Time-conditional Propensity Scores Research Articles

Glucosamine and cancer incidence in osteoarthritis: A prevalent new-user cohort design.

Observational studies have associated glucosamine, used to treat joint pain and osteoarthritis, with reductions in cancer incidence, though their study design was affected by selection bias. We assessed this association using a study design that mitigates this selection bias. We used the UK Clinical Practice Research Datalink to identify a cohort of patients diagnosed with osteoarthritis during 1995-2017. The prevalent new-user cohort design was used to match glucosamine initiators with non-users on time-conditional propensity scores and followed until cancer incidence. Hazard ratios (HR) and 95% confidence intervals (CI) of cancer incidence were estimated to compare glucosamine use with non-use. The study cohort of osteoarthritis patients included 20,541 glucosamine initiators who were matched to 20,541 non-users. Over an average follow-up of 8 years, the overall incidence rate of any cancer was 16.4 per 1000 per year. The HR of any cancer incidence with glucosamine use was 0.97 (95% CI 0.91-1.02), compared with non-use. For lung cancer, the HR with glucosamine use was 0.99 (95% CI 0.83-1.18), while it was 1.11 (95% CI 0.93-1.33) for colorectal cancer, 1.07 (95% CI 0.93-1.23) for breast cancer in women and 1.03 (95% CI 0.88-1.22) for prostate cancer. In this large, real-world study of patients with osteoarthritis, designed to emulate a trial, treatment with glucosamine did not reduce the incidence of cancer. This finding reinforces that previous studies, not based on new users, were affected by selection bias. Our study does not support the use of glucosamine to prevent cancer in patients with osteoarthritis.

Clarifying the causal contrast: An empirical example applying the prevalent new user study design.

The prevalent new user design extends the active comparator new user design to include patients switching to a treatment of interest from a comparator. We examined the impact of adding "switchers" to incident new users on the estimated hazard ratio (HR) of hospitalized heart failure. Using MarketScan claims data (2000-2014), we estimated HRs of hospitalized heart failure between patients initiating GLP-1 receptor agonists (GLP-1 RA) and sulfonylureas (SU). We considered three estimands: (1) the effect of incident new use; (2) the effect of switching; and (3) the effect of incident new use or switching, combining the two population. We used time-conditional propensity scores (TCPS) and time-stratified standardized morbidity ratio (SMR) weighting to adjust for confounding. We identified 76 179 GLP-1 RA new users, of which 12% were direct switchers (within 30 days) from SU. Among incident new users, GLP-1 RA was protective against heart failure (adjHRSMR = 0.74 [0.69, 0.80]). Among switchers, GLP-1 RA was not protective (adjHRSMR = 0.99 [0.83, 1.18]). Results in the combined population were largely driven by the incident new users, with GLP-1 RA having a protective effect (adjHRSMR = 0.77 [0.72, 0.83]). Results using TCPS were consistent with those estimated using SMR weighting. When analyses were conducted only among incident new users, GLP-1 RA had a protective effect. However, among switchers from SU to GLP-1 RA, the effect estimates substantially shifted toward the null. Combining patients with varying treatment histories can result in poor confounding control and camouflage important heterogeneity.

Association between sodium-glucose cotransporter-2 inhibitors and arrhythmic outcomes in patients with diabetes and pre-existing atrial fibrillation.

Prior studies suggest that sodium-glucose cotransporter-2 inhibitors (SGLT2is) may decrease the incidence of atrial fibrillation (AF). However, it is unknown whether SGLT2i can attenuate the disease course of AF among patients with pre-existing AF and Type II diabetes mellitus (DM). In this study, our objective was to examine the association between SGLT2i prescription and arrhythmic outcomes among patients with DM and pre-existing AF. We conducted a population-based cohort study of adults with DM and AF between 2014 and 2019. Using a prevalent new-user design, individuals prescribed SGLT2i were matched 1:1 to those prescribed dipeptidyl peptidase-4 inhibitors (DPP4is) based on time-conditional propensity scores. The primary endpoint was a composite of AF-related healthcare utilization (i.e. hospitalization, emergency department visits, electrical cardioversion, or catheter ablation). Secondary outcome measures included all-cause mortality, heart failure (HF) hospitalization, and ischaemic stroke or transient ischaemic attack (TIA). Cox proportional hazard models were used to examine the association of SGLT2i with the study endpoint. Among 2242 patients with DM and AF followed for an average of 3.0 years, the primary endpoint occurred in 8.7% (n = 97) of patients in the SGLT2i group vs. 10.0% (n = 112) of patients in the DPP4i group [adjusted hazard ratio 0.73 (95% confidence interval 0.55-0.96; P = 0.03)]. Sodium-glucose cotransporter-2 inhibitors were associated with significant reductions in all-cause mortality and HF hospitalization, but there was no difference in the risk of ischaemic stroke/TIA. Among patients with DM and pre-existing AF, SGLT2is are associated with decreased AF-related health resource utilization and improved arrhythmic outcomes compared with DPP4is.

Gabapentinoids and Risk for Severe Exacerbation in Chronic Obstructive Pulmonary Disease : A Population-Based Cohort Study.

North American and European health agencies recently warned of severe breathing problems associated with gabapentinoids, including in patients with chronic obstructive pulmonary disease (COPD), although supporting evidence is limited. To assess whether gabapentinoid use is associated with severe exacerbation in patients with COPD. Time-conditional propensity score-matched, new-user cohort study. Health insurance databases from the Régie de l'assurance maladie du Québec in Canada. Within a base cohort of patients with COPD between 1994 and 2015, patients initiating gabapentinoid therapy with an indication (epilepsy, neuropathic pain, or other chronic pain) were matched 1:1 with nonusers on COPD duration, indication for gabapentinoids, age, sex, calendar year, and time-conditional propensity score. The primary outcome was severe COPD exacerbation requiring hospitalization. Hazard ratios (HRs) associated with gabapentinoid use were estimated in subcohorts according to gabapentinoid indication and in the overall cohort. The cohort included 356 gabapentinoid users with epilepsy, 9411 with neuropathic pain, and 3737 with other chronic pain, matched 1:1 to nonusers. Compared with nonuse, gabapentinoid use was associated with increased risk for severe COPD exacerbation across the indications of epilepsy (HR, 1.58 [95% CI, 1.08 to 2.30]), neuropathic pain (HR, 1.35 [CI, 1.24 to 1.48]), and other chronic pain (HR, 1.49 [CI, 1.27 to 1.73]) and overall (HR, 1.39 [CI, 1.29 to 1.50]). Residual confounding, including from lack of smoking information. In patients with COPD, gabapentinoid use was associated with increased risk for severe exacerbation. This study supports the warnings from regulatory agencies and highlights the importance of considering this potential risk when prescribing gabapentin and pregabalin to patients with COPD. Canadian Institutes of Health Research and Canadian Lung Association.

Association between proton pump inhibitors use and risk of asthma in Korea: A prevalent new-user cohort study.

There have been conflicting mechanisms that proton pump inhibitors (PPIs) may promote or prevent asthma development. However, the evidence on the association of PPI use with the risk of asthma and its exposure-response relationship has been limited. We aim to identify the association between the use of PPIs and the incidence of asthma, compared with use of histamine 2 receptor antagonists (H2RAs). A nationwide, prevalent new-user cohort study was conducted using Korea's National Sample Cohort database. Patients were defined as PPI or H2RA users between 2003 and 2019. PPI users matched to H2RA users based on time-conditional propensity score. Cox proportional hazards model was used to estimate adjusted hazard ratios with 95% confidence intervals of incident asthma associated with PPI use by duration of use, cumulative dose, and average dose per duration. Among the 250,041 pairs, PPI users (51.3% male; mean [SD] age, 42.6 [16.5]; mean follow-up, 6.7 years) showed a higher incidence rate of asthma (7.94 events per 1000 person-year) compared to H2RA users (3.70 events per 1000 person-year) with adjusted hazard ratio of 2.15 (95% confidence interval = 2.08-2.21). The risk of asthma was significantly increased across all observed groups of duration of use, cumulative dose, and average dose per duration. This study suggested that PPI use is associated with an increased risk of developing asthma compared to H2RA use.

Survival Benefit of Kidney Transplantation in Patients With End-Stage Kidney Disease and Prior Acute Myocardial Infarction.

Patients with end stage kidney disease (ESKD) and a previous acute myocardial infarction (AMI) have less access to KT. Data on ESKD patients with an AMI history who underwent first KT or dialysis between January 2007 and December 2018 were extracted from the Korean National Health Insurance Service. Patients who underwent KT (n = 423) were chronologically matched in a 1:3 ratio with those maintained on dialysis (n = 1,269) at the corresponding dates, based on time-conditional propensity scores. The 1, 5, and 10years cumulative incidences for all-cause mortality were 12.6%, 39.1%, and 60.1% in the dialysis group and 3.1%, 7.2%, and 14.5% in the KT group. Adjusted hazard ratios (HRs) of KT versus dialysis were 0.17 (95% confidence interval [CI], 0.12-0.24; p < 0.001) for mortality and 0.38 (95% CI, 0.23-0.51; p < 0.001) for major adverse cardiovascular events (MACE). Of the MACE components, KT was most protective against cardiovascular death (HR, 0.23; 95% CI, 0.12-0.42; p < 0.001). Protective effects of KT for all-cause mortality and MACE were consistent across various subgroups, including patients at higher risk (e.g., age >65years, recent AMI [<6months], congestive heart failure). KT is associated with lower all-cause mortality and MACE than maintenance dialysis patients with a prior AMI.

JAK-inhibitors and risk on serious viral infection, venous thromboembolism and cardiac events in patients with rheumatoid arthritis: A protocol for a prevalent new-user cohort study using the Danish nationwide DANBIO register.

Janus Kinase inhibitors (JAKis) are targeted synthetic disease-modifying antirheumatic drugs and represent an important alternative to treat patients with moderate to high rheumatoid arthritis (RA) disease activity. Safety concerns associated with increased risk for venous thromboembolism (VTE), serious viral infection, and, more recently, major adverse cardiovascular events (MACE) in JAKi users have emerged worldwide. However, as the exact mechanisms to explain these safety concerns remain unclear, the increased risk of VTE, MACE, and serious viral infection in JAKi users is heavily debated. In light of the need to enrich the safety profile of JAKis in real-world data, we aim to quantify the incidence and risk of MACE, VTE, and serious viral infections in RA patients registered in the Danish DANBIO registry, a nationwide registry of biological therapies used in rheumatology. Therefore, we will conduct a population-based cohort study using a prevalent new-user design. We will identify all RA patients in the DANBIO, ≥ 18 years old, receiving a JAKi or a tumor necrosis factor α inhibitor (TNF-αi) from January 2017 to December 2022. Prevalent and new users of JAKis will be matched to TNF-αi comparators with similar exposure history using time-conditional propensity scores (TCPS). We will describe the cumulative incidence of the outcomes (VTE, MACE, serious viral infection) in each exposure group (JAKi users; TNF-αi users), stratified by outcome type. Additionally, the Aalen-Johansen method will be used to estimate the time-to-event survival function stratified by outcome type. We will also estimate the hazard ratio (HR) with 95% confidence interval (CI) of each outcome in both exposure groups using the time-dependent Cox proportional hazards model. Results will enrich the safety profile of JAKis in real-world data.

Comparative effectiveness of sodium-glucose co-transporter 2 inhibitors and dipeptidyl peptidase-4 inhibitors on cardiorenal function and treatment adherence: A Prevalent New-User Design Study in tertiary hospitals

Abstract Objectives Data on the long-term effects comparing sodium-glucose co-transporter 2 inhibitors (SGLT2i) and dipeptidyl peptidase-4 inhibitors (DPP4i) are scarce, especially from middle-income countries. To examine the effects of SGLT2i and DPP4i on the cardiorenal function and treatment adherence for people with type 2 diabetes (T2D) using prevalent new-user design in real-world setting. Methods We conducted a retrospective cohort study in two tertiary hospitals in Malaysia and matched T2D patients initiated on SGLT2i or DPP4i from 2010 to 2021 using time-conditional propensity score. Outcomes of interest included cardiovascular and renal outcomes, as well as clinical lab outcomes, adherence and non-persistence. The hazard ratios for cardiorenal outcomes was inferred using Cox proportional hazards model. Key findings The cohort included 1528 patients, with 406 SGLT2i users matched with 406 DPP4i users. Over a median follow-up of 1.52 years, no differences in cardiorenal outcomes were observed. Patients initiated with SGLT2i had lower HbA1c at 12-month (-0.79%,p&amp;lt;0.001) compared to DPP4i (-0.49%,p&amp;lt;0.05; difference:-0.30%,p&amp;lt;0.05). No differences in the renal, lipid, weight and blood pressure parameters were observed between both groups. Higher medication persistence was noted among SGLT2i users compared to DPP4i users (92% vs 87%,P=0.03). Conclusions Both medications were comparable in exerting distinct effects on cardiorenal risk factors, with better HbA1c control and medication persistence among SGLT2i users. The long-term cardiorenal outcomes remains undetermined.

268-OR: The Combined Use of SGLT2 Inhibitors and GLP-1 Receptor Agonists on the Risk of Cardiovascular Events among Patients with Type 2 Diabetes

Background: While sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are known to have cardiovascular benefits when used individually, it remains unknown whether their combined use is associated with further reductions in cardiovascular events in the real-world setting. Objective: To determine whether the SGLT2 inhibitor-GLP-1 RA combination is associated with a decreased risk of major adverse cardiovascular events (MACE) compared with SGLT-2 inhibitors alone. Methods: Using the United Kingdom Clinical Practice Research Datalink linked with the Hospital Episode Statistics and Office for National Statistics databases, we identified all patients, &amp;gt;18 years of age, who initiated an SGLT2 inhibitor from 2013 to 2020. Using a prevalent new-user design, we matched 8980 patients initiating an SGLT2 inhibitor-GLP-1 RA combination, in a 1:1 ratio, with patients using SGLT2 inhibitors alone on time-conditional propensity scores. The primary outcome was MACE (myocardial infarction, ischemic stroke, and cardiovascular mortality). Secondary outcomes were the individual components of MACE and heart failure. Patients were followed using an on-treatment approach and Cox proportional hazards regression models were fit to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for each outcome. Results: Compared with SGLT2 inhibitors alone, the SGLT2 inhibitor-GLP-1 RA combination was associated with a 34% decreased risk of MACE (HR: 0.66, 95% CI: 0.48-0.91). In secondary analyses, the combination was associated with a decreased risk of myocardial infarction (HR: 0.64, 95 CI: 0.42-0.98), while the other outcomes generated more modest effects with CIs including the null. Conclusions: The results of this real-world study suggest that the SGLT2 inhibitor-GLP-1 RA combination is associated with further reductions in the risk of MACE, compared with the SGLT2 inhibitors alone. Disclosure L.Azoulay: Advisory Panel; Pfizer Inc., Consultant; Pfizer Inc., Speaker's Bureau; Roche Diagnostics. N.Simms-williams: None. H.Yin: None. S.Lu: None. N.Treves: None. O.Yu: Consultant; Novo Nordisk. Funding Canadian Institutes of Health Research (FDN143328)

123-OR: SGLT2 Inhibitors Are Associated with Kidney Benefits at All Degrees of Proteinuria—A Cohort Study

Background: The kidney benefits of sodium-glucose lowering co-transporter 2 inhibitors (SGLT2i) in adults with non-severe albuminuria, under-represented in SGLT2i trials, are not well established. Objective: We performed a retrospective cohort study to examine the effectiveness of SGLT2i compared to dipeptidyl peptidase-4 inhibitors (DPP4i), in Alberta, Canada. Methods: Using administrative data, we derived a cohort of SGLT2i new-users (2014-2018) with diabetes and eGFR ≥ 30 mL/min/1.73 m2. New SGLT2i users were matched 1:2 to DPP4i users by CKD stage, albuminuria, and diabetes therapy, and by time-conditional propensity-score (age, sex, A1c, etc.). Non-severe albuminuria was defined as a urine albumin to creatinine ratio ≤ 30 mg/mmol. Linear and Poisson regression models were used to determine the association of SGLT2i use with each outcome: eGFR decline (acute [≤ 60 days] and total), adverse kidney events, and all-cause mortality. An adverse kidney event was defined as sustained 40% loss of eGFR, initiation of kidney replacement therapy, or death from kidney causes. Results: SGLT2i users (n=19,238) had a mean age of 57.9 years (male 59.1%) and non-severe albuminuria in 94.4%. Mean eGFR was 91.7 mL/min/1.73m2, and 62.0% were dispensed ACE inhibitor or ARB. Median follow-up was 1.58 years (IQR 0.91-2.49). The acute change in eGFR was -2.79 (SGLT2i) vs -1.43 (DPP4i), for a difference of -1.36 (95% CI -1.74-[-0.98], p &amp;lt; 0.001). After day 60, SGLT2i use was associated with 0.83 (0.66-1.01, p &amp;lt; 0.001) less annual eGFR loss than in DPP4i users. SGLT2i use was associated with fewer adverse kidney events (IRR 0.58 [0.47-0.71], p &amp;lt; 0.001), driven mostly by less sustained loss of eGFR, but was not associated with all-cause mortality (IR 0.82 [0.66-1.01], p = 0.06). Similar findings were observed in those with non-severe albuminuria. Interpretation: SGLT2i may prevent eGFR decline and reduce the risk of adverse kidney events in adults with diabetes, regardless of baseline albuminuria status. Disclosure K.K.Fujita: None. F.Ye: None. D.Collister: None. S.Klarenbach: Research Support; Bayer Inc., Allergan, GlaxoSmithKline plc., CSL Behring, Lundbeck, University Hospital Foundation (University of Alberta), Purdue Canada. D.J.T.Campbell: None. D.Chew: None. A.E.Quinn: None. P.E.Ronksley: None. D.Lau: None.

The Prevalent New-user Design for Studies With no Active Comparator: The Example of Statins and Cancer.

Observational studies evaluating the effect of a drug versus "non-use" are challenging, mainly when defining cohort entry for non-users. The approach using successive monthly cohorts to emulate the randomized trial can be perceived as somewhat opaque and complex. Alternatively, the prevalent new-user design can provide a potentially simpler more transparent emulation. This design is illustrated in the context of statins and cancer incidence. We used the Clinical Practice Research Datalink to identify a cohort of subjects with low-density lipoprotein cholesterol level <5 mmol/L. We used a prevalent new-user design, matching each statin initiator to a non-user from the same time-based exposure set on time-conditional propensity scores with all subjects followed for 10 years for cancer incidence. We estimated the hazard ratio and 95% confidence interval (CI) of cancer incidence with statin use versus non-use using a Cox proportional hazards model, and the results were compared with those using the method of successive monthly cohorts. The study cohort included 182,073 statin initiators and 182,073 matched non-users. The hazard ratio of any cancer after statin initiation versus non-use was 1.01 (95% CI = 0.98, 1.04), compared with 1.04 (95% CI = 1.02, 1.06) under the successive monthly cohorts approach. We estimated similar effects for specific cancers. Using the prevalent new-user design to emulate a randomized trial when compared to "non-use" led to results comparable with the more complex successive monthly cohorts approach. The prevalent new-user design emulates the trial in a potentially more intuitive and palpable manner, providing simpler data presentations in line with those portrayed in a classical trial while producing comparable results.

Development of Osteoarthritis in Adults With Type 2 Diabetes Treated With Metformin vs a Sulfonylurea

Metformin may have a protective association against developing osteoarthritis (OA), but robust epidemiological data are lacking. To determine the risk of OA and joint replacement in individuals with type 2 diabetes treated with metformin compared with a sulfonylurea. This retrospective cohort study used claims data from the Optum deidentified Clinformatics Data Mart Database between December 2003 and December 2019. Participants included individuals aged 40 years or older with at least 1 year of continuous enrollment and type 2 diabetes. Individuals with type 1 diabetes or a prior diagnosis of OA, inflammatory arthritis, or joint replacement were excluded. Time-conditional propensity score matching was conducted using age, sex, race, Charlson comorbidity score, and treatment duration to create a prevalent new-user cohort. Data were analyzed from April to December 2021. Treatment with metformin or a sulfonylurea. The outcomes of interest were incident OA and joint replacement. Cox proportional hazard models were used to calculate adjusted hazard ratios (aHRs) of incident OA and joint replacement. In a sensitivity analysis, individuals only ever treated with metformin were compared with individuals only ever treated with a sulfonylurea, allowing for longer-term follow up of the outcome (even after stopping the medication of interest). After time-conditional propensity score matching, the metformin and control groups each included 20 937 individuals (mean [SD] age 62.0 [11.5] years; 24 379 [58.2%] males). In the adjusted analysis, the risk of developing OA was reduced by 24% for individuals treated with metformin compared with a sulfonylurea (aHR, 0.76; 95% CI, 0.68-0.85; P < .001), but there was no significant difference for risk of joint replacement (aHR, 0.80; 95% CI, 0.50-1.27; P = .34). In the sensitivity analysis, the risk of developing OA remained lower in individuals treated with metformin compared with a sulfonylurea (aHR, 0.77; 95% CI, 0.65-0.90; P < .001) and the risk of joint replacement remained not statistically significant (aHR, 1.04; 95% CI, 0.60-1.82; P = .89). In this cohort study of individuals with diabetes, metformin treatment was associated with a significant reduction in the risk of developing OA compared with sulfonylurea treatment. These results further support preclinical and observational data that suggest metformin may have a protective association against the development of OA; future interventional studies with metformin for the treatment or prevention of OA should be considered.

Reduction of Cardiovascular Disease and Mortality Versus Risk of New-Onset Diabetes Mellitus With Statin Use in Patients With Rheumatoid Arthritis.

To assess the effect of statin use on the risk of cardiovascular disease (CVD), all-cause mortality, and type 2 diabetes mellitus (DM) in patients with rheumatoid arthritis (RA). We identified a cohort of patients with RA between 1989 and 2018, within the UK Clinical Practice Research Datalink. We employed a prevalent new-user cohort design by which patients initiating statins were each matched to 2 concurrent nonusers by the time-conditional propensity score (TCPS). Patients were followed until the occurrence of the composite end point of myocardial infarction, stroke, hospitalized heart failure or CVD mortality, all-cause mortality, and incident type 2 DM. The Cox proportional hazards model was used to estimate the hazard ratio (HR) of each outcome associated with as-treated statin use, with adjustment for TCPS deciles and imbalanced covariables. Among 1,768 statin initiators and 3,528 nonusers, 63 versus 340 CVD (3.0 per 100 person-years versus 2.7 per 100 person-years) and 62 versus 525 deaths (2.8 per 100 person-years versus 4.1 per 100 person-years) occurred. Incident type 2 DM was noted in 128 of 3,608 statin initiators (3.0 per 100 person-years) and 518 of 7,208 nonusers (2.0 per 100 person-years). Statin initiation was associated with 32% (HR 0.68 [95% confidence interval (95% CI) 0.51-0.90]) reduction in CVD, 54% (HR 0.46 [95% CI 0.35-0.60]) reduction in all-cause mortality, and 33% increase in type 2 DM (HR 1.33 [95% CI 1.09-1.63]). The number needed to treat/number needed to harm to prevent a CVD or all-cause mortality or to cause type 2 DM in 1 year was 102, 42, and 127, respectively. Statins are associated with important reductions in CVD and mortality that outweigh the modest increase in type 2 DM risk in RA patients.

Non-Renal Risk Factors for Chronic Kidney Disease in Liver Recipients with Functionally Intact Kidneys at 1 Month.

Chronic kidney disease (CKD) is a critical complication of liver transplants, of which non-renal risk factors are not fully understood yet. This study aimed to reveal pre- and post-transplant risk factors for CKD (<60 mL/min/1.73 m2), examining liver recipients with functionally intact kidneys one month after grafting using nationwide cohort data. Baseline risk factors were analyzed with multivariable Cox regression analyses and post-transplant risk factors were investigated with the time-dependent Cox model and matched analyses of time-conditional propensity scores. Of the 2274 recipients with a one-month eGFR ≥ 60 mL/min/1.73 m2, 494 (22.3%) developed CKD during a mean follow-up of 36.6 ± 14.4 months. Age, female sex, lower body mass index, pre-transplant diabetes mellitus, and lower performance status emerged as baseline risk factors for CKD. Time-dependent Cox analyses revealed that recurrent hepatocellular carcinoma (HR = 1.93, 95% CI 1.06–3.53) and infection (HR = 1.44, 95% CI 1.12–1.60) were significant post-transplant risk factors for CKD. Patients who experienced one of those factors showed a significantly higher risk of subsequent CKD compared with the matched controls who lacked these features (p = 0.013 for recurrent hepatocellular carcinoma, and p = 0.003 for infection, respectively). This study clarifies pre- and post-transplant non-renal risk factors, which lead to renal impairment after LT independently from patients’ renal functional reserve.

Second-Generation Long-Acting Injectable Antipsychotics and the Risk of Treatment Failure in a Population-Based Cohort.

Introduction: Second-generation long-acting injectable antipsychotics (SG-LAIAs) may improve outcomes compared to other antipsychotics. Real-world studies using linked administrative databases play an important role in assessing the comparative effectiveness of antipsychotic medications. Methods: We used a prevalent new-user design in a population-based cohort of antipsychotic users with diagnosis of a psychotic disorder to compare the primary outcome of treatment failure, defined as psychiatric hospitalization, completed suicide, incarceration, or treatment discontinuation. Additional outcomes were all-cause mortality. SG-LAIA users were matched on a 1:1 basis with other antipsychotic users based on the time-conditional propensity score, calendar time, and prior antipsychotic exposure. Results: The use of LAIAs was not associated with a lower risk of treatment failure than other antipsychotics (adjusted hazard ratio 1.07 and 95% confidence interval 0.98–1.15) but did reduce all-cause mortality (adjusted hazard ratio 0.69 and 95% confidence interval 0.48–0.99). Monotherapy with LAIAs was superior to other antipsychotic monotherapy (adjusted hazard ratio for treatment failure 0.83 and 95% confidence interval 0.78–0.89), and LAIAs were superior to other antipsychotics in antipsychotic-naïve users (adjusted hazard ratio for treatment failure 0.57 and 95% confidence interval 0.47–0.70). Conclusion: In this population-based cohort, SG-LAIAs reduced the risk of treatment failure in incident new users but not in prevalent new users.

Safety of Tacrolimus Monotherapy within 12 Months after Liver Transplantation in the Era of Reduced Tacrolimus and Mycophenolate Mofetil: National Registry Study.

Tacrolimus monotherapy is accepted as a feasible option during early post-liver transplantation as per current international consensus guidelines. However, its effects in the recent era of reduced tacrolimus (TAC) and mycophenolate mofetil (MMF) remain unclear. Liver recipients who either received TAC monotherapy from the treatment onset or switched from TAC/MMF to TAC-mono within 12 months (TAC-mono group; n = 991) were chronologically matched to patients who continued to receive TAC/MMF (TAC/MMF group; n = 991) at the corresponding time points on time-conditional propensity scores. Outcomes within 12 months after matched time points were compared. Biopsy-proven rejection (TAC/MMF: 3.5% vs. TAC-mono: 2.6%; p = 0.381) and graft failure (0.2% vs. 0.7%; p = 0.082) were similar in both groups. However, the decline in eGFR was 3.1 mL/min/1.73 m2 (95% CI: 0.8–5.3) greater at six months (p = 0.008) and 2.4 mL/min/1.73 m2 (95% CI: −0.05–4.9) greater at 12 months (p = 0.048) after the matched time points in TAC-mono group than that in TAC/MMF group. TAC trough levels were also higher in the TAC-mono group throughout the study period. TAC-mono within 12 months after liver transplantation is immunologically safe. However, it can increase the required TAC dose and the decline in renal function than that in TAC/MMF combination therapy.

Alternative analytic and matching approaches for the prevalent new-user design: A simulation study.

To describe the creation of prevalent new user (PNU) cohorts and compare the relative bias and computational efficiency of several alternative analytic and matching approaches in PNU studies. In a simulated cohort, we estimated the effect of a treatment of interest vs a comparator among those who switched to the treatment of interest using the originally proposed time-conditional propensity score (TCPS) matching, standardized morbidity ratio weighting (SMRW), disease risk scores (DRS), and several alternative propensity score matching approaches. For each analytic method, we compared the average RR (across 2000 replicates) to the known risk ratio (RR) of 1.00. SMRW and DRS yielded unbiased results (RR=0.998 and 0.997, respectively). TCPS matching with replacement was also unbiased (RR=0.999). TCPS matching without replacement was unbiased when matches were identified starting with patients with the shortest treatment history as initially proposed (RR=0.999), but it resulted in very slight bias (RR=0.983) when starting with patients with the longest treatment history. Similarly, creating a match pool without replacement starting with patients with the shortest treatment history yielded an unbiased estimate (RR=0.997), but matching with the longest treatment history first resulted in substantial bias (RR=0.903). The most biased strategy was matching after selecting one random comparator observation per individual that continued on the comparator (RR=0.802). Multiple analytic methods can estimate treatment effects without bias in a PNU cohort. Still, researchers should be wary of introducing bias when selecting controls for complex matching strategies beyond the initially proposed TCPS.

Discontinuation of Inhaled Corticosteroids from Triple Therapy in COPD: Effects on Major Outcomes in Real World Clinical Practice

Recent reports provide evidence-based guidelines for the withdrawal of inhaled corticosteroids (ICS) in COPD, but data on patients treated with ICS-based triple therapy are sparse and contradictory. We assessed the effect of ICS discontinuation on the incidence of severe exacerbation and pneumonia in a real-world population of patients with COPD who initiated triple therapy. We identified a cohort of patients with COPD treated with LAMA-LABA-ICS triple therapy during 2002–2018, age 50 or older, from the UK’s CPRD database. Subjects who discontinued ICS were matched 1:1 on time-conditional propensity scores to those continuing ICS and followed for one year. Hazard ratios (HR) of severe exacerbation and pneumonia were estimated using Cox regression. The cohort included 42,667 patients who discontinued ICS matched to 42,667 who continued ICS treatment. The hazard ratio of a severe exacerbation with ICS discontinuation relative to ICS continuation was 0.86 (95% CI: 0.78–0.95), while for severe pneumonia it was 0.96 (95% CI: 0.88–1.05). The incidence of severe exacerbation after ICS discontinuation was numerically higher than after continuation among patients with two or more exacerbations in the prior year (HR 1.09; 95% CI: 0.94–1.26) and among those with FEV1 <30% predicted (HR 1.29; 95% CI: 1.04–1.59). This large real-world study in the clinical setting of COPD treatment suggests that certain patients on triple therapy can be safely withdrawn from ICS and remain on bronchodilator therapy. As residual confounding cannot be ruled out, ICS discontinuation is not warranted for patients with multiple exacerbations and with very severe airway obstruction.

Biological Disease-Modifying Antirheumatic Drugs and Osteoporotic Fracture Risk in Patients with Rheumatoid Arthritis: A Danish Cohort Study

ObjectivesClinical trials have shown a beneficial effect from biological disease-modifying antirheumatic drugs (bDMARDs) on hand or axial bone loss in patients with rheumatoid arthritis; however, it is unclear if this translates to a reduced fracture risk. We investigated the effect of bDMARDs on osteoporotic fracture risk compared to no biological treatment in rheumatoid arthritis. MethodsA cohort of patients with rheumatoid arthritis aged 18+ from DANBIO was linked to population-based health registries in Denmark (2006-2016). Adopting a prevalent new-user design, we matched bDMARD users to bDMARD-naïve patients using time-conditional propensity scores. The risk of incident osteoporotic fractures (including hip, vertebrae, humerus, and forearm) was estimated among the matched patients by Cox proportional hazards models. ResultsOut of 24,678 patients with rheumatoid arthritis, 4265 bDMARD users were matched to the same number of bDMARD-naïve patients (mean age 56.2 years, 74% female). During follow-up, 229 osteoporotic fractures occurred among bDMARD users and 205 fractures among bDMARD-naïve patients (incidence rates 12.1 and 13.0 per 1000 person-years, respectively). The use of bDMARDs was not associated with a reduced risk of osteoporotic fractures among patients with rheumatoid arthritis (hazard ratio 0.97, 95% confidence interval 0.78-1.20), compared with no biological treatment. The risk estimates were similar for all osteoporotic fracture sites. ConclusionWe found no independent beneficial effect from using bDMARDs on reducing the risk of osteoporotic fractures in patients with rheumatoid arthritis.

Sodium glucose cotransporter 2 inhibitors and risk of major adverse cardiovascular events: multi-database retrospective cohort study

ObjectiveTo compare the risk of cardiovascular events between sodium glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors among people with type 2 diabetes in a real world context...