Reducing short-acting beta-agonist use in asthma: Impact of national incentives on prescribing practices in England and the findings from SENTINEL Plus early adopter sites.

Short-acting beta-agonist (SABA) over-use in asthma is harmful for patients and the environment. The Investment and Impact Fund (IIF) 2022/2023 financially rewarded English primary care networks that achieved specific targets, including reducing SABA over-use (RESP-02) and lowering the mean carbon footprint per salbutamol inhaler prescribed (ES-02). SENTINEL Plus is a co-designed quality improvement package that aims to improve asthma outcomes and reduce asthma's environmental impact by addressing SABA over-use. We investigated the impact of (i) the IIF incentives and (ii) SENTINEL Plus implementation on asthma prescribing. Using Openprescribing.net data, we demonstrate that IIF 2022-2023 had no significant impact on the total number of SABA prescribed in England (25,927,252 during 12-months pre- and 25,885,213 12-months post-IIF; 0.16% decrease; p=NS), but lower carbon footprint SABA inhaler use increased (Salamol™ prescribing increased from 5.1% to 19% of SABA prescriptions, p < 0.01). In contrast, SENTINEL Plus sites significantly reduced SABA prescribing post-implementation (5.43% decrease, p < 0.05).

Electrophysiological characteristics of atrial tachycardia recurrence: Relevance to catheter ablation strategies in adults with congenital heart disease.

BACKGROUND: Catheter ablation outcomes for adults with congenital heart disease (ACHD) are described, but recurrence mechanisms remain largely unknown. OBJECTIVE: The purpose of this study was to identify the electrophysiological characteristics of atrial tachycardia (AT) recurrence in ACHD. METHODS: ACHD atrial tachycardia procedures over a 10-year period were explored for AT or atrial fibrillation (AF) recurrence. RESULTS: At 299 procedures in 250 ACHD (mean age 39 ± 15 years; 130 [52%] male), 464 ATs (360 intra-atrial reentrant tachycardia, 104 focal AT; median 2 [IQR 1-3] ATs per procedure) were targeted. Complete (n = 256 [86%]) or partial (n = 37 [12%]) success was achieved in 98% of procedures. Over a median of 3.0 (IQR 1.4-5.3) years of follow-up, 67 patients (27%) developed AT/AF recurrence after the index procedure. Repeat vs index tachycardias were more often focal AT (26/69 [38%] vs 73/378 [19%]; P < .001), demonstrated longer cycle length (325 ms vs 280 ms; P = .003), required isoproterenol (34/69 [50%] vs 121/378 [32%]; P = .03), and involved the pulmonary venous atrium (PVA)/septum (26/69 [38%] vs 67/378 [18%]; P < .001). AF history (hazard ratio [HR] 2.0; interquartile range [IQR] 1.2-3.4; P = .01), incomplete success (HR 3.6; IQR 2.1-6.4; P < .001), and PVA substrate (HR 2.1; IQR 1.2-3.5; P = .006) were independently associated with AT/AF recurrence. With complete index procedure success and no AF history, 5-year actuarial freedom from AT/AF and AT alone were 77% and 80%. CONCLUSION: After catheter ablation in ACHD, repeat ATs were more frequently focal, required isoproterenol administration, or involved intra-atrial reentrant tachycardia within the PVA or atrial septum. Negative factors were partial success, index PVA substrate, and remote history of AF. These data support aggressive pharmacological provocation to eliminate all inducible tachycardias and coexisting PVA substrates at index procedures for ACHD.

The association between developing Parkinson's disease and ß-Adrenoceptor acting agents use: A systematic review and meta-analysis.

INTRODUCTION: Parkinson's disease (PD) ranks the second most common neurodegenerative disease. Aside from genetic predisposition, many external factors such as traumatic brain injury and exposure of substances including pesticides also contribute to PD's pathogenesis. Many previous studies observed the association between the use of ß-adrenoceptor acting agents and risk of PD. OBJECTIVE: To conduct systematic review and meta-analysis to summarize whether the use of ß-agonist and ß-antagonist agents were associated with risk of PD. METHOD: We independently searched for published studies from EMBASE and MEDLINE databases from inception to February 2021. This meta-analysis includes 9 case-control studies and 1 cohort study meeting the eligibility criteria, with a total of 380,105 participants. RESULTS: Overall ß-antagonists use appeared to associate with increase PD risk with an odd ratio (OR) of 1.2 (95% CI 1.07-1.34). Propranolol and metoprolol had a statistically significant association with higher risk of PD: pooled OR was 1.67 (95% CI 1.22-2.29) and 1.07 (95% CI 1.03-1.1), respectively. On the other hand, ß-agonists significantly inverse association with PD risk with OR of 0.88 (95% CI 0.85-0.92). Salbutamol unexpectedly showed no statistical significance in reduced risk of PD with a pooled risk ratio of 1.0 (95% CI 0.87-1.16). CONCLUSION: Overall ß-antagonists, including propranolol and metoprolol, were associated with an increased risk of PD, in contrast to ß-agonists, which were associated with decreased the risk.

Betalain exerts cardioprotective and anti-inflammatory effects against the experimental model of heart failure.

Betalain is a natural plant pigment known to elicit various biological activities. However, studies on the protective effect of betalain against heart failure have not reported yet. The experimental model of heart failure was created in Wistar rats using isoproterenol (ISO). The animals were randomly assigned into four groups such as sham-control, ISO-induced heart failure, betalain pretreated before ISO induction (50 mg/kg/day), and betalain drug control group were maintained for 6 weeks. At the end of the experimental period, anti-oxidant enzymes, inflammatory markers, matrix proteins, cardiac-specific markers, and micro RNAs were elucidated using RT-PCR, and ELISA analysis. The results demonstrated that the rats induced with ISO displayed an abnormality in cardiac functions, increased oxidative stress markers (p < 0.01), inflammatory cytokines (p < 0.01) while abrogated the expression of miR-18a, and increased miR-199a. While betalain pre-treated rats prevented the cardiac failure significantly (p < 0.01) with improved anti-oxidant enzymes, abrogated the inflammatory signals with restored matrix proteins, cardiac biomarker genes, and attenuated miR-423 and miR-27 compared to heart failure rats. The results of the study suggest that the betalain treatment protected the hearts from failing via microRNA mediated activation the anti-inflammatory signaling and restoring the matrix protein modulation.

COPD maintenance medication is linked to left atrial size: Results from the COSYCONET cohort.

BACKGROUND: Lung function impairment in COPD is known to be related to reductions of left heart size, while short-term interventional trials with bronchodilators showed positive effects on cardiac parameters. We investigated whether COPD maintenance therapy has analogous long-term effects. METHODS: Pooled data of GOLD grade 1-4 patients from visits 1 and 3 (1.5 y apart) of the COSYCONET cohort were used. Medication was categorized as use of ICS, LABA + ICS, LABA + LAMA and triple therapy (LABA + LAMA + ICS), contrasting "always" versus "never". Echocardiographic parameters comprised left ventricular end-diastolic and -systolic diameter (LVEDD, LVESD), ejection fraction (LVEF) and left atrial diameter (LA). Associations were identified by multiple regression analysis, as well as propensity score analysis. RESULTS: Overall, 846 patients (mean age 64.5 y; 41% female) were included, 53% using ICS at both visits, 51% LABA + ICS, 56% LABA + LAMA, 40% LABA + LAMA + ICS (triple) therapy. Conversely, 30%, 32%, 28% and 42% had no ICS, LABA + ICS, LABA + LAMA or triple therapy, respectively, at both visits. Among echocardiographic measures, only LA showed statistically significant associations (increases) with medication, whereby significant effects were linked to ICS, LABA + ICS and LABA + LAMA (p < 0.05 each, "always" versus "never") and propensity score analyses underlined the role of LABA + LAMA. CONCLUSIONS: In this observational study, COPD maintenance therapy, especially LABA + LAMA, was linked to left atrial size, consistent with the results of short-term interventional trials. These findings suggest that maintenance medication for COPD does not only improve lung function and patient reported outcomes but may also have an impact on the cardiovascular system. TRIAL REGISTRATION: NCT01245933.

Prescribing pathways to triple therapy in patients with chronic obstructive pulmonary disease in the United States.

BACKGROUND: Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend triple therapy (TT) for chronic obstructive pulmonary disease (COPD) patients based on severity. TT utilization by severity is infrequently studied in real-world settings and may deviate significantly from current clinical recommendations. This study describes prescribing pathways to TT among patients with COPD in the United States. METHODS: This study analyzed Geisinger Health System electronic medical records from 1 January 2004 to 30 November 2016. Two retrospective cohorts of COPD patients were included: (1) incident COPD, and (2) incident TT users. COPD treatment patterns, including time to TT, were summarized. Time to TT was estimated using Kaplan-Meier methods. Predictors of the relative hazard for TT among incident COPD patients were estimated using Cox proportional hazards regressions. RESULTS: Incident COPD and TT cohorts included 57,141 and 8173 patients, respectively. TT was used by 9.6% of incident COPD patients. In the year before TT, 34.3% of incident TT patients received treatment combinations recommended before TT according to GOLD recommendations, which mainly included: long-acting muscarinic antagonists (LAMAs), long-acting beta agonists (LABAs) + LAMAs, and inhaled corticosteroids + LABAs. Among incident TT patients, median time from COPD diagnosis to TT exceeded 2 years. The hazard for TT over time was associated with lower forced expiratory volume in 1 s values, more frequent exacerbations, current/previous smoking, and comorbid lung conditions such as pulmonary vascular disease, acute respiratory failure, and lung cancer. About 15-20% of the incident TT patients stepped down to a one- or two-drug regimen. Median time to TT discontinuation or step-down were 2 and 9 months, respectively. CONCLUSION: The study has revealed discrepancies in the treatment of COPD patients between GOLD guidelines and actual clinical practices in the United States. Pathways to TT differed from recommended therapy regimes. Further studies are needed to understand barriers to the use of guideline-recommended TTs by healthcare providers.The reviews of this paper are available via the supplemental material section.

Position paper on stress cardiac magnetic resonance imaging in chronic coronary syndrome: Endorsed by the Société française de radiologie (SFR), the Société française d'imagerie cardiovasculaire (SFICV) and the Société française de cardiologie (SFC).

This paper is intended to update the former consensus between the French Societies of Radiology and Cardiology about the use of stress cardiac magnetic resonance imaging in chronic coronary syndrome, published in 2009. The Delphi method was used to build the present consensus. This expert panel consensus includes recommendations for indications, the procedure (with patient preparation), stress-inducing drugs, the acquisition protocol, interpretation and risk stratification by stress magnetic resonance imaging.

Randomised trial of epinephrine dose and flush volume in term newborn lambs.

OBJECTIVES: Neonatal resuscitation guidelines recommend 0.5-1 mL saline flush following 0.01-0.03 mg/kg of epinephrine via low umbilical venous catheter for persistent bradycardia despite effective positive pressure ventilation (PPV) and chest compressions (CC). We evaluated the effects of 1 mL vs 3 mL/kg flush volumes and 0.01 vs 0.03 mg/kg doses on return of spontaneous circulation (ROSC) and epinephrine pharmacokinetics in lambs with cardiac arrest. DESIGN: Forty term lambs in cardiac arrest were randomised to receive 0.01 or 0.03 mg/kg epinephrine followed by 1 mL or 3 mL/kg flush after effective PPV and CC. Epinephrine (with 1 mL flush) was repeated every 3 min until ROSC or until 20 min. Haemodynamics, blood gases and plasma epinephrine concentrations were monitored. RESULTS: Ten lambs had ROSC before epinephrine administration and 2 died during instrumentation. Among 28 lambs that received epinephrine, 2/6 in 0.01 mg/kg-1 mL flush, 3/6 in 0.01 mg/kg-3 mL/kg flush, 5/7 in 0.03 mg/kg-1 mL flush and 9/9 in 0.03 mg/kg-3 mL/kg flush achieved ROSC (p=0.02). ROSC was five times faster with 0.03 mg/kg epinephrine compared with 0.01 mg/kg (adjusted HR (95% CI) 5.08 (1.7 to 15.25)) and three times faster with 3 mL/kg flush compared with 1 mL flush (3.5 (1.27 to 9.71)). Plasma epinephrine concentrations were higher with 0.01 mg/kg-3 mL/kg flush (adjusted geometric mean ratio 6.0 (1.4 to 25.7)), 0.03 mg/kg-1 mL flush (11.3 (2.1 to 60.3)) and 0.03 mg/kg-3 mL/kg flush (11.0 (2.2 to 55.3)) compared with 0.01 mg/kg-1 mL flush. CONCLUSIONS: 0.03 mg/kg epinephrine dose with 3 mL/kg flush volume is associated with the highest ROSC rate, increases peak plasma epinephrine concentrations and hastens time to ROSC. Clinical trials evaluating optimal epinephrine dose and flush volume are warranted.

Dual-combination maintenance inhaler preferences in asthma and chronic obstructive pulmonary disease: A patient-centered benefit-risk assessment.

BACKGROUND: A variety of dual-combination maintenance inhalers are used to treat asthma and chronic obstructive pulmonary disease (COPD). Understanding patient preferences for treatment attributes may help select an optimal treatment from the patient perspective. METHODS: Patient preferences for maintenance inhaler device and medication attributes were elicited through a discrete choice experiment and used in benefit-risk assessments to calculate predicted choice probabilities (PrCPs) for 14 dual-combination maintenance inhalers in four treatment classes: lower- and higher-dose inhaled corticosteroid (ICS)/long-acting beta agonist (LABA) inhalers for asthma, and ICS/LABA and long-acting muscarinic antagonist (LAMA)/LABA inhalers for COPD. RESULTS: For all treatment classes, reduced exacerbations and faster onset of action were the most important attributes. For all classes, patients were willing to tolerate an extra yearly exacerbation to decrease the medication's onset of action from 30 to 5 min. For patients with asthma using lower-dose ICS/LABA (n = 497), budesonide/formoterol fumarate dihydrate (80 µg/4.5 µg) pressurized metered-dose inhaler (pMDI) had the highest PrCP (28.4%), and for those using a higher-dose ICS/LABA (n = 285), PrCPs were highest for mometasone furoate/formoterol fumarate dihydrate (200 µg/5 µg) pMDI (27.0%) and budesonide/formoterol fumarate dihydrate (160 µg/4.5 µg) pMDI (26.9%). For patients with COPD using an ICS/LABA (n = 574), budesonide/formoterol fumarate dihydrate (160 µg/4.5 µg) pMDI had the highest PrCP (56.6%), and for those using a LAMA/LABA inhaler (n = 217), tiotropium/olodaterol (2.5 µg/2.5 µg) soft mist inhaler had the highest PrCP (42.3%). CONCLUSIONS: Patient preference data for maintenance inhaler attributes can be used to identify a preference order of inhalers in different treatment classes.

Ractopamine changes in pork quality are not mediated by changes in muscle glycogen or lactate accumulation postmortem.

Pork quality is a product of the rate and extent of muscle pH decline paced by carbohydrate metabolism postmortem. The beta-adrenergic agonist ractopamine (RAC) alters muscle metabolism but has little impact on pork quality. The objective of this study was to determine how feeding RAC alters postmortem carbohydrate metabolism in muscle. Muscle pH was higher early postmortem in pigs fed RAC for 2 wks compared to control, while other time points and temperatures were largely unaffected. Early postmortem, muscle lactate levels were reduced (P < 0.05) after feeding RAC for 1 and 2 wks. Similarly, pigs fed RAC for 4 wks had reduced (P < 0.05) glycogen levels early postmortem compared to control pigs, but unexpectedly, L* values (lightness) increased (P < 0.05) after inclusion of RAC in the diet for 4 wk. These data show RAC feeding reduces glycogen content and changes lactate accumulation postmortem, but raise questions about the role glycolytic flux has in driving pork quality development.

Is It Time to Leave Behind the Concept of Asthma Control and Severity Steps?

After 25 years of GINA, we need an overarching strategy. The resounding changes in GINA 2019 should be accompanied by another major change in general strategy of asthma management. The concept of control asthma and step strategy was established in 1997 by GINA; but still there is a great gap between GINA objectives and outcomes. O'Byrne and colleagues proposed a continuum of care approach; where patient-adjusted therapy would comprise both a controller and reliever (usually ICS/fast-acting LABA) in a single inhaler. We use a similar approach in our asthma centre.

Usefulness of an isoproterenol infusion to differentiate a left atrial appendage thrombus in a patient with nonvalvular atrial fibrillation.

A 78-year-old male with a history of a cardiac embolic stroke due to persistent AF and cerebral bleeding (CHADS2 score 4, HAS-BLED score 4) was referred to our hospital to implant a left atrial appendage (LAA) closure (LAAC) device. A trans esophageal echocardiography was performed and a high echoic lesion that was difficult to differentiate the spontaneous echo contrast or thrombus was found in the LAA cavity. After isoproterenol infusion, a high echoic lesion disappeared and we confirmed that it was not an LAA thrombus. Successful LAAC device implantation was performed without any thromboembolic events.

Gastroesophageal reflux-like symptoms are associated with hyposalivation and oropharyngeal problems in patients with asthma.

BACKGROUND: Previous studies have suggested a significant relationship between hyposalivation and inhalation therapy-induced oropharyngeal problems. However, salivary secretion tests are not widely performed in daily clinical practice. In fact, xerostomia, the complaint of dry mouth, may not indicate hyposalivation. Therefore, we determined the clinical factors associated with hyposalivation in patients with asthma. METHODS: This study is a post-hoc analysis of our previous studies. Adult patients with asthma on maintenance inhalation therapy were enrolled. The participants completed questionnaires on oropharyngeal symptoms and underwent a salivary secretion test. Symptom severity was evaluated using a numerical rating scale (NRS), and salivary secretion was measured using the modified cotton roll method. Using logistic regression analysis, we identified the clinical factors associated with hyposalivation. RESULTS: In total, 531 patients completed the questionnaire (43.8 ± 16.9 years and male/female = 171/360), and 234 patients successfully performed a salivary secretion test, of which 126 (53.8%) were diagnosed with hyposalivation (<0.25 g/min). The patients with hyposalivation were significantly older (p < 0.0001) and had severe xerostomia and/or gastroesophageal reflux-like symptoms (GERLS) (p < 0.0001). Many of these patients had also used inhaled long-acting beta agonists (p = 0.012) and high-dose inhaled corticosteroids (p = 0.024). Multivariate analysis revealed that advanced age (odds ratio [OR] 1.05, p < 0.0001), severe xerostomia (OR 1.02, p = 0.0006) and severe GERLS (OR 1.02, p = 0.001) were independently and significantly associated with hyposalivation. CONCLUSIONS: Age, xerostomia, and GERLS were significantly related to hyposalivation in patients with asthma. To identify oropharyngeal problems in these patients, a careful assessment of the suspected symptoms of gastroesophageal reflux may be useful.

Medication Discontinuation in Adults With COPD Discharged From the Hospital: A Population-Based Cohort Study.

BACKGROUND: Patients admitted to the hospital with COPD are commonly managed with inhaled short-acting bronchodilators, sometimes in lieu of the long-acting bronchodilators they take as outpatients. If held on admission, these long-acting inhalers should be re-initiated upon discharge; however, health-care transitions sometimes result in unintentional discontinuation. RESEARCH QUESTION: What is the risk of unintentional discontinuation of long-acting muscarinic antagonist (LAMA) and long-acting beta-agonist and inhaled corticosteroid (LABA-ICS) combination medications following hospital discharge in older adults with COPD? STUDY DESIGN AND METHODS: A retrospective cohort study was conducted by using health administrative data from 2004 to 2016 from Ontario, Canada. Adults with COPD aged ≥ 66 years who had filled prescriptions for a LAMA or LABA-ICS continuously for ≥ 1 year were included. Log-binomial regression models were used to determine risk of medication discontinuation following hospitalization in each medication cohort. RESULTS: Of the 27,613 hospitalization discharges included in this study, medications were discontinued 1,466 times. Among 78,953 patients with COPD continuously taking a LAMA or LABA-ICS, those hospitalized had a higher risk of having medications being discontinued than those who remained in the community (adjusted risk ratios of 1.50 [95% CI, 1.34-1.67; P < .001] and 1.62 [95% CI, 1.39, 1.90; P < .001] for LAMA and LABA-ICS, respectively). Crude rates of discontinuation for people taking LAMAs were 5.2% in the hospitalization group and 3.3% in the community group; for people taking LABA-ICS, these rates were 5.5% in the hospitalization group and 3.1% in the community group. INTERPRETATION: In an observational study of highly compliant patients with COPD, hospitalization was associated with an increased risk of long-acting inhaler discontinuation. These Results suggest a likely larger discontinuation problem among less adherent patients and should be confirmed and quantified in a prospective cohort of patients with COPD and average compliance. Quality improvement efforts should focus on safe transitions and patient medication reconciliation following discharge.

Asthma-Chronic Obstructive Pulmonary Disease Overlap.

Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) defines a subgroup of patients with asthma who have persistent airflow obstruction or patients with COPD who may exhibit variable airflow limitation and/or evidence of type 2 inflammation. Additional investigations are needed to determine whether ACO represents a distinct disorder with unique underlying pathophysiology, whether ACO patients should be managed differently from those with asthma or COPD, and whether the diagnosis affects long-term outcomes. This article presents the data about the clinical features of ACO, the current information regarding the underlying pathophysiology of the syndrome, and current understanding of therapeutic options.

Diagnostic practices for patients with shortness of breath and presumed obstructive airway disorders: a cross-sectional analysis.

BACKGROUND: Dyspnea is a common symptom that has many causes, including obstructive airway disorders. We sought to examine previous diagnosis of obstructive airway disorders and other conditions in patients receiving treatment with inhaled medications for shortness of breath in a community setting. METHODS: This cross-sectional study included consecutive patients aged 18 years and older receiving treatment for shortness of breath with inhaled medications for a minimum of 6 months. Study participants were recruited through community pharmacies in Edmonton and Saskatoon, Canada, between February 2009 and February 2012. Previous diagnosis of obstructive airway disorders by a primary care provider was assessed by patient self-report and review of health records. We conducted an assessment (as per guidelines from the American Thoracic Society and the European Respiratory Society), including pulmonary function tests; diagnoses were adjudicated by an expert physician panel (2 respirologists and 1 emergency physician). The agreement between diagnoses derived from pulmonary function tests and diagnoses from primary care providers was evaluated. RESULTS: A total of 328 patients (median age 50 yr, 57.3% female) underwent assessment; 134 (40.9%) of patients reported ever having a pulmonary function test performed. After adjudication, 138 (42.1%) were diagnosed with asthma only, 86 (26.2%) with chronic obstructive pulmonary disease only and 11 (3.4%) with both. Some patients (93, 28.4%) had no evidence of obstructive airway disorders and 20 (6.1%) had evidence of other conditions that cause shortness of breath, such as heart failure and pulmonary hypertension. Overall, 62 (18.9%) patients could not be assigned a diagnosis. INTERPRETATION: In a group of community-based patients with shortness of breath being treated with inhalers, less than half ever had pulmonary function tests performed, and a considerable proportion had no evidence of lung disease or other conditions. These findings highlight the need for confirmatory testing, including pulmonary function tests, before prescribing inhalers for patients with presumed obstructive airway disorders.