Sequential multiple assignment randomized trials (SMARTs) are the gold standard for estimating optimal dynamic treatment regimes (DTRs), but are costly and require a large sample size. We introduce ...the multi-stage augmented Q-learning estimator (MAQE) to improve efficiency of estimation of optimal DTRs by augmenting SMART data with observational data. Our motivating example comes from the Back Pain Consortium, where one of the overarching aims is to learn how to tailor treatments for chronic low back pain to individual patient phenotypes, knowledge which is lacking clinically. The Consortium-wide collaborative SMART and observational studies within the Consortium collect data on the same participant phenotypes, treatments, and outcomes at multiple time points, which can easily be integrated. Previously published single-stage augmentation methods for integration of trial and observational study (OS) data were adapted to estimate optimal DTRs from SMARTs using Q-learning. Simulation studies show the MAQE, which integrates phenotype, treatment, and outcome information from multiple studies over multiple time points, more accurately estimates the optimal DTR, and has a higher average value than a comparable Q-learning estimator without augmentation. We demonstrate this improvement is robust to a wide range of trial and OS sample sizes, addition of noise variables, and effect sizes.
Machine learning and artificial intelligence are generating significant attention in the scientific community and media. Such algorithms have great potential in medicine for personalizing and ...improving patient care, including in the diagnosis and management of heart failure. Many physicians are familiar with these terms and the excitement surrounding them, but many are unfamiliar with the basics of these algorithms and how they are applied to medicine. Within heart failure research, current applications of machine learning include creating new approaches to diagnosis, classifying patients into novel phenotypic groups, and improving prediction capabilities. In this paper, we provide an overview of machine learning targeted for the practicing clinician and evaluate current applications of machine learning in the diagnosis, classification, and prediction of heart failure.
Animal and human studies support the importance of the coagulation cascade in pulmonary fibrosis.
In a cohort of subjects with progressive idiopathic pulmonary fibrosis (IPF), we tested the ...hypothesis that treatment with warfarin at recognized therapeutic doses would reduce rates of mortality, hospitalization, and declines in FVC.
This was a double-blind, randomized, placebo-controlled trial of warfarin targeting an international normalized ratio of 2.0 to 3.0 in patients with IPF. Subjects were randomized in a 1:1 ratio to warfarin or matching placebo for a planned treatment period of 48 weeks. International normalized ratios were monitored using encrypted home point-of-care devices that allowed blinding of study therapy.
The primary outcome measure was the composite outcome of time to death, hospitalization (nonbleeding, nonelective), or a 10% or greater absolute decline in FVC. Due to a low probability of benefit and an increase in mortality observed in the subjects randomized to warfarin (14 warfarin versus 3 placebo deaths; P = 0.005) an independent Data and Safety Monitoring Board recommended stopping the study after 145 of the planned 256 subjects were enrolled (72 warfarin, 73 placebo). The mean follow-up was 28 weeks.
This study did not show a benefit for warfarin in the treatment of patients with progressive IPF. Treatment with warfarin was associated with an increased risk of mortality in an IPF population who lacked other indications for anticoagulation.
A combination of prednisone, azathioprine, and N-acetylcysteine (NAC) has been widely used as a treatment for idiopathic pulmonary fibrosis. The safety and efficacy of this three-drug regimen is ...unknown.
In this randomized, double-blind, placebo-controlled trial, we assigned patients with idiopathic pulmonary fibrosis who had mild-to-moderate lung-function impairment to one of three groups -- receiving a combination of prednisone, azathioprine, and NAC (combination therapy), NAC alone, or placebo -- in a 1:1:1 ratio. The primary outcome was the change in longitudinal measurements of forced vital capacity during a 60-week treatment period.
When approximately 50% of data had been collected (with 77 patients in the combination-therapy group and 78 in the placebo group), a planned interim analysis revealed that patients in the combination-therapy group, as compared with the placebo group, had an increased rate of death (8 vs. 1, P=0.01) and hospitalization (23 vs. 7, P<0.001). These observations, coupled with no evidence of physiological or clinical benefit for combination therapy, prompted the independent data and safety monitoring board to recommend termination of the combination-therapy group at a mean follow-up of 32 weeks. Data from the ongoing comparison of the NAC-only group and the placebo group are not reported here.
Increased risks of death and hospitalization were observed in patients with idiopathic pulmonary fibrosis who were treated with a combination of prednisone, azathioprine, and NAC, as compared with placebo. These findings provide evidence against the use of this combination in such patients. (Funded by the National Heart, Lung, and Blood Institute and the Cowlin Family Fund; ClinicalTrials.gov number, NCT00650091.).
The effect of vericiguat, a novel oral soluble guanylate cyclase stimulator, in patients with heart failure and reduced ejection fraction who had recently been hospitalized or had received ...intravenous diuretic therapy is unclear.
In this phase 3, randomized, double-blind, placebo-controlled trial, we assigned 5050 patients with chronic heart failure (New York Heart Association class II, III, or IV) and an ejection fraction of less than 45% to receive vericiguat (target dose, 10 mg once daily) or placebo, in addition to guideline-based medical therapy. The primary outcome was a composite of death from cardiovascular causes or first hospitalization for heart failure.
Over a median of 10.8 months, a primary-outcome event occurred in 897 of 2526 patients (35.5%) in the vericiguat group and in 972 of 2524 patients (38.5%) in the placebo group (hazard ratio, 0.90; 95% confidence interval CI, 0.82 to 0.98; P = 0.02). A total of 691 patients (27.4%) in the vericiguat group and 747 patients (29.6%) in the placebo group were hospitalized for heart failure (hazard ratio, 0.90; 95% CI, 0.81 to 1.00). Death from cardiovascular causes occurred in 414 patients (16.4%) in the vericiguat group and in 441 patients (17.5%) in the placebo group (hazard ratio, 0.93; 95% CI, 0.81 to 1.06). The composite of death from any cause or hospitalization for heart failure occurred in 957 patients (37.9%) in the vericiguat group and in 1032 patients (40.9%) in the placebo group (hazard ratio, 0.90; 95% CI, 0.83 to 0.98; P = 0.02). Symptomatic hypotension occurred in 9.1% of the patients in the vericiguat group and in 7.9% of the patients in the placebo group (P = 0.12), and syncope occurred in 4.0% of the patients in the vericiguat group and in 3.5% of the patients in the placebo group (P = 0.30).
Among patients with high-risk heart failure, the incidence of death from cardiovascular causes or hospitalization for heart failure was lower among those who received vericiguat than among those who received placebo. (Funded by Merck Sharp & Dohme a subsidiary of Merck and Bayer; VICTORIA ClinicalTrials.gov number, NCT02861534.).
Acetylcysteine has been suggested as a beneficial treatment for idiopathic pulmonary fibrosis, although data from placebo-controlled studies are lacking.
In our initial double-blind, ...placebo-controlled trial, we randomly assigned patients who had idiopathic pulmonary fibrosis with mild-to-moderate impairment in pulmonary function to receive a three-drug regimen of prednisone, azathioprine, and acetylcysteine; acetylcysteine alone; or placebo. The study was interrupted owing to safety concerns associated with the three-drug regimen. The trial continued as a two-group study (acetylcysteine vs. placebo) without other changes; 133 and 131 patients were enrolled in the acetylcysteine and placebo groups, respectively. The primary outcome was the change in forced vital capacity (FVC) over a 60-week period.
At 60 weeks, there was no significant difference in the change in FVC between the acetylcysteine group and the placebo group (-0.18 liters and -0.19 liters, respectively; P=0.77). In addition, there were no significant differences between the acetylcysteine group and the placebo group in the rates of death (4.9% vs. 2.5%, P=0.30 by the log-rank test) or acute exacerbation (2.3% in each group, P>0.99).
As compared with placebo, acetylcysteine offered no significant benefit with respect to the preservation of FVC in patients with idiopathic pulmonary fibrosis with mild-to-moderate impairment in lung function. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00650091.).
Abnormal acid gastro-oesophageal reflux is common in patients with idiopathic pulmonary fibrosis (IPF) and is considered a risk factor for development of IPF. Retrospective studies have shown ...improved outcomes in patients given anti-acid treatment. The aim of this study was to investigate the association between anti-acid treatment and disease progression in IPF.
In an analysis of data from three randomised controlled trials, we identified patients with IPF assigned to receive placebo. Case report forms had been designed to prospectively obtain data about diagnosis and treatment of abnormal acid gastro-oesophageal reflux in each trial. The primary outcome was estimated change in forced vital capacity (FVC) at 30 weeks (mean follow-up) in patients who were and were not using a proton-pump inhibitor or histamine-receptor-2 (H2) blocker.
Of the 242 patients randomly assigned to the placebo groups of the three trials, 124 (51%) were taking a proton-pump inhibitor or H2 blocker at enrolment. After adjustment for sex, baseline FVC as a percentage of predicted, and baseline diffusing capacity of the lung for carbon monoxide as a percentage of predicted, patients taking anti-acid treatment at baseline had a smaller decrease in FVC at 30 weeks (-0·06 L, 95% CI -0·11 to -0·01) than did those not taking anti-acid treatment (-0·12 L, -0·17 to -0·08; difference 0·07 L, 95% CI 0-0·14; p=0·05).
Anti-acid treatment could be beneficial in patients with IPF, and abnormal acid gastro-oesophageal reflux seems to contribute to disease progression. Controlled clinical trials of anti-acid treatments are now needed.
National Institutes of Health.
Enhanced recovery after surgery (ERAS) is a multimodal approach to perioperative care that combines a range of interventions to enable early mobilization and feeding after surgery. We investigated ...the feasibility, clinical effectiveness, and cost savings of an ERAS program at a major U. S. teaching hospital.
Data were collected from consecutive patients undergoing open or laparoscopic colorectal surgery during 2 time periods, before and after implementation of an ERAS protocol. Data collected included patient demographics, operative, and perioperative surgical and anesthesia data, need for analgesics, complications, inpatient medical costs, and 30-day readmission rates.
There were 99 patients in the traditional care group, and 142 in the ERAS group. The median length of stay (LOS) was 5 days in the ERAS group compared with 7 days in the traditional group (P < 0.001). The reduction in LOS was significant for both open procedures (median 6 vs 7 days, P = 0.01), and laparoscopic procedures (4 vs 6 days, P < 0.0001). ERAS patients had fewer urinary tract infections (13% vs 24%, P = 0.03). Readmission rates were lower in ERAS patients (9.8% vs 20.2%, P = 0.02).
Implementation of an enhanced recovery protocol for colorectal surgery at a tertiary medical center was associated with a significantly reduced LOS and incidence of urinary tract infection. This is consistent with that of other studies in the literature and suggests that enhanced recovery programs could be implemented successfully and should be considered in U.S. hospitals.
Abnormal cardiac metabolism contributes to the pathophysiology of advanced heart failure with reduced left ventricular ejection fraction (LVEF). Glucagon-like peptide 1 (GLP-1) agonists have shown ...cardioprotective effects in early clinical studies of patients with advanced heart failure, irrespective of type 2 diabetes status.
To test whether therapy with a GLP-1 agonist improves clinical stability following hospitalization for acute heart failure.
Phase 2, double-blind, placebo-controlled randomized clinical trial of patients with established heart failure and reduced LVEF who were recently hospitalized. Patients were enrolled between August 2013 and March 2015 at 24 US sites.
The GLP-1 agonist liraglutide (n = 154) or placebo (n = 146) via a daily subcutaneous injection; study drug was advanced to a dosage of 1.8 mg/d during the first 30 days as tolerated and continued for 180 days.
The primary end point was a global rank score in which all patients, regardless of treatment assignment, were ranked across 3 hierarchical tiers: time to death, time to rehospitalization for heart failure, and time-averaged proportional change in N-terminal pro-B-type natriuretic peptide level from baseline to 180 days. Higher values indicate better health (stability). Exploratory secondary outcomes included primary end point components, cardiac structure and function, 6-minute walk distance, quality of life, and combined events.
Among the 300 patients who were randomized (median age, 61 years interquartile range {IQR}, 52-68 years; 64 21% women; 178 59% with type 2 diabetes; median LVEF of 25% IQR, 19%-33%; median N-terminal pro-B-type natriuretic peptide level of 2049 pg/mL IQR, 1054-4235 pg/mL), 271 completed the study. Compared with placebo, liraglutide had no significant effect on the primary end point (mean rank of 146 for the liraglutide group vs 156 for the placebo group, P = .31). There were no significant between-group differences in the number of deaths (19 12% in the liraglutide group vs 16 11% in the placebo group; hazard ratio, 1.10 95% CI, 0.57-2.14; P = .78) or rehospitalizations for heart failure (63 41% vs 50 34%, respectively; hazard ratio, 1.30 95% CI, 0.89-1.88; P = .17) or for the exploratory secondary end points. Prespecified subgroup analyses in patients with diabetes did not reveal any significant between-group differences. The number of investigator-reported hyperglycemic events was 16 (10%) in the liraglutide group vs 27 (18%) in the placebo group and hypoglycemic events were infrequent (2 1% vs 4 3%, respectively).
Among patients recently hospitalized with heart failure and reduced LVEF, the use of liraglutide did not lead to greater posthospitalization clinical stability. These findings do not support the use of liraglutide in this clinical situation.
clinicaltrials.gov Identifier: NCT01800968.
Definitive evidence of clinical efficacy in a Phase 3 trial is best shown by a beneficial impact on a clinically meaningful endpoint-that is, an endpoint that directly measures how a patient feels ...(symptoms), functions (the ability to perform activities in daily life), or survives. In idiopathic pulmonary fibrosis (IPF), we believe the endpoints that best meet these criteria are all-cause mortality and all-cause nonelective hospitalization. There are no validated measures of symptoms or broader constructs such as health status or functional status in IPF. A surrogate endpoint is defined as an indirect measure that is intended to substitute for a clinically meaningful endpoint. Surrogate endpoints can be appropriate outcome measures if validated. However, validation requires substantial evidence that the effect of an intervention on a clinically meaningful endpoint is reliably predicted by the effect of an intervention on the surrogate endpoint. For patients with IPF, there are currently no validated surrogate endpoints.
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