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BMJ (Clinical Research Ed.) Sep 2023To evaluate the association between recently raised anticholinergic burden and risk of acute cardiovascular events in older adults.
OBJECTIVE
To evaluate the association between recently raised anticholinergic burden and risk of acute cardiovascular events in older adults.
DESIGN
Case-case-time-control study (ie, incorporating a case crossover design and a control crossover design consisting of future cases).
SETTING
Taiwan's National Health Insurance Research Database.
PARTICIPANTS
317 446 adults aged ≥65 who were admitted to hospital because of an incident acute cardiovascular event between 2011 and 2018. Acute cardiovascular events included myocardial infarction, strokes, arrhythmias, conduction disorders, and cardiovascular death.
MAIN OUTCOME MEASURES
The anticholinergic burden was measured for each participant by adding up the anticholinergic scores for individual drugs using the Anticholinergic Cognitive Burden Scale. Scores were classified into three levels (0 points, 1-2 points, and ≥3 points). For each participant, anticholinergic burden levels during hazard periods (day -1 to -30 before the cardiovascular event) were compared with randomly selected 30 day reference periods (ie, periods between days -61 and -180). Conditional logistic regression determined odds ratios with 95% confidence intervals to evaluate the association between acute cardiovascular events and recently raised anticholinergic burden.
RESULTS
The crossover analyses included 248 579 current cases. Participants' average age on the index date was 78.4 years (standard deviation 0.01), and 53.4% were men. The most frequently prescribed drugs with anticholinergic activity were antihistamines (68.9%), gastrointestinal antispasmodics (40.9%), and diuretics (33.8%). Among patients with varying levels of anticholinergic burden in different periods, more patients carried higher levels of anticholinergic burden during hazard periods than during reference periods. For example, 17 603 current cases had 1-2 points of anticholinergic burden in the hazard period with 0 points in the reference period, while 8507 current cases had 0 points in the hazard period and 1-2 points in the reference period. In the comparison of 1-2 points versus 0 points of anticholinergic burden, the odds ratio was 1.86 (95% confidence interval 1.83 to 1.90) in the case crossover analysis and 1.35 (1.33 to 1.38) in the control crossover analysis, which yielded a case-case-time-control odds ratio of 1.38 (1.34 to 1.42). Similar results were found in the comparison of ≥3 versus 0 points (2.03, 1.98 to 2.09) and ≥3 versus 1-2 points (1.48, 1.44 to 1.52). The findings remained consistent throughout a series of sensitivity analyses (eg, cut-off points for anticholinergic burden categories were redefined and different scales were used to measure anticholinergic burden).
CONCLUSIONS
An association was found between recently raised anticholinergic burden and increased risk of acute cardiovascular events. Furthermore, a greater increase in anticholinergic burden was associated with a higher risk of acute cardiovascular events.
Topics: Male; Humans; Aged; Female; Cholinergic Antagonists; Case-Control Studies; Hospitalization; Hospitals; Myocardial Infarction
PubMed: 37758279
DOI: 10.1136/bmj-2023-076045 -
American Journal of Respiratory and... Dec 2023Obstructive sleep apnea (OSA) is a common sleep disorder for which the principal treatment option, continuous positive airway pressure, is often poorly tolerated. There... (Randomized Controlled Trial)
Randomized Controlled Trial
Obstructive sleep apnea (OSA) is a common sleep disorder for which the principal treatment option, continuous positive airway pressure, is often poorly tolerated. There is currently no approved pharmacotherapy for OSA. However, recent studies have demonstrated improvement in OSA with combined antimuscarinic and noradrenergic drugs. The aim of this study was to evaluate the efficacy and safety of AD109, a combination of the novel antimuscarinic agent aroxybutynin and the norepinephrine reuptake inhibitor atomoxetine, in the treatment of OSA. Phase II randomized, double-blind, placebo-controlled, parallel-group, 4-week trial comparing AD109 2.5/75 mg, AD109 5/75 mg, atomoxetine 75 mg alone, and placebo (www.clinicaltrials.gov identifier NCT05071612). Of 211 randomized patients, 181 were included in the prespecified efficacy analyses. Sleep was assessed by two baseline and two treatment polysomnograms. Apnea-hypopnea index with a 4% desaturation criterion (primary outcome) was reduced from a median (IQR) of 20.5 (12.3-27.2) to 10.8 (5.6-18.5) in the AD109 2.5/75 mg arm (-47.1%), from 19.4 (13.7-26.4) to 9.5 (6.1-19.3) in the AD109 5/75 mg arm (-42.9%; both < 0.0001 vs. placebo), and from 19.0 (11.8-28.8) to 11.8 (5.5-21.5) with atomoxetine alone (-38.8%; < 0.01 vs. placebo). Apnea-hypopnea index with a 4% desaturation criterion decreased from 20.1 (11.9-25.9) to 16.3 (11.1-28.9) in the placebo arm. Subjectively, there was improvement in fatigue with AD109 2.5/75 mg ( < 0.05 vs. placebo and atomoxetine). Atomoxetine taken alone decreased total sleep time ( < 0.05 vs. AD109 and placebo). The most common adverse events were dry mouth, insomnia, and urinary hesitancy. AD109 showed clinically meaningful improvement in OSA, suggesting that further development of the compound is warranted. Clinical trial registered with www.clinicaltrials.gov (NCT05071612).
Topics: Humans; Atomoxetine Hydrochloride; Sleep Apnea, Obstructive; Sleep; Polysomnography; Fatigue; Continuous Positive Airway Pressure; Muscarinic Antagonists
PubMed: 37812772
DOI: 10.1164/rccm.202306-1036OC -
Nederlands Tijdschrift Voor Geneeskunde Nov 2023In this Clinical Lesson, using two illustrating cases, we explain how to do the initial assessment and treatment of an intoxicated patient. An approach aimed at...
In this Clinical Lesson, using two illustrating cases, we explain how to do the initial assessment and treatment of an intoxicated patient. An approach aimed at toxidromes can serve as a stepping stone. A toxidrome is a combination of symptoms and clinical features that can occur with the use of certain drugs and substances. The most commonly encountered toxidromes are sympathomimetic, serotonergic, anticholinergic, cholinergic, sedative-hypnotic and opioid. All patients need to be approach according to the ABCDE method. The treatment is based on pharmacokinetics by means of the ADME principle (absorption, distribution, metabolism and excretion) and based on pharmacodynamics, aimed at the toxidrome.
Topics: Humans; Analgesics, Opioid; Autonomic Nervous System Diseases; Cholinergic Antagonists; Hypnotics and Sedatives
PubMed: 38175605
DOI: No ID Found -
JAMA Internal Medicine Jul 2023Clinical guidelines on chronic obstructive pulmonary disease (COPD) recommend inhalers containing long-acting muscarinic antagonists (LAMAs) and long-acting β-agonists...
IMPORTANCE
Clinical guidelines on chronic obstructive pulmonary disease (COPD) recommend inhalers containing long-acting muscarinic antagonists (LAMAs) and long-acting β-agonists (LABAs) over inhalers containing inhaled corticosteroids (ICSs) and LABAs. However, data from randomized clinical trials comparing these combination inhalers (LAMA-LABAs vs ICS-LABAs) have been conflicting and raised concerns of generalizability.
OBJECTIVE
To assess whether LAMA-LABA therapy is associated with reduced COPD exacerbations and pneumonia hospitalizations compared with ICS-LABA therapy in routine clinical practice.
DESIGN, SETTING, AND PARTICIPANTS
This was a 1:1 propensity score-matched cohort study using Optum's Clinformatics Data Mart, a large commercial insurance-claims database. Patients must have had a diagnosis of COPD and filled a new prescription for a combination LAMA-LABA or ICS-LABA inhaler between January 1, 2014, and December 31, 2019. Patients younger than 40 years were excluded, as were those with a prior diagnosis of asthma. The current analysis was performed from February 2021 to March 2023.
EXPOSURES
Combination LAMA-LABA inhalers (aclidinium-formoterol, glycopyrronium-formoterol, glycopyrronium-indacaterol, tiotropium-olodaterol, or umeclidinium-vilanterol) and combination ICS-LABA inhalers (budesonide-formoterol, fluticasone-salmeterol, fluticasone-vilanterol, or mometasone-formoterol).
MAIN OUTCOME
The primary effectiveness outcome was first moderate or severe COPD exacerbation, and the primary safety outcome was first pneumonia hospitalization. Propensity score matching was used to control for confounding between the 2 groups. Logistic regression analysis was used to estimate propensity scores. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models stratified on matched pairs.
RESULTS
Among 137 833 patients (mean [SD] age, 70.2 [9.9] years; 69 530 [50.4%] female) (107 004 new ICS-LABA users and 30 829 new LAMA-LABA users), 30 216 matched pairs were identified for the primary analysis. Compared with ICS-LABA use, LAMA-LABA use was associated with an 8% reduction in the rate of first moderate or severe COPD exacerbation (HR, 0.92; 95% CI, 0.89-0.96) and a 20% reduction in the rate of first pneumonia hospitalization (HR, 0.80; 95% CI, 0.75-0.86). These findings were robust across a range of prespecified subgroup and sensitivity analyses.
CONCLUSION
In this cohort study, LAMA-LABA therapy was associated with improved clinical outcomes compared with ICS-LABA therapy, suggesting that LAMA-LABA therapy should be preferred for patients with COPD.
Topics: Humans; Female; Aged; Male; Glycopyrrolate; Cohort Studies; Adrenergic beta-2 Receptor Agonists; Administration, Inhalation; Fluticasone; Adrenal Cortex Hormones; Nebulizers and Vaporizers; Muscarinic Antagonists; Formoterol Fumarate; Pulmonary Disease, Chronic Obstructive; Pneumonia; Bronchodilator Agents; Drug Therapy, Combination
PubMed: 37213116
DOI: 10.1001/jamainternmed.2023.1245