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Importance: Drug shortages are a chronic and worsening issue that compromises patient safety. Despite the destabilizing impact of the COVID-19 pandemic on pharmaceutical production, it remains unclear whether issues affecting the drug supply chain were more likely to result in meaningful shortages during the pandemic., Objective: To estimate the proportion of supply chain issue reports associated with drug shortages overall and with the COVID-19 pandemic., Design, Setting, and Participants: This longitudinal cross-sectional study used data from the IQVIA Multinational Integrated Data Analysis database, comprising more than 85% of drug purchases by US pharmacies from wholesalers and manufacturers, from 2017 to 2021. Data were analyzed from January to May 2023., Exposure: Presence of a supply chain issue report to the US Food and Drug Administration or the American Society of Health-Systems Pharmacists (ASHP)., Main Outcomes and Measures: The main outcome was drug shortage, defined as at least 33% decrease in units purchased within 6 months of a supply chain issue report. Random-effects logistic regression models compared the marginal odds of shortages for drugs with vs without reports. Interaction terms assessed heterogeneity prior to vs during the COVID-19 pandemic and by drug characteristics (formulation, age, essential medicine status, clinician- vs self-administered, sales volume, and number of manufacturers)., Results: A total of 571 drugs exposed to 731 supply chain issue reports were matched to 7296 comparison medications with no reports. After adjusting for drug characteristics, 13.7% (95% CI, 10.4%-17.8%) of supply chain issue reports were associated with subsequent drug shortages vs 4.1% (95% CI, 3.6%-4.8%) of comparators (marginal odds ratio [mOR], 3.7 [95% CI, 2.6-5.1]). Shortages increased among both drugs with and without reports in February to April 2020 (34.2% of drugs with supply chain issue reports and 9.5% of comparison drugs; mOR, 4.9 [95% CI, 2.1-11.6]), and then decreased after May 2020 (9.8% of drugs with reports and 3.6% of comparison drugs; mOR, 2.9 [95% CI, 1.6-5.3]). Significant associations were identified by formulation (parenteral mOR, 1.9 [95% CI, 1.1-3.2] vs oral mOR, 5.4 [95% CI, 3.3-8.8]; P for interaction = .008), WHO essential medicine status (essential mOR, 2.2 [95% CI, 1.3-5.2] vs nonessential mOR, 4.6 [95% CI, 3.2-6.7]; P = .02), and for brand-name vs generic status (brand-name mOR, 8.1 [95% CI, 4.0-16.0] vs generic mOR, 2.4 [95% CI, 1.7-3.6]; P = .002)., Conclusions and Relevance: In this national cross-sectional study, supply chain issues associated with drug shortages increased at the beginning of the COVID-19 pandemic. Ongoing policy work is needed to protect US drug supplies from future shocks and to prioritize clinically valuable drugs at greatest shortage risk.

Importance: Virtual visits became more common after the COVID-19 pandemic, but it is unclear in what context they are best used., Objective: To investigate whether there was a difference in subsequent emergency department use between patients who had a virtual visit with their own family physician vs those who had virtual visits with an outside physician., Design, Setting, and Participants: This propensity score-matched cohort study was conducted among all Ontario residents attached to a family physician as of April 1, 2021, who had a virtual family physician visit in the subsequent year (to March 31, 2022)., Exposure: The type of virtual family physician visit, with own or outside physician, was determined. In a secondary analysis, own physician visits were compared with visits with a physician working in direct-to-consumer telemedicine., Main Outcome and Measure: The primary outcome was an emergency department visit within 7 days after the virtual visit., Results: Among 5 229 240 Ontario residents with a family physician and virtual visit, 4 173 869 patients (79.8%) had a virtual encounter with their own physician (mean [SD] age, 49.3 [21.5] years; 2 420 712 females [58.0%]) and 1 055 371 patients (20.2%) had an encounter with an outside physician (mean [SD] age, 41.8 [20.9] years; 605 614 females [57.4%]). In the matched cohort of 1 885 966 patients, those who saw an outside physician were 66% more likely to visit an emergency department within 7 days than those who had a virtual visit with their own physician (30 748 of 942 983 patients [3.3%] vs 18 519 of 942 983 patients [2.0%]; risk difference, 1.3% [95% CI, 1.2%-1.3%]; relative risk, 1.66 [95% CI, 1.63-1.69]). The increase in the risk of emergency department visits was greater when comparing 30 216 patients with definite direct-to-consumer telemedicine visits with 30 216 patients with own physician visits (risk difference, 4.1% [95% CI, 3.8%-4.5%]; relative risk, 2.99 [95% CI, 2.74-3.27])., Conclusions and Relevance: In this study, patients whose virtual visit was with an outside physician were more likely to visit an emergency department in the next 7 days than those whose virtual visit was with their own family physician. These findings suggest that primary care virtual visits may be best used within an existing clinical relationship.

Importance: Opioid-related harms constitute a major public health crisis in the US, and this crisis has worsened during the COVID-19 pandemic., Objectives: To characterize the societal burden of unintentional opioid-related deaths in the US and describe changing mortality patterns during the COVID-19 pandemic., Design, Setting, and Participants: A serial cross-sectional study examined all unintentional opioid-related deaths in the US, evaluated annually from calendar years 2011 to 2021., Main Outcomes and Measures: The public health burden of opioid toxicity-related deaths was estimated in 2 ways. First, the proportion of all deaths that were attributable to unintentional opioid toxicity by year (2011, 2013, 2015, 2017, 2019, and 2021) and age group (15-19, 20-29, 30-39, 40-49, 50-59, and 60-74 years) were calculated, using age-specific estimates of all-cause mortality as the denominator. Second, the total years of life lost (YLL) due to unintentional opioid toxicity was estimated, overall and by sex and age group, for each year studied., Results: Among the 422 605 unintentional deaths due to opioid toxicity between 2011 and 2021, the median age of the individuals was 39 (IQR, 30-51) years, and 69.7% were male. The number of unintentional deaths due to opioid toxicity increased 289% over the study period, from 19 395 (2011) to 75 477 (2021). Similarly, the percentage of all deaths that were attributed to opioid toxicity increased from 1.8% in 2011 to 4.5% in 2021. By 2021, opioid toxicity was responsible for 10.2% of all deaths among those aged 15 to 19 years, 21.7% of deaths among those aged 20 to 29 years, and 21.0% of deaths among those aged 30 to 39 years. The YLL due to opioid toxicity increased 276% over the study period, from 777 597 in 2011 to 2 922 497 in 2021. While YLL plateaued between 2017 (7.0 YLL per 1000) and 2019 (7.2 YLL per 1000), it increased by 62.9% between 2019 and 2021 coincident with the COVID-19 pandemic, reaching 11.7 YLL per 1000 population. This relative increase was similar across all age groups and sexes with the exception of those aged 15 to 19 years, in whom the YLL nearly tripled, from 1.5 to 3.9 YLL per 1000 population., Conclusions and Relevance: In this cross-sectional study, deaths due to opioid toxicity increased substantially during the COVID-19 pandemic. By 2021, 1 of every 22 deaths in the US was attributable to unintentional opioid toxicity, underscoring the urgent need to support people at risk of substance-related harm, particularly men, younger adults, and adolescents.

Importance: The incidence of SARS-CoV-2 infection, including among individuals who have received 2 doses of COVID-19 vaccine, increased substantially following the emergence of the Omicron variant in Ontario, Canada. Understanding the estimated effectiveness of 2 or 3 doses of COVID-19 vaccine against outcomes associated with Omicron and Delta infections may aid decision-making at the individual and population levels., Objective: To estimate vaccine effectiveness (VE) against symptomatic infections due to the Omicron and Delta variants and severe outcomes (hospitalization or death) associated with these infections., Design, Setting, and Participants: This test-negative case-control study used linked provincial databases for SARS-CoV-2 laboratory testing, reportable disease, COVID-19 vaccination, and health administration in Ontario, Canada. Participants were individuals aged 18 years or older who had COVID-19 symptoms or severe outcomes (hospitalization or death) and were tested for SARS-CoV-2 between December 6 and 26, 2021., Exposures: Receipt of 2 or 3 doses of the COVID-19 vaccine and time since last dose., Main Outcomes and Measures: The main outcomes were symptomatic Omicron or Delta infection and severe outcomes (hospitalization or death) associated with infection. Multivariable logistic regression was used to estimate the effectiveness of 2 or 3 COVID-19 vaccine doses by time since the latest dose compared with no vaccination. Estimated VE was calculated using the formula VE = (1 - [adjusted odds ratio]) × 100%., Results: Of 134 435 total participants, 16 087 were Omicron-positive cases (mean [SD] age, 36.0 [14.1] years; 8249 [51.3%] female), 4261 were Delta-positive cases (mean [SD] age, 44.2 [16.8] years; 2199 [51.6%] female), and 114 087 were test-negative controls (mean [SD] age, 42.0 [16.5] years; 67 884 [59.5%] female). Estimated VE against symptomatic Delta infection decreased from 89% (95% CI, 86%-92%) 7 to 59 days after a second dose to 80% (95% CI, 74%-84%) after 240 or more days but increased to 97% (95% CI, 96%-98%) 7 or more days after a third dose. Estimated VE against symptomatic Omicron infection was 36% (95% CI, 24%-45%) 7 to 59 days after a second dose and 1% (95% CI, -8% to 10%) after 180 days or longer, but 7 or more days after a third dose, it increased to 61% (95% CI, 56%-65%). Estimated VE against severe outcomes was high 7 or more days after a third dose for both Delta (99%; 95% CI, 98%-99%) and Omicron (95%; 95% CI, 87%-98%)., Conclusions and Relevance: In this study, in contrast to high estimated VE against symptomatic Delta infection and severe outcomes after 2 doses of COVID-19 vaccine, estimated VE was modest and short term against symptomatic Omicron infection but better maintained against severe outcomes. A third dose was associated with improved estimated VE against symptomatic infection and with high estimated VE against severe outcomes for both variants. Preventing infection due to Omicron and potential future variants may require tools beyond the currently available vaccines.

Importance: Use of stimulants continues to increase among older adults for a variety of indications. An association between stimulant use and increased risk of cardiovascular (CV) events has been established among children and young adults, but few studies have explored the risk of CV events among older patients, a group with increased baseline risk., Objective: To evaluate the association between stimulant use and risk of CV events among older adults., Design, Setting, and Participants: This propensity score-matched cohort study, with 4 nonusers per 1 user, was conducted from July 1, 2017, to June 27, 2019, using data from population-based health care databases from Ontario, Canada, from January 1, 2002, to December 31, 2016. Included individuals were outpatients aged 66 years or older., Exposures: Initiation of a prescription stimulant., Main Outcomes and Measures: The primary outcome was a CV event, defined as a composite of emergency department visit or hospitalization for myocardial infarction, stroke or transient ischemic attack (TIA), or ventricular arrhythmia. Risk of CV event was assessed at 30 days, 180 days, and 365 days after initiation of stimulants from Cox proportional hazard models. A secondary analysis assessed each component of the primary outcome separately., Results: Among 6457 older adults who initiated a prescription stimulant (ie, the exposed group) and 24 853 older adults who did not initiate such treatment (ie, the unexposed group), the distribution of baseline patient characteristics was well balanced after matching (sex: 3173 [49.1%] men vs 12 112 [48.7%] men; standardized difference, 0.01; median [IQR] age: 74 [69-80] years vs 74 [69-80] years; standardized difference, 0.01). Within this cohort, there were 932 CV events during the 365-day follow-up (5.11 events per 100 person-years among individuals who initiated stimulants). In the primary analysis, stimulant initiation was associated with increased risk of CV events at 30 days (hazard ratio [HR], 1.4; 95% CI, 1.1-1.8) but not at 180 days (HR, 1.2; 95% CI, 0.9-1.6) or 365 days (HR, 1.0; 95% CI, 0.6 to 1.8). In the secondary analysis, stimulant initiation was associated with increased risk of ventricular arrhythmias (HR, 3.0; 95% CI, 1.1-8.7) and stroke or TIA (HR, 1.6; 95% CI, 1.1-2.1) at 30 days., Conclusions and Relevance: This cohort study found that stimulant use was associated with an early increase in CV events among older adults with no association for long-term use.

Importance: COVID-19 has had devastating effects on the health and well-being of older adult residents and health care professionals in nursing homes. Uncertainty about the associated consequences of these adverse effects on the use of medications common to this care setting remains., Objective: To examine the association between the COVID-19 pandemic and prescription medication changes among nursing home residents., Design, Setting, and Participants: This population-based cohort study with an interrupted time-series analysis used linked health administrative data bases for residents of all nursing homes (N = 630) in Ontario, Canada. During the observation period, residents were divided into consecutive weekly cohorts. The first observation week was March 5 to 11, 2017; the last observation week was September 20 to 26, 2020., Exposures: Onset of the COVID-19 pandemic on March 1, 2020., Main Outcomes and Measures: Weekly proportion of residents dispensed antipsychotics, benzodiazepines, antidepressants, anticonvulsants, opioids, antibiotics, angiotensin receptor blockers (ARBs), and angiotensin-converting enzyme (ACE) inhibitors. Autoregressive integrated moving average models with step and ramp intervention functions tested for level and slope changes in weekly medication use after the onset of the pandemic and were fit on prepandemic data for projected trends., Results: Across study years, the annual cohort size ranged from 75 850 to 76 549 residents (mean [SD] age, 83.4 [10.8] years; mean proportion of women, 68.9%). A significant increased slope change in the weekly proportion of residents who were dispensed antipsychotics (parameter estimate [β] = 0.051; standard error [SE] = 0.010; P < .001), benzodiazepines (β = 0.026; SE = 0.003; P < .001), antidepressants (β = 0.046; SE = 0.013; P < .001), trazodone hydrochloride (β = 0.033; SE = 0.010; P < .001), anticonvulsants (β = 0.014; SE = 0.006; P = .03), and opioids (β = 0.038; SE = 0.007; P < .001) was observed. The absolute difference in observed vs estimated use in the last week of the pandemic period ranged from 0.48% (for anticonvulsants) to 1.52% (for antipsychotics). No significant level or slope changes were found for antibiotics, ARBs, or ACE inhibitors., Conclusions and Relevance: In this population-based cohort study, statistically significant increases in the use of antipsychotics, benzodiazepines, antidepressants, anticonvulsants, and opioids followed the onset of the COVID-19 pandemic, although absolute differences were small. There were no significant changes for antibiotics, ARBs, or ACE inhibitors. Studies are needed to monitor whether changes in pharmacotherapy persist, regress, or accelerate during the course of the pandemic and how these changes affect resident-level outcomes.

Importance: Strategies to reduce the inappropriate prescription of antipsychotics have been the focus of recent attention but have shown considerable variation in their effectiveness., Objective: To evaluate the effectiveness of academic detailing in nursing homes targeting appropriate prescribing of antipsychotics., Design, Setting, and Participants: We conducted a pragmatic, cluster randomized clinical trial comparing the effect of academic detailing vs usual care on prescribing antipsychotics in 40 nursing homes with 5363 residents in Ontario, Canada. Data were collected from October 2015 to March 2016 and analyzed from April to August 2018. Primary analyses were conducted using intention to treat., Intervention: Academic detailing delivered by health professionals (eg, nurses or pharmacists) who arranged meetings (with administrators, physicians, pharmacists, nurses, and support workers), presentations, group visits (with 2-6 clinicians), and 1-on-1 visits (traditional academic detailing visits). Academic detailers had direct and ongoing contact with the nursing homes from the time of launch., Main Outcomes and Measures: The primary outcome, defined at the level of the resident, was whether continuous antipsychotics were dispensed in the past week. Secondary outcomes included prescribing of other psychotropic medications and clinical outcomes and scores. Prescribing outcomes were assessed at baseline and at 3, 6, and 12 months, and clinical outcomes and scores were assessed at baseline and 3 and 6 months., Results: A total of 40 nursing homes with 5363 residents were randomized, with 18 intervention homes (45.0%; 2303 [42.9%] residents) and 22 control homes (55.0%; 3060 [57.1%] residents). Participants in the intervention and control groups had similar median (interquartile range) age (86 [79-91] years vs 85 [78-90] years) and sex (674 [29.3%] men vs 970 [31.7%] men). At 12 months, there was no statistically significant difference in the frequency of daily antipsychotic use (intervention: 569 patients [25.2%]; control: 769 [25.6%]; odds ratio, 1.06; 95% CI, 0.93-1.20; P = .49). There were no significant differences in the rates of health care utilization, but the intervention group did experience a statistically significant reduction in pain compared with the control group (mean [SD] pain score, 0.30 [0.59] vs 0.38 [0.66]; P < .001) and depression (mean [SD] Depression Rating Scale score, 2.18 [2.37] vs 2.81 [2.65]; P < .001) at 6 months., Conclusions and Relevance: The intervention did not further reduce antipsychotic prescribing in nursing homes beyond system-level secular trends occurring alongside usual care. Our findings highlight the need for a more targeted approach to quality improvement strategies, including academic detailing, that account for the timing and topic of interventions., Trial Registration: ClinicalTrials.gov Identifier: NCT02604056.

Importance: The renin-angiotensin system has been implicated in mood disorders. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are among the most commonly used medications, yet their effects on mental health outcomes, particularly suicide, are poorly understood. This study examined the association between suicide and exposure to ACEIs and ARBs. Because of differences in their mode of action, it was speculated that ARBs would be associated with a higher risk of suicide than ACEIs., Objective: To examine the association between suicide and exposure to ARBs compared with ACEIs., Design, Setting, and Participants: This population-based nested case-control study of individuals aged 66 years and older used administrative claims databases in Ontario, Canada, from January 1, 1995, to December 31, 2015. Data analysis was performed from January to April 2019. Cases were individuals who died by suicide within 100 days of receiving an ACEI or ARB. The date of death served as the index date. For each case, 4 controls were identified and matched by age (within 1 year), sex, and presence of hypertension and diabetes. All individuals received an ACEI or ARB within 100 days before the index date., Exposures: Use of an ACEI or ARB., Main Outcomes and Measures: Conditional logistic regression was used to estimate odds ratios for the association between suicide and exposure to ARBs compared with ACEIs., Results: Nine hundred sixty-four cases were matched to 3856 controls. The median (interquartile range) age of cases and controls was 76 (70-82) years. Most cases (768 [79.7%]) and controls (3068 [79.6%]) were men. Among cases, 260 (26.0%) were exposed to ARBs, and 704 (18.4%) were exposed to ACEIs. Among controls, 741 (74.0%) were exposed to ARBs, and 3115 (81.6%) were exposed to ACEIs. Compared with ACEI exposure, ARB exposure was associated with higher risk of death by suicide (adjusted odds ratio, 1.63; 95% CI, 1.33-2.00). The findings were consistent in a sensitivity analysis excluding individuals with a history of self-harm (odds ratio, 1.60; 95% CI, 1.29-1.98)., Conclusions and Relevance: The use of ARBs may be associated with an increased risk of suicide compared with ACEIs. Preferential use of ACEIs over ARBs should be considered whenever possible, particularly in patients with severe mental health illness.

Importance: Opioid prescribing and overdose are leading public health problems in North America, yet the precise public health burden has not been quantified., Objective: To examine the burden of opioid-related mortality across the United States over time., Design, Setting, and Participants: This study used a serial cross-sectional design in which cross sections were examined at different time points to investigate deaths from opioid-related causes in the United States between January 1, 2001, and December 31, 2016., Main Outcomes and Measures: Opioid-related deaths, defined as those in which a prescription or illicit opioid contributed substantially to an individual's cause of death as determined by death certificates. We compared the percentage of deaths attributable to opioids and the associated person-years of life lost by age group., Results: Between 2001 and 2016, the number of opioid-related deaths in the United States increased by 345%, from 9489 to 42 245 deaths (33.3 to 130.7 deaths per million population). By 2016, men accounted for 67.5% of all opioid-related deaths, and the median (interquartile range) age at death was 40 (30-52) years. The percentage of deaths attributable to opioids increased in a similar fashion. In 2001, 0.4% of deaths (1 in 255) were opioid related, rising to 1.5% of deaths (1 in 65) by 2016, an increase of 292%. This burden was highest among adults aged 24 to 35 years. In this age group, 20.0% of deaths were attributable to opioids in 2016. Among those aged 15 to 24 years, 12.4% of deaths were attributable to opioids in 2016. Overall, opioid-related deaths resulted in 1 681 359 years of life lost (5.2 per 1000 population) in the United States in 2016, most of which (1 125 711 years of life lost) were among men. Adults aged 25 to 34 years had 12.9 years of life lost per 1000 population, and those aged 35 to 44 years had 9.9 years of life lost per 1000 population., Conclusions and Relevance: Premature death from opioid-related causes imposes an enormous public health burden across the United States. The recent increase in deaths attributable to opioids among those aged 15 to 34 years highlights a need for targeted programs and policies that focus on improved addiction care and harm reduction measures in this high-risk population.