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BACKGROUND: One in 7 adults have chronic kidney disease (CKD), which is associated with high morbidity and mortality and substantial health care costs, especially in more advanced disease. Our data from a US commercial payer show rising per-member-per-year costs for renal and cardiac complications associated with CKD. OBJECTIVE: To predict the clinical and economic impact of treatment with or without dapagliflozin from the perspective of a US commercial payer using a cost-offset model (COM). METHODS: The COM used real-world cost and member count data from a US employer-sponsored commercial payer and results of the double-blind, randomized, phase 3 Dapagliflozin and Prevention of Adverse Outcomes in CKD clinical trial (NCT03036150) to predict the incidence of clinical events, including a greater than or equal to 50% decline in estimated glomerular filtration rate (eGFR), end-stage kidney disease, and hospitalization for heart failure, and their associated costs over a 3-year period. The COM compared a hypothetical scenario of the experience with or without dapagliflozin in members with CKD stages 2-4, aged younger than 65 years. RESULTS: In the simulated populations of 130 members, the COM projected 9 events of a greater than or equal to 50% decline in estimated glomerular filtration rate for the experience with dapagliflozin vs 15 events for the experience without dapagliflozin (6 fewer events; number needed to treat [NNT] = 20, amounting to estimated cumulative cost offsets of $0.57 million [M] over a 3-year period). The COM projected similar results for end-stage kidney disease (8 events with dapagliflozin vs 14 events without dapagliflozin; NNT = 24, amounting to $1.92 M in cumulative cost offsets) and for hospitalization for heart failure (13 events with dapagliflozin vs 33 events without dapagliflozin; NNT = 7, amounting to $0.79 M in cumulative cost offsets). These projections translated to total mean, cumulative cost offsets of $3.89 M for all clinical events evaluated over the 3-year period (36.6% reduction with dapagliflozin vs without dapagliflozin), and net mean, cumulative cost offsets of $2.58 M over the 3-year period (24.2% reduction with dapagliflozin vs without dapagliflozin) after factoring in a discounted wholesale acquisition cost for dapagliflozin expenditure ($1.31 M over 3 years). Thus, the net mean, cumulative cost offsets were $19,843 per member over 3 years, representing a 197% return on investment for dapagliflozin expenditure. CONCLUSIONS: Results of our COM suggest that dapagliflozin can reduce clinical events and their associated costs over a 3-year period when compared with a scenario without dapagliflozin. Cost offsets increased with each year, indicating that US commercial payers can substantially reduce costs associated with CKD morbidity and mortality.
Subject(s)
Benzhydryl Compounds , Cost-Benefit Analysis , Glucosides , Renal Insufficiency, Chronic , Humans , Benzhydryl Compounds/therapeutic use , Benzhydryl Compounds/economics , Glucosides/economics , Glucosides/therapeutic use , Renal Insufficiency, Chronic/drug therapy , Renal Insufficiency, Chronic/economics , United States , Middle Aged , Male , Female , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Sodium-Glucose Transporter 2 Inhibitors/economics , Glomerular Filtration Rate , Adult , Double-Blind Method , Aged , Health Care Costs/statistics & numerical data , Models, EconomicABSTRACT
INTRODUCTION: Cardiovascular-kidney-metabolic (CKM) syndrome is highly prevalent in the US Medicare population and is projected to increase further. Sodium-glucose co-transporter 2 inhibitors have indications in chronic kidney disease (CKD), heart failure (HF), and type 2 diabetes (T2D), providing protective efficacy across conditions within CKM syndrome. The objective of this study was to develop a model to extrapolate key outcomes observed in pivotal clinical trials to the US Medicare population, and to assess the potential direct cost offsets associated with dapagliflozin therapy. METHODS: All US 2022 Medicare beneficiaries (≥ 65 years of age) eligible to receive dapagliflozin were estimated according to drug label indication and Medicare enrollment and claims data. Incidence of key outcomes from the dapagliflozin clinical program were modelled over a 4-year time horizon based on patient-level data with CKD, HF, and T2D. Published cost data of relevant clinical outcomes were used to calculate direct medical care cost-offset associated with treatment with dapagliflozin. RESULTS: In a population of 13.1 million patients with CKM syndrome, treatment with dapagliflozin in addition to historical standard of care (hSoC) versus hSoC alone led to fewer incidents of HF-related events (hospitalization for HF, 613,545; urgent HF visit, 98,896), renal events (kidney failure, 285,041; ≥ 50% sustained decline in kidney function, 375,137), and 450,355 fewer deaths (of which 225,346 and 13,206 incidences of cardiovascular and renal death were avoided). In total this led to medical care cost offsets of $99.3 billion versus treatment with hSoC only (dapagliflozin plus hSoC, $310.3 billion; hSoC, $211.0 billion). CONCLUSION: By extrapolating data from trials across multiple indications within CKM syndrome, this broader perspective shows that considerable medical care cost offsets may result through attenuated incidence of clinical events in CKD, T2D, and HF populations if treated with dapagliflozin in addition to hSoC over a 4-year time horizon. Graphical abstract available for this article.
Subject(s)
Benzhydryl Compounds , Glucosides , Medicare , Metabolic Syndrome , Sodium-Glucose Transporter 2 Inhibitors , Humans , Benzhydryl Compounds/therapeutic use , Benzhydryl Compounds/economics , United States , Glucosides/therapeutic use , Glucosides/economics , Medicare/statistics & numerical data , Aged , Male , Metabolic Syndrome/epidemiology , Metabolic Syndrome/drug therapy , Female , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Sodium-Glucose Transporter 2 Inhibitors/economics , Cardio-Renal Syndrome/drug therapy , Cardio-Renal Syndrome/economics , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/complications , Aged, 80 and over , Renal Insufficiency, Chronic/epidemiologyABSTRACT
BACKGROUND: Lung cancer diagnosis, staging and treatment may be enhanced by multidisciplinary participation and presentation in multidisciplinary meetings (MDM). We performed a systematic review and meta-analysis to explore literature evidence of clinical impacts of MDM exposure. METHODS: A study protocol was registered (PROSPERO identifier CRD42021258069). Randomised controlled trials and observational cohort studies including adults with nonsmall cell lung cancer and who underwent MDM review, compared to no MDM, were included. MEDLINE, CENTRAL, Embase and ClinicalTrials.gov were searched on 31 May 2021. Studies were screened and extracted by two reviewers. Outcomes included time to diagnosis and treatment, histological confirmation, receipt of treatments, clinical trial participation, survival and quality of life. Risk of bias was assessed using the ROBINS-I (Risk of Bias in Non-randomised Studies - of Interventions) tool. RESULTS: 2947 citations were identified, and 20 studies were included. MDM presentation significantly increased histological confirmation of diagnosis (OR 3.01, 95% CI 2.30-3.95; p<0.00001) and availability of clinical staging (OR 2.55, 95% CI 1.43-4.56; p=0.002). MDM presentation significantly increased likelihood of receipt of surgery (OR 2.01, 95% CI 1.29-3.12; p=0.002) and reduced the likelihood of receiving no active treatment (OR 0.32, 95% CI 0.21-0.50; p=0.01). MDM presentation was protective of both 1-year survival (OR 3.23, 95% CI 2.85-3.68; p<0.00001) and overall survival (hazard ratio 0.63, 95% CI 0.55-0.72; p<0.00001). DISCUSSION: MDM presentation was associated with increased likelihood of histological confirmation of diagnosis, documentation of clinical staging and receipt of surgery. Overall and 1-year survival was better in those presented to an MDM, although there was some clinical heterogeneity in participants and interventions delivered. Further research is required to determine the optimal method of MDM presentation, and address barriers to presentation.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/therapy , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/therapy , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Patient Care Team , Interdisciplinary Communication , Neoplasm Staging , Treatment OutcomeABSTRACT
Importance: Kidney health has received increasing focus as part of comprehensive heart failure (HF) treatment efforts. However, the occurrence of clinically relevant kidney outcomes in contemporary populations with HF has not been well studied. Objective: To examine rates of incident dialysis and acute kidney injury (AKI) among Medicare beneficiaries after HF hospitalization. Design, Setting, and Participants: This retrospective cohort study evaluated adults aged 65 years or older who were hospitalized for HF across 372 sites in the Get With The Guidelines-Heart Failure registry in the US between January 1, 2014, and December 31, 2018. Patients younger than 65 years or requiring dialysis either during or prior to hospitalization were excluded. Data were analyzed from May 4, 2021, to March 8, 2024. Main Outcomes and Measures: The primary outcome was inpatient dialysis initiation in the year after HF hospitalization and was ascertained via linkage with Medicare claims data. Other all-cause and cause-specific hospitalizations were also evaluated. The covariate-adjusted association between discharge estimated glomerular filtration rate (eGFR) and 1-year postdischarge outcomes was examined using Cox proportional hazards regression models. Results: Overall, among 85â¯298 patients included in the analysis (mean [SD] age, 80 [9] years; 53% women) mean (SD) left ventricular ejection fraction was 47% (16%) and mean (SD) eGFR was 53 (29) mL/min per 1.73 m2; 54â¯010 (63%) had an eGFR less than 60 mL/min per 1.73 m2. By 1 year after HF hospitalization, 6% had progressed to dialysis, 7% had progressed to dialysis or end-stage kidney disease, and 7% had been readmitted for AKI. Incident dialysis increased steeply with lower discharge eGFR category: compared with patients with an eGFR of 60 mL/min per 1.73 m2 or more, individuals with an eGFR of 45 to less than 60 and of less than 30 mL/min per 1.73 m2 had higher rates of dialysis readmission (45 to <60: adjusted hazard ratio [AHR], 2.16 [95% CI, 1.86-2.51]; <30: AHR, 28.46 [95% CI, 25.25-32.08]). Lower discharge eGFR (per 10 mL/min per 1.73 m2 decrease) was independently associated with a higher rate of readmission for dialysis (AHR, 2.23; 95% CI, 2.14-2.32), dialysis or end-stage kidney disease (AHR, 2.34; 95% CI, 2.24-2.44), and AKI (AHR, 1.25; 95% CI, 1.23-1.27), with similar findings for all-cause mortality, all-cause readmission, and HF readmission. Baseline left ventricular ejection fraction did not modify the covariate-adjusted association between lower discharge eGFR and kidney outcomes. Conclusions and Relevance: In this study, older adults with HF had substantial risk of kidney complications, with an estimated 6% progressing to dialysis in the year after HF hospitalization. These findings emphasize the need for health care approaches prioritizing kidney health in this high-risk population.
Subject(s)
Acute Kidney Injury , Glomerular Filtration Rate , Heart Failure , Hospitalization , Medicare , Humans , Heart Failure/therapy , Heart Failure/epidemiology , Male , Female , United States/epidemiology , Aged , Hospitalization/statistics & numerical data , Retrospective Studies , Aged, 80 and over , Acute Kidney Injury/therapy , Acute Kidney Injury/epidemiology , Renal Dialysis/statistics & numerical data , RegistriesABSTRACT
BACKGROUND: Little is known regarding differences in cause-specific costs between heart failure (HF) with ejection fraction (EF) ≤40% vs >40%, and potential cost implications of sodium glucose co-transporter 2 inhibitor (SGLT2i) therapy. OBJECTIVES: This study sought to compare cause-specific health care costs following hospitalization for HF with EF ≤40% vs >40% and estimate the cost offset with implementation of SGLT2i therapy. METHODS: This study examined Medicare beneficiaries hospitalized for HF in the Get With The Guidelines-Heart Failure registry from 2016 to 2020. Mean per-patient total (excluding drug costs) and cause-specific costs from discharge through 1-year follow-up were calculated and compared between EF ≤40% vs >40%. Next, risk reductions on total all-cause and HF hospitalizations were estimated in a trial-level meta-analysis of 5 pivotal trials of SGLT2is in HF. Finally, these relative treatment effects were applied to Medicare beneficiaries eligible for SGLT2i therapy to estimate the projected cost offset with implementation of SGLT2i, excluding drug costs. RESULTS: Among 146,003 patients, 50,598 (34.7%) had EF ≤40% and 95,405 (65.3%) had EF >40%. Mean total cost through 1 year was $40,557. Total costs were similar between EF groups overall but were higher for EF ≤40% among patients surviving the 1-year follow-up period. Patients with EF >40% had higher costs caused by non-HF and noncardiovascular hospitalizations, and skilled nursing facilities (all P < 0.001). Trial-level meta-analysis of the 5 SGLT2i clinical trials estimated 11% (rate ratio: 0.89; 95% CI: 0.84-0.93; P < 0.001) and 29% (rate ratio: 0.71; 95% CI: 0.66-0.76; P < 0.001) relative reductions in rates of total all-cause and HF hospitalizations, respectively, regardless of EF. Reductions in all-cause and HF hospitalizations were projected to reduce annual costs of readmission by $2,451 to $2,668 per patient with EF ≤40% and $1,439 to $2,410 per patient with EF >40%. CONCLUSIONS: In this large cohort of older U.S. adults hospitalized for HF, cause-specific costs of care differed among patients with EF ≤40% vs >40%. SGLT2i significantly reduced the rate of HF and all-cause hospitalizations irrespective of EF in clinical trials, and implementation of SGLT2i therapy in clinical practice is projected to reduce costs by $1,439 to $2,668 per patient over the 1 year post-discharge, excluding drug costs.
Subject(s)
Health Care Costs , Heart Failure , Hospitalization , Medicare , Sodium-Glucose Transporter 2 Inhibitors , Humans , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Sodium-Glucose Transporter 2 Inhibitors/economics , Heart Failure/economics , Heart Failure/therapy , Heart Failure/drug therapy , Hospitalization/economics , Aged , Female , Male , United States , Health Care Costs/statistics & numerical data , Medicare/economics , Stroke Volume/physiology , Aged, 80 and over , RegistriesABSTRACT
BACKGROUND: Normothermic machine perfusion (NMP) allows for the assessment and resuscitation of ex-vivo human livers prior to transplantation. Commercially available NMP systems are closed circuits that accumulate metabolic waste and cytokines over time, potentially limiting organ preservation times. Dialysis has been proposed as a method to remove waste and excess fluid from such systems. This study aimed to demonstrate the utility of integrating dialysis into a commercially available system by quantifying solute removal. METHODS: A dialysis filter was attached in parallel to a commercially available liver perfusion system. Three livers declined for transplantation were split before undergoing long-term NMP with blood using the modified system. During perfusion, dialysate flow rates were set in the range of 100-600 mL/h for short periods of time. At each flow rate, perfusate and spent dialysate samples were collected and analyzed for solute clearance. RESULTS: The addition of dialysis to a commercial NMP system removed water-soluble waste and helped regulate electrolyte concentrations. Interleukin-6 was successfully removed from the perfusate. Solute clearance was proportional to dialysate flow rate. A guide for our perfusion setup was created for the appropriate selection of dialysis flow rates and duration based on real-time perfusate composition. CONCLUSIONS: Dialysis circuits can efficiently remove waste and regulate perfusate composition, and can be easily incorporated to improve the performance of commercially available systems. Quantification of the effect of dialysis on perfusate composition enables refined dialysis control to optimize electrolyte profiles and avoid the over- or under-correction of key solutes.
Subject(s)
Liver , Organ Preservation , Perfusion , Renal Dialysis , Humans , Perfusion/methods , Perfusion/instrumentation , Organ Preservation/methods , Organ Preservation/instrumentation , Renal Dialysis/instrumentation , Renal Dialysis/methods , Liver/blood supply , Liver Transplantation/methods , Male , Dialysis Solutions/chemistry , Middle Aged , FemaleABSTRACT
Importance: Intracerebral hemorrhage (ICH) is the deadliest stroke subtype, and mortality rates are especially high in anticoagulation-associated ICH. Recently, specific anticoagulation reversal strategies have been developed, but it is not clear whether there is a time-dependent treatment effect for door-to-treatment (DTT) times in clinical practice. Objective: To evaluate whether DTT time is associated with outcome among patients with anticoagulation-associated ICH treated with reversal interventions. Design, Setting, and Participants: This cohort study used data from the American Heart Association Get With The Guidelines-Stroke quality improvement registry. Patients with ICH who presented within 24 hours of symptom onset across 465 US hospitals from 2015 to 2021 were included. Data were analyzed from January to September 2023. Exposures: Anticoagulation-associated ICH. Main Outcomes and Measures: DTT times and outcomes were analyzed using logistic regression modeling, adjusted for demographic, history, baseline, and hospital characteristics, with hospital-specific random intercepts to account for clustering by site. The primary outcome of interest was the composite inpatient mortality and discharge to hospice. Additional prespecified secondary outcomes, including functional outcome (discharge modified Rankin Scale score, ambulatory status, and discharge venue), were also examined. Results: Of 9492 patients with anticoagulation-associated ICH and documented reversal intervention status, 4232 (44.6%) were female, and the median (IQR) age was 77 (68-84) years. A total of 7469 (78.7%) received reversal therapy, including 4616 of 5429 (85.0%) taking warfarin and 2856 of 4069 (70.2%) taking a non-vitamin K antagonist oral anticoagulant. For the 5224 patients taking a reversal intervention with documented workflow times, the median (IQR) onset-to-treatment time was 232 (142-482) minutes and the median (IQR) DTT time was 82 (58-117) minutes, with a DTT time of 60 minutes or less in 1449 (27.7%). A DTT time of 60 minutes or less was associated with decreased mortality and discharge to hospice (adjusted odds ratio, 0.82; 95% CI, 0.69-0.99) but no difference in functional outcome (ie, a modified Rankin Scale score of 0 to 3; adjusted odds ratio, 0.91; 95% CI, 0.67-1.24). Factors associated with a DTT time of 60 minutes or less included White race, higher systolic blood pressure, and lower stroke severity. Conclusions and Relevance: In US hospitals participating in Get With The Guidelines-Stroke, earlier anticoagulation reversal was associated with improved survival for patients with ICH. These findings support intensive efforts to accelerate evaluation and treatment for patients with this devastating form of stroke.
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BACKGROUND: Normothermic machine perfusion permits the ex vivo preservation of human livers before transplantation. Long-term perfusion for days-to-weeks provides the opportunity for enhanced pretransplant assessment and potential regeneration of organs. However, this risks microbial contamination and infection of the recipient if the organ is transplanted. An understanding of perfusate microbial contamination is required to inform infection control procedures and antimicrobial prophylaxis for this technology. METHODS: We modified a liver perfusion machine for long-term use by adding long-term oxygenators and a dialysis filter. Human livers that were not suitable for transplantation were perfused using a red-cell-based perfusate under aseptic and normothermic conditions (36 °C) with a goal of 14 d. Cephazolin was added to the perfusate for antimicrobial prophylaxis. Perfusate and bile were sampled every 72 h for microbial culture. RESULTS: Eighteen partial human livers (9 left lateral segment grafts and 9 extended right grafts) were perfused using our perfusion system. The median survival was 7.2 d. All organs surviving longer than 7 d (9/18) had negative perfusate cultures at 24 and 48 h. Half of the grafts (9/18) became culture-positive by the end of perfusion. Microbial contaminants included Gram-negative ( Pseudomonas species, Proteus mirabilis, Stenotrophomonas maltophilia ) and Gram-positive bacteria ( Staphylococcus epidermidis , Enterococcus faecalis , and Bacillus species) as well as yeast ( Candida albicans ). CONCLUSIONS: Microbial contamination of perfusate is common during long-term perfusion of human livers with both exogenous and endogenous sources. Enhanced infection control practices and review of targeted antimicrobial prophylaxis are likely to be necessary for translation into the clinical arena.
Subject(s)
Anti-Infective Agents , Liver Transplantation , Humans , Liver Transplantation/adverse effects , Liver Transplantation/methods , Organ Preservation/methods , Liver , Perfusion/adverse effects , Perfusion/methodsABSTRACT
BACKGROUND: Patients hospitalized with heart failure (HF) and diabetes mellitus (DM) are at risk for worsening clinical status. Little is known about the frequency of therapeutic changes during hospitalization. We characterized the use of medical therapies before, during and after hospitalization in patients with HF and DM. METHODS: We identified Medicare beneficiaries in Get With The Guidelines-Heart Failure (GWTG-HF) hospitalized between July 2014 and September 2019 with Part D prescription coverage. We evaluated trends in the use of 7 classes of antihyperglycemic therapies (metformin, sulfonylureas, GLP-1RA, SGLT2-inhibitors, DPP-4 inhibitors, thiazolidinediones, and insulins) and 4 classes of HF therapies (evidence-based ß-blockers, ACEi or ARB, MRA, and ARNI). Medication fills were assessed at 6 and 3 months before hospitalization, at hospital discharge and at 3 months post-discharge. RESULTS: Among 35,165 Medicare beneficiaries, the median age was 77 years, 54% were women, and 76% were white; 11,660 (33%) had HFrEF (LVEF ≤ 40%), 3700 (11%) had HFmrEF (LVEF 41%-49%), and 19,805 (56%) had HFpEF (LVEF ≥ 50%). Overall, insulin was the most commonly prescribed antihyperglycemic after HF hospitalization (nâ¯=â¯12,919, 37%), followed by metformin (nâ¯=â¯7460, 21%) and sulfonylureas (nâ¯=â¯7030, 20%). GLP-1RA (nâ¯=â¯700, 2.0%) and SGLT2i (nâ¯=â¯287, 1.0%) use was low and did not improve over time. In patients with HFrEF, evidence-based beta-blocker, RASi, MRA, and ARNI fills during the 6 months preceding HF hospitalization were 63%, 62%, 19%, and 4%, respectively. Fills initially declined prior to hospitalization, but then rose from 3 months before hospitalization to discharge (beta-blocker: 56%-82%; RASi: 51%-57%, MRA: 15%-28%, ARNI: 3%-6%, triple therapy: 8%-20%; P < 0.01 for all). Prescription rates 3 months after hospitalization were similar to those at hospital discharge. CONCLUSIONS: In-hospital optimization of medical therapy in patients with HF and DM is common in participating hospitals of a large US quality improvement registry.
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Diabetes Mellitus , Heart Failure , Metformin , Humans , Female , Aged , United States/epidemiology , Male , Heart Failure/drug therapy , Heart Failure/epidemiology , Angiotensin Receptor Antagonists/therapeutic use , Aftercare , Patient Discharge , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Stroke Volume , Medicare , Diabetes Mellitus/drug therapy , Diabetes Mellitus/epidemiology , Hospitalization , Adrenergic beta-Antagonists/therapeutic use , Hypoglycemic Agents/therapeutic use , Registries , Metformin/therapeutic useABSTRACT
Crohn's disease (CD) is a chronic, relapsing and remitting inflammatory bowel disease (IBD) that is increasing in incidence and prevalence globally. Management aims to achieve endoscopic healing, symptom resolution and improvement in quality of life. Therapeutic approaches in CD vary depending on disease phenotype. Thiopurines are important in steroid-sparing maintenance therapy, while anti-tumour necrosis factor agents play a fundamental role, especially in fistulising CD. Suboptimal response to these medications may require escalation to other immunosuppressive and biologic therapies, and surgical intervention is still required in a proportion of patients. Tailoring treatment to target specific patient phenotypes, disease severity and patient wishes is becoming more feasible with the growing array of therapeutic options in CD.
Subject(s)
Crohn Disease , Humans , Crohn Disease/diagnosis , Crohn Disease/drug therapy , Quality of Life , Immunosuppressive Agents/therapeutic use , Remission InductionABSTRACT
Purpose/Background: We evaluate how a deep learning model can be applied to extract refractive error metrics from pupillary red reflex images taken by a low-cost handheld fundus camera. This could potentially provide a rapid and economical vision-screening method, allowing for early intervention to prevent myopic progression and reduce the socioeconomic burden associated with vision impairment in the later stages of life. Methods: Infrared and color images of pupillary crescents were extracted from eccentric photorefraction images of participants from Choithram Hospital in India and Dargaville Medical Center in New Zealand. The pre-processed images were then used to train different convolutional neural networks to predict refractive error in terms of spherical power and cylindrical power metrics. Results: The best-performing trained model achieved an overall accuracy of 75% for predicting spherical power using infrared images and a multiclass classifier. Conclusions: Even though the model's performance is not superior, the proposed method showed good usability of using red reflex images in estimating refractive error. Such an approach has never been experimented with before and can help guide researchers, especially when the future of eye care is moving towards highly portable and smartphone-based devices.
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Current machine perfusion technology permits livers to be preserved ex situ for short periods to assess viability prior to transplant. Long-term normothermic perfusion of livers is an emerging field with tremendous potential for the assessment, recovery, and modification of organs. In this study, we aimed to develop a long-term model of ex situ perfusion including a surgical split and simultaneous perfusion of both partial organs. Human livers declined for transplantation were perfused using a red blood cell-based perfusate under normothermic conditions (36 °C) and then split and simultaneously perfused on separate machines. Ten human livers were split, resulting in 20 partial livers. The median ex situ viability was 125 h, and the median ex situ survival was 165 h. Long-term survival was demonstrated by lactate clearance, bile production, Factor-V production, and storage of adenosine triphosphate. Here, we report the long-term ex situ perfusion of human livers and demonstrate the ability to split and perfuse these organs using a standardised protocol.
Subject(s)
Liver Transplantation , Humans , Liver Transplantation/methods , Liver , Perfusion/methods , Bile , Preservation, BiologicalABSTRACT
BACKGROUND AND AIMS: Patients hospitalized for acute heart failure (AHF) continue to be discharged on an inadequate number of guideline-directed medical therapies (GDMT) despite evidence that inpatient initiation is beneficial. This study aimed to examine whether a tailored electronic health record (EHR) alert increased rates of GDMT prescription at discharge in eligible patients hospitalized for AHF. METHODS: Pragmatic trial of messaging to providers about treatment of acute heart failure (PROMPT-AHF) was a pragmatic, multicenter, EHR-based, and randomized clinical trial. Patients were automatically enrolled 48 h after admission if they met pre-specified criteria for an AHF hospitalization. Providers of patients in the intervention arm received an alert during order entry with relevant patient characteristics along with individualized GDMT recommendations with links to an order set. The primary outcome was an increase in the number of GDMT prescriptions at discharge. RESULTS: Thousand and twelve patients were enrolled between May 2021 and November 2022. The median age was 74 years; 26% were female, and 24% were Black. At the time of the alert, 85% of patients were on ß-blockers, 55% on angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, 20% on mineralocorticoid receptor antagonist (MRA) and 17% on sodium-glucose cotransporter 2 inhibitor. The primary outcome occurred in 34% of both the alert and no alert groups [adjusted risk ratio (RR): 0.95 (0.81, 1.12), P = .99]. Patients randomized to the alert arm were more likely to have an increase in MRA [adjusted RR: 1.54 (1.10, 2.16), P = .01]. At the time of discharge, 11.2% of patients were on all four pillars of GDMT. CONCLUSIONS: A real-time, targeted, and tailored EHR-based alert system for AHF did not lead to a higher number of overall GDMT prescriptions at discharge. Further refinement and improvement of such alerts and changes to clinician incentives are needed to overcome barriers to the implementation of GDMT during hospitalizations for AHF. GDMT remains suboptimal in this setting, with only one in nine patients being discharged on a comprehensive evidence-based regimen for heart failure.
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OBJECTIVES: To report stage-specific patterns of treatment and the influence of management and treatment type on survival rates for people newly diagnosed with small cell lung cancer (SCLC). DESIGN: Cross-sectional patterns of care study; analysis of data prospectively collected for the Victorian Lung Cancer Registry (VLCR). SETTING, PARTICIPANTS: All people diagnosed with SCLC in Victoria during 1 April 2011 - 18 December 2019. MAIN OUTCOME MEASURES: Stage-specific management and treatment of people with SCLC; median survival time. RESULTS: During 2011-19, 1006 people were diagnosed with SCLC (10.5% of all lung cancer diagnoses in Victoria); their median age was 69 years (interquartile range [IQR], 62-77 years), 429 were women (43%), and 921 were current or former smokers (92%). Clinical stage was defined for 896 people (89%; TNM stages I-III, 268 [30%]; TNM stage IV, 628 [70%]) and ECOG performance status at diagnosis for 663 (66%; 0 or 1, 489 [49%]; 2-4, 174 [17%]). The cases of 552 patients had been discussed at multidisciplinary meetings (55%), 377 people had received supportive care screening (37%), and 388 had been referred for palliative care (39%). Active treatment was received by 891 people (89%): chemotherapy, 843 (84%); radiotherapy, 460 (46%); chemotherapy and radiotherapy, 419 (42%); surgery, 23 (2%). Treatment had commenced within fourteen days of diagnosis for 632 of 875 patients (72%). Overall median survival time from diagnosis was 8.9 months (IQR, 4.2-16 months; stage I-III: 16.3 [IQR, 9.3-30] months; stage IV: 7.2 [IQR, 3.3-12] months). Multidisciplinary meeting presentation (hazard ratio [HR], 0.66; 95% CI, 0.58-0.77), multimodality treatment (HR, 0.42; 95% CI, 0.36-0.49), and chemotherapy within fourteen days of diagnosis (HR, 0.68; 95% CI, 0.48-0.94) were each associated with lower mortality during follow-up. CONCLUSION: Rates of supportive care screening, multidisciplinary meeting evaluation, and palliative care referral for people with SCLC could be improved. A national registry of SCLC-specific management and outcomes data could improve the quality and safety of care.
Subject(s)
Lung Neoplasms , Small Cell Lung Carcinoma , Humans , Female , Middle Aged , Aged , Male , Small Cell Lung Carcinoma/drug therapy , Retrospective Studies , Cross-Sectional Studies , Routinely Collected Health Data , Lung Neoplasms/epidemiology , Lung Neoplasms/therapyABSTRACT
Importance: Clinical guidelines for patients with heart failure with reduced ejection fraction (HFrEF) strongly recommend treatment with a sodium-glucose cotransporter-2 inhibitor (SGLT2i) to reduce cardiovascular mortality or HF hospitalization. Nationwide adoption of SGLT2i for HFrEF in the US is unknown. Objective: To characterize patterns of SGLT2i use among eligible US patients hospitalized for HFrEF. Design, Setting, and Participants: This retrospective cohort study analyzed 49â¯399 patients hospitalized for HFrEF across 489 sites in the Get With The Guidelines-Heart Failure (GWTG-HF) registry between July 1, 2021, and June 30, 2022. Patients with an estimated glomerular filtration rate less than 20 mL/min/1.73 m2, type 1 diabetes, and previous intolerance to SGLT2i were excluded. Main Outcomes and Measures: Patient-level and hospital-level prescription of SGLT2i at hospital discharge. Results: Of 49â¯399 included patients, 16â¯548 (33.5%) were female, and the median (IQR) age was 67 (56-78) years. Overall, 9988 patients (20.2%) were prescribed an SGLT2i. SGLT2i prescription was less likely among patients with chronic kidney disease (CKD; 4550 of 24â¯437 [18.6%] vs 5438 of 24â¯962 [21.8%]; P < .001) but more likely among patients with type 2 diabetes (T2D; 5721 of 21â¯830 [26.2%] vs 4262 of 27â¯545 [15.5%]; P < .001) and those with both T2D and CKD (2905 of 12â¯236 [23.7%] vs 7078 vs 37â¯139 [19.1%]; P < .001). Patients prescribed SGLT2i therapy were more likely to be prescribed background triple therapy with an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, ß-blocker, and mineralocorticoid receptor antagonist (4624 of 9988 [46.3%] vs 10â¯880 of 39â¯411 [27.6%]; P < .001), and 4624 of 49â¯399 total study patients (9.4%) were discharged with prescriptions for quadruple medical therapy including SGLT2i. Among 461 hospitals with 10 or more eligible discharges, 19 hospitals (4.1%) discharged 50% or more of patients with prescriptions for SGLT2i, whereas 344 hospitals (74.6%) discharged less than 25% of patients with prescriptions for SGLT2i (including 29 [6.3%] that discharged zero patients with SGLT2i prescriptions). There was high between-hospital variance in the rate of SGLT2i prescription in unadjusted models (median odds ratio, 2.53; 95% CI, 2.36-2.74) and after adjustment for patient and hospital characteristics (median odds ratio, 2.51; 95% CI, 2.34-2.71). Conclusions and Relevance: In this study, prescription of SGLT2i at hospital discharge among eligible patients with HFrEF was low, including among patients with comorbid CKD and T2D who have multiple indications for therapy, with substantial variation among US hospitals. Further efforts are needed to overcome implementation barriers and improve use of SGLT2i among patients with HFrEF.
Subject(s)
Diabetes Mellitus, Type 2 , Heart Failure , Renal Insufficiency, Chronic , Sodium-Glucose Transporter 2 Inhibitors , Ventricular Dysfunction, Left , Humans , Female , Aged , Male , Heart Failure/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/epidemiology , Stroke Volume , Retrospective Studies , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Ventricular Dysfunction, Left/drug therapy , Renal Insufficiency, Chronic/drug therapy , Registries , Glucose/pharmacology , Glucose/therapeutic use , SodiumABSTRACT
BACKGROUND: Split liver transplantation permits the transplant of two recipients using a single donor liver. Liver splitting can be performed using the ex-vivo technique (more convenient), or the in-situ technique (shorter cold ischaemic time). We aimed to develop a technique for liver splitting during normothermic machine perfusion which combines the advantages of both techniques and permits graft assessment prior to transplant. METHODS: Human livers declined for transplantation were perfused at 36 °C using a modified-commercial perfusion machine. We developed a six-step method to split whole livers into left lateral segment grafts and extended right grafts. Both partial livers were then perfused on separate machines for individual assessment. RESULTS: Using our technique, 10 whole livers were successfully split during normothermic perfusion resulting in 20 partial grafts. Apart from a single graft which failed due to a technical error, all grafts survived for 24-h after splitting. Survival was demonstrated by lactate clearance, bile production and synthesis of coagulation factors. CONCLUSIONS: Liver splitting during normothermic machine perfusion has the potential to revolutionise split liver transplantation. We describe a novel technique that reliably achieves two grafts from a single donor liver. This raises the possibility of semi-elective transplantation, and sophisticated graft assessment prior to implant.
Subject(s)
Liver Transplantation , Humans , Liver Transplantation/methods , Living Donors , Liver/surgery , Cold Ischemia/methods , Perfusion/methodsABSTRACT
Acute Heart failure (AHF) is among the most frequent causes of hospitalization in the United States, contributing to substantial health care costs, morbidity, and mortality. Inpatient initiation of guideline-directed medical therapy (GDMT) is recommended for patients with heart failure with reduced ejection fraction (HFrEF) to reduce the risk of cardiovascular death or HF hospitalization. However, underutilization of GDMT prior to discharge is pervasive, representing a valuable missed opportunity to optimize evidence-based care. The PRagmatic Trial Of Messaging to Providers about Treatment of Acute Heart Failure tests the effectiveness of an electronic health record embedded clinical decision support system that informs providers during hospital management about indicated but not yet prescribed GDMT for eligible AHF patients with HFrEF. PRagmatic Trial Of Messaging to Providers about Treatment of Acute Heart Failureis an open-label, multicenter, pragmatic randomized controlled trial of 1,012 patients hospitalized with HFrEF. Eligible patients randomized to the intervention group are exposed to a tailored best practice advisory embedded within the electronic health record that alerts providers to prescribe omitted GDMT. The primary outcome is an increase in the proportion of additional GDMT medication classes prescribed at the time of discharge compared to those in the usual care arm.
Subject(s)
Heart Failure , Humans , Heart Failure/drug therapy , Hospitalization , Patient Discharge , Stroke Volume , United StatesABSTRACT
Introduction: While serious liver injury among statin users is extremely rare, baseline liver enzyme testing is still recommended prior to initiating therapy. The benefit of such screening should be reevaluated based on empirical evidence. This study compared the risk of severe acute liver injury (SALI) between statin initiators with an elevated ALT (>35U/L) matched to statin initiators with a normal ALT level (≤35U/L). Statin initiators with an elevated ALT were additionally compared against matched non-users. Methods: The study created cohorts from Optum and MarketScan claims data. Exposed and comparison cohorts were propensity score (PS) matched in each dataset and findings were pooled using meta-analysis. Proportional hazards regression was used to estimate hazard ratios (HRs), and a prespecified non-inferiority margin for SALI was set at a HR of 1.8. Results: 232,889 patients with elevated ALT were PS-matched to 232,889 with normal ALT level. The overall incidence rate of SALI was about 19/100,000 person-years among statin initiators. Statin initiators with elevated ALT had no meaningfully increased risk of SALI compared to those with normal ALT (HR=1.15; 95% CI 0.75 to 1.75). Comparing statin initiators with non-initiators with elevated ALT values equally yielded no increased risk (HR=0.76; 95% CI 0.52 to 1.11). Conclusion: In this large population-based study, SALI in statin users was rare. Importantly, the results showed no evidence that baseline ALT status is a reliable indicator for an increased risk of severe liver injury among statin initiators.
ABSTRACT
Stroke is a leading cause of death and disability in the world, and the provision of reperfusion therapy and endovascular therapy, in particular, have revolutionized the treatment of patients with stroke and opened opportunities to look at brain clots retrieved after the procedure. The use of histopathology and molecular profiling of clots is of growing research and clinical interest. However, its clinical implications and incorporation within stroke workflows remain suboptimal. Recent studies have indicated that the study of brain clots may inform the mechanism of stroke and hence guide treatment decision-making in select groups of patients, especially patients without a defined cause or known mechanism. This article provides a comprehensive overview of various clot histopathological examinations in acute stroke-care settings, their clinical utility, and existing gaps and opportunities for further research. We also provide targeted recommendations to improve clot analysis workflow, hence standardizing its incorporation into clinical practice.
Subject(s)
Brain Ischemia , Ischemic Stroke , Stroke , Thrombosis , Humans , Brain Ischemia/pathology , Thrombectomy/adverse effects , Stroke/pathology , Thrombosis/pathology , Decision MakingABSTRACT
Background: Brain clots retrieved following endovascular thrombectomy in acute ischemic stroke patients may offer unique opportunities to characterise stroke aetiology and aid stroke decision-making in select groups of patients. However, the evidence around the putative association of clot morphology with stroke aetiology is limited and remains inconclusive. This study aims to perform a systematic review and meta-analysis to delineate the association of brain clot composition with stroke aetiology and post-reperfusion outcomes in patients receiving endovascular thrombectomy. Methods: The authors conducted a systematic literature review and meta-analysis by extracting data from several research databases (MEDLINE/PubMed, Cochrane, and Google Scholar) published since 2010. We used appropriate key search terms to identify clinical studies concerning stroke thrombus composition, aetiology, and clinical outcomes, in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: The authors identified 30 articles reporting on the relationship between stroke thrombus composition or morphology and aetiology, imaging, or clinical outcomes, of which 21 were included in the meta-analysis. The study found that strokes of cardioembolic origin (SMD = 0.388; 95% CI, 0.032-0.745) and cryptogenic origin (SMD = 0.468; 95% CI, 0.172-0.765) had significantly higher fibrin content than strokes of non-cardioembolic origin. Large artery atherosclerosis strokes had significantly lower fibrin content than cardioembolic (SMD = 0.552; 95% CI, 0.099-1.004) or cryptogenic (SMD = 0.455; 95% CI, 0.137-0.774) strokes. Greater red blood cell content was also significantly associated with a thrombolysis in cerebral infarction score of 2b-3 (SMD = 0.450; 95% CI, 0.177-0.722), and a positive hyperdense middle cerebral artery sign (SMD = 0.827; 95% CI, 0.472-1.183). No significant associations were found between red blood cell, platelet, or white blood cell content and aetiology, or between clot composition and bridging thrombolysis. Conclusions: This meta-analysis found that fibrin composition is significantly higher in strokes of cardioembolic and cryptogenic origin, and that red blood cell content is positively associated with the hyperdense middle cerebral artery sign and better reperfusion outcomes. Important advances to stroke clinical workup can be derived from these findings, in which many aspects of stroke workflow remain to be optimised. As data are still limited in terms of the association of various thrombus components with stroke aetiology as well as a standardised method of analysis, further studies are required to validate these findings to guide their use in clinical decision-making.