Long-term Endpoints Research Articles

Optimal Designs With Interim Analyses for Randomized Studies With Long-Term Time-Specific Endpoints

With the advent of novel cancer therapies targeting molecular pathways or the immune system, time-to-event variables evaluated at longer times (e.g., 6 or 12 months) are increasingly used as the primary endpoint in randomized Phase II trials. Two-stage “Simon” designs have often been used in single-group phase II oncology trials to reduce the expected sample size under the null hypothesis. We develop optimal two-stage and three-stage randomized two-group designs with analogous optimality criteria. Accurate implementation of the Simon design can be difficult, and the difficulty increases with a longer-term endpoint, because it requires complete information from each accrued patient. Earlier work of Case and Morgan generalized the Simon design so it can be implemented without an accrual pause. We derive optimal designs that allow a brief preplanned pause (⩾ 0) in accrual before interim analyses to more efficiently use data from the accrued patients, and to allow focused data collection before the interim analyses. We provide software (R package OptInterim) that creates the optimal designs and also simulates their properties to check asymptotic approximations and the robustness of the designs to differing conditions. Various design options are illustrated using an example based on a recent colorectal cancer drug trial.

Use of Bayesian Multivariate Meta-Analysis to Estimate the HAQ for Mapping Onto the EQ-5D Questionnaire in Rheumatoid Arthritis

BackgroundIn health technology assessment, decisions about reimbursement for new health technologies are largely based on effectiveness estimates. Sometimes, however, the target effectiveness estimates are not readily available. This may be because many alternative instruments measuring these outcomes are being used (and not all always reported) or an extended follow-up time of clinical trials is needed to evaluate long-term end points, leading to the limited data on the target clinical outcome. In the areas of highest priority in health care, decisions are required to be made on a short time scale. Therefore, alternative clinical outcomes, including surrogate end points, are increasingly being considered for use in evidence synthesis as part of economic evaluation. ObjectiveTo illustrate the potential effect of reduced uncertainty around the clinical outcome on the utility when estimating it from a multivariate meta-analysis. MethodsBayesian multivariate meta-analysis has been used to synthesize data on correlated outcomes in rheumatoid arthritis and to incorporate external data in the model in the form of informative prior distributions. Estimates of Health Assessment Questionnaire were then mapped onto the health-related quality-of-life measure EuroQol five-dimensional questionnaire, and the effect was compared with mapping the Health Assessment Questionnaire obtained from the univariate approach. ResultsThe use of multivariate meta-analysis can lead to reduced uncertainty around the effectiveness parameter and ultimately uncertainty around the utility. ConclusionsBy allowing all the relevant data to be incorporated in estimating clinical effectiveness outcomes, multivariate meta-analysis can improve the estimation of health utilities estimated through mapping methods. While reduced uncertainty may have an effect on decisions based on economic evaluation of new health technologies, the use of short-term surrogate end points can allow for early decisions. More research is needed to determine the circumstances under which uncertainty is reduced.

Abstract 278: Sodium Nitroprusside Combined With Epinephrine for Prolonged Ventricular Fibrillation Cardiac Arrest

Background: A new approach to resuscitation using the potent vasodilator sodium nitroprusside (SNP) combined with mechanical efforts to maintain both coronary and cerebral perfusion pressures (active compression/decompression CPR combined with an impedance threshold device and abdominal binding) has reported improved survival with good neurological function. We hypothesized that a potent vasoconstricting agent like epinephrine (E) might replace the multiple mechanical components of this approach without compromising outcomes. Methods: We studied a total of 24 swine (25±5 kg) utilizing a 10-min period of untreated ventricular fibrillation. This was followed by 2-min of chest compressions and then an attempted defibrillation. The 2-min compression and subsequent defibrillation effort was repeated. Next another 2-min of chest compressions, during which both medications were administered, followed by attempted defibrillation. This first drug administration period occurred at 14 min 20 seconds after the onset of cardiac arrest. A total of five such 2-min of chest compressions followed by drug administration were performed if needed for ROSC. Animals were randomized to receive either SNP/E or placebo. Doses included 0.5 mg of SNP every 2 min for a maximum dose of 2.5 mg over 15 min and 1.3 mg of E every 2 min for a maximum dose of 6.75 mg. The primary endpoint was normal neurological function (CPC =1) at 24 hours. Statistical analysis utilized Fisher’s Exact testing. Results: Three subjects were successfully resuscitated prior to receiving any medications and were eliminated from this comparison. A total of 7/9 SNP/E animals were resuscitated in contrast to 6/13 animal receiving placebo (p=0.2). At 24 hours a CPC score of 1 was seen in 1/7 SNP/E animals compared to 5/6 placebo animals (p=0.03). Conclusion: Sodium nitroprusside combined with epinephrine failed to improve 24-hour neurological function in this protocol designed to mimic the late administration of medications during ACLS resuscitation. Epinephrine was unable to successfully replace the previously reported mechanical components of sodium nitroprusside-enhanced CPR (SNPeCPR). The propensity for epinephrine to increase ROSC, but not longer-term endpoints, remains a concern.

Similar Incidence Of Febrile Neutropenia With Same-Day Versus Subsequent Day G-CSF Administration In Non-Hodgkin Lymphoma Patients Receiving R-CHOP Chemotherapy

▪ BackgroundThe chemotherapy regimen of Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) every 21 days remains a standard first line treatment for many subtypes of B-cell non-Hodgkin lymphoma (NHL). R-CHOP chemotherapy carries a significant risk of febrile neutropenia (FN). FN is a potentially life threatening complication which typically requires hospital admission and empiric administration of broad spectrum antibiotics. FN can also cause delays and dose reductions with treatment, which are associated with poorer outcomes. Granulocyte colony stimulating factors (G-CSF) are indicated for primary prophylaxis with high risk patients to ameliorate this serious complication of treatment. Prescribing guidelines recommend that G-CSF's not be given until 24 hours after receiving chemotherapy. However, due to logistical issues of outpatient insurance coverage, travel, and patient convenience, it is not always practical to delay G-CSF administration until the day after chemotherapy. Therefore, some patients at our institution received G-CSF on the same day as chemotherapy. Patients and MethodsWe identified 113 lymphoma patients treated with R-CHOP who also received G-CSF primary prophylaxis at our institution from 6/21/04-1/12/12. G-CSF primary prophylaxis with daily filgrastim or a single dose of pegfilgrastim was administered within the first six days of starting R-CHOP, categorized as either same day (D1) or later (D2+). We retrospectively analyzed FN incidence and associated outcomes in patients receiving growth factor as primary prophylaxis administered the same day compared with >24 hours after chemotherapy. FN was estimated using the cumulative incidence method and compared between groups with the Pepe-Mori test. Cox analysis was used to identify prognostic factors for survival and relapse-free survival. ResultsIn our study, 113 patients received R-CHOP and G-CSF as primary prophylaxis (31 D1, 82 D2+). FN occurred in 8 out of 31 D1 patients (25.8%), and in 21 out of 82 patients in the D2+ group (25.6%). FN incidence did not differ between the two groups (P=0.91). No significant differences in relapse-free or overall survival were observed. Risk factors associated with mortality in multivariable analysis included development of FN (hazard ratio 4.33, 95% CI 1.88-10.0, P<0.001) and receiving R-CHOP while hospitalized as an inpatient (hazard ratio 7.16, 95% CI 3.08-16.6, P<0.001). ConclusionsAmong patients receiving G-CSF as primary prophylaxis with R-CHOP, we observed no difference in FN between G-CSF administered the same day and D2+. Not surprisingly, the development of FN and receiving R-CHOP while hospitalized, were both found to be significant risk factors associated with mortality. Previous prospective studies showed more severe and prolonged level of neutropenia, with higher rates of FN with same day versus next day administration in a small cohort of R-CHOP treated NHL patients (Burris et al, 2010). In our retrospective study, we were not able to evaluate neutrophil levels at multiple time points throughout each cycle, and longer follow-up is necessary to evaluate other long-term endpoints of potential interest, such as the incidence of secondary myeloid malignancies after same-day versus next-day G-CSF treatment. For patients who require G-CSF support, next day administration remains the recommended schedule. However, same day administration may be a reasonable alternative if access to care and patient compliance are concerns. Disclosures:Hill:Celgene: Honoraria, Research Funding.

Peroral endoscopic myotomy for achalasia

Treatment of achalasia is complicated by symptom recurrence and a significant risk for severe complications. Endoscopic myotomy was developed in the search for a highly efficacious treatment with lower risks. Since its introduction in 2010, several centers have adopted the technique and published excellent short-term results of open label series. Randomized trials with long-term endpoint comparing per-oral endoscopic myotomy (POEM) with the established treatments such as balloon dilation and surgical myotomy are now warranted, before POEM can be regarded as the routine clinical care for achalasia patients. This review describes the development, technical aspects, efficacy, and complications of POEM.

Adjusting overall survival for treatment switches: commonly used methods and practical application

In parallel group trials, long-term efficacy endpoints may be affected if some patients switch or cross over to the alternative treatment arm prior to the event. In oncology trials, switch to the experimental treatment can occur in the control arm following disease progression and potentially impact overall survival. It may be a clinically relevant question to estimate the efficacy that would have been observed if no patients had switched, for example, to estimate 'real-life' clinical effectiveness for a health technology assessment. Several commonly used statistical methods are available that try to adjust time-to-event data to account for treatment switching, ranging from naive exclusion and censoring approaches to more complex inverse probability of censoring weighting and rank-preserving structural failure time models. These are described, along with their key assumptions, strengths, and limitations. Best practice guidance is provided for both trial design and analysis when switching is anticipated. Available statistical software is summarized, and examples are provided of the application of these methods in health technology assessments of oncology trials. Key considerations include having a clearly articulated rationale and research question and a well-designed trial with sufficient good quality data collection to enable robust statistical analysis. No analysis method is universally suitable in all situations, and each makes strong untestable assumptions. There is a need for further research into new or improved techniques. This information should aid statisticians and their colleagues to improve the design and analysis of clinical trials where treatment switch is anticipated.

Intensity-modulated adjuvant whole breast radiation delivered with static angle tomotherapy (TomoDirect): a prospective case series

To report the 2-year outcomes of whole breast intensity-modulated radiotherapy (IMRT) after conserving surgery for early breast cancer (EBC) delivered with static angle tomotherapy (TomoDirect) (TD). A prospective cohort of 120 EBC patients underwent whole breast IMRT with TD between 2010 and 2012. Radiation was delivered to a conventionally fractionated whole breast total dose of 50 Gy with TD, followed by a sequential conventionally fractionated tumor bed boost dose of 10-16 Gy with helical tomotherapy (HT). Clinical endpoints include acute and late toxicity, cosmesis, quality of life and local control. Median follow-up was 24 months (range 12-36 months); maximum detected acute skin toxicity was G0 22 %; G1 63 %; G2 12 % and G3 3 %. Predictors of acute dermatitis were as follows: volume of the whole breast minus boost volume receiving 105, 110 and 115 % of prescription dose, whole breast and boost volume, breast thickness and soft tissue thickness. Late skin toxicity was mild with no >G2 events. Cosmesis was good/excellent in 91.7 % of patients and fair/poor in 8.3 %. Quality of life was preserved over time, but for fatigue, transiently increased. Adjuvant whole breast IMRT delivered sequentially with both TD and HT provides consistent clinical results. An observed unintended excessive dose outside the tumor bed might increase acute toxicity and eventually affect long-term clinical endpoints. The incorporation of the boost dose within the whole breast phase employing a simultaneous integrated boost (SIB) approach might mitigate this issue.

Carotid Revascularization: A Systematic Review of the Evidence

The aim of this study is to provide an evidence-based review of the periprocedural safety and long-term effectiveness of carotid artery stenting (CAS) compared to carotid endarterectomy (CEA), with particular attention paid to the use of embolic protection devices and patients at high risk for CEA. Electronic databases (Ovid Medline, Cochrane central register of controlled trials, Pubmed, and Embase) were searched to identify: (1) randomized controlled trials (RCT) comparing outcomes of CEA and CAS, and (2) prospective clinical trials assessing the safety of CAS in patients at high surgical risk. Pooled incidence rates and one-sided 95% confidence interval for the periprocedural and long-term composite end-point of stroke, myocardial infarction, or death among high surgical risk patients were generated and compared to objective performance criteria (OPC) reported by previous trials. Six RCTs and 14 prospective clinical trials met our search criteria. Selected RCTs showed inconsistency in reported periprocedural and long-term outcome rates. Pooled incidence rates of the periprocedural and long-term composite end-point of stroke, myocardial infarction or death in high surgical risk candidates were 5.59% and 7.92%, respectively. These results were noninferior to selected OPCs (P-value <0.001). CAS represents a safe and effective stroke prevention strategy in high surgical risk patients when compared with CEA. The inconsistent results from the RCTs and the improved outcomes in the prospective clinical trials are likely related to variability in operator experience, use of embolic protection devices, and patient selection strategies.

Is Stenting as “a Bridge to Surgery” an Oncologically Safe Strategy for the Management of Acute, Left-Sided, Malignant, Colonic Obstruction? A Comparative Study With a Propensity Score Analysis

Self-expanding metallic stent (SEMS) insertion has been suggested as a promising alternative to emergency surgery for left-sided malignant colonic obstruction (LMCO). However, the literature on the long-term impact of SEMS as "a bridge to surgery" is limited and contradictory. From January 1998 to June 2011, we retrospectively identified patients operated on for LMCO with curative intent. The primary outcome criterion was overall survival. Short-term secondary endpoints included the technical success rate and overall success rate and long-term secondary endpoints included 5-year overall survival, 5-year cancer-specific mortality, 5-year disease-free survival, the recurrence rate, and mean time to recurrence. Patients treated with SEMS were analyzed on an intention-to-treat basis. Overall survival was analyzed after using a propensity score to correct for selection bias. There were 48 patients in the SEMS group and 39 in the surgery-only group. In the overall population, overall survival (P = 0.001) and 5-year overall survival (P = 0.0003) were significantly lower in the SEMS group than in the surgery-only group, and 5-year cancer-specific mortality was significantly higher in the SEMS group (48% vs 21%, respectively (P = 0.02)). Five-year disease-free survival, the recurrence rate, and the mean time to recurrence were better in the surgery-only group (not significant). For patients with no metastases or perforations at hospital admission, overall survival (P = 0.003) and 5-year overall survival (30% vs 67%, respectively, P = 0.001) were significantly lower in the SEMS group than in the surgery-only group. Our study results suggest worse overall survival of patients with LMCO with SEMS insertion compared with immediate surgery.

Patient preference for involvement, experienced involvement, decisional conflict, and satisfaction with physician: a structural equation model test

BackgroundA comprehensive model of the relationships among different shared decision-making related constructs and their effects on patient-relevant outcomes is largely missing. Objective of our study was the development of a model linking decision-making in medical encounters to an intermediate and a long-term endpoint. The following hypotheses were tested: physicians are more likely to involve patients who have a preference for participation and are willing to take responsibility in the medical decision-making process, increased patient involvement decreases decisional conflict, and lower decisional conflict favourably influences patient satisfaction with the physician.MethodsThis model was tested in a German primary care sample (N = 1,913). Psychometrically tested instruments were administered to assess the following: patients’ preference for being involved in medical decision-making, patients’ experienced involvement in medical decision-making, decisional conflict, and satisfaction with the primary care provider. Structural equation modelling was used to explore multiple associations. The model was tested and adjusted in a development sub-sample and cross-validated in a confirmatory sample. Demographic and clinical characteristics were accounted for as possible confounders.ResultsLocal and global indexes suggested an acceptable fit between the theoretical model and the data. Increased patient involvement was strongly associated with decreased decisional conflict (standardised regression coefficient Β = −.73). Both high experienced involvement (Β = .34) and low decisional conflict (B = -.28) predicted higher satisfaction with the physician. Patients’ preference for involvement was negatively associated with the experienced involvement (B = −.24).ConclusionAltogether, our model could be largely corroborated by the collected empirical data except the unexpected negative association between preference for involvement and experienced involvement. Future research on the associations among different SDM-related constructs should incorporate longitudinal studies in order to strengthen the hypothesis of causal associations.

Determinants of Mortality After Hospital Discharge in ICU Patients

First, to conduct a literature review on the long-term mortality of ICU patients and its determinants. Second, to assess the influence of the found determinants at 3, 6, and 12 months mortality after hospital discharge in the Dutch ICU population. Combination of a literature review to evaluate determinants of long-term mortality and a Dutch cohort study in which the found determinants are applied. PubMed and EMBASE were searched on English written articles published between 1966 and 2011. The cohort study was conducted in ICU patients from 81 Dutch mixed ICUs. A total of 24 articles with a main focus on describing or predicting the case-mix adjusted long-term mortality of the general ICU population were identified. The cohort study consisted of 48,107 ICU patients who were discharged alive from the hospital between January 1, 2007, and October 1, 2010. None. The included articles are summarized on patient and study characteristics, methods, results, and determinants used for case-mix adjustment. Additionally, the quality of the included articles was assessed using a checklist for studies on long-term survival. The median mortality rate of the general ICU population 1 year after ICU admission was 24% (range 16% to 44%). The determinants used for case-mix adjustment differed widely between the studies. In the cohort study, we found that age, reason for ICU admission, and comorbidities were associated with all long-term mortality endpoints. However, the magnitude and direction of the influence by these determinants differed for the different endpoints (i.e., 3, 6, and 12 mo after hospital discharge). The long-term mortality found in the included articles was difficult to compare due to low quality, variation in case-mix, study design, and differences in case-mix adjustment. The most commonly used determinants in the literature were comparable to the most important determinants found in the Dutch cohort study.

ASSA13-13-1 Long-Term Results with Coenzyme Q10 as Adjunctive Therapy in Chronic Heart Failure

<h3>Objective</h3> Dysfunction of bioenergetics and energy starvation of the myocardium may be a dominant feature of heart failure and attention has been directed towards agents which may stabilise myocardial metabolism and maintain adequate energy stores. The myocardial tissue level of the essential redox component of the respiratory chain Coenzyme Q10 (CoQ10) has been found inversely related to the severity of heart failure. We investigated in a double-blind trial the effects of CoQ10 on patients symptoms, functional capacity and biomarker status (NT-proBNP) and the long-term outcome with morbidity and mortality. <h3>Methods</h3> Patients in New York Heart Association Class III or IV heart failure who were receiving current pharmacologic therapy were randomly assigned in parallel groups to either CoQ10 100 mg three times daily versus placebo. The primary long-term endpoint was the time to first MACE (major adverse cardiovascular event) including unplanned hospitalisation due to worsening of heart failure, cardiovascular death, urgent cardiac transplantation and mechanical support, using a time to first event analysis. <h3>Results</h3> A total of 420 patients – CoQ10 (N = 202), placebo (N = 218) - from 17 international centres were enrolled with a follow-up time of 2 years. The two groups were similar with respect to a range of baseline characteristics. After 3 months there was a trend with reduced NT-proBNP in the CoQ10 group. After 2 years there was a significant improvement of NYHA Class in the CoQ10 group (p = 0.047). The primary endpoint was reached by 29 patients in the CoQ10 group, as compared with 55 patients in the placebo group (14 percent vs. 25 percent; hazard ratio CoQ10 vs. placebo: 2.0 (95% CI: 1.3–3.2); P = 0.003) by intention to treat analysis. CoQ10 treated patients had significant lower cardiovascular mortality (p = 0.02) and lower occurrence of hospitalizations for heart failure (p = 0.05). All cause mortality was also lower in the CoQ10 group, 18 patients vs. 36 patients in the placebo-group (9 percent vs. 17 percent; hazard ratio CoQ10 vs. placebo: 2.1 (95% CI: 1.2–3.8); p = 0.01). There were fewer adverse events in the CoQ10 group compared to the placebo group (p = 0.073). <h3>Conclusions</h3> Q-SYMBIO is the first double-blind clinical trial in chronic heart failure addressing whether CoQ10 supplementation might improve survival. The CoQ10 treated patients had reduced hospital admission rates for worsening heart failure and lower cardiovascular death both of which may reflect a significant improvement in cardiac function. CoQ10 treatment was safe with a reduced all cause mortality rate. CoQ10 supplementation should be considered as a part of the maintenance therapy of patients with chronic heart failure.

Estimating the effect of sulfonylurea on HbA1c in diabetes: a systematic review and meta-analysis

Aims/hypothesisSulfonylureas are widely prescribed glucose-lowering medications for diabetes, but the extent to which they improve glycaemia is poorly documented. This systematic review evaluates how sulfonylurea treatment affects glycaemic control.MethodsMedline, EMBASE, the Cochrane Library and clinical trials registries were searched to identify double-blinded randomised controlled trials of fixed-dose sulfonylurea monotherapy or sulfonylurea added on to other glucose-lowering treatments. The primary outcome assessed was change in HbA1c, and secondary outcomes were adverse events, insulin dose and change in body weight.ResultsThirty-one trials with a median duration of 16 weeks were included in the meta-analysis. Sulfonylurea monotherapy (nine trials) lowered HbA1c by 1.51% (17 mmol/mol) more than placebo (95% CI, 1.25, 1.78). Sulfonylureas added to oral diabetes treatment (four trials) lowered HbA1c by 1.62% (18 mmol/mol; 95% CI 1.0, 2.24) compared with the other treatment, and sulfonylurea added to insulin (17 trials) lowered HbA1c by 0.46% (6 mmol/mol; 95% CI 0.24, 0.69) and lowered insulin dose. Higher sulfonylurea doses did not reduce HbA1c more than lower doses. Sulfonylurea treatment resulted in more hypoglycaemic events (RR 2.41, 95% CI 1.41, 4.10) but did not significantly affect the number of other adverse events. Trial length, sulfonylurea type and duration of diabetes contributed to heterogeneity.Conclusions/interpretationSulfonylurea monotherapy lowered HbA1c level more than previously reported, and we found no evidence that increasing sulfonylurea doses resulted in lower HbA1c. HbA1c is a surrogate endpoint, and we were unable to examine long-term endpoints in these predominately short-term trials, but sulfonylureas appear to be associated with an increased risk of hypoglycaemic events.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-013-2856-6) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Long-Term Clinical Outcome of Women with Stage I-II Endometrial Adenocarcinoma after Adjuvant Intravaginal High-Dose-Rate Brachytherapy Alone

Vaginal cuff brachytherapy is proven to be an effective and well tolerated adjuvant radiation treatment modality after hysterectomy in women with early stage endometrial carcinoma. However, there remains paucity of data in regards to long-term clinical outcome endpoints. In this IRB-approved retrospective study, 141 women with 2009 FIGO stage I-II endometrial adenocarcinoma were identified. All patients underwent hysterectomy followed by adjuvant intravaginal HDR brachytherapy. Various prognostic factors were analyzed using Cox proportional hazards regression. All patients underwent hysterectomy between 1990 and 2010 with at least one year followup after hysterectomy. Median followup was 48 months (range 13-245). Median age at diagnosis for the study cohort was 62 years (range of 39 to 91). Ninety-six patients (68.1%), 38 patients (27%), and 7 patients (5%) had stages IA, IB, and II endometrial adenocarcinoma, respectively. One hundred twenty-six patients (89.4%) had endometrioid carcinoma. The median number of lymph nodes sampled was 10 (range of 5-68). Peritoneal cytology was negative for malignant cells in all patients. All patients received adjuvant high-dose-rate vaginal brachytherapy through single channel vaginal cylinder. Median brachytherapy surface dose was 37.5 Gy in 5 fractions to the upper 3-4 cm of the vagina. Thirteen patients (9.2%) had adjuvant platinum-based chemotherapy. None of the patients reported more than grade 1 vaginal toxicity according to common toxicities criteria version 3.0. Only 6 patients (4.3%) were diagnosed with tumor recurrence including only one patient with an isolated vaginal recurrence. Five-year relapse-free, disease-specific, and overall survival rates were 93.2%, 96.3% and 89%, respectively. Due to small number of recurrences and based on exploratory analysis, there were no significant predictors of relapse-free or disease-specific survival. As expected, age as a continuous variable was the only variable that was a significant predictor of overall survival (p<0.001). Our results suggest that vaginal cuff brachytherapy alone provides excellent long-term control in patients with early stage endometrial carcinoma after surgical staging. The treatment is very well tolerated with minimal patient-reported side effects.

Verbal short-term memory development and spoken language outcomes in deaf children with cochlear implants.

Cochlear implants (CIs) help many deaf children achieve near-normal speech and language (S/L) milestones. Nevertheless, high levels of unexplained variability in S/L outcomes are limiting factors in improving the effectiveness of CIs in deaf children. The objective of this study was to longitudinally assess the role of verbal short-term memory (STM) and working memory (WM) capacity as a progress-limiting source of variability in S/L outcomes after CI in children. Longitudinal study of 66 children with CIs for prelingual severe-to-profound hearing loss. Outcome measures included performance on digit span forward (DSF), digit span backward (DSB), and four conventional S/L measures that examined spoken-word recognition (Phonetically Balanced Kindergarten word test), receptive vocabulary (Peabody Picture Vocabulary Test ), sentence-recognition skills (Hearing in Noise Test), and receptive and expressive language functioning (Clinical Evaluation of Language Fundamentals Fourth Edition Core Language Score; CELF). Growth curves for DSF and DSB in the CI sample over time were comparable in slope, but consistently lagged in magnitude relative to norms for normal-hearing peers of the same age. For DSF and DSB, 50.5% and 44.0%, respectively, of the CI sample scored more than 1 SD below the normative mean for raw scores across all ages. The first (baseline) DSF score significantly predicted all endpoint scores for the four S/L measures, and DSF slope (growth) over time predicted CELF scores. DSF baseline and slope accounted for an additional 13 to 31% of variance in S/L scores after controlling for conventional predictor variables such as: chronological age at time of testing, age at time of implantation, communication mode (auditory-oral communication versus total communication), and maternal education. Only DSB baseline scores predicted endpoint language scores on Peabody Picture Vocabulary Test and CELF. DSB slopes were not significantly related to any endpoint S/L measures. DSB baseline scores and slopes taken together accounted for an additional 4 to 19% of variance in S/L endpoint measures after controlling for the conventional predictor variables. Verbal STM/WM scores, process measures of information capacity, develop at an average rate in the years after cochlear implantation, but were found to consistently lag in absolute magnitude behind those reported for normal-hearing peers. Baseline verbal STM/WM predicted long-term endpoint S/L outcomes, but verbal STM slopes predicted only endpoint language outcomes. Verbal STM/WM processing skills reflect important underlying core elementary neurocognitive functions and represent potential intervention targets for improving endpoint S/L outcomes in pediatric CI users.

Telomere length in patients with systemic lupus erythematosus and its associations with carotid plaque

To evaluate telomere length (TL) between patients with SLE and healthy controls and to test if TL is associated with carotid plaque. A pilot study of 154 patients with SLE and 152 controls was performed from the SOLVABLE (Study of Lupus Vascular and Bone Long-Term Endpoints) cohort. Demographic and cardiovascular disease (CVD) factors were collected at baseline. The presence or absence of plaque was evaluated by B-mode US. Genomic DNA was isolated from whole peripheral blood. TL was quantified using real-time quantitative PCR. SLE women had a short TL compared with healthy controls (4.57 vs 5.44 kb, P = 0.03). SLE women showed shorter TL than controls across all age groups: <35 years (4.38 vs 6.37 kb), 35-44 years (4.52 vs 5.30 kb), 45-54 years (4.77 vs 5.68 kb) and ≥55 years (4.60 vs 4.71 kb). Among patients with SLE and carotid plaque there was a trend towards shorter TL at a younger age and it was significantly lower in the 35- to 44-year age group when compared with controls (P = 0.025). Multiple logistic regression analysis indicated a risk of carotid plaque with older age [odds ratio (OR) 1.09; 95% CI 1.06, 1.12] but not with TL (OR 1.05; 95% CI 0.97, 1.13). SLE women had significantly shorter TL than controls. SLE women trended towards shorter TL at a younger age. When carotid plaque was identified, the younger SLE women had shorter TL. Only older age but not shorter TL was independently associated with carotid plaque. Additional studies are needed to confirm if TL is a novel biomarker for cardiovascular disease in SLE.

Effect of coenzyme Q10 in Europeans with chronic heart failure: A sub-group analysis of the Q-SYMBIO randomized double-blind trial.

Geographical differences in patient characteristics, management and outcomes in heart failure (HF) trials are well recognized. The aim of this study was to assess the consistency of the treat- ment effect of coenzyme Q10 (CoQ10) in the European sub-population of Q-SYMBIO, a randomized double-blind multinational trial of treatment with CoQ10, in addition to standard therapy in chronic HF. Patients with moderate to severe HF were randomized to CoQ10 300 mg daily or placebo in addition to standard therapy. At 3 months the primary short-term endpoints were changes in New York Heart Association (NYHA) functional classification, 6-min walk test, and levels of N-terminal pro-B type natriuretic peptide. At 2 years the primary long-term endpoint was major adverse cardiovascular events (MACE). There were no significant changes in short-term endpoints. The primary long-term endpoint of MACE was reached by significantly fewer patients in the CoQ10 group (n = 10, 9%) compared to the placebo group (n = 33, 27%, p = 0.001). The following secondary endpoints were significantly improved in the CoQ10 group compared with the placebo group: all-cause and cardiovascular mortality, NYHA classification and left ventricular ejection fraction (LVEF). In the European sub-population, when compared to the whole group, there was greater adherence to guideline directed therapy and similar results for short- and long-term endpoints. A new finding revealed a significant improvement in LVEF. The therapeutic efficacy of CoQ10 demonstrated in the Q-SYMBIO study was confirmed in the European sub-population in terms of safely reducing MACE, all-cause mortality, cardiovascular mortality, hospitalization and improvement of symptoms.

Group Sequential Tests for Delayed Responses (with discussion)

SummaryGroup sequential methods are used routinely to monitor clinical trials and to provide early stopping when there is evidence of a treatment effect, a lack of an effect or concerns about patient safety. In many studies, the response of clinical interest is measured some time after the start of treatment and there are subjects at each interim analysis who have been treated but are yet to respond. We formulate a new form of group sequential test which gives a proper treatment of these ‘pipeline’ subjects; these tests can be applied even when the continued accrual of data after the decision to stop the trial is unexpected. We illustrate our methods through a series of examples. We define error spending versions of these new designs which handle unpredictable group sizes and provide an information monitoring framework that can accommodate nuisance parameters, such as an unknown response variance. By studying optimal versions of our new designs, we show how the benefits of lower expected sample size that are normally achieved by a group sequential test are reduced when there is a delay in response. The loss of efficiency for larger delays can be ameliorated by incorporating data on a correlated short-term end point, fitting a joint model for the two end points but still making inferences on the original, longer-term end point. We derive p-values and confidence intervals on termination of our new tests.

Decision Analysis, Economic Evaluation, and Newborn Screening

Decision Analysis, Economic Evaluation, and Newborn Screening

Impact of different exercise training modalities on the coronary collateral circulation and plaque composition in patients with significant coronary artery disease (EXCITE trial): study protocol for a randomized controlled trial

BackgroundExercise training (ET) in addition to optimal medical therapy (OMT) in patients with stable coronary artery disease (CAD) has been demonstrated to be superior to percutaneous coronary interventions (PCI) with respect to the composite endpoint of death, myocardial infarction, stroke, revascularization and hospitalization due to worsening of angina. One mechanism leading to this superiority discussed in the literature is the increase in coronary collateral blood flow due to ET. Until now, data demonstrating the positive effect of ET on the collateral blood flow and the functional capacity of the coronary collateral circulation are still lacking.Methods/designThe EXCITE trial is a three-armed randomized, prospective, single-center, open-label, controlled study enrolling 60 patients with stable CAD and at least one significant coronary stenosis (fractional flow reserve ≤0.75). The study is designed to compare the influence and efficacy of two different 4-week ET programs [high-intensity interval trainings (IT) versus moderate-intensity exercise training (MT) in addition to OMT] versus OMT only on collateral blood flow (CBF). The primary efficacy endpoint is the change of the CBF of the target vessel after 4 weeks as assessed by coronary catheterization with a pressure wire during interruption of the antegrade flow of the target vessel by balloon occlusion. Secondary endpoints include the change in plaque composition as assessed by intravascular ultrasound (IVUS) after 4 weeks, myocardial perfusion as analyzed in MRI after 4 weeks and 12 months, peak oxygen uptake (V02 peak), change in endothelial function and biomarkers after 4 weeks, 3, 6 and 12 months. The safety endpoint addresses major adverse cardiovascular events (death from cardiovascular cause, myocardial infarction, stroke, TIA, target vessel revascularization or hospitalization) after 12 months.DiscussionThe trial investigates whether ET for 4 weeks increases the CBF in patients with significant CAD compared to a sedentary control group. It also examines the impact of two intensities of ET on the CBF as well as the histological plaque composition. The trial started recruitment in June 2009 and will complete recruitment until June 2012. First results are expected in December 2012 (4-week follow-up), final results (12-month long-term secondary endpoint) in December 2013.Trial registrationClinical trial registration information-URL: http://www.clinicaltrials.gov.Unique identifier: NCT01209637