The impact of early remission on disease trajectory and patient outcomes in major depression disorder (MDD): A targeted literature review and microsimulation modeling approach based on the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study.

BACKGROUND: While literature has suggested that the duration of a major depressive episode (MDE) may affect both symptomatic and functional outcomes in major depressive disorder (MDD), study designs are limited in their ability to isolate a causal relationship. METHODS: A targeted literature review was conducted using the MEDLINE database to assess whether there was an association between (1) shorter duration of an MDE, or (2) increased rapidity of symptom improvement, and MDD outcomes in adult patients. Given findings from the literature, we hypothesized that rapid symptom improvement could be associated with other longer-term clinical outcomes and used a previously-developed microsimulation model to test this hypothesis. The base case of the model replicated step-therapy treatment patterns, for 10,000 simulated patients, based on lines of therapy related to standard of care, observed remission rates, and observed time to relapse from the STAR*D study. In alternative scenario analyses, the step 1 remission rate was varied by +25 % and +50 % from the base case value to simulate the potential impact of improved earlier remission on disease trajectory and patient-level clinical outcomes. RESULTS: The literature review (N = 35 studies) suggests a statistically significant relationship between the duration of MDE or early symptom improvement and MDD outcomes. The microsimulation model corroborated these findings and demonstrated that increasing the rate of remission in step 1 results in patients experiencing decreased number of treatment steps, faster time to remission, decreased rate of reaching treatment-resistant depression, and delayed time to relapse. LIMITATIONS: Rates of relapse in STAR*D were deemed unreliable due to the high-loss of follow-up; rates of relapse for the MDD DTM were instead derived using parametric extrapolation methods (i.e., exponential, Weibull, log-logistic, Gaussian, log-normal, logistic). Adherence to treatment was assumed to be 100 %; however, non-adherence is expected to result in lower cumulative remission rates. CONCLUSION: Findings from the literature, coupled with quantification through a novel microsimulation model, demonstrate the potential impact of increased remission on disease trajectory and patient outcomes in MDD. While additional analyses with the model may be warranted to explore the impact of novel interventions on population health, including long-term outcomes (i.e., 5-year follow-up, lifetime follow-up), efforts by clinicians to increase remission early in the disease trajectory may improve long-term outcomes.

The burden of undertreatment and non-treatment among patients with non-valvular atrial fibrillation and elevated stroke risk: a systematic review.

OBJECTIVE: Global treatment guidelines recommend treatment with oral anticoagulants (OACs) for patients with non-valvular atrial fibrillation (NVAF) and an elevated stroke risk. However, not all patients with NVAF and an elevated stroke risk receive guideline-recommended therapy. A literature review and synthesis of observational studies were undertaken to identify the body of evidence on untreated and undertreated NVAF and the association with clinical and economic outcomes. METHODS: An extensive search (1/2010-4/2020) of MEDLINE, the Cochrane Library, conference proceedings, and health technology assessments (HTAs) was conducted. Studies must have evaluated rates of nontreatment or undertreatment in NVAF. Nontreatment was defined as absence of OACs (but with possible antiplatelet treatment), while undertreatment was defined as treatment with only antiplatelet agents. RESULTS: Sixteen studies met our inclusion criteria. Rates of nontreatment for patients with elevated stroke risk ranged from 2.0-51.1%, while rates of undertreatment ranged from 10.0-45.1%. The clinical benefits of anticoagulation were reported in the evaluated studies with reductions in stroke and mortality outcomes observed among patients treated with anticoagulants compared to untreated or undertreated patients. Adverse events associated with all bleeding types (i.e. hemorrhagic stroke, major bleeding or gastrointestinal hemorrhaging) were found to be higher for warfarin patients compared to untreated patients in real-world practice. Healthcare resource utilization was found to be lower among patients highly-adherent to warfarin compared to untreated patients. CONCLUSIONS: Rates of nontreatment and undertreatment among NVAF patients remain high and are associated with preventable cardiovascular events and death. Strategies to increase rates of treatment may improve clinical outcomes.

A systematic review of the treatment of residual below the knee venous reflux after endovenous thermal ablation of the great saphenous vein.

BACKGROUND: Great saphenous vein (GSV) antireflux procedures have evolved during the past few decades to reduce elevated venous pressure. Untreated reflux in the below knee (BK) GSV (BK-GSV) can lead to persistent venous hypertension and deterioration of the venous circulation. The purpose of the present systematic review was to study the influence of BK-GSV intervention on venous disease progression. METHODS: A search was conducted, adhering to the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. The PubMed and Embase databases were searched and cross-referenced. Studies were included if they had met the inclusion criterion of BK-GSV disease as a primary or secondary outcome. Two of the authors independently determined the eligibility and extracted the relevant data. RevMan, version 5.3 (Cochrane Training, London, UK), and SPSS (IBM Corp, Armonk, NY) were used for statistical computation. RESULTS: Fifteen studies that had assessed BK-GSV reflux recurrence after ablative intervention were included in our analysis. Of the 15 studies, 6 had assessed patients after above knee (AK) high ligation and stripping (HLS), 7 after AK endovenous laser ablation (AK-EVLA), and 2 after AK- and BK-EVLA (AK+BK EVLA). In total, 525 limbs had undergone HLS, 696 AK-EVLA, and 147 AK+BK EVLA. AK+BK EVLA was associated with significantly lower odds of BK-GSV reflux recurrence compared with AK-EVLA only (odds ratio [OR], 0.1857; 95% confidence interval [CI], 0.076-0.4734; P < .0001). Although the odds of recurrent BK-GSV reflux appeared to be greater for patients who had undergone AK-HLS compared with AK+BK HLS, the difference was not statistically significant (OR, 0.62; CI, 0.27-1.43; P = .69). Finally, no statistically significant difference was observed in BK-GSV reflux recurrence between patients receiving AK-EVLA and those receiving AK-HLS (OR, 0.85; 95% CI, 0.52-1.39; P = .31). CONCLUSIONS: Axial hydrostatic reflux from the groin to ankle is best controlled with AK+BK-GSV ablation. However, GSV ablation can result in saphenous nerve injury. For C4 to C6 disease, more aggressive treatment of the AK+BK-GSV is justified if the duplex ultrasound findings demonstrate groin to ankle reflux. Thermal ablation of the BK-GSV has a lower incidence of saphenous nerve injury than does BK saphenous stripping. More randomized controlled trials are needed to answer questions involving disease recurrence and the best techniques to mitigate these recurrences.

The IMPact of untReated nOn-Valvular atrial fibrillation on short-tErm clinical and economic outcomes in the US Medicare population: the IMPROVE-AF model.

BACKGROUND: Despite treatment guidelines recommending the use of oral anticoagulants (OACs) for patients with non-valvular atrial fibrillation (NVAF) and moderate to high risk of stroke (CHA2DS2-VASc score ≥1), many patients remain untreated. A study conducted among Medicare beneficiaries with AF and a CHA2DS2-VASc score of ≥2 found that 51% of patients were not prescribed an OAC despite being eligible for treatment. When left untreated, NVAF poses an enormous burden to society, as stroke events are estimated to cost the US healthcare system about $34 billion each year in both direct medical costs and indirect productivity losses. This research explored the short-term clinical implications and budget impact (BI) of increasing OAC use among Medicare beneficiaries with NVAF. METHODS: A decision-analytic model was developed from the payer and societal perspectives to estimate the impact of increasing treatment rates among Medicare-eligible NVAF patients with a moderate-to-high risk of stroke over 1 year. Results of the model compared (1) a base case scenario using literature-derived rates of OAC use, and (2) a hypothetical scenario assuming an absolute 5% increase in overall OAC use. Clinical outcomes included the incremental annual number of ischemic stroke, hemorrhagic stroke, and gastrointestinal bleeding events, and stroke-related deaths. Economic outcomes included incremental annual and per-member per-month (PMPM) direct medical costs for the payer perspective and the incremental sum of annual direct medical and indirect costs from productivity loss and caregiver burden for the societal perspective. RESULTS: In total, 1.95 million Medicare patients with NVAF were estimated to be treated with OACs in the base case (3.8% of beneficiaries). In the hypothetical scenario analysis, nearly 200,000 more patients were treated resulting in 3,705 fewer ischemic strokes, 14 fewer gastrointestinal bleeds, 141 more hemorrhagic strokes, and 175 fewer deaths. The total incremental BI was $399.16 million ($0.65 PMPM) from the payer perspective and $377.10 million from the societal perspective due to indirect cost savings ($22.06 million). CONCLUSION: Our findings suggest that increased overall OAC use has a positive clinical benefit on the annual number of ischemic stroke events and deaths avoided in the Medicare population, while maintaining a modest increase in the overall BI to the Medicare system.

Applying State-of-the-Art Survival Extrapolation Techniques to the Evaluation of CAR-T Therapies: Evidence from a Systematic Literature Review.

INTRODUCTION: Traditional statistical techniques for extrapolating short-term survival data for anticancer therapies assume the same mortality rate for noncured and "cured" patients, which is appropriate for projecting survival of non-curative therapies but may lead to an underestimation of the treatment effectiveness for potentially curative therapies. Our objective was to ascertain research trends in survival extrapolation techniques used to project the survival benefits of chimeric antigen receptor T cell (CAR-T) therapies. METHODS: A global systematic literature search produced a review of survival analyses of CAR-T therapies, published between January 1, 2015 and December 14, 2020, based on publications sourced from MEDLINE, scientific conferences, and health technology assessment agencies. Trends in survival extrapolation techniques used, and the rationale for selecting advanced techniques, are discussed. RESULTS: Twenty publications were included, the majority of which (65%, N = 13) accounted for curative intent of CAR-T therapies through the use of advanced extrapolation techniques, i.e., mixture cure models [MCMs] (N = 10) or spline-based models (N = 3). The authors' rationale for using the MCM approach included (a) better statistical fits to the observed Kaplan-Meier curves (KMs) and (b) visual inspection of the KMs indicated that a proportion of patients experienced long-term remission and survival which is not inherently captured in standard parametric distributions. DISCUSSION: Our findings suggest that an advanced extrapolation technique should be considered in base case survival analyses of CAR-T therapies when extrapolating short-term survival data to long-term horizons extending beyond the clinical trial duration. CONCLUSION: Advanced extrapolation techniques allow researchers to account for the proportion of patients with an observed plateau in survival from clinical trial data; by only using standard-partitioned modeling, researchers may risk underestimating the survival benefits for the subset of patients with long-term remission. Sensitivity analysis with an alternative advanced extrapolation technique should be implemented and re-assessment using clinical trial extension data and/or real-world data should be conducted as longer-term data become available.

Do all cardiac surgery patients benefit from antifibrinolytic therapy?

BACKGROUND: In trauma patients, the recognition of fibrinolysis phenotypes has led to a re-evaluation of the risks and benefits of antifibrinolytic therapy (AF). Many cardiac patients also receive AF, but the distribution of fibrinolytic phenotypes in that population is unknown. The purpose of this hypothesis-generating study was to fill that gap. METHODS: Seventy-eight cardiac surgery patients were retrospectively reviewed. Phenotypes were defined as hypofibrinolytic (LY30 <0.8%), physiologic (0.8%-3.0%), and hyperfibrinolytic (>3%) based on thromboelastogram. RESULTS: The population was 65 ± 10-years old, 74% male, average body mass index of 29 ± 5 kg/m2 . Fibrinolytic phenotypes were distributed as physiologic = 45% (35 of 78), hypo = 32% (25 of 78), and hyper = 23% (18 of 78). There was no obvious effect of age, gender, race, or ethnicity on this distribution; 47% received AF. For AF versus no AF, the time with chest tube was longer (4 [1] vs. 3 [1] days, p = .037), and all-cause morbidity was more prevalent (51% vs. 25%, p = .017). However, when these two groups were further stratified by phenotypes, there were within-group differences in the percentage of patients with congestive heart failure (p = .022), valve disease (p = .024), on-pump surgery (p < .0001), estimated blood loss during surgery (p = .015), transfusion requirement (p = .015), and chest tube output (p = .008), which highlight other factors along with AF that might have affected all-cause morbidity. CONCLUSION: This is the first description of the prevalence of three different fibrinolytic phenotypes and their potential influence on cardiac surgery patients. The use of AF was associated with increased morbidity, but because of the small sample size and treatment allocation bias, additional confirmatory studies are necessary. We hope these present findings open the dialog on whether it is safe to administer AFs to cardiac surgery patients who are normo- or hypofibrinolytic.

Comparative Effectiveness Research for CAR-T Therapies in Multiple Myeloma: Appropriate Comparisons Require Careful Considerations of Data Sources and Patient Populations.

BACKGROUND AND OBJECTIVE: Registrational trials for ciltacabtagene autoleucel [cilta-cel]) and idecabtagene vicleucel [ide-cel] chimeric antigen receptor T-cell (CAR-T) therapies were single-arm studies conducted with relapse refractory multiple myeloma (MM) patients who were triple-class-exposed (TCE) or triple-class-refractory (TCR). It is critical for researchers conducting comparative effectiveness research (CER) to carefully consider the most appropriate data sources and comparable patient populations. The aim of this study was to identify potential data sources and populations for comparing to single-arm CAR-T trials CARTITUDE-1 (cilta-cel) and KarMMa (ide-cel). METHODS: A 2-part global systematic literature search produced a review of (1) clinical trials of National Comprehensive Cancer Network (NCCN) guideline preferred regimens in previously treated MM, and (2) real-world data cohorts of TCE or TCR populations, published between 1/1/2015 and 12/10/2020, with sample sizes of > 50 patients and reporting survival-related outcomes. Implications on CER and accepted best practices are discussed. RESULTS: Nine clinical trials of NCCN preferred regimens were identified along with five real-world data-based publications. No clinical trials evaluated patients with TCE or TCR MM. Among the real-world data-based publications, two evaluated patients exclusively with TCR MM, two analyzed a mixed population of patients with TCE or TCR MM, and one publication assessed patients exclusively with TCE MM. Real-world data treatment patterns were heterogeneous. CONCLUSION: Current NCCN preferred regimens were not specifically studied in TCE or TCR MM patients, although some studies do include a proportion of these types of patients. Therefore, appropriate matching of populations using either real-world data or patient level clinical trial data is critical to putting trials of novel CAR-Ts (i.e., CARTITUDE-1 or KarMMa) into appropriate comparative context.

The Key to Combat Readiness Is a Strong Military-Civilian Partnership.

INTRODUCTION: In peacetime, it is challenging for Army Forward Resuscitative Surgical Teams (FRST) to maintain combat readiness as trauma represents <0.5% of military hospital admissions and not all team members have daily clinical responsibilities. Military surgeon clinical experience has been described, but no data exist for other members of the FRST. We test the hypothesis that the clinical experience of non-physician FRST members varies between active duty (AD) and Army reservists (AR). METHODS: Over a 3-year period, all FRSTs were surveyed at one civilian center. RESULTS: Six hundred and thirteen FRST soldiers were provided surveys and 609 responded (99.3%), including 499 (81.9%) non-physicians and 110 (18.1%) physicians/physician assistants. The non-physician group included 69% male with an average age of 34 ± 11 years and consisted of 224 AR (45%) and 275 AD (55%). Rank ranged from Private to Colonel with officers accounting for 41%. For AD vs. AR, combat experience was similar: 50% vs. 52% had ≥1 combat deployment, 52% vs. 60% peri-deployment patient load was trauma-related, and 31% vs. 32% had ≥40 patient contacts during most recent deployment (all P > .15). However, medical experience differed for AD and AR: 18% vs. 29% had >15 years of experience in practice and 4% vs. 17% spent >50% of their time treating critically injured patients (all P < .001). These differences persisted across all specialties, including perioperative nurses, certified registered nurse anesthetists, operating room (OR) techs, critical-care nurses, emergency room (ER) nurses, licensed practical nurse (LPN), and combat medics. CONCLUSIONS: This is the first study of clinical practice patterns in AD vs. AR, non-physician members of Army FRSTs. In concordance with previous studies of military surgeons, FRST non-physicians seem to be lacking clinical experience as well. To maintain readiness and to provide optimal care for our injured warriors, the entire FRST, not just individuals, should embed within civilian centers.

Acute Kidney Injury Risk in Patients Treated with Vancomycin Combined with Meropenem or Cefepime.

Background: No previous studies have determined the incidence of acute kidney injury (AKI) in trauma patients treated with vancomycin + meropenem (VM) versus vancomycin + cefepime (VC). The purpose of this study was to fill this gap. Methods: A series of 99 patients admitted to an American College of Surgeons-verified level 1 trauma center over a two-year period who received VC or VM for >48 hours were reviewed retrospectively. Exclusion criteria were existing renal dysfunction or on renal replacement therapy. The primary outcome was AKI as defined by a rise in serum creatinine (SCr) to 1.5 times baseline. Multi-variable analysis was performed to control for factors associated with AKI (age, obesity, gender, length of stay [LOS], nephrotoxic agent(s), and baseline SCr), with significance defined as p < 0.05. Results: The study population was 50 ± 19 years old, 76% male, with a median LOS of 21 [range 15-39] days, and baseline SCr of 0.9 ± 0.2 mg/dL. Antibiotics, diabetes mellitus, and Injury Severity Score were independent predictors of AKI (odds ratio [OR] 4.4; 95% confidence interval [CI] 1.4-12; OR 9.3; 95% CI 1-27; OR 1.2; 95% CI 1.023-1.985, respectively). The incidence of AKI was higher with VM than VC (10/26 [38%] versus 14/73 [19.1%]; p = 0.049). Conclusions: The renal toxicity of vancomycin is potentiated by meropenem relative to cefepime in trauma patients. We recommend caution when initiating vancomycin combination therapy, particularly with meropenem.

Geodemographic analysis of pediatric firearm injuries in Miami, FL.

PURPOSE: Firearm injuries (GSW) are a growing public health concern and leading cause of morbidity and mortality among children, yet predictors of injury remain understudied. This study examines the correlates of pediatric GSW within our county. METHODS: We retrospectively queried an urban Level 1 trauma center registry for pediatric (0-18 years) GSW from September 2013 to January 2019, examining demographic, clinical, and injury information. We used a geographic information system to map GSW rates and perform spatial and spatiotemporal cluster analysis to identify zip code "hot spots." RESULTS: 393 cases were identified. The cohort was 877% male, 87% African American, 10% Hispanic, and 22% Caucasian/Other. Injuries were 92% violence-related and 4% accidental, with 63% occurring outside school hours. Mortality was 12%, with 53% of deaths occurring in the resuscitation unit. Zip-level GSW rates ranged from 0 to 9 (per 1000 < 18 years) by incident address and 0-6 by home address. Statistically significant hot spots were in predominantly underserved African American and Hispanic neighborhoods. CONCLUSIONS: Geodemographic analysis of pediatric GSW injuries can be utilized to identify at-risk neighborhoods. This methodology is applicable to other metropolitan areas where targeted interventions can reduce the burden of gun violence among children. TYPE OF STUDY: Retrospective study. LEVEL OF EVIDENCE: Level III.