End Point Research Articles

Association Between Alcohol Consumption and Disability Accumulation in Multiple Sclerosis.

Previous studies have indicated that alcohol consumption is associated with multiple sclerosis (MS) disease progression. We aimed to study the influence of alcohol consumption habits on disease progression and health-related quality of life in MS. We categorized patients from 2 population-based case-control studies by alcohol consumption habits at diagnosis and followed them up to 15 years after diagnosis through the Swedish MS registry regarding changes in the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Impact Scale 29 (MSIS-29). We used Cox regression models with 95% confidence intervals (CIs) using 24-week confirmed disability worsening, EDSS 3, EDSS 4, and physical and psychological worsening from the patient's perspective as end points. Our study comprised 9,051 patients with MS, with a mean age of 37.5 years at baseline/diagnosis. Compared with nondrinking, low and moderate alcohol consumption was associated with reduced risk of EDSS-related unfavorable outcomes (hazard ratios between 0.81 and 0.90) and with reduced risk of physical worsening. The inverse association was confined to relapsing-remitting MS and was more pronounced among women. High alcohol consumption did not significantly affect disease progression. The inverse relationship between low-moderate alcohol consumption and disability progression became stronger when we only included those who had not changed their alcohol consumption during follow-up (hazard ratios between 0.63 and 0.71). There were no differences in measures of disability at baseline between drinkers who continued drinking alcohol after diagnosis and those who later discontinued. Our findings speak against bias due to reverse causation. Low and moderate alcohol consumption was associated with more favorable outcomes in relapsing-remitting MS, compared with nondrinking, while there was no significant influence of high alcohol consumption on disease outcomes.

Outcomes of Atrial Fibrillation Ablation in Heart Failure Subtypes.

Catheter ablation (CA) improves clinical outcomes in patients with atrial fibrillation (AF) and heart failure (HF) with reduced ejection fraction (HFrEF). We aimed to evaluate the impact of CA on clinical and quality-of-life outcomes across HF subtypes. All patients undergoing AF ablation at a tertiary center were enrolled in a prospective registry and included in this study (2013-2021). The primary end point was AF recurrence. Secondary end points included AF-related hospitalizations and quality-of-life outcomes. Patients were categorized according to their HF status: no HF, HFrEF, HF with mildly reduced ejection fraction (HFmrEF), and HF with preserved ejection fraction (HFpEF). A total of 7020 patients were included (80% no HF, 8% HFrEF, 7% HFmrEF, and 5% HFpEF). Over 3 years, the cumulative incidence of AF recurrence after ablation was as follows: HFpEF (53%), HFmrEF (41%), HFrEF (41%), and no HF (34%); P<0.01. Multivariable Cox analyses confirmed these findings using no HF group as reference (HFpEF: hazard ratio, 1.47 [95% CI, 1.21-1.78]; HFmrEF: hazard ratio, 1.23 [95% CI, 1.04-1.45]; and HFrEF: hazard ratio, 1.17 [95% CI, 1.01-1.37]; P<0.05 for all). In all groups, CA resulted in a significant reduction of AF-related hospitalization (mean rate per 1 patient-years [before and after CA]; HFpEF [1.8 versus 0.3], HFmrEF [1.1 versus 0.2], HFrEF [1.1 versus 0.2], and no HF [1 versus 0.1]; P<0.01 for each comparison) and significant improvement in quality of life as measured by both the AF symptom severity score and the AF burden score (P<0.01 for the comparison between baseline and follow-up for each score when tested separately). AF recurrence rates after CA were higher in patients with HF compared with those without HF, with patients with HFpEF being at the highest risk of recurrence. Nonetheless, CA was associated with a significant reduction in AF symptoms, AF-related hospitalization, and HF symptoms in most patients irrespective of HF subtypes.

The future of clinical trials in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with a poor prognosis and limited therapeutic options. A multitude of promising compounds are currently being investigated; however, the design and conductance of late-phase clinical trials in IPF has proven particularly challenging. Despite promising phase 2 data, ziritaxestat, an autotaxin inhibitor, pentraxin-2, an endogenous protein that regulates wound healing and fibrosis, and pamrevlumab, a human monoclonal antibody against connective tissue growth factor, failed to show efficacy in phase 3 trials. Endpoint selection is critical for the design, execution, and success of clinical trials; recently, attention has been paid to the assessment of how patients feel, function, and survive with the aim of aligning scientific objectives and patient needs in IPF. External control arms are control patients that derive from historical randomized controlled trials, registries, or electronic health records. They are increasingly used to assess treatment efficacy in clinical trials owing to their potential to reduce study duration and cost and increase generalizability of findings. Advances in study design, end point selection and statistical analysis, and innovative strategies for more efficient enrolment of study participants have the potential to increase the likelihood of success of late-phase clinical trials in IPF.

Diabetes mellitus in stable chronic heart failure and the combination with humoral activation, their association, and prediction of 2-year adverse outcomes. Data from the FAR NHL registry.

The study aims to describe the role of diabetes in patients with heart failure. In all, 1052 chronic heart failure patients were included in the FARmacology and NeuroHumoral Activation (FAR NHL) multicenter prospective registry. They had ejection fraction below 50% and were on stable medication for at least 1 month. More than one-third (38.9%) of the patients had diabetes mellitus (DM). Diabetic patients (N = 409) were older (median 67 vs. 64, p < 0.001), had higher body mass index (BMI) (30 vs. 28 kg/m2, p < 0.001), much more frequently had ischemic heart disease (71 vs. 47%, p < 0.001), hypertension (80 vs. 67%, p < 0.001), dyslipidemia (89 vs. 69%, p < 0.001), worse renal function (estimated glomerular filtration rate [eGFR] median 63 vs. 73 mL/min/1.73 m2, p < 0.001), and higher N-terminal pro-brain natriuretic peptide (NT-proBNP) (median 681 vs. 463 pg/mL, p = 0.003). All-cause death, left ventricle assist device implantation, and orthotopic heart transplantation were set as the combined primary end point, which was present in 15.5% (163 patients) within the 2-year follow-up. In the 2-year follow-up, 81.0% of patients with diabetes survived without a primary end point, while 85.4% of the patients without diabetes survived, the difference being on the verge of statistical significance (p = 0.089). DM is a statistically significant predictor of NT-proBNP value in univariate analysis, but it is not an independent predictor in a multivariate analysis. When the NT-proBNP level was high, the presence of DM did not influence the prognosis. The combination of diabetes and NT-proBNP levels may better stratify the prognosis of patients with chronic heart failure.

625. PHASE II TRIAL OF INDUCTION CHEMOTHERAPY FOLLOWED BY CHEMORADIATION AND MINIMALLY INVASIVE SURGERY FOR LOCALLY ADVANCED CARCINOMA OF THE ESOPHAGUS

Abstract Background Most patients with esophageal cancer (EC) present locally advanced disease. Currently, multimodal strategies as neoadjuvant chemoradiotherapy or perioperative chemotherapy are employed, but still have high local and distant failures rates. This study evaluated the results of a phase II protocol with induction chemotherapy (IC) and concurrent chemoradiation (CR) before surgery for locally advanced carcinoma of the esophagus and esophagogastric junction (EGJ). The primary end point was to evaluate pathological complete remission (PCR) rate at surgical specimen. A PCR ≥ 30% was considered promising for further study. Methods Patients with squamous cell carcinoma (SCC) or adenocarcinoma (AC) of the thoracic esophagus and JEG, clinical stage T1b-3, N0-2, M0, PS 0-2, underwent two cycles of IC with carboplatin and paclitaxel followed by CR with the same agents and minimally invasive esophagectomy. At the screening, 14 days after the first cycle of IC and 6-8 weeks after the CR, metabolic responses were accessed by PET-CT and classified according the PERCIST criteria. Results One hundred and twenty-nine patients were accrued from January 2017 to April 2023. Forty-seven patients started the trial and 45 completed the neoadjuvant part of the protocol. Most patients were male (73.3%), the median age of was 55 years and AC was the most prevalent histological subtype (53.3%). Grade 3/4 toxicity during IC were infrequent and included neutropenia (12.5%), anemia (6.2%) and dysphagia (10.4%). Lymphopenia (10.7%) and dysphagia (6.5%) were the most common grade 3/4 toxicity during CR. All cases received the full radiotherapy dose of 45 Gy by IMRT technique. Thirty-seven patients underwent surgery and 31 had minimally invasive MacKeown esophagectomy with complete tumor resection (R0). Sixty-four percent of all included patients completed the neoadjuvant therapy and survived for 30 days after surgery. The most prevalent postoperative complications were anastomotic fistula (29%) and pneumonia (19%). Median hospital stay was 12 (7-56) days. Six patients (19.3%) had major postoperative morbidity (Clavien-Dindo ≥ IIIb), 4 were reoperated and one (3.2%) died during hospitalization. The median number of lymph nodes retrieved was 24. Eleven patients (33.5%) had pathological positive lymph nodes. The overall pathological complete response rate was 25.8%, 41.8% for SCC and 15.8% for AC. The early metabolic evaluation by PERCIST showed that 2 cases (4.4%) had progressive disease (PD), 26 (57.7%) stable disease (SD), 15 (33.3%) partial response (PR) and 2 (4.4%) complete response (CR). All the CR were SCC. The late metabolic response analysis showed that 1 (2.4%) patient had PD, 6 (14.6%) SD, 23 (56%) PR and 11 (27%) CR. On the basis of an intention-to-treat analysis, the median overall survival was 31.4 months, whereas the five-year overall survival was 31.2%. After curative surgery, 12 patients had recurrence disease. Six (19%) patients had recurrences at distant sites, 4 (12.9%) had loco-regional recurrence and 2 (6.4%) had both patterns. Conclusion This intensified neoadjuvant regimen was efficacious and safe in patients with locally advanced EC, but failed to reach the defined efficacy goal for further investigation, especially for AC.

Lack of Validity of Absolute Percentage Errors in Estimated Operating Room Case Durations as a Measure of Operating Room Performance: A Focused Narrative Review.

Commonly reported end points for operating room (OR) and surgical scheduling performance are the percentages of estimated OR times whose absolute values differ from the actual OR times by ≥15%, or by various intervals from ≥5 to ≥60 minutes. We show that these metrics are invalid assessments of OR performance. Specifically, from 19 relevant articles, multiple OR management decisions that would increase OR efficiency or productivity would also increase the absolute percentage error of the estimated case durations. Instead, OR managers should check the mean bias of estimated OR times (ie, systematic underestimation or overestimation), a valid and reliable metric.

Comparing Analytical Methods for Composite End Points in Clinical Trials: Insights from the Vericiguat Global Study in Subjects with Heart Failure With Reduced Ejection Fraction Trial

In VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction), participants with heart failure (HF) and reduced ejection fraction, vericiguat decreased the primary composite outcome (time to first HF hospitalization [HFH] or cardiovascular death [CVD]) (897 events) compared with placebo (972 events) (hazard ratio, 0.90; 95% confidence interval [CI], 0.82-0.98; P = .02). In this prespecified secondary analysis, we applied the weighted composite end point (WCE) and the win ratio (WR) methods to provide complementary assessments of treatment effect. The WCE method estimated the mean HFH-adjusted survival based on prespecified weights from a Delphi panel of the VICTORIA executive committee and national leaders: mild (weight per event, 0.39), moderate (0.5), or severe (0.67) HFH, and CVD (1.0). The unmatched WR was estimated for the descending hierarchy of CVD, then recurrent HFH. The WCE used all 3412 primary clinical events: 875 severe HFH (vericiguat, 416/ placebo, 459), 1614 moderate HFH (767/847), 68 mild HFH (38/30), and 855 CVD (414/441). Improved HFH-adjusted survival occurred with vericiguat (mean 78.2% vs 75.6%, difference 2.4%, 95% CI, 1.7%-3.2%, P < .0001). Based on a comparison of 6,375,624 pairs, the WR of 1.13 (95% CI 1.03-1.24, P = .01) also indicated improved clinical outcomes with vericiguat. The results of the WCE and WR methods were consistent with the primary analysis of the time to first HFH or CVD. Although both WCE and WR assessed recurrent events, the WCE allowed inclusion of all recurrent events, insights on the severity of HFH events, and an absolute measure of the participant-treatment experience. This approach complements conventional assessment, better informing consumers of new therapeutics and future trial designs.

Prognostication Following Aneurysmal Subarachnoid Hemorrhage: The Modified Hunt and Hess Grading Scale

Background This study proposes a modification to the traditional Hunt and Hess (tHH) grading scale for prognostication in aneurysmal subarachnoid hemorrhage (aSAH), which differentiates the most severe‐grade patients based on the presence or absence of brainstem dysfunction [determined by Glasgow Coma Scale (GCS) scores 3‐5]. Methods Weighted aSAH hospitalizations were retrospectively identified in the National Inpatient Sample from 2015 to 2019 and were stratified by tHH and modified HH (mHH) grades. mHH grade 5 was defined as tHH grade 5 with GCS score 3–5, while mHH grade 4 comprised tHH grade 5 with GCS score 6–8 and tHH grade 4. HH grades 1–3 do not differ between the traditional and modified scales. Measures of diagnostic performance were compared for the primary study end point [poor outcome as determined by the previously validated NIS‐SAH Outcome Measure (NIS‐SOM), shown to have high concordance with modified Rankin Scale scores &gt; 2]. External validation of the mHH was performed using data from a prospectively maintained aSAH registry. Results Among 6130 aSAH hospitalizations, 2245 (36%) were tHH grade 5. Seven hundred and eighty‐five (35%) of these had a GCS 3–5 and were designated as mHH grade 5. Poor outcomes were identified in 78% and 77% of grade 4 tHH and mHH, respectively, and in 83% and 95% of grade 5 tHH and mHH, respectively. In comparison with the tHH, the mHH achieved superior discrimination [c‐statistic 0.793 (95% CI 0.768, 0.818) versus 0.780 (95% CI 0.750, 0.807); DeLong p &lt; 0.001] for poor outcome, as well as improved specificity (0.929 versus 0.304) and positive predictive value (PPV) (0.949 versus 0.827). External registry validation of the mHH demonstrated excellent discrimination [c‐statistic 0.835 (95% CI 0.801, 0.870)], with a specificity of 0.950 and PPV of 0.905. Conclusion The mHH achieved a favorable diagnostic performance profile using retrospective data and may aid in the prognostication of high‐severity patients with aSAH.

360. RECURRENCE PATTERNS AFTER PRIMARY SURGERY AND NEOADJUVANT CHEMORADIOTHERAPY FOR ESOPHAGEAL ADENOCARCINOMA: ACROSS THE CROSS RECURRENCES

Abstract Background Our publication Across the CROSS in daily practice challenged the routine use of neoadjuvant chemoradiotherapy for locally advanced esophageal adenocarcinoma, showing a comparable 5-year overall and disease-free survival after primary surgery. This current study reevaluated overall and disease-free survival on long term and aimed to differentiate recurrence patterns and its final impact on overall survival. Methods This retrospective cohort study with propensity score-matched analysis included all surgically treated patients between 2000 and 2018 with locally advanced adenocarcinoma (cT1/2N+ or cT3/4N0/+). Exclusion criteria of the CROSS trial were applied. Patients were matched on age, Charlson comorbidity score, clinical tumor length, and lymph node status. The primary end point was time to recurrence. Results 149 propensity score-matched cases were defined in each group. There was still no significant difference after 10 years in median overall survival (33.6 vs 34.9 months, p=0.52) and median disease-free survival (14.1 vs 14.0 months, p=0.13) between both groups. Furthermore, nCRT resulted in a shorter time to overall recurrence (6.3 vs 11.5 months, p=0.004) and locoregional recurrence (6.3 vs 13.6 months, p=0.005). Additionally, overall survival after diagnosis of recurrence was also significantly shorter for nCRT patients than for primary surgery patients (6.9 vs 9.6 months, p=0.032). Conclusion Our propensity score-matched results indicate that primary surgery can offer a comparable long-term overall and disease-free survival as nCRT followed by surgery. Both overall and locoregional recurrences occur earlier in nCRT patients and overall survival after recurrence is significantly longer after primary surgery.

Lessons on the use of real-world data in medical device research: findings from the National Evaluation System for Health Technology Test-Cases.

Aim: Although the US FDA encourages manufacturers of medical devices to submit real-world evidence (RWE) to support regulatory decisions, the ability of real-world data (RWD) to generate evidence suitable for decision making remains unclear. The 2017 Medical Device User Fee Amendments (MDUFA IV), authorized the National Evaluation System for health Technology Coordinating Center (NESTcc) to conduct pilot projects, or 'Test-Cases', to assess whether current RWD captures the information needed to answer research questions proposed by industry stakeholders. We synthesized key lessons about the challenges conducting research with RWD and the strategies used by research teams to enhance their ability to generate evidence from RWD based on 18 Test-Cases conducted between 2020 and 2022. Materials & methods: We reviewed study protocols and reports from each Test-Case team and conducted 49 semi-structured interviews with representatives of participating organizations. Interview transcripts were coded and thematically analyzed. Results: Challenges that stakeholders encountered in working with RWD included the lack of unique device identifiers, capturing key data elements and their appropriate meaning in structured data, limited reliability of diagnosis and procedure codes in structured data, extracting information from unstructured electronic health record (EHR) data, limited capture of long-term study end points, missing data and data sharing. Successful strategies included using manufacturer and supply chain data, leveraging clinical registries and registry reporting processes to collect and aggregate data, querying standardized EHR data, implementing natural language processing algorithms and using multidisciplinary research teams. Conclusion: The Test-Cases identified numerous challenges working with RWD but also opportunities to address these challenges and improve researchers' ability to use RWD to generate evidence on medical devices.

The Ross Procedure in Active Infective Endocarditis: A Comparison With Conventional Prostheses

BackgroundThe Ross procedure can be an ideal option in infective endocarditis (IE) due to greater resistance to infection. However, limited literature has highlighted the comparison with conventional prostheses in this setting. MethodsBetween February 2013 and September 2022, 25 patients (median age, 50 years) underwent a Ross procedure for IE (Ross group). The results were compared with those after other aortic valve procedures (aortic valve replacement and aortic root replacement) for IE (n = 37, other group. ResultsThe patients in the Ross group included more intravenous drug users and had more prosthetic valve endocarditis and annular abscess formation compared with the other group. Although cardiopulmonary bypass time and aortic cross-clamp time were significantly longer (P < .001 and P = .003, respectively) and the blood requirements were significantly higher (P = .001) in the Ross group, most postoperative short-term outcomes were equivalent between the 2 groups. During follow-up, 1 patient (4%) required reoperation in the Ross group, whereas 6 patients (16%) required reoperation in the other group. Freedom from composite events was significantly better in the Ross group (P = .04). Multivariable analysis found the Ross procedure, compared with other procedures, was a significant independent protective factor for composite end points (P = .03). ConclusionsFor IE, despite surgical complexity, the Ross procedure yielded short-term outcomes similar to other procedures. In the midterm, the Ross procedure provides a lower reoperation rate, resulting in significantly fewer composite events. The Ross procedure appears to be a better option for patients with IE, but long-term follow-up is necessary.

Effect of Switching the Histamine-1 Receptor Antagonist Clemastine to Cetirizine in Paclitaxel Premedication Regimens: The H1-Switch Study.

Premedication, including a histamine-1 receptor (H1) antagonist, is recommended to all patients treated with paclitaxel chemotherapy to reduce the incidence of hypersensitivity reactions (HSRs). However, the scientific basis for this premedication is not robust, which provides opportunities for optimization. Substitution of intravenously administered first-generation H1 antagonist for orally administered second-generation H1 antagonist could reduce side effects, and improve efficiency and sustainability. This study investigates the efficacy and safety of substituting intravenous clemastine for oral cetirizine as prophylaxis for paclitaxel-induced HSRs. This single-center, prospective, noninferiority study compares a historic cohort receiving a premedication regimen with intravenous clemastine to a prospective cohort receiving oral cetirizine. Primary end point of the study is HSR grade ≥3. The difference in incidence was calculated together with the 90% CI. We determined that the two-sided 90% CI of HSR grade ≥3 incidence in the oral cetirizine cohort should not be more than 4% higher (ie, the noninferiority margin) compared with the intravenous clemastine cohort. Two hundred and twelve patients were included in the oral cetirizine cohort (June 2022 and May 2023) and 183 in the intravenous clemastine cohort. HSR grade ≥3 incidence was 1.6% (n = 3) in the intravenous clemastine cohort and 0.5% (n = 1) in the oral cetirizine cohort, resulting in a difference of -1.2% (90% CI, -3.4 to 1.1). Premedication containing oral cetirizine is as safe as premedication containing intravenous clemastine in preventing paclitaxel-induced HSR grade ≥3. These findings could contribute to optimization of care for patients and improve efficiency and sustainability.

Impact of VO 2peak on the Clinical Outcomes of Older Patients With Coronary Heart Disease in China.

The aim of this study was to explore the role of cardiopulmonary exercise test parameters, especially peak oxygen uptake (VO 2peak ), in predicting the incidence of adverse cardiovascular events in older Chinese patients with coronary heart disease (CHD). Older patients with CHD who underwent cycle ergometer cardiopulmonary exercise test at the Cardiac Rehabilitation Clinic of Chinese PLA General Hospital from July 1, 2015 to January 31, 2020 were enrolled. The follow-up intervals were 6mo. Cox regression was used to analyze the relationship between VO 2peak and adverse cardiovascular events. Restricted cubic splines and subgroup analyses were used to observe the relationship between VO 2peak and the hazard ratio (HR) of the primary end point event (PEE), which included a composite of all-cause death, nonfatal recurrent myocardial infarction, unscheduled revascularization, and stroke. The composite end point event was the PEE combined with cardiac rehospitalization. A total of 1223 participants (mean age 68±5yr) were included. Median follow-up was 68mo. Mean VO 2peak was 16.5±4.0 mL/kg/min, and VO 2peak was an independent predictor of the PEE (HR=0.929; 95% CI, 0.891-0.970; P =.001). This association was further validated by restricted cubic spline and subgroup analyses. Peak oxygen uptake was also an independent risk factor for the composite end point event (HR=0.968; 95% CI, 0.941-0.996; P =.025). In conclusion, VO 2peak is an independent risk factor for adverse cardiovascular events in older Chinese patients with CHD, and more optimal therapy should be recommended to patients with lower VO 2peak .

AI for Multistructure Incidental Findings and Mortality Prediction at Chest CT in Lung Cancer Screening.

Background Incidental extrapulmonary findings are commonly detected on chest CT scans and can be clinically important. Purpose To integrate artificial intelligence (AI)-based segmentation for multiple structures, coronary artery calcium (CAC), and epicardial adipose tissue with automated feature extraction methods and machine learning to detect extrapulmonary abnormalities and predict all-cause mortality (ACM) in a large multicenter cohort. Materials and Methods In this post hoc analysis, baseline chest CT scans in patients enrolled in the National Lung Screening Trial (NLST) from August 2002 to September 2007 were included from 33 participating sites. Per scan, 32 structures were segmented with a multistructure model. For each structure, 15 clinically interpretable radiomic features were quantified. Four general codes describing abnormalities reported by NLST radiologists were applied to identify extrapulmonary significant incidental findings on the CT scans. Death at 2-year and 10-year follow-up and the presence of extrapulmonary significant incidental findings were predicted with ensemble AI models, and individualized structure risk scores were evaluated. Area under the receiver operating characteristic curve (AUC) analysis was used to evaluate the performance of the models for prediction of ACM and extrapulmonary significant incidental findings. The Pearson χ2 test and Kruskal-Wallis rank sum test were used for statistical analyses. Results A total of 24 401 participants (median age, 61 years [IQR, 57-65 years]; 14 468 male) were included. In 3880 of 24 401 participants (16%), 4283 extrapulmonary significant incidental findings were reported. During the 10-year follow-up, 3389 of 24 401 participants (14%) died. CAC had the highest feature importance for predicting the three study end points. The 10-year ACM model demonstrated the best AUC performance (0.72; per-year mortality of 2.6% above and 0.8% below the risk threshold), followed by 2-year ACM (0.71; per-year mortality of 1.13% above and 0.3% below the risk threshold) and prediction of extrapulmonary significant incidental findings (0.70; probability of occurrence of 25.4% above and 9.6% below the threshold). Conclusion A fully automated AI model indicated extrapulmonary structures at risk on chest CT scans and predicted ACM with explanations. ClinicalTrials.gov Identifier: NCT00047385 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Yanagawa and Hata in this issue.

P148 EFFICACY AND SAFETY OF SACUBITRIL/ALLISARTAN FOR THE TREATMENT OF PRIMARY HYPERTENSION: A PHASE 3 RANDOMIZED, DOUBLE-BLIND STUDY

Background: This randomized, double-blind, phase 3 study assessed the efficacy and safety of sacubitril/allisartan, an angiotensin receptor neprilysin inhibitor, compared with olmesartan in Chinese patients with mild to moderate hypertension. Methods: Eligible patients aged 18-75 years (n=1197) with mild to moderate hypertension were randomized to receive sacubitril/allisartan 240 mg (n=399), sacubitril/allisartan 480 mg (n=399), or olmesartan 20 mg (n=399) once daily for 12 weeks. Patients who completed the 12-week treatment then received another 12-week extended treatment (n=1084) and 28-week prolonged treatment (n=189). The primary end point was a reduction in clinic mean sitting systolic blood pressure (msSBP) from baseline with various doses of sacubitril/allisartan versus olmesartan at 12 weeks. Secondary efficacy variables included clinic and 24-h ambulatory blood pressure for the comparison between sacubitril/allisartan and olmesartan at week 12, 24, and 52. Results: Sacubitril/allisartan 240 mg/day provided a greater reduction in msSBP than olmesartan at 12 weeks (between-group difference: -1.9 mmHg [95% confidence interval -4.2 to 0.4 mmHg], P=0.0007, for non-inferiority). Sacubitril/allisartan 480 mg/day provided a significantly greater reduction in msSBP than olmesartan at 12 weeks (between-treatment difference: -5.0 mmHg [95% confidence interval -7.3 to -2.8 mmHg], P&lt;0.001, for superiority). Greater reductions in 24-h, daytime and nighttime systolic and diastolic blood pressure were also observed with both doses of sacubitril/allisartan compared with olmesartan (P≤0.001 for 480 mg/day). The blood pressure reductions tended to be dose-dependent for sacubitril/allisartan. Sacubitril/allisartan was well tolerated, and no cases of angioedema or death were reported. Conclusions: Sacubitril/allisartan is effective for the treatment of hypertension and well tolerated in Chinese patients.

234. EFFECTS OF TRANSCUTANEOUS ELECTRICAL STIMULATION SYSTEM ON HEARTBURN, REGURGITATION AND ESOPHAGEAL ACID EXPOSURE IN GERD PATIENTS

Abstract Background Chronic PPI treatment in GERD is associated with high failure rate and concerns regarding PPI's side effects. In a previously published proof of concept study, a non-pharmacological, non-invasive transcutaneous, electrical stimulation system, reduced esophageal acid exposure in GERD patients unresponsive to standard dose PPI. However, in that study, a symptomatic response to electrical stimulation was not assessed. Aim To determine the effect of a transcutaneous electrical stimulation system (TESS) on symptoms (heartburn and regurgitation) and the percentage of esophageal acid exposure time in GERD patients. Methods Patients suffering from heartburn and regurgitation were recruited into this multicenter study. The first phase of this study was a one week, run-in period, off-PPI's, during which, patients completed symptoms diaries and demographic questionnaires. Thereafter, all patients underwent upper endoscopy with subsequently wireless esophageal pH capsule placement (off PPI). Based on pH analysis in the first 24-hours, (day 0) only those with increased acid exposure time (percent total time pH &amp;lt;4 above 6%) continued to the next phase. During phase two of the study, patients were treated for two weeks with TESS and documented their symptoms. Primary end points included the reduction of baseline (pretreatment) number of heartburn and regurgitation episodes as well as 24-hour percent total time pH &amp;lt;4 and/or DeMeester score by at least 50%. Results 26 GERD patients (16 male, aged 47±15 years, mean BMI 25±3 kg/m2) completed the study. At baseline, mean number of daily heartburn and regurgitation events was 2.41±0.36 and 1.38±0.35, respectively. Following TESS, mean number of daily heartburn and regurgitation events dropped to 0.69±0.16 and 0.31±0.19, respectively (p=0.01). At baseline, mean percent total time pH &amp;lt; 4 was 11.8±0.9. Following TESS, mean percent total time pH &amp;lt; 4 dropped to 7.3±0.8, 7.8±1.0, 6.7±1.1 and 5.0±0.7 for day 1, 2, 3 and 4, respectively (p=0.01). At baseline, mean DeMeester score was 31.4±2.1. Following TESS, mean DeMeester score dropped to 20.1±2.0, 20.4±2.5, 17.3±2.6 and 14.3±2.0 for day 1, 2, 3 and 4, respectively (p=0.01). Conclusions TESS is effective in reducing both symptoms (heartburn and regurgitation) and esophageal acid exposure time in GERD patients.

538. COMPARISON OF EARLY POSTOPERATIVE OUTCOMES OF CERVICAL ANASTOMOSIS TO HIGH INTRATHORACIC ANASTOMOSIS AMONG PATIENTS WITH UPPER THORACIC ESOPHAGEAL CANCER

Abstract Background For upper thoracic esophageal cancer, esophagectomy combined with cervical esophagogastrostomy (cervical anastomosis, CA) and three-field lymph node dissection (3FLND) has been proposed as the standard surgical approach. However, while CA provides sufficient length of proximal resection margins, it is associated with a higher incidence of postoperative complications such as anastomotic leaks, recurrent laryngeal nerve (RLN) injury, and increased mortality. As an alternative, high-intrathoracic esophagogastric anastomosis (high-ITA) with 3FLND has been performed. We aimed to evaluate the benefits and limitations of high-ITA compared to conventional CA in terms of early postoperative outcomes. Methods A total of 232 patients, who underwent curative esophagogastrostomy with 3FLND and either of high-intrathoracic anastomosis (high-ITA) or cervical anastomosis (CA) for upper thoracic esophageal cancer a tertiary hospital from January 2010 to December 2021. Collected data from medical records were analyzed retrospectively regarding morbidity and mortality rates. The primary end point was recurrence. Anastomotic leak, RLN palsy, hospital stay, and 90-day mortality and in-hospital mortality were evaluated using Chi-squared test, Fisher’s exact test, and T-test. The risk of mortality and recurrence were analyzed using Cox-proportional hazard regression with a median follow-up of 39.1(IQR 17.8, 80.2) months. Results Among the fifty patients with high-ITA and 182 patients with CA, the high-ITA group reported fewer anastomotic leaks (6.0% vs. 19.8%, p=0.02) and a shorter hospital stay (median 12days vs. 15 days, p&amp;lt;0.001). No significant difference was observed in RLN palsy (6.0% vs. 13.7%, p=0.22) and the 90-day or in-hospital mortality rate (2.0% vs. 2.2%, p=1.0). The number of lymph nodes dissected (LND) was similar between the groups (47.4(±15.4) vs. 52.7(±18.3), p=0.06), and there was no difference in the risk of mortality and recurrence according to the high-ITA method (HR 0.9, 95% CI 0.6-1.6; HR 1.0, 95% CI 0.6-1.7) after adjustment for age, sex, and stage. Conclusion In the esophagogastrostomy with three-field lymph node dissection, performing high-intrathoracic anastomosis may reduce the incidence of anastomotic leaks and shorten the hospital stay without adversely affecting overall survival.

Design of a Multicenter, Randomized Controlled Trial for the Treatment of Peripheral Neuropathic Pain (COMFORT Study) with a Micro-Implantable Pulse Generator.

Peripheral Nerve Stimulation (PNS) is an established therapy for chronic neuropathic pain of peripheral origin, typically following nerve injury. However, there is a paucity of Randomized Controlled Trials (RCTs) demonstrating the therapeutic benefits of PNS. The goals of the current study (COMFORT Study) are to document the safety and efficacy of the Nalu Neurostimulation in a PNS RCT, compared to conventional medical management (CMM). This is a prospective, multicenter, RCT evaluating the treatment of neuropathic pain with PNS therapy. One of the following four regions will be targeted for treatment: low back, shoulder, knee or foot/ankle. Consented subjects will undergo a baseline evaluation, after which they are randomized 2:1 (PNS+CMM arm to CMM arm). Subjects randomized to PNS+CMM arm will undergo a trial implant period using best clinical practices. Subjects who pass the trial phase, by showing a ≥ 50% reduction in pain relative to baseline, will receive the permanent implant. All subjects receiving a permanent implant will be followed for a total of 36 months. At the 3-month primary end point, subjects in CMM arm will be given the option to crossover into PNS+CMM arm, beginning with a trial implant. The study duration is expected to be 5.5 years from first enrollment to last follow-up of last subject and subsequent study closure. Adverse events will be captured throughout the study. The COMFORT study, described here, has the potential to demonstrate the efficacy and safety of the Nalu Neurostimulation System in the treatment of peripheral neuropathy. Results of this study will be the first Level-I evidence, out to 36 months, validating the use of this PNS system in the treatment of chronic pain. This study is designed to enroll the largest cohort, to date, of subjects comparing PNS+CMM vs CMM alone.

Increasing Power in Phase III Oncology Trials With Multivariable Regression: An Empirical Assessment of 535 Primary End Point Analyses.

A previous study demonstrated that power against the (unobserved) true effect for the primary end point (PEP) of most phase III oncology trials is low, suggesting an increased risk of false-negative findings in the field of late-phase oncology. Fitting models with prognostic covariates is a potential solution to improve power; however, the extent to which trials leverage this approach, and its impact on trial interpretation at scale, is unknown. To that end, we hypothesized that phase III trials using multivariable PEP analyses are more likely to demonstrate superiority versus trials with univariable analyses. PEP analyses were reviewed from trials registered on ClinicalTrials.gov. Adjusted odds ratios (aORs) were calculated by logistic regressions. Of the 535 trials enrolling 454,824 patients, 69% (n = 368) used a multivariable PEP analysis. Trials with multivariable PEP analyses were more likely to demonstrate PEP superiority (57% [209 of 368] v 42% [70 of 167]; aOR, 1.78 [95% CI, 1.18 to 2.72]; P = .007). Among trials with a multivariable PEP model, 16 conditioned on covariates and 352 stratified by covariates. However, 108 (35%) of 312 trials with stratified analyses lost power by categorizing a continuous variable, which was especially common among immunotherapy trials (aOR, 2.45 [95% CI, 1.23 to 4.92]; P = .01). Trials increasing power by fitting multivariable models were more likely to demonstrate PEP superiority than trials with unadjusted analysis. Underutilization of conditioning models and empirical power loss associated with covariate categorization required by stratification were identified as barriers to power gains. These findings underscore the opportunity to increase power in phase III trials with conventional methodology and improve patient access to effective novel therapies.

Outcomes With the WATCHMAN FLX in Everyday Clinical Practice From the NCDR Left Atrial Appendage Occlusion Registry.

PINNACLE FLX (Protection Against Embolism for Nonvalvular AF Patients: Investigational Device Evaluation of the WATCHMAN FLX LAA Closure Technology) demonstrated improved outcomes and low incidence of adverse events with the WATCHMAN FLX device in a controlled setting. The National Cardiovascular Disease Registry's Left Atrial Appendage Occlusion Registry was utilized to assess the safety and effectiveness of WATCHMAN FLX in contemporary clinical practice in the United States. The WATCHMAN FLX Device Surveillance Post Approval Analysis Plan used data from the Left Atrial Appendage Occlusion registry to identify patients undergoing WATCHMAN FLX implantation between August 2020 and September 2022. The key safety end point was defined as all-cause death, ischemic stroke, systemic embolism, or device or procedure-related events requiring open cardiac surgery or major endovascular intervention between device implantation and hospital discharge. Major adverse events were reported at hospital discharge, 45 days, and 1 year. Among 97 185 patients in the Left Atrial Appendage Occlusion registry undergoing WATCHMAN FLX, successful implantation occurred in 97.5% (n=94 784) of patients. The key safety end point occurred in 0.45% of patients. At 45 days post-procedure, all-cause death occurred in 0.81% patients, ischemic stroke in 0.23%, major bleeding in 3.1%, pericardial effusion requiring intervention in 0.50%, device-related thrombus in 0.44%, and device embolism in 0.04% patients. No peri-device leak was observed in 83.1% of patients at 45 days. At 1 year, the rate of all-cause death was 8.2%, the rate of any stroke was 1.5% (ischemic stroke, 1.2%), and major bleeding occurred in 6.4% of patients. In a large contemporary cohort of patients with the WATCHMAN FLX device, the rates of implant success and clinical outcomes through 1 year were comparable with the PINNACLE FLX study, demonstrating that favorable outcomes achieved in the pivotal approval study can be replicated in routine clinical practice.