Smaller Differences in the Comparative Effectiveness of Biologics in Reducing Asthma-Related Hospitalizations Compared With Overall Exacerbations.

BACKGROUND: Evidence on the comparative effectiveness of respiratory biologics remains sparse. OBJECTIVE: We sought to evaluate the comparative effectiveness of omalizumab, mepolizumab, benralizumab, and dupilumab in a matched retrospective cohort of patients with asthma. METHODS: We identified patients with asthma aged ≥18 years who were incident users of these biologics between November 1, 2018, and June 30, 2023, in administrative claims data from the Food and Drug Administration's Sentinel System and Merative MarketScan Commercial Database. We compared asthma-related exacerbations and hospitalizations in the 12 months since biologic prescription in pairwise comparisons of propensity score-matched cohorts. Covariates used in matching included age, sex, allergic comorbidities, baseline asthma medications use, and the Charlson Comorbidity Index. Incidence rate ratios (IRR) and 95% confidence intervals (CI) were estimated using negative binomial regression models. RESULTS: A total of 893 patients on mepolizumab, 1300 on benralizumab, 1170 on omalizumab, and 1863 on dupilumab were identified. The average age was 55 years, and two-thirds of the participants were female. At baseline, over 80% of these individuals had an active prescription for an inhaled corticosteroid. Almost half of patients on dupilumab had concomitant nasal polyposis compared with 6% to 13% of patients on the other biologics. Covariates were balanced after matching. In matched analyses, dupilumab was associated with the lowest incidence of exacerbations over the follow-up period (vs dupilumab): mepolizumab (IRR: 1.36; 95% CI: 1.12, 1.64), omalizumab (IRR: 1.33; 95% CI: 1.13, 1.58), benralizumab (IRR: 1.19; 95% CI: 1.00, 1.41). For exacerbations leading to hospitalizations, benralizumab and mepolizumab were associated with the lowest incidence of hospitalizations, and the greatest difference was between mepolizumab versus dupilumab (IRR: 0.76; 95% CI: 0.56, 1.03). CONCLUSIONS: Dupilumab was associated with the lowest incidence of overall exacerbations, and mepolizumab with the lowest incidence of asthma hospitalizations in this administrative claims-based cohort of individuals with asthma. Despite matching propensity scores, residual confounding, such as baseline eosinophil count, may explain some of these findings.

Real-world Evidence Comparing Tofacitinib and Vedolizumab in Anti-TNF-experienced Patients With Ulcerative Colitis.

BACKGROUND: Antitumor necrosis factor (anti-TNF) inhibitors are first-line treatment among patients with ulcerative colitis (UC). With time, patients tend to lose response or become intolerant, necessitating switching to small cell biologics such as tofacitinib or vedolizumab. In this real-world study of a large, geographically diverse US population of TNF-experienced patients with UC, we evaluated the effectiveness and safety of newly initiating treatment with tofacitinib vs vedolizumab. METHODS: We conducted a cohort study using secondary data from a large US insurer (Anthem, Inc.). Our cohort included patients with UC newly initiating treatment with tofacitinib or vedolizumab. Patients were required to have evidence of treatment with anti-TNF inhibitors in the 6 months prior to cohort entry. The primary outcome was treatment persistence >52 weeks. Additionally, we evaluated the following secondary outcomes as additional measures of effectiveness and safety: (1) all-cause hospitalization; (2) total abdominal colectomy; (3) hospitalization for infection; (4) hospitalization for malignancy; (5) hospitalization for cardiac events; and (6) hospitalization for thromboembolic events. We used fine stratification by propensity scores to control for confounding by demographics, clinical factors, and treatment history at baseline. RESULTS: Our primary cohort included 168 new users of tofacitinib and 568 new users of vedolizumab. Tofacitinib was associated with lower treatment persistence (adjusted risked ratio, 0.77; 95% CI, 0.60 -0.99). Differences in secondary measures of effectiveness or safety between tofacitinib initiators vs vedolizumab initiators were not statistically significant (all-cause hospitalization, adjusted hazard ratio, 1.23; 95% CI, 0.83-1.84; total abdominal colectomy, adjusted HR, 1.79; 95% CI, 0.93-3.44;and hospitalization for any infection, adjusted HR, 1.94; 95% CI, 0.83-4.52). DISCUSSION: Ulcerative colitis patients with prior anti-TNF experience initiating tofacitinib demonstrated lower treatment persistence compared with those initiating vedolizumab. This finding is in contrast to other recent studies suggesting superior effectiveness of tofacitinib. Ultimately, head-to-head randomized, controlled trials that focus on directly measured end points may be needed to best inform clinical practice.

Anti-TNF-experienced patients with UC initiating vedolizumab demonstrated higher treatment persistence compared with those initiating tofacitinib in this real-world evaluation of comparative effectiveness. Ultimately, head-to-head randomized trials that focus on directly measured end points are needed to best inform clinical practice.

Real-World Evidence Comparing Vedolizumab and Ustekinumab in Antitumor Necrosis Factor-Experienced Patients With Crohn's Disease.

INTRODUCTION: Many patients with Crohn's disease (CD) lose response or become intolerant to antitumor necrosis factor (TNF) therapy and subsequently switch out of class. We compared the effectiveness and safety of ustekinumab to vedolizumab in a large, geographically diverse US population of TNF-experienced patients with CD. METHODS: We conducted a retrospective cohort study using longitudinal claims data from a large US insurer (Anthem, Inc.). We identified patients with CD initiating vedolizumab or ustekinumab with anti-TNF treatment in the prior 6 months. Our primary outcome was treatment persistence for >52 weeks. Secondary outcomes included (i) all-cause hospitalization, (ii) hospitalization for CD with surgery, (iii) hospitalization for CD without surgery, and (iv) hospitalization for infection. Propensity score fine stratification was used to control for demographic and baseline clinical characteristics and prior treatments. RESULTS: Among 885 new users of ustekinumab and 490 new users of vedolizumab, we observed no difference in treatment persistence (adjusted risk ratio 1.09 [95% confidence interval 0.95-1.25]). Ustekinumab was associated with a lower rate of all-cause hospitalization (adjusted hazard ratio 0.73 [0.59-0.91]), nonsurgical CD hospitalization (adjusted hazard ratio 0.58 [0.40-0.83]), and hospitalization for infection (adjusted hazard ratio 0.56 [0.34-0.92]). DISCUSSION: This real-world comparative effectiveness study of anti-TNF-experienced patients with CD initiating vedolizumab or ustekinumab showed similar treatment persistence rates beyond 52 weeks, although secondary outcomes such as all-cause hospitalizations, nonsurgical CD hospitalizations, and hospitalizations for infection favored ustekinumab initiation. We, therefore, advocate for individualized decision making in this medically refractory population, considering patient preference and other factors such as cost and route of administration.

Estimating total small solute clearance in patients treated with continuous ambulatory peritoneal dialysis without urine and dialysate collection.

BACKGROUND: International Society for Peritoneal Dialysis guidelines recommend to routinely monitor the total measured clearance (mCl) of small solutes such as creatinine; however, collection of 24-h urine and peritoneal dialysis (PD) fluid is burdensome to patients and prone to errors. We hypothesized that equations could be developed to estimate mCl (estimated clearance (eCl)) using endogenous filtration markers. METHODS: In the Guangzhou PD Study (n = 980), we developed eCl equations using linear regression in two-third and validated them in the remaining one-third. Reference tests were mCl for urea nitrogen (UN) (mClUN, ml/min) and average mCl for UN and creatinine (mClUN-cr, ml/min/1.73 m2). Index tests were various eCl equations using UN, creatinine, low-molecular-weight proteins (LMWPs) (beta-trace protein (BTP), beta-2 microglobulin (B2M), and cystatin C), demographic variables, and body size. After reexpression of the equations in the combined data set, we analyzed accuracy (eCl within ± 2.0 units of mCl) and the predictive value of eCl to detect a weekly total standard Kt/V (weekly mClUN indexed for total body water) > 1.7 using receiver operating characteristic curve. RESULTS: Mean age of the cohort was 50 ± 15 years, 53% were male; mClUN was 6.9 ± 1.8 and mClUN-cr was 7.5 ± 2.8. Creatinine but not UN contributed to eCl for both mCl. LMWP did not improve accuracy for mClUN (range 88-89%). BTP and B2M improved the accuracy for mClUN-cr (82% vs. 80%); however, differences were small. The area under the curve for predicting a weekly Kt/V > 1.7 was similar for all equations (range 0.79-0.80). CONCLUSIONS: Total small solute clearance can be estimated moderately well in continuous ambulatory PD patients using serum creatinine and demographic variables without urine and dialysate collection.

GFR Slope as a Surrogate End Point for Kidney Disease Progression in Clinical Trials: A Meta-Analysis of Treatment Effects of Randomized Controlled Trials.

BACKGROUND: Surrogate end points are needed to assess whether treatments are effective in the early stages of CKD. GFR decline leads to kidney failure, but regulators have not approved using differences in the change in GFR from the beginning to the end of a randomized, controlled trial as an end point in CKD because it is not clear whether small changes in the GFR slope will translate to clinical benefits. METHODS: To assess the use of GFR slope as a surrogate end point for CKD progression, we performed a meta-analysis of 47 RCTs that tested 12 interventions in 60,620 subjects. We estimated treatment effects on GFR slope (mean difference in GFR slope between the randomized groups), for the total slope starting at baseline, chronic slope starting at 3 months after randomization, and on the clinical end point (doubling of serum creatinine, GFR<15 ml/min per 1.73 m2, or ESKD) for each study. We used Bayesian mixed-effects analyses to describe the association of treatment effects on GFR slope with the clinical end point and to test how well the GFR slope predicts a treatment's effect on the clinical end point. RESULTS: Across all studies, the treatment effect on 3-year total GFR slope (median R2=0.97; 95% Bayesian credible interval [BCI], 0.78 to 1.00) and on the chronic slope (R2 0.96; 95% BCI, 0.63 to 1.00) accurately predicted treatment effects on the clinical end point. With a sufficient sample size, a treatment effect of 0.75 ml/min per 1.73 m2/yr or greater on total slope over 3 years or chronic slope predicts a clinical benefit on CKD progress with at least 96% probability. CONCLUSIONS: With large enough sample sizes, GFR slope may be a viable surrogate for clinical end points in CKD RCTs.

Change in albuminuria as a surrogate endpoint for progression of kidney disease: a meta-analysis of treatment effects in randomised clinical trials.

BACKGROUND: Change in albuminuria has strong biological plausibility as a surrogate endpoint for progression of chronic kidney disease, but empirical evidence to support its validity is lacking. We aimed to determine the association between treatment effects on early changes in albuminuria and treatment effects on clinical endpoints and surrograte endpoints, to inform the use of albuminuria as a surrogate endpoint in future randomised controlled trials. METHODS: In this meta-analysis, we searched PubMed for publications in English from Jan 1, 1946, to Dec 15, 2016, using search terms including "chronic kidney disease", "chronic renal insufficiency", "albuminuria", "proteinuria", and "randomized controlled trial"; key inclusion criteria were quantifiable measurements of albuminuria or proteinuria at baseline and within 12 months of follow-up and information on the incidence of end-stage kidney disease. We requested use of individual patient data from the authors of eligible studies. For all studies that the authors agreed to participate and that had sufficient data, we estimated treatment effects on 6-month change in albuminuria and the composite clinical endpoint of treated end-stage kidney disease, estimated glomerular filtration rate of less than 15 mL/min per 1·73 m2, or doubling of serum creatinine. We used a Bayesian mixed-effects meta-regression analysis to relate the treatment effects on albuminuria to those on the clinical endpoint across studies and developed a prediction model for the treatment effect on the clinical endpoint on the basis of the treatment effect on albuminuria. FINDINGS: We identified 41 eligible treatment comparisons from randomised trials (referred to as studies) that provided sufficient patient-level data on 29 979 participants (21 206 [71%] with diabetes). Over a median follow-up of 3·4 years (IQR 2·3-4·2), 3935 (13%) participants reached the composite clinical endpoint. Across all studies, with a meta-regression slope of 0·89 (95% Bayesian credible interval [BCI] 0·13-1·70), each 30% decrease in geometric mean albuminuria by the treatment relative to the control was associated with an average 27% lower hazard for the clinical endpoint (95% BCI 5-45%; median R2 0·47, 95% BCI 0·02-0·96). The association strengthened after restricting analyses to patients with baseline albuminuria of more than 30 mg/g (ie, 3·4 mg/mmol; R2 0·72, 0·05-0·99]). For future trials, the model predicts that treatments that decrease the geometric mean albuminuria to 0·7 (ie, 30% decrease in albuminuria) relative to the control will provide an average hazard ratio (HR) for the clinical endpoint of 0·68, and 95% of sufficiently large studies would have HRs between 0·47 and 0·95. INTERPRETATION: Our results support a role for change in albuminuria as a surrogate endpoint for the progression of chronic kidney disease, particularly in patients with high baseline albuminuria; for patients with low baseline levels of albuminuria this association is less certain. FUNDING: US National Kidney Foundation.

Development and Validation of Residual Kidney Function Estimating Equations in Dialysis Patients.

RATIONALE & OBJECTIVE: Measurement of residual kidney function is recommended for the adjustment of the dialysis prescription, but timed urine collections are difficult and prone to errors. Equations to calculate residual kidney function from serum concentrations of endogenous filtration markers and demographic parameters would simplify monitoring of residual kidney function. However, few equations to estimate residual kidney function using serum concentrations of small solutes and low-molecular-weight proteins have been developed and externally validated. STUDY DESIGN: Study of diagnostic test accuracy. SETTING & PARTICIPANTS: 823 Chinese peritoneal dialysis (PD) patients (development cohort) and 826 PD and hemodialysis patients from the Netherlands NECOSAD study (validation cohort). TESTS COMPARED: Equations to estimate residual kidney function (estimated clearance [eCl]) using serum creatinine, urea nitrogen, cystatin C, ß2-microglobulin (B2M), ß-trace protein (BTP), and combinations, as well as demographic variables (age, sex, height, and weight). Equations were developed using multivariable linear regression analysis in the development cohort and then tested in the validation cohort. Equations were compared with published validated equations. OUTCOMES: Residual kidney function measured as urinary clearance (mCl) of urea nitrogen (mClUN) and average of creatinine and urea nitrogen clearance (mClUN-cr). RESULTS: In external validation, bias (difference between mCl and eCl) was within ± 1.0 unit for all equations. Accuracy (percent of differences within ± 2.0 units) was significantly better for eClBTP, eClB2M, and eClBTP-B2M than eClUN-cr for both mClUN (78%, 80%, and 81% vs 72%; P < 0.05 for all) and mClUN-cr (72%, 78%, and 79% vs 68%; P < 0.05 for all). The area under the curve for predicting mClUN > 2.0 mL/min was highest for eClB2M (0.853) and eClBTP-B2M (0.848). Results were similar for other validated equations. LIMITATIONS: Development cohort only consisted of PD patients, no gold-standard method for residual kidney function measurement. CONCLUSIONS: These results confirm the validity and extend the generalizability of residual kidney function estimating equations from serum concentrations of low-molecular-weight proteins without urine collection.