Variation In Treatment Effects Research Articles

A comparison of the statistical performance of different meta-analysis models for the synthesis of subgroup effects from randomized clinical trials

BackgroundWhen investigating subgroup effects in meta-analysis, it is unclear whether accounting in meta-regression for between-trial variation in treatment effects, but not between-trial variation in treatment interaction effects when such effects are present, leads to biased estimates, coverage problems, or wrong standard errors, and whether the use of aggregate data (AD) or individual-patient-data (IPD) influences this assessment.MethodsSeven different models were compared in a simulation study. Models differed regarding the use of AD or IPD, whether they accounted for between-trial variation in interaction effects, and whether they minimized the risk of ecological fallacy.ResultsModels that used IPD and that allowed for between-trial variation of the interaction effect had less bias, better coverage, and more accurate standard errors than models that used AD or ignored this variation. The main factor influencing the performance of models was whether they used IPD or AD. The model that used AD had a considerably worse performance than all models that used IPD, especially when a low number of trials was included in the analysis.ConclusionsThe results indicate that IPD models that allow for the between-trial variation in interaction effects should be given preference whenever investigating subgroup effects within a meta-analysis.

Phase I trial of caudate deep brain stimulation for treatment-resistant tinnitus.

The objective of this open-label, nonrandomized trial was to evaluate the efficacy and safety of bilateral caudate nucleus deep brain stimulation (DBS) for treatment-resistant tinnitus. Six participants underwent DBS electrode implantation. One participant was removed from the study for suicidality unrelated to brain stimulation. Participants underwent a stimulation optimization period that ranged from 5 to 13 months, during which the most promising stimulation parameters for tinnitus reduction for each individual were determined. These individual optimal stimulation parameters were then used during 24 weeks of continuous caudate stimulation to reach the endpoint. The primary outcome for efficacy was the Tinnitus Functional Index (TFI), and executive function (EF) safety was a composite z-score from multiple neuropsychological tests (EF score). The secondary outcome for efficacy was the Tinnitus Handicap Inventory (THI); for neuropsychiatric safety it was the Frontal Systems Behavior Scale (FrSBe), and for hearing safety it was pure tone audiometry at 0.5, 1, 2, 3, 4, and 6 kHz and word recognition score (WRS). Other monitored outcomes included surgery- and device-related adverse events (AEs). Five participants provided full analyzable data sets. Primary and secondary outcomes were based on differences in measurements between baseline and endpoint. The treatment effect size of caudate DBS for tinnitus was assessed by TFI [mean (SE), 23.3 (12.4)] and THI [30.8 (10.4)] scores, both of which were statistically significant (Wilcoxon signed-rank test, 1-tailed; alpha = 0.05). Based on clinically significant treatment response categorical analysis, there were 3 responders determined by TFI (≥ 13-point decrease) and 4 by THI (≥ 20-point decrease) scores. Safety outcomes according to EF score, FrSBe, audiometric thresholds, and WRS showed no significant change with continuous caudate stimulation. Surgery-related and device-related AEs were expected, transient, and reversible. There was only one serious AE, a suicide attempt unrelated to caudate neuromodulation in a participant in whom stimulation was in the off mode for 2 months prior to the event. Bilateral caudate nucleus neuromodulation by DBS for severe, refractory tinnitus in this phase I trial showed very encouraging results. Primary and secondary outcomes revealed a highly variable treatment effect size and 60%-80% treatment response rate for clinically significant benefit, and no safety concerns. The design of a phase II trial may benefit from targeting refinement for final DBS lead placement to decrease the duration of the stimulation optimization period and to increase treatment effect size uniformity.Clinical trial registration no.: NCT01988688 (clinicaltrials.gov).

Nerve transfers in the upper extremity following cervical spinal cord injury. Part 1: Systematic review of the literature.

Patients with cervical spinal cord injury (SCI)/tetraplegia consistently rank restoring arm and hand function as their top functional priority to improve quality of life. Motor nerve transfers traditionally used to treat peripheral nerve injuries are increasingly being used to treat patients with cervical SCIs. In this study, the authors performed a systematic review summarizing the published literature on nerve transfers to restore upper-extremity function in tetraplegia. A systematic literature search was conducted using Ovid MEDLINE 1946-, Embase 1947-, Scopus 1960-, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and clinicaltrials.gov to identify relevant literature published through January 2019. The authors included studies that provided original patient-level data and extracted information on clinical characteristics, operative details, and strength outcomes after nerve transfer procedures. Critical review and synthesis of the articles were performed. Twenty-two unique studies, reporting on 158 nerve transfers in 118 upper limbs of 92 patients (87 males, 94.6%) were included in the systematic review. The mean duration from SCI to nerve transfer surgery was 18.7 months (range 4 months-13 years) and mean postoperative follow-up duration was 19.5 months (range 1 month-4 years). The main goals of reinnervation were the restoration of thumb and finger flexion, elbow extension, and wrist and finger extension. Significant heterogeneity in transfer strategy and postoperative outcomes were noted among the reports. All but one case report demonstrated recovery of at least Medical Research Council grade 3/5 strength in recipient muscle groups; however, there was greater variation in the results of larger case series. The best, most consistent outcomes were demonstrated for restoration of wrist/finger extension and elbow extension. Motor nerve transfers are a promising treatment option to restore upper-extremity function after SCI. Flexor reinnervation strategies show variable treatment effect sizes; however, extensor reinnervation may provide more consistent, meaningful recovery. Despite numerous published case reports describing good patient outcomes with nerve transfers, there remains a paucity in the literature regarding optimal timing and long-term clinical outcomes with these procedures.

Heterogeneous Impacts Across Schools in the First Four Years of the Louisiana Scholarship Program

The Louisiana Scholarship Program (LSP) is a school voucher initiative that offers publicly- funded scholarships to students from economically-disadvantaged families to attend a participating private school of their choice. While school choice theory suggests that market- based reforms such as the LSP should improve student outcomes, experimental evaluations of the program instead find significant negative effects of the program on math and reading scores after its first year. Those effects diminish to insignificant differences by the end of the third year before becoming negative again in the fourth year. Our study builds on previous work with an exploratory analysis of the variation in treatment effects across 13 school characteristics in the first four years of the program. In general, we do not observe effect heterogeneity across school characteristics, though we find evidence suggesting students who preferred larger schools, schools with higher tuition, and schools with longer school days experienced more favorable impacts from participating in the LSP relative to their peers who did not prefer such schools.

How do climate change experiments alter plot-scale climate?

To understand and forecast biological responses to climate change, scientists frequently use field experiments that alter temperature and precipitation. Climate manipulations can manifest in complex ways, however, challenging interpretations of biological responses. We reviewed publications to compile a database of daily plot-scale climate data from 15 active-warming experiments. We find that the common practices of analysing treatments as mean or categorical changes (e.g. warmed vs. unwarmed) masks important variation in treatment effects over space and time. Our synthesis showed that measured mean warming, in plots with the same target warming within a study, differed by up to 1.6 C (63% of target), on average, across six studies with blocked designs. Variation was high across sites and designs: for example, plots differed by 1.1 C (47% of target) on average, for infrared studies with feedback control (n=3) vs. by 2.2 C (80% of target) on average for infrared with constant wattage designs (n=2). Warming treatments produce non-temperature effects as well, such as soil drying. The combination of these direct and indirect effects is complex and can have important biological consequences. With a case study of plant phenology across five experiments in our database, we show how accounting for drier soils with warming tripled the estimated sensitivity of budburst to temperature. We provide recommendations for future analyses, experimental design, and data sharing to improve our mechanistic understanding from climate change experiments, and thus their utility to accurately forecast species' responses.

Assessing Treatment Effect Variation in Observational Studies: Results from a Data Challenge

A growing number of methods aim to assess the challenging question of treatment effect variation in observational studies. This special section of Observational Studies reports the results of a workshop conducted at the 2018 Atlantic Causal Inference Conference designed to understand the similarities and differences across these methods. We invited eight groups of researchers to analyze a synthetic observational data set that was generated using a recent large-scale randomized trial in education. Overall, participants employed a diverse set of methods, ranging from matching and flexible outcome modeling to semiparametric estimation and ensemble approaches. While there was broad consensus on the topline estimate, there were also large differences in estimated treatment effect moderation. This highlights the fact that estimating varying treatment effects in observational studies is often more challenging than estimating the average treatment effect alone. We suggest several directions for future work arising from this workshop.

A Patient‐Centered Approach to Comparative Effectiveness Research Focused on Older Adults: Lessons From the Patient‐Centered Outcomes Research Institute

The mission of the Patient‐Centered Outcomes Research Institute (PCORI) is to fund the production of high‐quality evidence that will enable patients and clinicians to make informed, personalized healthcare decisions. Since 2012, the PCORI has invested $177 million in patient‐centered comparative effectiveness research (CER) that specifically targets the health needs of older adults, with additional relevant studies in its broader portfolio. Developing the PCORI's research portfolio has provided us with significant insights into what factors to consider when conducting CER in older adult populations. When comparing the net benefit of two or more interventions for older adults, investigators should consider the following: absolute risk difference, competing risks, life expectancy, the difference between chronologic and physiologic age, the importance of patient preferences, and other potential drivers of variable treatment effects. Investigators should also engage older adults and their caregivers as partners throughout the research process. Their input helps to identify key outcomes of interest and insights about the conduct of the research. As the PCORI continues to support research that addresses the healthcare decisions of the rapidly growing older adult population, it needs to partner with patients and researchers to identify the most important questions to address. J Am Geriatr Soc 67:21–28, 2019.

Effects of Ischemic Preconditioning on Abdominal Aortic Aneurysm Repair: A Systematic Review and Meta-analysis

BackgroundIschemic preconditioning is an innate mechanism of cytoprotection against ischemia, with potential for end-organ protection. The primary goal of this study was to systematically review the literature to determine the effect of ischemic preconditioning on outcomes after open and endovascular abdominal aortic aneurysm (AAA) repair. MethodsThe methodology followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. We included randomized clinical trials that evaluated the effect of remote ischemic preconditioning (RIPC) in reducing morbidity and mortality in patients undergoing open or endovascular AAA repair surgery. The primary outcomes were death, myocardial infarction, and renal impairment. Outcomes were addressed separately for open AAA repair and endovascular AAA repair (EVAR). Data were collected on patient characteristics, methodology, and preconditioning protocol for each trial. ResultsNine trials of ischemic preconditioning in aortic aneurysm surgery were included with a total of 599 patients; 336 patients were included in the open AAA repair meta-analysis, and 263 patients were included in the EVAR meta-analysis. For both open and endovascular repairs, ischemic preconditioning did not have a significant effect on death, myocardial infarction, or renal impairment requiring dialysis. ConclusionsThe randomized clinical trials investigating the effect of ischemic preconditioning on outcomes after open and endovascular AAA repair that have been completed to date have not been adequately powered to evaluate improvements in patient-important outcomes. The evidence is insufficient to support the use of ischemic preconditioning for AAA repair in clinical practice. The variability in treatment effect across studies may be explained by clinical and methodological heterogeneity.

PHP102 - ARE SPECIFIC METHODOLOGICAL FRAMEWORKS REQUIRED FOR THE ECONOMIC EVALUATION OF GENE THERAPIES?

Several gene therapies are getting close to marketing authorization and cost-effectiveness analysis (CEA) we will be needed for HTA. Unlike most current pharmaceuticals, gene therapies offer the potential for a one-time treatment that produces long-term benefits. Our objective was to evaluate whether new methodological frameworks would be required for the economic evaluation of gene therapies. We ran a search on Clinicaltrials.gov focussing on the gene therapies assessed or currently being assessed in a Phase III Clinical trial. We extracted the sample size, the primary and secondary outcomes, planned duration of follow-up. We developed categories of product profiles, presented them to modelling experts, and asked them how they would conceptualise cost-effectiveness model for such products if they had to prepare HTA submissions. Of 248 clinical studies identified, 96 (39%) were related cancer and 65 (26%) were related to orphan diseases. The average planned follow-up was 4.6 years with a median at 3.4 years whereas the expected impact of gene therapy could be lifetime. For 20% of trials, the number of patients included was lower than 50. The median sample size was 213 patients per trial. Populations could be highly heterogeneous, e.g. with 20% of studies mixing adults and children. The main challenge associated with modelling gene therapy was uncertainty around long-term efficacy and safety, due to utilisation of surrogate outcomes, small patient numbers and relatively short observation period. Other challenges included model complexity related to variability in treatment effects across heterogeneous patient profiles and valuation of health benefits of children. Although standard economic evaluation approaches based on CEA are theoretically applicable to gene therapies, they may in reality be of little use to decision-makers, due to substantial uncertainty around results.

PairedFB: a full hierarchical Bayesian model for paired RNA-seq data with heterogeneous treatment effects.

Several methods have been proposed for the paired RNA-seq analysis. However, many of them do not consider the heterogeneity in treatment effect among pairs that can naturally arise in real data. In addition, it has been reported in literature that the false discovery rate (FDR) control of some popular methods has been problematic. In this paper, we present a full hierarchical Bayesian model for the paired RNA-seq count data that accounts for variation of treatment effects among pairs and controls the FDR through the posterior expected FDR. Our simulation studies show that most competing methods can have highly inflated FDR for small to moderate sample sizes while PairedFB is able to control FDR close to the nominal levels. Furthermore, PairedFB has overall better performance in ranking true differentially expressed genes (DEGs) on the top than others, especially when the sample size gets bigger or when the heterogeneity level of treatment effects is high. In addition, PairedFB can be applied to identify the biologically significant DEGs with controlled FDR. The real data analysis also indicates PairedFB tends to find more biologically relevant genes even when the sample size is small. PairedFB is also shown to be robust with respect to the model misspecification in terms of its relative performance compared to others. Software to implement this method (PairedFB) can be downloaded at: https://sites.google.com/a/udel.edu/qiujing/publication. Supplementary data are available at Bioinformatics online.

Individualized treatment effects with censored data via fully nonparametric Bayesian accelerated failure time models.

Individuals often respond differently to identical treatments, and characterizing such variability in treatment response is an important aim in the practice of personalized medicine. In this article, we describe a nonparametric accelerated failure time model that can be used to analyze heterogeneous treatment effects (HTE) when patient outcomes are time-to-event. By utilizing Bayesian additive regression trees and a mean-constrained Dirichlet process mixture model, our approach offers a flexible model for the regression function while placing few restrictions on the baseline hazard. Our nonparametric method leads to natural estimates of individual treatment effect and has the flexibility to address many major goals of HTE assessment. Moreover, our method requires little user input in terms of model specification for treatment covariate interactions or for tuning parameter selection. Our procedure shows strong predictive performance while also exhibiting good frequentist properties in terms of parameter coverage and mitigation of spurious findings of HTE. We illustrate the merits of our proposed approach with a detailed analysis of two large clinical trials (N = 6769) for the prevention and treatment of congestive heart failure using an angiotensin-converting enzyme inhibitor. The analysis revealed considerable evidence for the presence of HTE in both trials as demonstrated by substantial estimated variation in treatment effect and by high proportions of patients exhibiting strong evidence of having treatment effects which differ from the overall treatment effect.

Procedural and anatomical predictors of renal denervation efficacy using two radiofrequency renal denervation catheters in a porcine model

Introduction:Several renal denervation (RDN) systems are currently under investigation for treatment of hypertension by ablation of renal sympathetic nerves. The procedural efficacy of devices, however, is variable and incompletely understood. This study aimed at investigating procedural and anatomical predictors of RDN efficacy by comparing two radiofrequency catheter systems in a porcine model.Methods:Domestic swine were assigned into two treatment groups (n = 10) and one sham group (n = 3). Bilateral RDN in main and in branch segments of renal arteries was performed using two different multielectrode catheter systems [Symplicity Spyral (SPY) and IberisBloom (IBB)]. After 7 days, measurement of norepinephrine (NEPI) tissue concentrations and histological analyses have been performed.Results:Renal NEPI tissue concentration following RDN was significantly reduced when compared with Sham (SPY: −95 ± 3% vs. Sham, P < 0.001; IBB: −88 ± 11% vs. Sham, P < 0.001). Histological evaluation showed comparable lesion depth and lesion area (lesion depth: SPY-main 6.26 ± 1.62 mm vs. SPY-branch 3.49 ± 1.11 mm; IBB-main 5.93 ± 1.88 mm vs. IBB-branch: 3.26 ± 1.26 mm, P < 0.001; lesion area: SPY-main 43.5 ± 29.5 mm2 vs. SYP-branch 45.0 ± 38.0 mm2; IBB-main 52.3 ± 34.8 mm2 vs. IBB-branch 44.0 ± 42.6 mm2, P = 0.77; intergroup SPY vs. IBB, P = 0.73). Histological investigations documented a significant correlation between number of ablations per millimeter length of renal artery and reduction in NEPI tissue concentration.Conclusion:The two devices under investigation demonstrated similar histopathological lesion characteristics and similar reduction of renal NEPI levels. An increase in number of ablations per millmeter length of renal artery resulted in improved efficacy and reduced variability in treatment effects.

Decomposing Treatment Effect Variation

ABSTRACTUnderstanding and characterizing treatment effect variation in randomized experiments has become essential for going beyond the “black box” of the average treatment effect. Nonetheless, traditional statistical approaches often ignore or assume away such variation. In the context of randomized experiments, this article proposes a framework for decomposing overall treatment effect variation into a systematic component explained by observed covariates and a remaining idiosyncratic component. Our framework is fully randomization-based, with estimates of treatment effect variation that are entirely justified by the randomization itself. Our framework can also account for noncompliance, which is an important practical complication. We make several contributions. First, we show that randomization-based estimates of systematic variation are very similar in form to estimates from fully interacted linear regression and two-stage least squares. Second, we use these estimators to develop an omnibus test for systematic treatment effect variation, both with and without noncompliance. Third, we propose an R2-like measure of treatment effect variation explained by covariates and, when applicable, noncompliance. Finally, we assess these methods via simulation studies and apply them to the Head Start Impact Study, a large-scale randomized experiment. Supplementary materials for this article are available online.

Taq1A polymorphism and medication effects on inhibitory action control in Parkinson disease.

BackgroundDopamine therapy in Parkinson disease (PD) can have differential effects on inhibitory action control, or the ability to inhibit reflexive or impulsive actions. Dopamine agonist (DAAg) medications, which preferentially target D2 and D3 receptors, can either improve or worsen control of impulsive actions in patients with PD. We have reported that the direction of this effect depends on baseline levels of performance on inhibitory control tasks. This observation suggests that there may exist certain biologic determinants that contribute to these patient‐specific differences. We hypothesized that one important factor might be functional polymorphisms in D2‐like receptor genes.AimThe goal of this study was to determine whether the direction of DAAg effects on inhibitory control depends on functional polymorphisms in the DRD2 and DRD3 genes.MethodsTwenty‐eight patients with PD were genotyped for known functional polymorphisms in DRD2 (rs6277 and rs1800497) and DRD3 (rs6280) receptors. These patients then completed the Simon conflict task both on and off DAAg therapy in a counterbalanced manner.ResultsWe found that patients with the rs1800497 Taq1A (A1) polymorphism (A1/A1 or A1/A2: 11 subjects) showed improved proficiency to suppress impulsive actions when on DAAg; conversely, patients with the A2/A2 allele (14 patients) became less proficient at suppressing incorrect response information on DAAg therapy (Group × Medication, F(1, 23) = 5.65, p < 0.05). Polymorphisms in rs6277 and rs6280 were not associated with a differential medication response.ConclusionThese results suggest that certain DRD polymorphisms may determine the direction of DAAg effects on critical cognitive control processes impaired in PD. Our findings have implications for understanding pharmacogenomics interactions on a larger scale and the role these may play in the wide variability of treatment effects seen in the PD population.

TESTING THE THEORY OF MULTITASKING: EVIDENCE FROM A NATURAL FIELD EXPERIMENT IN CHINESE FACTORIES

AbstractUsing a natural field experiment, we quantify the impact of one‐dimensional performance‐based incentives on incentivized (quantity) and nonincentivized (quality) dimensions of output for factory workers with a flat‐rate or a piece‐rate base salary. In particular, we observe output quality by hiring quality inspectors unbeknownst to the workers. We find that workers trade off quality for quantity, but the effect is statistically significant only for workers under a flat‐rate base salary. This variation in treatment effects is consistent with a simple theoretical model that predicts that when agents are already incented at the margin, the quantity–quality trade‐off resulting from performance pay is less prominent.

Abstract P3-17-02: Influence of non-measurable disease on progression-free survival in patients with metastatic breast cancer

Abstract Background: Progression free-survival (PFS) is the dominant endpoint in phase 3 randomized controlled trials (RCTs) in women with metastatic breast cancer (MBC), and requires the ability to measure target lesions. It is unknown whether treatment effect on PFS is consistent among patients with measurable and non-measurable disease. Methods: We searched MEDLINE, EMBASE and COCHRANE for phase 3 RCTs in MBC that reported outcomes in subgroups with non-measurable (or bone only disease, if not reported explicitly) and measurable disease. Data were extracted and a single hazard ratio (HR) and 95% confidence intervals (CI) were computed to compare the individual trial treatment effect in non-measurable versus measurable disease. Data were then pooled in a meta-analysis. We repeated the analysis comparing bone only to non-bone only disease and performed subgroup analyses based on drug mechanism of action. Results: Of 82 RCTs that enrolled patients with non-measurable disease, 16 trials comprising 8516 patients were eligible for analysis. All included RCTs used PFS or time to progression as primary endpoints. There was no difference in pooled treatment effect between patients with non-measurable and measurable disease (HR 1.01, 95% CI 0.89-1.15, p=0.82). However, compared to non-bone only disease, a significantly greater effect on PFS was seen in those with bone only disease (HR 0.82, 95% CI 0.70-0.98, p=0.03). Subgroups analyses according to drug mechanism are shown in Table 1 Intra-study comparison, according to evaluated drug mechanismCohort/ Investigational drugNo. studies includedMeasurable HR (95% CI)Non measurable HR (95% CI)Intra- study comparison HR (95% CI)P – for intra-study comparisonAll160.69 (0.65-0.73)0.72 (0.64-0.80)1.01 (0.89-1.15)0.82Chemotherapy30.99 (0.87-1.13)0.67 (0.44-1.02)0.73 (0.44-1.21)0.22Endocrine treatment40.86 (0.77-0.96)0.94 (0.80-1.10)1.13 (0.92-1.40)0.23Signal transduction inhibitors40.52 (0.48-0.57)0.41 (0.33-0.50)0.74 (0.59-0.94)0.01Anti-angiogenetic agents50.66 (0.59-0.73)0.84 (0.67-1.04)1.34 (1.05-1.71)0.02CI- confidence interval, HR- hazard ratio . Compared to patients with measurable disease, there was a greater effect on PFS in those with non-measurable disease in RCTs of signal transduction inhibitors and endocrine therapy (HR 0.74, 95% CI 0.59-0.94, p=0.01). There was a lesser effect on PFS in patients with non-measurable disease in RCTs of antiangiogenic drugs (HR 1.34, 95% CI 1.05-1.71, p=0.02). Comparable effect on PFS was shown in RCTs evaluating endocrine therapy and chemotherapy. Conclusions: There is variability in treatment effect on PFS in patients with measurable and non-measurable disease. There is greater effect on PFS in RCTs of endocrine therapy and signal transduction inhibitors and in patients with bone only disease. Standardization of PFS determination in patients with non-measurable and bone only disease is warranted. Citation Format: Goldvaser H, Ribnikar D, Fazelzad R, Seruga B, Templeton AJ, Ocana A, Amir E. Influence of non-measurable disease on progression-free survival in patients with metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-17-02.

Molecular Imaging in Drug Discovery and Development.

Noninvasive imaging has played an increasing role in the process of cardiovascular drug development. This review focuses specifically on the use of molecular imaging, which has been increasingly applied to improve and accelerate certain preclinical steps in drug development, including the identification of appropriate therapeutic targets, evaluation of on-target and off-target effects of candidate therapies, assessment of dose response, and the evaluation of drug or biological biodistribution and pharmacodynamics. Unlike the case in cancer medicine, in cardiovascular medicine, molecular imaging has not been used as a primary surrogate clinical end point for drug approval. However, molecular imaging has been applied in early clinical trials, particularly in phase 0 studies, to demonstrate proof-of-concept or to explain variation in treatment effect. Many of these applications where molecular imaging has been used in drug development have involved the retasking of technologies that were originally intended as clinical diagnostics. With greater experience and recognition of the rich information provided by in vivo molecular imaging, it is anticipated that it will increasingly be used to address the enormous time and costs associated with bringing a new drug to clinical launch.

Outcomes of the Latarjet Procedure Compared With Bankart Repair for Recurrent Traumatic Anterior Shoulder Instability.

Are clinical and patient-reported outcomes different between the Latarjet and Bankart repair stabilization procedures when performed for recurrent traumatic anterior shoulder instability? Ovid MEDLINE, PubMed, Cochrane databases, American College of Physicians Journal Club, and Database of Abstracts of Review of Effectiveness were searched up to June 2015. The search terms used were Bankart AND Latarjet OR Bristow. Criteria used to include studies that (1) were written in English; (2) compared the outcomes of any Latarjet procedure (Bristow-Latarjet, coracoid transfer, or modified Bristow) with Bankart repair (anatomic); (3) reported a minimum of 1 outcome of recurrence, redislocation, revision, or patient-reported outcome measure; and (4) reported original data. Data presented in any format (text, table, figure) were extracted from all included studies. The quality of each study was assessed using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist. Summary statistics were reported as relative risks and weighted mean differences. Fixed-effects (the assumed treatment effect was the same across studies) and random-effects (variations in treatment effect were assumed among studies) models were tested. Heterogeneity between trials was assessed using the χ2 statistic, and the amount (percentage) of variation across studies due to heterogeneity was calculated using the I 2 statistic. Forest plots were used to present pooled results. After the initial search, 245 articles were identified. After we applied the inclusion criteria, a total of 8 studies reporting on 795 patients (Latarjet = 379, Bankart = 416) were included in this review. Using the National Health and Medical Research Council's level of evidence, the authors scored 7 of the studies at level III and 1 study at level II. All Latarjet procedures were performed using an open technique, whereas the Bankart procedure was performed open in 6 studies and arthroscopically in 2 studies. The demographics of the patients (age, proportion of males to females, proportion with surgery on the dominant side, and proportion of revisions) were similar between the 2 surgical procedures. Four groups reported that patients who underwent the Latarjet procedure had fewer recurrences than patients in the Bankart repair group (11.6% versus 21.1%, respectively), irrespective of whether the Bankart was performed open or arthroscopically. Similarly, 4 groups observed that the Latarjet procedure resulted in fewer postsurgical redislocations (5.0%) than the Bankart (9.5%) procedure, irrespective of whether the repair was open or arthroscopic. The authors of 7 studies noted no differences between the 2 procedures in revision rates (Latarjet: 3.4%, Bankart: 4.5%), and 8 studies demonstrated no differences in complications requiring reoperation (Latarjet: 5.0%, Bankart: 3.1%). Investigators in 7 studies used the Rowe score to measure patient-reported satisfaction and function; patients who underwent the Latarjet procedure reported better Rowe scores postsurgically than patients who underwent the Bankart repair (scores: 79.0 and 85.4, respectively). Researchers in 4 studies reported a loss of external-rotation range of motion, which was less in the Latarjet (11.5°) compared with the Bankart (20.9°) procedure. Of the 5 groups that reported return to function, a trend suggested that a greater proportion of patients who underwent the Latarjet procedure returned to work, sport, and throwing activities compared with those who underwent the Bankart repair. The Latarjet procedure produced fewer recurrences, better patient-reported outcomes, and less restricted external-rotation motion than the Bankart repair.

Editors’ Introduction: Theme Issue on Variation in Treatment Effects

Editors’ Introduction: Theme Issue on Variation in Treatment Effects

Blood Pressure Response to Main Renal Artery and Combined Main Renal Artery Plus Branch Renal Denervation in Patients With Resistant Hypertension.

BackgroundSingle‐electrode ablation of the main renal artery for renal sympathetic denervation showed mixed blood pressure (BP)‐lowering effects. Further improvement of the technique seems crucial to optimize effectiveness of the procedure. Because sympathetic nerve fibers are closer to the lumen in the distal part of the renal artery, treatment of the distal main artery and its branches has been shown to reduce variability in treatment effects in preclinical studies and a recent randomized trial. Whether this optimized technique improves clinical outcomes remains uncertain. We report a 2‐center experience of main renal artery and combined main renal artery plus branches renal denervation in patients with resistant hypertension using a multielectrode catheter.Methods and ResultsTwenty‐five patients with therapy‐resistant hypertension underwent renal sympathetic denervation with combined main renal artery and renal branch ablation and were compared to matched controls undergoing an ablation of the main renal artery only. BP change was assessed by ambulatory measurement at baseline and after 3 months. At baseline, BP was balanced between the groups. After 3 months, BP changed significantly in the combined ablation group (systolic/diastolic 24‐hour mean and daytime mean BP −8.5±9.8/−7.0±10.7 and −9.4±9.8/−7.1±13.5 mm Hg, P<0.001/0.003 and <0.001/0.016, respectively), but not in patients with main artery treatment (−3.5±11.1/−2.0±7.6 and −2.8±10.9/−1.8±7.7 mm Hg, P=0.19/0.20 and 0.19/0.24, respectively). Systolic daytime BP was significantly more reduced in patients with combined ablation than in patients with main artery ablation (P=0.033).ConclusionsCombined ablation of the main renal artery and branches appears to improve BP‐lowering efficacy and should be further investigated.