Integrating Evidence to Guide Use of Biologics and Small Molecules for Inflammatory Bowel Diseases.

Advances in science have led to the development of multiple biologics and small molecules for the treatment of inflammatory bowel diseases (IBDs). This growth in advanced medical therapies has been accompanied by an increase in methodological innovation to study and compare therapies. Guidelines provide an evidence-based approach to integrating therapies into routine practice, but they are often unable to provide timely recommendations as new therapies come to market, and they have limited incorporation of real-world evidence when making recommendations. This limits the scope and usability of guidelines, and a gap remains in defining how best to position and integrate advanced medical therapies for IBD. In this review, we provide a framework for clinicians and researchers to understand key differences in sources of evidence, how different methodologies are applied to study the comparative effectiveness of advanced medical therapies in IBD, and considerations for how these sources of evidence can be used to better integrate current guideline recommendations. Over time, we anticipate this framework will allow for a transition to living guidelines and/or practice recommendations.

Comparative Efficacy of Advanced Therapies for Management of Moderate-to-Severe Ulcerative Colitis: 2024 American Gastroenterological Association Evidence Synthesis.

BACKGROUND & AIMS: We performed an updated systematic review and network meta-analysis to inform the 2024 American Gastroenterological Association (AGA) Clinical Guidelines on the management of moderate-to-severe ulcerative colitis (UC). METHODS: We searched multiple electronic databases through November 21, 2023, to identify randomized controlled trials in adults with moderate-to-severe UC, comparing different advanced therapies (tumor necrosis factor antagonists, vedolizumab, sphingosine-1-phosphate receptor modulators, interleukin 12/23 or selective interleukin 23 antagonists, and Janus kinase [JAK] inhibitors) against placebo or another active comparator. Our primary outcomes were induction and maintenance of clinical remission, and our secondary outcome was endoscopic improvement. We performed a network meta-analysis using a frequentist approach and applied Grading of Recommendations, Assessment, Development and Evaluation (GRADE) to appraise certainty of evidence. RESULTS: After excluding JAK inhibitors as potential first-line treatment (in accordance with the United States Food and Drug Administration), low-certainty evidence supports clinically important benefit with infliximab, ozanimod, risankizumab, and guselkumab over adalimumab and mirikizumab for achieving remission with induction therapy in biologically naïve patients with moderate-to-severe UC, with risankizumab and ozanimod being ranked the highest for induction of clinical remission. With the inclusion of JAK inhibitors as first-line therapy, upadacitinib was more efficacious compared with all other medications except ozanimod and risankizumab, with low- to moderate-certainty evidence. In patients with prior biologic exposure, upadacitinib, tofacitinib, and ustekinumab were ranked highest for achieving remission. CONCLUSIONS: Using Grading of Recommendations, Assessment, Development and Evaluation to appraise quality of evidence, this updated network meta-analysis will be used to inform comparative efficacy and positioning of advanced therapies for the treatment of biologic-naïve and biologic-exposed patients with moderate-to-severe UC.

Comparative Effectiveness and Cost-Effectiveness of Colorectal Cancer Screening With Blood-Based Biomarkers (Liquid Biopsy) vs Fecal Tests or Colonoscopy.

BACKGROUND & AIMS: Colorectal cancer (CRC) screening is highly effective but underused. Blood-based biomarkers (liquid biopsy) could improve screening participation. METHODS: Using our established Markov model, screening every 3 years with a blood-based test that meets minimum Centers for Medicare & Medicaid Services' thresholds (CMSmin) (CRC sensitivity 74%, specificity 90%) was compared with established alternatives. Test attributes were varied in sensitivity analyses. RESULTS: CMSmin reduced CRC incidence by 40% and CRC mortality by 52% vs no screening. These reductions were less profound than the 68%-79% and 73%-81%, respectively, achieved with multi-target stool DNA (Cologuard; Exact Sciences) every 3 years, annual fecal immunochemical testing (FIT), or colonoscopy every 10 years. Assuming the same cost as multi-target stool DNA, CMSmin cost $28,500/quality-adjusted life-year gained vs no screening, but FIT, colonoscopy, and multi-target stool DNA were less costly and more effective. CMSmin would match FIT's clinical outcomes if it achieved 1.4- to 1.8-fold FIT's participation rate. Advanced precancerous lesion (APL) sensitivity was a key determinant of a test's effectiveness. A paradigm-changing blood-based test (sensitivity >90% for CRC and 80% for APL; 90% specificity; cost ≤$120-$140) would be cost-effective vs FIT at comparable participation. CONCLUSIONS: CMSmin could contribute to CRC control by achieving screening in those who will not use established methods. Substituting blood-based testing for established effective CRC screening methods will require higher CRC and APL sensitivities that deliver programmatic benefits matching those of FIT. High APL sensitivity, which can result in CRC prevention, should be a top priority for screening test developers. APL detection should not be penalized by a definition of test specificity that focuses on CRC only.

Pulmonary arterial hypertension treatment: an individual participant data network meta-analysis.

BACKGROUND AND AIMS: Effective therapies that target three main signalling pathways are approved to treat pulmonary arterial hypertension (PAH). However, there are few large patient-level studies that compare the effectiveness of these pathways. The aim of this analysis was to compare the effectiveness of the treatment pathways in PAH and to assess treatment heterogeneity. METHODS: A network meta-analysis was performed using individual participant data of 6811 PAH patients from 20 Phase III randomized clinical trials of therapy for PAH that were submitted to the US Food and Drug Administration. Individual drugs were grouped by the following treatment pathways: endothelin, nitric oxide, and prostacyclin pathways. RESULTS: The mean (±standard deviation) age of the sample was 49.2 (±15.4) years; 78.4% were female, 59.7% had idiopathic PAH, and 36.5% were on background PAH therapy. After covariate adjustment, targeting the endothelin + nitric oxide pathway {ß: 43.7 m [95% confidence interval (CI): 32.9, 54.4]}, nitric oxide pathway [ß: 29.4 m (95% CI: 22.6, 36.3)], endothelin pathway [ß: 25.3 m (95% CI: 19.8, 30.8)], and prostacyclin pathway [oral/inhaled ß: 19.1 m (95% CI: 14.2, 24.0), intravenous/subcutaneous ß: 24.4 m (95% CI: 15.1, 33.7)] significantly increased 6 min walk distance at 12 or 16 weeks compared with placebo. Treatments also significantly reduced the likelihood of having clinical worsening events. There was significant heterogeneity of treatment effects by age, body mass index, hypertension, diabetes, and coronary artery disease. CONCLUSIONS: Drugs targeting the three traditional treatment pathways significantly improve outcomes in PAH, with significant treatment heterogeneity in patients with some comorbidities. Randomized clinical trials are warranted to identify the most effective treatment strategies in a personalized approach.

One-food versus 4-food elimination diet for pediatric eosinophilic esophagitis: A multisite randomized trial.

BACKGROUND: A 6-food elimination diet in pediatric eosinophilic esophagitis (EoE) is difficult to implement and may negatively affect quality of life (QoL). Less restrictive elimination diets may balance QoL and efficacy. OBJECTIVE: We performed a multisite, randomized comparative efficacy trial of a 1-food (milk) elimination diet (1FED) versus 4-food (milk, egg, wheat, soy) elimination diet (4FED) in pediatric EoE. METHODS: Patients aged 6 to 17 years with histologically active and symptomatic EoE were randomized 1:1 to 1FED or 4FED for 12 weeks. Primary end point was symptom improvement by Pediatric Eosinophilic Esophagitis Symptom Score (PEESS). Secondary end points were proportion experiencing histologic remission (<15 eosinophils per high-power field); change in histologic features (histology scoring system), endoscopic severity (endoscopic reference score), transcriptome (EoE diagnostic panel), and QoL scores; and predictors of remission. RESULTS: Sixty-three patients were randomly assigned to 1FED (n = 38) and 4FED (n = 25). In 4FED versus 1FED, mean PEESS improved -25.0 versus -14.5 (P = .04), but remission rates (41% vs 44%; P = 1.00), histology scoring system (-0.25 vs -0.29; P = .77), endoscopic reference score (-1.10 vs -0.58; P = .47), and QoL scores were similar between groups. The EoE transcriptome normalized in those with histologic response to both diets. Baseline peak eosinophil count predicted remission (odds ratio, 0.975 [95% confidence interval, 0.953-0.999], P = .04; cutoff ≤42 eosinophils per high-power field). The 4FED withdrawal rate (32%) exceeded that of 1FED (11%) (P = .0496). CONCLUSIONS: Although 4FED moderately improved symptoms compared with 1FED, the histologic, endoscopic, QoL, and transcriptomic outcomes were similar in both groups. 1FED is a reasonable first-choice therapy for pediatric EoE, given its effects, tolerability, and relative simplicity.

Comparative effectiveness of dupilumab and omalizumab on asthma exacerbations and systemic corticosteroid prescriptions: Real-world US ADVANTAGE study.

BACKGROUND: In the United States, dupilumab is approved for moderate-to-severe eosinophilic or oral corticosteroid-dependent asthma, and omalizumab is approved for managing moderate-to-severe allergic asthma uncontrolled by inhaled corticosteroids. However, limited comparative effectiveness data exist for these biologics due to differing patient characteristics and treatment histories. OBJECTIVE: This study assessed the real-world effectiveness of dupilumab and omalizumab for asthma in patients in the United States. METHODS: In this retrospective observational study, TriNetX Dataworks electronic medical record data were used to identify patients with asthma age ≥12 years who initiated (index) dupilumab or omalizumab between November 2018 and September 2020 and who had at least 12 months of pre- and post-index clinical information. Inverse probability of treatment weighting was applied to balance potential confounding in treatment groups. Asthma exacerbation rates and systemic corticosteroid (SCS) prescriptions were compared using a doubly robust negative binomial regression model, adjusting for baseline exacerbation/SCS rates and patient characteristics with ≥10% standardized differences after inverse probability of treatment weighting. RESULTS: All inclusion and exclusion criteria were met by 2138 dupilumab patients and 1313 omalizumab patients. After weighting, the majority of baseline characteristics were balanced (standard difference <10%) between the 2 groups. Dupilumab was associated with a 44% lower asthma exacerbation rate (P < .0001) versus omalizumab. Additionally, dupilumab treatment significantly (P < .05) reduced SCS prescriptions by 28% during the follow-up period compared with omalizumab treatment. CONCLUSIONS: The US ADVANTAGE real-world study demonstrated a significant reduction in severe asthma exacerbations and SCS prescriptions for patients prescribed dupilumab compared with patients prescribed omalizumab during 12 months of follow-up.

Antipsychotic drugs in first-episode psychosis: a target trial emulation in the FEP-CAUSAL Collaboration.

Good adherence to antipsychotic therapy helps prevent relapses in first-episode psychosis (FEP). We used data from the FEP-CAUSAL Collaboration, an international consortium of observational cohorts, to emulate a target trial comparing antipsychotics, with treatment discontinuation as the primary outcome. Other outcomes included all-cause hospitalization. We benchmarked our results to estimates from the European First Episode Schizophrenia Trial, a randomized trial conducted in the 2000s. We included 1097 patients with a psychotic disorder and less than 2 years since psychosis onset. Inverse-probability weighting was used to control for confounding. The estimated 12-month risks of discontinuation for aripiprazole, first-generation agents, olanzapine, paliperidone, quetiapine, and risperidone were 61.5% (95% CI, 52.5-70.6), 73.5% (95% CI, 60.5-84.9), 76.8% (95% CI, 67.2-85.3), 58.4% (95% CI, 40.4-77.4), 76.5% (95% CI, 62.1-88.5), and 74.4% (95% CI, 67.0-81.2), respectively. Compared with aripiprazole, the 12-month risk differences were -15.3% (95% CI, -30.0 to 0.0) for olanzapine, -12.8% (95% CI, -25.7 to -1.0) for risperidone, and 3.0% (95% CI, -21.5 to 30.8) for paliperidone. The 12-month risks of hospitalization were similar between agents. Our estimates support use of aripiprazole and paliperidone as first-line therapies for FEP. Benchmarking yielded similar results for discontinuation and absolute risks of hospitalization as in the original trial, suggesting that data from the FEP-CAUSAL Collaboration sufficed to remove confounding for these clinical questions. This article is part of a Special Collection on Mental Health.

Evaluating recommendation-based dietary and physical activity strategies for prostate cancer prevention: a target trial emulation in the Health Professionals Follow-up Study.

The 2018 World Cancer Research Fund/American Institute for Cancer Research recommends sustained strategies of physical activity and diet for cancer prevention, but evidence for long-term prostate cancer risk is limited. Using observational data from 27,859 men in the Health Professionals Follow-up Study, we emulated a target trial of recommendation-based physical activity and dietary strategies and 26-year risks of prostate cancer, adjusting for risk factors via the parametric g-formula. Compared with no intervention, limiting sugar-sweetened beverages showed a 0.4% (0.0-0.9%) lower risk of lethal (metastatic or fatal) disease and 0.5% (0.1-0.9%) lower risk of fatal disease. Restricting consumption of processed foods showed a 0.4-0.9% higher risk of all prostate cancer outcomes. Estimated risk differences for clinically significant disease were close to null for strategies involving fruits and non-starchy vegetables, whole grains and legumes, red meat, and processed meat, as well as under a joint strategy of physical activity and diet. Compared with a "low adherence" strategy, maintaining recommended physical activity levels showed a 0.4% (0.1-0.8%) lower risk of lethal and 0.5% (0.2-0.8%) lower risk of fatal disease. Adhering to specific components of current physical activity and dietary recommendations may help to prevent lethal and fatal prostate cancer over 26 years.

Improving the Validity of Non-Interventional Comparative Effectiveness Research by Basing Study Design on a Specified Existing Randomised Controlled Trial.

This issue of AJE includes three articles (two reporting original analyses and one systematic review) in which non-interventional studies used an existing randomized controlled trial (RCT) as a reference standard to both inform non-interventional study design, and to benchmark results against. This commentary provides a brief background on the challenges of non-interventional comparative effectiveness research, before elaborating on (i) the potential benefits and challenges of basing non-interventional study design on a specified existing RCT, and (ii) the distinction between designing analysis based upon a specified existing RCT and studies based solely upon a hypothetical target trial. Finally, a number of recommendations for the conduct and reporting of non-interventional studies based upon existing RCTs are provided.

Separable effects for adherence.

Comparing different medications is complicated when adherence to these medications differs. We can overcome the adherence issue by assessing effectiveness under sustained use, as in usual causal 'per-protocol' estimands. However, when sustained use is challenging to satisfy in practice, the usefulness of these estimands can be limited. Here we propose a different class of estimands: separable effects for adherence. These estimands compare modified medications, holding fixed a component responsible for non-adherence. Under assumptions about treatment components' mechanisms of effect, a separable effects estimand can quantify the effectiveness of medication initiation strategies on an outcome of interest under the adherence mechanism of one of the medications. These assumptions are amenable to interrogation by subject-matter experts and can be evaluated using causal graphs. We describe an algorithm for constructing causal graphs for separable effects, illustrate how these graphs can be used to reason about assumptions required for identification, and provide semi-parametric weighted estimators.

Evaluating the Effectiveness of Systemic Heparin During Arteriovenous Fistula Creation by Emulating a Target Trial.

Most of the 800,000 people living with end-stage kidney disease in the United States rely on a functioning vascular access to provide life-sustaining hemodialysis, yet one-third of arteriovenous fistulas experience early failures. Determining the safety and effectiveness of systemic heparin during fistula creation could improve the quality and quantity of life for these vulnerable patients. In this paper, a pragmatic randomized trial was emulated to assess the effect of systemic heparin administration (vs. none) during radiocephalic arteriovenous fistula creation on early bleeding and thrombosis using data from two international multicenter randomized trials performed between 2014 and 2019. Marginal risks were estimated using inverse probability weighted parametric survival analysis and confidence intervals were generated with bootstrapping. A total of 914 patients were enrolled and 61% received systemic heparin; median (IQR) age was 58 (49, 67) years and 45% were on hemodialysis at enrollment. No difference in the risk of bleeding events was observed, with a risk difference (95% CI) at 14 days of -0.1% (-1.6, 1.4). The risk of access thrombosis was lower in the heparin group, with a risk of 3.7% (2.6, 4.8) after heparin and 5.3% (3.4, 7.4) without heparin at 14 days (risk ratio 0.72, 95% CI 0.50, 0.98).

Effect of BMI and hemoglobin A1c on survival of veterans with metastatic castration-resistant prostate cancer treated with abiraterone or enzalutamide.

BACKGROUND: Abiraterone acetate and enzalutamide are two common therapies for metastatic castration-resistant prostate cancer (mCRPC) that have shown improved overall survival (OS). The drugs have different mechanisms of action with limited comparative trials to evaluate treatment in patients with comorbidities such as obesity and diabetes. This is important since abiraterone requires the co-administration of prednisone. We assessed the relationship between body mass index (BMI), hemoglobin A1c (HbA1c), treatment, and survival in mCRPC. METHODS: Veterans treated with abiraterone or enzalutamide within the Veterans Health Administration between September 10, 2014 and June 2, 2017 with BMI and HbA1c were identified. Additional variables included age, baseline prostate-specific antigen at first treatment for mCRPC, race, and the Charlson comorbidity index. Differences in survival were compared using the Kaplan-Meier method. Cox proportional hazards regression modeling was used to assess the association between initial treatment, BMI, and HbA1c while adjusting for confounding variables. RESULTS: A total of 5231 patients were identified with a mean age of 75.2 years and 1241 (23.7%) were of black race. BMI was associated with OS with longest median survival of 29.8 months in BMI ≥ 30 (n = 1903), 23.9 months in BMI 25-30 (n = 1879), 15.9 months in BMI 18.5-25 (n = 1336), and 9.2 months in BMI < 18.5 (n = 113, p < 0.001). In a multivariable model compared to normal BMI, increased mortality was observed in BMI < 18.5 (adjusted hazard ratio (aHR) = 1.583, 95% confidence interval [CI]: 1.29-1.94) and a decreased mortality in BMI 25-30 (aHR = 0.751, 95% CI: 0.69-0.81) and BMI > 30 (aHR = 0.644, 95% CI: 0.59-0.70). In 3761 patients with BMI > 25, there was longer OS in patients treated with enzalutamide (28.4 months, n = 1615) compared to abiraterone (25.8 months, n = 2146, p = 0.002). In 1470 patients with BMI < 25, there was no difference in OS between patients treated with enzalutamide (16.0 months, n = 597, p = 0.513) or abiraterone (16.1 months, n = 873). In 1333 veterans with HbA1c ≥ 6.5%, initial prescription of enzalutamide was associated with longer OS compared with abiraterone (24.4 vs. 20.5 months, p = 0.0005). In 2088 patients with HbA1c < 6.5%, there was no difference in OS in patients who were initially prescribed enzalutamide versus abiraterone (25.7 vs. 23.5 months, p = 0.334). CONCLUSIONS: In veterans with mCRPC, increased BMI was associated with longer survival. Veterans with BMI > 25 had longer survival with enzalutamide compared to abiraterone. In patients with HbA1c ≥ 6.5%, enzalutamide was associated with longer survival compared to abiraterone. These results may facilitate prognostication of survival and improve treatment selection based on patient comorbidities.

Project Baby Bear: Rapid precision care incorporating rWGS in 5 California children's hospitals demonstrates improved clinical outcomes and reduced costs of care.

Genetic disorders are a leading contributor to mortality in neonatal and pediatric intensive care units (ICUs). Rapid whole-genome sequencing (rWGS)-based rapid precision medicine (RPM) is an intervention that has demonstrated improved clinical outcomes and reduced costs of care. However, the feasibility of broad clinical deployment has not been established. The objective of this study was to implement RPM based on rWGS and evaluate the clinical and economic impact of this implementation as a first line diagnostic test in the California Medicaid (Medi-Cal) program. Project Baby Bear was a payor funded, prospective, real-world quality improvement project in the regional ICUs of five tertiary care children's hospitals. Participation was limited to acutely ill Medi-Cal beneficiaries who were admitted November 2018 to May 2020, were <1 year old and within one week of hospitalization, or had just developed an abnormal response to therapy. The whole cohort received RPM. There were two prespecified primary outcomes-changes in medical care reported by physicians and changes in the cost of care. The majority of infants were from underserved populations. Of 184 infants enrolled, 74 (40%) received a diagnosis by rWGS that explained their admission in a median time of 3 days. In 58 (32%) affected individuals, rWGS led to changes in medical care. Testing and precision medicine cost $1.7 million and led to $2.2-2.9 million cost savings. rWGS-based RPM had clinical utility and reduced net health care expenditures for infants in regional ICUs. rWGS should be considered early in ICU admission when the underlying etiology is unclear.

Real-world comparative effectiveness of venetoclax-obinutuzumab versus Bruton tyrosine kinase inhibitors for frontline chronic lymphocytic leukaemia.

Real-world evidence comparing clinical outcomes between venetoclax and Bruton tyrosine kinase inhibitors (BTKis) in patients with frontline (1 L) chronic lymphocytic leukaemia (CLL) is lacking. We compared treatment effectiveness of 1 L venetoclax plus obinutuzumab (VenO) versus BTKi-based regimens. This retrospective observational study using Optum Clinformatics Data Mart® included adult patients with CLL (≥2 outpatient or ≥1 inpatient claim) who received VenO or BTKi-based regimens in 1 L (1/2019-9/2022). Baseline characteristics were balanced using stabilised inverse probability weighting. Outcomes included duration of therapy (DoT), persistence, time to next treatment or death (TTNT-D), and time off-treatment. Among 1506 eligible patients (VenO: 203; BTKi: 1303), the median follow-up duration was 12.6 (VenO) and 16.2 months (BTKi). Median DoT for VenO was 12.3 months; persistence remained higher in VenO versus BTKi through expected 1 L fixed treatment duration. Median TTNT-D was not reached for VenO; however, more VenO- versus BTKi-treated patients had not switched therapies/experienced death through Month 12 (87.1% vs. 75.3%). Among patients that discontinued, median time to discontinuation was 11.7 vs. 5.9 months for VenO versus BTKi and median time off-treatment was 11.3 vs. 4.3 months. In this real-world study, VenO was associated with better effectiveness outcomes than BTKi-based regimens in 1 L CLL.

Palbociclib plus aromatase inhibitors in patients with metastatic breast cancer and cardiovascular diseases: real-world effectiveness.

BACKGROUND: Patients with cardiovascular disease (CVD) comorbidities are often excluded from participating in breast cancer clinical trials. Consequently, data to inform treatment decisions for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) and CVD are limited. OBJECTIVE: We compared the effectiveness of first-line palbociclib plus an aromatase inhibitor (AI) vs an AI alone and evaluated palbociclib treatment patterns in patients with HR+/HER2- mBC and CVD in routine clinical practice. METHODS: Data from the Flatiron Health Analytic Database were captured for patients with HR+/HER2- mBC and CVD who initiated first-line treatment with palbociclib plus an AI or an AI alone between February 2015 and March 2020 (data cutoff: September 30, 2020). Overall survival (OS), real-world progression-free survival (PFS), and treatment patterns were evaluated. RESULTS: Of the 469 patients with identifiable CVD, 160 received palbociclib plus an AI, and 309 received an AI alone. After stabilized inverse probability treatment weighting, both median OS (40.7 vs 26.5 months; hazard ratio [HR], 0.732 [95% CI, 0.537-0.997]; P = .048) and median real-world PFS (20.0 vs 12.5 months; HR, 0.679 [95% CI, 0.512-0.900]; P = .007) were significantly prolonged in patients treated with palbociclib plus an AI vs an AI alone. Among patients with a documented palbociclib starting dose, 78.5% started palbociclib at 125 mg/day, and 38.6% experienced dose adjustment. CONCLUSIONS: In this real-world analysis, first-line palbociclib plus an AI was associated with improved effectiveness compared with an AI alone in patients with HR+/HER2- mBC and CVD. TRIAL REGISTRATION: NCT05361655 (ClinicalTrials.gov).

Impact of Treatment Response on Risk of Serious Infections in Patients With Crohn's Disease: Secondary Analysis of the PYRAMID Registry.

BACKGROUND & AIMS: Traditional risk factors for serious infections with advanced therapies in patients with Crohn's disease (CD) have been assessed at baseline before starting therapy. We evaluated the impact of treatment response on the risk of serious infections in adalimumab-treated patients with CD through secondary analysis of the PYRAMID registry (NCT00524537). METHODS: We included patients with CD who initiated adalimumab and classified them as treatment responders (achieved steroid-free clinical remission based on patient-reported outcomes) vs nonresponders (not in steroid-free clinical remission) at 6 months after treatment initiation (landmark). We compared the risk of serious infections between responders vs nonresponders between 6 and 36 months after treatment initiation through stabilized inverse probability of treatment weighting Cox proportional hazards model. RESULTS: Of 1515 adalimumab-treated patients, 763 (50.4%) were classified as responders at 6 months (37 ± 13 y; 56% female; disease duration, 9.5 ± 8.5 y). Compared with nonresponders, responders were less likely to have moderate to severe symptoms (55.6% vs 33%), or require steroids (45.5% vs 17.3%) or opiates (6.6% vs 1.3%) at baseline, without any differences in disease location, perianal disease, and prior CD complications. During follow-up evaluation, using stabilized inverse probability of treatment weighting, responders were 34% less likely to experience serious infections compared with nonresponders (hazard ratio, 0.66; 95% CI, 0.46-0.96). Risk of gastrointestinal and extraintestinal infections was lower in responders vs nonresponders. CONCLUSIONS: Patients with CD who respond to adalimumab have a lower risk of developing serious infections compared with nonresponders. These findings underscore that initiation of advanced therapy for CD may lower the risk of serious infections through effective disease control and avoidance of corticosteroids.

A Patient-Prioritized Research Agenda for Clinical Trials in Kidney Stone Disease.

PURPOSE: To ensure that research on kidney stones provides meaningful impact for the kidney stone community, patients and caregivers should be engaged as stakeholders in clinical trial design, starting at study inception. This project aimed to elicit, refine, and prioritize research ideas from kidney stone stakeholders to develop a patient-centered research agenda for clinical trials. MATERIALS AND METHODS: The Kidney Stone Engagement Core, a group of patients, caregivers, advocates, clinicians, and researchers, executed an iterative process of surveys and focus groups to elicit and refine research themes, which were then translated into research questions. A separate group of patients, caregivers, and clinicians prioritized these questions through parallel modified Delphi and crowd-sourced digital platforms. A research agenda was developed by the Kidney Stone Engagement Core based on the highest rated questions during a hybrid virtual/in-person capstone session. RESULTS: A total of 70 individuals (57 patients and caregivers, 13 researchers and clinicians) participated in the elicitation, 20 individuals (15 patients and caregivers, 5 researchers and clinicians) participated in refinement, and an additional 80 individuals (81 patients and caregivers, 9 researchers and clinicians) participated in prioritization. Key novel themes emerged from elicitation and refinement: ureteral stents, genetic evaluation, shared surgical decision-making, key subgroups, cumulative disease burden, genetic evaluation, and psychosocial support. Stakeholders generated 6 proposed trials from these themes focused on surveillance, surgical intervention, and medical prevention. CONCLUSIONS: Patients and caregivers valued comparative effectiveness kidney stone research that focused on individualized care, shared decision-making, and improvement of patient-reported experiences. This process provided actionable recommendations for future patient-centered clinical trials within kidney stone disease.

Comparison of mortality and amputation after lower extremity bypass versus peripheral vascular intervention in patients with chronic limb-threatening ischemia and comorbid chronic kidney disease.

OBJECTIVE: Comorbid chronic kidney disease (CKD) is associated with worse outcomes for patients with chronic limb-threatening ischemia (CLTI). However, comparative effectiveness data are limited for lower extremity bypass (LEB) vs peripheral vascular intervention (PVI) in patients with CLTI and CKD. We aimed to evaluate (1) 30-day all-cause mortality and amputation and (2) 5-year all-cause mortality and amputation for LEB vs PVI in patients with comorbid CKD. METHODS: Individuals who underwent LEB and PVI were queried from the Vascular Quality Initiative with Medicare claims-linked outcomes data. Propensity scores were calculated using 13 variables, and a 1:1 matching method was used. The mortality risk at 30 days and 5 years in LEB vs PVI by CKD was assessed using Kaplan-Meier and Cox proportional hazards models, with interaction terms added for CKD. For amputation, cumulative incidence functions and Fine-Gray models were used to account for the competing risk of death, with interaction terms for CKD added. RESULTS: Of 4084 patients (2042 per group), the mean age was 71.0 ± 10.8 years, and 69.0% were male. Irrespective of CKD status, 30-day mortality (hazard ratio [HR]: 0.94, 95% confidence interval [CI]: 0.63-1.42, P = .78) was similar for LEB vs PVI, but LEB was associated with a lower risk of 30-day amputation (sub-HR [sHR]: 0.66, 95% CI: 0.44-0.97, P = .04). CKD status, however, did not modify these results. Similarly, LEB vs PVI was associated with a lower risk of 5-year mortality (HR: 0.79, 95% CI: 0.71-0.88, P < .001) but no difference in 5-year amputation (sHR: 1.03, 95% CI: 0.89-1.20, P = .67). CKD status did not modify these results. CONCLUSIONS: Regardless of CKD status, patients had a lower risk of 5-year all-cause mortality and 30-day amputation with LEB vs PVI. Results may help inform preference-sensitive treatment decisions on LEB vs PVI for patients with CLTI and CKD, who may commonly be deemed too high risk for surgery.

Impact of Home Telehealth Expansion on High-Cost Utilization Among Veterans Health Administration Patients with Diabetes.

BACKGROUND: Home telehealth (HT) services have rapidly expanded in the Veterans Health Administration (VHA), but little is known about the real-world impact of the expansion of these services on utilization. OBJECTIVE: To evaluate the impact of expanding HT diabetes services in VHA on high-cost utilization. DESIGN: This cohort study used cross-temporal propensity score matching to identify patients with diabetes who would receive HT services (treatment group) with program expansion (treatment group) with a comparison group of patients with diabetes who did not receive HT services (control group) between 2010 and 2018. A difference-in-differences design was used to compare pre-post changes in high-cost utilization between propensity-matched groups. Data used was from the VHA's Corporate Data Warehouse. PARTICIPANTS: VHA patients with diabetes, n=7214 in the treatment group who received HT services, and n=1,067,138 in the control group who did not receive HT services. MAIN MEASURE(S): Emergency department (ED) visits, all-cause hospitalization, and hospitalizations for ambulatory care sensitive conditions (ACSCs). KEY RESULTS: In the baseline period, patients in our sample had a mean age of 67 years old (SD=11 years), were 97% male, and 78% had a hemoglobin A1c (HbA1c) < 8%. The increase in HT use was associated with a net increase of ED visits per patient (0.215 95% CI [0.152, 0.279]), all-cause hospitalization (0.053 95% CI [0.032, 0.074]), and ACSC hospitalization (0.032 95% CI [0.019, 0.045]). CONCLUSIONS: Expanding HT or remote monitoring services may lead to additional needs being identified for patients, including increased access to in-person care, such as ED or hospital services.

Comparative Effectiveness of Decision Aids for Cancer-Screening Decision Making: An Overview of Reviews.

BACKGROUND: Decision aids (DAs), compared to no DAs, help improve the key aspects of shared decision-making, including increased knowledge, discussion frequency, and reduction in decisional conflict. However, systematic reviews have reported varied conclusions on screening uptake, and which DAs are superior to alternative forms in shared decision-making for cancer screening has not been comprehensively reviewed. METHODS: An overview of systematic reviews was performed. Multiple databases were searched up to December 31, 2023, for systematic reviews of randomized controlled trials (RCTs) and non-randomized comparative studies (NRCSs) of any size that assessed a decision aid aimed to facilitate cancer-screening decision making communications. Dual screening of abstracts and full-text reports, dual data extraction and quality assessment, and qualitative synthesis were performed. RESULTS: The 22 eligible publications included 24 reviews on cancer screening DAs for a single specific cancer (8, 8, 7, and 1 on prostate, breast, colorectal, and lung cancer, respectively) and three reviews on multiple aggregate cancers. Individual reviews were based on different primary study designs (92 RCTs and 37 NRCSs); each study was infrequently cited (median citation count 2; range 1-9). Although the DAs had variable formats and delivery methods, the reviews generally focused on use and non-use comparisons. DAs decreased the intention or actual uptake for prostate and breast cancer screening, but increased it for colorectal cancer screening. DAs were associated with increased knowledge, well-informed choice, and reduced decisional conflict, regardless of cancer type. Only four reviews on comparative effectiveness between alternative formats of DAs (based on 14 RCTs and 2 NRCSs) failed to conclude on the specific format that was superior to others. DISCUSSION: DAs improve cancer screening shared decision-making by boosting cancer screening knowledge and informed choice and lowering decisional conflict and may facilitate preference-based, individualized screening participation. Comparative data on different cancer screening DAs are limited. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42021235957.