Comparative Safety Analysis of Nabilone Versus Opioids: A Population-Based Cohort Study.

BACKGROUND: Some have advocated that nabilone be used rather than opioids to manage chronic, noncancer pain, since the former drug may have a better safety profile. OBJECTIVE: We compared the safety of incident nabilone use relative to incident opioid use with respect to multiple clinically important outcomes. DESIGN: A population-based, retrospective cohort study. SETTING: Province of Ontario, Canada. PARTICIPANTS: Persons aged 12 years and older, diagnosed with a musculoskeletal condition within the past 3 years prior to the index date. EXPOSURES: Incident nabilone use, with incident opioid use serving as the reference group. MEASUREMENTS: Within 3 months following the index date, we separately evaluated for pneumonia, motor vehicle accidents, falls or fractures, mental and behavioral disorder due to psychoactive substance use, and all-cause mortality. RESULTS: A total of 18,863 incident nabilone users were propensity score matched to an equal number of opioid users. In the overall matched analysis, incident nabilone users vs. incident opioid users had significantly lower rates of pneumonia (hazard ratio [HR] 0.78, 95% CI 0.63-0.96), falls or fractures (HR 0.56, 95% CI 0.50-0.64), and all-cause mortality (HR 0.79, 95% CI 0.65-0.95), but significantly higher rate of mental or behavioral disorder (HR 2.23, 95% CI 1.45-3.43). There was no significant difference between groups with respect to rate of motor vehicle accidents. LIMITATIONS: Unmeasured confounding may have influenced results. CONCLUSIONS: While usage of nabilone relative to opioids was associated with reduced rates of pneumonia, falls or fractures, and all-cause mortality, it was simultaneously associated with an increased rate of adverse mental health outcomes. This picture of mixed safety results raises concerns with the policy approach of broadly substituting use of opioids with nabilone. FUNDING SOURCE: Ontario Ministry of Health.

Somatic Mutations in Vascular Malformations of Hereditary Hemorrhagic Telangiectasia Result in Bi-allelic Loss of ENG or ACVRL1.

Hereditary hemorrhagic telangiectasia (HHT) is a Mendelian disease characterized by vascular malformations (VMs) including visceral arteriovenous malformations and mucosal telangiectasia. HHT is caused by loss-of-function (LoF) mutations in one of three genes, ENG, ACVRL1, or SMAD4, and is inherited as an autosomal-dominant condition. Intriguingly, the constitutional mutation causing HHT is present throughout the body, yet the multiple VMs in individuals with HHT occur focally, rather than manifesting as a systemic vascular defect. This disconnect between genotype and phenotype suggests that a local event is necessary for the development of VMs. We investigated the hypothesis that local somatic mutations seed the formation HHT-related telangiectasia in a genetic two-hit mechanism. We identified low-frequency somatic mutations in 9/19 telangiectasia through the use of next-generation sequencing. We established phase for seven of nine samples, which confirms that the germline and somatic mutations in all seven samples exist in trans configuration; this is consistent with a genetic two-hit mechanism. These combined data suggest that bi-allelic loss of ENG or ACVRL1 may be a required event in the development of telangiectasia, and that rather than haploinsufficiency, VMs in HHT are caused by a Knudsonian two-hit mechanism.

Morbidity and mortality associated with prescription cannabinoid drug use in COPD.

INTRODUCTION: Respiratory-related morbidity and mortality were evaluated in relation to incident prescription oral synthetic cannabinoid (nabilone, dronabinol) use among older adults with chronic obstructive pulmonary disease (COPD). METHODS: This was a retrospective, population-based, data-linkage cohort study, analysing health administrative data from Ontario, Canada, from 2006 to 2016. We identified individuals aged 66 years and older with COPD, using a highly specific, validated algorithm, excluding individuals with malignancy and those receiving palliative care (n=185 876 after exclusions). An equivalent number (2106 in each group) of new cannabinoid users (defined as individuals dispensed either nabilone or dronabinol, with no dispensing for either drug in the year previous) and controls (defined as new users of a non-cannabinoid drug) were matched on 36 relevant covariates, using propensity scoring methods. Cox proportional hazard regression was used. RESULTS: Rate of hospitalisation for COPD or pneumonia was not significantly different between new cannabinoid users and controls (HR 0.87; 95% CI 0.61-1.24). However, significantly higher rates of all-cause mortality occurred among new cannabinoid users compared with controls (HR 1.64; 95% CI 1.14-2.39). Individuals receiving higher-dose cannabinoids relative to controls were observed to experience both increased rates of hospitalisation for COPD and pneumonia (HR 2.78; 95% CI 1.17-7.09) and all-cause mortality (HR 3.31; 95% CI 1.30-9.51). CONCLUSIONS: New cannabinoid use was associated with elevated rates of adverse outcomes among older adults with COPD. Although further research is needed to confirm these observations, our findings should be considered in decisions to use cannabinoids among older adults with COPD.

Morbidity and mortality reduction associated with polysomnography testing in idiopathic pulmonary fibrosis: a population-based cohort study.

BACKGROUND: It is not well-known if diagnosing and treating sleep breathing disorders among individuals with idiopathic pulmonary fibrosis (IPF) improves health outcomes. We evaluated the association between receipt of laboratory-based polysomnography (which is the first step in the diagnosis and treatment of sleep breathing disorders in Ontario, Canada) and respiratory-related hospitalization and all-cause mortality among individuals with IPF. METHODS: We used a retrospective, population-based, cohort study design, analyzing health administrative data from Ontario, Canada, from 2007 to 2019. Individuals with IPF were identified using an algorithm based on health administrative codes previously developed by IPF experts. Propensity score matching was used to account for potential differences in 41 relevant covariates between individuals that underwent polysomnography (exposed) and individuals that did not undergo polysomnography (controls), in order minimize potential confounding. Respiratory-related hospitalization and all-cause mortality were evaluated up to 12 months after the index date. RESULTS: Out of 5044 individuals with IPF identified, 201 (4.0%) received polysomnography, and 189 (94.0%) were matched to an equal number of controls. Compared to controls, exposed individuals had significantly reduced rates of respiratory-related hospitalization (hazard ratio [HR] 0.43, 95% confidence interval [CI] 0.24-0.75), p = 0.003) and all-cause mortality (HR 0.49, 95% CI 0.30-0.80), p = 0.004). Significantly reduced rate of respiratory-related hospitalization (but not all-cause mortality) was also observed among those with > = 1 respiratory-related hospitalization (HR 0.38, 95% CI 0.15-0.99) and systemic corticosteroid receipt (HR 0.37, 95% CI 0.19-0.94) in the year prior to the index date, which reflect sicker subgroups of persons. CONCLUSIONS: Undergoing polysomnography was associated with significantly improved clinically-important health outcomes among individuals with IPF, highlighting the potential importance of incorporating this testing in IPF disease management.

Serotonergic antidepressant use and morbidity and mortality among older adults with COPD.

We evaluated the relationship between new selective serotonin reuptake inhibitor (SSRI) or serotonin-noradrenaline reuptake inhibitor (SNRI) drug use and respiratory-related morbidity and mortality among older adults with chronic obstructive pulmonary disease (COPD).This was a retrospective population-based cohort study using heath administrative data from Ontario, Canada. Individuals aged ≥66 years, with validated, physician-diagnosed COPD (n=131 718) were included. New SSRI/SNRI users were propensity score matched 1:1 to controls on 40 relevant covariates to minimise potential confounding.Among propensity score matched community-dwelling individuals, new SSRI/SNRI users compared to non-users had significantly higher rates of hospitalisation for COPD or pneumonia (hazard ratio (HR) 1.15, 95% CI 1.05-1.25), emergency room visits for COPD or pneumonia (HR 1.13, 95% CI 1.03-1.24), COPD or pneumonia-related mortality (HR 1.26, 95% CI 1.03-1.55) and all-cause mortality (HR 1.20, 95% CI 1.11-1.29). In addition, respiratory-specific and all-cause mortality rates were higher among long-term care home residents newly starting SSRI/SNRI drugs versus controls.New use of serotonergic antidepressants was associated with small, but significant, increases in rates of respiratory-related morbidity and mortality among older adults with COPD. Further research is needed to clarify if the observed associations are causal or instead reflect unresolved confounding.

Incident diuretic drug use and adverse respiratory events among older adults with chronic obstructive pulmonary disease.

AIMS: Diuretic drugs may theoretically improve respiratory health outcomes in chronic obstructive pulmonary disease (COPD) through several possible mechanisms, but they might also lead to respiratory harm. We evaluated the association of incident oral diuretic drug use with respiratory-related morbidity and mortality among older adults with COPD. METHODS: This was a population-based, retrospective cohort study using health administrative data from Ontario, Canada, for the period 2008-2013. We identified adults aged 66 years and older with nonpalliative COPD using a validated algorithm. Respiratory-related morbidity and mortality were evaluated within 30 days of incident oral diuretic drug use compared to nonuse using Cox proportional hazard regression and applying inverse probability of treatment weighting using the propensity score to minimize confounding. RESULTS: Out of 99 766 individuals aged 66 years and older with COPD identified, incident diuretic receipt occurred in 51.7%. Relative to controls, incident diuretic users had significantly increased rates for hospitalization for COPD or pneumonia [hazard ratio (HR) 1.22, 95% confidence interval (CI) 1.07-1.40], as well as more emergency room visits for COPD or pneumonia (HR 1.35, 95% CI 1.18-1.56), COPD or pneumonia-related mortality (HR 1.41; 95% CI 1.04-1.92) and all-cause mortality (HR 1.20, 95% CI 1.06-1.35). The increased respiratory-related morbidity and mortality observed were specifically as a result of loop diuretic use. CONCLUSIONS: Incident diuretic drugs, and more specifically loop diuretics, were associated with increased rates of respiratory-related morbidity and mortality among older adults with nonpalliative COPD. Further studies are needed to determine if this association is causative or due to unresolved confounding.

Adverse cardiac events associated with incident opioid drug use among older adults with COPD.

PURPOSE: We evaluated whether incident opioid drug use was associated with adverse cardiac events among older adults with chronic obstructive pulmonary disease (COPD). METHODS: This was an exploratory, retrospective cohort study using health administrative data from Ontario, Canada, from 2008 to 2013. Using a validated algorithm, we identified adults aged 66 years and older with non-palliative COPD. Hazard ratios (HR) were estimated for adverse cardiac events within 30 days of incident opioid receipt compared to controls using inverse probability of treatment weighting using the propensity score. RESULTS: There were 134,408 community-dwelling individuals and 14,685 long-term care residents with COPD identified, 67.0 and 60.6% of whom received an incident opioid. Incident use of any opioid was associated with significantly decreased rates of emergency room (ER) visits and hospitalizations for congestive heart failure (CHF) among community-dwelling older adults (HR 0.84; 95% CI 0.73-0.97), but significantly increased rates of ischemic heart disease (IHD)-related mortality among long-term care residents (HR 2.15; 95% CI 1.50-3.09). In the community-dwelling group, users of more potent opioid-only agents without aspirin or acetaminophen combined had significantly increased rates of ER visits and hospitalizations for IHD (HR 1.38; 95% CI 1.08-1.77) and IHD-related mortality (HR 1.83; 95% CI 1.32-2.53). CONCLUSIONS: New opioid use was associated with elevated rates of IHD-related morbidity and mortality among older adults with COPD. Adverse cardiac events may need to be considered when administering new opioids to older adults with COPD, but further studies are required to establish if the observed associations are causal or related to residual confounding.

Inhaled Long-acting Anticholinergics and Urinary Tract Infection in Individuals with COPD.

Inhaled, long-acting anticholinergic medication (LAA), commonly used for moderate-to-severe chronic obstructive pulmonary disease (COPD), has been shown to decrease COPD hospitalizations, emergency department visits, and acute exacerbations but has also been associated with urinary tract infection (UTI) in a prior meta-analysis. The objective of this study was to verify if there was an association between LAA and UTI in older individuals with COPD. A population-based, real-world cohort study using health administrative data from Ontario, Canada was conducted. Incidence of UTI was compared between older people with physician-diagnosed COPD, who were new users of inhaled long-acting anticholinergics and new users of inhaled corticosteroids-a reference medication used in similar clinical settings that has no known association with UTI. Propensity score matching was used to minimize the effects of confounding. An overall association between LAA and various measures of UTI in older individuals was not found. However, in a priori defined stratified analyses, men newly initiated on LAA were 75% more likely to develop a UTI than men newly started on an inhaled corticosteroid (hazard ratio 1.75; 95% confidence interval 1.05-2.92). No significant association was seen in women. In conclusion, older men with COPD newly started on LAA are at increased risk of UTI. Men considering an inhaled LAA should be informed of this risk and, if they decide to take it, be provided with appropriate monitoring.

Incident opioid drug use and adverse respiratory outcomes among older adults with COPD.

We evaluated risk of adverse respiratory outcomes associated with incident opioid use among older adults with chronic obstructive pulmonary diseases (COPD).This was a retrospective population-based cohort study using a validated algorithm applied to health administrative data to identify adults aged 66 years and older with COPD. Inverse probability of treatment weighting using the propensity score was used to estimate hazard ratios comparing adverse respiratory outcomes within 30 days of incident opioid use compared to controls.Incident opioid use was associated with significantly increased emergency room visits for COPD or pneumonia (HR 1.14, 95% CI 1.00-1.29; p=0.04), COPD or pneumonia-related mortality (HR 2.16, 95% CI 1.61-2.88; p<0.0001) and all-cause mortality (HR 1.76, 95% CI 1.57-1.98; p<0.0001), but significantly decreased outpatient exacerbations (HR 0.88, 95% CI 0.83-0.94; p=0.0002). Use of more potent opioid-only agents was associated with significantly increased outpatient exacerbations, emergency room visits and hospitalisations for COPD or pneumonia, and COPD or pneumonia-related and all-cause mortality.Incident opioid use, and in particular use of the generally more potent opioid-only agents, was associated with increased risk for adverse respiratory outcomes, including respiratory-related mortality, among older adults with COPD. Potential adverse respiratory outcomes should be considered when prescribing new opioids in this population.

Incident opioid drug use among older adults with chronic obstructive pulmonary disease: a population-based cohort study.

AIMS: The purpose of the present study was to describe the scope, pattern and patient characteristics associated with incident opioid use among older adults with chronic obstructive pulmonary disease (COPD). METHODS: This was a retrospective population-based cohort study using Ontario, Canada, healthcare administrative data. Study participants were individuals aged 66 years and older with physician-diagnosed COPD, identified using a validated algorithm, who were not receiving palliative care. We examined the incidence of oral opioid receipt between 1 April 2003 and 31 March 2012, as well as several patterns of incident opioid drug use. RESULTS: Among 107,109 community-dwelling and 16,207 long-term care resident older adults with COPD, 72,962 (68.1%) and 8811 (54.4%), respectively, received an incident opioid drug during the observation period. Among long-term care residents, multiple opioid dispensings (8.8%), dispensings for >30 days' duration (up to 19.8%), second dispensings (35-43%) and early refills (24.2%) were observed. Incident opioid dispensing was also observed to occur during COPD exacerbations (6.9% among all long-term care residents; 18.1% among long-term care residents with frequent exacerbations). These same patterns of incident opioid use occurred among community-dwelling individuals, but with relatively lower frequencies. CONCLUSIONS: New opioid use was high among older adults with COPD. Potential safety concerns are raised by the degree and pattern of new opioid use, but further studies are needed to evaluate if adverse events are associated with opioid drug use in this older and respiratory-vulnerable population.

Benzodiazepine drug use and adverse respiratory outcomes among older adults with COPD.

Our purpose was to evaluate the association of new benzodiazepine use relative to non-use with adverse clinical respiratory outcomes among older adults with chronic obstructive pulmonary disease (COPD). This was a retrospective population-based cohort study of Ontario, Canada, residents between 2003 and 2010. A validated algorithm was applied to health administrative data to identify adults aged 66 years and older with COPD. Relative risks (RRs) of several clinically important respiratory outcomes were examined within 30 days of incident benzodiazepine use compared with non-use, applying propensity score matching. New benzodiazepine users were at significantly higher risk for outpatient respiratory exacerbations (RR 1.45, 95% CI 1.36-1.54) and emergency room visits for COPD or pneumonia (RR 1.92, 95% CI 1.69-2.18) compared to non-users. Risk of hospitalisation for COPD or pneumonia was also increased in benzodiazepine users, but was nonsignificant (RR 1.09, 95% CI 1.00-1.20). There were no significant differences in intensive care unit admissions between the two groups and all-cause mortality was slightly lower among new versus non-users. Benzodiazepines were associated with increased risk for several serious adverse respiratory outcomes among older adults with COPD. The findings suggest that decisions to use benzodiazepines in older patients with COPD need to consider potential adverse respiratory outcomes.

Sleep breathing disorder frequency, risk factors, and treatment among adults with cystic fibrosis.

BACKGROUND: Our understanding of the epidemiology of sleep breathing disorders among adults with cystic fibrosis (CF) is limited. Our purpose was to describe the frequency, risk factors and treatment of sleep breathing disorders among adults with CF. METHODS: This was a retrospective analysis of linked data from laboratory-based diagnostic polysomnography (PSG) undertaken at St. Michael's Hospital (Toronto, Canada) and the Canadian CF Registry. Adults (≥19 years old) with CF that underwent a diagnostic PSG at St. Michael's Hospital between 2002 and 2021 were included. Sleep breathing disorder frequency, risk factors, and treatment were described, using descriptive statistics and logistic regression. RESULTS: There were 42 patients included (33.3 % women and median age at diagnostic PSG was 34.7 years). Obstructive sleep apnea [OSA] was the most commonly observed sleep breathing disorder (found in 64.3 %), followed by sustained nocturnal hypoxemia (16.7 %), and sleep hypoventilation (9.5 %). Only 41 % of individuals with an elevated total apnea-hypopnea index were receiving positive airway pressure [PAP] therapy. Corticosteroid use (either oral or inhaled) was the only factor with a significant positive association with presence of any sleep breathing disorder (odds ratio 5.00, 95 % confidence interval 1.28-22.78). CONCLUSIONS: Among adults with CF, OSA occurs more commonly than previously appreciated and the majority of sleep breathing disorders were not being treated with PAP or supplemental oxygen. Management of sleep breathing disorders among adults with CF reflects a potentially important care gap, but further research is needed to determine the health impacts of treating sleep breathing disorders in CF.

Mode of delivery and birth outcomes before and during COVID-19 -A population-based study in Ontario, Canada.

There is lack of clarity on whether pregnancies during COVID-19 resulted in poorer mode of delivery and birth outcomes in Ontario, Canada. We aimed to compare mode of delivery (C-section), birth (low birthweight, preterm birth, NICU admission), and health services use (HSU, hospitalizations, ED visits, physician visits) outcomes in pregnant Ontario women before and during COVID-19 (pandemic periods). We further stratified for pre-existing chronic diseases (asthma, eczema, allergic rhinitis, diabetes, hypertension). Deliveries before (Jun 2018-Feb 2020) and during (Jul 2020-Mar 2022) pandemic were from health administrative data. We used multivariable logistic regression analyses to estimate adjusted odds ratios (aOR) of delivery and birth outcomes, and negative binomial regression for adjusted rate ratios (aRR) of HSU. We compared outcomes between pre-pandemic and pandemic periods. Possible interactions between study periods and covariates were also examined. 323,359 deliveries were included (50% during pandemic). One in 5 (18.3%) women who delivered during the pandemic had not received any COVID-19 vaccine, while one in 20 women (5.2%) lab-tested positive for COVID-19. The odds of C-section delivery during the pandemic was 9% higher (aOR = 1.09, 95% CI: 1.08-1.11) than pre-pandemic. The odds of preterm birth and NICU admission were 15% (aOR = 0.85, 95% CI: 0.82-0.87) and 10% lower (aOR = 0.90, 95% CI: 0.88-0.92), respectively, during COVID-19. There was a 17% reduction in ED visits but a 16% increase in physician visits during the pandemic (aRR = 0.83, 95% CI: 0.81-0.84 and aRR = 1.16, 95% CI: 1.16-1.17, respectively). These aORs and aRRs were significantly higher in women with pre-existing chronic conditions. During the pandemic, healthcare utilization, especially ED visits (aRR = 0.83), in pregnant women was lower compared to before. Ensuring ongoing prenatal care during the pandemic may reduce risks of adverse mode of delivery and the need for acute care during pregnancy.

An analysis of sex differences in pulmonary arteriovenous malformation presentation, complications and management in a large, multinational registry of patients with hereditary haemorrhagic telangiectasia.

This large, multinational, sex-based analysis among individuals with HHT showed that pulmonary AVM frequency, physical characteristics, presentation, complications and management do not generally significantly differ between males and females https://bit.ly/3TNLA6v.

Cannabis use and risks of respiratory and all-cause morbidity and mortality: a population-based, data-linkage, cohort study.

INTRODUCTION: Although cannabis is frequently used worldwide, its impact on respiratory health is characterised by controversy. OBJECTIVE: To evaluate the association between cannabis use and respiratory-related emergency room (ER) visits and hospitalisations. METHODS: A retrospective, population-based, cohort study was carried out, linking health survey and health administrative data for residents of Ontario, Canada, aged 12-65 years, between January 2009 and December 2015. Individuals self-reporting cannabis use within the past year were matched to control individuals (people who reported never using cannabis, or used cannabis only once, and more than 12 months ago) in upwards of a 1:3 ratio on 31 different variables, using propensity score matching methods. Respiratory-related and all-cause ER visits or hospitalisations, and all-cause mortality, were evaluated up to 12 months following the index date. RESULTS: We identified 35 114 individuals who had either used cannabis in the past year or were controls, of whom 6425 (18.3%) used cannabis in the past year. From this group, 4807 (74.8%) were propensity-score matched to 10 395 control individuals. In the propensity score matched cohort, there was no significant difference in odds of respiratory-related ER visit or hospitalisation between cannabis users and the control group (OR 0.91, 95% CI 0.77 to 1.09). Compared with control individuals, cannabis users had significantly increased odds of all-cause ER visit or hospitalisation (OR 1.22, 95% CI 1.13 to 1.31) and there was no significant difference with respect to all-cause mortality (OR 0.99, 95% CI 0.49 to 2.02). CONCLUSIONS: Although no significant association was observed between cannabis use and respiratory-related ER visits or hospitalisations, the risk of an equally important morbidity outcome, all-cause ER visit or hospitalisation, was significantly greater among cannabis users than among control individuals. Therefore, cannabis use is associated with increased risk for serious adverse health events and its recreational consumption is not benign.