Summary Background Bevacizumab has been suggested to have similar effectiveness to ranibizumab for treatment of neovascular age-related macular degeneration. The Inhibition of VEGF in Age-related ...choroidal Neovascularisation (IVAN) trial was designed to compare these drugs and different regimens. Here, we report the findings at the prespecified 2-year timepoint. Methods In a multicentre, 2×2 factorial, non-inferiority randomised trial, we enrolled adults aged at least 50 years with active, previously untreated neovascular age-related macular degeneration and a best corrected distance visual acuity (BCVA) of at least 25 letters from 23 hospitals in the UK. Participants were randomly assigned (1:1:1:1) to intravitreal injections of ranibizumab (0·5 mg) or bevacizumab (1·25 mg) in continuous (every month) or discontinuous (as needed) regimens, with monthly review. Study participants and clinical assessors were masked to drug allocation. Allocation to continuous or discontinuous treatment was masked up to 3 months, at which point investigators and participants were unmasked. The primary outcome was BCVA at 2 years, with a prespecified non-inferiority limit of 3·5 letters. The primary safety outcome was arterial thrombotic event or hospital admission for heart failure. Analyses were by modified intention to treat. This trial is registered, number ISRCTN92166560. Findings Between March 27, 2008, and Oct 15, 2010, 628 patients underwent randomisation. 18 were withdrawn; 610 received study drugs (314 ranibizumab; 296 bevacizumab) and were included in analyses. 525 participants reached the visit at 2 years: 134 ranibizumab in continuous regimen, 137 ranibizumab in discontinuous regimen, 127 bevacizumab in continuous regimen, and 127 bevacizumab in discontinuous regimen. For BCVA, bevacizumab was neither non-inferior nor inferior to ranibizumab (mean difference −1·37 letters, 95% CI −3·75 to 1·01; p=0·26). Discontinuous treatment was neither non-inferior nor inferior to continuous treatment (−1·63 letters, −4·01 to 0·75; p=0·18). Frequency of arterial thrombotic events or hospital admission for heart failure did not differ between groups given ranibizumab (20 6% of 314 participants) and bevacizumab (12 4% of 296; odds ratio OR 1·69, 95% CI 0·80–3·57; p=0·16), or those given continuous (12 4% of 308) and discontinuous treatment (20 7% of 302; 0·56, 0·27–1·19; p=0·13). Mortality was lower with continuous than discontinuous treatment (OR 0·47, 95% CI 0·22–1·03; p=0·05), but did not differ by drug group (0·96, 0·46–2·02; p=0·91). Interpretation Ranibizumab and bevacizumab have similar efficacy. Reduction in the frequency of retreatment resulted in a small loss of efficacy irrespective of drug. Safety was worse when treatment was administered discontinuously. These findings highlight that the choice of anti-VEGF treatment strategy is less straightforward than previously thought. Funding UK National Institute for Health Research Health Technology Assessment programme.
Abstract Background Although generally better outcomes are reported in patients undergoing early repair of type A aortic dissection, patients who survive the first 48 hours self-select themselves ...toward better outcomes as well. Malperfusion is another important determinant of outcome in these patients. The aim of this study was to examine the hypothesis that malperfusion, not the timing of operation, is the dominant determinant of outcome in repair of type A aortic dissection. Methods A total of 205 patients underwent operative repair of acute type A aortic dissection in our hospital over a 17-year period. The time from symptom onset to surgical repair was reliably established in 152 cases. Patients were grouped into those who had undergone surgery within 12 hours of symptom onset (early surgery group; n = 72 47%) and those who underwent surgery beyond 12 hours of symptom onset (late surgery group; n = 80 53%). Results Thirty-day mortality was similar in the 2 groups (early surgery: 19.4% 95% confidence interval CI 12.0%-30.6%; late surgery: 13.8% 95% CI, 7.9%-23.5%; P = .08). The log-rank test for equality of survivor functions was 0.08. However, malperfusion with hemodynamic compromise was more common in the early surgery group (47% vs 31%; P = .029) and was identified as an independent predictor of long-term mortality (hazard ratio, 2.65; 95% CI, 1.21-5.79; P = .014). Conclusions Malperfusion at presentation rather than timing of intervention is the major risk factor of death both in the hospital and at long-term follow-up in patients undergoing surgery for type A aortic dissection.
Abstract Pain in cancer patients is common, yet it is often inadequately managed. Although poor assessment has been implicated, how patients contribute to this process has not been explicated. This ...study aims to uncover patients' contributions to discussions about pain during oncology outpatient consultations. Seventy-four medical encounters were observed and audiotaped. Verbatim transcriptions of pain talk were examined using conversational analysis. Thirty-nine of 74 patients talked about pain with 15 different doctors during consultations for follow-up or active treatment. Patients' talk about pain varied consistently according to how pain talk was initiated. In 20 consultations where pain was put on the agenda by patients, they used communication tactics that emphasized their pain experiences, seemingly to attract and maintain their doctors' attention. These tactics appear necessary, as the cancer treatment agenda restricts opportunities for patients to have supportive care needs addressed. On the other hand, in 19 consultations where doctors elicited information about pain, patients used communication tactics that minimized their pain experiences, seemingly to conceal potential disease progression or recurrence, the very focus of these specialist consultations. Where cancer was implicated as the source of pain, chemotherapy or radiotherapy was offered, and where cancer was suspected, referrals for investigations were made. Two of the 20 patients appeared to influence the treatment-focused agenda and were given referrals to pain clinic rather than further cancer therapy as initially recommended.
Many countries are exploring the potential of telehealth interventions to manage the rising number of people with chronic disorders. However, evidence of the effectiveness of telehealth is ambiguous. ...Based on an evidence-based conceptual framework, we developed an integrated telehealth service (the Healthlines Service) for chronic disorders and assessed its effectiveness in patients with depression. We aimed to compare the Healthlines Depression Service plus usual care with usual care alone.
This study was a pragmatic, multicentre, randomised controlled trial with participants recruited from 43 general practices in three areas of England. To be eligible, participants needed to have access to the internet and email, a Patient Health Questionnaire 9 (PHQ-9) score of at least 10, and a confirmed diagnosis of depression. Participants were individually assigned (1:1) to either the Healthlines Depression Service plus usual care or usual care alone. Random assignment was done by use of a web-based automated randomisation system, stratified by site and minimised by practice and PHQ-9 score. Participants were aware of their allocation, but outcomes were analysed masked. The Healthlines Service consisted of regular telephone calls from non-clinical, trained health advisers who followed standardised scripts generated by interactive software. After an initial assessment and goal-setting telephone call, the advisers called each participant on six occasions over 4 months, and then made up to three more calls at intervals of roughly 2 months to provide reinforcement and to detect relapse. Advisers supported participants in the use of online resources (including computerised cognitive behavioural therapy) and sought to encourage healthier lifestyles, optimise medication, and improve treatment adherence. The primary outcome was the proportion of participants responding to the intervention (defined as PHQ-9 <10 and reduction in PHQ-9 of ≥5 points) at 4 months after randomisation. The primary analysis was based on the intention-to-treat principle without imputation and all serious adverse events were investigated. This trial is registered with Current Controlled Trials, number ISRCTN 14172341.
Between July 24, 2012, and July 31, 2013, we recruited 609 participants, randomly assigning 307 to the Healthlines Service plus usual care and 302 to usual care. Primary outcome data were available for 525 (86%) participants. At 4 months, 68 (27%) of 255 individuals in the intervention group had a treatment response compared with 50 (19%) of 270 individuals in the usual care group (adjusted odds ratio 1·7, 95% CI 1·1–2·5, p=0·019). Compared with usual care alone, intervention participants reported improvements in anxiety, better access to support and advice, greater satisfaction with the support they received, and improvements in self-management and health literacy. During the trial, 70 adverse events were reported by participants, one of which was related to the intervention (increased anxiety from discussing depression) and was not serious.
This telehealth service based on non-clinically trained health advisers supporting patients in use of internet resources was both acceptable and effective compared with usual care. Our results provide support for the development and assessment of similar interventions in other chronic disorders to expand care provision.
National Institute for Health Research (NIHR).
Objective To determine neurodevelopmental outcome at 2 years' corrected age in children randomized to treatment with dextrose gel or placebo for hypoglycemia soon after birth (The Sugar Babies ...Study). Study design This was a follow-up study of 184 children with hypoglycemia (<2.6 mM 47 mg/dL) in the first 48 hours and randomized to either dextrose (90/118, 76%) or placebo gel (94/119, 79%). Assessments were performed at Kahikatea House, Hamilton, New Zealand, and included neurologic function and general health (pediatrician assessed), cognitive, language, behavior, and motor skills (Bayley Scales of Infant and Toddler Development, Third Edition), executive function (clinical assessment and Behaviour Rating Inventory of Executive Function-Preschool Edition), and vision (clinical examination and global motion perception). Coprimary outcomes were neurosensory impairment (cognitive, language or motor score below −1 SD or cerebral palsy or blind or deaf) and processing difficulty (executive function or global motion perception worse than 1.5 SD from the mean). Statistical tests were two sided with 5% significance level. Results Mean (±SD) birth weight was 3093 ± 803 g and mean gestation was 37.7 ± 1.6 weeks. Sixty-six children (36%) had neurosensory impairment (1 severe, 6 moderate, 59 mild) with similar rates in both groups (dextrose 38% vs placebo 34%, relative risk 1.11, 95% CI 0.75-1.63). Processing difficulty also was similar between groups (dextrose 10% vs placebo 18%, relative risk 0.52, 95% CI 0.23-1.15). Conclusions Dextrose gel is safe for the treatment of neonatal hypoglycemia, but neurosensory impairment is common among these children. Trial registration Australian New Zealand Clinical Trials Registry: ACTRN 12608000623392.
Summary Background Childhood CNS primitive neuro-ectodermal brain tumours (PNETs) are very aggressive brain tumours for which the molecular features and best treatment approaches are unknown. We ...assessed a large cohort of these rare tumours to identify molecular markers to enhance clinical management of this disease. Methods We obtained 142 primary hemispheric CNS PNET samples from 20 institutions in nine countries and examined transcriptional profiles for a subset of 51 samples and copy number profiles for a subset of 77 samples. We used clustering, gene, and pathway enrichment analyses to identify tumour subgroups and group-specific molecular markers, and applied immunohistochemical and gene-expression analyses to validate and assess the clinical significance of the subgroup markers. Findings We identified three molecular subgroups of CNS PNETs that were distinguished by primitive neural (group 1), oligoneural (group 2), and mesenchymal lineage (group 3) gene-expression signatures with differential expression of cell-lineage markers LIN28 and OLIG2. Patients with group 1 tumours were most often female (male:female ratio 0·61 for group 1 vs 1·25 for group 2 and 1·63 for group 3; p=0·043 group 1 vs groups 2 and 3), youngest (median age at diagnosis 2·9 years 95% CI 2·4–5·2 for group 1 vs 7·9 years 6·0–9·7 for group 2 and 5·9 years 4·9–7·8 for group 3; p=0·005), and had poorest survival (median survival 0·8 years 95% CI 0·5–1·2 in group 1, 1·8 years 1·4–2·3 in group 2 and 4·3 years 0·8–7·8 in group 3; p=0·019). Patients with group 3 tumours had the highest incidence of metastases at diagnosis (no distant metastasis:metastasis ratio 0·90 for group 3 vs 2·80 for group 1 and 5·67 for group 2; p=0·037). Interpretation LIN28 and OLIG2 are promising diagnostic and prognostic molecular markers for CNS PNET that warrant further assessment in prospective clinical trials. Funding Canadian Institute of Health Research, Brainchild/SickKids Foundation, and the Samantha Dickson Brain Tumour Trust.
Objective Our objective was to compare off-pump coronary artery bypass surgery carried out via a left anterolateral thoracotomy (ThoraCAB) or via a conventional median sternotomy (OPCAB). Background ...Recent advances in minimally invasive cardiac surgery have extended the technique to allow complete surgical revascularization on the beating heart via thoracotomy. Methods Patients undergoing nonemergency primary surgery were enrolled between February 2007 and September 2009 at 2 centers. The primary outcome was the time from surgery to fitness for hospital discharge as defined by objective criteria. Results A total of 93 patients were randomized to off-pump coronary artery bypass surgery via a median sternotomy (OPCAB) and 91 to off-pump coronary artery bypass surgery via a left anterolateral thoracotomy (ThoraCAB). The surgery was longer for patients in the ThoraCAB group (median, 4.1 vs 3.3 hours) and there were fewer with more than 3 grafts (2% vs 17%). The median time from surgery to fitness for discharge was 6 days (interquartile range, 4-7) in the ThoraCAB group versus 5 days (interquartile range, 4-7) in the OPCAB group ( P = .53). The intubation time was shorter, by on average 65 minutes, in the ThoraCAB group ( P = .017), although the time in intensive care was similar ( P = .91). Pain scores were similar ( P = .97), but more analgesia was required in the ThoraCAB group (median duration, 38.8 vs 35.5 hours, P < .001; tramadol use, 66% vs 49%, P = .024). ThoraCAB was associated with significantly worse lung function at discharge (average difference, −0.25 L, P = .01) but quality of life scores at 3 and 12 months were similar ( P = .52). The average total cost was 10% higher with ThoraCAB ( P = .007). Conclusions ThoraCAB resulted in no overall clinical benefit relative to OPCAB.
Objectives This study investigates the effects of controlled reoxygenation cardiopulmonary bypass on oxidative stress, inflammatory response, and organ function in children undergoing repair of ...cyanotic congenital heart defects. Methods Sixty-seven cyanotic patients (median age 15 months, interquartile range 6–49 months) undergoing corrective cardiac surgery were randomized to receive either controlled normoxic (50–0 mm Hg; n = 35) or hyperoxic (150–180 mm Hg; n = 32) cardiopulmonary bypass. Troponin I and 8-isoprostane, C3a, interleukins 6, 8, and 10, cortisol, protein S100, and alpha-glutamate transferase were measured preoperatively and 10 and 30 minutes after starting bypass, on removal of the aortic crossclamp, and 12 and 24 hours thereafter. Results Overall, troponin I and 8-isoprostane levels were lower in the controlled normoxic group (−29%, 95% CI −48% to −3%, P = .03, and −26%, 95% CI −44% to −2%, P = .03, respectively). Protein S100 release was also lower in the normoxic group 10 minutes after starting bypass (−26%, 95% CI −40% to −9%, P = .005) and 10 minutes after aortic crossclamp removal (−23%, 95% CI −38% to −3%, P = .02, respectively), but similar at other time points in the two groups ( P ≥ .17). The alpha-glutamate transferase release was significantly lower in the normoxic group 10 minutes after aortic crossclamp removal (−28%, 95% CI −44% to −9%, P = .006, respectively) but was similar at other times ( P ≥ .11). Release of C3a, interleukins 6, 8, and 10, and cortisol was similar in the two groups throughout ( P ≥ .15). Conclusion Controlled reoxygenation on starting cardiopulmonary bypass is associated with reduced myocardial damage, oxidative stress, and cerebral and hepatic injury compared with hyperoxic bypaass and similar whole body inflammatory and stress response in cyanotic children undergoing open cardiac surgery.
Propofol cardioplegia: A single-center, placebo-controlled, randomized controlled trial Rogers, Chris A., PhD; Bryan, Alan J., DM, FRCS (CTh); Nash, Rachel, MSc ...
Journal of thoracic and cardiovascular surgery/The Journal of thoracic and cardiovascular surgery/The journal of thoracic and cardiovascular surgery,
12/2015, Volume:
150, Issue:
6
Journal Article
Peer reviewed
Open access
Abstract Objectives Cardiac surgery with cardiopulmonary bypass and cardioplegic arrest is an effective treatment for coronary artery and aortic valve diseases. However, the myocardium sustains ...reperfusion injury after ischemic cardioplegic arrest. Our objective was to assess the benefits of supplementing cardioplegia solution with the general anesthetic propofol in patients undergoing either coronary artery bypass grafting (CABG) or aortic valve replacement (AVR). Methods A single-center, double-blind randomized controlled trial was carried out to compare cardioplegia solution supplemented with propofol (concentration 6 μg/mL) versus intralipid (placebo). The primary outcome was cardiac troponin T release over the first 48 hours after surgery. Results We recruited 101 participants (51 in the propofol group, 50 in the intralipid group); 61 underwent CABG and 40 underwent AVR. All participants were followed to 3 months. Cardiac troponin T release was on average 15% lower with propofol supplementation (geometric mean ratio, 0.85; 95% confidence interval CI, 0.73-1.01; P = .051). There were no differences for CABG participants but propofol-supplemented participants undergoing AVR had poorer postoperative renal function (geometric mean ratio, 1.071; 95% CI, 1.019-1.125; P = .007), with a trend toward longer intensive care stay (median, 89.5 vs 47.0 hours; hazard ratio, 0.58; 95% CI, 0.31-1.09; P = .09) and fewer with perfect health (based on the EQ-5D health utility index) at 3 months (odds ratio, 0.26; 95% CI, 0.06-1.05; P = .058) compared with the intralipid group. Safety profiles were similar. There were no deaths. Conclusions Propofol supplementation in cardioplegia appears to be cardioprotective. Its influence on early clinical outcomes may differ between CABG and AVR surgery. A larger, multicenter study is needed to confirm or refute these suggestions.
To determine if prespecified genetic polymorphisms influence responsiveness to vascular endothelial growth factor (VEGF) inhibition in neovascular age-related macular degeneration (nAMD). The ...objectives were to replicate 3 reported pharmacogenetic associations of response in nAMD and to test for novel associations.
Cohort study, combining information about patients' genotypes with information from a randomized controlled trial about responsiveness to anti-VEGF therapy for nAMD.
Five hundred nine participants with nAMD, enrolled in the Alternative Treatments to Inhibit VEGF in Patients with Age-Related Choroidal Neovascularisation (IVAN) trial.
Participants were classified as responders or nonresponders to VEGF inhibition based on the optical coherence tomography (OCT) metric of total retinal thickness (TRT). We computed the change in TRT from baseline to the latest time point for which OCT data were available (3, 6, 9, or 12 months). Eyes with changes in TRT greater than or equal to the 75th percentile or more were classified as responders, and those with changes less than or equal to the 25th percentile or lower were classified as non-responders. Three previously reported associations of response to VEGF inhibition in nAMD involving single nucleotide polymorphisms (SNPs) at the CFH, FZD4, and HTRA1/ARMS2 loci were tested for replication. An additional 482 SNPs also were tested using a candidate gene approach. Associations were estimated as odds ratios (ORs) with confidence intervals (CIs).
The primary outcome was evidence of a genetic association with response to VEGF inhibition as measured by change in TRT.
One hundred twenty-six participants were classified as responders and 128 were classified as nonresponders. The SNP rs10490924 in HTRA1/ARMS2 showed a borderline association with responsiveness after Bonferroni correction (OR, 1.53; CI, 0.99-2.36; P = 0.055, Bonferroni correction). None of the other 484 additional SNPs tested for association was significant after Bonferroni correction for multiple testing. The smallest corrected P value was 0.84 (P = 0.002, uncorrected) for rs9679290 in the EPAS1 (HIF2A) gene on chromosome 2. Four of the 10 most significant results were in this gene.
We estimated pharmacogenetic associations using high-quality phenotype data from a randomized controlled clinical trial of nAMD. No significant association or replication of previous associations were observed. Further investigation of the EPAS1 (HIF2A) gene, however, may, be merited.
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