Best Estimate Of Effect Research Articles

Effect of tranexamic acid in vascular surgery- a sub-study of the POISE-3 randomized clinical trial

Abstract Background/Introduction In the POISE-3 trial involving patients undergoing noncardiac surgery, tranexamic acid (TXA) reduced the incidence of the composite outcome of life-threatening bleeding, major bleeding, or bleeding into a critical organ at 30 days. Bleeding is a major issue in vascular surgery. However, TXA use may be limited due to concerns about its safety in this high-risk population. With 1,399 participants in POISE-3 undergoing vascular surgery, this is the largest trial assessing TXA's efficacy in this population. Purpose In this post hoc subgroup analysis, we aimed to investigate the interaction between surgery type (vascular/non-vascular) and the effects of TXA vs placebo on bleeding and cardiovascular (CV) safety outcomes in the POISE-3 population. Methods: Eligible patients were ≥45 years, undergoing inpatient noncardiac surgery, and at risk for bleeding and CV complications. Patients were randomised (1:1) to TXA 1 gm IV bolus at start and end of surgery (total 2 gm) or placebo. We used Cox proportional hazards models incorporating tests for interaction to analyse time to the first occurrence of the composite bleeding outcome, and the CV safety outcome (composite of myocardial injury after noncardiac surgery, non-hemorrhagic stroke, peripheral arterial thrombosis, or symptomatic proximal venous thromboembolism) at 30 days. Estimates of hazard ratios (HR) with 95% confidence intervals (CI) were calculated for each subgroup with the interaction P value. Results 9,468 of 9535 (99.3%) POISE-3 patients are included in this analysis; 1399 of whom underwent vascular surgery (699 TXA, 700 placebo). Majority (89.8%) of the vascular surgeries were aorto-iliac, peripheral vascular and extracranial surgeries. In the vascular surgery group, 12.6% of patients receiving TXA experienced the composite bleeding outcome versus 14.7% with placebo (HR 0.85, 95% CI 0.64-1.13). For non-vascular surgery patients, these rates were 8.6% with TXA and 11.3% with placebo (HR 0.74, 95% CI 0.65-0.86), with an interaction P value of 0.42. In vascular surgery patients, the CV safety outcome occurred in 20.2% with TXA versus 18.1% with placebo (HR 1.12, 95% CI 0.88-1.42). In the non-vascular surgery group, both TXA and placebo arms showed a 13.1% incidence rate (HR 1.00, 95% CI 0.89-1.13), with an interaction P value of 0.43. Conclusion In vascular surgery patients, there were higher rates of bleeding and cardiovascular events compared to those undergoing non-vascular surgeries; however, there was no significant interaction between the effects of TXA and the type of surgery. The overall POISE-3 trial provides the best estimate of effect with TXA for all patients including those undergoing vascular surgery. The main limitation is that this subgroup analysis was not pre-specified.

Development of a Shared Decision-Making Tool for Adolescents With Scoliosis to Decide Between Observation Versus Fusion Surgery.

Adolescent patients with moderate to severe idiopathic scoliosis who have completed their skeletal growth face a significant choice in their treatment path: watchful waiting or spinal fusion. Shared decision making (SDM) assists patients and clinicians to find treatments that make intellectual, practical and emotional sense. Our objective was to develop a tool that supports SDM for patients with scoliosis and their families. We used a user-centered design approach that included collaboration between patients, surgeons and SDM experts, observation of clinician encounters, and literature review. We focused on adolescent idiopathic scoliosis patients 13 or more years of age with less than 1 year of growth remaining (Risser stage 3 or greater) and curves between 40 and 65 degrees. We included 22 patients, and collected 22 video recordings. From these videos, we identified salient patient priorities for decision making including treatment benefits, surgical complications, pain, scheduling and recovery, and cost. For each theme, we conducted a focused review to obtain the best estimate of effect. Then, an expert SDM designer developed an electronic prototype called Scoliosis Choice. The initial prototype of the scoliosis SDM was finalized and is currently being field tested in clinic. Scoliosis Choice may help patients and surgeons better understand the potential risks and benefits of spinal fusion vs. observation for scoliosis treatment and improve validated measures of quality in patient-parent-surgeon communication.

Systematic Review and Meta-analysis: Sometimes Bigger Is Indeed Better.

Clinicians encounter an ever increasing and frequently overwhelming amount of information, even in a narrow scope or area of interest. Given this enormous amount of scientific information published every year, systematic reviews and meta-analyses have become indispensable methods for the evaluation of medical treatments and the delivery of evidence-based best practice. The present basic statistical tutorial thus focuses on the fundamentals of a systematic review and meta-analysis, against the backdrop of practicing evidence-based medicine. Even if properly performed, a single study is no more than tentative evidence, which needs to be confirmed by additional, independent research. A systematic review summarizes the existing, published research on a particular topic, in a well-described, methodical, rigorous, and reproducible (hence "systematic") manner. A systematic review typically includes a greater range of patients than any single study, thus strengthening the external validity or generalizability of its findings and the utility to the clinician seeking to practice evidence-based medicine. A systematic review often forms the basis for a concomitant meta-analysis, in which the results from the identified series of separate studies are aggregated and statistical pooling is performed. This allows for a single best estimate of the effect or association. A conjoint systematic review and meta-analysis can provide an estimate of therapeutic efficacy, prognosis, or diagnostic test accuracy. By aggregating and pooling the data derived from a systemic review, a well-done meta-analysis essentially increases the precision and the certainty of the statistical inference. The resulting single best estimate of effect or association facilitates clinical decision making and practicing evidence-based medicine. A well-designed systematic review and meta-analysis can provide valuable information for researchers, policymakers, and clinicians. However, there are many critical caveats in performing and interpreting them, and thus, like the individual research studies on which they are based, there are many ways in which meta-analyses can yield misleading information. Creators, reviewers, and consumers alike of systematic reviews and meta-analyses would thus be well-served to observe and mitigate their associated caveats and potential pitfalls.

Cardiovascular event reduction with PCSK9 inhibition among 1578 patients with familial hypercholesterolemia: Results from the SPIRE randomized trials of bococizumab

Familial hypercholesterolemia (FH) is a dominant genetic disorder associated with elevated low-density lipoprotein cholesterol (LDL-C) and premature atherosclerotic events. Although therapeutic monoclonal antibodies that inhibit proprotein convertase subtilisin-kexin type 9 (PCSK9) are indicated for LDL-C reduction among adult patients with FH, placebo-controlled outcome data among FH patients are scant. Directly compare the efficacy of PCSK9 inhibition as compared to placebo on hard cardiovascular outcomes in FH patients enrolled in the Studies of PCSK9 Inhibition and the Reduction of vascular Events (SPIRE) program. We estimated the efficacy of PCSK9 inhibition with bococizumab on future cardiovascular event rates among 1578 FH patients and 15,959 patients without FH who were selected for comparable lipid levels (on-statin levels of LDL-C >100mg/dL or non-high-density lipoprotein cholesterol>130mg/dL). All patients were randomized by computer generated codes to bococizumab 150mg subcutaneously every 2weeks or to matching placebo in the SPIRE clinical trials program and were followed over a median period of 11.2months for major adverse cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death). Analysis is by intention to treat. The SPIRE trials are closed and registered at ClinicalTrials.gov: NCT01968954, NCT01968967, NCT02100514, NCT01968980, NCT01975376, and NCT01975389. Compared to non-FH patients, FH patients enrolled in the SPIRE trials were on average younger (58 vs 63years), more likely to be women (42 vs 35%), more likely to be primary prevention patients (42 vs 23%), had higher mean baseline LDL-C levels (151 vs 127mg/dL), and lower rates of diabetes (25 vs 52%) and hypertension (59 vs 82%). FH and non-FH patients both had 55% reductions in LDL-C with bococizumab. Among FH patients, major adverse cardiovascular events occurred among 18 of 781 allocated to bococizumab and 22 of 797 allocated to placebo (hazard ratio 0.83; 95% confidence interval 0.44-1.54, P=.55). This best estimate of effect was similar in magnitude to that observed in the much larger group of patients without FH (hazard ratio 0.79, 95% confidence interval 0.64-0.97, P=.023) with no statistically significant evidence of heterogeneity between groups (P=.87). Incidence rate ratios comparing bococizumab to placebo for adverse events were similar among those with and without FH. The proportion of patients developing antidrug antibodies was higher among those with FH compared to those without FH (43% vs 36%, P<.001). In these randomized placebo-controlled data, the subgroup of statin-treated FH patients had a similar magnitude of risk reduction for hard cardiovascular events with the PCSK9 inhibitor bococizumab as did patients without FH, with no evidence of statistical heterogeneity between groups.

One side or two?

One side or two?

Effects of repeated pulsed herbicide exposures on the growth of aquatic macrophytes

Many contaminants are released into aquatic systems intermittently in a series of pulses. Pulse timing and magnitude can vary according to usage, compound-specific physicochemical properties, and use area characteristics. Standard laboratory ecotoxicity tests typically employ continuous exposure concentrations over defined durations and thus may not accurately and realistically reflect the effects of certain compounds on aquatic organisms, resulting in potential over- or underestimation. Consequently, the relative effects of pulsed (2 and 4 d) and continuous exposures of the duckweed Lemna minor to isoproturon, metsulfuron-methyl, and pentachlorophenol over a period of 42 d were explored in the present study. At the highest test concentrations, exposure of L. minor to pulses of metsulfuron-methyl resulted in effects on growth similar to those of an equivalent continuous exposure. For isoproturon, pulsed exposures had a lower impact than a corresponding continuous exposure, whereas the effect of pentachlorophenol delivered in pulses was greater. These differences may be explained by compound-specific uptake and degradation or dissipation rates in plants and the recovery potential that occurs following pulses for different pesticides. Given these results, use of a simple time-weighted average approach to estimate effects of intermittent exposures from short-term standard toxicity studies may not provide an accurate prediction that reflects realistic exposure scenarios. Development of mechanistic modeling approaches may facilitate better estimates of effects from intermittent exposures.

Balance and agility training does not always decrease lower limb injury risks: a cluster-randomised controlled trial

The objective of this study was to examine the effects on lower limb injury rates of adding structured balance and agility exercises to the 80-day basic training programme of army recruits. A blocked (stratified), cluster-randomised controlled trial was employed, with one intervention group (IG) and one control group (CG), in which 732 male and 47 female army recruits from the Australian Army Recruit Training Centre participated through to analysis. The IG performed specified balance and agility exercises in addition to normal physical training. The incidence of lower limb injury during basic training was used to measure effect. Analysis, which adhered to recommendations for this type of trial, used a weighted paired t-test based on the empirical logistic transform of the crude event rates. The intervention had no statistically significant effect on lower limb injury incidence (RR = 1.25, 95% CI 0.97–1.53, 90% CI 1.04–1.47), on knee and ankle injury incidence (RR = 1.08, 95% CI 0.83–1.38), and on knee and ankle ligament injury incidence (RR = 0.98, 95% CI 0.64–1.47). We conclude that the intervention, implemented in this fashion, is possibly harmful, with our best estimate of effect being a 25% increase in lower limb injury incidence rates. This type of structured balance and agility training added to normal military recruit physical training did not significantly reduce lower limb, knee and ankle, or knee and ankle ligament injury rates. Caution needs to be used when adding elements to training programmes with the aim of reducing injury, as fatigue associated with the addition may actually raise injury risk.

A systematic review of metformin to limit weight-gain with atypical antipsychotics

Weight-gain is commonly reported in patients taking atypical antipsychotic agents. A systematic review was performed to evaluate the effectiveness of metformin for attenuation of weight-gain induced by atypical antipsychotic agents. A PubMed database (1966-May 2010) search was conducted, using metformin, atypical antipsychotic and weight-gain as search terms. Review articles, letters and commentaries were excluded. Thirteen trials were identified (eight randomized, double-blind, placebo-controlled trials, one crossover adult trial, one open-label uncontrolled adult trial, two open-label uncontrolled paediatric trials and one case report). Of the eight randomized, double-blind, placebo-controlled trials, three studied adult subjects and one studied children. Metformin was well tolerated. The heterogeneity of the trials did not justify meta-analytic pooling of outcomes, and we provide a best evidence synthesis. There is limited evidence for the efficacy of metformin in limiting weight-gain induced by atypical antipsychotic agents. However, the evidence is weak and further well-powered randomized, double-blind, placebo-controlled studies of longer duration should be conducted to confirm the preliminary evidence and provide better estimates of effect.

Preventing and treating posttraumatic seizures: The human experience

Posttraumatic epilepsy presents an ideal target for prevention efforts. Traumatic brain injury (TBI) is common, characteristics that put people at high risk such as penetrating injury or subdural hematoma or provoked seizures are easily identified, and the latency between the injury and the onset of epileptic seizures is frequently short. Several drugs have been tested for their ability to prevent provoked seizures and epilepsy after TBI. We describe the design of those studies and their results. Phenytoin and carbamazepine significantly reduce the incidence of provoked seizures. Phenobarbital and the combination of phenobarbital and phenytoin also look promising for reducing provoked seizures, but small sample sizes in the studies evaluating these drugs do not allow definitive conclusions. None of the drugs studied (phenytoin, phenobarbital, their combination, carbamazepine, valproate, or magnesium) have shown reliable evidence that they prevent, or even suppress, epileptic seizures after TBI. For most of the regimens tested (the phenytoin/phenobarbital combination being the exception), the best estimate of effect is under a 25% reduction in posttraumatic seizures, well less than the 50% reduction most studies were designed to detect. The evaluation of the tested drugs has serious limitations, however, and antiepileptic drugs (AEDs) developed since 1980 and other compounds have barely been tested at all. Better understanding the process of epileptogenesis, testing treatments that demonstrate antiepileptogenic effects in the laboratory, and performing thorough preclinical and phase II evaluations before attempting definitive trials should greatly improve the chance of identifying ways to prevent posttraumatic epilepsy, providing the ultimate cure for this condition.

Comment on: efficacy and safety of balloon kyphoplasty in the treatment of vertebral compression fractures: a systematic review (C. Bouza et al.)

In their work C. Bouza and coauthors present the results from a systematic review conducted to ‘analyze the collected body of evidence regarding the efficacy and safety on balloon kyphoplasty in the treatment of vertebral compression fractures’. The authors conclude from their work that balloon kyphoplasty seems effective and safe. It is generally accepted that, in the absence of conclusive results from methodological rigorous studies, a systematic review can increase the accuracy of estimated treatment effect by pooling previously published data [1]. The authors have chosen to evaluate a relatively new minimal invasive technique using a systematic review as research tool, which makes good sense since large-scale randomized controlled trials on this subject are absent while interest in balloon kyphoplasty is considerable, having led to lively debate on multiple occasions. One of the most interesting topics under discussion is the difference of kyphoplasty versus vertebroplasty versus medical therapy for the treatment of vertebral compression fractures in terms of indications, outcome, complications and cost effectiveness. Following preliminary publications reporting success with kyphoplasty and vertebroplasty compared to medical therapy for vertebral compression fractures, both techniques seem to have been embraced and promoted by their respective advocates with uncontrolled case-series and anecdotes put forward as evidence. Although preliminary data from new techniques obtained from low level of evidence studies can certainly be interesting to discover potential benefits and/or pitfalls, it will not lead to proof of effectiveness. The spine community is unfortunate to have witnessed the introduction of numerous (surgical) techniques without proper controlled unbiased investigation of their merits. The ongoing controversy about the optimal treatment of traumatic thoracolumbar fractures, initiated more than 20 years ago and unlikely to be solved in the coming twenty, serves as a good example of what can happen without careful early evaluation of a new type of treatment. Vertebroplasty and kyphoplasty are recent examples of this practice and, with respect to the availability of evidence of their effectiveness and/or safety, we are in the dark. Conclusive statements on the performance of these new techniques must be regarded invalid if not backed up by solid data from methodological sound studies. Acknowledging the lack of good quality clinical trials, the present authors have taken a different route to find evidence and combined data from existing material to achieve better estimates of effect. The quality of a systematic review, and therewith the strength of its conclusions and recommendations, is directly dependent on the methodological quality of the studied material. Some limitations of the present study become apparent after close review of the primary papers. Critical quality parameters such as study design, duration of follow up, number of patients lost to follow up, validation of outcome parameters point to grade IV level of evidence instead of the grade II–III as suggested by the authors (http://www.cebm.net/levels_of_evidence.asp). The authors seem to have overestimated the quality of the material under investigation which is surprising for a study aiming to find evidence. Although the authors do an excellent job of recognizing the limitations of their work in the discussion section, they do not succeed in eliminating all bias when assessing the papers their manuscript is based on. This is something the reader should keep in mind when reading the article and contemplating the conclusions. In the end, I think this work is a good summary of the available papers describing balloon kyphoplasty for vertebral compression fractures but I am not sure if it has advanced the field besides stressing once more the necessity of high quality clinical research.