Standardized Mortality Ratio Weighting Research Articles

Effects of beta-blockers use on mortality of patients with acute respiratory distress syndrome: a retrospective cohort study.

Introduction: Acute respiratory distress syndrome (ARDS) remains a challenging disease with limited prevention and treatment options. The usage of beta-blockers may have potential benefits in different critical illnesses. This study aimed to investigate the correlation between beta-blocker therapy and mortality in patients with ARDS. Materials and methods: This retrospective cohort study utilized data from the Medical Information Mart for Intensive Care (MIMIC) IV database and focused on patients diagnosed with ARDS. The primary outcome of the study was 30-day mortality. To account for confounding factors, a multivariable analysis was performed. Propensity score matching (PSM) was carried out on a 1:1 ratio. Robust assessments were conducted using inverse probability weighting (IPTW), standardized mortality ratio weighting (SMRW), pairwise algorithms (PA), and overlap weights (OW). Results: A total of 1,104 patients with ARDS were included in the study. Univariate and multivariate Cox regression analyses found that the 30-day mortality for 489 patients (23.7%) who received beta-blockers was significantly lower than the mortality rate of 615 patients (35.9%) who did not receive beta-blockers. After adjusting for potential confounders through PSM and propensity score, as well as utilizing IPTW, SMRW, PA, and OW, the results remained robust, with the hazard ratios (HR) ranging from 0.42 to 0.58 and all p-values < 0.001. Evaluation of the E-values indicated the robustness of the results even in the presence of unmeasured confounding. Conclusion: The findings suggest a potential association between beta-blocker usage and reduced mortality in critically ill patients with ARDS. However, further validation of this observation is needed through randomized controlled trials.

An Updated Comparison of Clinical Outcomes from 4-Year Follow-up of Zuma-5 (Axicabtagene Ciloleucel) and the International Scholar-5 External Control Cohort in Relapsed/Refractory Follicular Lymphoma

Introduction: Axicabtagene ciloleucel (axi-cel; an autologous anti-CD19 chimeric antigen receptor T-cell therapy), led to durable responses in relapsed/refractory (R/R) follicular lymphoma (FL) in the pivotal ZUMA-5 trial. When 3-year efficacy data from ZUMA-5 were compared to the SCHOLAR-5 external control cohort (ASH 2022, Ghione et al.), axi-cel showed a substantial improvement in clinical endpoints including overall response rate, complete response, progression-free survival (PFS), time-to-next treatment (TTNT), and overall survival (OS). Here we provide an updated analysis of this comparison using an additional 12-months of follow-up data for ZUMA-5. Methods: SCHOLAR-5 is an international, external control cohort of R/R FL patients who initiated a ≥3rd line of therapy (LoT) after July 2014. Patients were recruited from seven institutions in five countries. In addition, patients initiating therapy after receiving idelalisib in the pivotal DELTA trial were included. ZUMA-5 eligibility criteria were applied to SCHOLAR-5 patients, and propensity score and standardized mortality ratio weighting were used to balance prognostic factors between both cohorts. A standardized mean difference (SMD) of &amp;lt;0.1 was considered as balanced. Kaplan-Meier (KM) curves and weighted Cox proportional hazards models were used to evaluate OS, PFS, and TTNT. Best response did not change with longer follow-up, so is not included in the updated analysis. Results: Following propensity score weighting, 143 patients from SCHOLAR-5 were reduced to 129 patients and were compared to the 127 patients from the intention-to-treat population of ZUMA-5. Median follow-up times for each cohort were 26.2 and 47.6 months, respectively. Progression of disease within 24 months of initiation of first-line chemoimmunotherapy (POD24), number of prior LoT, R/R to prior LoT, prior stem cell transplant, size of largest nodal mass, response to prior LoT, and time since last therapy were successfully balanced (SMD&amp;lt;0.1). The median PFS was 57.3 months in ZUMA-5 compared to 13.0 months in SCHOLAR-5 (Figure 1a, hazard ratio [HR]: 0.27, 95% confidence interval [CI]: 0.18-0.40), and median TTNT was 62.2 months compared to 26.6 months (HR: 0.62, 95%CI 0.40-0.95), respectively. Median OS was not reached in ZUMA-5 or SCHOLAR-5 (Figure 1b, HR: 0.58, 95% CI: 0.35-0.96). At 48 months, PFS was 53.0% (95% CI: 43.1-61.9) in ZUMA-5 but was not evaluable in SCHOLAR-5, as all patients had progressed or been censored. Forty-eight-month TTNT was 56.6% (95% CI: 47.4-64.8) in ZUMA-5 compared to 41.9% (95% CI: 28.7-55.0) in SCHOLAR-5. Forty-eight-month OS was 72.4% (95% CI: 63.6-79.4) in ZUMA-5 compared to 61.4% (95% CI: 49.1-73.7) in SCHOLAR-5. Conclusion: These results demonstrate that axi-cel continues to show superior efficacy for R/R FL compared to other available therapies. The response to axi-cel is durable, and offers a clinically meaningful and significant benefit in PFS, TTNT, and OS. These longer follow-up results are particularly important in this indolent disease, where survival outcomes take time to reach maturity. Axi-cel continues to address an unmet medical need for this population of R/R FL patients.

Favorable effect of CD26/DPP-4 inhibitors on postoperative outcomes after lung transplantation: A propensity-weighted analysis

We have shown the efficacy of CD26/dipeptidyl peptidase 4 (CD26/DPP-4) inhibitors, antidiabetic agents, in allograft protection after experimental lung transplantation (LTx). We aimed to elucidate whether CD26/DPP-4 inhibitors effectively improve postoperative outcomes after clinical LTx. We retrospectively reviewed the records of patients undergoing LTx at our institution between 2010 and 2021 and extracted records of patients with diabetes mellitus (DM) at 6months post-LTx. The patient characteristics and postoperative outcomes were analyzed. We established 6months post-LTx as the landmark point for predicting overall survival (OS) and chronic lung allograft dysfunction (CLAD)-free survival. Hazard ratios were estimated by Cox regression after propensity score weighting, using CD26/DPP-4 inhibitor treatment up to 6months post-LTx as the exposure variable. We evaluated CLAD samples pathologically, including for CD26/DPP-4 immunohistochemistry. Of 102 LTx patients with DM, 29 and 73 were treated with and without CD26/DPP-4 inhibitors, respectively. Based on propensity score adjustment using standardized mortality ratio weighting, the 5-year OS rates were 77.0% and 44.3%, and the 5-year CLAD-free survival rates 77.8% and 49.1%, in patients treated with and without CD26/DPP-4 inhibitors, respectively. The hazard ratio for CD26/DPP-4 inhibitor use was 0.34 (95% confidence interval (CI) 0.14-0.82, p=0.017) for OS and 0.47 (95% CI 0.22-1.01, p=0.054) for CLAD-free survival. We detected CD26/DPP-4 expression in the CLAD grafts of patients without CD26/DPP-4 inhibitors. Analysis using propensity score weighting showed that CD26/DPP-4 inhibitors positively affected the postoperative prognosis of LTx patients with DM.

Causal inference between aggressive extrathyroidal extension and survival in papillary thyroid cancer: a propensity score matching and weighting analysis.

Extrathyroidal extension is a major risk factor for poor prognosis in papillary thyroid cancer. However, the effect of different degrees of extrathyroidal extension on prognosis remains controversial. We performed a retrospective study to elucidate how the extent of extrathyroidal extension in papillary thyroid cancer affected the clinical prognosis of patients and its covariates. The study included 108,426 patients with papillary thyroid cancer. We categorized the extent of extension into none, capsule, strap muscles, and other organs. Three causal inference methods for retrospective studies, namely, inverse probability of treatment weighting, standardized mortality ratio weighting, and propensity score matching analysis, were used to minimize potential selection bias. Kaplan-Meier analysis and univariate Cox regression analyses were applied to analyze the precise effect of ETE on survival in papillary thyroid cancer patients. In the Kaplan-Meier survival analysis, only extrathyroidal extension into or beyond the strap muscles was statistically significant for both overall survival (OS) and thyroid cancer-specific survival (TCSS). In univariate Cox regression analyses before and after matching or weighting based on causal inference, extrathyroidal extension into soft tissues or other organs is a high-risk factor for both overall survival and thyroid cancer-specific survival. Sensitivity analysis revealed that lower overall survival was observed in patients with older age (≥55) and larger tumor size (>2cm) of papillary thyroid cancer with extrathyroidal extension into or beyond the strap muscles. Our study indicates that extrathyroidal extension into soft tissues or other organs is a high-risk factor in all papillary thyroid cancer. Even though invasion into the strap muscles did not seem to be a marker for poor prognosis, it still impaired the overall survival of patients with older age (≥55 years old) or larger tumor size (>2cm). Further investigation is needed to confirm our results and to clarify further risk factors independent of extrathyroidal extension.

Association between different MAP levels and 30-day mortality in sepsis patients: a propensity-score-matched, retrospective cohort study

BackgroundSepsis is a life-threatening organ dysfunction caused by the infection-related host response disorder. Adequate mean arterial pressure is an important prerequisite of tissue and organ perfusion, which runs through the treatment of sepsis patients, and an appropriate mean arterial pressure titration in the early-stage correlates to the positive outcome of the treatment. Therefore, in the present study, we aimed to elucidate the relationship between early mean arterial pressure levels and short-term mortality in sepsis patients.MethodsWe included all suspected sepsis patients from MIMIC-III database with average mean arterial pressure ≥ 60 mmHg on the first day of intensive care unit stay. Those patients were then divided into a permissive low-mean arterial pressure group (60–65 mmHg) and a high-mean arterial pressure group (> 65 mmHg). Multivariate Cox regression analysis was conducted to analyze the relationship between MAP level and 30-day, 60-day, and 100-day mortality of suspected sepsis patients in the two groups. Propensity score matching, inverse probability of treatment weighing, standardized mortality ratio weighting, PA weighting, overlap weighting, and doubly robust analysis were used to verify our results.ResultsA total of 14,031 suspected sepsis patients were eligible for inclusion in our study, among which 1305 (9.3%) had an average first-day mean arterial pressure of 60–65 mmHg, and the remaining 12,726 patients had an average first-day mean arterial pressure of more than 65 mmHg. The risk of 30-day mortality was reduced in the high mean arterial pressure group compared with the permissive low-mean arterial pressure group (HR 0.67 (95% CI 0.60–0.75; p < 0.001)). The higher mean arterial pressure was also associated with lower 60-day and 100-day in-hospital mortality as well as with shorter duration of intensive care unit stay. Patients in the high-mean arterial pressure group also had more urine output on the first and second days of intensive care unit admission.ConclusionsAfter risk adjustment, the initial mean arterial pressure of above 65 mmHg was associated with reduced short-term mortality, shorter intensive care unit stay, and higher urine volume in the first two days among patients with sepsis.

A 24-month updated analysis of the comparative effectiveness of ZUMA-5 (axi-cel) vs. SCHOLAR-5 external control in relapsed/refractory follicular lymphoma

ABSTRACT Background In the ZUMA-5 trial (Clinical trials identification: NCT03105336), axicabtagene ciloleucel (axi-cel; a chimeric antigen receptor T-cell therapy) demonstrated high rates of durable response in relapsed/refractory (r/r) follicular lymphoma (FL) patients and clear superiority relative to the SCHOLAR-5 external control cohort. We update this comparison using the ZUMA-5 24-month data. Research design and methods The SCHOLAR-5 cohort is comprised of r/r FL patients who initiated ≥3rd line of therapy after July 2014 and meeting ZUMA-5 eligibility criteria. Groups were balanced for patient characteristics through propensity scoring on prespecified prognostic factors using standardized mortality ratio (SMR) weighting. The overall response rate was compared using a weighted logistic regression. Time-to-event outcomes were evaluated using a Cox regression. Results For SCHOLAR-5, the sum of weights for the 143 patients was 85 after SMR weighting, versus 86 patients in ZUMA-5. The median follow-up was 29.4 months and 25.4 months for ZUMA-5 and SCHOLAR-5, respectively. The hazard ratios for overall survival and progression-free survival were 0.52 (95% confidence interval (CI): 0.28–0.95) and 0.28 (95% CI: 0.17–0.45), favoring axi-cel. Conclusion This updated analysis, using a longer minimum follow-up than a previously published analysis, shows that the improved efficacy of axi-cel, relative to available therapies, in r/r FL is durable. .

A 3-Year Follow-up Comparison of Clinical Outcomes from Zuma-5 (Axicabtagene Ciloleucel) and the International Scholar-5 External Control Cohort in Relapsed/Refractory Follicular Lymphoma (R/R FL)

Introduction: In the pivotal ZUMA-5 trial, axicabtagene ciloleucel (axi-cel; an autologous anti-CD19 chimeric antigen receptor T-cell therapy) demonstrated high rates of durable response in r/r FL patients. When ZUMA-5 24-month data were compared to SCHOLAR-5, clinically significant benefits in overall response rate (ORR) and survival outcomes were shown in patients treated with axi-cel (ASH 2021, Palomba et al., abstract 3543). The aim of this study was to compare clinical outcomes from updated 36-month ZUMA-5 to a weighted sample from the SCHOLAR-5 cohort. Methods: The international SCHOLAR-5 external control cohort consists of r/r FL patients from 7 institutions in 5 countries who initiated a third or higher (3L+) line of therapy (LOT) after July 2014 as well as patients from the pivotal DELTA trial initiating treatment following idelalisib. ZUMA-5 trial eligibility criteria were applied to the SCHOLAR-5 cohort with patients excluded or censored upon transformation. The SCHOLAR-5 and ZUMA-5 cohorts were balanced for patient characteristics through propensity scoring on prespecified prognostic factors and standardized mortality ratio weighting. Characteristics with a standardized mean difference (SMD) <0.1 were deemed balanced. Overall survival (OS), progression-free survival (PFS) and time-to-next treatment (TTNT) were evaluated using Kaplan-Meier analysis. Results: 143 patients were identified in SCHOLAR-5, reducing to 129 patients after applying propensity score weights versus 127 patients in ZUMA-5. Median follow-up time for ZUMA-5 and SCHOLAR-5 were 36.8 and 26.2 months, respectively. Variables that were successfully balanced (SMD<0.1) included POD24, number of prior LOT, relapsed vs refractory, prior stem cell transplant, size of largest nodal mass, response to prior LOT, time since last therapy, and age. ORR was 54.0% (69/129) in SCHOLAR-5 compared to 93.7% (119/127) in ZUMA-5. CR was 45/129 (34.9%) in SCHOLAR-5 compared to 100/127 (78.7%) in ZUMA-5. The median PFS was 13.0 months in SCHOLAR-5 compared to 40.2 months in ZUMA-5 (Figure 1a). Median TTNT was 26.5 months in SCHOLAR-5 and was not reached in ZUMA-5. Median OS was not reached in SCHOLAR-5 or ZUMA-5 (Figure 1b). The hazard ratios for PFS, TTNT and OS were 0.27 (95%CI: 0.18-0.41), 0.60 (95%CI: 0.39 - 0.93), and 0.56 (95%CI: 0.33-0.95), respectively. PFS at 36 months was 6.5% (95%CI: 0.0 - 17.0) in SCHOLAR-5, compared to 54.4% (95% CI: 44.2 - 63.5) in ZUMA-5. TTNT at 36 months was 45.7% (95%CI: 33.1 - 58.3) in SCHOLAR-5, compared to 59.5% (95%CI: 50.2 - 67.6) in ZUMA-5. OS at 36 months was 64.3% (95%CI: 52.2 - 76.4) in SCHOLAR-5, compared to 75.5% (95% CI: 66.9 - 82.2) in ZUMA-5. Conclusion: After follow-up, axi-cel continues to demonstrate a substantial and statistically significant improvement in meaningful clinical endpoints including ORR, CR, PFS, TTNT and OS compared to currently available therapies for r/r FL patients, highlighting the durable treatment effect of axi-cel. These findings suggest that axi-cel addresses an important unmet medical need for r/r FL patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Selective serotonin reuptake inhibitors and the risk of type 2 diabetes mellitus in youths

BackgroundSelective serotonin reuptake inhibitors (SSRIs) have been associated with type 2 diabetes mellitus (T2DM) in youths, possibly via 5-HT2C, H1 receptors and serotonin transporter (SERT). SSRIs have similar affinity for SERT but variable affinity for 5-HT2C and H1. This study assessed whether SSRIs with strong affinity for 5-HT2C and H1 (relative to SERT) were associated with T2DM risk compared with weak-affinity SSRIs. MethodsUsing the UK Clinical Practice Research Datalink, we assembled a cohort of patients aged 5–24, newly prescribed a strong-affinity SSRI (citalopram, escitalopram, fluoxetine) or weak affinity (paroxetine, sertraline, fluvoxamine) between 1990 and 2019. We controlled for confounding using standardized mortality ratio weighting, estimated from calendar time-specific propensity scores. We used weighted Cox proportional hazards models to estimate hazard ratios (HRs) of incident T2DM with 95 % confidence intervals (CIs). ResultsThe cohort included 347,368 new users of strong-affinity SSRIs and 131,359 of weak-affinity SSRIs. Strong-affinity SSRIs were not associated with an increased T2DM risk compared with weak-affinity SSRIs (incidence rate 2.8 vs 2.7 per 1000 person-years; HR 1.03, 95 % CI 0.85–1.25). T2DM risk did not vary with duration of use, age or sex. However, the HR was numerically higher in youths with normal or low weight (HR 1.30, 95 % CI 0.85–1.98) and with prior antipsychotic use (HR 1.62, 95 % CI 0.83–3.18). LimitationsMedian duration of SSRI use, in line with real-world SSRI prescribing, was relatively short. ConclusionT2DM risk did not differ between strong- and weak-affinity SSRIs, providing reassurance for clinicians when choosing between SSRIs in youths.

Comparative effectiveness of ZUMA-5 (axi-cel) vs SCHOLAR-5 external control in relapsed/refractory follicular lymphoma

AbstractIn the pivotal ZUMA-5 trial, axicabtagene ciloleucel (axi-cel; an autologous anti-CD19 chimeric antigen receptor T-cell therapy) demonstrated high rates of durable response in relapsed/refractory (r/r) follicular lymphoma (FL) patients. Here, outcomes from ZUMA-5 are compared with the international SCHOLAR-5 cohort, which applied key ZUMA-5 trial eligibility criteria simulating randomized controlled trial conditions. SCHOLAR-5 data were extracted from institutions in 5 countries, and from 1 historical clinical trial, for r/r FL patients who initiated a third or higher line of therapy after July 2014. Patient characteristics were balanced through propensity scoring on prespecified prognostic factors using standardized mortality ratio (SMR) weighting. Time-to-event outcomes were evaluated using weighted Kaplan-Meier analysis. Overall response rate (ORR) and complete response (CR) rate were compared using weighted odds ratios. The 143 ScHOLAR-5 patients reduced to an effective sample of 85 patients after SMR weighting vs 86 patients in ZUMA-5. Median follow-up time was 25.4 and 23.3 months for SCHOLAR-5 and ZUMA-5. Median overall survival (OS) and progression-free survival (PFS) in SCHOLAR-5 were 59.8 months and 12.7 months and not reached in ZUMA-5. Hazard ratios for OS and PFS were 0.42 (95% confidence interval [CI], 0.21-0.83) and 0.30 (95% CI, 0.18-0.49). The ORR and CR rate were 49.9% and 29.9% in SCHOLAR-5 and 94.2% and 79.1% in ZUMA-5, for odds ratios of 16.2 (95% CI, 5.6-46.9) and 8.9 (95% CI, 4.3-18.3). Compared with available therapies, axi-cel demonstrated an improvement in meaningful clinical endpoints, suggesting axi-cel addresses an important unmet need for r/r FL patients. This trial was registered at www.clinicaltrials.gov as #NCT03105336.

Effectiveness and Safety of Apixaban versus Rivaroxaban in Patients with Atrial Fibrillation and Type 2 Diabetes Mellitus.

To evaluate the effectiveness and safety of apixaban versus rivaroxaban among patients with nonvalvular atrial fibrillation (NVAF) and type 2 diabetes mellitus (T2DM). Using the United Kingdom's Clinical Practice Research Datalink linked to the Hospital Episode Statistics repository, and the Office for National Statistics database, we identified a cohort of patients with NVAF and T2DM newly treated with apixaban or rivaroxaban between 2013 and 2020. Propensity scores with standardized mortality ratio weighting were used to control for confounding. We used weighted Cox proportional hazards models to estimate separately the hazard ratios (HRs) with 95% confidence intervals (CIs) of ischemic stroke, major bleeding, and major adverse limb events associated with the use of apixaban compared with rivaroxaban. We also evaluated whether the risk was modified by age, sex, duration of diabetes, microvascular and macrovascular complications of diabetes, nephropathy, CHA2DS2-VASc and HAS-BLED scores, and by dose (standard vs. low dose). The cohort included 11,561 apixaban and 8,265 rivaroxaban users. Apixaban was associated with a similar risk of stroke (HR: 0.99, 95% CI: 0.79-1.23), and a 32% reduced risk of major bleeding (HR: 0.68, 95% CI: 0.59-0.78), compared with rivaroxaban. The risk of major adverse limb events was similar between apixaban and rivaroxaban (HR: 0.75, 95% CI: 0.54-1.04). Overall, the risk of ischemic stroke and major bleeding was consistent in stratified analyses. Among patients with NVAF and T2DM, apixaban was associated with a similar risk of stroke and a lower risk of major bleeding compared with rivaroxaban.

Inverse Association Between Persistence With Antidepressant Medication and Onset of Chronic Pain in Patients With Depression: A Retrospective Cohort Study.

Despite the known involvement of depression in chronic pain, the association between persistence with and adherence to antidepressant medication and onset of chronic pain in patients with depression remains unclear. This retrospective cohort study used a Japanese claims database to extract data for adult patients with depression who were prescribed antidepressants between April 2014 and March 2020. Patients were divided into groups according to duration of continuous prescription of antidepressants (≥6 months [persistent group] and <6 months [nonpersistent group]) and medication possession ratio (≥80% [good adherence group] and <80% [poor adherence group]). The outcome was onset of chronic pain, which was defined as continuous prescription >3 months of analgesics and diagnosis of pain-related condition after discontinuation of the first continuous antidepressant prescription. The risk of onset of chronic pain was compared between the paired groups. A total of 1859 patients were selected as the study population and categorized as the persistent (n = 406) and nonpersistent (n = 1453) groups, and good adherence (n = 1551) and poor adherence (n = 308) groups. Risk of onset of chronic pain was significantly lower in the persistent group than in the nonpersistent group after controlling for confounding via standardized mortality ratio weighting (hazard ratio, 0.38; 95% confidence interval, 0.18-0.80; P = 0.011). There was no significant difference between the good and poor adherence groups. Antidepressant persistence for ≥6 months is recommended and may reduce the onset of chronic pain in patients with depression.

The prognostic role of anticoagulants in COVID-19 patients: national COVID-19 cohort in South Korea.

There currently exists a paucity of data on whether pre-admission anticoagulants use may have benefits among COVID-19 patients by preventing COVID-19 associated thromboembolism. The aim of this study was to assess the association between pre-admission anticoagulants use and COVID-19 adverse outcomes. We conducted a population-based cohort studying using the Health Insurance Review and Assessment Service (HIRA) claims data released by the South Korean government. Our study population consisted of South Koreans who were aged 40 years or older and hospitalized with COVID-19 between 1 January 2020 through 15 May 2020. We defined anticoagulants users as individuals with inpatient and outpatient prescription records in 120 days before cohort entry. Our primary endpoint was a composite of all-cause death, intensive care unit (ICU) admission, and mechanical ventilation use. Individual components of the primary endpoint were secondary endpoints. We compared the risk of endpoints between the anticoagulants users and non-users by logistic regression models, with the standardized mortality ratio weighting (SMRW) adjustment. In our cohort of 4,349 patients, for the primary endpoint of mortality, mechanical ventilation and ICU admission, no difference was noted between anticoagulants users and non-users (SMRW OR 1.11, 95% CI: 0.60-2.05). No differences were noted, among individual components. No effect modification was observed by age, sex, history of atrial fibrillation and thromboembolism, and history of cardiovascular disease. When applying the inverse probability of treatment weighting (IPTW) and SMRW with doubly robust methods in sensitivity analysis, anticoagulants use was associated with increased odds of the primary endpoint. Pre-admission anticoagulants were not determined to have a protective role against severe COVID-19 outcomes.

Theory and practice of propensity score analysis.

Propensity score analysis has been widely used in observational studies to make a causal inference. This study introduces three assumptions for causal inferences-conditional exchangeability, positivity, and consistency-and five steps for propensity score (PS) analysis-1) construct appropriate PS models, 2) check overlap in PS, 3) apply appropriate weighting (inverse probability of treatment weighting, standardized mortality ratio weighting, matching weights, and overlap weights) or matching methods according to the target of inference, 4) check the balance of covariates, and 5) estimate the effect of exposure appropriately. Finally, the advantages of PS analyses over conventional multivariable regression are discussed.

Comparing the Survival Outcomes of Radical Prostatectomy Versus Radiotherapy for Patients With De Novo Metastasis Prostate Cancer: A Population-Based Study.

PurposeThe efficacy of local treatments (LTs) in selected patients with metastatic prostate cancer (mPCa) had been demonstrated. However, the comparative effectiveness between LTs is unclear. Here, we compared the impact of radical prostatectomy (RP) and brachytherapy (RT) on the survival outcomes of mPCa patients.Materials and MethodsmPCa patients who received RT or RP between 2004 and 2016 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Multivariable Cox proportional hazards analysis was used to evaluate the comparative risk of prostate cancer-specific mortality (CSM) and all-cause mortality (ACM) between LTs. A 1:1 propensity score matching (PSM) and adjusted standardized mortality ratio weighting (SMRW) were performed to balance the clinicopathological characteristics of the groups.ResultsOf 684 mPCa patients, 481 underwent RP and 203 received RT. After PSM, both groups included 148 cases, and RT resulted in comparable CSM versus RP [CSM: hazard ratio (HR) = 0.77, p = 0.325; ACM: HR = 0.73, p = 0.138], which was consistent with the SMRW model [CSM: HR = 0.83, p = 0.138; overall survival (OS): HR = 0.75, p = 0.132]. However, RP was associated with a lower CSM in the T1–2 subgroup (HR = 0.42, p = 0.048) and a lower ACM in the T1–2 (HR = 0.55, p = 0.031) and prostate-specific antigen (PSA) ≤20ng/ml (HR = 0.48, p = 0.022) subgroups. Besides, the results showed that the mortality risk was similar between the two groups in the T3–4, Gleason score (GS) >7, PSA >20 ng/ml, and all metastatic subgroups (all p > 0.100).ConclusionsRP could confer better survival outcomes than could RT in mPCa patients with favorable primary tumor features, but not in those with advanced primary tumor features. Moreover, the metastatic substage has limited impact on the comparative effectiveness between RP and RT. Further clinical trials are necessary to confirm the present results.

A Comparison of Clinical Outcomes from Updated Zuma-5 (Axicabtagene Ciloleucel) and the International Scholar-5 External Control Cohort in Relapsed/Refractory Follicular Lymphoma (R/R FL)

A Comparison of Clinical Outcomes from Updated Zuma-5 (Axicabtagene Ciloleucel) and the International Scholar-5 External Control Cohort in Relapsed/Refractory Follicular Lymphoma (R/R FL)

Prognostic Analysis of Gastric Signet Ring Cell Carcinoma and Hepatoid Adenocarcinoma of the Stomach: A Propensity Score-Matched Study.

BackgroundHepatoid adenocarcinoma of the stomach (HAS) is a rare type of primary gastric cancer, and most previous studies have reported that HAS has a poor prognosis due to its aggressive biological behavior. The aim of this study was to compare the prognosis of HAS to that of gastric signet ring cell carcinoma (SRC).MethodsThis was a single-center, retrospective, observational cohort study (January 2010 to January 2016) of gastric cancer patients with pathological HAS and SRC. Overall survival was compared between HAS and SRC patients. We used univariate Cox regression, multivariate Cox regression, propensity score matching (PSM), inverse probability of treatment weighting, standardized mortality ratio weighting, standardized mortality ratio weighting, and overlap weighting to perform a prognostic analysis.ResultsA total of 725 (672 SRC and 53 HAS) patients were included. After nearest-neighbor 1:4 PSM, 200 SRC patients and 50 HAS patients were matched. Only in univariate Cox regression analysis with the cohort before PSM did HAS show a significantly worse prognosis than SRC [hazard ratio (HR), 1.66; 95% confidence interval (CI), 1.02–2.69, p = 0.040]. However, in the analysis of multivariate Cox regression with the cohort before PSM and series analysis based on the propensity score, all of the results indicated that there was no statistically significant difference in overall survival between HAS and SRC (all p > 0.05). Furthermore, in the subgroup of proximal location (p = 0.027), T stage 4a & 4b (p = 0.001), N stage 3a & 3b (p = 0.022), with cancer nodules (p = 0.026), serum CEA higher than the normal value (p = 0.038), and serum CA199 higher than the normal value (p = 0.023), the prognosis of HAS was significantly worse than that of SRC.ConclusionBased on our study, there was no statistically significant difference in overall survival between HAS and gastric SRC patients. However, in patients with an advanced tumor stage, HAS may have a worse overall survival than SRC.

Tracheostomy Practices for Mechanically Ventilated Patients in Malawi.

BackgroundTracheostomy is used for patients who require prolonged mechanical ventilation. Extensive research has described the provision and optimal timing of tracheostomy, but very little describes tracheostomy utilization in low- and middle-income countries, particularly in sub-Saharan Africa.MethodsThis prospective cohort study describes patients admitted to the intensive care unit (ICU) of a tertiary hospital in Malawi who received tracheostomy versus those who did not, with a primary outcome of hospital mortality. We performed subgroup analysis of patients with severe head injuries.ResultsThe analysis included 451 patients admitted to the study ICU between September 2016 and July 2018. Overall hospital mortality was 40% for patients who received tracheostomy and 63% for patients who did not. Logistic regression modeling revealed an odds ratio (OR) of 0.34 (95% CI 0.18–0.64) for hospital mortality among patients who received tracheostomy versus those who did not (p < 0.001). Standardized mortality ratio weighting revealed an odds ratio of 0.81 (95% CI 0.65–0.99, p < 0.001) for hospital death among patients who received tracheostomy versus those who did not. In the subgroup excluding severe head injury, both ICU (50%) and hospital mortality (75%) were higher overall, but hospital mortality was not more common for patients with tracheostomy versus without (OR 1.28, 95% CI 0.94–1.74, p = 0.104).ConclusionsTracheostomy is not associated with hospital mortality in a Malawi ICU cohort, but these results are affected by the presence of head injury. Research may focus on home tracheostomy care given the lack of hospital discharge options for patients in austere settings.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00268-021-06176-3.

Liver Transplantation Versus Liver Resection for Stage I and II Hepatocellular Carcinoma: Results of an Instrumental Variable Analysis.

BackgroundThis study aimed to compare the long-term outcomes of liver transplantation (LT) and liver resection (LR) among patients with stage I and II hepatocellular carcinoma (HCC).MethodsSEER 18 registry from 2004 to 2015 was retrieved for this study. We included 1,765 and 1,746 cases with stage I–II (AJCC, 7th) HCC in the multivariable analyses and instrumental variable (IV) analyses, respectively. Propensity score matching (PSM) was further carried out to ensure comparability. Propensity score to receive LT was adjusted by stabilized inverse probability of treatment weighting (IPTW) and standardized mortality ratio weighting (SMRW) methods. In addition, IV analysis was performed to adjust both measured and unmeasured confounding factors.ResultsWe identified 1,000 (56.7%) and 765 (43.3%) patients treated with LR and LT, respectively. In the multivariable adjusted cohort, after adjusting potential confounders, patients undergoing LT offered significant prognostic advantages over LR in overall survival (OS, P < 0.001) and disease-free survival (DSS, P < 0.001). The instrument variable in this study is LT rates in various Health Service Areas (HSAs). Results from the IV analysis showed that cases treated with LT had significantly longer OS (P = 0.001) and DSS (P < 0.001). In IV analysis stratified by clinicopathologic variables, the treatment effect of LT vs. LR in OS was consistent across all subgroups. Regarding DSS in IV analyses, the subgroup analyses observed that LT had better DSS across all subgroups, except for similar results in the older patients (interaction P value = 0.039) and the non-White patients (interaction P value = 0.041). In the propensity-matched cohort, patients with LT still had better OS (P < 0.001) and DSS (P < 0.001) in comparison to cases who underwent LR. In both IPTW and SMRW cohorts, patients who underwent LT had better OS (both P values < 0.001) and DSS (both P values < 0.001).ConclusionsLT provided a survival benefit for cases with stage I–II HCC. These results indicated that if LT rate was to increase in the future, average long-term survival may also increase. However, for some special populations such as the elderly patients, owing to the similar outcomes between LT and LR, the selection of LT should be cautious.

Building External Control Arms From Patient-Level Electronic Health Record Data to Replicate the Randomized IMblaze370 Control Arm in Metastatic Colorectal Cancer.

PURPOSEExternal control (EC) arms derived from electronic health records (EHRs) can provide appropriate comparison groups when randomized control arms are not feasible, but have not been explored for metastatic colorectal cancer (mCRC) trials. We constructed EC arms from two patient-level EHR-derived databases and evaluated them against the control arm from a phase III, randomized controlled mCRC trial.METHODSIMblaze370 evaluated atezolizumab with or without cobimetinib versus regorafenib in patients with mCRC. EC arms were constructed from the Flatiron Health (FH) EHR-derived de-identified database and the combined FH/Foundation Medicine Clinico-Genomic Database (CGDB). IMblaze370 eligibility criteria were applied to the EC cohorts. Propensity scores and standardized mortality ratio weighting were used to balance baseline characteristics between the IMblaze370 and EC arms; balance was assessed using standardized mean differences. Kaplan-Meier method estimated median overall survival (OS). Cox proportional hazards models estimated hazard ratios with bootstrapped 95% CIs to compare differences in OS between study arms.RESULTSThe FH EC included 184 patients; the CGDB EC included 108 patients. Most characteristics were well-balanced (standardized mean difference < 0.1) between each EC arm and the IMblaze370 population. Median OS was similar between the IMblaze370 control arm (8.5 months [95% CI, 6.41 to 10.71]) and both EC arms: FH (8.5 months [6.93 to 9.92]) and CGDB (8.8 months [7.85 to 9.92]). OS comparisons between the IMblaze370 experimental arm and the FH EC (hazard ratio, 0.85 [0.64 to 1.14]) and CGDB EC (0.86 [0.65 to 1.18]) yielded similar results as the comparison with the IMblaze370 control arm (1.01 [0.75 to 1.37]).CONCLUSIONEC arms constructed from the FH database and the CGDB closely replicated the control arm from IMblaze370. EHR-derived EC arms can provide meaningful comparators in mCRC trials when recruiting a randomized control arm is not feasible.

A Pharmacoepidemiologic Approach to Evaluate Real-world Effectiveness of Hormonal Contraceptives in the Presence of Drug-drug Interactions.

Background:Accurate estimation of conception is critical in the assessment of the effects of drugs used during pregnancy or to prevent pregnancy. In a novel application, we studied the effectiveness of oral contraceptives (OCs), where misclassification of conception relative to OC exposure may obscure effect estimates.Methods:We studied OC failure, in a large claims database, among women who used antiepileptic drugs with metabolizing enzyme-inducing properties (carbamazepine or oxcarbazepine), which reduce OC’s effectiveness or enzyme-neutral properties (lamotrigine or levetiracetam), with no expected impact on OC effectiveness. We compared conception rates in women 12–48 years of age concomitantly using OCs and enzyme-inducing drugs with rates in concomitant users of OCs and enzyme-neutral drugs. We measured conception with a validated algorithm that estimates gestational age based on pregnancy endpoints. We estimated relative and attributable risk using generalized estimating equation models after standardized mortality ratio weighting.Results:We identified 89,777 concomitant use episodes with adjusted contraceptive failure rates of 1.6 (95% confidence interval (CI) = 1.4, 1.8) per 100 person–years among users of enzyme-neutral drugs and 18,964 episodes with a rate of 2.3 (1.9, 2.8) among users of enzyme-inducing drugs. The relative risk of conception for enzyme-inducing group was 1.4 (1.1, 1.8), and the rate difference was 0.7 (0.2, 1.2).Conclusions:OCs in combination with antiepileptic drugs that interact with metabolic enzymes were associated with increased contraceptive failure rates. Measurement of conception in claims data had adequate accuracy to uncover a strong drug–drug interaction, offering promise for broader application in comparative effectiveness studies on hormonal contraceptives to inform clinical and regulatory decisionmaking.