Opioid-related deaths between 2019 and 2021 across 9 Canadian provinces and territories.

BACKGROUND: The drug toxicity crisis continues to accelerate across Canada, with rapid increases in opioid-related harms following the onset of the COVID-19 pandemic. We sought to describe trends in the burden of opioid-related deaths across Canada throughout the pandemic, comparing these trends by province or territory, age, and sex. METHODS: We conducted a repeated cross-sectional analysis of accidental opioid-related deaths between Jan. 1, 2019, and Dec. 31, 2021, across 9 Canadian provinces and territories using aggregated national data. Our primary measure was the burden of premature opioid-related death, measured by potential years of life lost. Our secondary measure was the proportion of all deaths attributable to opioids; we used the Cochrane-Armitage test for trend to compare proportions. RESULTS: Between 2019 and 2021, the annual number of opioid-related deaths increased from 3007 to 6222 and years of life lost increased from 126 115 to 256 336 (from 3.5 to 7.0 yr of life lost per 1000 population). In 2021, the highest number of years of life lost was among males (181 525 yr) and people aged 30-39 years (87 045 yr). In 2019, we found that 1.7% of all deaths among those younger than 85 years were related to opioids, rising to 3.2% in 2021. Significant increases in the proportion of deaths related to opioids were observed across all age groups (p < 0.001), representing 29.3% and 29.0% of deaths among people aged 20-29 and 30-39 years in 2021, respectively. INTERPRETATION: Across Canada, the burden of premature opioid-related deaths doubled between 2019 and 2021, representing more than one-quarter of deaths among younger adults. The disproportionate loss of life in this demographic group highlights the critical need for targeted prevention efforts.

Alpha-1 adrenergic antagonists and the risk of hospitalization or death in non-hospitalized patients with COVID-19: A population-based study.

BACKGROUND: Alpha-1 receptor antagonists may interfere with IL-6 signaling and could therefore be a potential treatment for COVID-19. However, the effectiveness of these drugs in mitigating the risk of clinical deterioration among non-hospitalized patients with COVID-19 is unknown. OBJECTIVES: The aim of this study is to examine the association between alpha-1 antagonist exposure and the 30-day risk of a hospital encounter or death in nonhospitalized patients with COVID-19. METHODS: We conducted a population-based cohort study of Ontario residents aged 35 years and older who were eligible for public drug coverage and who had a positive test for SARS-CoV-2 between January 1, 2020, and March 1, 2021. We matched each individual receiving an alpha-1 antagonist at the time of their positive test with two non-exposed individuals using propensity scores. Our outcome was a composite of a hospital admission, emergency department visit, or death, 1 to 30 days following the positive test. RESULTS: We matched 3289 alpha-1 antagonist exposed patients to 6189 unexposed patients. Overall, there was no difference in the 30-day risk of the primary outcome among patients exposed to alpha-1 antagonists at the time of their diagnosis relative to unexposed individuals (28.8% vs. 28.0%; OR 1.00, 95% CI 0.91 to 1.11). In a secondary analysis, individuals exposed to alpha-1 antagonists had a lower risk of death in the 30 days following a COVID diagnosis (OR 0.79; 95% CI 0.66 to 0.93). CONCLUSION: Alpha-1 antagonists did not mitigate the 30-day risk of clinical deterioration in non-hospitalized patients with COVID-19. Our findings do not support the general repurposing of alpha-1 antagonists as a treatment for such patients, although there may be subgroups of patients in whom further research is warranted.

Characteristics of primary care practices by proportion of patients unvaccinated against SARS-CoV-2: a cross-sectional cohort study.

BACKGROUND: Variations in primary care practices may explain some differences in health outcomes during the COVID-19 pandemic. We sought to evaluate the characteristics of primary care practices by the proportion of patients unvaccinated against SARS-CoV-2. METHODS: We conducted a population-based, cross-sectional cohort study using linked administrative data sets in Ontario, Canada. We calculated the percentage of patients unvaccinated against SARS-CoV-2 enrolled with each comprehensive-care family physician, ranked physicians according to the proportion of patients unvaccinated, and identified physicians in the top 10% (v. the other 90%). We compared characteristics of family physicians and their patients in these 2 groups using standardized differences. RESULTS: We analyzed 9060 family physicians with 10 837 909 enrolled patients. Family physicians with the largest proportion (top 10%) of unvaccinated patients (n = 906) were more likely to be male, to have trained outside of Canada, to be older, and to work in an enhanced fee-for-service model than those in the remaining 90%. Vaccine coverage (≥ 2 doses of SARS-CoV-2 vaccine) was 74% among patients of physicians with the largest proportion of unvaccinated patients, compared with 87% in the remaining patient population. Patients in the top 10% group tended to be younger and live in areas with higher levels of ethnic diversity and immigration and lower incomes. INTERPRETATION: Primary care practices with the largest proportion of patients unvaccinated against SARS-CoV-2 served marginalized communities and were less likely to use team-based care models. These findings can guide resource planning and help tailor interventions to integrate public health priorities within primary care practices.

Drug Shortages Prior to and During the COVID-19 Pandemic.

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.

Effects of the valsartan recall on heart failure patients: A nationwide analysis.

BACKGROUND: Valsartan is commonly used for cardiac conditions. In 2018, the Food and Drug Administration recalled generic valsartan due to the detection of impurities. Our objective was to determine if heart failure patients receiving valsartan at the recall date had a greater likelihood of unfavorable outcomes than patients using comparable antihypertensives. METHODS: We conducted a cohort study of Optum's de-identified Clinformatics® Datamart (July 2017-January 2019). Heart failure patients with commercial or Medicare Advantage insurance who received valsartan were compared to persons who received non-recalled angiotensin receptor blockers (ARBs) and angiotensin converting enzyme-inhibitors (ACE-Is) for 1 year prior and including the recall date. Outcomes included a composite for all-cause hospitalization, emergency department (ED), and urgent care (UC) use and a measure of cardiac events which included hospitalizations for acute myocardial infarction and hospitalizations/ED/UC visits for stroke/transient ischemic attack, heart failure or hypertension at 6-months post-recall. Cox proportional hazard models with propensity score weighting compared the risk of outcomes between groups. RESULTS: Of the 87 130 adherent patients, 15% were valsartan users and 85% were users of non-recalled ARBs/ACE-Is. Valsartan use was not associated with an increased risk of all-cause hospitalization/ED/UC use six-months post-recall (HR 1.00; 95% CI 0.96-1.03), compared with individuals taking non-recalled ARBs/ACE-Is. Similarly, cardiac events 6-months post-recall did not differ between individuals on valsartan and non-recalled ARBs/ACE-Is (HR 1.04; 95% CI 0.97-1.12). CONCLUSIONS: The valsartan recall did not affect short-term outcomes of heart failure patients. However, the recall potentially disrupted the medication regimens of patients, possibly straining the healthcare system.

Cost-effectiveness of the top 100 drugs by public spending in Canada, 2015-2021: a repeated cross-sectional study.

OBJECTIVES: To assess the distribution and spending by cost-effectiveness category among those drugs with the highest public spending levels in Canada. DESIGN: Repeated cross-sectional study. SETTING: The Canadian provinces of Manitoba, Ontario, New Brunswick, Nova Scotia, Prince Edward Island and Newfoundland. MAIN OUTCOMES AND MEASURES: Cost-effectiveness assessments by the Canadian Agency for Drugs and Technologies in Health (CADTH) for top-100 brand-name outpatient drugs by gross public plan spending in any year between 2015 and 2021 in Canada Institute for Health Information's National Prescription Drug Utilization Information System data. Gross public plan spending by cost-effectiveness category. RESULTS: From 2015 to 2021, 152 brand-name drugs occupied a top-100 rank and were included in the analysis. Of those, 117 had been assessed by CADTH. During the 7-year period, there was an increase in both top-100 drugs with cost-effective (from 18 to 24) and cost-ineffective (from 29 to 41) assessments, while drugs not assessed or with an unclear assessment declined (from 31 to 19 and from 22 to 16, respectively). As a share of spending on top-100 drugs with an assessment, spending on cost-effective drugs was mostly stable at 40%-46% from 2015 to 2021, while spending on cost-ineffective drugs increased from 30% to 45%. CONCLUSION: A large and growing share of public drug spending has been allocated to cost-ineffective drugs in Canada. Dedicating large budgets to such treatments prevents spending with greater health impact elsewhere in the healthcare system and could restrain the capacity to pay for groundbreaking pharmaceutical innovation in the future.

Trends in opioid toxicities among people with and without opioid use disorder and the impact of the COVID-19 pandemic in Ontario, Canada: A population-based analysis.

BACKGROUND: Across Canada, the COVID-19 pandemic occurred amidst an ongoing drug toxicity crisis. Although elevated rates of substance-related harms have been observed nationally, it remains unknown if the pandemic state of emergency led to disproportionate increases in opioid toxicities among people with opioid use disorder (OUD) compared to those without. METHODS: We conducted a population-based repeated cross-sectional time series analysis of fatal and non-fatal opioid toxicities between January 1, 2014, and December 31, 2021, in Ontario, Canada. We used interventional autoregressive integrated moving average models to examine the impact of the pandemic on monthly rates of opioid toxicities per 100,000 Ontario residents stratified by people with and without OUD. RESULTS: We identified 80,296 opioid toxicities of which 53.5 % occurred among people with OUD. Among 52,052 unique individuals, 60.5 % were male and 46.2 % were 25-44 years old. Between January 2014 and December 2021, the rate of opioid toxicities increased from 2.6 to 10.5 per 100,000 (rate ratio [RR]=4.07). The magnitude of this increase differed among people with OUD (0.8 to 7.4 per 100,000; RR=9.35) and without OUD (1.8 to 3.1 per 100,000; RR=1.74). We observed a significant ramp increase in the overall rate of opioid toxicities following the declaration of the pandemic emergency in March 2020 (+0.19 per 100,000 monthly, 95 % CI: 0.029, 0.36, p = 0.021). In a stratified analysis, we found a similar ramp increase among people with OUD (+0.19 per 100,000 monthly, 95 % CI: 0.10, 0.28, p < 0.001); however, this was not observed among people without OUD (p = 0.95). CONCLUSIONS: The rate of opioid toxicities accelerated across Ontario following the pandemic-related state of emergency, with the majority of this increase among people with OUD. The important differences observed among people with OUD compared with those without, highlights the critical need for improved access to harm reduction and treatment interventions among this population.

A multiprovincial retrospective analysis of the incidence of myocarditis or pericarditis after mRNA vaccination compared to the incidence after SARS-CoV-2 infection.

Objective: To compare myocarditis/pericarditis risk after COVID-19 mRNA vaccination versus SARS-CoV-2 infection, and to assess if myocarditis/pericarditis risk varies by vaccine dosing interval. Methods: In this retrospective cohort study, we used linked databases in Quebec, Ontario, and British Columbia between January 26, 2020, and September 9, 2021. We included individuals aged 12 or above who received an mRNA vaccine as the second dose or were SARS-CoV-2-positive by RT-PCR. The outcome was hospitalization/emergency department visit for myocarditis/pericarditis within 21 days of exposure. We calculated age- and sex-stratified incidence ratios (IRs) of myocarditis/pericarditis following mRNA vaccination versus SARS-CoV-2 infection. We also calculated myocarditis/pericarditis incidence by vaccine type, homologous/heterologous schedule, and dosing interval. We pooled province-specific estimates using meta-analysis. Results: Following 18,860,817 mRNA vaccinations and 860,335 SARS-CoV-2 infections, we observed 686 and 160 myocarditis/pericarditis cases, respectively. Myocarditis/pericarditis incidence was lower after vaccination than infection (IR [BNT162b2/SARS-CoV-2], 0.14; 95%CI, 0.07-0.29; IR [mRNA-1273/SARS-CoV-2], 0.28; 95%CI, 0.20-0.39). Within the vaccinated cohort, myocarditis/pericarditis incidence was lower with longer dosing intervals; IR (56 or more days/15-30 days) was 0.28 (95%CI, 0.19-0.41) for BNT162b2 and 0.26 (95%CI, 0.18-0.38) for mRNA-1273. Conclusion: Myocarditis/pericarditis risk was lower after mRNA vaccination than SARS-CoV-2 infection, and with longer intervals between primary vaccine doses.

Trends in Phenylephrine and Pseudoephedrine Sales in the US.

This study examines purchasing patterns regarding oral decongestants, concerns about their efficacy, and the need for timelier postmarket evaluation.

Patterns of publicly funded naltrexone use among patients diagnosed with alcohol use disorder in Ontario.

AIMS: Naltrexone is recommended first-line to manage alcohol use disorder (AUD). With previous studies indicating poor retention on naltrexone, we determined duration of naltrexone use and assessed the association between prescription setting and time to discontinuation in Ontario. METHODS: We conducted a retrospective population-based cohort study among Ontario public drug beneficiaries diagnosed with AUD who initiated publicly funded naltrexone from June 2018 to September 2019. The primary outcome was time to naltrexone discontinuation, with a secondary analysis assessing receipt of at least one prescription refill. We used Cox proportional hazards models and logistic regression to test the association between prescription setting and each medication persistence outcome. RESULTS: Among 2531 new naltrexone patients with AUD, the median duration of naltrexone use was 31 days and 394 (15.6%) continued naltrexone for 6 months or longer. There was no association between setting of initiation and duration of naltrexone use; however, those initiating naltrexone following an acute inpatient hospital stay were more likely to fill a second prescription (aOR 1.43, 95% CI 0.96-2.14), while those initiating after an ED visit were less likely to be dispensed a second prescription (aOR = 0.69, 95% CI 0.52-0.90) compared to those starting in a physician's office. CONCLUSION: Persistence on naltrexone to treat an AUD is low, regardless of the setting of initiation. Further research is needed to elucidate the barriers encountered by patients with AUD that lead to poor treatment persistence in order to develop interventions that facilitate patient-centered access to evidence-based treatment for AUD in the province.

Engaging critically: exploring the varying roles of lived experience advisors in an implementation science study on management of opioid prescribing.

Involvement of individuals with lived experience, also called "patient partners", is a key element within implementation science, the study of how to put evidence into practice. While conducting a 4-year implementation study focused on improving physician management of opioid prescribing, our research team worked closely with Lived Experience Advisors (LEAs). LEAs were involved throughout the study, including developing patient-facing recruitment material, informing the analysis of results, and as a regular reminder of the real-world impact of this work. However, through regular critical reflection, we acknowledged that we were still uncertain how to articulate the impact of LEA involvement. As a team, we continually discussed why and how people with lived experience were involved in this study. We probed ill-defined concepts such as "patient perspective", which was particularly complex for a study focused on changing physician behaviour with indirect impact on patients. This critical reflection strengthened trust and rapport between team members (characteristics deemed essential to meaningful patient involvement), while underscoring the value of including concerted time to explore the muddier aspects of engagement. In short, patient engagement did not proceed as smoothly as planned. We advocate that "best practices" in the engagement of people with lived experience include regularly setting aside time outside of practical study tasks to interrogate complex aspects of patient engagement, including reflecting on how and why individuals with lived experience are involved.

Involvement of individuals with lived experience, also called "patient partners", is often a required element of applied research. Although there is a lot of guidance on how to engage individuals with lived experience, there is no single best-practice that always applies. Each team is different and must adapt to meet the needs of their study and team. While conducting a 4-year study focused on improving physician management of opioid prescribing, our research team worked closely with Lived Experience Advisors (LEAs). The LEAs were involved in developing patient-facing recruitment material, informing the analysis of results, and were a regular reminder of the real-world impact of this work. As a team, we continually discussed why and how individuals with lived experience were involved in this study and probed concepts such as "patient perspective", which is complex in a study focused on changing physician behaviour. Setting aside time to not just work on a task but to critically reflect and ask questions led to new insights into why and how we do this work. For example, one of the patient handouts that was co-designed with patients and praised by some physicians we interviewed, was found by LEAs to be objectifying and lacking nuance, which further highlighted how the same material can be received in different ways. Our discussions also helped build trust and rapport, which are characteristics deemed essential to meaningful patient involvement. We advocate for study teams to dedicate time to interrogate the less straightforward aspects of patient engagement. In other words - "embrace the messiness".

Effect of statin use for the primary prevention of cardiovascular disease among older adults: a cautionary tale concerning target trials emulation.

OBJECTIVES: Evidence concerning the effect of statins in primary prevention of cardiovascular disease (CVD) among older adults is lacking. Using Quebec population-wide administrative data, we emulated a hypothetical randomized trial including older adults >65 years on April 1, 2013, with no CVD history and no statin use in the previous year. STUDY DESIGN AND SETTING: We included individuals who initiated statins and classified them as exposed if they were using statin at least 3 months after initiation and nonexposed otherwise. We followed them until March 31, 2018. The primary outcome was the composite endpoint of coronary events (myocardial infarction, coronary bypass, and percutaneous coronary intervention), stroke, and all-cause mortality. The intention-to-treat (ITT) effect was estimated with adjusted Cox models and per-protocol effect with inverse probability of censoring weighting. RESULTS: A total of 65,096 individuals were included (mean age = 71.0 ± 5.5, female = 55.0%) and 93.7% were exposed. Whereas we observed a reduction in the composite outcome (ITT-hazard ratio (HR) = 0.75; 95% CI: 0.68-0.83) and mortality (ITT-HR = 0.69; 95% CI: 0.61-0.77) among exposed, coronary events increased (ITT-HR = 1.46; 95% CI: 1.09-1.94). All multibias E-values were low indicating that the results were not robust to unmeasured confounding, selection, and misclassification biases simultaneously. CONCLUSION: We cannot conclude on the effectiveness of statins in primary prevention of CVD among older adults. We caution that an in-depth reflection on sources of biases and careful interpretation of results are always required in observational studies.

Impact of COVID-19 pandemic on prescription stimulant use among children and youth: a population-based study.

COVID-19 associated public health measures and school closures exacerbated symptoms in some children and youth with attention-deficit hyperactivity disorder (ADHD). Less well understood is how the pandemic influenced patterns of prescription stimulant use. We conducted a population-based study of stimulant dispensing to children and youth ≤ 24 years old between January 1, 2013, and June 30, 2022. We used structural break analyses to identify the pandemic month(s) when changes in the dispensing of stimulants occurred. We used interrupted time series models to quantify changes in dispensing following the structural break and compare observed and expected stimulant use. Our main outcome was the change in the monthly rate of stimulant use per 100,000 children and youth. Following an initial immediate decline of 60.1 individuals per 100,000 (95% confidence interval [CI] - 99.0 to - 21.2), the monthly rate of stimulant dispensing increased by 11.8 individuals per 100,000 (95% CI 10.0-13.6), with the greatest increases in trend observed among females, individuals in the highest income neighbourhoods, and those aged 20 to 24. Observed rates were between 3.9% (95% CI 1.7-6.2%) and 36.9% (95% CI 34.3-39.5%) higher than predicted among females from June 2020 onward and between 7.1% (95% CI 4.2-10.0%) and 50.7% (95% CI 47.0-54.4%) higher than expected among individuals aged 20-24 from May 2020 onward. Additional research is needed to ascertain the appropriateness of stimulant use and to develop strategies supporting children and youth with ADHD during future periods of long-term stressors.

Impact of the COVID-19 pandemic on prescription drug use and costs in British Columbia: a retrospective interrupted time series study.

OBJECTIVES: To assess the impact of the COVID-19 pandemic on prescription drug use and costs. DESIGN: Interrupted time series analysis of comprehensive administrative health data linkages in British Columbia, Canada, from 1 January 2018 to 28 March 2021. SETTING: Retrospective population-based analysis of all prescription drugs dispensed in community pharmacies and outpatient hospital pharmacies and irrespective of the drug insurance payer. PARTICIPANTS: Between 4.30 and 4.37 million individuals (52% women) actively registered with the publicly funded medical services plan. INTERVENTION: COVID-19 pandemic and associated mitigation measures. MAIN OUTCOME MEASURES: Weekly dispensing rates and costs, both overall and stratified by therapeutic groups and pharmacological subgroups, before and after the declaration of the public health emergency related to the COVID-19 pandemic. Relative changes in post-COVID-19 outcomes were expressed as ratios of observed to expected rates. RESULTS: After the onset of the pandemic and subsequent COVID-19 mitigation measures, overall medication dispensing rates dropped by 2.4% (p<0.01), followed by a sustained weekly increase to return to predicted levels by the end of January 2021. We observed abrupt level decreases in antibacterials (30.3%, p<0.01) and antivirals (22.4%, p<0.01) that remained below counterfactuals over the first year of the pandemic. In contrast, there was a week-to-week trend increase in nervous system drugs, yielding an overall increase of 7.3% (p<0.01). No trend changes in the dispensing of respiratory system agents, ACE inhibitors, antidiabetic drugs and antidepressants were detected. CONCLUSION: The COVID-19 pandemic impact on prescription drug dispensing was heterogeneous across medication subgroups. As data become available, dispensing trends in nervous system agents, antibiotics and antivirals warrant further monitoring and investigation.

The Use of Metformin in Overactive Bladder: A Retrospective Nested Case-control, Population-based Analysis.

OBJECTIVE: To determine if metformin use is associated with a lower rate of overactive bladder (OAB) medication use. Metformin facilitates the proliferation and migration of stem cells, which have been shown to improve bladder overactivity in animal models. METHODS: We conducted a retrospective nested case-control cohort study using population-based health-care administrative databases. Our cohort included patients with diabetes mellitus type 2 (DM2) ≥69years. Cases received a prescription for an OAB medication, matched with up to 4 controls based on age, sex, and DM2 diagnosis date. Exposure was a new prescription for metformin prior to receiving an OAB medication. Adjusted odds ratios were estimated using conditional logistic regression. Sensitivity analysis was done to assess the relationship between cumulative days' supply of metformin and use of OAB medications. RESULTS: Within our cohort of 2,233,084 patients with DM2, there were 16,549 case subjects who received a prescription for an OAB medication, and 64,171 matched controls. We found a positive association between OAB medication use and metformin use (adjusted odds ratios=1.07, 95% CI=1.03-1.12). Summed days' supply of metformin was also associated with OAB medication use, except when summed metformin days was >2220. CONCLUSION: Older patients with DM2 exposed to metformin had a slightly higher rate of OAB medication use, until 2220+ days' metformin supply, whereafter no association was found. This suggests no protective role for metformin in the prevention of OAB in this patient population.

Test negative design for vaccine effectiveness estimation in the context of the COVID-19 pandemic: A systematic methodology review.

BACKGROUND: During the height of the global COVID-19 pandemic, the test-negative design (TND) was extensively used in many countries to evaluate COVID-19 vaccine effectiveness (VE). Typically, the TND involves the recruitment of care-seeking individuals who meet a common clinical case definition. All participants are then tested for an infection of interest. OBJECTIVES: To review and describe the variation in TND methodology, and disclosure of potential biases, as applied to the evaluation of COVID-19 VE during the early vaccination phase of the pandemic. METHODS: We conducted a systematic review by searching four biomedical databases using defined keywords to identify peer-reviewed articles published between January 1, 2020, and January 25, 2022. We included only original articles that employed a TND to estimate VE of COVID-19 vaccines in which cases and controls were evaluated based on SARS-CoV-2 laboratory test results. RESULTS: We identified 96 studies, 35 of which met the defined criteria. Most studies were from North America (16 studies) and targeted the general population (28 studies). Outcome case definitions were based primarily on COVID-19-like symptoms; however, several papers did not consider or specify symptoms. Cases and controls had the same inclusion criteria in only half of the studies. Most studies relied upon administrative or hospital databases assembled for a different (non-evaluation) clinical purpose. Potential unmeasured confounding (20 studies), misclassification of current SARS-CoV-2 infection (16 studies) and selection bias (10 studies) were disclosed as limitations by some studies. CONCLUSION: We observed potentially meaningful deviations from the validated design in the application of the TND during the COVID-19 pandemic.