trial is in progress to possibly provide more definitive answers to this question. Until the trial is complete, β-blockers should not be withheld in COPD patients who have concurrent cardiovascular conditions, especially where there is a mortality benefit.

β-blockers are a fundamental component of cardiovascular disease (CVD) management, while β2-agonists are used to treat chronic obstructive pulmonary disease (COPD). Current guidelines recommend that these conditions be treated as usual, even when they coexist. However, there have been concerns over COPD exacerbation risk with β-blockers and attenuation of the beneficial effects of β2-agonists in this comorbid population, leading to β-blocker underuse. Recent evidence suggests that β-blockers, particularly cardioselective β-blockers, do not increase COPD exacerbations, demonstrate good efficacy and safety, and improve survival in patients with COPD after first-time myocardial infarction. In atrial fibrillation with COPD, both cardioselective and nonselective β-blockers may be associated with a lower COPD exacerbation risk than calcium channel blockers, as well as improving outcomes and reducing mortality risk. In this review, we summarize the β-blocker prescribing patterns in patients with CVD and COPD; describe the reasons for β-blocker underuse in patients with CVD with COPD; collate up-to-date evidence on the effects of β-blockers on symptoms and outcomes in each of these comorbid populations; and review the current treatment guidelines for coexisting COPD and CVD to support the rational prescribing of β-blockers. Finally, we provide recommendations for future research needed to demonstrate the clinical rationale of prescribing β-blockers and to encourage the generation of more robust evidence-based guidelines for β-blockers use. Future large-scale, prospective, randomized controlled trials are needed to expand the body of evidence and better understand the effects of β-blockers in CVD with comorbid COPD.

Chronic obstructive pulmonary disease (COPD) exacerbations are important events in the natural history of the disease with debilitating consequences which include more rapid lung function decline, quality of life deterioration and increased risk of cardiovascular events and mortality. Inflammation in COPD is complex and is intrinsically less responsive to corticosteroids compared to asthma. Biologics could possibly reduce the burden of inflammation in selected patients. In this single center retrospective study, we evaluated the eligibility of COPD patients hospitalized during the last 6 years in the respiratory department of a tertiary hospital for a severe COPD exacerbation, to receive either dupilumab or mepolizumab according to the inclusion criteria of their respective randomized controlled trials and GOLD 2026 recommendations. 496 patients were included in the study, 83 (16.7%) patients were eligible for treatment with mepolizumab and 29 (5.8%) for treatment with dupilumab, while 413 (83.3%) were not eligible for any of the biologics currently approved for COPD treatment. Patients who were eligible for biologics had lower FEV1/FVC ratio and had experienced more COPD exacerbations and more hospitalizations for COPD exacerbations in the previous year compared to those characterized as non-eligible. The main factor missing from non-eligible patients was treatment with triple inhaled medication, prior to hospitalization. Only a minority of patients hospitalized due to severe COPD exacerbation would have been eligible to receive biologic therapy. Optimization of medical treatment including inhaled medication in addition to disease phenotyping are pivotal for the recognition of the patients which will benefit from the use of biologics.

Rationale: Individuals with chronic obstructive pulmonary disease (COPD) have different clinical trajectories, some with minimal symptom burden, others experiencing recurrent exacerbations, the most severe of which require hospitalization. Existing diagnostics, including spirometry and symptom assessments, lack the precision to identify high-risk patients who may benefit from timely preventive therapies. Nuclear cell-free DNA (ncfDNA) is a well-established marker of systemic tissue injury, implicated in amplifying inflammation by triggering type 1 interferon release by activating DNA-sensing pathways. Because COPD is accompanied by inflammation and tissue injury systemically, we hypothesized that ncfDNA is associated with increased risk of severe exacerbations requiring hospitalization. Methods: Design: We utilized baseline plasma samples randomly selected from 672 individuals with COPD from the Subpopulations and Intermediate Outcomes Measures in COPD Study (SPIROMICS) cohort, which prospectively collected exacerbation numbers and type. The primary endpoint was exacerbation requiring hospitalization. Secondary endpoints included total number of exacerbations (defined as use of oral steroids, antibiotics, or healthcare utilization) and severe exacerbations (defined as requiring emergency room care or hospitalization). Measure: We measured plasma ncfDNA using digital droplet PCR. Analysis: We assessed the association of ncfDNA with exacerbation outcomes using negative binomial regression or Cox regression, adjusting for age, percent post-bronchodilator forced expiratory volume in one second (FEV1), supplemental oxygen use, and smoking status. Results: In total, 57% (n=383) of COPD participants experienced exacerbations, 29% (n=197) at least one severe, and 22% (n=145) requiring hospitalization, the latter at a median of 622 days from enrollment (IQR=287-997). Higher ncfDNA levels at enrollment correlated with measures of COPD severity, including baseline FEV1 (beta = -0.12, 95% CI -0.18 to -0.049, p <0.001). Higher ncfDNA associated with increased risk of COPD exacerbation requiring hospitalization (incidence rate ratio (IRR) 1.40, 95% CI 1.12-1.75, p =0.003) and severe exacerbations (IRR 1.36, 95% CI 1.11-1.67, p=0.002) and a trend towards total exacerbations (IRR 1.11, 95% CI 0.98-1.26, p= 0.09). The primary outcome, risk of time-to-first hospitalization, correlated significantly with higher ncfDNA with hazard ratio (HR) 1.23, 95% CI 1.01-1.49, p=0.037. Conclusion: These results suggest that ncfDNA may serve as a predictor for severe and hospitalization-associated COPD exacerbations. To better understand the relationship between ncfDNA and COPD pathophysiology, follow-up studies should explore longitudinal trends and cfDNA tissue sources, and their link to COPD exacerbations.

A community-based, time-matched, case-control study of respiratory viruses and exacerbations of COPD

Background: Chronic Obstructive Pulmonary Disease (COPD) is a disease with high morbidity and mortality globally. Exacerbations of COPD are major contributors to disease progression and a decline in health-related quality of life (HRQoL). High-flow nasal cannula (HFNC) oxygen therapy is an innovative therapy that provides humidified and heated blended air and oxygen through a nasal cannula. There is some preliminary evidence supporting the effectiveness of HFNC in managing COPD exacerbations, but there are limited data on its effectiveness when used at home for patients with stable, severe COPD. The aim of the present study is to test the hypothesis that home HFNC can decrease the COPD exacerbations rate and hospital admissions and improve HRQoL measures in severe COPD patients with frequent COPD exacerbations. Methods: In a prospective proof-of-concept interventional multicenter study, 40 GOLD stage III and IV COPD patients with a high disease burden (≥2 exacerbations treated with antibiotics and/or corticosteroids) and ≥1 hospital admission in the last year were included. Patients were given instructions on the usage of HFNC by a ventilation practitioner during a group session. The flow rate was 25–30 L/min and FiO2 was 21–35%. Outcome measures included the COPD exacerbations rate, hospital admissions, in-hospital days, Medical Research Council dyspnea (MRC) score, Clinical COPD Questionnaire (CCQ) score, Hospital Anxiety Depression Scale (HADS) scores and capillary pCO2. Repeated analysis of variance (ANOVA) was used to analyze the data. Significant effects identified in the ANOVA were further examined using Student’s t-tests. Results: After 1 year, 27 patients could be evaluated. The COPD exacerbations rate decreased by 1.40 (mean difference ± SD: 1.40 ± 2.09; p = 0.002), hospital admissions decreased by 0.96 admissions per year (0.96 ± 1.37; p = 0.001), and in-hospital days decreased by 7.22 days (7.22 ± 9.26; p = 0.001). Capillary pCO2 decreased by 0.02 kPa (0.02 ± 0.52; p = 0.85). The CCQ score decreased by 0.06 (0.06 ± 0.96; p = 0.76). The MRC dyspnea score decreased by 0.04 (0.04 ± 0.80; p = 0.81). The HADS anxiety score decreased by 0.63 (0.63 ± 3.12; p = 0.31). And finally, the HADS depression score decreased by 0.32 (0.32 ± 3.48; p = 0.64). There was a significant difference between the normocapnic (capillary pCO2 < 6.0 kPa) group and the hypercapnic group in terms of change in the CCQ score (−0.24 ± 0.55 and 0.49 ± 1.32 decrease, respectively, p = 0.05) and the HADS depression score (−0.76 ± 1.86 and 2.20 ± 4.75 decrease, respectively, p = 0.03) after 1 year of HFNC treatment. Conclusions: One-year-long HFNC therapy significantly decreased the COPD exacerbations rate, hospital admissions, and in-hospital days in severe COPD patients with a high disease burden and frequent COPD exacerbations irrespective of them having hypercapnia and with the HRQoL measures only improving in the hypercapnic group. This may imply that severe COPD patients with a high disease burden and frequent COPD exacerbations, irrespective being hypercapnic, are candidates for treatment with home HFNC oxygen therapy.

Is It the Heart or the Lung? Sometimes It Is Both.

The Association of Depressive Symptoms With Rates of Acute Exacerbations in Patients With COPD: Results From a 3-year Longitudinal Follow-up of the ECLIPSE Cohort

Management of chronic obstructive pulmonary disease: Moving beyond the asthma algorithm

While β-blockers are associated with decreased mortality in cardiovascular disease (CVD), exacerbation-prone patients with chronic obstructive pulmonary disease (COPD) who received metoprolol in the Beta-Blockers for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease (BLOCK-COPD) trial experienced increased risk of exacerbations requiring hospitalization. However, the study excluded individuals with established indications for the drug, raising questions about the overall risk and benefit in patients with COPD following acute myocardial infarction (AMI). To investigate whether β-blocker prescription at hospital discharge is associated with increased risk of mortality or adverse cardiopulmonary outcomes in patients with COPD and AMI. This prospective, longitudinal cohort study with 6 months of follow-up enrolled patients aged 35 years or older with COPD who underwent cardiac catheterization for AMI at 18 BLOCK-COPD network hospitals in the US from June 2020 through May 2022. Prescription for any β-blocker at hospital discharge. The primary outcome was time to the composite outcome of death or all-cause hospitalization or revascularization. Secondary outcomes included death, hospitalization, or revascularization for CVD events, death or hospitalization for COPD or respiratory events, and treatment for COPD exacerbations. Among 3531 patients who underwent cardiac catheterization for AMI, prevalence of COPD was 17.1% (95% CI, 15.8%-18.4%). Of 579 total patients with COPD and AMI, 502 (86.7%) were prescribed a β-blocker at discharge. Among the 562 patients with COPD included in the final analysis, median age was 70.0 years (range, 38.0-94.0 years) and 329 (58.5%) were male; 553 of the 579 patients (95.5%) had follow-up information. Among those discharged with β-blockers, there was no increased risk of the primary end point of all-cause mortality, revascularization, or hospitalization (hazard ratio [HR], 1.01; 95% CI, 0.66-1.54; P = .96) or of cardiovascular events (HR, 1.11; 95% CI, 0.65-1.92; P = .69), COPD-related or respiratory events (HR, 0.75; 95% CI, 0.34-1.66; P = .48), or treatment for COPD exacerbations (rate ratio, 1.01; 95% CI, 0.53-1.91; P = .98). In this cohort study, β-blocker prescription at hospital discharge was not associated with increased risk of adverse outcomes in patients with COPD and AMI. These findings support use of β-blockers in patients with COPD and recent AMI.