Imbalances In Patient Characteristics Research Articles

A multicenter nonrandomized controlled trial to evaluate the efficacy of surgery versus radiofrequency ablation for small hepatocellular carcinoma (SURF cohort trial).

4581 Background: In parallel with a multicenter randomized controlled trial that reported an equal recurrence-free survival (RFS) of early-stage hepatocellular carcinoma (HCC) patients who underwent either surgery (SUR) or radiofrequency ablation (RFA), we also enrolled HCC patients who fulfilled the enrollment criteria but did not give consent to participate in the RCT. Methods: All patients gave informed consent to participate in this study. Inclusion criteria were as follows: primary HCC with less than or equal to 3 tumors, each measuring 3 cm or smaller; without vascular invasion or extrahepatic metastasis; Child-Pugh score of 7 or less; and ages between 20 and 79 years. The feasibility for both treatments was confirmed by a joint chart review by surgeons and hepatologists. The primary endpoint was RFS and overall survival. A pre-specified interim analysis was performed to compare RFS. Results: Between April 2009 and August 2015, 740 patients (371 in SUR, 369 in RFA) were enrolled from 49 participating hospitals in Japan. The SUR group had significantly fewer patients with chronic hepatitis C (56.6% vs. 69.4%), higher median value of platelet count (145 vs. 120 × 109/L), and more patients with > 2 cm tumors (49.9% vs. 27.9%); most patients had a single tumor (91.1% vs. 88.3%). During the median follow-up period of 5 years, tumor recurrence was observed in 192 of SUR and 218 of RFA with 3-year RFS being 66.0% and 61.7%, respectively ( P = 0.091). In subgroup analysis, RFS was significantly better in SUR in patients with ≤ 2 cm tumors (62.9% vs. 51.7% in 3 years; hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.56-0.93; P = 0.014), whereas the difference was not significant in those with > 2 cm tumors (52.7% vs. 46.4%; HR 0.85, 95% CI 0.63-1.18; P = 0.34). The adjusted HR for RFS using inversed probability of treatment weighting was 0.89 (95% CI, 0.72-1.10; P = 0.287). Conclusions: The imbalance in patient characteristics reflected a real-world practice. Factors related to background liver disease rather than tumor characteristics might have a larger impact on the recurrence in early HCC. Clinical trial information: C000001796 .

Admission Neutrophil–Lymphocyte Ratio Predicts Rebleeding Following Aneurismal Subarachnoid Hemorrhage

The relationship between neutrophil-lymphocyte ratio (NLR) and the occurrence of rebleeding in aneurysmal subarachnoid hemorrhage (aSAH) is poorly understood. Our study aimed to investigate the association between NLR on admission and rebleeding following aSAH. Clinical and laboratorial data from patients with aSAH were retrospectively collected, including leukocyte, neutrophil, lymphocyte, and NLR. Univariate and multivariate analyses were performed to assess for the association of NLR with rebleeding. We performed propensity-score matching analyses to correct imbalances in patient characteristics between the rebleeding group and nonrebleeding group. Rebleeding occurred in 30 of 716 (4.19%) patients with aSAH in this cohort. Patients with rebleeding had significantly higher NLR comparing with patients without rebleeding (11.27 vs. 5.5; P < 0.05) in the univariate analysis. In the multivariate analysis, NLR was considered as a risk factor of rebleeding (odds ratio, 0.283; 95% confidence interval, 0.130-0.620; P= 0.002), as well as Fisher grade (odds ratio, 0.353, 95% confidence interval, 0.151-0.824; P= 0.016). The area under the curve of the NLR and combined NLR-Fisher grade model was 0.702 and 0.744 (sensitivity was 39.94%, and specificity was 100%) for predicting rebleeding, respectively. After propensity-score matching, the optimal cutoff value for NLR as a predictor for rebleeding following aSAH was determined as 5.4 (sensitivity was 83.33%, and the specificity was 63.33%). Higher NLR predicts the occurrence of rebleeding and poor outcome, and NLR combined with Fisher grade significantly improves the prediction of rebleeding following aSAH.

Does Patient Blinding Influence Clinical Outcomes After Annular Closure Device Implantation? A Propensity Score-Matched Analysis.

BackgroundAwareness of treatment group assignment in a clinical trial may influence patient behavior and bias outcome reporting. The objective of this study was to compare 2-year clinical outcomes in blinded vs unblinded patients who were treated with lumbar discectomy and a bone-anchored annular closure device (ACD) for prevention of lumbar disc reherniation.MethodsThis was a secondary analysis of a randomized trial comparing lumbar discectomy with (n=272) vs without (n=278) implantation of a bone-anchored ACD. Among patients who received ACD implantation, 35 (13%) were blinded and 237 (87%) were unblinded to treatment allocation. In patients treated with ACD, propensity score-matching (1:1) was performed to account for imbalances in patient characteristics between blinded and unblinded groups. Key clinical outcomes were back pain severity (0–100 scale), leg pain severity (0–100 scale), Oswestry Disability Index (ODI, 0–100 scale), symptomatic reherniation, reoperation at the treated lumbar level, and device- or procedure-related serious adverse events (AEs). Outcomes were reported through 2 years of follow-up, which coincided with the time at which blinded patients were unblinded.ResultsThere were no statistically significant differences in 2-year outcomes between propensity score-matched blinded (n=35) and unblinded (n=35) patients treated with the ACD. In blinded vs unblinded ACD patients compared to baseline, back pain severity decreased by 40 vs 37 points (P=0.61), leg pain severity decreased by 75 points in each group (P>0.99), and ODI decreased by 47 vs 43 points (P=0.19). The risks of symptomatic reherniation (5.7% vs 9.1%; P=0.59), reoperation (8.6% vs 12.2%, P=0.62), and device- or procedure-related serious AEs (5.7% vs 8.9%, P=0.63) were comparably low in blinded and unblinded patients.ConclusionIn patients treated with lumbar discectomy and a bone-anchored ACD, there were no clinically important or statistically significant differences in back pain, leg pain, ODI, symptomatic reherniation, reoperation, or serious AEs over 2 years of follow-up when comparing patients who were blinded vs unblinded to their treatment assignment. The main limitations of this study were the post hoc nature of the analysis and the potential for bias due to surgeon awareness of treatment assignment.

Lower Serum Iron and Hemoglobin Levels are Associated with Acute Seizures in Patients with Ruptured Cerebral Aneurysms.

The aim of the study is to investigate the value of serum iron and hemoglobin levels for predicting acute seizures following aneurysmal subarachnoid hemorrhage (aSAH). Clinical and laboratorial data from patients with ruptured intracranial aneurysms were collected in the retrospective study. Age, sex, symptom onset, history of diabetes and hypertension, history of coronary artery disease, temperature, Hunt-Hess grade, Fisher grade, aneurysm location, hemoglobin, serum potassium, sodium, calcium, phosphorus, and iron were collected. Acute seizures were determined as seizures within 1week following aSAH. Propensity score matching (PSM) analyses were performed to correct imbalances in patient characteristics between seizure and non-seizure groups. A total of 760 patients were included. Incidence of acute seizures following aSAH was 6.4%. In the univariate analysis, significant differences were detected in age, admission Hunt-Hess grade, Fisher grade, hemoglobin, serum sodium, and serum iron between seizure and non-seizure groups. In multivariate logistic regression model, lower serum iron was considered as a risk factor for acute seizures (OR 0.182, 95% CI 0.084-0.393, p = 0.000), as well as lower hemoglobin (OR 0.977, 95% CI 0.962-0.993, p = 0.004) and higher serum sodium (OR 1.072, 95% CI 1.003-1.145, p = 0.039). After PSM, there were no significant differences in age, admission Hunt-Hess grade, Fisher grade, and serum sodium between seizure and non-seizure groups. The matched seizure group had lower serum iron and hemoglobin levels compared with the matched non-seizure group (p < 0.05). The optimal cutoff value for serum iron and hemoglobin levels as a predictor of acute seizure after aSAH was determined as 9.9mmol/L (sensitivity was 81.63% and the specificity was 65.40%) and 119g/L (sensitivity was 63.27% and the specificity was 70.18%), respectively. Serum iron and hemoglobin levels were inversely associated with a high risk of acute seizures following aSAH.

Outcome Differences Between First- and Second-generation EGFR Inhibitors in Advanced EGFR Mutated NSCLC in a Large Population-based Cohort

IntroductionSecond-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) appear superior to first-generation TKIs in clinical trials, but at the cost of greater toxicity. It is unclear whether real-world patients, who often suffer worse outcomes, experience similar survival benefits. Using population-based data, we aim to characterize outcome differences by type of treatment. Patients and MethodsWe reviewed all patients with advanced non–small-cell lung cancer who initiated treatment with an EGFR TKI at BC Cancer between 2010 and 2015. A propensity score was generated to account for imbalances in patient characteristics between treatment groups. A Cox proportional hazards model based on the propensity score was then used to estimate effects of treatment on survival. ResultsA total of 484 patients were identified for analysis. Patients in the second-generation cohort were younger (62 vs. 67 years), had less baseline central nervous system metastases (9% vs. 22%), and more uncommon EGFR mutations (13% vs. 7%). Patients receiving a second-generation TKI had an improved overall survival (hazard ratio, 0.69; P = .05), driven by the subgroup with an EGFR exon 19 deletion. Patients with a L858R mutation did not appear to derive benefit from a second-generation TKI (hazard ratio, 0.91; P = .74). Overall, 40% of patients receiving a second-generation TKI required a dose reduction, but only 1% required discontinuation. ConclusionsSecond-generation TKIs tended to be chosen over first-generation TKIs as frontline therapy in younger patients with uncommon EGFR mutations and without central nervous system metastases. The survival benefit of a second-generation TKI seen in clinical trials appeared to be generalizable to real-world patients and is a reasonable first-line therapy.

Lower Iron Levels Predict Acute Hydrocephalus Following Aneurysmal Subarachnoid Hemorrhage

We tested the hypothesis that low serum iron levels are associated with acute hydrocephalus following aneurysmal subarachnoid hemorrhage (aSAH). Patients presenting with ruptured intracranial aneurysms were enrolled in the prospective observational study. Age, sex, history of diabetes, hypertension and hyperlipidemia, symptom onset, Fisher grade, Hunt-Hess grade, aneurysm location, hemoglobin, and serum iron were collected. Acute hydrocephalus was determined within 72 hours after subarachnoid hemorrhage. A propensity-score matching analysis was performed to correct imbalances in patient characteristics between hydrocephalus and non-hydrocephalus groups. A total of 535 patients were included. Incidence of acute hydrocephalus was 20.0%. In multivariate logistic regression analysis, lower serum iron was considered as a risk factor of acute hydrocephalus, as well as delayed ischemic neurologic deficit and lower hemoglobin (P= 0.000). After propensity-score matching, lower serum iron was considered as an independent risk factor for acute hydrocephalus, whereas hemoglobin and delayed ischemic neurologic deficit were not. The matched hydrocephalus group had lower serum iron comparing with the matched non-hydrocephalus group (10.26 ± 5.33 mmol/L vs. 13.44 ± 5.18 mmol/L; P= 0.000). The optimal cut-off value for serum iron levels as a predictor for acute hydrocephalus in patients with aSAH was determined as 13.1 mmol/L in the receiver operating characteristic curve. Furthermore, lower serum iron levels (odds ratio 0.305; 95% confidence interval, 0.178-0.524; P= 0.000) and acute hydrocephalus (odds ratio 0.372; 95% confidence interval, 0.202-0.684; P= 0.001) were predictors of poor outcome, as well as higher Hunt-Hess grade and Fisher grade. Lower serum iron levels after aSAH was a predictor of acute hydrocephalus and unfavorable outcome.

The Impact of Blood Transfusion on Recurrence and Mortality Following Colorectal Cancer Resection: A Propensity Score Analysis of 4,030 Patients

Whether blood transfusion exacerbates cancer outcomes after surgery in humans remains inconclusive. We utilized a large cohort to investigate the effect of perioperative blood transfusion on cancer prognosis following colorectal cancer (CRC) resection. Patients with stage I through III CRC undergoing tumour resection at a tertiary medical center between 2005 and 2014 were identified and evaluated through August 2016. Propensity score matching was used to cancel out imbalances in patient characteristics. Postoperative disease-free survival (DFS) and overall survival (OS) were analysed using Cox regression model. A total of 4,030 and 972 patients were analysed before and after propensity score matching. Cox regression analyses demonstrated blood transfusion associated with shorter DFS and OS before and after matching (hazard ratio: 1.41, 95% CI: 1.2–1.66 for DFS; 1.97, 95% CI: 1.6–2.43 for OS). Larger transfusion volume was linked to higher overall mortality (≤4 units vs. nil, HR = 1.58; >4 units vs. nil, HR = 2.32) but not more cancer recurrence. Preoperative anemia was not associated with decreased survival after adjusting covariates. Perioperative blood transfusion was associated with worse cancer prognosis after curative colorectal resection, independently of anemia status. Strategies aimed at minimizing transfusion requirements should be further developed.

Racial disparity in quality of care and overall survival among black vs. white patients with muscle-invasive bladder cancer treated with radical cystectomy: A national cancer database analysis

ObjectivesTo examine the impact of race on quality of care and overall survival (OS) among patients with muscle invasive bladder cancer (MIBC) treated with radical cystectomy (RC) in the U.S. Materials & MethodsOur cohort consisted of 12,652 patients receiving RC for MIBC within the National Cancer Database from 2004 to 2012. Patients were stratified by race (Black non-Hispanic vs. White non-Hispanic) and imbalances in patient characteristics mitigated using propensity score weighting. Logistic and Cox regressions examined the impact of race on quality of care metrics (receipt of pelvic lymph node dissection (PLND), lymph node count, hospital volume, length of stay, delay of treatment) and on OS. The difference in OS was expressed as Delta, and stratified by facility-type, hospital volume, and region. ResultsBlacks were less likely to receive PLND (odds ratio [OR] 0.70, 95% confidence interval [CI]: 0.55–0.91), or to have a greater number of lymph nodes removed (OR 0.76, 95%CI: 0.64–0.90). They exhibited greater length of stay (OR 1.34, 95%CI: 1.13–1.59), and delay of RC among recipients of neoadjuvant chemotherapy (OR 2.59, 95%CI: 1.77–3.85) (all P ≤ 0.001). Notably, utilization of neoadjuvant chemotherapy in advanced disease stages was more common in blacks (OR 2.82, 95%CI: 1.93–4.13, P < 0.001). Additionally, Black race was associated with inferior OS (Hazard ratio 0.87, 95%CI: 0.79–0.97, P < 0.014). Disparities in OS varied based on facility type and geographical region, but not hospital volume. Specifically, Blacks had worse OS when treated in a community cancer program (Delta 0.42, 95%CI: 0.28–0.57,P < 0.001), or within New England/Middle Atlantic region (Delta 0.16, 95% CI: 0.07–0.24,P < 0.001). ConclusionBlack race is an independent predictor of inferior quality of care and OS in patients undergoing RC for MIBC. Survival disparities vary based on geographical region and facility type. Notably, the OS disparity appears to have narrowed in comparison to previous studies.

A group sequential test for treatment effect based on the Fine-Gray model.

Competing risks endpoints arise when patients can fail therapy from several causes. Analyzing these outcomes allows one to assess directly the benefit of treatment on a primary cause of failure in a clinical trial setting. Regression models can be used in clinical trials to adjust for residual imbalances in patient characteristics, improving the power to detect treatment differences. But, none of the competing risks methods currently available for use in group sequential trials adjust for covariates. We propose a group sequential test for treatment effect that, because it is based on the Fine-Gray model, permits adjustment for covariates. Our derivations show that its sequence of test statistics has an asymptotic distribution with an independent increments structure, which allows standard techniques such as O'Brien-Fleming designs and error spending functions to be employed to meet type I error rate and power specifications. We demonstrate the test in a reanalysis of BMT CTN 0402, a phase III clinical trial that evaluated an experimental treatment for the prevention of adverse outcomes following blood and marrow transplant. Moreover, using a simulation study of randomized group sequential trials, we demonstrate that the proposed method preserves the type I error rate and power at their nominal levels in the presence of influential covariates.

Characteristics of Desaturation and Respiratory Rate in Postoperative Patients Breathing Room Air Versus Supplemental Oxygen: Are They Different?

Routine monitoring of postoperative patients with pulse oximetry-based surveillance monitoring has been shown to reduce adverse events. However, there is some concern that pulse oximetry is limited in its ability to detect deterioration quickly enough to allow for intervention in patients receiving supplemental oxygen. To address such concerns, this study expands on the current limited knowledge of differences in desaturation and respiratory rate characteristics between patients breathing room air and those receiving supplemental oxygen. Pulse oximetry-derived data and patient characteristics were used to examine overnight desaturation patterns of 67 postoperative patients who were receiving either supplemental oxygen or breathing room air. The 2 modalities with respect to the speed of desaturation, in addition to magnitude and duration of desaturation events, are compared. Night-time pulse rate, oxygen saturation, respiratory rate, and the transition times from normal oxygen saturation levels to desaturated states are also compared. The behavior of respiratory rate in proximity to desaturation events is described. Statistical methods included multivariable regression and inverse probability of treatment weighted to adjust for any imbalance in patient characteristics between the oxygen and room air patients and linear mixed effect models to account for clustering by patient. The study included 33 patients on room air and 34 receiving supplemental oxygen. The speed of desaturation was not different for room air versus oxygen for 2 types of desaturation (adjusted % difference, 95% confidence interval [CI]: type I; 22.4%, -51.5% to 209%; P = .67, type II; -17.3%, -53.8% to 47.6%; P = .52). Patients receiving supplemental oxygen had a higher mean oxygen saturation (adjusted difference, 95% CI, 2.4 [0.7-4.0]; P = .006). No differences were found for the average overnight respiratory or pulse rate, or proportion of time in desaturation states between the 2 groups.The time to transition from a normal oxygen saturation (92%) to 88% or below was not longer for supplemental oxygen patients (P = .42, adjusted difference 26.1%: 95% CI, -28.1% to 121%). Respiratory rates did not differ between the overall mean and desaturation or recovery phases or between the oxygen and room air group. In this study, desaturation characteristics did not differ between patients receiving supplemental oxygen and breathing room air with regard to speed, depth, or duration of desaturation. Transition time for desaturations to reach low oxygen saturation alarms was not different, while respiratory rate remained in the normal range during these events. These findings suggest that pulse oximetry-based surveillance monitoring for deterioration detection can be used equally effectively for patients on supplemental oxygen and for those on room air.

Increased Utilization of Chemotherapy for Early Stage Oropharyngeal Squamous Cell Carcinoma Despite Evidence for Benefit

Definitive radiotherapy (RT) offers the potential for organ preservation in patients with early stage oropharyngeal squamous cell carcinoma (OPSCC). For locally advanced OPSCC, the addition of chemotherapy to RT improves overall survival (OS) at the expense of increased acute and late toxicity. However, ASTRO recently presented guidelines recommending against chemoradiotherapy (CRT) in early stage OPSCC given prospective and retrospective evidence of equivalent locoregional control with RT alone. We used the National Cancer Database (NCDB) to evaluate the trends in utilization of chemotherapy in conjunction with RT in early stage OPSCC. This study compared outcomes following definitive CRT or RT in T1N0-1 and T2N0 OPSCC patients diagnosed between 1998 and 2012. Chi squared analysis was used to compare CRT to RT for clinicopathologic factors and trends in use over time. Logistic regression (LR) was performed to determine the odds ratio (OR) for factors associated with receipt of CRT. HPV/p16 was not assessable due to limited reporting prior to 2010. Due to significant imbalances in patient characteristics, propensity-score matching was performed based on probability of receipt of CRT and quartile of patients most likely to receive CRT were evaluated with Kaplan Meier for OS. We identified 3,346 early stage OPSCC patients with median age of 61 years. Use of CRT increased significantly from 14.5% in 1998 to a peak of 57.8% in 2007 and remained elevated at 54.3% in 2012 (OR 1.16/year, 95% CI 1.147 – 1.189, p<0.01). Those patients who received CRT were younger (52.7 vs 42.1% < 60 years, p<0.01), had private insurance (58.0 vs 42.2%, p<0.01), with less tonsil primaries (35.8 vs 47.5%, p<0.01), had lower comorbidity scores (86.3 vs 82.5% Charlson/Deyo score 0, p<0.01), and more often had T2 (52.6 vs 41.4% T1, p<0.01) and N1 (43.7 vs 15.3%, p<0.01) disease. In propensity-score matching, 3-year OS for the quartile most likely to receive chemotherapy was not significantly different for CRT vs RT (91.1%, 95% CI 89.8 – 92.4; vs 87.6%, 95% CI 85.3 – 89.9, log rank p=0.37). There has been a remarkable increase in the utilization of chemotherapy for early stage OPSCC despite lack of evidence showing improvement in outcomes and at the expense of increased toxicity. Further work is needed to determine if the ASTRO consensus guidelines will impact the addition of chemotherapy to radiation in this patient population.

Minimizing imbalances on patient characteristics between treatment groups in randomized trials using classification tree analysis.

Randomization ensures that treatment groups do not differ systematically in their characteristics, thereby reducing threats to validity that may otherwise explain differences in outcomes. Large observed imbalances in patient characteristics may indicate that selection bias is being introduced into the treatment allocation process. We introduce classification tree analysis (CTA) as a novel algorithmic approach for identifying potential imbalances in characteristics and their interactions when provisionally assigning each new participant to one or the other treatment group. The participant is then permanently assigned to the treatment group that elicits either no or less imbalance than if assigned to the alternate group. Using data on participant characteristics from a clinical trial, we compare 3 different treatment allocation approaches: permuted block randomization (the original allocation method), minimization, and CTA. Treatment allocation performance is assessed by examining balance of all 17 patient characteristics between study groups for each of the allocation techniques. While all 3 treatment allocation techniques achieved excellent balance on main effect variables, Classification tree analysis further identified imbalances on interactions and in the distributions of some of the continuous variables. Classification tree analysis offers an algorithmic procedure that may be used with any randomization methodology to identify and then minimize linear, nonlinear, and interactive effects that induce covariate imbalance between groups. Investigators should consider using the CTA approach as a real-time complement to randomization for any clinical trial to safeguard the treatment allocation process against bias.

Continuing or ceasing bevacizumab beyond progression in recurrent glioblastoma: an exploratory randomized phase II trial.

In patients with recurrent glioblastoma, the benefit of bevacizumab beyond progression remains uncertain. We prospectively evaluated continuing or ceasing bevacizumab in patients who progressed while on bevacizumab. CABARET, a phase II study, initially randomized patients to bevacizumab with or without carboplatin (Part 1). At progression, eligible patients underwent a second randomization to continue or cease bevacizumab (Part 2). They could also receive additional chemotherapy regimens (carboplatin, temozolomide, or etoposide) or supportive care. Of 120 patients treated in Part 1, 48 (80% of the anticipated 60-patient sample size) continued to Part 2. Despite randomization, there were some imbalances in patient characteristics. The best response was stable disease in 7 (30%) patients who continued bevacizumab and 2 (8%) patients who stopped receiving bevacizumab. There were no radiological responses. Median progression-free survival was 1.8 vs 2.0 months (bevacizumab vs no bevacizumab; hazard ratio [HR], 1.08; 95% CI, .59-1.96; P = .81). Median overall survival was 3.4 vs 3.0 months (HR, .84; 95% CI, .47-1.50; P = .56 and HR .70; 95% CI .38-1.29; P = .25 after adjustment for baseline factors). Quality-of-life scores did not significantly differ between arms. While the maximum daily steroid dose was lower in the continuation arm, the difference was not statistically significant. Patients who continued bevacizumab beyond disease progression did not have clear survival improvements, although the study was not powered to detect other than very large differences. While these data provide the only randomized evidence related to continuing bevacizumab beyond progression in recurrent glioblastoma, the small sample size precludes definitive conclusions and suggests this remains an open question.

National Cancer Database Analysis of Proton Versus Photon Radiation Therapy in Non-Small Cell Lung Cancer

Toanalyze outcomes and predictors associated with proton radiation therapy for non-small cell lung cancer (NSCLC) in the National Cancer Database. The National Cancer Database was queried to capture patients with stage I-IV NSCLC treated with thoracic radiation from 2004 to 2012. A logistic regression model was used to determine the predictors for utilization of proton radiation therapy. The univariate and multivariable association with overall survival were assessed by Cox proportional hazards models along with log-rank tests. A propensity score matching method was implemented to balance baseline covariates and eliminate selection bias. A total of 243,822 patients (photon radiation therapy: 243,474; proton radiation therapy: 348) were included in the analysis. Patients in a ZIP code with a median income of <$46,000 per year were less likely to receive proton treatment, with the income cohort of $30,000 to $35,999 least likely to receive proton therapy (odds ratio 0.63 [95% confidence interval (CI) 0.44-0.90]; P=.011). On multivariate analysis of all patients, non-proton therapy was associated with significantly worse survival compared with proton therapy (hazard ratio 1.21 [95% CI 1.06-1.39]; P<.01). On propensity matched analysis, proton radiation therapy (n=309) was associated with better 5-year overall survival compared with non-proton radiation therapy (n=1549), 22% versus 16% (P=.025). For stage II and III patients, non-proton radiation therapy was associated with worse survival compared with proton radiation therapy (hazard ratio 1.35 [95% CI 1.10-1.64], P<.01). Thoracic radiation with protons is associated with better survival in this retrospective analysis; further validation in the randomized setting is needed to account for any imbalances in patient characteristics, including positron emission tomography-computed tomography staging.

Selective admission into stroke unit and patient outcomes: a tale of four cities.

Care of stroke patients costs considerably more in specialized stroke units (SU) compared to care in general medical wards (GMW) but the technology may be cost effective if it leads to significantly improved outcomes. While randomized control trials show better outcomes for stroke patients admitted to SU, observational studies report mixed findings. In this paper we use individual level data from first-ever stroke patients in four European cities and find evidence of selection by the initial severity of stroke into SU in some cities. In these cases, the impact of admission to SU on outcomes is overestimated by multivariate logit models even after controlling for case-mix. However, when the imbalance in patient characteristics and severity of stroke by admission to SU and GMW is adjusted using propensity score methods, the differences in outcomes are no longer statistically significant in most cases. Our analysis explains why earlier studies using observational data have found mixed results on the benefits of admission to SU.

Comparison of adherence and persistence with bimatoprost 0.01% versus bimatoprost 0.03% topical ophthalmic solutions

Objective:To compare patient adherence and persistence with bimatoprost 0.01%, a new formulation that offers equivalent intraocular pressure-lowering efficacy to bimatoprost 0.03% and improved tolerability, with that of the original bimatoprost 0.03% formulation.Methods:Pharmacy claims from a longitudinal database of prescription and medical claims for >115 million patients were analyzed. Patients with an initial (index) prescription for bimatoprost 0.01% or 0.03% between April and June 2011, and with no claim for ophthalmic prostaglandin or prostamide analogs during the preceding 18 months, were identified. Treatment adherence was expressed as the proportion of days covered (PDC) with study medication over the first 365 days after the index prescription. Treatment persistence over the first 12 months following the index prescription was assessed using Kaplan–Meier analyses, assuming a 30 day grace period for prescription refill. Treatment status (on/off study medication) was determined monthly for 12 months post-index.Results:In total, 6150 patients were assessed for treatment adherence and 7660 for persistence. Adherence was significantly better with bimatoprost 0.01% than bimatoprost 0.03% (mean PDC 0.540 vs. 0.438; p < 0.001). Significantly more patients had high adherence (PDC > 0.80) with bimatoprost 0.01% than 0.03% (29.1% vs. 17.3%; p < 0.001). Persistence was also significantly better with bimatoprost 0.01%, with 29.5% (95% confidence interval [CI]: 28.3%, 30.8%) versus 18.3% (95% CI: 16.8%, 19.9%) of patients remaining on continuous treatment for 12 months (p < 0.001). At 12 months, significantly more patients were ‘on treatment’ (continuing/restarting treatment) with bimatoprost 0.01% than 0.03% (48.8% vs. 33.9%; p < 0.001). Sensitivity analyses demonstrated similar findings in cohorts of ocular hypotensive treatment-naïve and elderly (≥65 years) patients.Conclusions:Bimatoprost 0.01% offers adherence and persistency advantages over bimatoprost 0.03% in patients requiring ocular hypotensive therapy. Study limitations included the observational design, lack of control for imbalances in patient characteristics, and assumption that prescription refill is synonymous with medication use.

Bayesian Hierarchical Models Combining Different Study Types and Adjusting for Covariate Imbalances: A Simulation Study to Assess Model Performance

BackgroundBayesian hierarchical models have been proposed to combine evidence from different types of study designs. However, when combining evidence from randomised and non-randomised controlled studies, imbalances in patient characteristics between study arms may bias the results. The objective of this study was to assess the performance of a proposed Bayesian approach to adjust for imbalances in patient level covariates when combining evidence from both types of study designs.Methodology/Principal FindingsSimulation techniques, in which the truth is known, were used to generate sets of data for randomised and non-randomised studies. Covariate imbalances between study arms were introduced in the non-randomised studies. The performance of the Bayesian hierarchical model adjusted for imbalances was assessed in terms of bias. The data were also modelled using three other Bayesian approaches for synthesising evidence from randomised and non-randomised studies. The simulations considered six scenarios aimed at assessing the sensitivity of the results to changes in the impact of the imbalances and the relative number and size of studies of each type. For all six scenarios considered, the Bayesian hierarchical model adjusted for differences within studies gave results that were unbiased and closest to the true value compared to the other models.Conclusions/SignificanceWhere informed health care decision making requires the synthesis of evidence from randomised and non-randomised study designs, the proposed hierarchical Bayesian method adjusted for differences in patient characteristics between study arms may facilitate the optimal use of all available evidence leading to unbiased results compared to unadjusted analyses.

Post-Hospital Medical Respite Care and Hospital Readmission of Homeless Persons

Medical respite programs offer medical, nursing, and other care as well as accommodation for homeless persons discharged from acute hospital stays. They represent a community-based adaptation of urban health systems to the specific needs of homeless persons. This article examines whether post-hospital discharge to a homeless medical respite program was associated with a reduced chance of 90-day readmission compared to other disposition options. Adjusting for imbalances in patient characteristics using propensity scores, respite patients were the only group that was significantly less likely to be readmitted within 90 days compared to those released to Own Care. Respite programs merit attention as a potentially efficacious service for homeless persons leaving the hospital.

Use of biological assignment in hematopoietic stem cell transplantation clinical trials

When comparing treatments for a specific illness, it is sometimes impractical or impossible to conduct a randomized clinical trial (RCT). Biological assignment trials are one alternative design. In hematopoietic stem cell transplantation (HCT) trials, a human leukocyte antigen (HLA)-matched sibling donor is considered optimal, but such donors are available for only 20-30% of otherwise eligible patients. Rather than randomizing only those with a matched sibling donor, in a recent multiple myeloma trial, the type of HCT each patient received was biologically based, i.e., chosen according to whether or not the patient had a matched sibling donor. This article describes the design and implementation of biological assignment trials as well as their advantages and disadvantages. We focus on several aspects of such trials, including efficiency of trial duration, ethical issues, and potential sources of bias. Statistical issues are considered including sample size calculations, monitoring for biased enrollment, and adjustments for imbalances in patient characteristics. A multiple myeloma trial is used as an illustration. Although they often require a larger sample size, biological assignment trials can provide substantial efficiency in terms of study duration over randomized trials when accrual to a randomized trial would be slow. Determination of sample size requires consideration of the anticipated proportion of patients with a biologically favored (HLA-matched sibling) donor. An add-on randomization of patients without a matched sibling donor may alleviate ethical concerns about applicability of study results to all patients regardless of whether the biological assignment groups differ with respect to outcome. Prognostic factor imbalance and enrollment bias can occur in a biological assignment trial. Statistical adjustment for potential imbalance in prognostic factors is important, as is monitoring center accrual for enrollment bias and performing an appropriate intention-to-treat analysis. A biological assignment trial can be a reasonable way to compare treatments which are biologically based, such as HLA-matched sibling transplants, when the gold-standard randomized trial design is impractical or impossible. Implementing such a trial requires careful consideration of the ethical issues and potential biases.

Continuous versus intermittent renal replacement therapy for critically ill patients with acute kidney injury: A meta-analysis*

To appraise the literature on the effect of initial renal replacement therapy (RRT) modality on clinical outcomes. Systematic review and meta-analysis. Academic medical center. Adult critically ill patients with acute kidney injury. Continuous vs. intermittent RRT. MEDLINE, EMBASE, Cochrane Controlled Clinical Trials Register, and other sources were searched. We identified nine unique randomized trials (n = 1,403). No trial satisfied all quality indicators and several had limitations related to selection bias, randomization, imbalances in patient characteristics, and high treatment crossover. No trial standardized the timing, criteria, for initiation or dose of RRT. There was no statistical evidence that initial modality influenced mortality (odds ratio, 0.99; 95% confidence interval, 0.78-1.26, p = .93; I2 = 11%; nine trials, n = 1,403) or recovery to RRT independence (odds ratio, 0.76; 95% confidence interval, 0.28-2.07, p = .59; I2 = 0%; four trials, n = 306). There was suggestion that continuous RRT had fewer episodes of hemodynamic instability and better control of fluid balance. We identified numerous issues related to study design, conduct, and quality that dispute the validity and question any inferences that can be drawn from these trials. In the context of these limitations, the initial RRT modality did not seem to affect mortality or recovery to RRT independence. There is urgent need for additional high-quality and suitably powered trials to adequately address this issue.