Events Of Clinical Significance Research Articles

Detection of Residual Peritoneal Metastases Following Cytoreductive Surgery Using Pegsitacianine, a pH-Sensitive Imaging Agent: Final Results from a Phase II Study.

For patients with peritoneal carcinomatosis, extent of disease and completeness of cytoreductive surgery (CRS) are major prognostic factors for long-term survival. Assessment of these factors could be improved using imaging agents. Pegsitacianine is a pH-sensitive polymeric micelle conjugated to thefluorophore indocyanine green. The micelle disassembles in acidic microenvironments, such as tumors, resulting in localized fluorescence unmasking. We assessed the utility of pegsitacianine in detecting residual disease following CRS. NCT04950166 was a phase II, non-randomized, open-label, multicenter US study. Patients eligible for CRS were administered an intravenous dose of pegsitacianine at 1 mg/kg 24-72 h before surgery. Following CRS, the peritoneal cavity was reexamined under near-infrared (NIR) illumination to evaluate for fluorescent tissue. Fluorescent tissue identified was excised and evaluated by histopathology. The primary outcome was the rate of clinically significant events (CSE), defined as detection of histologically confirmed residual disease excised with pegsitacianine or a revision in the assessment of completeness of CRS. Secondary outcomes included acceptable safety and pegsitacianine performance. A total of 53 patients were screened, 50 enrolled, and 40 were evaluable for CSE across six primary tumor types. Residual disease was detected with pegsitacianine in 20 of 40 (50%) patients. Pegsitacianine showed high sensitivity and was well tolerated with no serious adverse events (SAEs). Transient treatment-related, non-anaphylactic infusion reactions occurred in 28% of patients. Pegsitacianine was well tolerated and facilitated the recognition of occult residual disease following CRS. The high rate of residual disease detected suggests that the use of pegsitacianine augmented surgeon assessment and performance during CRS.

Incidence and Costs of Clinically Significant Events with Systemic Therapy in Patients with Unresectable Hepatocellular Carcinoma: A Retrospective Cohort Study.

Systemic therapies have been associated with clinically significant events (CSEs) in patients with unresectable hepatocellular carcinoma (uHCC). We evaluated the incidence of CSEs (bleeding, clotting, encephalopathy, and portal hypertension), and their impact on healthcare resource utilization (HCRU) and costs, in patients with uHCC treated with first-line (1L) atezolizumab plus bevacizumab (A + B), lenvatinib (LEN), or sorafenib (SOR) in the USA. A retrospective cohort study was performed using medical/pharmacy claims from Optum® Clinformatics® Data Mart. Patients diagnosed with HCC who initiated 1L A + B between June 01, 2020 and December 31, 2020 or LEN/SOR between January 01, 2016 and May31, 2020 were included. Outcomes included incidence rates of CSEs, HCRU, and costs. Subgroup analysis was performed in patients with no CSEs or ≥ 1 CSE. In total, 1379 patients were selected (A + B, n = 271; LEN, n = 217; SOR, n = 891). Clotting (incidence rate per 100 patient-years [PY] 94.9) and bleeding (88.1 per 100 PY) were the most common CSEs in the A + B cohort. The most common CSEs in the LEN cohort were clotting (78.6per 100 PY) and encephalopathy (66.3 per 100 PY). Encephalopathy (73.0per 100 PY) and portal hypertension (72.3 per 100 PY) were the most common CSEs in the SOR cohort. Mean total all-cause healthcare costs per patient per month (PPPM) were $32,742, $35,623, and $29,173 in the A + B, LEN, and SOR cohorts, respectively. Mean total all-cause healthcare costs PPPM were higher in patients who had ≥ 1 CSE versus those who did not (A + B $34,304 versus $30,889; LEN $39,591 versus $30,621; SOR $31,022 versus $27,003). Despite improved efficacy of 1L systemic therapies, CSEs remain a concern for patients with uHCC, as well as an economic burden to the healthcare system. Newer treatments that reduce the risk of CSEs, while improving long-term survival in patients with uHCC, are warranted.

Evaluation of NAVA-PAP in premature neonates with apnea of prematurity: minimal backup ventilation and clinically significant events.

Neonates with apnea of prematurity (AOP) clinically deteriorate because continuous positive airway pressure (CPAP) provides inadequate support during apnea. Neurally adjusted ventilatory assist (NAVA) provides proportional ventilator support from the electrical activity of the diaphragm. When the NAVA level is 0 cmH2O/mcV (NAVA-PAP), patients receive CPAP when breathing and backup ventilation when apneic. This study evaluates NAVA-PAP and time spent in backup ventilation. This was a prospective, two-center, observational study of preterm neonates on NAVA-PAP for AOP. Ventilator data were downloaded after 24 h. The number of clinically significant events (CSEs) was collected. A paired t-test was used to perform statistical analysis. The study was conducted on 28 patients with a gestational age of 25 ± 1.8 weeks and a study age of 28 ± 23 days. The number of CSEs was 4 ± 4.39/24 h. The patients were on NAVA-PAP for approximately 90%/min, switched to backup mode 2.5 ± 1.1 times/min, and spent 10.6 ± 7.2% in backup. Preterm neonates on NAVA-PAP had few CSEs with minimal time in backup ventilation.

Detection of peritoneal metastases during cytoreductive surgery using pegsitacianine, a pH sensitive imaging agent: Final results from a phase 2 study.

3003 Background: For patients with peritoneal metastatic disease, extent of cytoreductive surgery (CRS) is a major prognostic factor for long-term survival, regardless of primary tumor type. Pegsitacianine is a systemically delivered pH-sensitive polymeric micellar fluorescent nanoprobe developed to intraoperatively identify residual disease and augment the completeness of CRS following standard of care radiographic imaging, visualization, palpation, and intended resection. Methods: NCT04950166 was a Phase 2, non-randomized, open-label, multi-center U.S. study. Patients eligible for CRS were administered a single intravenous dose of pegsitacianine at 1 mg/kg within 24-72 hours prior to surgery. After completion of intended CRS, the peritoneal cavity was systematically re-examined under near-infrared (NIR) illumination to evaluate for fluorescent tissue. Post-standard of care fluorescent tissue detected by pegsitacianine guidance was excised and sent for evaluation for presence of residual tumor by histopathology. Clinically significant events (CSE) were defined as detection of histologically confirmed residual disease excised under pegsitacianine guidance following standard CRS, resulting in additional excision or a change in the assessment of completeness of CRS. Treatment-related and treatment-emergent adverse events were coded by CTCAE (v5.01). Results: A total of 40 patients were enrolled and evaluable for CSE. Evaluable patients were defined as patients who completed pegsitacianine dosing, underwent CRS with post-SOC evaluation of the peritoneal cavity, and had evidence of disease upon histopathological evaluation of surgical specimens. These 40 patients represented 6 different primary tumor types (appendiceal, colorectal, endometrial, mesothelioma, ovarian, pancreatic). At the patient level, CSEs were detected in 20 of 40 (50%) patients. Patient-level false positive rate – wherein all pegsitacianine-guided fluorescent tissue specimens resected post-CRS were determined to be negative for cancer by histopathology – occurred in 12.5% of patients. Pegsitacianine was well tolerated with no SAEs. Treatment-related, non-anaphylactic infusion reactions occurred in 26% of patients and were transient, with a median duration of 9 minutes. Conclusions: Pegsitacianine received Breakthrough Therapy Designation from the U.S. Food and Drug Administration as a result of data collected in this trial. Pegsitacianine is well-tolerated and facilitates the recognition of occult residual disease following CRS. The high rate of residual disease detection suggests pegsitacianine has the potential to augment surgeon performance during CRS, leading to improved completeness of cytoreduction and patient outcomes. Clinical trial information: NCT04950166 .

Incidence and costs associated with clinically significant events in real-world patients with unresectable hepatocellular carcinoma on systemic therapy.

514 Background: First-line (1L) treatments for unresectable HCC (uHCC) include atezolizumab plus bevacizumab (ATEZO+BEV), and the tyrosine kinase inhibitors (TKIs) sorafenib (SOR) and lenvatinib (LEN). In clinical trials, these therapies were associated with clinically significant events (CSEs): bleeding, clotting, encephalopathy, and portal hypertension. The objective of this study was to evaluate the real-world incidence of these CSEs and their impact on healthcare resource utilization (HCRU) and costs in patients with uHCC receiving ATEZO+BEV or a TKI. Methods: We conducted a retrospective, observational, cohort study using Clinformatics Data Mart to characterize 1379 US patients diagnosed with uHCC between January 2007 and June 2021 who received treatment with ATEZO+BEV (n=271) or a TKI (SOR, n=891; LEN, n=217). Incidence of the selected CSEs was evaluated as incident cases per 100-person-years (PY) of treatment. Descriptive statistics assessed patient characteristics, HCRU, and medical costs. Results: Mean age at diagnosis was 67.7 years; most patients were male (76.1%), white (52.4%), and had Medicare (74.2%); these characteristics were consistent across treatment groups. While on ATEZO+BEV, SOR or LEN, 147 (54.2%), 481 (54.0%), and 121 (55.8%) patients experienced ≥1 CSEs, respectively. For the ATEZO+BEV group, the most common CSEs were clotting (61.2 cases/100-PY [95% confidence interval {CI}: 45.1, 81.1]) and bleeding (55.4 [40.3, 74.4]). For the SOR group the most common CSEs were encephalopathy (54.5 [46.9, 63.1]) and clotting events (51.3 [44.1, 59.4]), for the LEN group the most common CSEs were clotting events (63.5 [47.4, 83.3]) and encephalopathy (56.7 [42.2, 74.5]). Overall, mean HCRU was high in the outpatient visits, while increases in the cohorts and among events (e.g., for surgery and inpatient visits) were seen in patients with ≥1 CSEs versus those without CSEs. Mean monthly medical costs were also substantially higher with ≥1 CSEs (Table). Conclusions: There were high levels of CSEs in patients receiving ATEZO+BEV or TKIs for 1L uHCC, and the occurrence of these events is associated with an economic burden to the healthcare system. Safety should continue to be monitored for patients treated for uHCC and new therapy options with reduced risks for developing CSEs are needed. [Table: see text]

Clinically significant events associated with metastatic castration-resistant prostate cancer (mCRPC) treatments.

61 Background: We describe the association between clinically significant events (CSEs) and mCRPC treatments in US-insured patients using an administrative claims database. Methods: Adult men in a large administrative claims database from Jan 2008 to Mar 2019 with ≥1 claim for prostate cancer, codes for pharmacologic or surgical castration, and incident metastatic disease during the identification period were included in the study. Patients who had ≥6 months of continuous enrollment before and after the index date (first metastatic claim) were included. Patients were followed until death, end of study, or disenrollment. Claims-based algorithms were used to identify patients with mCRPC, lines of therapy (LOTs), and CSEs of interest. CSEs were assessed in the first LOT in which an mCRPC regimen was used. Time on treatment was used as a person-time denominator to assess rates of CSEs per 365 days (treatment year) to control for differing times on treatment regimens. Results: Overall, we identified 3690 patients with mCRPC, of which 3150 (85%) received ≥1 LOT, among whom 1680/3150 (53%) received a regimen indicated for mCRPC. Average follow-up time was 705 days. CSEs occurred in 664/1680 (40%) patients, an average of 1.15 CSE per treatment year (Table). Patients had an average of 2 CSEs. The most common CSEs were anemia (14%), fatigue (15%), and back pain (10%). CSE rates per treatment year were highest among patients who received a taxane (1.7 per treatment year), taxane + gonadotropin-releasing hormone (GnRH) modulator (1.6 per treatment year), and other chemotherapy (1.6 per treatment year). Conclusions: Among treatments for patients with mCRPC, chemotherapy-based regimens showed the highest CSE rates per treatment year. These data indicate the burden of treatment for patients and can inform treatment decisions. [Table: see text]

Interfacility Transport of the Pregnant Patient: A 5-year Retrospective Review of a Single Critical Care Transport Program

Introduction: Interfacility transport of the pregnant patient poses a challenge for prehospital providers as it is an infrequent but potentially high acuity encounter. Knowledge of clinically significant events (CSEs) that occur during these transports is important both to optimize patient safety and also to help enhance crew training and preparedness. This study evaluated a critical care transport program’s 5-year longitudinal experience transporting pregnant patients by ground and air, and described CSEs that occurred during the out-of-hospital phase of care. Methods: This study was a retrospective review of pregnant patients transported by a single critical care transport system into and within a large academic healthcare system. Patients who were pregnant, and were transported from a referring facility to one of the 2 receiving centers within Johns Hopkins Health System between January 1, 2012 and December 31, 2016 were included in this study. The primary outcome of interest was the occurrence of a predefined clinically significant event (CSE) during transport, while a secondary outcome of interest was the indication for transfer. Results: During the study period 1,223 pregnant patients were transported by our critical care transport service. There were 1,101 patients who met inclusion criteria; 693 (62.9%) of whom were transported by ground and 408 (37.1%) who were transported by rotor wing aircraft. The top 3 indications for transfer comprised 71.4% of all patients and included; preterm labor, hypertensive disorder of pregnancy, and other maternal life threatening disorder. The most common events that occurred across all transports were: exacerbation of hypertensive disease requiring intervention (4.5%), hypotension (1.3%), and altered mental status (0.2%). Conclusions: Incidence of CSEs during the interfacility transport of pregnant patients within our critical care transport system is low (6.0%). Knowledge of the clinically significant events that occur during EMS transport is a vital component of ensuring system quality and optimizing patient safety. This data can be used to augment and focus provider education and training to mitigate and optimize response to future events.

Effect of altering alarm settings: a randomized controlled study.

Medical alarm signals are important for alerting clinicians to life-threatening conditions, but the high rate of false alarms can be problematic. Reduction in alarm signals may lead to increased staff responsiveness to alarms and create a quieter environment for patients. The effect of these changes on patient outcomes is uncertain. We conducted a pilot, prospective, randomized, controlled trial in the cardiac care unit (CCU) to test a study protocol and data collection instruments and to examine the differences in alarms between usual care and altered settings. Subjects were randomized daily to either standard or altered CCU alarm settings. Secondary outcomes included the number of clinically significant events (CSEs) detected, event-triggered interventions (ETIs), frequency of alarms per monitored bed, and patient complications. Over the two-week study time frame, 22 unique patients were enrolled. There were 1,710 alarms over 163 hours of monitoring in the standard group and 1,165 alarms over 169 hours in the study group (P < 0.001). There were more CSEs detected (14 vs. 3) and ETIs (12 vs. 2) in the study group, but sample size was too small to determine efficacy. No cardiac arrests or adverse patient outcomes were observed in either group. All patients were discharged from the hospital. Study protocol and outcomes were feasible and lessons were learned. This study demonstrated feasibility of a study protocol for conducting a randomized controlled trial to evaluate CSEs, ETIs, frequency of alarms, and adverse patient outcomes when altering default alarm settings. A longer study can be performed using a similar study design.

Cardiopulmonary Monitors and Clinically Significant Events in Critically Ill Children

Cardiopulmonary monitors (CPMs) generate false alarm rates ranging from 85%-99% with few of these alarms actually representing serious clinical events. The overabundance of clinically insignificant alarms in hospitals desensitizes the clinician to true-positive alarms and poses significant safety issues. In this IRB-approved externally funded study, we sought to assess the clinical conditions associated with true and false-positive CPM alarms and attempted to define optimal alarm parameters that would reduce false-positive alarm rates (as they relate to clinically significant events) and thus improve overall CPM performance in critically ill children. Prior to the study, clinically significant events (CSEs) were defined and validated. Over a seven-month period in 2009, critically ill children underwent evaluation of CSEs while connected to a CPM. Comparative CPM and CSE data were analyzed with an aim to estimate sensitivity, specificity, and positive and negative predictive values for CSEs. CPM and CSE data were evaluated in 98 critically ill children. Overall, 2,245 high priority alarms were recorded with 68 CSEs noted in 45 observational days. During the course of the study, the team developed a firm understanding of CPM functionality, including the pitfalls associated with aggregation and analysis of CPM alarm data. The inability to capture all levels of CPM alarms represented a significant study challenge. Selective CPM data can be easily queried with standard reporting, however the default settings with this reporting exclude critical information necessary in compiling a coherent study denominator database. Although the association between CPM alarms and CSEs could not be comprehensively evaluated, preliminary analysis reflected poor CPM alarm specificity. This study provided the necessary considerations for the proper design of a future study that improves the positive predictive value of CPM alarms. In addition, this investigation has resulted in improved awareness of CPM alarm parameter settings and associated false-positive alarms. This information has been incorporated into nursing educational programs.

Characteristics, healthcare utilization and costs of bipolar disorder type I patients with and without frequent psychiatric intervention in a Medicaid population

Objective:To compare characteristics, healthcare resource utilization and costs of Medicaid bipolar disorder (BPD) type I (BP-I) patients with and without frequent psychiatric intervention (FPI).Methods:Adults with BP-I, ≥1 prescription claim for a mood stabilizer/atypical antipsychotic and 24 months’ continuous medical/prescription coverage were identified (MarketScan Medicaid database). Patients with ≥2 clinically significant events (CSEs) during a 12-month identification period had FPI. CSEs included emergency department (ED) visits or hospitalizations with a principal diagnosis of BPD, addition of a new medication to the first observed treatment regimen or ≥50% increase in BPD medication dose. Demographic and clinical characteristics were evaluated for the identification period, and healthcare utilization and costs for the 12-month follow-up. Multivariate generalized linear modeling and multivariate logistic regression, respectively, were used to evaluate the impact of FPI on all-cause and psychiatric-related costs and risk of psychiatric-related hospitalization and ED visit during follow-up.Results:Of 5,527 BP-I patients, 53% had FPI. Relative to patients without FPI, those with FPI were younger and more likely to be female, had higher adjusted all-cause (+US$3,232, p < 0.001) and psychiatric-related (+US$2,519, p < 0.001) costs and higher risk of hospitalization (adjusted odds ratio [OR] = 3.681, 95% confidence interval [CI] = 2.85–4.75) and ED visit (OR = 3.094, 95% CI = 2.55–3.76).Limitations:Analysis used a convenience sample of Medicaid enrollees in several geographically dispersed states, limiting generalizability. Analyses of administrative claims data depend on accurate diagnoses and data entry.Conclusion:BP-I patients with FPI incurred significantly higher healthcare resource utilization and costs during the follow-up period than those without FPI.

Clinical characteristics and resource utilization of patients with bipolar disorder who have frequent psychiatric interventions

Objective:To compare the demographics, clinical characteristics and resource utilization of patients with bipolar disorder who required frequent psychiatric interventions (FPIs) with those needing fewer interventions in the Duke Healthcare System database between 1999 and 2005.Methods:This retrospective analysis was conducted using electronic medical records of bipolar patients with FPIs, defined as having ≥4 clinically significant events (CSEs) in any 12-month period while in the Duke University Healthcare System. CSEs were composed of emergency room visits, inpatient hospitalizations, or a change in psychotropic medication due to psychiatric symptoms (score ≥4 on the Clinical Global Impressions–Severity scale). Data were compared between patients with and without FPIs.Results:Of 632 patients with bipolar disorder 52.5% were identified as having FPIs. These patients were younger and more often female and African American than those with fewer interventions (p < 0.01 for all). Patients with FPIs were generally prescribed more psychotropic and non-psychotropic medications, utilized more healthcare resources and experienced more psychiatric co-morbidities than those who did not require FPIs (p < 0.01 for all).Limitations:These results are from a single healthcare system and may not be generalizable to all patients with bipolar disorder. This analysis was retrospective and relied on availability of adequate information recording and coding of diagnoses by physicians.Conclusions:Patients with bipolar disorder who required FPIs were significantly different from those with fewer clinically defined interventions with respect to their demographic and clinical characteristics and prescribed medications.