Risks of Zolpidem among Patients with Chronic Obstructive Pulmonary Disease.

Rationale: Nonbenzodiazepine benzodiazepine receptor agonists (NBZRA, e.g., zolpidem) are frequently used to treat insomnia among patients with chronic obstructive pulmonary disease (COPD). However, multiple observational studies find that patients with COPD who are prescribed NBZRAs have greater risks for mortality and respiratory complications than patients without such prescriptions. Without an active comparator, these studies are susceptible to confounding by indication. Objectives: Compare the risk of death or inpatient COPD exacerbation among patients receiving zolpidem relative to patients receiving other hypnotics. Methods: Using nationwide Veterans Health Administration (VA) data, we identified patients with clinically diagnosed COPD and new receipt of zolpidem or another hypnotic available on VA formulary without prior authorization (melatonin, trazodone, doxepin). We excluded those receiving traditional benzodiazepines or multiple concurrent hypnotics. We propensity-matched patients receiving zolpidem to other hypnotics on 32 variables, including demographics, comorbidities, and markers of COPD severity. We compared risk of the primary composite outcome of death or inpatient COPD exacerbation over 1 year. In secondary analyses, we propensity-matched patients receiving zolpidem to those without hypnotic receipt. Results: Among 283,740 patients meeting inclusion criteria, 1,126 (0.4%) received zolpidem and 3,057 (1.1%) received other hypnotics. We propensity-matched patients receiving zolpidem 1:1 to peers receiving other hypnotics. We did not find a difference in the primary composite outcome of death or inpatient exacerbation (hazard ratio, 0.97; 95% confidence interval [CI], 0.77-1.23). In secondary analyses comparing patients receiving zolpidem to matched peers without hypnotic receipt, we observed greater risk of death or inpatient exacerbation with zolpidem (hazard ratio, 1.40; 95% CI, 1.09-1.81). Conclusions: Among patients with COPD, we did not observe greater risks after new receipt of zolpidem relative to other hypnotics. However, we did observe greater risks relative to those without hypnotic receipt. This latter finding may reflect: 1) residual, unmeasured confounding related to insomnia; or 2) true adverse effects of hypnotics across classes. Future work is needed to better understand the risks of hypnotics in COPD.

The Impact of Changing Race-Specific Equations for Lung Function Tests among Veterans with Chronic Obstructive Pulmonary Disease.

Rationale: The American Thoracic Society recommended a single reference equation for spirometry, but the impact on patients is not known. Objectives: To estimate the effect of changing to a single reference equation among veterans with chronic obstructive pulmonary disease (COPD). Methods: A cross-sectional study was conducted including veterans aged ⩾40 to ⩽89 years with COPD and spirometry results from 21 facilities between 2010 and 2019. We collected race and ethnicity data from the electronic health record. We estimated the percentage change in the number of veterans with lung function meeting clinical thresholds used to determine eligibility for lung resection for cancer, lung volume reduction surgery (LVRS), and lung transplantation referral. We estimated the change for each level of U.S. Department of Veterans Affairs service connection and financial impact. Results: We identified 44,892 veterans (Asian, 0.5%; Black, 11.8%; White, 80.8%; and Hispanic, 1.8%). When changing to a single reference equation, Asian and Black veterans had reduced predicted lung function that could result in less surgical lung resection (4.4% and 11.1%, respectively) while increasing LVRS (1.7% and 3.8%) and lung transplantation evaluation for Black veterans (1.2%). White veterans had increased predicted lung function and could experience increased lung resection (8.1%), with less LVRS (3.3%) and lung transplantation evaluation (0.9%). Some Asian and Black veterans could experience increases in monthly disability payments (+$540.38 and +$398.38), whereas White veterans could see a decrease (-$588.79). When aggregated, Hispanic veterans experienced changes attributable to their racial identity and, because this sample was predominantly Hispanic White, had similar results to White veterans. Conclusions: Changing the reference equation could affect access to treatment and disability benefits, depending on race. If adopted, the use of discrete clinical thresholds needs to be reassessed, considering patient-centered outcomes.

The lung allocation score and other available models lack predictive accuracy for post-lung transplant survival.

BACKGROUND: Improved predictive models are needed in lung transplantation in the setting of a proposed allocation system that incorporates longer-term post-transplant survival in the United States. Allocation systems require accurate mortality predictions to justly allocate organs. METHODS: Utilizing the United Network for Organ Sharing database (2005-2017), we fit models to predict 1-year mortality based on the Lung Allocation Score (LAS), the Chan, et al, 2019 model, a novel "clinician" model (a priori clinician selection of pre-transplant covariates), and two machine learning models (Least Absolute Shrinkage and Selection Operator; LASSO and Random Forests) for predicting 1-year and 3-year post-transplant mortality. We compared predictive accuracy among models. We evaluated the calibration of models by comparing average predicted probability vs observed outcome per decile. We repeated analyses fit for 3-year mortality, disease category, including donor covariates, and LAS era. RESULTS: The area under the cure for all models was low, ranging from 0.55 to 0.62. All exhibited reasonable negative predictive values (0.87-0.90), but the positive predictive value for was poor (all <0.25). Evaluating LAS calibration found 1-year post-transplant estimates consistently overestimated risk of mortality, with greater differences in higher deciles. LASSO, Random Forests, and clinician models showed no improvement when evaluated by disease category or with the addition of donor covariates and performed worse for 3-year outcomes. CONCLUSIONS: The LAS overestimated patients' risk of post-transplant death, thus underestimating transplant benefit in the sickest candidates. Novel models based on pre-transplant recipient covariates failed to improve prediction. There should be wariness in post-transplant survival predictions from available models.

Hemoptysis and the Risk for Lung Transplant or Death without Transplant in Individuals with Cystic Fibrosis in the United States.

Rationale: Hemoptysis is a common and important complication in persons with cystic fibrosis (PwCF). Despite this, there is limited literature on the impact of hemoptysis on contemporary cystic fibrosis (CF) outcomes. Objectives: Evaluate whether hemoptysis increases the risk of lung transplant or death without a transplant in PwCF. Methods: We reviewed a dataset of PwCF ages 12 years or older from the CFFPR (CF Foundation Patient Registry) that included 29,587 individuals. We identified hemoptysis as our predictor of interest and categorized PwCF as either no hemoptysis, any hemoptysis (submassive and/or massive), or massive hemoptysis. We subsequently evaluated whether hemoptysis, as defined above, was associated with death without transplant or receipt of lung transplant via logistic regression. We adjusted for age, sex, body mass index, forced expiratory volume in one second (FEV1), number of exacerbations, supplemental oxygen use, CF-related diabetes, and Pseudomonas aeruginosa colonization status. Subgroup analyses were performed in advanced lung disease, defined as PwCF with an FEV1 <40% predicted. Results: PwCF with any form of hemoptysis were more likely to progress to lung transplant or die without transplant than PwCF who did not have hemoptysis (odds ratio [OR], 1.3 [95% confidence interval (CI), 1.1-1.7]). The effect size of these associations was larger when hemoptysis events were classified as "massive" (massive hemoptysis OR, 2.2 [95% CI, 1.2-3.8]) or in PwCF with advanced lung disease (massive hemoptysis in advanced lung disease OR, 3.2 [95% CI 1.3-8.2]). Conclusions: Hemoptysis is associated with an increased risk of lung transplant and death without a transplant in PwCF, especially among those with massive hemoptysis or advanced lung disease. Our results suggest that hemoptysis functions as a useful predictor of serious outcomes in PwCF and may be important to incorporate into risk prediction models and/or transplant decisions in CF.

Development and Internal Validation of a Prognostic Model of the Probability of Death or Lung Transplantation Within 2 Years for Patients With Cystic Fibrosis and FEV1 ≤ 50% Predicted.

BACKGROUND: Improved methods are needed to risk-stratify patients with cystic fibrosis (CF) and reduced FEV1. RESEARCH QUESTIONS: What are the predictors of death or lung transplantation (LTx) within 2 years among patients with CF whose FEV1 ≤ 50% predicted? Do these markers similarly predict outcomes among G551D patients taking ivacaftor since 2012? STUDY DESIGN AND METHODS: Patients with CF, age ≥ 6 years with FEV1 ≤ 50% predicted as of December 31, 2014, were identified in a data set that merged Cystic Fibrosis Foundation and United Network for Organ Sharing (UNOS) registries. The least absolute shrinkage and selection operator (LASSO) method was applied to a randomly selected training set to select important prognostic variables. Accuracy and association of the model with death or LTx with 2 years (2-year death or LTx) were validated via logistic regression on an independent test set. Sensitivity analyses explored predictors for patients with UNOS data. RESULTS: FEV1 percent predicted (OR, 1.51 for 5% decrease; 95% CI, 1.27-1.81), number of pulmonary exacerbations treated with IV antibiotics (OR, 1.35; 95% CI, 1.11-1.65), and continuous or nocturnal oxygen (OR, 3.71; 95% CI, 1.81-7.59) were significantly associated with 2-year death or LTx. Our model predicted outcomes with greater sensitivity (ratio of sensitivity, 1.26; 95% CI, 1.02-1.54), ratio of positive predictive value (1.25; 95% CI, 1.05-1.51), and ratio of negative predictive value (1.04; 95% CI, 1.01-1.07) than FEV1 < 30% predicted. Among those taking ivacaftor in 2014, only FEV1 remained associated with 2-year death or LTx. For patients with UNOS data, LASSO identified additional covariates of interest, including noninvasive ventilation use, low hemoglobin, pulmonary arterial systolic pressure, supplemental oxygen, mechanical ventilation, FEV1 percent predicted, and cardiac index. INTERPRETATION: Among individuals with CF and FEV1 ≤ 50% predicted, FEV1 percent predicted, oxygen therapy, and number of pulmonary exacerbations predicted 2-year death or LTx. Although limited by small sample size, only FEV1 remained predictive in patients receiving highly effective modulator therapy. Additional physiologic variables could improve prognostication in CF.