Summary Background Hyperglycaemia is associated with increased risk of cardiovascular complications in people with type 2 diabetes. We investigated whether reduction of blood glucose concentration ...decreases the rate of microvascular complications in people with type 2 diabetes. Methods ACCORD was a parallel-group, randomised trial done in 77 clinical sites in North America. People with diabetes, high HbA1c concentrations (>7·5%), and cardiovascular disease (or ≥2 cardiovascular risk factors) were randomly assigned by central randomisation to intensive (target haemoglobin A1c HbA1c of <6·0%) or standard (7·0–7·9%) glycaemic therapy. In this analysis, the prespecified composite outcomes were: dialysis or renal transplantation, high serum creatinine (>291·7 μmol/L), or retinal photocoagulation or vitrectomy (first composite outcome); or peripheral neuropathy plus the first composite outcome (second composite outcome). 13 prespecified secondary measures of kidney, eye, and peripheral nerve function were also assessed. Investigators and participants were aware of treatment group assignment. Analysis was done for all patients who were assessed for microvascular outcomes, on the basis of treatment assignment, irrespective of treatments received or compliance to therapies. ACCORD is registered with ClinicalTrials.gov , number NCT00000620. Findings 10 251 patients were randomly assigned, 5128 to the intensive glycaemia control group and 5123 to standard group. Intensive therapy was stopped before study end because of higher mortality in that group, and patients were transitioned to standard therapy. At transition, the first composite outcome was recorded in 443 of 5107 patients in the intensive group versus 444 of 5108 in the standard group (HR 1·00, 95% CI 0·88–1·14; p=1·00), and the second composite outcome was noted in 1591 of 5107 versus 1659 of 5108 (0·96, 0·89–1·02; p=0·19). Results were similar at study end (first composite outcome 556 of 5119 vs 586 of 5115 HR 0·95, 95% CI 0·85–1·07, p=0·42; and second 1956 of 5119 vs 2046 of 5115, respectively 0·95, 0·89–1·01, p=0·12). Intensive therapy did not reduce the risk of advanced measures of microvascular outcomes, but delayed the onset of albuminuria and some measures of eye complications and neuropathy. Six secondary measures at study end favoured intensive therapy (p<0·05). Interpretation Microvascular benefits of intensive therapy should be weighed against the increase in total and cardiovascular disease-related mortality, increased weight gain, and high risk for severe hypoglycaemia. Funding US National Institutes of Health; National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Aging; National Eye Institute; Centers for Disease Control and Prevention; and General Clinical Research Centers.
Background Cardiac contractility modulation (CCM) delivers nonexcitatory electrical signals to the heart during the absolute refractory period intended to improve contraction. Methods We tested CCM ...in 428 New York Heart Association class III or IV, narrow QRS heart failure patients with ejection fraction (EF) ≤35% randomized to optimal medical therapy (OMT) plus CCM (n = 215) versus OMT alone (n = 213). Efficacy was assessed by ventilatory anaerobic threshold (VAT), primary end point, peak V o2 (pV o2 ), and Minnesota Living with Heart Failure Questionnaire (MLWFQ) at 6 months. The primary safety end point was a test of noninferiority between groups at 12 months for the composite of all-cause mortality and hospitalizations (12.5% allowable delta). Results The groups were comparable for age (58 ± 13 vs 59 ± 12 years), EF (26% ± 7% vs 26% ± 7%), pV o2 (14.7 ± 2.9 vs 14.8 ± 3.2 mL kg−1 min−1 ), and other characteristics. While VAT did not improve at 6 months, CCM significantly improved pV o2 and MLWHFQ (by 0.65 mL kg−1 min−1 P = .024 and −9.7 points P < .0001, respectively) over OMT. Forty-eight percent of OMT and 52% of CCM patients experienced a safety end point, which satisfied the noniferiority criterion ( P = .03). Post hoc, hypothesis-generating analysis identified a subgroup (characterized by baseline EF ≥25% and New York Heart Association class III symptoms) in which all parameters were improved by CCM. Conclusions In the overall target population, CCM did not improve VAT (the primary end point) but did improve pV o2 and MLWHFQ. Cardiac contractility modulation did not have an adverse affect on hospitalizations or mortality within the prespecified boundaries. Further study is required to clarify the role of CCM as a treatment for medically refractory heart failure.
Abstract Health care reform is directing clinical practice towards improving outcomes and minimizing complications. Preoperative identification of high-risk patients and modifiable risk factors ...present opportunity for clinical research. A total of 49,475 total hip arthroplasty patients were identified from National Surgical Quality Improvement Program between 2006 and 2013. We compared morbidly obese patients (BMI ≥ 40 kg/m2 ) and non-morbidly obese patients (BMI 18.5–40 kg/m2 ). We also compared patients with hypoalbuminemia (serum albumin < 3.5 g/dL) against those with normal albumin. Our study demonstrates that hypoalbuminemia is a significant risk factor for mortality and major morbidity among total hip arthroplasty patients, while morbid obesity was only associated with an increased risk of superficial surgical site infection. Impressively, hypoalbuminemia patients carried a 5.94-fold risk of 30-day mortality.
Limited data exist regarding the outcome of atrial fibrillation (AF) surgery and catheter ablation in patients with hypertrophic cardiomyopathy (HCM).
The purpose of this study was to evaluate the ...safety and efficacy of nonpharmacologic treatment of AF in HCM.
One hundred forty-seven patients (46 female, age 55 ± 11 years, ejection fraction EF 58% ± 8%) with symptomatic paroxysmal (58%), persistent (31%), and long-standing persistent AF (11%) refractory to antiarrhythmic drugs who presented for their first catheter ablation (n = 79) or AF surgery (n = 68) were included.
After follow-up of 35 months (interquartile range 13, 60), 29% of patients who underwent catheter ablation and 51% of those who had undergone AF surgery had no documented recurrent atrial arrhythmia after a single procedure. Repeat ablation was performed in 55% of patients with recurrent arrhythmia in the catheter group and 24% in the surgery group, increasing the success rate to 39% and 53%, respectively, after 1 or more procedures. Predictors of success after the first procedure in a multivariable setting included higher baseline EF and male gender. Persistent or long-standing AF and log of AF duration were associated with lower success. Major complications occurred in 6% of the catheter ablation group and 18% of the AF surgery group. During follow-up, 16 patients died (9 in catheter group, 7 in surgery group) and 1 underwent heart replacement. Lower baseline EF and older age were independently associated with death.
Catheter ablation and AF surgery are associated with symptomatic improvement in HCM patients. However, long-term success is lower and complications are higher than previously reported.
Abstract Background Cardiac contractility modulation (CCM) signals are nonexcitatory electrical signals delivered during the absolute refractory period intended to improve contraction. We previously ...tested the safety and efficacy of CCM in 428 NYHA functional class III/IV heart failure patients with EF ≤35% and narrow QRS randomized to optimal medical treatment (OMT) plus CCM (n = 215) versus OMT alone (n = 213) and found no significant effect on ventilatory anaerobic threshold (VAT), the study’s primary end point. In the present analysis, we sought to identify if there was a subgroup of patients who showed a response to CCM. Methods and Results The protocol specified that multiregression analysis would be used to determine if baseline EF, NYHA functional class, pVO2 , or etiology of heart failure influenced the impact of CCM on AT. Etiology and baseline pVO2 did not affect efficacy. However, baseline NYHA functional class III and EF ≥25% were significant predictors of increased efficacy. In this subgroup (comprising 97 OMT and 109 CCM patients, ∼48% of the entire population) VAT increased by 0.10 ± 2.36 in CCM versus −0.54 ± 1.83 mL kg−1 min−1 in OMT ( P = .03) and pVO2 increased by 0.34 ± 3.11 in CCM versus −0.97 ± 2.31 ( P = .001) at 24 weeks compared with baseline; 44% of CCM versus 23% of OMT subjects showed improvement of ≥1 class in NYHA functional class ( P = .002), and 59% of CCM versus 42% of OMT subjects showed a ≥10-point reduction in Minnesota Living with Heart Failure Questionnaire ( P = .01). All of these findings were similar to those seen at 50 weeks. Conclusions The results of this retrospective hypothesis-generating analysis indicate that CCM significantly improves objective parameters of exercise tolerance in a subgroup of patients characterized by normal QRS duration, NYHA functional class III symptoms, and EF >25%.
Current guidelines for esophageal cancer contouring are derived from traditional 2-dimensional fields based on bony landmarks, and they do not provide sufficient anatomic detail to ensure consistent ...contouring for more conformal radiation therapy techniques such as intensity modulated radiation therapy (IMRT). Therefore, we convened an expert panel with the specific aim to derive contouring guidelines and generate an atlas for the clinical target volume (CTV) in esophageal or gastroesophageal junction (GEJ) cancer.
Eight expert academically based gastrointestinal radiation oncologists participated. Three sample cases were chosen: a GEJ cancer, a distal esophageal cancer, and a mid-upper esophageal cancer. Uniform computed tomographic (CT) simulation datasets and accompanying diagnostic positron emission tomographic/CT images were distributed to each expert, and the expert was instructed to generate gross tumor volume (GTV) and CTV contours for each case. All contours were aggregated and subjected to quantitative analysis to assess the degree of concordance between experts and to generate draft consensus contours. The panel then refined these contours to generate the contouring atlas.
The κ statistics indicated substantial agreement between panelists for each of the 3 test cases. A consensus CTV atlas was generated for the 3 test cases, each representing common anatomic presentations of esophageal cancer. The panel agreed on guidelines and principles to facilitate the generalizability of the atlas to individual cases.
This expert panel successfully reached agreement on contouring guidelines for esophageal and GEJ IMRT and generated a reference CTV atlas. This atlas will serve as a reference for IMRT contours for clinical practice and prospective trial design. Subsequent patterns of failure analyses of clinical datasets using these guidelines may require modification in the future.
Objective The aim of the study was to describe the rationale, design, and end points of a randomized, double-blind, controlled trial evaluating frequent systematic optimization of atrioventricular ...(AV) and interventricular (VV) delays in patients receiving cardiac resynchronization therapy (CRT). Methods One thousand five hundred eighty heart failure patients, with standard clinical indications for CRT, were enrolled at 178 sites in 16 countries. Within 2 weeks after implantation of a CRT system capable of using a new device-based algorithm for AV and VV optimization, patients were randomly assigned to frequent optimization arm versus empiric device programming or any other non–device-based method of CRT optimization (standard of care arm). In patients in the frequent optimization arm, the AV and VV delays were calculated, reevaluated, and, if necessary, reprogrammed every 3 months. In patients in the standard of care arm, device programming was left to the implanting physician's discretion and remained unchanged throughout the trial unless mandated by a change in clinical status. The primary end point of the trial is the heart failure clinical composite, which classifies patients as worsened, unchanged, or improved based on prespecified definitions. Secondary end points include hospitalizations for cardiovascular reasons and all-cause mortality. End points are adjudicated by an independent committee blinded to study assignment. Conclusions The FREEDOM trial, expected to conclude late in 2009, will determine whether frequent optimization of CRT, using a new device-based algorithm, is associated with better clinical outcomes than current standard of care. In addition to improving patient care, this approach might alleviate the workload and economic burden imposed by current approaches to optimization of CRT devices.
Objectives The purpose of this study was to define the incidence and predictors of implantable cardioverter-defibrillator (ICD) therapy in patients with arrhythmogenic right ventricular ...dysplasia/cardiomyopathy (ARVD/C) after placement of an ICD for primary prevention. Background Patients with a diagnosis of ARVD/C often receive an ICD for prevention of sudden cardiac death. Methods Patients (n = 84) from the Johns Hopkins registry with definite or probable ARVD/C who underwent ICD implantation for primary prevention were studied. Detailed phenotypic, genotype, and ICD event information was obtained and appropriate ICD therapies were adjudicated based on intracardiac electrograms. Results Over a mean follow-up of 4.7 ± 3.4 years, appropriate ICD therapy was seen in 40 patients (48%), of whom 16 (19%) received interventions for potentially fatal ventricular fibrillation/flutter episodes. Proband status (p < 0.001), inducibility at electrophysiologic study (p = 0.005), presence of nonsustained ventricular tachycardia (p < 0 .001), and Holter premature ventricular complex count >1,000/24 h (p = 0.024) were identified as significant predictors of appropriate ICD therapy. The 5-year survival free of appropriate ICD therapy for patients with 1, 2, 3, and 4 risk factors was 100%, 83%, 21%, and 15%, respectively. Inducibility at electrophysiologic study (hazard ratio: 4.5, 95% confidence interval: 1.4 to 15, p = 0.013) and nonsustained ventricular tachycardia (hazard ratio: 10.5, 95% confidence interval: 2.4 to 46.2, p = 0.002) remained as significant predictors on multivariable analysis. Conclusions Nearly one-half of the ARVD/C patients with primary prevention ICD implantation experience appropriate ICD interventions. Inducibility at electrophysiologic study and nonsustained ventricular tachycardia are independent strong predictors of appropriate ICD therapy. An increase in ventricular ectopy burden was associated with progressively lower event-free (appropriate ICD interventions) survival. Incremental risk of ventricular arrhythmias and ICD therapy was observed with the presence of multiple risk factors.
Abstract Cardiac contractility modulation (CCM) signals are nonexcitatory electrical signals delivered during the cardiac absolute refractory period that enhance the strength of cardiac muscular ...contraction. The FIX-HF-5 study was a prospective randomized study comparing CCM plus optimal medical therapy (OMT) to OMT alone that included 428 New York Heart Association (NYHA) functional class III or IV heart failure patients with ejection fraction (EF) ≤45% according to core laboratory assessment. The study met its primary safety end point, but did not reach its primary efficacy end point: a responders analysis of changes in ventilatory anaerobic threshold (VAT). However, in a prespecified subgroup analysis, significant improvements in primary and secondary end points, including the responder VAT end point, were observed in patients with EFs ranging from 25% to 45%, who constituted about one-half of the study subjects. We therefore designed a new study to prospectively confirm the efficacy of CCM in this population. A hierarchic bayesian statistical analysis plan was developed to take advantage of the data already available from the first study. In addition, based on technical difficulties encountered in reliably quantifying VAT and the relatively large amount of nonquantifiable studies, the primary efficacy end point was changed to peak VO2 , with significant measures incorporated to minimize the influence of placebo effect. In this paper, we provide the details and rationale of the FIX-HF-5C study design to study CCM plus OMT compared with OMT alone in subjects with normal QRS duration, NYHA functional class III or IV, and EF 25%–45%. This study is registered on www.clinicaltrials.gov with identifier no. NCT01381172.
Background Phosphate binders are the cornerstone of hyperphosphatemia management in dialysis patients. Ferric citrate is an iron-based oral phosphate binder that effectively lowers serum phosphorus ...levels. Study Design 52-week, open-label, phase 3, randomized, controlled trial for safety-profile assessment. Setting & Participants Maintenance dialysis patients with serum phosphorus levels ≥6.0 mg/dL after washout of prior phosphate binders. Intervention 2:1 randomization to ferric citrate or active control (sevelamer carbonate and/or calcium acetate). Outcomes Changes in mineral bone disease, protein-energy wasting/inflammation, and occurrence of adverse events after 1 year. Measurements Serum calcium, intact parathyroid hormone, phosphorus, aluminum, white blood cell count, percentage of lymphocytes, serum urea nitrogen, and bicarbonate. Results There were 292 participants randomly assigned to ferric citrate, and 149, to active control. Groups were well matched. For mean changes from baseline, phosphorus levels decreased similarly in the ferric citrate and active control groups (−2.04 ± 1.99 SD vs −2.18 ± 2.25 mg/dL, respectively; P = 0.9); serum calcium levels increased similarly in the ferric citrate and active control groups (0.22 ± 0.90 vs 0.31 ± 0.95 mg/dL; P = 0.2). Hypercalcemia occurred in 4 participants receiving calcium acetate. Parathyroid hormone levels decreased similarly in the ferric citrate and active control groups (−167.1 ± 399.8 vs −152.7 ± 392.1 pg/mL; P = 0.8). Serum albumin, bicarbonate, serum urea nitrogen, white blood cell count and percentage of lymphocytes, and aluminum values were similar between ferric citrate and active control. Total and low-density lipoprotein cholesterol levels were lower in participants receiving sevelamer than those receiving ferric citrate and calcium acetate. Fewer participants randomly assigned to ferric citrate had serious adverse events compared with active control. Limitations Open-label study, few peritoneal dialysis patients. Conclusions Ferric citrate was associated with similar phosphorus control compared to active control, with similar effects on markers of bone and mineral metabolism in dialysis patients. There was no evidence of protein-energy wasting/inflammation or aluminum toxicity, and fewer participants randomly assigned to ferric citrate had serious adverse events. Ferric citrate is an effective phosphate binder with a safety profile comparable to sevelamer and calcium acetate.
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