Assessment of algorithms for identifying patients with triple-class refractory multiple myeloma using real-world data.

Objective: Patients with triple-class refractory (TCR) multiple myeloma (MM) have limited treatment options and poor prognoses. This high unmet need has prompted the development of new therapies allowing for improved outcomes for these patients. Recently, new targeted therapies for the treatment of patients with relapsed or refractory MM have been approved based on single-arm clinical trial results. Real-world (RW) data enable a better understanding of the effectiveness of new therapies in clinical practice and provide external controls for single-arm studies. However, using RW data to identify patients with TCR MM is challenging and subject to limitations. Methods: In this retrospective cohort study of an analysis of the COTA electronic health record (EHR) database, we used four algorithms to define refractory status and created four groups of patients with TCR MM initiating post-TCR therapy. Each algorithm relied on slightly different criteria to identify TCR patients, but all were based on the International Myeloma Working Group (IMWG)-derived and/or healthcare provider (HCP)-reported progressions within the database. Results: A total of 3815 patients with newly diagnosed MM met the eligibility criteria for this study. The choice of the algorithm did not impact the characteristics of identified patients with TCR MM (Algorithm 1 [n = 404], Algorithm 2 [n = 123], Algorithm 3 [n = 404], and Algorithm 4 [n = 375]), including their demographic and disease characteristics, MM treatment history, or treatment patterns received after becoming TCR. However, identifying TCR MM using a combination of IMWG-derived and HCP-reported progressions allowed up to a 70% increase in the size of the identified group of patients compared with using only IMWG-derived progressions. Conclusion: In RW settings, progressions from both IMWG-derived data and physician reports may be used to identify patients with TCR MM.

Elranatamab efficacy in MagnetisMM-3 compared with real-world control arms in triple-class refractory multiple myeloma.

Elranatamab efficacy in the single-arm, registrational MagnetisMM-3 trial (NCT04649359) was compared with that of physician's choice of treatment (PCT) for triple-class refractory multiple myeloma. MagnestisMM-3 eligibility criteria were applied to two USA-based oncology electronic health record databases, COTA and Flatiron Health (FH), to identify cohorts for this study (NCT05932290). Applied statistical techniques accounted for cohort imbalances. MagnetisMM-3 (BCMA-naive; n = 123) outcomes were compared with those from COTA (n = 239) and FH (n = 152). Elranatamab was associated with a significantly higher objective response rate (risk ratios, 1.88-2.25), significantly longer progression-free survival (hazard ratios [HRs], 0.37-0.57), and, across most analyses, significantly longer overall survival (HRs, 0.46-0.66) versus PCT. BCMA-naive patients who were treated with elranatamab exhibited significantly better outcomes than patients treated in real-world clinical practice.

Elranatamab is a new medicine for the treatment of people with multiple myeloma. In the ongoing clinical trial MagnetisMM-3, most people had fewer myeloma cells when treated with elranatamab. However, MagnetisMM-3 only looks at the effects of elranatamab without comparing it to other myeloma treatments. Therefore, a new study was designed to compare the effectiveness of elranatamab in the MagnetisMM-3 study with other treatments used in real-world clinical practice (not in a clinical trial). Data from people in MagnetisMM-3 was compared with data from two US databases (COTA and Flatiron Health) containing health records of patients treated for multiple myeloma in real-life clinical practice. The same criteria used to select patients for the MagnetisMM-3 trial (123 people) were used to identify people with similar characteristics in COTA (239 people) and Flatiron Health (152 people). More people treated with elranatamab had fewer myeloma cells in their bodies after treatment than people who received their doctor's choice of treatment in clinical practice. In fact, six out of ten people treated with elranatamab had fewer myeloma cells versus about three in ten people from each real-world database. People treated with elranatamab versus physician's choice of treatment lived longer without their disease getting worse and lived longer overall. In conclusion, this study found that more people treated with elranatamab responded to treatment and lived longer than similar people from the COTA and Flatiron Health databases who were given treatments available in a real-world clinical setting.Clinical Trial Registration: NCT05932290 (ClinicalTrials.gov).

Growth differentiation factor-15 as a biomarker of atherosclerotic coronary plaque: Value in people living with and without HIV.

Background: Increased rates of cardiovascular diseases (CVD) and larger subclinical high-risk coronary plaques in coronary CT angiography have been observed in people living with HIV (PLWH) treated with antiretroviral therapy (ART) compared to HIV-uninfected people. Growth differentiation factor-15 (GDF-15) is a cytokine emerging as an optimal marker for CVD in the general population. Methods: We cross-sectionally analyzed plasma of 95 PLWH on ART and 52 controls. We measured GDF-15, fibroblast growth factor-21 (FGF-21), glucagon-like peptide-2 (GLP-2), soluble urokinase plasminogen activator receptor (suPAR), CRP, and anti-CMV and anti-EBV IgG levels. All participants had no clinical CVD and underwent coronary CT angiography with the 3D reconstruction of coronary artery atherosclerotic plaques. Total plaque volume (TPV) and low attenuation plaque volume (LAPV, defined as density <30 Hounsfield Units) were calculated (mm3). Results: In both PLWH and controls, GDF-15 levels were increased in participants with presence of coronary plaque vs. without (p = 0.04 and p < 0.001, respectively) and correlated with TPV (r = 0.27, p = 0.009 and r = 0.62, p < 0.001, respectively) and LAPV (r = 0.28, p = 0.008, r = 0.60, p < 0.001, respectively). However, in a multivariate model, GDF-15 was independently associated with LAPV in controls only (adjusted OR 35.1, p = 0.04) and not in PLWH, mainly due to confounding by smoking. Other markers were not independently associated with plaque volume, except for anti-EBV IgGs in controls (adjusted OR 3.51, p = 0.02). Conclusion: In PLWH, GDF-15 and smoking seemed to synergistically contribute to coronary plaque volume. Conversely, increased GDF-15 levels were associated with the presence of coronary artery plaques in people without HIV, independently of CV risk factors.

Willingness of Older Canadians with HIV to Participate in HIV Cure Research Near and After the End of Life: A Mixed-Method Study.

HIV cure research requires interrogating latent HIV reservoirs in deep tissues, which necessitates autopsies to avoid risks to participants. An HIV autopsy biobank would facilitate this research, but such research raises ethical issues and requires participant engagement. This study explores the willingness to participate in HIV cure research at the end of life. Participants include Canadians with HIV [people with HIV (PWHIV)] aged 55 years or older. Following a mixed-method study design, all participants completed a phone or online survey, and a subset of participants participated in in-depth phone or videoconference interviews. We produced descriptive statistics of quantitative data and a thematic analysis of qualitative data. Barriers and facilitators were categorized under domains of the Theoretical Domains Framework. From April 2020 to August 2021, 37 participants completed the survey (mean age = 69.9 years old; mean duration of HIV infection = 28.5 years), including 15 interviewed participants. About three quarters of participants indicated being willing to participate in hypothetical medical studies toward the end of life (n = 30; 81.1%), in HIV biobanking (n = 30; 81.1%), and in a research autopsy (n = 28; 75.7%) to advance HIV cure research, mainly for altruistic benefits. The main perceived risks had to do with physical pain and confidentiality. Barriers and facilitators were distributed across five domains: social/professional role and identity, environmental context and resources, social influences, beliefs about consequences, and capabilities. Participants wanted more information about study objectives and procedures, possible accommodations with their last will, and rationale for studies or financial interests funding studies. Our results indicate that older PWHIV would be willing to participate in HIV cure research toward the end of life, HIV biobanking, and research autopsy. However, a dialogue should be initiated to inform participants thoroughly about HIV cure studies, address concerns, and accommodate their needs and preferences. Additional work is required, likely through increased community engagement, to address educational needs.

Corticosteroids Use and Incidence of Severe Infections in People Living with HIV Compared to a Matched Population.

BACKGROUND: People living with HIV (PLWH) have been shown to have an increased risk of autoimmune diseases. Corticosteroids are the cornerstone of autoimmune diseases treatment, but their use is associated with an increased risk of infections. It is unclear how HIV status affects the risk of infection associated with corticosteroids use. METHODS: We conducted a retrospective cohort study from 1991 to 2011, using a medico-administrative database from Quebec. Medical billing codes were used to identify PLWH, and we matched them on age, sex, and index date with up to 4 HIV-negative controls. The exposure of interest was the use of corticosteroids, defined as a systemic corticosteroid dispensation lasting at least 20 days. The outcome of interest was hospitalization for severe infection. Crude and adjusted incidence rates ratios of infection were obtained using a random effect Poisson model, and results were stratified by HIV status. RESULTS: In total, 4798 PLWH were matched to 17 644 HIV-negative controls, among which 1083 (22.6%) PLWH and 1854 (10.5%) HIV-negative controls received at least one course of corticosteroid. The mean duration of corticosteroids use was 4 ± 4.4 months in PLWH and 1.6 ± 5.5 months in HIV-negative controls. The incidence rate ratio (IRR) for infections associated with corticosteroids use was 2.49[1.71-3.60] in PLWH and 1.32[0.71-2.47] in HIV-negative controls (P value for interaction 0.18). The most frequent infections were pulmonary infections (50.4%), followed by urinary tract infections (26%) and opportunistic infections (10.5%). CONCLUSION: Although our interaction term did not reach significance, the increased risk of infection associated with corticosteroids use was more pronounced in PLWH. However, further research with contemporary data is warranted to confirm if the risk associated with corticosteroids use remains high in PLWH with well-controlled HIV infection.

Defining the duration of the dispensation of oral anticoagulants in administrative healthcare databases.

PURPOSE: In clinical practice, warfarin therapy requires frequent dose adjustments. In pharmacy claims, the days supplied value may not reflect the true duration of warfarin dispensation. This may affect the measures of association comparing the safety of direct oral anticoagulants (DOACs) versus warfarin. METHODS: Using Quebec healthcare administrative databases, we formed a cohort of 55 230 patients newly treated with oral anticoagulants between 2010 and 2016. The duration of dispensations was defined using two approaches: the recorded days supplied value, and the longitudinal coverage approximation (data-driven) that may account for individual variation in drug usage patterns. Propensity scores adjusted Cox proportional hazards regression models were used to estimate the hazard ratio (HR) of major bleeding with dabigatran or rivaroxaban versus warfarin. RESULTS: Using the days supplied, the mean (and standard deviation) dispensation durations for dabigatran, rivaroxaban, and warfarin were 19 (15), 19 (14), and 13 (12) days, respectively. Using the data-driven approach, the durations were 20 (16), 19 (15), and 15 (16) days, respectively. The choice of the approach had no impact on the HR estimates. CONCLUSIONS: In our settings, the data-driven approach closely approximated the recorded days supplied value for the standard dose therapies such as dabigatran and rivaroxaban. For warfarin, the data-driven approach captured more variability in the duration of dispensations compared to the days supplied value, which may better reflect the true drug-taking behavior of warfarin. Both approaches may provide valid estimates when comparing the safety of DOACs versus warfarin.

Evidence of the Different Associations of Prognostic Factors With Censoring Across Treatment Groups and Impact on Censoring Weight Model Specification: The Example of Anticoagulation in Atrial Fibrillation.

Inverse probability of censoring weights (IPCWs) may reduce selection bias due to informative censoring in longitudinal studies. However, in studies with an active comparator, the associations between predictors and censoring may differ across treatment groups. We used the clinical example of anticoagulation treatment with warfarin or a direct oral anticoagulant (DOAC) in atrial fibrillation to illustrate this. The cohort of individuals initiating an oral anticoagulant during 2010-2016 was identified from the Régie de l'assurance maladie du Québec (RAMQ) databases. The parameter of interest was the hazard ratio (HR) of the composite of stroke, major bleeding, myocardial infarction, or death associated with continuous use of warfarin versus DOACs. Two strategies for the specification of the model for estimation of censoring weights were explored: exposure-unstratified and exposure-stratified. The HR associated with continuous treatment with warfarin versus DOACs adjusted with exposure-stratified IPCWs was 1.26 (95% confidence interval: 1.20, 1.33). Using exposure-unstratified IPCWs, the HR differed by 15% in favor of DOACs (1.41, 95% confidence interval: 1.34, 1.48). Not accounting for the different associations between the predictors and informative censoring across exposure groups may lead to misspecification of censoring weights and biased estimate on comparative effectiveness and safety.

Incidence of autoimmune diseases in people living with HIV compared to a matched population: a cohort study.

The objective of this paper is to estimate incidence and relative risk of autoimmune conditions in patients living with HIV compared to an HIV-negative matched population. We conducted a retrospective study in the medico-administrative database of the province of Québec, Canada. All HIV-positive patients treated with antiretrovirals were matched to up to 4 HIV-negative controls for age, sex, and period of follow-up. The following autoimmune conditions were identified using medical billing codes: vasculitis, hematological (immune thrombocytopenic purpura and immune hemolytic anemia), ankylosing spondylitis, psoriasis and psoriatic arthritis, inflammatory bowel disease and associated arthritis, connectivitis, and systemic lupus erythematosus. Incidence rates and adjusted hazard ratios (aHR) were obtained using survival models. A total of 4245 HIV-positive patients were matched to 16493 HIV-negative patients. Autoimmune diseases were diagnosed in 407 (9.6%) HIV-positive and 508 (3%) HIV-negative patients. The aHR for autoimmune diseases associated to HIV was 2.40 95% CI [2.10-2.75]. The strongest associations were seen for hematological disorders (aHR 8.34 95% CI [6.13-11.36]), followed by ankylosing spondylitis (1.82 95% CI [1.03-3.21]), inflammatory bowel disease and associated arthritis (1.80 95% CI [1.37-2.35]), psoriasis and associated arthritis (1.69 95% CI [1.23-2.33]), and rheumatoid arthritis (1.51 95% CI [1.08-2.11]).We found no association between HIV and the incidence of vasculitis, connectivitis, and systemic lupus erythematosus, but the number of cases for these diseases were few. Autoimmune diseases are more frequent among people living with HIV than age and sex-matched population-based controls. Key Points • Strength: The major strength of this study is its large sample size of 4200 people treated as HIV infection, matched to 16000 HIV negative for sex and age. • Novelty: We found that people living with HIV were more than twice as likely to suffer from auto-immune diseases than their matched counterparts.

Methodological challenges in assessment of current use of warfarin among patients with atrial fibrillation using dispensation data from administrative health care databases.

PURPOSE: Algorithms to define current exposure to warfarin using administrative data may be imprecise. Study objectives were to characterize dispensation patterns, to measure gaps between expected and observed refill dates for warfarin and direct oral anticoagulants (DOACs). METHODS: Retrospective cohort study using administrative health care databases of the Régie de l'assurance-maladie du Québec. We identified every dispensation of warfarin, dabigatran, rivaroxaban, or apixaban for patients with AF initiating oral anticoagulants between 2010 and 2015. For each dispensation, we extracted date and duration. Refill gaps were calculated as difference between expected and observed dates of successive dispensation. Refill gaps were summarized using descriptive statistics. To account for repeated observations nested within patients and to assess the components of variance of refill gaps, we used unconditional multilevel linear models. RESULTS: We identified 61 516 new users. Majority were prescribed warfarin (60.3%), followed by rivaroxaban (16.4%), dabigatran (14.5%), apixaban (8.8%). Most frequent recorded duration of dispensation was 7 days, suggesting use of pharmacist-prepared weekly pillboxes. The average refill gap from multilevel model was higher for warfarin (9.28 days, 95%CI:8.97-9.59) compared with DOACs (apixaban 3.08 days, 95%CI: 2.96-3.20, dabigatran 3.70, 95%CI: 3.56-3.84, rivaroxaban 3.15, 95%CI: 3.03-3.27). The variance of refill gaps was greater among warfarin users than among DOAC users. CONCLUSIONS: Greater refill gaps for warfarin may reflect inadequate capture of the period covered by the number of dispensed pills recorded in administrative data. A time-dependent definition of exposure using dispensation data would lead to greater misclassification of warfarin than DOACs use.

Comparative effect of statins on the risk of incident Alzheimer disease.

OBJECTIVE: To investigate whether fungus-derived statins are associated with a lower risk of incident Alzheimer disease (AD) compared with synthetic statins using real-world clinical practice data. METHODS: We identified a population-based retrospective cohort of patients aged ≥60 years newly prescribed a statin between January 1, 1994, and December 31, 2012, and followed until March 31, 2015, using the UK Clinical Practice Research Datalink. Statins were consecutively classified according to their type, lipophilicity, and potency. For each group, we calculated the crude AD incidence rates per 1,000 person-years. Time-dependent Cox proportional hazards models adjusted for propensity score deciles were used to estimate hazard ratios (HRs) with 95% confidence interval (CIs) of incident AD associated with different statin categories. RESULTS: Over the 18-year study period, we identified 465,085 statin users, including 7,669 patients who developed AD during 2,891,268 person-years of follow-up (incidence rate 2.65 [95% CI 2.59-2.71] per 1,000 person-years). Compared to synthetic, fungus-derived statins were associated with an increased risk of AD (HR 1.09, 95% CI 1.03-1.15). Lipophilic statins also were associated with higher AD risk (HR 1.18, 95% CI 1.09-1.27) compared to hydrophilic statins, while statin potency did not modify the risk of AD (adjusted HR 1.03, 95% CI 0.98-1.08). The risk was further reduced in sensitivity analyses. CONCLUSION: Fungus-derived and lipophilic statins were not associated with decreased incidence of AD compared to synthetic and hydrophilic statins. The modest variations in the risk of incident AD observed between statin characteristics needs to be evaluated in future studies on their possible heterogeneous neuroprotective effect.

The early impact of human papillomavirus vaccination on anogenital warts in Québec, Canada.

In Québec province in Canada, a public school-based and catch-up HPV vaccination programs with the quadrivalent vaccine have been introduced in September 2008 for girls aged 9-17 years. We assessed the early impact of the HPV vaccination program on the incidence of anogenital warts (AGW) in the Quebec general population. We used the provincial health administrative data of the Régie de l'assurance maladie du Québec (RAMQ). AGW were identified either through a prescription of podofilox, or a medical procedure code specific to AGW, or a diagnostic code for viral warts followed by a prescription of imiquimod or fluorouracil. Sex- and age-specific incidence rates were calculated for pre-vaccination (2004-2007) and vaccination (2009-2012) periods. We found a significant decline of 45% and 19% in the incidence of AGWs among females aged 15-19 and 20-24 years, respectively. A decline of 21% was also seen among males aged 15-19 years. The median age at an episode of AGW increased from 27 years in 2004 to 31 years in 2012 among females and remained stable in males. Our findings indicate that the HPV public vaccination program is associated with an important reduction in the incidence of AGW among young females and males. The benefit is more pronounced among females 15-19 years of age, who were eligible for the public vaccination program. The observed decline among young males could be due to herd immunity and/or privately paid vaccination.

Metformin and the incidence of viral associated cancers in patients with type 2 diabetes.

Limited studies have associated metformin with a reduced risk of viral associated cancers, however these had a number of methodological shortcomings. This study investigated whether the use of metformin is associated with a reduced risk of viral associated cancers in patients with type 2 diabetes. A cohort of 137,754 patients newly-prescribed non-insulin antidiabetic drugs between January 1, 1988 and March 31, 2016 was identified from the UK Clinical Practice Research Datalink and followed until a first-ever diagnosis of a viral associated cancer, death from any cause, end of registration with the practice, or March 31, 2016. Time-varying use of metformin was compared with use of other antidiabetic drugs, with exposures lagged by one year for latency purposes. Time-dependent Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of incident viral associated cancer with use of metformin overall, by cumulative duration of use and viral etiology. Overall, there were 424 viral associated cancers during 759,810 person-years of follow-up (crude rate of 5.6 per 10,000 person-years). Metformin was not associated with a decreased rate of viral associated cancer (HR: 0.93, 95% CI: 0.65-1.32). There was no evidence of a duration-response relationship in terms of cumulative duration of use (p trend = 0.69), including with use of metformin for more than 10 years (HR 1.02, 95% CI: 0.52-1.99), or by viral etiology. In this large population-based cohort study, the use of metformin was not associated with a reduced risk of viral associated cancer.

Effect of Pre-Operative Use of Medications on the Risk of Surgical Site Infections in Patients Undergoing Cardiac Surgery.

BACKGROUND: Median sternotomy, the most common means of accessing the heart for cardiac procedures, is associated with higher risk of surgical site infections (SSIs). A limited number of studies reporting the impact of medication use prior to cardiac surgery on the subsequent risk of SSIs usually focused on antibacterial prophylaxis. The objective of the current study was to evaluate the effect of medications prescribed commonly to cardiac patients on the risk of incident SSIs. METHODS: The study analyzed data on consecutive cardiac surgery patients undergoing median sternotomy at a McGill University teaching hospital between April 1, 2011 and October 31, 2013. Exposure of interest was use of medications for heart disease and cardiovascular conditions in the seven days prior to surgery and those for comorbid conditions. The main outcome was SSIs occurring within 90 d after surgery. Univariate and multivariate logistic regression (adjusted odds ratio [AOR]) was used to evaluate the effect. RESULTS: The cohort included 1,077 cardiac surgery patients, 79 of whom experienced SSIs within 90 d of surgery. The rates for sternal site infections and harvest site infections were 5.8 (95% confidence interval [CI]: 4.4-7.3) and 2.5 (95% CI: 1.4-3.7) per 100 procedures, respectively. The risk of SSI was increased with the pre-operative use of immunosuppressors/steroids (AOR 3.47, 95% CI: 1.27-9.52) and α-blockers (AOR 3.74, 95% CI: 1.21-1.47). CONCLUSIONS: Our findings support the effect of immunosuppressors/steroids on the risk of SSIs and add evidence to the previously reported association between the use of anti-hypertensive medications and subsequent development of infection/sepsis.

Oral corticosteroids and the risk of serious infections in patients with elderly-onset inflammatory bowel diseases.

OBJECTIVES: Systemic corticosteroids are among the most common anti-inflammatory treatments in elderly-onset inflammatory bowel disease (IBD) patients. Steroid use and older age each independently predisposes to infections, and infections increase mortality in hospitalized older IBD patients. Therefore, our objective was to examine the risk of serious infections in elderly-onset IBD patients treated with oral corticosteroids, and explore how the timing of exposure affects the risk estimates. METHODS: Using the health-care databases of the province of Quebec, Canada, we conducted a population-based cohort study with a nested case-control analysis. Incident IBD patients aged ≥66 years were identified. Conditional logistic regression was performed to estimate crude and adjusted rate ratios (aRRs) with 95% confidence intervals (CIs). RESULTS: We identified 3,522 elderly-onset patients, of which 564 cases with serious infections were identified during a mean 4.4 years of follow-up (incidence rate 3.7 per 100 per year) and matched to 2,646 controls. The rate of serious infections was significantly higher in those exposed to oral corticosteroids any time during the previous 6-month period compared with those nonexposed (aRR 2.3; 95% CI 1.8-2.9). Those currently exposed (within 45 days) had a higher risk (aRR 2.8; 95% CI 2.1-3.7). The residual effect of oral corticosteroids remained marginally statistically significant up to the 90-day period before the index date (aRR 1.7; 95% CI 1.0-2.7). CONCLUSIONS: We found an excess relative risk for serious infections in elderly-onset IBD patients on oral corticosteroid therapy. Those with current exposure demonstrated a higher vulnerability to infections.

Burden of HIV and tuberculosis co-infection in Montreal, Quebec.

OBJECTIVE: Define the burden of HIV-TB co-infection and predictors of HIV screening among incident TB cases. METHODS: Analysis of surveillance data on TB incident cases reported to Montreal's Public Health Department from 2004 to 2009. Among all reported TB cases, proportions of cases with HIV testing and HIV infection were calculated by patient characteristics. A test for linear trends was performed on the annual proportions of HIV-tested and HIV-positive cases. Adjusted odds ratios (AOR) for HIV testing at time of TB diagnosis were computed. RESULTS: A total of 778 incident TB cases were included in the analysis. HIV testing was reported for 50.8% (n=395) of cases. The proportion of HIV-tested cases increased significantly from 43% in 2004 to 70% in 2009. HIV-TB co-infection was found in 9.3% of patients with reported HIV status or in 4.2% of the overall cohort. HIV prevalence was high in men, individuals aged 40-59, those originating from Sub-Saharan Africa and the Caribbean, and the homeless. Multivariate analysis revealed that HIV testing at time of TB diagnosis was performed mainly for subjects born in the Caribbean, Central or South America, or Sub-Saharan Africa, those with pulmonary disease, and injection drug users. CONCLUSIONS: Although reporting of HIV testing among incident TB patients increased, targeted HIV testing still occurs. HIV prevalence in TB cases remained stable during the study period; however, it may be underestimated due to missed opportunities for HIV testing and under-reporting.