Nirmatrelvir-Ritonavir and COVID-19 Mortality and Hospitalization Among Patients With Vulnerability to COVID-19 Complications.

Importance: Postmarket analysis of individuals who receive nirmatrelvir and ritonavir (Paxlovid [Pfizer]) is essential because they differ substantially from individuals included in published clinical trials. Objective: To examine the association of nirmatrelvir and ritonavir with prevention of death or admission to hospital in individuals with different risks of complications from COVID-19 infection. Design, Setting, and Participants: This is a cohort study of adult patients in British Columbia, Canada, between February 1, 2022, and February 3, 2023. Patients were eligible if they belonged to 1 of 4 higher-risk groups of individuals who received priority for COVID-19 vaccination. Two groups included clinically extremely vulnerable (CEV) people who were severely (CEV1) or moderately immunocompromised (CEV2). CEV3 individuals were not immunocompromised but had medical conditions associated with a high risk for complications from COVID-19. A fourth expanded eligibility (EXEL) group was added to allow wider access to nirmatrelvir and ritonavir for certain other higher-risk individuals who were not in a CEV group, such as those older than 70 years who were unvaccinated. Exposures: Patients with COVID-19 who received nirmatrelvir and ritonavir were matched to patients in the same vulnerability group; who were of the same sex, age, and propensity score for nirmatrelvir and ritonavir treatment; and who were also infected within 1 month of the individual treated with nirmatrelvir and ritonavir. Main Outcomes and Measures: The primary outcome was death from any cause or emergency hospitalization with COVID-19 within 28 days. Results: There were 6866 individuals included in the study, of whom 3888 (56.6%) were female and whose median (IQR) age was 70 (57-80) years. Compared with unexposed controls, treatment with nirmatrelvir and ritonavir was associated with statistically significant relative reductions in the primary outcome in the CEV1 group (560 patients; risk difference [RD], -2.5%, 95% CI, -4.8% to -0.2%) and the CEV2 group (2628 patients; RD, -1.7%; 95% CI, -2.9% to -0.5%). In the CEV3 group, the RD was -1.3%, but the findings were not statistically significant (2100 patients; 95% CI, -2.8% to 0.1%). In the EXEL group, treatment was associated with higher risk of the outcome (RD, 1.0%), but the findings were not statistically significant (1578 patients; 95% CI, -0.9% to 2.9%). Conclusions and Relevance: In this cohort study of 6866 individuals in British Columbia, nirmatrelvir and ritonavir treatment was associated with reduced risk of COVID-19 hospitalization or death in CEV individuals, with the greatest benefit observed in severely immunocompromised individuals. No reduction in the primary outcome was observed in lower-risk individuals, including those aged 70 years or older without serious comorbidities.

Trends in antihypertensive drug utilization in British Columbia, 2004-2019: a descriptive study.

BACKGROUND: Clinical guidelines for hypertension were updated with lower blood pressure targets following new studies in 2015; the real-world impact of these changes on antihypertensive drug use is unknown. We aimed to describe trends in antihypertensive drug utilization from 2004 to 2019 in British Columbia. METHODS: We conducted a longitudinal study to describe the annual prevalence and incidence rate of use of 5 antihypertensive drug classes (thiazides, angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor blockers [ARBs], calcium channel blockers and ß-blockers) among BC residents aged 30-75 years. We also conducted a cohort study to compare the risk of discontinuation and switch or add-on therapy between incident users of the above drug classes. We used linkable administrative health databases from BC. We performed a Fine-Gray competing risk analysis to estimate subhazard ratios. RESULTS: Among BC residents aged 30-75 years (population: 2 376 282 [2004] to 3 014 273 [2019]), the incidence rate of antihypertensive drug use decreased from 23.7 per 1000 person-years in 2004 to 18.3 per 1000 person-years in 2014, and subsequently increased to 22.6 per 1000 person-years in 2019. The incidence rate of thiazide use decreased from 8.9 per 1000 person-years in 2004 to 3.2 per 1000 person-years in 2019, and incidence rates for the other drug classes increased. Incident users receiving thiazide monotherapy had an increased risk of discontinuing any antihypertensive treatment compared with ACE inhibitor monotherapy (subhazard ratio 0.96, 95% confidence interval [CI] 0.95-0.97), ARB monotherapy (subhazard ratio 0.84, 95% CI 0.81-0.87) and thiazide combination with ACE inhibitor or ARB (subhazard ratio 0.86, 95% CI 0.84-0.88), and had the highest risk of switching or adding on. INTERPRETATION: First-line use of thiazides continued to decrease despite a marked increase in incident antihypertensive therapy following updated guidelines; incident users receiving ARB monotherapy were least likely to discontinue, and incident users receiving thiazide monotherapy were more likely to switch or add on than users of other initial monotherapy or combination. Further research is needed on the factors influencing treatment decisions to understand the differences in trends and patterns of antihypertensive drug use.

Monitoring a Mandatory Nonmedical Switching Policy from Originator to Biosimilar Infliximab in Patients with Inflammatory Bowel Diseases: A Population-Based Cohort Study.

Background: On September 5, 2019, British Columbia announced a new policy (the Biosimilars Initiative) to switch from originator to biosimilar infliximab for patients with inflammatory bowel diseases. Objective: To monitor the impacts of the policy on the use of medications and health services during the first year of the policy. Methods: In this population-based cohort study, we used administrative health data to construct three historical cohorts and one policy cohort of patients with inflammatory bowel diseases who used the originator infliximab. We then monitored the cumulative incidence of medications and health services. Log-likelihood ratios were used to quantify differences between the policy cohort and the average of the historical cohorts. Results: The cohorts included 1839-2368 users of the originator infliximab, ages 4-90 years, mean age 43 years. During the first year of follow-up, we found: (1) a 0.9% increase in the first dispensation of infliximab, biosimilar, or originator; (2) a 16.2% increase in infliximab dose escalation; (3) a decrease of 2.4% in the dispensation of antibiotics and a 2.6% decrease in new use of prednison; (4) an anticipated increase in visits to physicians and gastroenterologists to manage switching to biosimilars (24.0%); (5) a 4.0% decrease in discharges from hospital; and (6) a 2.9% decrease in emergency admissions to hospital. Conclusion: British Columbia's Biosimilars Initiative for nonmedical switching from originator to biosimilar infliximab for inflammatory bowel diseases was not associated with harmful impacts on medications and health services use. An increase in dose escalation was accompanied by an improvement in health status proxies.

Treatment pattern trends of medications for type 2 diabetes in British Columbia, Canada.

INTRODUCTION: Several new oral drug classes for type 2 diabetes (T2DM) have been introduced in the last 20 years accompanied by developments in clinical evidence and guidelines. The uptake of new therapies and contemporary use of blood glucose-lowering drugs has not been closely examined in Canada. The objective of this project was to describe these treatment patterns and relate them to changes in provincial practice guidelines. RESEARCH DESIGN AND METHODS: We conducted a longitudinal drug utilization study among persons with T2DM aged ≥18 years from 2001 to 2020 in British Columbia (BC), Canada. We used dispensing data from community pharmacies with linkable physician billing and hospital admission records. Laboratory results were available from 2011 onwards. We identified incident users of blood glucose-lowering drugs, then determined sequence patterns of medications dispensed, with stratification by age group, and subgroup analysis for patients with a history of cardiovascular disease. RESULTS: Among a cohort of 362 391 patients (mean age 57.7 years old, 53.5% male) treated for non-insulin-dependent diabetes, the proportion who received metformin monotherapy as first-line treatment reached a maximum of 90% in 2009, decreasing to 73% in 2020. The proportion of patients starting two-drug combinations nearly doubled from 3.3% to 6.4%. Sulfonylureas were the preferred class of second-line agents over the course of the study period. In 2020, sodium-glucose cotransporter type 2 inhibitors and glucagon-like peptide-1 receptor agonists accounted for 21% and 10% of second-line prescribing, respectively. For patients with baseline glycated hemoglobin (A1C) results prior to initiating diabetic treatment, 41% had a value ≤7.0% and 27% had a value over 8.5%. CONCLUSIONS: Oral diabetic medication patterns have changed significantly over the last 20 years in BC, primarily in terms of medications used as second-line therapy. Over 40% of patients with available laboratory results initiated T2DM treatment with an A1C value ≤7.0%, with the average A1C value trending lower over the last decade.

The Impact of Mandatory Nonmedical Switching From Originator to Biosimilar Insulin Glargine.

PURPOSE: This study monitors for early changes in health services utilization after a mandatory policy to switch patients from originator to biosimilar insulin glargine in British Columbia, Canada. METHODS: We conducted a prospective cohort study of patients treated with originator insulin glargine. The policy cohort included patients treated with originator insulin glargine in the 6 months before the policy change (May 27, 2019). Three historical control cohorts included users of originator insulin glargine during the 6 months before May 27 each year in 2016, 2017, and 2018. Patients who discontinued or switched use of the originator insulin glargine and those without cost coverage by the provincial drug plan were excluded. Using likelihood ratios, we compared the daily use of medications, outpatient visits, and hospitalizations in the 12 months after the policy change with the daily use in 3 historical control cohorts. A sustained likelihood ratio above a predefined threshold of 7.1 was interpreted as an early signal of a possible policy impact. FINDINGS: Each cohort included 15,344 to 17,310 patients. In the first year of the policy, we observed increases in (1) insulin glargine use (the cumulative incidence increased by 2.5% compared with the mean of the 3 historical cohorts), (2) oral antidiabetic medication use (increased by 2.8%), and (3) outpatient visits (increased by 1.4%). Likelihood ratios greater than the threshold of 7.1 were detected for these 3 outcomes. IMPLICATIONS: We observed marginal changes in health services utilization without detecting signals of negative health impacts on patients targeted by the British Columbia policy of mandatory switching from originator to biosimilar insulin glargine.

Mandatory nonmedical switching from originator to biosimilar infliximab in patients with inflammatory arthritis and psoriasis in British Columbia: a cohort study.

BACKGROUND: In 2019, British Columbia's public drug plan, PharmaCare, was the first in Canada to implement a nonmedical switching policy from originator infliximab to its biosimilar, for patients with inflammatory arthritis or psoriasis. We aimed to detect signals of impact on health services utilization during the first year of policy implementation and to provide early data to policy-makers. METHODS: We constructed cohorts of users of originator infliximab: 3 historical cohorts (2016-2018) and 1 policy cohort (2019). We extracted data from BC Ministry of Health databases from 2015 to 2020, as we followed each cohort for 365 days from May 27 of each cohort's respective year. We excluded patients with gastrointestinal conditions and those not covered by PharmaCare. We examined the cumulative incidence of infliximab prescription refills, switching to other biologic drugs and use of additional health services. A log-likelihood ratio of 1.96 compared with the null hypothesis was used as the threshold for differences between the policy cohort and the historical cohorts. RESULTS: The study included a total of 572 unique patients: 520 in the 2016 historical cohort, 461 in the 2017 historical cohort, 423 in the 2018 historical cohort and 377 in the policy cohort (with some patients included in multiple cohorts; 335 [58.6%] were included in all 4 cohorts). During months 8 and 9 of follow-up, a transient signal was observed in infliximab refills (7.2% decrease in refilling infliximab for the fourth time for the policy cohort, log-likelihood ratio > 1.96). An anticipated increase in visits to specialists was observed from month 4 forward (15.0%, log-likelihood ratio > 1.96). No signal was observed for increased use of other health services (log-likelihood ratio < 1.96). INTERPRETATION: Early monitoring did not detect signals of negative impacts on health services use during the first year of the policy. Detailed, longer-term cohort studies and hypothesis-testing methods could provide additional assurance about the safety of the policy.

Rapid monitoring of health services use following a policy to switch patients from originator to biosimilar etanercept-a cohort study in British Columbia.

BACKGROUND: Drug coverage policies that incentivize switching patients from originator to biosimilar products may result in significant health care savings. Our study aimed to detect early impacts on health services utilization following a mandated switch from originator to biosimilar etanercept in British Columbia (BC), Canada. METHODS: We conducted a prospective, population-based cohort study using linked administrative health data from BC (2010-2020). The policy cohort consisted of patients with inflammatory arthritis who used originator etanercept in 2019, prior to BC's Biosimilars Initiative switching policy. Three historical cohorts included patients with inflammatory arthritis who used originator etanercept in the years 2016, 2017, and 2018. We compared the daily cumulative incidences of drug refills and outpatient and inpatient services between the policy and historical cohorts. A likelihood ratio sustained (≥ 31 days) at 7.1 or higher compared with the null hypothesis was chosen a priori as a threshold for a potential impact of the policy. RESULTS: Each cohort contained between 1694 and 1963 patients. We detected several potential impacts: 1) a transient increase in etanercept refills between months three and eight (cumulative incidence difference of + 3.0%); 2) an anticipated increase in visits to physicians of any specialty between months three and eight (+ 2.6%); and 3) an anticipated increase in visits to a rheumatologist from the end of month three onwards (+ 12.8%). The policy had no impact on incidences of switching to a different biologic antirheumatic drug, visits to emergency departments, or admissions to hospitals. CONCLUSIONS: Only transient and/or anticipated increases in drug refills and physician visits were observed during the study period. Additional research on clinical outcomes is recommended to strengthen the evidence that no long-term unintended negative health impacts are associated with BC's Biosimilars Initiative [switching policy].

Variation in surgical demand and time to hip fracture repair: a Canadian database study.

BACKGROUND: Competing demands for operative resources may affect time to hip fracture surgery. We sought to determine the time to hip fracture surgery by variation in demand in Canadian hospitals. METHODS: We obtained discharge abstracts of 151,952 patients aged 65 years or older who underwent surgery for a hip fracture between January, 2004 and December, 2012 in nine Canadian provinces. We compared median time to surgery (in days) when demand could be met within a two-day benchmark and when demand required more days, i.e. clearance time, to provide surgery, overall and stratified by presence of medical reasons for delay. RESULTS: For persons admitted when demand corresponded to a 2-day clearance time, 68% of patients underwent surgery within the 2-day benchmark. When demand corresponded to a clearance time of one week, 51% of patients underwent surgery within 2 days. Compared to demand that could be served within the two-day benchmark, adjusted median time to surgery was 5.1% (95% confidence interval [CI] 4.1-6.1), 12.2% (95% CI 10.3-14.2), and 22.0% (95% CI 17.7-26.2) longer, when demand required 4, 6, and 7 or more days to clear the backlog, respectively. After adjustment, delays in median time to surgery were similar for those with and without medical reasons for delay. CONCLUSION: Increases in demand for operative resources were associated with dose-response increases in the time needed for half of hip fracture patients to undergo surgery. Such delays may be mitigated through better anticipation of day-to-day supply and demand and increased response capability.

Rapid monitoring of health services utilization following a shift in coverage from brand name to biosimilar drugs in British Columbia-An interim report.

PURPOSE: We explored changes in health services utilization associated with the Biosimilars Initiative introduced in British Columbia on May 27, 2019. To maintain drug coverage, the policy requires users of originator infliximab or etanercept to transition to biosimilar versions. We present a three-month interim analysis of this initiative. METHODS: We conducted a rapid monitoring analysis to evaluate changes in health services utilization three months after the policy was introduced compared with a three-year period before the policy's introduction. Using the administrative claims data of the British Columbia Ministry of Health, we assembled three historical cohorts and one policy cohort of users of each originator drug (8 cohorts in total). Cumulative incidences of medication refills, switching, and visits to physicians were the outcome measures used to compare policy and historical cohorts. Likelihood ratios were used to quantify statistical differences between each policy cohort and its respective historical controls. Likelihood ratios above 7.1 were considered statistically significant. RESULTS: The four infliximab cohorts included 436 patients on average, mean age 56 to 59, 53% to 55% females. The four etanercept cohorts included 1826 patients on average, mean age 57 to 58, 60% to 63% females. Three months after the policy's introduction, 21% of patients treated in the policy cohorts transitioned to the biosimilar versions. Health services utilization in the policy cohorts were consistent with the historical cohorts. CONCLUSIONS: An increase in visits to physicians was expected but not detected in the first three months of the Biosimilars Initiative. The impacts of the policy will continue to be monitored.

Mortality effects of timing alternatives for hip fracture surgery.

BACKGROUND: The appropriate timing of hip fracture surgery remains a matter of debate. We sought to estimate the effect of changes in timing policy and the proportion of deaths attributable to surgical delay. METHODS: We obtained discharge abstracts from the Canadian Institute for Health Information for hip fracture surgery in Canada (excluding Quebec) between 2004 and 2012. We estimated the expected population-average risks of inpatient death within 30 days if patients were surgically treated on day of admission, inpatient day 2, day 3 or after day 3. We weighted observations with the inverse propensity score of surgical timing according to confounders selected from a causal diagram. RESULTS: Of 139 119 medically stable patients with hip fracture who were aged 65 years or older, 32 120 (23.1%) underwent surgery on admission day, 60 505 (43.5%) on inpatient day 2, 29 236 (21.0%) on day 3 and 17 258 (12.4%) after day 3. Cumulative 30-day in-hospital mortality was 4.9% among patients who were surgically treated on admission day, increasing to 6.9% for surgery done after day 3. We projected an additional 10.9 (95% confidence interval [CI] 6.8 to 15.1) deaths per 1000 surgeries if all surgeries were done after inpatient day 3 instead of admission day. The attributable proportion of deaths for delays beyond inpatient day 2 was 16.5% (95% CI 12.0% to 21.0%). INTERPRETATION: Surgery on admission day or the following day was estimated to reduce postoperative mortality among medically stable patients with hip fracture. Hospitals should expedite operating room access for patients whose surgery has already been delayed for nonmedical reasons.

Urban and rural differences in outcomes of head and neck cancer.

OBJECTIVES/HYPOTHESIS: To assess for potential urban and rural disparities in head and neck cancer (HNC) outcomes within a single-payer healthcare system. STUDY DESIGN: A large retrospective population-based cohort analysis of consecutive HNC patients treated in British Columbia, Canada between 2001 and 2010 was conducted. METHODS: All patients diagnosed with HNC from 2001 to 2010 and referred to any one of five British Columbia Cancer Agency centers for management were reviewed. Based on census data, patients were classified into: 1) rural, 2) small urban, 3) moderate urban, and 4) large urban areas. Kaplan-Meier methods and Cox regression models were used to correlate site of residence with overall survival (OS), controlling for prognostic factors that included sociodemographic and other tumor and treatment-related characteristics. RESULTS: We identified 3,036 patients; the median age was 64 years, 26% were women, and 32% had Eastern Cooperative Oncology Group (ECOG) 0 or 1. The majority resided in large urban areas (55%) followed by rural (22%), moderate urban (13%), and small urban (10%). In regression analyses, smoking (hazard ratio [HR]: 2.10, 95% confidence interval [CI]: 1.28-3.45, P < .001), ECOG 2 + (HR: 3.44, 95% CI: 2.26-5.22, P < .001), oral cavity (HR: 1.54, 95% CI: 1.03-2.32, P = .04) and hypopharyngeal tumors (HR: 2.31, 95% CI: 1.42-3.77, P = .00), and large tumor size (HR: 1.69, 95% CI: 1.08-2.64, P = .02) were correlated with inferior OS, but site of residence was not. When stratified by type of treatment, OS remained similar irrespective of urban or rural residence. CONCLUSIONS: Urban-rural differences in HNC survival outcomes were not observed. LEVEL OF EVIDENCE: 2c. Laryngoscope, 128:852-858, 2018.

Teriparatide Treatment Improves Bone Defect Healing Via Anabolic Effects on New Bone Formation and Non-Anabolic Effects on Inhibition of Mast Cells in a Murine Cranial Window Model.

Investigations of teriparatide (recombinant parathyroid hormone [rPTH]) as a potential treatment for critical defects have demonstrated the predicted anabolic effects on bone formation, and significant non-anabolic effects on healing via undefined mechanisms. Specifically, studies in murine models of structural allograft healing demonstrated that rPTH treatment increased angiogenesis (vessels <30 µm), and decreased arteriogenesis (>30 µm) and mast cell numbers, which lead to decreased fibrosis and accelerated healing. To better understand these non-anabolic effects, we interrogated osteogenesis, vasculogenesis, and mast cell accumulation in mice randomized to placebo (saline), rPTH (20 µg/kg/2 days), or the mast cell inhibitor sodium cromolyn (SC) (24 µg/kg/ 2days), via longitudinal micro-computed tomography (µCT) and multiphoton laser scanning microscopy (MPLSM), in a critical calvaria defect model. µCT demonstrated that SC significantly increased defect window closure and new bone volume versus placebo (p < 0.05), although these effects were not as great as rPTH. Interestingly, both rPTH and SC have similar inhibitory effects on arteriogenesis versus placebo (p < 0.05) without affecting total vascular volume. MPLSM time-course studies in untreated mice revealed that large numbers of mast cells were detected 1 day postoperation (43 ± 17), peaked at 6 days (76 ± 6), and were still present in the critical defect at the end of the experiment on day 30 (20 ± 12). In contrast, angiogenesis was not observed until day 4, and functional vessels were first observed on 6 days, demonstrating that mast cell accumulation precedes vasculogenesis. To confirm a direct role of mast cells on osteogenesis and vasculogenesis, we demonstrated that specific diphtheria toxin-α deletion in Mcpt5-Cre-iDTR mice results in similar affects as SC treatment in WT mice. Collectively, these findings demonstrate that mast cells inhibit bone defect healing by stimulating arteriogenesis associated with fibrotic scaring, and that an efficacious non-anabolic effect of rPTH therapy on bone repair is suppression of arteriogenesis and fibrosis secondary to mast cell inhibition. © 2017 American Society for Bone and Mineral Research.

Asian and non-Asian disparities in outcomes of non-nasopharyngeal head and neck cancer.

OBJECTIVES/HYPOTHESIS: To evaluate disparities in overall survival (OS) between Asian and non-Asian patients diagnosed with non-nasopharyngeal head and neck cancer (HNC). STUDY DESIGN: This was a population-based, retrospective study of patients diagnosed with non-nasopharyngeal HNC of squamous cell carcinoma histology between 2001 and 2010 in British Columbia, Canada. METHODS: Using Kaplan-Meier methods and Cox regression models, we examined the relationship between race and OS. RESULTS: A total of 3,036 patients were included in the study. Median age was 64 years, 74% were men, and 7% were Asians. Asians had worse Eastern Cooperative Oncology Group (ECOG) status (29% vs. 23%, P = .07) and larger tumors (33% vs. 21%, P = .02), and were more likely to be diagnosed with oral cavity cancers (38% vs. 25%, P < .001) than non-Asians. Asians were also less likely to receive multimodality therapy than non-Asians (90% vs. 95%, P = .02). Asians were more likely to have never smoked (49% vs. 15%, P < .001) and to be married or with a partner (80% vs. 69%, P = .02). Multivariate models showed that Asians had better OS than non-Asians (hazard ratio [HR] = 0.50, 95% confidence interval [CI] = 0.25-0.99, P = .05). Three-year OS did not differ significantly between Asians and non-Asians (41% vs. 42%, P = .18); however, 5-year OS did (22% vs. 19% P = .03). Stratifying by treatment type, outcomes were comparable in both groups except for radiotherapy alone, where Asians showed significantly better OS (HR = 0.71, 95% CI = 0.51-0.99, P = .04). Advanced age, worse ECOG, greater tumor size, and lack of treatment also correlated with inferior OS. CONCLUSIONS: Despite several worse prognostic features and less aggressive treatment, Asians tended to exhibit better OS than non-Asians. LEVEL OF EVIDENCE: 2c. Laryngoscope, 127:2528-2533, 2017.