Previous Randomized Controlled Trials Research Articles

Determining the Optimal Adjuvant Therapy for Improving Survival in Elderly Patients with Glioblastoma: A Systematic Review and Network Meta-analysis.

Older patients with glioblastoma (GBM) are underrepresented in clinical trials. Several abbreviated and standard chemoradiotherapy regimens are advocated with no consensus on the optimal approach. Our objective was to quantitatively evaluate which of these regimens would provide the most favorable survival outcomes in older patients with GBM using a network meta-analysis. MEDLINE, Embase, Google Scholar, and the Cochrane Library were searched. Patients >60 years of age with histologically confirmed GBM were included. Primary outcome of interest was the pooled HR from randomized controlled trials (RCTs). Secondary outcomes of interest included pooled HR from studies controlling for MGMT promoter methylation status, and safety. Fourteen studies, including 5 RCTs, reporting 4,561 patients were included. Using highest quality data from RCTs, our network-based approach demonstrated that standard radiotherapy (SRT) and temozolomide (TMZ) provided similar survival benefit when compared with hypofractionated radiotherapy (HRT) and TMZ [HR = 0.90; 95% confidence interval (CI), 0.43-1.87], TMZ alone (HR 1.25; 95% CI, 0.69-2.26), HRT alone (HR = 1.34; 95% CI, 0.73-2.45), or SRT alone (HR = 1.43; 95% CI, 0.87-2.36). HRT-TMZ had the highest probability (85%) of improving survival in older patients with GBM followed by SRT-TMZ (72%). Pooled analysis of trials controlling for MGMT promoter methylation status demonstrated that TMZ monotherapy confers similar survival benefit to combined chemoradiotherapy. Statistical comparisons using a network approach demonstrates that the common treatment regimens for older patients with GBM in previous RCTs confer similar survival benefits. Adjustments for MGMT promoter methylation status demonstrated that radiotherapy alone was inferior to TMZ-based approaches. Head-to-head comparison of TMZ monotherapy to combined TMZ and radiation is warranted.

Long-Term Influence of Platelet-Rich Plasma (PRP) on Dental Implants after Maxillary Augmentation: Retrospective Clinical and Radiological Outcomes of a Randomized Controlled Clinical Trial.

The long-term clinical and radiological outcomes of dental implants inserted in augmented bone treated with platelet-rich plasma (PRP) has not been well addressed in the literature yet. This study is based on a collection of patients from a randomized controlled trial (RCT) that did not report any short-term positive effects of PRP on bone healing after sinus lift surgery using autologous iliac crest bone graft. This study aimed to evaluate the long-term impact of PRP regarding clinical and radiological outcomes on the inserted implants in the previous RCT. For this evaluation, we considered the following variables: plaque index, probing depth, bleeding index, mobility grade, Periotest® values, and radiological bone loss. Out of 53 patients (n = 306 implants) included in the previous study we were able to reinvestigate 37 patients (n = 210 implants) in two centers (31 in Giessen, Germany and 6 in Erlangen, Germany). Clinical and radiographic parameters suggested overall healthy conditions of the peri-implant tissue. The PRP-group and the control group did not differ significantly in the majority of the parameters. The overall evaluation showed that result data of the PRP-group was inferior to the control group in 64 percent of the evaluated parameters. The present study cannot provide evidence of a positive effect of PRP on the long-term implant clinical and radiological outcomes. In fact, a tendency towards inferior long-term results in the PRP-group was detected without reaching a significant threshold. Further controlled trials need to be conducted to investigate this correlation.

Nalmefene in alcohol‐dependent patients with a high drinking risk: A limited efficacy in reducing alcohol consumption

Nalmefene authorization in Europe for reducing alcohol consumption in alcohol-dependent patients with high or very high drinking risk level and maintaining a high drinking risk level 2 weeks after initial assessment was granted on the grounds of controversial data. There had been no randomized controlled trial (RCT) conducted in the target population at that point. The market authorization was based on data from subgroup analyses of the pivotal studies: ESENSE1 (NCT00811720), ESENSE2 (NCT00812461), and SENSE (NCT00811941). However, subgroup analyses are only exploratory. It is therefore reasonable to question if the new RCT assessing the efficacy of nalmefene in patients with a high drinking risk1 can add to the previous body of evidence. We argue that this study shares the weaknesses of the previous phase 3 trials that led to questioning the efficacy of nalmefene in reducing alcohol consumption.2 Overall, although the effect sizes observed on the consumption outcomes were higher than in the previous studies, the clinical relevance of such differences remains questionable. Regarding total alcohol consumption, the difference in the adjusted change from baseline between nalmefene 20 mg and placebo (expressed in least square mean) at 6 months was −11 g of alcohol/day (i.e., about a 100-mL glass of wine). It is also not known how much these differences were due to attrition bias. Compared to placebo (89.4%), the treatment completion rates were significantly lower in the nalmefene 20-mg (76.2%, P < 0.001) and nalmefene 10-mg (75.5%, P < 0.001) groups. Whereas a loss to follow-up of 5% or lower is usually of little concern, such a loss of >20% prevents good-quality intention-to-treat analysis and can cause biased estimates of the treatment effect.3, 4 The rate of discontinuation due to adverse events was higher in the groups receiving nalmefene than in the placebo group (18.1%, 18.5%, and 4.5%, respectively, for nalmefene 20-mg, nalmefene 10-mg, and placebo). These characteristics were already observed in a meta-analysis of the initial trials submitted to the European Medicine Agency.5 In addition, a primary outcome assessed at 12 weeks and a follow-up ending at 24 weeks is too short to evaluate a drug intending to reduce harm. No RCT has assessed the efficacy of nalmefene in the long term. Only one RCT has assessed the efficacy of nalmefene after 1 year of treatment, and showed limited and inconsistent efficacy on consumption outcomes.5 Currently, the harm-reduction approach is based on models that are basically an extrapolation of the results from subgroup analyses of the previous pivotal RCT beyond the trial time horizon.6 Moreover, it is unlikely that a slight reduction in consumption, even if sustained, could be clinically relevant considering that the model is dealing with patients who had experienced high consumption for a long time, which is different to subjects with excessive use. None of the previous trials demonstrated any benefit of nalmefene on harm related to alcohol use, and the current study failed to show significant effect of nalmefene on health-related quality of life (i.e., Alcohol Quality of Life Scale, Short Form – 36 Health Survey, and EuroQol - 5 Dimension) at 24 weeks. In several European countries, such as in Germany, agencies for efficiency in health care have concluded that studies of nalmefene showed no additional benefit for alcohol dependence compared to naltrexone, another opioid antagonist that was an earlier and less costly comparator therapy.7 A recent independent indirect comparison concluded a lack of advantage of nalmefene versus naltrexone.8 Long-term psychosocial interventions by trained professionals remain the cornerstone of successful care.9 Further, treatment would be a Sisyphean task and would demonize vulnerable people who cannot stop their problem drinking if no comprehensive public health policy for alcohol control is implemented. Finally, readers must be aware that a Californian winery, Ridge Vineyards Inc., is a subsidiary company of Otsuka Holdings Co., Ltd. In conclusion, it should be recalled that the clinical significance of a statistically significant difference on a surrogate outcome should be critically appraised. A.B. and F.N. served as unpaid experts for several taskforces for the French drug agency (Agence Nationale de Sécurité du Médicament et des Produits de Santé), none of which were related to the topic. A.B. was a late co-investigator for NCT01738282 trial (baclofen) but did not recruit. C.P. has no conflict of interest to declare.

The Role of Zinc in Depressed Pregnant and Non-Pregnant Women: A Systematic Review and Meta-Analysis

AbstractPerinatal depression is a depressive illness that affects 10–15% of women in the UK with an estimated cost of £1.8 billion/year. Zinc deficiency is associated with the development of mood disorders and zinc supplementation has been shown to help reduce the symptoms of depression. Women who are pregnant and breastfeeding are at risk of lower levels of zinc because of the high demand from the developing and feeding baby. However, studies in the perinatal period are limited. With a long-term aim of designing a randomised controlled trial (RCT) to examine if zinc supplementation reduces depressive symptoms in pregnant and lactating women;the objective of this review was to systematically evaluate previous RCTs assessing zinc supplementation and depressive symptoms, in order to establish a zinc dosing regimen with regards to Galenic formulation, unit dose and frequency. The review was conducted by independent reviewers in accordance with PRISMA guidelines and is registered at Prospero (CRD42017059205). The Allied and Complimentary Medicine, CINAHL, Embase, MEDLINE, PsycINFO, PubMed, and Cochrane databases were searched since records began, with no restrictions, for intervention trials assessing Galenic formulation, unit dose and frequency of zinc supplementation to reduce the symptoms of depression. From a total of 66 identified records, 7 articles met the inclusion and exclusion criteria; all assessed the effect of zinc supplementation on mood. Risk of bias was independently assessed using the standard ‘Cochrane risk of bias tool’. Overall, 5 of the 7 papers were rated as high-quality trials; of the other two, one was rated poor and the other fair but both had a number of learning points. Preliminary findings indicate at the end of supplementing zinc, depression scores were reduced significantly. In one study, the Beck score decreased in the placebo group, but this reduction was not significant compared to the baseline. In two of the studies there was a significant correlation between serum zinc and self-reported mood questionnaires. Results also suggest that 25 mg zinc supplementation combined with antidepressant drugs can be effective in the treatment of major depression in women. This supports other work where researchers supplemented 25 mg of elemental zinc for 12 weeks or longer and found a reduction of symptoms in both pregnant and non-pregnant women. Thus, an early conclusion is that 25 mg of elemental zinc is an effective dose for improving low mood and is achievable in a trial setting.

I-CONECT PROJECT: CAN SOCIAL INTERACTION IMPROVE COGNITIVE FUNCTIONS AMONG SOCIALLY ISOLATED OLDER ADULTS?

Epidemiological studies have demonstrated that larger social networks or more frequent social interactions may have protective effects against cognitive decline and the incidence of dementia. Therefore, increasing social interaction could be a promising intervention for improving cognitive well-being in socially isolated older adults. We have conducted multiple NIH-funded randomized controlled trials (RCT) over 10 years, examining whether conversational interactions through webcam and internet can improve cognitive functions and enhance cognitive reserve. In this symposium, we will introduce this series of behavioral intervention trials through 4 presentations. First, Dodge will provide background and results of their previous RCT where they showed efficacy of conversational intervention on domain-specific cognitive functions and introduce the ongoing larger project called I-CONECT (https://www.i-conect.org). Second, Lindsey will introduce technological innovations used in the I-CONECT project including development of user-friendly video-chat devices, recording of audio and video data and innovative recruitment efforts. Third, Asgari will share results on how speech utterance and characteristics collected through the project could distinguish those with mild cognitive impairment from those with normal cognition using machine learning modelling approaches. Finally, Cerino and his team will show results of the study which examined whether cognitive improvements through conversation-based intervention depend on an individual’s personality, laying the groundwork for a personalized intervention trial in the future. The symposium is of interest for those who study social isolation and its prevention, the link among cognition, social isolation and personality, as well as those who focus on technology as a tool for improving well-being of older adults.

Switching antiretrovirals in older patients

In The Lancet HIV, Franco Maggiolo and colleagues1 report the results of the first phase 3 randomised controlled trial (RCT) of antiretroviral therapy in people living with HIV aged 60 years or older (mean 66 years). The median age of people living with HIV enrolled in previous RCTs of first-line regimens was younger than 35 years2,3 and the median age at enrolment in RCTs of switching regimens was 40–50 years.4–6 However, in developed countries half of people living with HIV are aged 50 years or older.

Recombinant Human Platelet-Derived Growth Factor BB in Combination With a Beta-Tricalcium Phosphate (rhPDGF-BB/β-TCP)-Collagen Matrix as an Alternative to Autograft.

Joint arthrodesis often employs autograft to promote union; graft harvesting can lead to perioperative morbidity. A Canadian randomized controlled trial (RCT) demonstrated that recombinant human platelet-derived growth factor BB homodimer (rhPDGF-BB) combined with beta-tricalcium phosphate (β-TCP)-collagen was a safe, effective alternative to autograft. This multicenter North American RCT compared the safety and efficacy of rhPDGF-BB/β-TCP-collagen with autograft for ankle and hindfoot fusion. Subclassification using propensity scores (PS) incorporated patients from previous trials for enhanced statistical power for noninferiority testing and broader review of treatments. Patients requiring ankle or hindfoot arthrodesis and supplemental bone graft were treated with rhPDGF-BB/β-TCP-collagen (n = 69) or autograft (n = 35). Outcomes included joint fusion on computed tomography (24 weeks), clinical healing status, visual analog scale (VAS) pain, Short-Form 12 (SF-12), American Orthopaedic Foot & Ankle Society (AOFAS) Ankle-Hindfoot Scale, and Foot Function Index (FFI) scores over 52 weeks. PS methodology addressed potential selection bias arising from pooling data among these patients and 2 previous RCTs with similar inclusion criteria, surgical techniques, graft harvest techniques, and outcomes. All 132 rhPDGF-BB/β-TCP-collagen-treated patients and 167 of 189 candidate autograft-treated controls were selected for comparison by an independent statistician blinded to outcomes. In the PS subclassification, 68.1% treatment patients and 68.4% controls achieved >50% osseous bridging at fusion sites. Clinical healing status was achieved in 84.8% of treated patients and 90.7% of controls at 52 weeks. Clinical, functional, and quality of life results demonstrated noninferiority of rhPDGF-BB/β-TCP-collagen to autograft. Safety-related outcomes were equivalent. PS subclassification analysis of 3 RCTs demonstrated that rhPDGF-BB/β-TCP-collagen was as effective as autograft for ankle and hindfoot fusions, with less pain and morbidity than treatment with autograft. Level I, prospective randomized study.

From randomised controlled trial to real world implementation of a novel home-based heart failure tool: pooled and comparative analyses of two clinical controlled trials

ObjectivesA home-based tool for heart failure (HF) patients, was evaluated in a specialist setting as a randomised controlled trial (RCT) and also in a validation cohort in a primary care...

(405) What is the Effect on Acute Pain when a Patient's Sleep is Disturbed by Opioid-Induced Nausea and Vomiting (OINV)?

Sleep is an important factor in postoperative recovery, especially for patients experiencing moderate-to-severe acute pain. In contrast, sleep disturbance may have deleterious effects on patient recovery, including increased pain and length-of-stay.1 However, it is unclear if nausea and vomiting interfere with sleep and with what analgesic consequence. Is there evidence of OINV-related sleep disturbance and its effect on acute pain in a randomized controlled trial (RCT)? In a previous RCT,2 it was noted that some patients using hydrocodone 7.5mg/acetaminophen 325mg (HC/APAP) awoke with nausea, retching and/or vomiting, requesting antiemetic therapy. In the current RCT,3 therefore, patients were observed while asleep so that emetic symptoms and pain could be documented if they awoke. Following first metatarsal bunionectomy, patients with moderate or severe pain on a categorical pain intensity scale and a 0-to-10 pain intensity scale (PI-NRS) were randomly assigned to take HC/APAP or placebo under double-blind conditions every 4-6 hours. Patients were monitored regularly as in-patients over 48 hours, including, in particular, during periods of sleeping between 9 pm and 7 am: if patients awoke from sleep, episodes of retching, vomiting and other adverse events were documented if present and patients rated nausea intensity on a 0-to-10 Likert scale and pain intensity on the PI-NRS. Of 113 HC/APAP-treated patients who developed OINV over the 48-hour treatment period, 29 patients (26%) awoke from sleep complaining of moderate-to-severe nausea, retching or vomiting, requesting an antiemetic. Compared to the summed pain intensity differences (SPID48) of these patients with OINV-related sleep disturbance (63.2), SPID48 values were 108% higher for the 137 HC/APAP-treated patients without OINV-related sleep disturbance (131.1, p<0.001). We conclude that OINV causes sleep disturbance, interfering with pain reduction and contributing to less effective pain relief. Future research should examine the effect of sleep disturbance of any etiology on pain control. Sleep is an important factor in postoperative recovery, especially for patients experiencing moderate-to-severe acute pain. In contrast, sleep disturbance may have deleterious effects on patient recovery, including increased pain and length-of-stay.1 However, it is unclear if nausea and vomiting interfere with sleep and with what analgesic consequence. Is there evidence of OINV-related sleep disturbance and its effect on acute pain in a randomized controlled trial (RCT)? In a previous RCT,2 it was noted that some patients using hydrocodone 7.5mg/acetaminophen 325mg (HC/APAP) awoke with nausea, retching and/or vomiting, requesting antiemetic therapy. In the current RCT,3 therefore, patients were observed while asleep so that emetic symptoms and pain could be documented if they awoke. Following first metatarsal bunionectomy, patients with moderate or severe pain on a categorical pain intensity scale and a 0-to-10 pain intensity scale (PI-NRS) were randomly assigned to take HC/APAP or placebo under double-blind conditions every 4-6 hours. Patients were monitored regularly as in-patients over 48 hours, including, in particular, during periods of sleeping between 9 pm and 7 am: if patients awoke from sleep, episodes of retching, vomiting and other adverse events were documented if present and patients rated nausea intensity on a 0-to-10 Likert scale and pain intensity on the PI-NRS. Of 113 HC/APAP-treated patients who developed OINV over the 48-hour treatment period, 29 patients (26%) awoke from sleep complaining of moderate-to-severe nausea, retching or vomiting, requesting an antiemetic. Compared to the summed pain intensity differences (SPID48) of these patients with OINV-related sleep disturbance (63.2), SPID48 values were 108% higher for the 137 HC/APAP-treated patients without OINV-related sleep disturbance (131.1, p<0.001). We conclude that OINV causes sleep disturbance, interfering with pain reduction and contributing to less effective pain relief. Future research should examine the effect of sleep disturbance of any etiology on pain control.

Cephalometric evaluation of rapid and slow maxillary expansion in patients with BCLP: Secondary data analysis from a randomized clinical trial.

To compare the dentoskeletal effects of rapid (RME) and slow (SME) maxillary expansion in patients with bilateral complete cleft lip and palate (BCLP). This was a secondary analysis of a previous randomized controlled trial (RCT). Forty-six patients (34 male, 12 female) with BCLP and posterior crossbite (mean age of 9.2 years) were randomly assigned to two study groups. Group RME comprised subjects treated with Haas/Hyrax expander. Group SME included patients treated with quad-helix appliance. Cone-beam computed tomography (CBCT) was performed before expansion (T1) and after appliance removal at the end of a 6-month retention period (T2) for a previous RCT that compared the transverse skeletal effects of RME and SME. CBCT-derived cephalometric images were generated and cephalometric analysis was performed using Dolphin Imaging Software (Chatsworth, Calif). Intergroup comparisons were performed using t tests (P < .05). Baseline forms were similar between groups. No significant differences between RME and SME groups were found. Rapid and slow maxillary expansion produced similar sagittal and vertical changes in patients with BCLP. Both Haas/Hyrax and quad-helix appliances can be used in patients with vertical facial pattern. Clinical relevance: RME and SME can be equally indicated in the treatment of maxillary arch constriction in patients with BCLP.

Comparing different ways of calculating sample size for two independent means: A worked example.

We discuss different methods of sample size calculation for two independent means, aiming to provide insight into the calculation of sample size at the design stage of a parallel two-arm randomised controlled trial (RCT). We compare different methods for sample size calculation, using published results from a previous RCT. We use variances and correlation coefficients to compare sample sizes using different methods, including1. The choice of the primary outcome measure: post-intervention score vs. change from baseline score.2. The choice of statistical methods: t-test without using correlation coefficients vs. analysis of covariance (ANCOVA).We show that the required sample size will depend on whether the outcome measure is the post-intervention score, or the change from baseline score, with or without baseline score included as a covariate. We show that certain assumptions have to be met when using simplified sample size equations, and discuss their implications in sample size calculation when planning an RCT. We strongly recommend publishing the crucial result “mean change (SE, standard error)” in a study paper, because it allows (i) the calculation of the variance of the change score in each arm, and (ii) to pool the variances from both arms. It also enables us to calculate the correlation coefficient in each arm. This subsequently allows us to calculate sample size using change score as the outcome measure. We use simulation to demonstrate how sample sizes by different methods are influenced by the strength of the correlation.

(Cost-)effectiveness of an internet-based physical activity support program (with and without physiotherapy counselling) on physical activity levels of breast and prostate cancer survivors: design of the PABLO trial

BackgroundHigher levels of physical activity (PA) after treatment are associated with beneficial effects on physical and psychosocial functioning of cancer survivors. However, survivors often do not meet the recommended levels of PA. In order to promote PA, we developed a closed internet-based program. The aim of the study is to evaluate the (cost-)effectiveness of an internet-based PA-promotion program, alone or combined with physiotherapy counselling, compared to usual care, on PA-levels of breast or prostate cancer survivors. In this multicenter randomised controlled trial (RCT), breast or prostate cancer survivors who completed their primary treatment 3–12 months earlier, will be randomised to either 6-months access to a fully-automated internet-based intervention alone, an internet-based intervention plus remote support by a physiotherapist, or a control group. The intervention is based on the Transtheoretical Model and includes personalized feedback, information, video’s and assignments. Additionally, in a second arm, physiotherapy counselling is provided through monthly scheduled and on-demand telephone calls. The control group will receive usual care and a leaflet with PA guidelines.MethodsAt baseline, 6 and 12 months, the primary outcome (PA) will be measured during 7 consecutive days by accelerometers. Secondary outcomes are self-reported PA, fatigue, mood, health-related quality of life, and costs. The group differences for primary and secondary outcomes will be analyzed using linear mixed models.DiscussionIf proven to be (cost)effective, this internet-based intervention, either alone or in combination with telephone support, will be a welcome addition to previous RCT’s.Trial registrationNetherlands trial register (NTR6911), Date of trial registration: December 21, 2017.

Nocebos in rheumatology: emerging concepts and their implications for clinical practice.

Nocebo effects are noxious reactions to therapeutic interventions that occur because of negative expectations of the patient. In the past decade, neurobiological data have revealed specific neural pathways induced by nocebos (that is, interventions that cause nocebo effects), as well as the associated mechanisms and predisposing factors of nocebo effects. Epidemiological data suggest that nocebos can have a notable effect on medication adherence, clinical outcomes and health-care policy. Meta-analyses of randomized controlled trials (RCTs) of patients with rheumatic and musculoskeletal diseases (RMDs) indicate that withdrawal of treatment by placebo-arm participants owing to adverse events is common; a proportion of these events could be nocebo effects. Moreover, in large-scale, open-label studies of patients with RMDs who transition from bio-originator to biosimilar therapeutics, biosimilar retention rates were much lower than in previous double-blind switch RCTs. This discrepancy suggests that in addition to thelack of response in some patients because of intrinsic differences between the drugs, nocebosmight have an important role in low biosimilar retention, thus increasing the need for awareness and early identification of nocebo effects by rheumatologists and allied health-careprofessionals.

Models of brain injury vocational rehabilitation: The evidence for resource facilitation from efficacy to effectiveness.

BACKGROUND:Resource Facilitation (RF) is an intervention developed to improve return to work (RTW) following brain injury. RF is an individualized treatment specializing in connecting patients and caregivers with community-based resources and services to mitigate barriers to return to work.OBJECTIVES:Examine the effectiveness of the RHI RF program for a clinical prospective cohort of participants referred to this program from the State Vocational Rehabilitation agency.METHODS:Participants were 243 participants with data drawn from the two sources: 33 from previous randomized controlled trial (RCT) control groups who did not receive RF and 210 from clinical patients discharged from the RHI RF program.RESULTS:At discharge from RF, a greater proportion of the treatment group obtained employment than the control group [X2 (1) = 5.39, p = 0.018]. When controlling for baseline level of disability, treatment group significantly predicted employment outcome (Wald = 4.52, p = 0.033) and participants in the treatment group were 2.3 times more likely to return to work than controls.CONCLUSIONS:Previous RCTs have studied the RHI RF model and demonstrated significant efficacy. The findings from the present study are consistent with the employment rates found in the previous RCT’s following RF, and also provide initial support for the clinical effectiveness of RF.

Randomized controlled trials and real-world data: differences and similarities to untangle literature data.

Randomized controlled trials (RCTs) represent the gold-standard of medical evidence to assess the efficacy and safety of therapeutic interventions. However, the need to minimize bias and ensure the correct design to explore the study aims often affects the generalizability of results. As a consequence, the evidence derived from the most rigorous research strategy available is not always representative of the real-world settings for which this evidence is ultimately intended. Observational studies, in contrast, although affected by a number of potential confounders, can more effectively capture treatment characteristics and safety issues that had not been identified by previous RCTs, owing to the short duration of follow-up or highly selective inclusion criteria. The aim of this review is to provide a comparative summary of the main advantages and pitfalls of RCTs and real-world data, emphasizing the need for a constant integration of all available levels of evidence to provide the best care for patients.

Omega-3 Fatty Acid Supplementation and Cardiovascular Disease Risk: Glass Half Full or Time to Nail the Coffin Shut?

There has been a great deal of controversy in recent years about the potential role of dietary supplementation with long-chain omega-3 polyunsaturated fatty acids (n-3 PUFA) in the prevention of cardiovascular disease (CVD). Four recent meta-analyses have been published that evaluated randomized, controlled trial (RCT) data from studies that assessed the effects of supplemental n-3 PUFA intake on CVD endpoints. The authors of those reports reached disparate conclusions. This review explores the reasons informed experts have drawn different conclusions from the evidence, and addresses implications for future investigation. Although RCT data accumulated to date have failed to provide unequivocal evidence of CVD risk reduction with n-3 PUFA supplementation, many studies were limited by design issues, including low dosage, no assessment of n-3 status, and absence of a clear biological target or pathophysiologic hypothesis for the intervention. The most promising evidence supports n-3 PUFA supplementation for prevention of cardiac death. Two ongoing trials have enrolled high cardiovascular risk subjects with hypertriglyceridemia and are administering larger dosages of n-3 PUFA than employed in previous RCTs. These are expected to clarify the potential role of long-chain n-3 PUFA supplementation in CVD risk management.

Pregabalin as an analgesic option for patients undergoing thoracotomy: cost analysis of pregabalin versus epidural analgesia for post-thoracotomy pain relief.

Our previous randomized controlled trial (RCT) to evaluate the effects of pregabalin on acute post-thoracotomy pain compared with epidural analgesia showed that pregabalin is a safe and effective treatment and that it may be an alternative to epidural analgesia for acute post-thoracotomy pain. In this analysis, to additionally analyze the economic aspects of pregabalin in patients undergoing thoracotomy, we compared the medical costs between pregabalin and epidural analgesia as an analgesic technique for post-thoracotomy pain. Costs for patients undergoing thoracotomy and receiving either pregabalin or epidural analgesia for post-thoracotomy pain relief in the previous RCT were retrospectively collected from health insurance claims data. The following five cost categories were compared between the groups: (I) surgery costs; (II) costs for surgical materials and medications; (III) costs for anesthetic management; (IV) total hospitalization costs; and (V) costs for outpatient pain-relief medications (from hospital discharge to 6 months after thoracotomy). We analyzed data from 90 patients (45 patients for each group). Median costs for surgical materials and medications and those for anesthetic management were significantly lower in the pregabalin group than in the epidural analgesia group [(Japanese yen) ¥69,720 vs. ¥77,180, P=0.017; ¥161,000 vs. ¥195,500, P<0.001, respectively]. However, total hospitalization costs and costs for outpatient pain-relief medications were similar between the groups. Pregabalin was prescribed to more patients in the pregabalin group than those in the epidural analgesia group as outpatient treatment (75.0% vs. 37.5%), but median prescribed doses were much smaller in the pregabalin group. Although the use of pregabalin did not result in lower total hospitalization costs, it may reduce fee-for-service surgery- and anesthesia-related costs. The economic benefits of pregabalin may reinforce its usefulness as an alternative to epidural analgesia, especially for patients who are unsuitable for epidural analgesia.

Preventing EVAR Associated Acute Kidney Injury: The Optimal Strategy Remains Elusive

Preventing EVAR Associated Acute Kidney Injury: The Optimal Strategy Remains Elusive

Effectiveness of viable cryopreserved placental membranes for management of diabetic foot ulcers in a real world setting.

In a multicenter randomized controlled trial (RCT), the use of viable cryopreserved placental membrane (vCPM) for chronic diabetic foot ulcers (DFUs) resulted in a higher proportion of wound closure in comparison to good wound care: 62% versus 21% (p < 0.01). However, patients in RCTs are not representative of daily physician practice. Healthcare databases serve as a valuable tool to evaluate therapy effectiveness and to supplement evidence from RCTs. The objective of this study was to evaluate the effectiveness of vCPM for DFU management using Net Health's WoundExpert® electronic health records (EHR). The primary endpoint was the proportion of DFUs that achieved complete closure. Other endpoints included time and number of grafts to closure, probability of wound closure by week 12, and the number of wound-related infections and amputations. De-identified EHR data for 360 patients with 441 wounds treated with vCPM were extracted from the database. Average patient age was 63.7 years with a mean wound size of 5.1 cm2 and an average wound duration of 102 days prior to vCPM treatment. For evaluation of clinical outcomes, 350 DFUs larger than 0.25 cm2 at baseline were analyzed. Closure at the end of treatment was achieved in 59.4% of wounds with a median treatment duration of 42.0 days and 4 applications of vCPM. The probability of wound closure at week 12 was 71%, and the number of amputations and wound-related infections was 13 (3.0%) and 9 (2.0%), respectively. Data also demonstrated a correlation between wound size and closure rate as well as a correlation between > 50% wound area reduction by week 4 and wound closure by week 12. The results of this study mirror previous RCT efficacy data, supporting the benefits of vCPM for DFU management. These results can also influence policy and treatment decisions regarding advanced vCPM technology.

Management of disseminated intravascular coagulation: current insights on antithrombin and thrombomodulin treatments.

Sepsis and septic shock are frequently complicated by disseminated intravascular coagulation (DIC), which decreases the survival rate of patients with sepsis. In the past, large international randomized controlled trials (RCTs) using physiological anticoagulants for sepsis-induced DIC were not performed; however, RCTs have been conducted for sepsis and/or septic shock. In these trials, physiological anticoagulants did not show any beneficial effects compared with placebo for the treatment of sepsis and/or septic shock. In Japan, DIC treatments using antithrombin (AT) and/or recombinant human soluble thrombomodulin (rhTM) are common for patients with sepsis-induced DIC. Recently, large propensity score analyses demonstrated that AT and rhTM improved survival in patients with sepsis-induced DIC. Furthermore, post hoc analyses and meta-analyses that selected patients with sepsis-induced DIC from the previous large international RCTs indicated that physiological anticoagulants improved survival without increasing the associated sepsis-induced DIC bleeding. DIC treatments, such as AT and rhTM, may demonstrate beneficial effects when they are targeted at patients with sepsis-induced DIC only.