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 Findings Between March 27, 2008, and Oct 15, 2010, 628 patients underwent randomisation. 18 were withdrawn; 610 received study drugs (314 ranibizumab; 296 bevacizumab) and were included in analyses. 525 participants reached the visit at 2 years: 134 ranibizumab in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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
In this study, patients were randomly assigned to a transfusion threshold of 9 or 7.5 g per deciliter after cardiac surgery. There was no significant between-group difference in infectious or ...ischemic events, but more deaths were associated with the lower threshold.
Perioperative anemia is common after cardiac surgery and is associated with significant increases in morbidity and mortality.
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The transfusion of allogeneic red cells is the preferred treatment for acute anemia and is also used in patients undergoing cardiac surgery; typically, more than 50% of patients receive a perioperative transfusion,
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which uses a substantial proportion of blood supplies.
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Observational studies suggest that transfusion is harmful after cardiac surgery; associations have been reported between transfusion and infection, low cardiac output, acute kidney injury, and death.
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In contrast, randomized, controlled trials of red-cell transfusion with restrictive thresholds (i.e., transfusions . . .
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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The aim of this study was to emulate the MERINO trial of piperacillin-tazobactam vs meropenem for the definitive treatment of bloodstream infection (BSI) caused by ceftriaxone-nonsusceptible E coli ...or Klebsiella spp.
Data from an observational study of BSI and a randomised controlled trial of a rapid diagnostic in BSI were used to emulate the MERINO trial. The primary outcome of the emulated trial was 28-day mortality after blood culture. Outcomes were compared using logistic regression adjusted for propensity score for emulated intervention.
Of the 6,371 observational study and RCT participants, 1,968 had a bloodstream infection with E. coli or Klebsiella spp. of which 121 met the eligibility criteria. In the emulated trial, a total of 14/82 patients (17.1%) allocated to piperacillin-tazobactam met the primary outcome compared with 6/39 (15.4%) in the meropenem group (unadjusted odds ratio 1.13 (95% CI 0.40 to 3.21)). After adjustment for propensity score, the odds ratio increased to 1.31 (95% CI 0.40 to 4.26). This difference is in the same direction but of a smaller magnitudethan observed in the MERINO trial, where 30-day mortality was met by 23/187 patients (12.3%) in the piperacillin-tazobactam and 7/191 (3.7%) in the meropenem group (unadjusted odds ratio of 3.69 (95% CI 1.48 to 10.41)).
The mortality rate in an emulated trial population was more than double the mortality rate in the MERINO trial. The methodology used attempts to address the concern that previous results could be explained by biases such as selection bias and uncontrolled confounding and provides information on how a trial such as the MERINO trial may have performed in the NHS.
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Red blood cell transfusion can both benefit and harm. To inform decisions about transfusion, we aimed to quantify associations of transfusion with clinical outcomes and cost in patients having ...cardiac surgery.
Clinical, hematology, and blood transfusion databases were linked with the UK population register. Additional hematocrit information was obtained from intensive care unit charts. Composite infection (respiratory or wound infection or septicemia) and ischemic outcomes (myocardial infarction, stroke, renal impairment, or failure) were prespecified as coprimary end points. Secondary outcomes were resource use, cost, and survival. Associations were estimated by regression modeling with adjustment for potential confounding. All adult patients having cardiac surgery between April 1, 1996, and December 31, 2003, with key exposure and outcome data were included (98%). Adjusted odds ratios for composite infection (737 of 8516) and ischemic outcomes (832 of 8518) for transfused versus nontransfused patients were 3.38 (95% confidence interval CI, 2.60 to 4.40) and 3.35 (95% CI, 2.68 to 4.35), respectively. Transfusion was associated with increased relative cost of admission (any transfusion, 1.42 times 95% CI, 1.37 to 1.46, varying from 1.11 for 1 U to 3.35 for >9 U). At any time after their operations, transfused patients were less likely to have been discharged from hospital (hazard ratio HR, 0.63; 95% CI, 0.60 to 0.67) and were more likely to have died (0 to 30 days: HR, 6.69; 95% CI, 3.66 to 15.1; 31 days to 1 year: HR, 2.59; 95% CI, 1.68 to 4.17; >1 year: HR, 1.32; 95% CI, 1.08 to 1.64).
Red blood cell transfusion in patients having cardiac surgery is strongly associated with both infection and ischemic postoperative morbidity, hospital stay, increased early and late mortality, and hospital costs.
To compare the efficacy and safety of ranibizumab and bevacizumab intravitreal injections to treat neovascular age-related macular degeneration (nAMD).
Multicenter, noninferiority factorial trial ...with equal allocation to groups. The noninferiority limit was 3.5 letters. This trial is registered (ISRCTN92166560).
People >50 years of age with untreated nAMD in the study eye who read ≥ 25 letters on the Early Treatment Diabetic Retinopathy Study chart.
We randomized participants to 4 groups: ranibizumab or bevacizumab, given either every month (continuous) or as needed (discontinuous), with monthly review.
The primary outcome is at 2 years; this paper reports a prespecified interim analysis at 1 year. The primary efficacy and safety outcome measures are distance visual acuity and arteriothrombotic events or heart failure. Other outcome measures are health-related quality of life, contrast sensitivity, near visual acuity, reading index, lesion morphology, serum vascular endothelial growth factor (VEGF) levels, and costs.
Between March 27, 2008 and October 15, 2010, we randomized and treated 610 participants. One year after randomization, the comparison between bevacizumab and ranibizumab was inconclusive (bevacizumab minus ranibizumab -1.99 letters, 95% confidence interval CI, -4.04 to 0.06). Discontinuous treatment was equivalent to continuous treatment (discontinuous minus continuous -0.35 letters; 95% CI, -2.40 to 1.70). Foveal total thickness did not differ by drug, but was 9% less with continuous treatment (geometric mean ratio GMR, 0.91; 95% CI, 0.86 to 0.97; P = 0.005). Fewer participants receiving bevacizumab had an arteriothrombotic event or heart failure (odds ratio OR, 0.23; 95% CI, 0.05 to 1.07; P = 0.03). There was no difference between drugs in the proportion experiencing a serious systemic adverse event (OR, 1.35; 95% CI, 0.80 to 2.27; P = 0.25). Serum VEGF was lower with bevacizumab (GMR, 0.47; 95% CI, 0.41 to 0.54; P<0.0001) and higher with discontinuous treatment (GMR, 1.23; 95% CI, 1.07 to 1.42; P = 0.004). Continuous and discontinuous treatment costs were £9656 and £6398 per patient per year for ranibizumab and £1654 and £1509 for bevacizumab; bevacizumab was less costly for both treatment regimens (P<0.0001).
The comparison of visual acuity at 1 year between bevacizumab and ranibizumab was inconclusive. Visual acuities with continuous and discontinuous treatment were equivalent. Other outcomes are consistent with the drugs and treatment regimens having similar efficacy and safety.
Proprietary or commercial disclosures may be found after the references.
IMPORTANCE: The optimal approach to airway management during out-of-hospital cardiac arrest is unknown. OBJECTIVE: To determine whether a supraglottic airway device (SGA) is superior to tracheal ...intubation (TI) as the initial advanced airway management strategy in adults with nontraumatic out-of-hospital cardiac arrest. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, cluster randomized clinical trial of paramedics from 4 ambulance services in England responding to emergencies for approximately 21 million people. Patients aged 18 years or older who had a nontraumatic out-of-hospital cardiac arrest and were treated by a participating paramedic were enrolled automatically under a waiver of consent between June 2015 and August 2017; follow-up ended in February 2018. INTERVENTIONS: Paramedics were randomized 1:1 to use TI (764 paramedics) or SGA (759 paramedics) as their initial advanced airway management strategy. MAIN OUTCOMES AND MEASURES: The primary outcome was modified Rankin Scale score at hospital discharge or 30 days after out-of-hospital cardiac arrest, whichever occurred sooner. Modified Rankin Scale score was divided into 2 ranges: 0-3 (good outcome) or 4-6 (poor outcome; 6 = death). Secondary outcomes included ventilation success, regurgitation, and aspiration. RESULTS: A total of 9296 patients (4886 in the SGA group and 4410 in the TI group) were enrolled (median age, 73 years; 3373 were women 36.3%), and the modified Rankin Scale score was known for 9289 patients. In the SGA group, 311 of 4882 patients (6.4%) had a good outcome (modified Rankin Scale score range, 0-3) vs 300 of 4407 patients (6.8%) in the TI group (adjusted risk difference RD, −0.6% 95% CI, −1.6% to 0.4%). Initial ventilation was successful in 4255 of 4868 patients (87.4%) in the SGA group compared with 3473 of 4397 patients (79.0%) in the TI group (adjusted RD, 8.3% 95% CI, 6.3% to 10.2%). However, patients randomized to receive TI were less likely to receive advanced airway management (3419 of 4404 patients 77.6% vs 4161 of 4883 patients 85.2% in the SGA group). Two of the secondary outcomes (regurgitation and aspiration) were not significantly different between groups (regurgitation: 1268 of 4865 patients 26.1% in the SGA group vs 1072 of 4372 patients 24.5% in the TI group; adjusted RD, 1.4% 95% CI, −0.6% to 3.4%; aspiration: 729 of 4824 patients 15.1% vs 647 of 4337 patients 14.9%, respectively; adjusted RD, 0.1% 95% CI, −1.5% to 1.8%). CONCLUSIONS AND RELEVANCE: Among patients with out-of-hospital cardiac arrest, randomization to a strategy of advanced airway management with a supraglottic airway device compared with tracheal intubation did not result in a favorable functional outcome at 30 days. TRIAL REGISTRATION: ISRCTN Identifier: 08256118
Randomised controlled trials (RCTs) are essential for evidence-based medicine and increasingly rely on front-line clinicians to recruit eligible patients. Clinicians' difficulties with negotiating ...equipoise is assumed to undermine recruitment, although these issues have not yet been empirically investigated in the context of observable events. We aimed to investigate how clinicians conveyed equipoise during RCT recruitment appointments across six RCTs, with a view to (i) identifying practices that supported or hindered equipoise communication and (ii) exploring how clinicians' reported intentions compared with their actual practices.
Six pragmatic UK-based RCTs were purposefully selected to include several clinical specialties (e.g., oncology, surgery) and types of treatment comparison. The RCTs were all based in secondary-care hospitals (n = 16) around the UK. Clinicians recruiting to the RCTs were interviewed (n = 23) to understand their individual sense of equipoise about the RCT treatments and their intentions for communicating equipoise to patients. Appointments in which these clinicians presented the RCT to trial-eligible patients were audio-recorded (n = 105). The appointments were analysed using thematic and content analysis approaches to identify practices that supported or challenged equipoise communication. A sample of appointments was independently coded by three researchers to optimise reliability in reported findings. Clinicians and patients provided full written consent to be interviewed and have appointments audio-recorded. Interviews revealed that clinicians' sense of equipoise varied: although all were uncertain about which trial treatment was optimal, they expressed different levels of uncertainty, ranging from complete ambivalence to clear beliefs that one treatment was superior. Irrespective of their personal views, all clinicians intended to set their personal biases aside to convey trial treatments neutrally to patients (in accordance with existing evidence). However, equipoise was omitted or compromised in 48/105 (46%) of the recorded appointments. Three commonly recurring practices compromised equipoise communication across the RCTs, irrespective of clinical context. First, equipoise was overridden by clinicians offering treatment recommendations when patients appeared unsure how to proceed or when they asked for the clinician's expert advice. Second, clinicians contradicted equipoise by presenting imbalanced descriptions of trial treatments that conflicted with scientific information stated in the RCT protocols. Third, equipoise was undermined by clinicians disclosing their personal opinions or predictions about trial outcomes, based on their intuition and experience. These broad practices were particularly demonstrated by clinicians who had indicated in interviews that they held less balanced views about trial treatments. A limitation of the study was that clinicians volunteering to take part in the research might have had a particular interest in improving their communication skills. However, the frequency of occurrence of equipoise issues across the RCTs suggests that the findings are likely to be reflective of clinical recruiters' practices more widely.
Communicating equipoise is a challenging process that is easily disrupted. Clinicians' personal views about trial treatments encroached on their ability to convey equipoise to patients. Clinicians should be encouraged to reflect on personal biases and be mindful of the common ways in which these can arise in their discussions with patients. Common pitfalls that recurred irrespective of RCT context indicate opportunities for specific training in communication skills that would be broadly applicable to a wide clinical audience.
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Descriptions are provided of the aerosol classification algorithms and the extinction-to-backscatter ratio (lidar ratio) selection schemes for the Cloud-Aerosol Lidar and Infrared Pathfinder ...Satellite Observations (CALIPSO) aerosol products. One year of CALIPSO level 2 version 2 data are analyzed to assess the veracity of the CALIPSO aerosol-type identification algorithm and generate vertically resolved distributions of aerosol types and their respective optical characteristics. To assess the robustness of the algorithm, the interannual variability is analyzed by using a fixed season (June-August) and aerosol type (polluted dust) over two consecutive years (2006 and 2007). The CALIPSO models define six aerosol types: clean continental, clean marine, dust, polluted continental, polluted dust, and smoke, with 532-nm (1064 nm) extinction-to-backscatter ratios S sub(a) of 35 (30), 20 (45), 40 (55), 70 (30), 65 (30), and 70 (40) sr, respectively. This paper presents the global distributions of the CALIPSO aerosol types, the complementary distributions of integrated attenuated backscatter, and the volume depolarization ratio for each type. The aerosol-type distributions are further partitioned according to surface type (land/ocean) and detection resolution (5, 20, and 80 km) for optical and spatial context, because the optically thick layers are found most often at the smallest spatial resolution. Except for clean marine and polluted continental, all the aerosol types are found preferentially at the 80-km resolution. Nearly 80% of the smoke cases and 60% of the polluted dust cases are found over water, whereas dust and polluted continental cases are found over both land and water at comparable frequencies. Because the CALIPSO observables do not sufficiently constrain the determination of the aerosol, the surface type is used to augment the selection criteria. Distributions of the total attenuated color ratios show that the use of surface type in the typing algorithm does not result in abrupt and artificial changes in aerosol type or extinction.
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Bariatric surgery is considered an effective treatment for individuals with severe and complex obesity. Besides reducing weight and improving obesity related comorbidities such as diabetes, bariatric ...surgery could improve patients' health-related quality of life. However, the frequently used instrument to measure quality of life, the EQ-5D has not been validated for use in bariatric surgery, which is a major limitation to its use in this clinical context. Our study undertook a psychometric validation of the 5 level EQ-5D (EQ-5D-5L) using clinical trial data to measure health-related quality of life in patients with severe and complex obesity undergoing bariatric surgery. Health-related quality of life was assessed at baseline (before randomisation) and six months later in 189 patients in a randomised controlled trial of bariatric surgery. Patients completed two generic health-related quality of life instruments, the EQ-5D-5L and SF-12, which were used together for the validation using data from all patients in the trial as the trial is ongoing. Psychometric analyses included construct and criterion validity and responsiveness to change. Of the 189 validation patients, 141 (75%) were female, the median age was 49 years old (range 23-70 years) and body mass index ranged from 33-70 kg/m2. For construct validity, there were significant improvements in the distribution of responses in all EQ-5D dimensions between baseline and 6 months after randomisation. For criterion validity, the highest degree of correlation was between the EQ-5D pain/discomfort and SF-12 bodily pain domain. For responsiveness the EQ-5D and SF-12 showed statistically significant improvements in health-related quality of life between baseline and 6 months after randomisation. The EQ-5D-5L is a valid generic measure for measuring health-related quality of life in bariatric surgery patients.
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