Summary Background Conventional treatment with epoetin to manage anaemia in chronic kidney disease needs frequent administrations, changes of dose, and close monitoring of haemoglobin concentrations. ...We aimed to compare the effectiveness of methoxy polyethylene glycol-epoetin beta, given intravenously at 2-week or 4-week intervals, with epoetin treatment one to three times per week for haemoglobin control in haemodialysis patients. Methods We screened 1115 adult patients from 96 centres who had stable chronic renal anaemia and were on dialysis treatment and intravenous maintenance epoetin. We did an open-label, parallel-group, non-inferiority trial to compare two dosing intervals of methoxy polyethylene glycol-epoetin beta with standard epoetin treatment. We established baseline haemoglobin concentration and eligibility over a 4-week run-in period. 223 patients were randomly assigned to receive methoxy polyethylene glycol-epoetin beta every 2 weeks, and 224 to receive it every 4 weeks. The initial dose was based on the average epoetin dose given during the week before the switch. The primary endpoint was change in haemoglobin concentration between baseline and the assessment period. We analysed patients both by intention to treat and per protocol. This study is registered with ClinicalTrials.gov , number NCT00077610. Findings We excluded 133 of the 673 randomised patients from the per-protocol analysis because they had inadequate iron status or fewer than five haemoglobin measurements during the assessment period or needed red blood cell transfusions. The mean change from baseline haemoglobin for patients who had switched to intravenous methoxy polyethylene glycol-epoetin beta every 2 weeks (−0·71 g/L, 95% CI −2·20 to 0·77) or every 4 weeks (−0·25 g/L, −1·79 to 1·29) was non-inferior to the mean change for patients who continued treatment with epoetin (−0·75 g/L, −2·26 to 0·75) (p<0·0001 for both comparisons). Of the 666 patients who received at least one dose of study drug, the incidence of adverse events or serious adverse events did not differ between groups (p=0·30 and p=0·40, respectively). Interpretation This long-acting erythropoiesis-stimulating agent is as safe as conventional epoetin treatment, and can maintain anaemia management in haemodialysis patients when given intravenously at 4-week dosing intervals.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
BACKGROUND FVC outcomes in clinical trials on idiopathic pulmonary fibrosis (IPF) can be substantially influenced by the analytic methodology and the handling of missing data. We conducted a series ...of sensitivity analyses to assess the robustness of the statistical finding and the stability of the estimate of the magnitude of treatment effect on the primary end point of FVC change in a phase 3 trial evaluating pirfenidone in adults with IPF. METHODS Source data included all 555 study participants randomized to treatment with pirfenidone or placebo in the Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND) study. Sensitivity analyses were conducted to assess whether alternative statistical tests and methods for handling missing data influenced the observed magnitude of treatment effect on the primary end point of change from baseline to week 52 in FVC. RESULTS The distribution of FVC change at week 52 was systematically different between the two treatment groups and favored pirfenidone in each analysis. The method used to impute missing data due to death had a marked effect on the magnitude of change in FVC in both treatment groups; however, the magnitude of treatment benefit was generally consistent on a relative basis, with an approximate 50% reduction in FVC decline observed in the pirfenidone group in each analysis. CONCLUSIONS Our results confirm the robustness of the statistical finding on the primary end point of change in FVC in the ASCEND trial and corroborate the estimated magnitude of the pirfenidone treatment effect in patients with IPF. TRIAL REGISTRY ClinicalTrials.gov ; No.: NCT01366209; URL: www.clinicaltrials.gov
Summary Objective To assess the effect of rivastigmine in patients with mild cognitive impairment (MCI) on the time to clinical diagnosis of Alzheimer's disease (AD) and the rate of cognitive ...decline. Methods The study was a double-blind, randomised, placebo-controlled trial of up to 48 months. All patients had MCI operationally defined by having cognitive symptoms, a global clinical dementia rating stage of 0·5, a score of less than 9 on the New York University delayed paragraph recall test, and by not meeting the diagnostic criteria for AD. Primary efficacy variables were time to clinical diagnosis of AD, and change in performance on a cognitive test battery. This study is registered with the US National Institutes of Health clinical trials database ( ClinicalTrials.gov ), number NCT00000174. Findings Of 1018 study patients enrolled, 508 were randomly assigned to rivastigmine and 510 to placebo; 17·3% of patients on rivastigmine and 21·4% on placebo progressed to AD (hazard ratio 0·85 95% CI 0·64–1·12; p=0·225). There was no significant difference between the rivastigmine and placebo groups on the standardised Z score for the cognitive test battery measured as mean change from baseline to endpoint (−0·10 95% CI −0·63 to 0·44, p=0·726). Serious adverse events were reported by 141 (27·9%) rivastigmine-treated patients and 155 (30·5%) patients on placebo; adverse events of all types were reported by 483 (95·6%) rivastigmine-treated patients and 472 (92·7%) placebo-treated patients. The predominant adverse events were cholinergic: the frequencies of nausea, vomiting, diarrhoea, and dizziness were two to four times higher in the rivastigmine group than in the placebo group. Interpretation There was no significant benefit of rivastigmine on the progression rate to AD or on cognitive function over 4 years. The overall rate of progression from MCI to AD in this randomised clinical trial was much lower than predicted. Rivastigmine treatment was not associated with any significant safety concerns.
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Objective The efficacy of tibial artery endovascular intervention (TAEI) for critical limb ischemia (CLI) and particularly for wound healing is not fully defined. The purpose of this study is to ...determine predictors of failure and success for TAEI in the setting of CLI. Methods All TAEI for tissue loss or rest pain (Rutherford classes 4, 5, and 6) from 2004 to 2008 were retrospectively reviewed. Clinical outcomes and patency rates were analyzed by multivariable Cox proportional hazards regression and life table analysis. Results One hundred twenty-three limbs in 111 patients (62% male, mean age 74) were treated. Sixty-seven percent of patients were diabetics, 55% had renal insufficiency, and 21% required hemodialysis. One hundred two limbs (83%) exhibited tissue loss; all others had ischemic rest pain. All patients underwent tibial angioplasty (PTA). Tibial excimer laser atherectomy was performed in 14% of the patients. Interventions were performed on multiple tibial vessels in 20% of limbs. Isolated tibial procedures were performed on 50 limbs (41%), while 73 patients had concurrent ipsilateral superficial femoral artery or popliteal interventions. The mean distal popliteal and tibial runoff score improved from 11.8 ± 3.6 to 6.7 ± 1.6 ( P < .001), and the mean ankle-brachial index increased from 0.61 ± 0.26 to 0.85 ± 0.22 ( P < .001). Surgical bypass was required in seven patients (6%). The mean follow up was 6.8 ± 6.6 months, while the 1-year primary, primary-assisted, and secondary patency rates were 33%, 50%, and 56% respectively. Limb salvage rate at 1 year was 75%. Factors found to be associated with impaired limb salvage included renal insufficiency (hazard ratio HR = 5.7; P = .03) and the need for pedal intervention (HR = 13.75; P = .04). TAEI in an isolated peroneal artery (odds ratio = 7.80; P = .01) was associated with impaired wound healing, whereas multilevel intervention (HR = 2.1; P = .009) and tibial laser atherectomy (HR = 3.1; P = .01) were predictors of wound healing. In patients with tissue loss, 41% achieved complete closure (mean time to healing, 10.7 ± 7.4 months), and 39% exhibited partial wound healing (mean follow up, 4.4 ± 4.8 months) at last follow up. Diabetes, smoking, statin therapy, and revascularization of >1 tibial vessel had no impact on limb salvage or wound healing. Re-intervention rate was 50% at 1 year. Conclusions TAEI is an effective treatment for CLI with acceptable limb salvage and wound healing rates, but requires a high rate of reintervention. Patients with renal failure, pedal disease, or isolated peroneal runoff have poor outcomes with TAEI and should be considered for surgical bypass.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The American Thoracic Society and European Respiratory Society guidelines for the diagnosis and treatment of idiopathic pulmonary fibrosis (IPF) have been published recently. However, the influence, ...practical application, and utility of the prior consensus statement for IPF have never been evaluated. Demographics, diagnostic criteria, pulmonary function data, and disposition of patients with IPF evaluated at an interstitial lung disease center between 2000 and 2009 were analyzed. Enrollment in clinical drug trials, lung transplantation, and mortality also were assessed. A total of 521 patients with IPF were evaluated, with pulmonary function testing available in 446. In the 64% of patients without surgical lung biopsy, the most common major criterion not fulfilled was bronchoscopy. Lung transplantation was performed in 16.1% of patients, whereas 27.4% of prescreened patients were enrolled in a prospective drug study. Patients with mild, moderate, and severe disease categorized by FVC % predicted had median survivals of 55.6, 38.7, and 27.4 months, respectively. The attrition rate of patients who survived beyond 5 years was attenuated in subsequent years. IPF remains a deadly disease with a poor prognosis. Bronchoscopy does not appear to be required for an accurate diagnosis. A minority of patients were accommodated within a clinical trial or with transplantation. Categorization by baseline FVC % predicted effectively discriminates groups with different long-term outcomes. Our analysis supports the view that the value of statements also can be realized in the subsequent demonstration of their impact on patient management, which might enable further refinements in a continuous, iterative rediscovery process.
Objectives Previous work in our institution has indicated that the Technical Performance Score (TPS) is highly associated with early outcomes in select subsets of procedures and age groups. We ...hypothesized that the TPS could predict early outcomes in a wide range of diagnoses and age groups. Methods Consecutive patients discharged from January 2011 to March 2013 were prospectively evaluated. The TPS was assigned according to the discharge echocardiographic findings and the need for reinterventions in the anatomic area of interest. Case complexity was determined using Risk Adjustment for Congenital Heart Surgery (RACHS-1) categories. Early mortality and postoperative adverse events were recorded. Relationships between the TPS and outcomes were assessed after adjusting for the baseline patient characteristics. Results The median age of the 1926 patients was 1.8 years (range, 0 days to 68 years). Bypass was used in 1740 (90%); 322 (17%) were neonates, 520 (27%) infants, 873 (45%) children, 211 (11%) adults. TPS was class 1 (optimal) in 956 (50%), class 2 (adequate) in 584 (30%), and class 3 (inadequate) in 226 (12%); 160 patients (8%) could not be scored. A total of 51 early deaths (2.6%) and 111 adverse events (5.7%) occurred. On univariate analysis, age, RACHS-1 category, and TPS were significantly associated with mortality and the occurrence of adverse events. On multivariate modeling, class 3 (inadequate) TPS was strongly associated with mortality (odds ratio, 16.9; 95% confidence interval, 6.7-42.9; P < .001), adverse events (odds ratio, 6.9; 95% confidence interval, 4.1-11.6; P < .001), and postoperative intensive care unit length of stay (coefficient, 2.3; 95% confidence interval, 2.0-2.6; P < .001) after adjusting for other covariates. Conclusions The TPS is strongly associated with early outcomes across a wide range of ages and disease complexity and can serve as important tool for self-assessment and quality improvement.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objective We have previously shown that surgical Technical Performance Scores (TPS) are important predictors of early postoperative morbidity across a wide spectrum of procedures and that ...intraoperative recognition and intervention of residual defects resulted in improved outcomes. We hypothesized that these scores would also be important predictors of midterm outcomes. Methods Neonates and infants aged younger 6 months were prospectively followed from the index surgery for a minimum of 1 year. The TPS were calculated using previously published criteria, including intraoperative course, predischarge echocardiograms or catheterizations, and clinical data, and graded as optimal, adequate, or inadequate. Case complexity was determined by the Risk Adjustment for Congenital Heart Surgery-1 category. The primary outcome was mortality, and the secondary outcome was the need for unplanned reinterventions. Outcomes were analyzed using nonparametric methods and a logistic regression model. Results A total of 166 patients were included in our study, with 7 early deaths. The remaining 159 patients (Risk Adjustment for Congenital Heart Surgery-1 category 4-6, 76 48%; neonates, 78 49%) were followed for a minimum of 1 year after surgery. There were 14 late deaths or late transplantations and 55 late reinterventions. On univariate analysis, the TPS were associated with mortality ( P < .001) and reintervention ( P = .04). On logistic regression analysis, inadequate TPS was associated with late mortality ( P < .001; odds ratio, 7.2; 95% confidence interval, 2.2-23.6), and Risk Adjustment for Congenital Heart Surgery-1 category ( P = .004; odds ratio, 3.7; 1.5-8.8) at index surgery was associated with need for late unplanned reintervention. Conclusions Technical performance affects midterm survival after infant heart surgery. Inadequate TPS can be used to prospectively identify patients at ongoing risk of demise and the need for reintervention. An aggressive approach to diagnosing and treating residual lesions at the initial operation is warranted.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objective Endovascular interventions for critical limb ischemia (CLI) continue to have variable reported results. The purpose of this study is to determine the effect of disease level and ...distribution on the outcomes of tibial interventions. Methods A retrospective analysis of all tibial interventions done for CLI between 2006 and 2009 was performed. Outcomes of isolated tibial (group I) and multilevel interventions (group II) (femoropopliteal and tibial) were compared. Results Endovascular interventions were utilized to treat 136 limbs in 123 patients for CLI: 54 isolated tibial (85% tissue loss), and 82 multilevel (80% tissue loss). Mean age and baseline comorbidities were comparable. The mean ankle-brachial index (ABI) was significantly lower prior to intervention in group II (0.53 vs 0.74; P < .001) but was similar postintervention (0.86 vs 0.88; P = NS). Wound healing or improvement was achieved in 69% in group I and in 87% in group II ( P = .05). Mean overall follow-up was 12.6 ± 5.3 months. Time to healing was significantly longer in group I: 11.5 ± 8.8 months vs 7.7 ± 6.6 months ( P = .03). Limb salvage was achieved in 81% of group I and 95% of group II ( P = .05). The rate of reintervention was similar (13% vs 18%, P = NS), so was the rate of late surgical conversion (0% vs 6%; P = NS). Limb loss resulted from lack of conduit or initial target vessel for bypass and high-risk systemic comorbidities. Overall mortality rates were similar among both groups. An isolated tibial intervention was a predictor of limb loss at 1 year on multivariate analysis and resulted in a lower rate of limb salvage at 1 year compared with multilevel interventions. Additionally, despite comparable primary patency rates, there was improved secondary patency with multilevel interventions compared with the isolated tibial interventions. Predictors of limb loss in patients treated with isolated tibial intervention included multiple synchronous tibial revascularization ( P = .005) and advanced coronary artery disease requiring revascularization ( P = .005). Conclusions Adequate rates of limb salvage can be achieved in patients undergoing multilevel interventions for CLI, and improved patency is seen with multilevel compared to isolated tibial interventions. Patients with isolated tibial disease appear to have a higher incidence of limb loss secondary to poor initial pedal runoff, more extensive distal disease, and severe comorbidities precluding surgical bypass. Other therapeutic strategies should be considered in these patients, including primary amputation or pedal bypass when applicable.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Background More than 3.8 million children sustain traumatic brain injuries annually. Treatment of posttraumatic headache (PTH) in the emergency department (ED) is variable, and benefits are ...unclear. Objective The objective of the study is to determine if intravenous migraine therapy reduces pain scores in children with PTH and factors associated with improved response. Methods This was a retrospective study of children, 8 to 21 years old, presenting to a tertiary pediatric ED with mild traumatic brain injury (mTBI) and PTH from November 2009 to June 2013. Inclusion criteria were mTBI (defined by diagnosis codes) within 14 days of ED visit, headache, and administration of one or more intravenous medications: ketorolac, prochlorperazine, metoclopramide, chlorpromazine, and ondansetron. Primary outcome was treatment success defined by greater than or equal to 50% pain score reduction during ED visit. Bivariate analysis and logistic regression were used to determine predictors of treatment success: age, sex, migraine or mTBI history, time since injury, ED head computed tomographic (CT) imaging, and pretreatment with oral analgesics. Results A total of 254 patients were included. Mean age was 13.8 years, 51% were female, 80% were white, mean time since injury was 2 days, and 114 patients had negative head CTs. Eighty-six percent of patients had treatment success with 52% experiencing complete resolution of headache. Bivariate analysis showed that patients who had a head CT were less likely to respond (80% vs 91%; P = .008). Conclusions Intravenous migraine therapy reduces PTH pain scores for children presenting within 14 days after mTBI. Further prospective work is needed to determine long-term benefits of acute PTH treatment in the ED.
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