Subsequent Randomized Clinical Trials Research Articles

A pilot study of a new app based on self-compassion for the prevention and promotion of mental health among Brazilian college students.

Epidemiological data suggest substantial issues on the mental health of university students worldwide. Self-compassion is associated with lower rates of psychological distress and better positive mental health. Thus, we have developed a app-based intervention based on self-compassion principles targeting the prevention and promotion of mental health in college students. The current pilot study assessed adherence to intervention, preliminary mental health benefits, and satisfaction and acceptability with the app among Brazilian college students. The study employed a pre-experimental single-group design along with pre-test and post-test assessments (n = 23). A mixed methods approach was utilized to comprehensively assess the outcomes of the intervention. The overall adherence rate for the intervention was 37.87%, with 26.26% of participants successfully completing all modules. Among the 21 outcomes assessed, 15 exhibited statistically significant results. Notably, there was a substantial increase in self-compassion, demonstrating a large effect size (d = 1.15), and a moderate effect size reduction in stress (d = 0.62) and anxiety (d = 0.52). All satisfaction indicators for the intervention received scores above 7. The intervention was well-received by participants who completed it, although a potential barrier identified was the volume of text within the app and the need to adopt a more playful and concise format for the intervention. Despite a notable participant dropout, the adherence to intervention aligns with patterns observed in other online interventions conducted in real-world settings. The observed mental health benefits, high satisfaction levels, and positive acceptance underscore the rationale for pursuing a subsequent randomized clinical trial.

Fractional Flow Reserve-Guided Coronary Revascularization: Evidence from Randomized and Non-Randomized Studies.

Simple visual estimation of coronary angiography is limited by several factors that can hinder the proper classification of coronary lesions. Fractional flow reserve (FFR) is the most widely used tool to perform a physiological evaluation of coronary stenoses. Compared to isolated angiography, FFR has been demonstrated to be more effective in selecting those lesions associated with myocardial ischemia and, accordingly, impaired outcomes. At the same time, deferring coronary intervention in those lesions that do not show ischemic FFR values has proven safe and not associated with adverse events. Despite a major randomized clinical trial (RCT) and several non-randomized studies showing that FFR-guided revascularization could be superior to isolated angiography in improving clinical outcomes, subsequent RCTs have reported conflicting results. In this review, we summarize the principles behind FFR and the data currently available in the literature, highlighting the main differences between randomized and non-randomized studies that investigated this topic.

Patent foramen ovale closure in non-lacunar cryptogenic ischemic stroke: where are we now?

Patent foram ovale (PFO) is the most common anatomical cause of an interarterial shunt. It is usually asymptomatic but may cause paradoxical embolism and is a risk factor for non-lacunar cryptogenic cerebral ischemia in young adults. Although the first clinical trials did not show a significant superiority of PFO closure in the secondary prevention of cerebral ischemia as compared with standard antithrombotic treatment, six subsequent randomized clinical trials (CLOSURE I, PC Trial, RESPECT, CLOSE, REDUCE, and DEFENSE-PFO) performed in a sample of cryptogenic stroke in patients aged 60 years or younger provided evidence of a significant reduction of recurrent cerebral ischemia after percutaneous PFO closure. However, the use of percutaneous PFO closure cannot be generalized to the entire population of patients with cerebral ischemia and PFO, but it is indicated in highly selected patients with non-lacunar cryptogenic cerebral infarction with a large right-to-left shunt, an atrial septal aneurysm and no evidence of atrial fibrillation, as well as in association with antithrombotic treatment for an optimal secondary prevention of cerebral ischemia.

Transcatheter Aortic Valve Replacement in Young Low-Risk Patients With Severe Aortic Stenosis: A Review.

In the last decades, transcatheter aortic valve replacement (TAVR) revolutionized the treatment of symptomatic severe aortic stenosis. The efficacy and safety of TAVR were first proven in inoperable and high-risk patients. Then, subsequent randomized clinical trials showed non-inferiority of TAVR as compared to surgical aortic valve replacement also in intermediate- and low-risk populations. As TAVR was progressively studied and clinically used in lower-risk patients, issues were raised questioning its opportunity in a younger population with a longer life-expectancy. As long-term follow-up data mainly derive from old studies with early generation devices on high or intermediate surgical risk patients, results can hardly be extended to most of currently treated patients who often show a low surgical risk and are treated with newer generation prostheses. Thus, in this low-risk younger population, decision making is difficult due to the lack of supporting data. The aim of the present review is to revise current literature regarding TAVR in younger patients.

A preclinical randomized controlled study of ischemia treated with Ginkgo biloba extracts: Are complex components beneficial for treating acute stroke?

The rigorous design of preclinical experimental studies of candidate neuroprotectants for the treatment of acute ischemic stroke is crucial for the success of subsequent randomized clinical trials. The efficacy of Ginkgo biloba extracts (GBEs) in complex mixtures for the treatment of acute ischemic stroke remains unclear. In this preclinical randomized controlled trail (pRCT), the effects of a novel (n)GBE containing pinitol versus traditional (t)GBE without pinitol were evaluated on the mouse models of acute transient and permanent stroke, separately. The sample size, an important aspect of study design, was calculated based on our experimental data. Mice with ischemia that were induced by transient middle cerebral artery occlusion (tMCAO) or permanent distal middle cerebral artery occlusion (pdMCAO), were treated with vehicle, nGBE, tGBE, or pinitol alone by tail-vein injection. Our results showed that nGBE significantly reduced infarct size in mice with tMCAO compared with vehicle-treated control mice. Both nGBE and tGBE significantly reduced infarct size in mice with pdMCAO compared with the vehicle-treated controls. None of the three treatments rescued weight loss or prevented the neurological deficits in either the tMCAO- or pdMCAO-model mice. These findings suggest that nGBE, which includes all of the components of tGBE and pinitol, is neuroprotective in two ischemic stroke models. Additional studies of complex GBE mixtures for stroke treatment compared to single component medications are undergoing evaluation.

Effect of footplate neuromuscular electrical stimulation on functional and quality-of-life parameters in patients with peripheral artery disease: pilot, and subsequent randomized clinical trial.

Supervised exercise programmes for intermittent claudication have poor access and limited compliance. Neuromuscular electrical stimulation (NMES) may be an effective alternative. A proof-of-concept study and RCT were conducted. In study 1, eligible patients underwent baseline assessment; treadmill testing for initial (ICD) and maximum (MCD) claudication distance; EuroQoL Five Dimensions five-level instrument (EQ-5D-5L™) and Intermittent Claudication Questionnaire (ICQ) assessment; and measurement of ultrasound haemodynamics of the superficial femoral artery. After familiarization with the NMES device, participants underwent a 30-min session of stimulation with concomitant recording of haemodynamic measures at 15 min, and after device cessation. Measurements were repeated after 6 weeks of daily use of NMES. In study 2, consecutive patients underwent baseline assessment before online randomization to a supervised exercise programme only, or adjunctive NMES treatment for 6 weeks, followed by repeat measurements. Study 1 (20 patients) showed a significant improvement in MCD (46 per cent; P < 0·001) and ICD (71 per cent; P < 0·001). The RCT (42 patients) showed a significant adjunctive benefit of NMES in ICD (46 per cent; P = 0·014). Improvements were seen in the ICQ (9 points; P = 0·009) and EQ-5D-5L™ (P = 0·007) in study 1, and there was a significant adjunctive benefit of NMES on the ICQ score in patients who did supervised exercise (11·2 points; P = 0·031). Blood volume flow and time-adjusted mean velocity increased significantly with the device on (P < 0·050). Overall, NMES compliance exceeded 95 per cent. Footplate NMES significantly improved walking distance in patients with intermittent claudication when used independently and also as an adjunct to supervised exercise. Registration number: trial 1, NCT02436200; trial 2, NCT02429310 (http://www.clinicaltrials.gov).

Fecal Microbiota Transplantation for Treating Hepatic Encephalopathy: Experimental and Clinical Evidence and Possible Underlying Mechanisms

Gut microbiota changes play a key role in the pathogenesis of hepatic encephalopathy (HE). Fecal microbiota transplantation (FMT) is an efficient way to manipulate the gut microbiota. This review collects the experimental and clinical evidence that supports the use of FMT in the treatment of HE. Animal experiments showed that the blood ammonia level, mortality and cognitive impairment were decreased when animals with HE were transplanted with the selected gut microbiota or the fecal material from human donor. Successful clinical application of FMT for treating HE was first reported in 2016. A subsequent randomized clinical trial demonstrated further that FMT from a “rationally selected donor” reduced hospitalizations and improved cognition and dysbiosis in patients with recurrent HE. Possible underlying mechanisms of FMT treating HE include restoration of the impaired gut-liver-brain axis, as well as reduction of ammonia production, systemic inflammation and blood-brain barrier permeability.

Repetitive transcranial magnetic stimulation for the treatment of drug-resistant epilepsy: A systematic review and individual participant data meta-analysis of real-world evidence.

SummaryObjectiveTo perform a systematic review and meta‐analysis of real‐world evidence for the use of low‐frequency repetitive transcranial magnetic stimulation (rTMS) in the treatment of drug‐resistant epilepsy.MethodsWe systematically searched PubMed, Scopus, Medline, and clinicaltrials.gov for all relevant articles. Relevant patient and stimulation predictors as well as seizure outcomes were assessed. For studies with and without individual participant data (IPD), the primary outcomes were the rate of “favorable response” (reduction in seizure frequency ≥50%) and pooled event rate of mean reduction in seizure frequency, respectively. Outcomes were assessed with comparative statistics and random‐effects meta‐analysis models.ResultsOf 3,477 identified articles, 12 met eligibility and were included in this review. We were able to obtain IPD for 5 articles constituting 34 participants. Univariate analysis on IPD identified greater favorable response event rates between participants with temporal seizure focus versus extratemporal (50% vs. 14%, p = 0.045) and between participants who were stimulated with a figure‐8 coil versus other types (47% vs. 0%, p = 0.01). We also performed study‐level meta‐analysis on the remaining 7 studies without IPD, which included 212 participants. The pooled mean event rate of 50% seizure reduction using low‐frequency rTMS was 30% (95% confidence interval [CI] 12–57%). Sensitivity analysis revealed that studies with a mean age ≤21 years and studies using targeted stimulation had the highest seizure reduction rates compared to studies with a mean age >21 years (69% vs. 18%) and not using a targeted stimulation (47% vs. 14–20%). Moreover, we identified high interstudy heterogeneity, moderate study bias, and high publication bias.SignificanceReal‐world evidence suggests that low‐frequency rTMS using a figure‐8 coil may be an effective therapy for the treatment of drug‐resistant epilepsy in pediatric patients. This meta‐analysis can inform the design and expedite recruitment of a subsequent randomized clinical trial.

Issues related to renal artery angioplasty and stenting.

Renal artery stenosis may play a significant role in the pathogenesis of secondary hypertension, renal dysfunction, and flash pulmonary edema. Currently correction of renal arterial inflow stenosis is reserved for resistant hypertension patients who have failed maximal medical therapy, have worsening renal function and/or unexplained proximal congestive failure. With the recent advances in minimally invasive percutaneous stent placement techniques, open surgical revascularization has been largely replaced by renal artery stenting. The potential benefit of revascularization seemed intuitive; however, the initial enthusiasm and rise in the number of percutaneous interventions have been tempered by many subsequent negative randomized clinical trials that failed to prove the proposed benefits of the percutaneous intervention. The negative randomized trial results have fallen under scrutiny due to trial design concerns and inconsistent outcomes of these studies compared to pivotal trials undertaken under US Food and Drug Administration scrutiny. Treatment of atherosclerotic renal artery occlusive disease has become one of the most debatable topics in the field of vascular disease. The results from recent randomized clinical trials of renal artery stenting have basically limited the utilization of the procedure in many centers, but not every clinical scenario was covered in those trials. There are potential areas for improvement focusing mainly on procedural details and patient selection with respect to catheter based treatment of atherosclerotic renal artery stenosis. We believe, limiting patient selection, enrollment criteria and outcomes measured functioned to reduce the benefit of renal artery stenosis stenting by not enrolling patients likely to benefit. Future studies incorporating potential procedural improvements and that include patients more likely to benefit from renal stenting than were included in ASTRAL and CORAL are needed to more carefully examine specific patient subgroups so that "the baby is not thrown out with the bath water." We also discuss several other concerns related to renal artery stenting which include diagnostic, procedure, indication, and reimbursement issues.

Evaluation of Evidence of Statistical Support and Corroboration of Subgroup Claims in Randomized Clinical Trials

Many published randomized clinical trials (RCTs) make claims for subgroup differences. To evaluate how often subgroup claims reported in the abstracts of RCTs are actually supported by statistical evidence (P < .05 from an interaction test) and corroborated by subsequent RCTs and meta-analyses. This meta-epidemiological survey examines data sets of trials with at least 1 subgroup claim, including Subgroup Analysis of Trials Is Rarely Easy (SATIRE) articles and Discontinuation of Randomized Trials (DISCO) articles. We used Scopus (updated July 2016) to search for English-language articles citing each of the eligible index articles with at least 1 subgroup finding in the abstract. Articles with a subgroup claim in the abstract with or without evidence of statistical heterogeneity (P < .05 from an interaction test) in the text and articles attempting to corroborate the subgroup findings. Study characteristics of trials with at least 1 subgroup claim in the abstract were recorded. Two reviewers extracted the data necessary to calculate subgroup-level effect sizes, standard errors, and the P values for interaction. For individual RCTs and meta-analyses that attempted to corroborate the subgroup findings from the index articles, trial characteristics were extracted. Cochran Q test was used to reevaluate heterogeneity with the data from all available trials. The number of subgroup claims in the abstracts of RCTs, the number of subgroup claims in the abstracts of RCTs with statistical support (subgroup findings), and the number of subgroup findings corroborated by subsequent RCTs and meta-analyses. Sixty-four eligible RCTs made a total of 117 subgroup claims in their abstracts. Of these 117 claims, only 46 (39.3%) in 33 articles had evidence of statistically significant heterogeneity from a test for interaction. In addition, out of these 46 subgroup findings, only 16 (34.8%) ensured balance between randomization groups within the subgroups (eg, through stratified randomization), 13 (28.3%) entailed a prespecified subgroup analysis, and 1 (2.2%) was adjusted for multiple testing. Only 5 (10.9%) of the 46 subgroup findings had at least 1 subsequent pure corroboration attempt by a meta-analysis or an RCT. In all 5 cases, the corroboration attempts found no evidence of a statistically significant subgroup effect. In addition, all effect sizes from meta-analyses were attenuated toward the null. A minority of subgroup claims made in the abstracts of RCTs are supported by their own data (ie, a significant interaction effect). For those that have statistical support (P < .05 from an interaction test), most fail to meet other best practices for subgroup tests, including prespecification, stratified randomization, and adjustment for multiple testing. Attempts to corroborate statistically significant subgroup differences are rare; when done, the initially observed subgroup differences are not reproduced.

In-home nighttime predictive low glucose suspend experience in children and adults with type 1 diabetes.

Overnight predictive low glucose suspend (PLGS) reduces hypoglycemia across all ages; however, there are no reports on behavior or experience differences across age groups, especially in pediatrics. As run-in for a subsequent randomized clinical trial (RCT), 127 subjects (50% male) ages 4-45 yr utilized the experimental PLGS system nightly for 5-10 nights (PLGS active phase). We analyzed the number of blood glucose (BG) checks and boluses given per age group. During the subsequent 42 night RCT phase, we analyzed sensor use, skin reactions, errors, and reasons why the experimental system was not used. In 821 nights of active PLGS, subjects ages 4-6 yr (and their parents) tested BG levels 75% of nights compared with 65% of nights (7-10 yr), 53% of nights (11-14 yr), 33% of nights (15-25 yr), and 28% of nights (26-45 yr), respectively (p < 0.001). Likewise, youngest subjects (and parents) administered insulin boluses 56% of nights during active PLGS use compared with 48%, 33%, 20%, and 25%, respectively (p < 0.001). This was unrelated to study requirements. During the RCT phase, subjects 4-6 yr experienced more frequent and severe skin reactions (p = 0.02), while adult subjects (26-45 yr) wore individual sensors a median of 26 h longer than the youngest subjects (p < 0.001). Technical problems with the sensor (errors, miscalibrations, etc.), traveling, and BG levels >270 at bedtime (study requirement) were primary contributors to non-system use. Understanding the different use patterns and challenges in pediatrics and adolescence is needed to direct patient education to optimize use of PLGS and future artificial pancreas systems.

Translation failure and medical reversal: Two sides to the same coin

Translation failure occurs when the results of preclinical, observational and/or early phase studies fail to predict the results of well done (i.e. appropriately controlled, adequately powered, and properly conducted) phase III or randomised clinical trials.Some failures occur when promising basic science findings fail to replicate in human studies, while others happen when promising uncontrolled trial data show an exaggerated effect that vanishes in the setting of a randomised trial.Medical reversals occur when the results of preclinical, observational and/or early phase studies fail to predict the results of subsequent randomized clinical trials, but the practice has already gained widespread acceptance. Oncologic examples include bevacizumab and the use of autologous stem cell transplant in metastatic breast cancer.In a well-intentioned effort to reduce the rate of translation failure, oncologists must be careful that changes to regulatory processes and clinical trial design do not actually work to increase the approval of ineffective compounds. By trying to cure translation failure, we should be careful to avoid medical reversal. The rise of surrogate end-points and role of hard-wired bias in oncology trials suggest that we may be currently ignoring the simple fact that translation failure and medical reversal are two sides to the same coin.

Comparison of vehicles to collect dentinal fluid for molecular analysis

ObjectivesTo test the hypothesis that a material with higher water absorption than polyvinylidene fluoride (PVDF) could increase the yield of target molecules from exposed dentine. MethodsIn a series of standard tests, different cellulose membranes were compared to a PVDF counterpart for their ability to absorb water and release protein. In a subsequent randomized clinical trial, the cellulose material with the most favourable values was compared to PVDF regarding the levels of MMP-2 that could be collected from exposed dentine of healthy human teeth during filling replacement. MMP-2 levels were determined by enzyme-linked immunosorbent assay (ELISA). Data from the laboratory experiments were compared between materials using the appropriate parametric tests. The frequency of cases yielding quantifiable levels of MMP-2 was compared between materials by Fisher's exact test. The level of significance was set at 5%. ResultsThe cellulose membrane with the largest pore size (12–15μm) absorbed significantly (P<0.05) more water than PVDF. It showed a protein release that was similar to that of PVDF, while the cellulose membranes with smaller pore size retained significantly more protein (P<0.05). Using the large-pore cellulose membrane, MMP-2 could be collected at a quantifiable level from the dentine of healthy teeth in 9 of 13 cases, compared to 1 of 13 with the PVDF membrane (P<0.05). ConclusionsUnder the current conditions, a large-pore cellulose membrane yielded more of a molecule of diagnostic value compared to a standard PVDF membrane. Clinical significanceMolecular diagnostics of dentinal fluid are hampered by low yields. In the current study, it was shown that cellulose membranes are more useful to collect MMP-2 from dentinal fluid than PVDF membranes.

Almotriptan: a review of 10 years’ clinical experience

Almotriptan, a serotonin 5-HT1B/1D agonist, was developed for the acute treatment of migraine with or without aura and has been available for 10 years. This article evaluates the wealth of experience that has been obtained with almotriptan, including large randomized clinical trials (RCTs) and post-marketing studies that more closely reflect everyday clinical practice. Initial RCTs required patients to take almotriptan when migraine pain was of moderate or severe intensity, and found that 12.5 mg provided optimal outcomes for both pain relief and tolerability. Almotriptan effectively improved 2-h pain-relief, reduced migraine-associated symptoms and demonstrated low recurrence rates. These findings were also shown in patient subgroups, such as adolescents and menstrual migraineurs. A secondary finding in these trials was that patients who took almotriptan early, when the pain was still mild, achieved better outcomes. This prompted the initiation of studies designed to assess the effect of almotriptan in early intervention. Open-label trials reported improvements in pain-free end points (2 h, 24 h), and subsequent RCTs confirmed these findings. Pharmacovigilance data from more than 100 million tablets dispensed worldwide have confirmed that almotriptan is associated with a low occurrence of adverse effects, which, in clinical trials, has been shown to be similar to that observed with placebo. The clinical evidence obtained and comparisons made over a decade of use have demonstrated that almotriptan is one of the more effective and fast-acting triptans available, with a placebo-like tolerability profile. This suggests that almotriptan is an excellent choice for patients requiring specific acute migraine treatment.

Iron Chelation for Amelioration of Liver Ischemia-Reperfusion Injury

Liver resections are frequently associated with significant ischemia-reperfusion (I-R) injury of the liver remnant. The aim of this study was to investigate whether deferoxamine (DFO) can ameliorate I-R injury during major hepatectomies performed under vascular exclusion of the liver in a porcine model. Twelve female domestic pigs were divided into control (n = 6) and DFO treatment (n = 6) groups and subjected to 150 min. liver ischemia followed by 70% hepatectomy and 24 hours reperfusion. Pigs in the DFO group received a continuous intravenous infusion of 100 mg/kg DFO. Liver remnant injury was evaluated by liver function tests, hepatic histology as well as serum and liver tissue malondialdehyde (MDA) concentrations. Deferoxamine-treated animals had reduced total bilirubin, γ-glutamyl transferase and ammonia levels as well as hepatocyte necrosis and oxidative injury. In a subsequent randomized clinical trial using DFO for I-R protection during major liver surgery, preliminary results revealed amelioration of hepatocellular damage, oxidative and inflammatory serum markers and apoptotic response in liver remnant biopsies.

Letter to the Editor

Letter to the Editor

Letter to the Editor

Dear Editor We are gratified to see that many of our answers to Kittleson and colleagues' 1st letter apparently provided satisfaction as these points were not mentioned in the second. Moreover, these authors now “do not dispute that ACE inhibitors (ACEI) may have other beneficial effects” than cardiac effects, which is substantially different from their statement in their 1st letter that ACEI “have been extensively studied without evidence of such benefits.” However, we believe that the criticisms put forth by Kittleson and colleagues are erroneous or merely personal opinions. The conclusion by Kittleson et al that all 3 published studies found that “ACEIs do not prolong the time to onset of heart failure in any breed with MVD” is incorrect, as the 16 authors of Vetproof concluded that “results suggest that enalapril modestly delays the onset of CHF in dogs with moderate to severe mitral regurgitation (MR).”1 Moreover, the implication that, in our study, we tried to hide results is unfounded: the fact that no significant differences in the time of onset of CHF were found between the ACEI and untreated groups is clearly stated on page 909.2 The statement that all-cause mortality should not be evaluated in such clinical trials is incorrect. A therapy that would reduce cardiac death but increase overall death rate would provide no overall benefit. As we wrote in our 1st letter, all-cause mortality is a standard endpoint in human cardiology. We do not agree with the statement that sudden death is not relevant to study in dogs with MVD. Time to sudden cardiac death was used as an endpoint in the recent QUEST study.3 Similarly, in a 56-month study period involving 71 dogs with MVD, 4 sudden deaths were recorded and only 2 dogs underwent cardiac-related euthanasia.4 Consequently, sudden death does occur in MVD and is relevant. On one hand, Kittleson and colleagues acknowledge retrospective studies' “contributions … to the standard of medical practice are incontrovertible.” On the other hand, they criticize such studies because “uncontrolled confounding” factors can lead to invalid conclusions “specifically for retrospective studies of treatment efficacy.” The concerns of Kittleson and colleagues seem surprising, while they have themselves published several retrospective studies dedicated to clinical outcome according to treatments.5, 6 Limitations of retrospective studies, which by definition are not randomized and blinded, are true regardless of the research topic and the authors. Such limitations, including the number of dogs, are clearly stated in our paper (pp. 912–913).2 Kittleson and colleagues state that “there are countless examples of observational studies of treatment efficacy whose findings have been refuted by subsequent randomized clinical trials” and provide as support 1 single reference, the New York Times Magazine, which is, in our view, not an appropriate nor peer-reviewed reference for such a strong statement. In contrast, it has been recently published in the New England Journal of Medicine that little evidence exists to show that observational studies find stronger treatment effects than randomized, controlled trials, contrary to what has been claimed for many years.7, 8 This conclusion applies exactly in the case of our study,2 which provides results in agreement with 2 previously published prospective trials.1, 9 Additionally, the practice of using retrospective trials to supplement randomized trials is justified and one need look no further than the prestigious journal Circulation to find a retrospective study designed to answer questions regarding treatment efficacy left unanswered by prospective clinical trials.10 Kittleson and colleagues state that “clinically unaffected dogs” with MVD “and a normal left atrial size” with “a moderate to severe mitral regurgitation (MR)” are “pathophysiologically impossible.” Firstly, it is “pathophysiologically” possible in humans.11 Secondly, Kittleson and colleagues refer to one of our papers in which 450/617 MVD dogs were asymptomatic.12 By comparison, in 1 retrospective study published by Kittleson and colleagues only 5/17 dogs with MVD were “judged clinically to have mild MVD.”13 Four of these 5 dogs had a regurgitant fraction (RF) between 22 and 41% (ie, for some of them moderate), and the other dog had a RF of 73% (ie, severe MR), but was arbitrarily considered by the authors as a “statistical outlier.” The authors of the letter have actually made similar observations to us but may have failed to recognize them or chose to term them “outliers.” If Kittleson and colleagues had included more than 5 dogs with “mild MVD,” they would have probably found more “statistical outliers.” Furthermore had they measured pulmonary arterial pressure, their statement about stage 1 MR and pulmonary hypertension would carry more weight.

2008 Emily Cooley Memorial Lecture: lessons learned from pediatric transfusion medicine clinical trials . . . a little child shall lead them

Many clinical practices in transfusion medicine are controversial and/or lack definitive guidelines established by sound clinical trials. Although recommendations based on results of clinical trials performed using infants and children may not always be applied directly to adults--and vice versa--lessons learned from pediatric trials can be useful when critically assessing the design/results/conclusions of adult trials. Four randomized clinical trials (RCTs) studying pediatric patients were critically reviewed. They addressed two red blood cell (RBC) transfusion issues: 1) transfusion guidelines by which RBC transfusions are "triggered" by liberal (LIB; high pretransfusion patient hematocrit [Hct] levels) versus being "triggered" by restricted (RES; low pretransfusion Hct levels) and 2) transfusion of fresh RBCs (<or=7 days' storage) versus RBCs (up to 42 days' storage). Findings established by primary outcomes generally were firm (e.g., fewer RBC transfusions were given to infants/children managed by RES guidelines; transfusing small volumes of RBCs stored up to 42 days to preterm infants diminished allogeneic donor exposures and were equally efficacious and safe as fresh RBCs stored <or=7 days). Findings based on secondary outcomes, subset, and post hoc analyses were inconsistent (e.g., clinical outcomes were equivalent after LIB or RES transfusions in only two of three RCTs; in the third, more neurologic problems were found in neonates given RES transfusions). Clinical practices should be based on data pertaining to the primary outcomes of RCTs, because trials are designed and statistically powered to address these issues. Clinical practices suggested by analysis of secondary outcomes, subsets of patients, and post hoc analyses should be applied cautiously until studied further-ideally, as primary outcomes in subsequent RCTs.

Estrogen-Eluting Stents

Coronary stenting is routinely utilized to treat symptomatic obstructive coronary artery disease. However, the efficacy of bare metal coronary stents has been historically limited by restenosis, which is primarily due to excessive neointima formation. Drug-eluting stents (DES) are composed of a stainless steel backbone encompassed by a polymer in which a variety of drugs that inhibit smooth muscle cell proliferation and excessive neointima formation are incorporated. DES have significantly reduced the incidence of restenosis but are also associated with a small (~0.5% per year) but significant risk of late stent thrombosis. In that regard, estrogen-eluting stents have also undergone clinical evaluation in reducing restenosis with the additional potential benefit of enhancing reendothelialization of the stent surface to reduce stent thrombosis. Estrogen directly promotes vasodilatation, enhances endothelial healing, and prevents smooth muscle cell migration and proliferation. Due to these mechanisms, estrogen has been postulated to reduce neointimal hyperplasia without delaying endothelial healing. In animal studies, estrogen treatment was effective in decreasing neointimal hyperplasia after both balloon angioplasty and stenting regardless of the method of drug delivery. The first uncontrolled human study using estrogen-coated stents demonstrated acceptable efficacy in reducing late lumen loss. However, subsequent randomized clinical trials did not show superiority of estrogen-eluting stents over bare metal stents or DES. Further studies are required to determine optimal dose and method of estrogen delivery with coronary stenting and whether this approach will be a viable alternative to the current DES armamentarium.

Critical Care Nephrology: Core Curriculum 2009

In the inpatient setting, a high proportion of nephrology consultations are requested for patients in the Intensive Care Unit (ICU). These patients may have acute kidney injury (AKI) or may be critically ill and have end-stage renal disease (ESRD). Thus, nephrologists need to understand recent evidence-based advances in the field of critical care, as well as areas of ongoing controversy and investigation. In this article, we summarize the diagnosis and management of shock, as well as the management of sepsis, acute lung injury/acute respiratory distress syndrome (ALI/ARDS), and fulminant hepatic failure, all of which are associated with high mortality in the critical care setting. We discuss infectious complications of critical care, including ventilator associated pneumonia and catheter related infections. Supportive care, including nutrition, insulin therapy and anemia management are reviewed. Dialysis considerations in critically ill patients are discussed. Lastly, we review the management of several life-threatening intoxications, many of which require early recognition and consideration of dialysis.