Krumholz, Harlan M.

Abstract Nonmyeloablative-related haploidentical allogeneic stem cell transplantation (NMAC-HID allo-HSCT) has emerged as an additional treatment to achieve durable remission in sickle cell disease (SCD), a prevalent blood disorder characterized by painful vaso-occlusive crises and chronic anemia. The standard of care (SOC) for SCD includes hydroxyurea, pain management, and blood transfusion, but patients with SCD still lose several decades of life expectancy. Gene therapy (GT) for SCD is the other treatment for lifelong disease amelioration in SCD, with accessibility limited by cost and manufacturing capacity in the United States and globally. Two recent prospective studies that evaluated NMAC-HID allo-HSCT validated haploidentical allotransplantation as an efficacious and accessible treatment option in the era of GT. Given the ongoing price negotiation across jurisdictions for GT implementation and the absence of cost-effectiveness data comparing NMAC-HID allo-HSCT and GT, we conducted a cost-effectiveness analysis of NMAC-HID allo-HSCT vs GT vs SOC for adults and children living with SCD. The primary outcomes were the incremental cost-effectiveness ratio and the net monetary benefits across these 3 strategies. The secondary outcome was the maximum cost-effective threshold price for GT compared with NMAC-HID allo-HSCT. Treatment with SOC, NMAC-HID allo-HSCT, and GT accrued 14.3, 20.1, and 22.1 quality-adjusted life-years at costs of $1.22 million, $1.15 million, and $2.75 million, respectively. NMAC-HID allo-HSCT was the cost-effective strategy compared with GT in 100% of 10 000 Monte Carlo iterations across the base case and all scenario analyses. The maximum cost-effective thresholds for GT vs SOC were $1.4 million in the United States and $4200 to $22 000 across India, Nigeria, and Tanzania, depending on willingness-to-pay thresholds.

Abstract Acute myocardial infarction complicated by cardiogenic shock (AMI-CS) is a heterogeneous clinical syndrome associated with substantial morbidity and mortality. We developed a machine learning-based mortality model to identify features and patient subgroups associated with the largest change in mortality risk when evaluating treatment with Impella devices or intra-aortic Balloon Pump (IABP). Our cohort comprised 369 sites and 15,796 patient visits to the cardiac catheterization laboratory from the National Cardiovascular Data Registry. The estimated population mean excess mortality effect of treatment with Impella devices vs IABP was 10.4 ± 0.8%. However, we identified clinical subgroups of 282 patients for whom a decreased risk of mortality was associated with use of Impella as compared with IABP. Those patients were on average younger, presented with higher systolic blood pressure, higher rate of salvage percutaneous coronary intervention, higher initial creatinine, and lower hemoglobin. While Impella devices were associated with higher mortality risk overall, certain clinical profiles were associated with lower risk, illustrating heterogeneity of treatment effects.

Abstract Intracranial hemorrhage (ICH) and resulting neurologic disability are severe complications for a subset of infants with severe hemophilia A (HA). Although prophylactic factor replacement reduces bleeding risk, it is typically delayed until after age 1 year due to risks associated with central venous access placement. Emicizumab, a subcutaneous activated factor VIII (FVIII) mimetic, has demonstrated safety and efficacy in preventing ICH in infants aged <12 months in the HAVEN 7 trial. Despite its high cost, the cost-effectiveness of emicizumab prophylaxis initiated during the first year of life for infants with severe HA is not known. We developed a Markov cohort model to compare emicizumab prophylaxis to standard care (no prophylaxis) in infants aged 0 to 1 year with severe HA without FVIII inhibitors. The analysis was conducted from a US societal perspective over a lifetime horizon across all accepted willingness-to-pay (WTP) thresholds. The primary outcome was the incremental cost-effectiveness ratio (ICER) in US dollar per quality-adjusted life-year (QALY). Emicizumab prophylaxis and standard care accrued 25.6 and 25.1 QALYs at costs of $13.12 million and $13.07 million, respectively, resulting in an ICER of $99 900 per QALY (95% credible interval [CI], 84 000-120 000). Scenario analysis examining prophylaxis with low-dose emicizumab resulted in an ICER of $19 600 per QALY (95% CI, 12 000-29 000). Probabilistic sensitivity analyses showed that standard-dose emicizumab is the cost-effective strategy in 100%, 66%, and 0% of 10 000 Monte Carlo iterations at WTP thresholds of $150 000, $104 000, and $50 000 per QALY, respectively, and in 100% across all WTP thresholds for low-dose emicizumab.

ImportanceStroke is a leading cause of death and disability in the US. Accurate and updated measures of stroke burden are needed to guide public health policies.ObjectiveTo present burden estimates of ischemic and hemorrhagic stroke in the US in 2019 and describe trends from 1990 to 2019 by age, sex, and geographic location.Design, Setting, and ParticipantsAn in-depth cross-sectional analysis of the 2019 Global Burden of Disease study was conducted. The setting included the time period of 1990 to 2019 in the US. The study encompassed estimates for various types of strokes, including all strokes, ischemic strokes, intracerebral hemorrhages (ICHs), and subarachnoid hemorrhages (SAHs). The 2019 Global Burden of Disease results were released on October 20, 2020.ExposuresIn this study, no particular exposure was specifically targeted.Main Outcomes and MeasuresThe primary focus of this analysis centered on both overall and age-standardized estimates, stroke incidence, prevalence, mortality, and DALYs per 100 000 individuals.ResultsIn 2019, the US recorded 7.09 million prevalent strokes (4.07 million women [57.4%]; 3.02 million men [42.6%]), with 5.87 million being ischemic strokes (82.7%). Prevalence also included 0.66 million ICHs and 0.85 million SAHs. Although the absolute numbers of stroke cases, mortality, and DALYs surged from 1990 to 2019, the age-standardized rates either declined or remained steady. Notably, hemorrhagic strokes manifested a substantial increase, especially in mortality, compared with ischemic strokes (incidence of ischemic stroke increased by 13% [95% uncertainty interval (UI), 14.2%-11.9%]; incidence of ICH increased by 39.8% [95% UI, 38.9%-39.7%]; incidence of SAH increased by 50.9% [95% UI, 49.2%-52.6%]). The downturn in stroke mortality plateaued in the recent decade. There was a discernible heterogeneity in stroke burden trends, with older adults (50-74 years) experiencing a decrease in incidence in coastal areas (decreases up to 3.9% in Vermont), in contrast to an uptick observed in younger demographics (15-49 years) in the South and Midwest US (with increases up to 8.4% in Minnesota).Conclusions and RelevanceIn this cross-sectional study, the declining age-standardized stroke rates over the past 3 decades suggest progress in managing stroke-related outcomes. However, the increasing absolute burden of stroke, coupled with a notable rise in hemorrhagic stroke, suggests an evolving and substantial public health challenge in the US. Moreover, the significant disparities in stroke burden trends across different age groups and geographic locations underscore the necessity for region- and demography-specific interventions and policies to effectively mitigate the multifaceted and escalating burden of stroke in the country.

Observational medical data present unique opportunities for analysis of medical outcomes and treatment decision making. However, because these datasets do not contain the strict pairing of randomized control trials, matching techniques are to draw comparisons among patients. A key limitation to such techniques is verification that the variables used to model treatment decision making are also relevant in identifying the risk of major adverse events. This article explores a deep mixture of experts approach to jointly learn how to match patients and model the risk of major adverse events in patients. Although trained with information regarding treatment and outcomes, after training, the proposed model is decomposable into a network that clusters patients into phenotypes from information available before treatment. This model is validated on a dataset of patients with acute myocardial infarction complicated by cardiogenic shock. The mixture of experts approach can predict the outcome of mortality with an area under the receiver operating characteristic curve of 0.85 ± 0.01 while jointly discovering five potential phenotypes of interest. The technique and interpretation allow for identifying clinically relevant phenotypes that may be used both for outcomes modeling as well as potentially evaluating individualized treatment effects.

Background This study aimed to compare percutaneous left atrial appendage occlusion (LAAO) with non‐vitamin K antagonist oral anticoagulants among patients with atrial fibrillation. Methods and Results Using a US administrative database, 562 850 patients with atrial fibrillation were identified, among whom 8397 were treated with LAAO and 554 453 were treated with non‐vitamin K antagonist oral anticoagulants between March 13, 2015 and December 31, 2018. Propensity score overlap weighting was used to balance baseline characteristics. The primary outcome was a composite end point of ischemic stroke or systemic embolism, major bleeding, and all‐cause mortality. The mean age was 76.4±7.6 years; 280 097 (49.8%) were female. Mean follow‐up was 1.5±1.0 years. LAAO was associated with no significant difference in the risk of the primary composite end point (hazard ratio [HR], 0.93 [0.84–1.03]), or the secondary outcomes including ischemic stroke/systemic embolism (HR, 1.07 [0.81–1.41]), and intracranial bleeding (HR, 1.08 [0.72–1.61]). LAAO was associated with a higher risk of major bleeding (HR, 1.22 [1.05–1.42], P =0.01) and a lower risk of mortality (HR, 0.73 [0.64–0.84], P <0.001). The lower risk of mortality associated with LAAO was most pronounced in patients with a prior history of intracranial bleeding. Conclusions In comparison to non‐vitamin K antagonist oral anticoagulants, LAAO was associated with no significant difference in the risk of the composite outcome and a lower risk of mortality, which suggests LAAO might be a reasonable option in select patients with atrial fibrillation. The observation of higher bleeding risk associated with LAAO highlights the need to optimize postprocedural antithrombotic regimens as well as systematic efforts to assess and address bleeding predispositions.

Background: While lack of insurance is known to be associated with worse outcomes after myocardial infarction (MI), it is unknown whether health insurance status is associated with rates of non-elective hospitalizations after MI. Methods: Using data on 3571 U.S. MI patients enrolled between April 2005 to December 2008 in the 24-center, prospective TRIUMPH registry, we examined the association between being insured (reference), underinsured, and uninsured on rates of non-elective readmissions (all-cause) in the 1 st year following MI. Insurance status was obtained from medical records, and underinsurance was defined as those patients with insurance but with financial concerns about accessing care from patient interviews. Multivariable modified Poisson regression models were used to adjust for site, demographics, MI severity, risk factors, socio-economic, and psychological factors. Results: A total of 2269 (63.5%) patients were insured; 650 (18.2%) were underinsured; and 652 (18.3%) were uninsured. Emergency readmissions were highest for uninsured patients (25.0%), followed by the underinsured (21.8%), and lowest in insured patients (19.5%) (P<.001). After multivariable adjustment, uninsured patients had significantly higher rates of emergency readmission (adjusted RR, 1.52 [95% CI: 1.22-1.90] while underinsured patients did not (adjusted RR, 0.99 [95% CI: 0.81-1.21]) (Figure). Conclusions: Uninsured patients had a significantly higher adjusted risk of non-elective readmissions after MI, while underinsured patients did not. Future studies are needed to determine if providing even modest insurance coverage to the uninsured can minimize readmission rates.

Background: One month following a myocardial infarction (MI), more than a third of older adults (age ≥65 years) are frail as demonstrated by slow gait speed (≤ 0.65 m/sec). The prognostic significance of frailty in a cardiovascular population in terms of future health states is unknown. Methods: The TRIUMPH longitudinal registry enrolled 1314 older adults (age ≥65 years) following an acute MI from 24 US centers. Gait speed (m/sec) was determined at one month (to allow for acute recovery) in 329 patients with in-home follow up. Using averages of 3 timed walks over 15-feet, patients were stratified by gait speed into 2 groups: slow (<0.65m/sec) and preserved (≥0.65m/sec). One year basic (mobility, self care) and instrumental activities of daily living (ADL) (phone, meds, travel, money), physical function score (SF12 PCS), quality of life (Seattle Angina Questionnaire (SAQ)), and mortality were assessed. Results: Slow gait speed was present in 38% (N=126) of older adults at 1 month. At 1 year, despite similar survival, frail adults were much more likely to need help with basic and instrumental (ADL), and had lower physical function and quality of life (QOL) compared to non-frail adults. ( table ) Slower gait speed remained a significant predictor of worse physical function at 1 year after adjustment for baseline physical function (p=0.013). Conclusions: Frailty is common in older adults following an MI, and those with frailty are at substantial risk for continued impairment over time. Understanding the mechanisms or reversibility of this vulnerable state would contribute to optimization of independence and quality of life among older adults with cardiovascular disease. Frailty Post MI and 1 Year Outcomes Frail (Gait <0.65m/sec)N=126 Not Frail (Gait ≥0.65m/sec)N=203 P value Mobility ADL (% need help) 45 23 <0.001 Self-Care ADL (% need help) 11 4 <0.001 Instrumental ADLs (% need help) 36 19 0.003 Physical Function (PCS) 39.2 ± 12.0 47.2 ± 9.7 <0.001 SAQ Quality of Life (QOL) 88.0 ± 15.9 91.3 ± 12.1 0.061 Mortality (%) 5.6 4.5 NS

Objective: To characterize changes in rates of hospitalization for digoxin toxicity and trends in the associated mortality and readmission among older adults over a 12-year period in the United States. Methods: We studied 33,952,331 Medicare fee-for-service beneficiaries 65 years or older with a hospital discharge diagnosis of digoxin toxicity in the United States from 1999 to 2011. Outcome measures were rates of hospitalization for digoxin toxicity; in-hospital mortality; 30-day mortality; and 30-day readmission. Results: There were 20,957 hospitalizations for a principal or secondary diagnosis of digoxin toxicity between 1999 and 2011. The rate declined significantly from 15.2 per 100,000 person-years (95% confidence interval [CI]: 14.7-15.7) in 1999 to 2.1 per 100,000 person-years (95% CI: 1.9-2.3) in 2011 (p<0.001), representing an adjusted annual decline of 17.0% (95% CI: 16.2-17.0) (Figure 1). Between 1999 and 2011, the observed in-hospital and 30-day mortality rates associated with hospitalization for digoxin toxicity declined significantly, from 6.0% (95% CI: 5.2-6.8) to 3.3% (95% CI: 2.0-5.1) (p<0.01) and 14.0% (95% CI: 13.0-15.2) to 10.6% (95% CI: 8.2-13.4) (p<0.05), respectively, representing an annual decline for in-hospital mortality of 5.0% (95% CI: 3.7-7.2) and for 30-day mortality of 4.0% (95% CI: 3.1-5.7). The overall observed 30-day readmission rate declined significantly from 23.5% (95% CI: 22.1-24.9) in 1999 to 18.9% (95% CI: 15.6-22.3) in 2011 (p<0.05), but there was no significant decline in the adjusted annual change in 30-day readmission (1.0%, 95% CI: 0.0-1.7). Conclusions: In a national sample of Medicare beneficiaries, the rate of hospitalization for digoxin toxicity and subsequent mortality declined significantly between 1999 and 2011.