Intensive Arm Research Articles

Effect of Intensive Blood Pressure Treatment on Heart Failure Events in the Systolic Blood Pressure Reduction Intervention Trial.

Acute decompensated heart failure (ADHF) was a frequent common outcome in SPRINT (Systolic Blood Pressure Intervention Trial). We examined whether there was differential reduction in ADHF events from intensive blood pressure [BP] treatment among the 6 key, prespecified subgroups in SPRINT: age ≥75 years, prior cardiovascular disease, chronic kidney disease, women, black race, and 3 levels of baseline systolic BP (≤132 versus >132 to <145 versus ≥145 mm Hg). ADHF was defined as hospitalization for ADHF, confirmed and formally adjudicated by a blinded events committee using standardized protocols. At 3.29 years follow-up, there were 103 ADHF events (2.2%) among 4683 standard arm participants and 65 ADHF events (1.4%) among 4678 intensive arm participants (Cox proportional hazards ratio, 0.63; 95% confidence interval, 0.46-0.85; P value =0.003). In multivariable analyses, including treatment arm, baseline covariates that were significant predictors for ADHF included chronic kidney disease, cardiovascular disease, age≥75 years, body mass index, and higher systolic BP. The beneficial effect of the intervention on incident ADHF was consistent across all prespecified subgroups. Participants who had incident ADHF had markedly increased risk of subsequent cardiovascular events, including a 27-fold increase (P<0.001) in cardiovascular death. Targeting a systolic BP<120 mm Hg, compared with <140 mm Hg, significantly reduced ADHF events, and the benefit was similar across all key, prespecified subgroups. Participants who developed ADHF had markedly increased risk for subsequent cardiovascular events and death, highlighting the importance of strategies aimed at prevention of ADHF, especially intensive BP reduction. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01206062.

Nonlinear mixed-effects model reveals a distinction between learning and performance in intensive reach training post-stroke

BackgroundWe recently showed that individuals with chronic stroke who completed two sessions of intensive unassisted arm reach training exhibited improvements in movement times up to one month post-training. Here, we study whether changes in movement times during training can predict long-term changes.MethodsSixteen participants with chronic stroke and ten non-disabled age-matched participants performed two sessions of reach training with 600 movements per session. Movement time data during training were fitted to a nonlinear mixed-effects model consisting of a decreasing exponential term to model improvements of performance due to learning and an increasing linear term to model worsening of performance due to activity-dependent fatigability and/or other factors unrelated to learning.ResultsFor non-disabled age-matched participants, movement times gradually decreased overall during training and overall changes in movement times during training predicted long-term changes. In contrast, for participants post-stroke, movement times often worsened near the end of training. As a result, overall changes in movement times during training did not predict long-term changes in movement times in the stroke group. However, improvements in movement times due to training, as estimated by the exponential term of the model, predicted long-term changes in movement times.ConclusionParticipants post-stroke showed a distinction between learning and performance in unassisted intensive arm reach training. Despite worsening of performance in later trials, extended training was beneficial for long-term gains.

Abstract P176: Impact of Serious Adverse Event Risks on the Cost-effectiveness of Intensive Blood Pressure Goals in Patients Aged ≥75 Years

Background: Compared to the overall Systolic Blood Pressure Intervention Trial (SPRINT) results, patients aged ≥75 years at baseline had a greater reduction in cardiovascular disease (CVD) events and all-cause mortality with an intensive systolic blood pressure (SBP) goal (&lt;120 mmHg) compared to a standard SBP goal (&lt;140 mmHg). Applying an intensive SBP goal in high-risk older patients represents a major shift in clinical practice and may increase concern for medication-related severe adverse events (SAEs). We hypothesized that the benefits of reduced CVD risk would outweigh the increased costs and SAE risk of intensive vs. standard SBP goals in SPRINT-eligible patients aged ≥75 years even when considering variable SAE risks. Methods: A microsimulation health-state transition model of 10,000 patients was created to estimate the CVD events, SAEs, quality-adjusted life years (QALYs), and direct healthcare costs of intensive vs. standard SBP goals. The model assumed patients were adherent to treatment during the median SPRINT follow-up, but that all patients would become non-adherent over 5 years. While adherent, CVD and SAE risks were derived from published SPRINT effect estimates for the ≥75 subgroup. Due to uncertainty in the SAE risk associated with intensive SBP goals in older adults, the intensive arm SAE risk was varied to determine the point at which treatment costs and harms outweighed CVD benefits at accepted willingness-to-pay thresholds. Healthcare costs and health state utilities were derived from national sources and other published estimates. Results: If SAE risk was equal to the observed rates in SPRINT, mean lifetime costs and QALYs were $268,000 and 7.85 for the intensive arm, and $262,000 and 7.60 for the standard arm. The resulting incremental cost-effectiveness ratio (ICER) was about $26,000 per QALY gained. However, as SAE risk in the intensive arm increased by 1.5, 2, and 2.5 times, the ICER increased to $33,000, $43,000, and $55,000 per QALY gained, respectively. Conclusion: Intensive SBP goals may be a cost-effective way to reduce CVD events and improve survival in patients aged ≥75 years, but safety and cost-effectiveness depend on medication-related SAE risk. However, these results are based on summary data and do not account for clustering of risks at the individual patient level. Thus, more precise prediction of risks and benefits is needed to guide selection of older patients for intensive SBP treatment goals.

Abstract P178: Cost-Effectiveness of Intensive versus Standard Blood Pressure Goals by Baseline Systolic Blood Pressure Levels in SPRINT-Eligible US Adults

Background: In high-risk adults, intensive systolic blood pressure (SBP) goals (&lt;120 mmHg) reduced cardiovascular disease (CVD) events and mortality, when compared to standard SBP goals (&lt;140 mmHg), in the Systolic Blood Pressure Intervention Trial (SPRINT). While average benefit of reduced CVD risk with intensive SBP goals outweighs the average risk of serious adverse events (SAEs) and treatment costs, net intensive SBP goal benefits may vary by baseline SBP. We hypothesized that intensive SBP goals would be cost-effective vs. standard SBP goals when stratified by baseline SBP level in SPRINT-eligible US adults from the payer’s perspective. Methods: Using CVD event, death, and SAE risks, a microsimulation model compared direct healthcare costs and quality-adjusted life-years (QALYs) in the SPRINT intensive and standard SBP goal arms over patients’ remaining lifetimes. Published literature and national estimates were used for model parameters. The model assumed that, after the planned duration of SPRINT, adherence to treatment goals decayed over time. To estimate the effect of baseline SBP on the cost-effectiveness of intensive SBP goals, baseline SBP was stratified into the following groups: 130-139 mmHg, 140-149 mmHg, 150-159 mmHg, 160-169 mmHg, and 170-180 mmHg. Results: With higher baseline SBP, patients in both arms experienced higher rates of CVD events or CVD deaths and accrued higher costs compared with patients starting with lower baseline SBP. However, with higher baseline SBP, there were slightly more incremental QALYs gained with intensive SBP treatment, from 0.29 to 0.31. This led to a modestly better incremental cost-effectiveness ratio (ICER) for intensive vs. standard SBP goals, decreasing from approximately $50,000 to $43,000 per QALY gained as baseline SBP increased. If SPRINT treatment effects and in-trial adherence persisted for the remaining lifetime, the ICER for intensive SBP goals decreased to approximately $25,000-$26,000 per QALY gained across baseline SBP groups. Conclusions: Treatment of all SPRINT-eligible patients led to lifetime cost-effectiveness below accepted willingness-to-pay thresholds and lifetime net benefit and cost-effectiveness varied only modestly by baseline SBP. However, this analysis was based on summary data and did not account for individual patient risks. Multiple predictors, in addition to baseline SBP, may be needed to identify which SPRINT-eligible patients derive maximal benefit from intensive SBP treatment.

Predictors and brain connectivity changes associated with arm motor function improvement from intensive practice in chronic stroke.

Background and Purpose: The brain changes that underlie therapy-induced improvement in motor function after stroke remain obscure. This study sought to demonstrate the feasibility and utility of measuring motor system physiology in a clinical trial of intensive upper extremity rehabilitation in chronic stroke-related hemiparesis. Methods: This was a substudy of two multi-center clinical trials of intensive robotic and intensive conventional therapy arm therapy in chronic, significantly hemiparetic, stroke patients. Transcranial magnetic stimulation was used to measure motor cortical output to the biceps and extensor digitorum communus muscles. Magnetic resonance imaging (MRI) was used to determine the cortical anatomy, as well as to measure fractional anisotropy, and blood oxygenation (BOLD) during an eyes-closed rest state. Region-of-interest time-series correlation analysis was performed on the BOLD signal to determine interregional connectivity. Functional status was measured with the upper extremity Fugl-Meyer and Wolf Motor Function Test. Results: Motor evoked potential (MEP) presence was associated with better functional outcomes, but the effect was not significant when considering baseline impairment. Affected side internal capsule fractional anisotropy was associated with better function at baseline. Affected side primary motor cortex (M1) activity became more correlated with other frontal motor regions after treatment. Resting state connectivity between affected hemisphere M1 and dorsal premotor area (PMAd) predicted recovery. Conclusions: Presence of motor evoked potentials in the affected motor cortex and its functional connectivity with PMAd may be useful in predicting recovery. Functional connectivity in the motor network shows a trends towards increasing after intensive robotic or non-robotic arm therapy. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00372411 \& NCT00333983.

Abstract P2-16-01: Relationship between overall survival and surrogate measures in patients with metastatic breast cancer treated with chemotherapy

Abstract Background: While metastatic breast cancer (MBC) is considered an incurable disease, nearly one-fifth of patients live longer than five years following diagnosis. In an effort to identify novel agents earlier, surrogate end points of overall survival (OS) such as response or progression are often employed in randomized controlled trials (RCTs). The goal of this analysis is to evaluate patterns of outcome reporting and the relationship of OS with surrogate measures in RCTs of patients with MBC. Methods: The analysis was based on data from a systematic review of patients with MBC evaluating the clinical impact of chemotherapy intensity on survival. Reports of phase 2-3 RCTs published between 1990-2013 comparing more intense chemotherapy regimens (higher dose intensity or use of additional agents) with less intense were identified. For each RCT, clinical, treatment, demographic and outcome data were extracted. Outcomes evaluated included OS, progression free survival (PFS), and time to progression (TTP) with a focus on median survival and hazard ratios (HRs) as measures of treatment effect. Survival post progression (SPP) was calculated as the difference between median survival and median progression free time. The relations between various outcome measures were estimated utilizing weighted Pearson correlation coefficient (CORR) adjusted by Fisher's transformation. Weights were assigned proportionally to the sample size of individual RCTs. Results: The review identified 70 eligible RCTs including 15,043 patients with MBC. Average median OS, PFS, and TTP were 19.2, 6.9, and 8.1 months reported in 96%, 60%, and 43% of studies, respectively. Progression could be determined in 66 studies, while 6 RCTs provided both outcomes. TTP was more often utilized in earlier studies (65% in 1990-2000, 35% in 2001-2008, and 33% in 2009-2013) and it was superseded by PFS in later years (20%, 70% and 81%, respectively). Only 37%, 33%, and 11% of RCTs reported HRs for OS, PFS, and TTP, respectively. HRs were more often available in recent publications (20% in 1990-2000, 22% in 2001-2008, 63% in 2009-2013 provided HR for OS). The correlation between reported HR and HR estimated by the ratio of arm-specific median survival times was high for OS (CORR=0.87, 95%CI: 0.73-0.94) and TTP (CORR=0.92, 95%CI: 0.61-0.99) and slightly lower for PFS (CORR=0.72, 95%CI: 0.44-0.87). The relationship between OS and surrogate measures (PFS, TTP) was weaker. The correlation between HR for OS and PFS was 0.49 (95%CI: 0.21-0.69) and for OS and TTP it was 0.26 (95%CI: -0.13-0.58). Survival time following progression was dependent on treatment type and was longer in less intense arms than more intense (mean SPP: 12.4 months vs. 11.4 months, P=0.0155). Conclusions: In RCTs of patients with MBC treated with chemotherapy, when HR is not reported and if necessary statistical conditions are met, the HR approximated by ratio of median survival times may be a suitable proxy estimate. In agreement with other reports, neither PFS nor TTP are acceptable surrogate outcomes for OS in MBC, as survival following progression may be substantial. In these patients, crossover and post-trial treatments may influence the relationship between OS and surrogate measures. Citation Format: Culakova E, Poniewierski MS, Crawford J, Dale DC, Lyman GH. Relationship between overall survival and surrogate measures in patients with metastatic breast cancer treated with chemotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-16-01.

Five Simple Steps to Optimize Bolus Insulin Therapy in Type 2 Diabetes.

The chronic consequences of hyperglycemia in diabetes are well documented. There is evidence that aggressive glycemic control is beneficial in certain populations. Therapy optimization occurs when ineffective medications are adjusted or new medications are added to achieve target glucose levels with minimal adverse events, specifically, hypoglycemia. Therapy selection and glycemic goals vary depending on diabetes type, duration, and comorbidities. Insulin is paramount in reaching A1C goals for many patients with type 2 diabetes. Relying on sliding-scale insulin, a method in which the patient reactively takes a predetermined number of units of bolus insulin per blood glucose level in response to hyperglycemic self-monitored blood glucose readings, as an effective means of controlling blood glucose is not supported by evidence-based medicine. Often, basal insulin alone is not sufficient because of declining β-cell function. Establishing a basal-bolus insulin regimen can achieve glycemic control even with daily fluctuations in carbohydrate intake. There are numerous anecdotal methods for initiating such therapy, but no consensus has developed. Health care providers must review recent literature on methods of optimizing bolus insulin to assist their patients in reaching glycemic targets and reducing the risk of hypoglycemia. Five simple steps to optimize bolus insulin therapy, as discussed below and summarized in Table 1, may provide people with diabetes and their health care teams with a guide for success. View this table: TABLE 1. Five Steps of Bolus Insulin Optimization In the landmark U.K. Prospective Diabetes Study (UKPDS), people with newly diagnosed type 2 diabetes in the intensive therapy arm were treated with sulfonylurea, metformin, or insulin and attained an A1C of 7% compared to 7.9% with standard therapy. Obtaining a lower A1C reduced microvascular complications by 25% over a median period of 11 years (1). Additionally, a long-term cohort follow-up demonstrated reduced cardiovascular events in the intensive therapy group (2). Results from …

Genetics of ancestry-specific risk for relapse in acute lymphoblastic leukemia.

The causes of individual relapses in children with acute lymphoblastic leukemia (ALL) remain incompletely understood. We evaluated the contribution of germline genetic factors to relapse in 2,225 children treated on Children’s Oncology Group trial AALL0232. We identified 302 germline single nucleotide polymorphisms (SNPs) associated with relapse after adjusting for treatment and ancestry and 715 additional SNPs associated with relapse in an ancestry-specific manner. We tested for replication of these relapse-associated SNPs in external data sets of antileukemic drug pharmacokinetics and pharmacodynamics and an independent clinical cohort. 224 SNPs were associated with rapid drug clearance or drug resistance, and 32 were replicated in the independent cohort. The adverse risk associated with black and Hispanic ancestries was attenuated by addition of the 4 SNPs most strongly associated with relapse in these populations [for blacks: model without SNPs hazard ratio (HR) =2.32, P=2.27×10−4, model with SNPs HR=1.07, P=0.79; for Hispanics: model without SNPs HR=1.7, P=8.23×10−5, model with SNPs HR=1.31, P=0.065]. Relapse SNPs associated with asparaginase resistance or allergy were overrepresented among SNPs associated with relapse in the more asparaginase intensive treatment arm (20/54 in Capizzi-methorexate arm vs. 8/54 in high-dose methotrexate arm, P=0.015). Inherited genetic variation contributes to race-specific and treatment-specific relapse risk.

Nonrandomized Trial of Feasibility and Acceptability of Strategies for Promotion of Soapy Water as a Handwashing Agent in Rural Bangladesh.

We conducted a nonrandomized trial of strategies to promote soapy water for handwashing in rural Bangladesh and measured uptake. We enrolled households with children < 3 years for three progressively intensive study arms: promotion of soapy water (N = 120), soapy water promotion plus handwashing stations (N = 103), and soapy water promotion, stations plus detergent refills (N = 90); we also enrolled control households (N = 72). Our handwashing stations included tap-fitted buckets and soapy water bottles. Community promoters visited households and held community meetings to demonstrate soapy water preparation and promote handwashing at key times. Field workers measured uptake 4 months later. In-depth interviews and focus group discussions assessed factors associated with uptake. More households had soapy water at the handwashing place in progressively intensive arms: 18% (promotion), 60% (promotion plus station), and 71% (promotion, station with refills). Compared with the promotion-only arm, more households that received stations had soapy water at the primary handwashing station (44%, P ≤ 0.001; 71%, P < 0.001 with station plus detergent refill). Qualitative findings highlighted several dimensions that affected use: contextual (shared courtyard), psychosocial (perceived value), and technology dimensions (ease of use, convenience). Soapy water may increase habitual handwashing by addressing barriers of cost and availability of handwashing agents near water sources. Further research should inform optimal strategies to scale-up soapy water as a handwashing agent to study health impact.

Increased Idarubicin Dosage during Consolidation Therapy for Adult Acute Myeloid Leukemia Improves Leukemia-Free Survival

Background: Anthracylines are one of the major classes of drugs active against acute myeloid leukemia (AML). Increased doses of daunorubicin during induction therapy for AML have been shown to improve remission rates and survival. The ALLG used idarubicin in induction therapy at a dose of 9 mg/m2 x 3 days (total dose 27 mg/m2) in combination with high-dose cytarabine and etoposide (Blood 2005, 105:481), but showed that a total idarubicin dose of 36 mg/m2 was too toxic in this context (Leukemia 2001, 15:1331). In order to further improve outcomes in adult AML by anthracycline dose escalation, we conducted a phase 3 trial comparing standard to an increased idarubicin dose during consolidation therapy. Methods: Patients achieving complete remission after 1 or 2 cycles of intensive induction therapy (idarubicin 9 mg/m2 daily x3, cytarabine 3 g/m2 twice daily on days 1,3,5 and 7, and etoposide 75 mg/m2 daily x7; ICE protocol) were randomized to receive 2 cycles of consolidation therapy with cytarabine 100 mg/m2 per day for 5 days, etoposide 75 mg/m2 for 5 days, and idarubicin 9mg/m2 daily for either 2 or 3 days (standard and intensive arms respectively). No further protocol therapy was given. The primary endpoint was leukemia-free survival from randomization to consolidation therapy (LFS) with overall survival (OS) as secondary endpoint. Results: A total of 422 patients with AML (excluding cases with CBF rearrangements or APL) aged 16 to 60 years were enrolled between 2003-10, with 345 (82%) achieving complete remission, and 293 being randomized to standard (n=146) or intensive (n=147) consolidation arms. The median age was 45 years in both arms (range 16- 60), and both groups were balanced for intermediate versus unfavorable karyotypes and for frequency of mutations involving FLT3-ITD and NPM1 genes. Of the randomized patients, 120 in the standard arm (82%) and 95 in the intensive arm (65%) received the second consolidation cycle (p Conclusion: We conclude that in adult patients in complete remission after intensive induction chemotherapy an increased dose of idarubicin delivered during consolidation therapy results in improved LFS, without increased non-hematologic toxicity. Disclosures Szer:Ra Pharma: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Alnylam: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Marlton:Amgen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Wei:Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; CTI: Consultancy, Honoraria; Abbvie: Honoraria, Research Funding; Servier: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Cartwright:ROCHE: Consultancy, Membership on an entity9s Board of Directors or advisory committees. Roberts:Servier: Research Funding; Janssen: Research Funding; Genentech: Research Funding; AbbVie: Research Funding. Mills:Novartis: Membership on an entity9s Board of Directors or advisory committees, Other: Meeting attendance sponsorship. Gill:Janssen: Membership on an entity9s Board of Directors or advisory committees. Seymour:Roche: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees.

Abstract 13850: Achievement of Target Systolic Blood Pressure for Lowering the Risk of Major Adverse Cardiovascular Events: From the Action to Control Cardiovascular Risk in Diabetes Blood Pressure Trial

Background: Prior epidemiologic studies have documented deleterious effects of more intensive systolic blood pressure (SBP) lowering in persons with diabetes mellitus (DM). Yet, whether the risk of adverse cardiovascular events might improve, as a function of achieving target SBP goals, remains to be elucidated. Objective: To test the efficacy of achieving target SBP less than 120 mm Hg, or below 140 mm Hg (versus those unable to achieve target SBP), for offsetting the risk of major adverse cardiovascular events (MACE). Methods: Data from the ACCORD BP trial were utilized, which comprised 4,732 (mean±SD age: 63±7 years; 2,258 [48%] women) persons presenting with advanced DM. Participants were randomly assigned to achieve either intensive (&lt;120 mm Hg) or standard (&lt;140 mm Hg) SBP control in an effort to offset the risk of MACE - defined as a composite of non-fatal myocardial infarction, non-fatal stroke, and death from cardiovascular causes. Results: During a median follow-up of 5.0 (interquartile range: 4.2-5.7) years, 1,939 (82%) and 2,038 (86%) persons achieved SBP targets below 120 mm Hg and 140 mm Hg in each treatment arm, respectively. In total, 208 (9%) and 237 (10%) persons belonging to the intensive and standard treatment arms experienced the composite endpoint. Multivariable Cox regression analyses revealed no significant reduction in risk of MACE for those in the intensive treatment arm, who achieved a target SBP below 120 mm Hg. Conversely, those in the standard treatment arm who achieved a target SBP of less than 140 mm Hg displayed a substantial reduction in risk of MACE (HR = 0.65, 95% CI: 0.48-0.88, P =0.005), all-cause death (HR = 0.64, 95% CI: 0.43-0.94, P =0.02), and non-fatal stroke (HR = 0.47, 95% CI: 0.26-0.87, P =0.02). Conclusion: Achieving a standard SBP goal between 120-140 mm Hg may prove useful for lowering the burden of cardiovascular risk in persons with DM, whereas achieving a target SBP &lt;120 mm Hg does not appear to reduce risk.

Self-Paced Reaching after Stroke: A Quantitative Assessment of Longitudinal and Directional Sensitivity Using the H-Man Planar Robot for Upper Limb Neurorehabilitation.

Technology aided measures offer a sensitive, accurate and time-efficient approach for the assessment of sensorimotor function after neurological insult compared to standard clinical assessments. This study investigated the sensitivity of robotic measures to capture differences in planar reaching movements as a function of neurological status (stroke, healthy), direction (front, ipsilateral, contralateral), movement segment (outbound, inbound), and time (baseline, post-training, 2-week follow-up) using a planar, two-degrees of freedom, robotic-manipulator (H-Man). Twelve chronic stroke (age: 55 ± 10.0 years, 5 female, 7 male, time since stroke: 11.2 ± 6.0 months) and nine aged-matched healthy participants (age: 53 ± 4.3 years, 5 female, 4 male) participated in this study. Both healthy and stroke participants performed planar reaching movements in contralateral, ipsilateral and front directions with the H-Man, and the robotic measures, spectral arc length (SAL), normalized time to peak velocities (TpeakN), and root-mean square error (RMSE) were evaluated. Healthy participants went through a one-off session of assessment to investigate the baseline. Stroke participants completed a 2-week intensive robotic training plus standard arm therapy (8 × 90 min sessions). Motor function for stroke participants was evaluated prior to training (baseline, week-0), immediately following training (post-training, week-2), and 2-weeks after training (follow-up, week-4) using robotic assessment and the clinical measures Fugl-Meyer Assessment (FMA), Activity-Research-Arm Test (ARAT), and grip-strength. Robotic assessments were able to capture differences due to neurological status, movement direction, and movement segment. Movements performed by stroke participants were less-smooth, featured longer TpeakN, and larger RMSE values, compared to healthy controls. Significant movement direction differences were observed, with improved reaching performance for the front, compared to ipsilateral and contralateral movement directions. There were group differences depending on movement segment. Outbound reaching movements were smoother and featured longer TpeakN values than inbound movements for control participants, whereas SAL, TpeakN, and RMSE values were similar regardless of movement segment for stroke patients. Significant change in performance was observed between initial and post-assessments using H-Man in stroke participants, compared to conventional scales which showed no significant difference. Results of the study indicate the potential of H-Man as a sensitive tool for tracking changes in performance compared to ordinal scales (i.e., FM, ARAT).

Cost-effectiveness of Intensive Blood Pressure Management

Among high-risk patients with hypertension, targeting a systolic blood pressure of 120 mm Hg reduces cardiovascular morbidity and mortality compared with a higher target. However, intensive blood pressure management incurs additional costs from treatment and from adverse events. To evaluate the incremental cost-effectiveness of intensive blood pressure management compared with standard management. This cost-effectiveness analysis conducted from September 2015 to August 2016 used a Markov cohort model to estimate cost-effectiveness of intensive blood pressure management among 68-year-old high-risk adults with hypertension but not diabetes. We used the Systolic Blood Pressure Intervention Trial (SPRINT) to estimate treatment effects and adverse event rates. We used Centers for Disease Control and Prevention Life Tables to project age- and cause-specific mortality, calibrated to rates reported in SPRINT. We also used population-based observational data to model development of heart failure, myocardial infarction, stroke, and subsequent mortality. Costs were based on published sources, Medicare data, and the National Inpatient Sample. Treatment of hypertension to a systolic blood pressure goal of 120 mm Hg (intensive management) or 140 mm Hg (standard management). Lifetime costs and quality-adjusted life-years (QALYs), discounted at 3% annually. Standard management yielded 9.6 QALYs and accrued $155 261 in lifetime costs, while intensive management yielded 10.5 QALYs and accrued $176 584 in costs. Intensive blood pressure management cost $23 777 per QALY gained. In a sensitivity analysis, serious adverse events would need to occur at 3 times the rate observed in SPRINT and be 3 times more common in the intensive management arm to prefer standard management. Intensive blood pressure management is cost-effective at typical thresholds for value in health care and remains so even with substantially higher adverse event rates.

Predictors and brain connectivity changes associated with arm motor function improvement from intensive practice in chronic stroke

Background and Purpose: The brain changes that underlie therapy-induced improvement in motor function after stroke remain obscure. This study sought to demonstrate the feasibility and utility of measuring motor system physiology in a clinical trial of intensive upper extremity rehabilitation in chronic stroke-related hemiparesis. Methods: This was a substudy of two multi-center clinical trials of intensive robotic and intensive conventional therapy arm therapy in chronic, significantly hemiparetic, stroke patients. Transcranial magnetic stimulation was used to measure motor cortical output to the biceps and extensor digitorum communus muscles. Magnetic resonance imaging (MRI) was used to determine the cortical anatomy, as well as to measure fractional anisotropy, and blood oxygenation (BOLD) during an eyes-closed rest state. Region-of-interest time-series correlation analysis was performed on the BOLD signal to determine interregional connectivity. Functional status was measured with the upper extremity Fugl-Meyer and Wolf Motor Function Test. Results: Motor evoked potential (MEP) presence was associated with better functional outcomes, but the effect was not significant when considering baseline impairment. Affected side internal capsule fractional anisotropy was associated with better function at baseline. Affected side primary motor cortex (M1) activity became more correlated with other frontal motor regions after treatment. Resting state connectivity between affected hemisphere M1 and dorsal premotor area (PMAd) predicted recovery. Conclusions: Presence of motor evoked potentials in the affected motor cortex and its functional connectivity with PMAd may be useful in predicting recovery. Functional connectivity in the motor network shows a trends towards increasing after intensive robotic or non-robotic arm therapy. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00372411 \\& NCT00333983.

Predictors and brain connectivity changes associated with arm motor function improvement from intensive robotic practice in chronic stroke

Background and Purpose: The brain changes that underlie therapy-induced improvement in motor function after stroke remain obscure. This study sought to demonstrate the feasibility and utility of measuring motor system physiology in a clinical trial of intensive upper extremity rehabilitation in chronic stroke-related hemiparesis. Methods: This was a substudy of two multi-center clinical trials of intensive robotic arm therapy in chronic, significantly hemiparetic, stroke patients. Transcranial magnetic stimulation was used to measure motor cortical output to the biceps and extensor digitorum communus muscles. Magnetic resonance imaging (MRI) was used to determine the cortical anatomy, as well as to measure fractional anisotropy, and blood oxygenation (BOLD) during an eyes-closed rest state. Region-of-interest time-series correlation analysis was performed on the BOLD signal to determine interregional connectivity. Functional status was measured with the upper extremity Fugl-Meyer and Wolf Motor Function Test. Results: Motor evoked potential (MEP) presence was associated with better functional outcomes, but the effect was not significant when considering baseline impairment. Affected side internal capsule fractional anisotropy was associated with better function at baseline. Affected side primary motor cortex (M1) activity became more correlated with other frontal motor regions after treatment. Resting state connectivity between affected hemisphere M1 and dorsal premotor area (PMAd) predicted recovery. Conclusions: Presence of motor evoked potentials in the affected motor cortex and its functional connectivity with PMAd may be useful in predicting recovery. Functional connectivity in the motor network shows a trends towards increasing after intensive robotic or non-robotic arm therapy. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifiers: CT00372411 &amp; NCT00333983.

Genetic Predictors of Cardiovascular Mortality During Intensive Glycemic Control in Type 2 Diabetes: Findings From the ACCORD Clinical Trial.

OBJECTIVETo identify genetic determinants of increased cardiovascular mortality among subjects with type 2 diabetes who underwent intensive glycemic therapy in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.RESEARCH DESIGN AND METHODSA total of 6.8 million common variants were analyzed for genome-wide association with cardiovascular mortality among 2,667 self-reported white subjects in the ACCORD intensive treatment arm. Significant loci were examined in the entire ACCORD white genetic dataset (n = 5,360) for their modulation of cardiovascular responses to glycemic treatment assignment and in a Joslin Clinic cohort (n = 422) for their interaction with long-term glycemic control on cardiovascular mortality.RESULTSTwo loci, at 10q26 and 5q13, attained genome-wide significance as determinants of cardiovascular mortality in the ACCORD intensive arm (P = 9.8 × 10−9 and P = 2 × 10−8, respectively). A genetic risk score (GRS) defined by the two variants was a significant modulator of cardiovascular mortality response to treatment assignment in the entire ACCORD white genetic dataset. Participants with GRS = 0 experienced a fourfold reduction in cardiovascular mortality in response to intensive treatment (hazard ratio [HR] 0.24 [95% CI 0.07–0.86]), those with GRS = 1 experienced no difference (HR 0.92 [95% CI 0.54–1.56]), and those with GRS ≥2 experienced a threefold increase (HR 3.08 [95% CI 1.82–5.21]). The modulatory effect of the GRS on the association between glycemic control and cardiovascular mortality was confirmed in the Joslin cohort (P = 0.029).CONCLUSIONSTwo genetic variants predict the cardiovascular effects of intensive glycemic control in ACCORD. Further studies are warranted to determine whether these findings can be translated into new strategies to prevent cardiovascular complications of diabetes.

Promoting weight loss through diet and exercise in overweight or obese breast cancer survivors (InForma): study protocol for a randomized controlled trial.

BackgroundMost women with breast cancer experience a progressive weight gain during and after treatment. Obesity is associated with an increased risk of recurrence, contralateral breast cancer, and death. Physical activity after cancer diagnosis has been reported to have positive effects on body composition and quality of life. We present the protocol of the InForma study, a trial testing the efficacy of an intervention on weight loss (≥5 % of the baseline body weight) in a group of overweight or obese breast cancer survivors.Methods/designThis is a four-arm randomized controlled trial. Patients will receive a 6-month intervention and be followed for a further 18 months. Intervention is designed to improve adherence to a healthy diet and/or to increase physical activity, taking advantage of a wrist-based activity monitor. Participants will be recruited among overweight or obese breast cancer patients treated at the European Institute of Oncology, after completion of eventual adjuvant chemotherapy and/or radiotherapy. It is envisaged that 260 patients will be randomized into four arms: Dietary Intervention; Physical Activity Intervention; Physical Activity and Dietary Intervention; and Less Intensive Intervention. Women will be offered individualized counseling consisting of face-to face discussion and phone calls in addition to group meetings. A motivational interviewing approach will be used to encourage health behavior change. All participants will be given a pedometer device to monitor their physical activity. Participants’ dietary intake will be repeatedly assessed using a validated food frequency questionnaire. Participants’ quality of life and anxiety will be assessed with the Functional Assessment of Cancer Therapy-Breast and the State-Trait Anxiety Inventory questionnaires. Blood samples will be collected at baseline and follow-up visits to assess lipid and hormone profiles. Body composition will be repeatedly assessed using bioelectrical impedance vector analysis for identifying changes of fat and fat-free mass. Women allocated to the less intensive intervention arm will be considered as the control group.DiscussionWhile there is a rising concern about the role of obesity in cancer recurrence and survival, this trial with its multi-arm design, motivational approach and use of a pedometer device will provide important insights regarding the most effective approach in promoting weight control in breast cancer survivors.Trial registrationISRCTN53325751 (registration date: 16 October 2015); ClinicalTrials.gov NCT02622711 (registration date: 2 December 2015).

Effects of combined high intensity arm and leg training on performance and cardio-respiratory measures.

The purpose of this study was to investigate the effects of combined arm and leg high-intensity low-volume interval training (HIITarm+leg) on maximal oxygen uptake, myocardial measures (i.e. stroke volume, cardiac output, ejection fraction), Tissue Oxygenation Index (TOI) of the vastus lateralis and triceps brachii, as well as power output in comparison to leg HIIT (HIITleg) only. The 20 healthy, male and female volunteers completed six sessions of either HIITleg on a cycle ergometer or HIITarm+leg on an arm and leg cycle ergometer. During pre- and post-testing, the volunteers completed a submaximal and incremental test to exhaustion on a cycle ergometer. Magnitude based interference revealed likely to very likely beneficial effects for HIITarm+leg compared to HIITleg in maximal oxygen uptake, cardiac measures as well peak power output. The TOI following HIITarm+leg demonstrated likely to very likely increased oxygenation in the triceps brachii or the vastus lateralis when compared to HIITleg. The results suggest that six sessions of HIITarm+leg may likely to very likely improve maximal oxygen uptake, some inotropy-related cardiac measures with improved tissue oxygenation of the triceps brachii and vastus lateralis muscles resulting in greater leg peak power output.

Intensive glycemic control and the risk of end-stage renal disease: an ADVANCE in the management of diabetes?

Posttrial follow-up of participants randomized to intensive versus standard glycemic control in the ADVANCE trial has demonstrated a significant benefit of intensive glycemic control on the risk of end-stage renal disease. In a more detailed analysis, intensive glycemic control appears to be of benefit only before the development of clinically evident kidney disease or in patients with documented early-stage chronic kidney disease.

SU‐C‐202‐04: Adapting Biologically Optimized Dose Escalation Based On Mid‐Treatment PET/CT for Non‐Small‐Cell Lung Cancer

Purpose:To develop a biological modeling strategy which incorporates the response observed on the mid‐treatment PET/CT into a dose escalation design for adaptive radiotherapy of non‐small‐cell lung cancer.Method:FDG‐PET/CT was acquired midway through standard fractionated treatment and registered to pre‐treatment planning PET/CT to evaluate radiation response of lung cancer. Each mid‐treatment PET voxel was assigned the median SUV inside a concentric 1cm‐diameter sphere to account for registration and imaging uncertainties. For each voxel, the planned radiation dose, pre‐ and mid‐treatment SUVs were used to parameterize the linear‐quadratic model, which was then utilized to predict the SUV distribution after the full prescribed dose. Voxels with predicted post‐treatment SUV≥2 were identified as the resistant target (response arm). An adaptive simultaneous integrated boost was designed to escalate dose to the resistant target as high as possible, while keeping prescription dose to the original target and lung toxicity intact. In contrast, an adaptive target volume was delineated based only on the intensity of mid‐treatment PET/CT (intensity arm), and a similar adaptive boost plan was optimized. The dose escalation capability of the two approaches was compared.Result:Images of three patients were used in this planning study. For one patient, SUV prediction indicated complete response and no necessary dose escalation. For the other two, resistant targets defined in the response arm were multifocal, and on average accounted for 25% of the pre‐treatment target, compared to 67% in the intensity arm. The smaller response arm targets led to a 6Gy higher mean target dose in the adaptive escalation design.Conclusion:This pilot study suggests that adaptive dose escalation to a biologically resistant target predicted from a pre‐ and mid‐treatment PET/CT may be more effective than escalation based on the mid‐treatment PET/CT alone. More plans and ultimately clinical protocols are needed to validate this approach.MSKCC has a research agreement with Varian Medical System