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PARADIGM-HF Trial: Secondary Analyses Address Unanswered Questions.
Smith, KR, Hsu, CC, Berei, TJ, Aldemerdash, A, Hollis, IB, Vardeny, O, Rodgers, JE
Pharmacotherapy. 2018;(2):284-298
Abstract
Our aim was to summarize published secondary analyses of the PARADIGM-HF trial. In the original trial, published in September 2014, sacubitril/valsartan significantly reduced the primary composite outcome of cardiovascular death or heart failure hospitalization compared to enalapril. This summary provides a resource for clinicians to review subsequent analyses of the landmark trial evaluating the benefit of sacubitril/valsartan in various subgroups and providing information regarding optimal use of this new therapy in the broader heart failure population. A full list of publications of the existing PARDADIGM-HF post hoc analyses was obtained and summarized, grouped by focus (e.g., severity of illness, tolerability). Twenty-six publications and one abstract analyzing the PARADIGM-HF trial were reviewed, summarizing the most important results that compared the benefits of sacubitril/valsartan to enalapril, including pertinent subgroup information from each analysis. Key publications evaluated the treatment effect of sacubitril/valsartan based on heart failure severity (i.e., ejection fraction or heart failure risk scores), impact on alternate outcomes, influence of additional therapies, tolerability in patients with comorbidities (i.e., diabetes), long-term benefits, and cost-effectiveness. In addition, nine ongoing phase III and phase IV clinical trials with sacubitril/valsartan were briefly summarized to address potential future uses in more extensive heart failure settings. The benefit of sacubitril/valsartan over enalapril for the primary endpoint in the PARADIGM-HF trial is maintained throughout numerous secondary analyses. Though the subgroups analyzed are based on participants from a single clinical trial, clinicians can more confidently incorporate this novel therapy into practice with expanded knowledge of these existing analyses as well as ongoing prospective trials.
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Emerging outcome measures for nutrition trials in the critically ill.
Bear, DE, Griffith, D, Puthucheary, ZA
Current opinion in clinical nutrition and metabolic care. 2018;(6):417-422
Abstract
PURPOSE OF REVIEW Mortality has long been the gold-standard outcome measure for intensive care clinical trials. However, as the critical care community begins to understand and accept that survivorship is associated with functional disability and a health and socioeconomic burden, the clinical and research focus has begun to shift towards long-term physical function RECENT FINDINGS To use mortality as a primary outcome measure, one would either have to choose an improbable effect (e.g. a difference of 5-10% in mortality as a result of a single intervention) or recruit a larger number of patients, the latter being unfeasible for most critical care trials.Outcome measures will need to match interventions. As an example, amino acids, or intermittent feeding, can stimulate muscle protein synthesis, and so prevention of muscle wasting may seem an appropriate outcome measure when assessing the effectiveness of these interventions. Testing the effectiveness of these interventions requires the development of novel outcome measures that are targeted and acceptable to patients. We describe advancements in dual-energy X-ray absorptiometry scanning, bio-impedence analysis, MRI and muscle ultrasound in this patient group that are beginning to address this development need. SUMMARY New approaches to outcome assessment are beginning to appear in post-ICU research, which promise to improve our understanding of nutrition and exercise interventions on skeletal muscle structure, composition and function, without causing undue suffering to the patient.
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Evaluating Whole Grain Intervention Study Designs and Reporting Practices Using Evidence Mapping Methodology.
Sawicki, CM, Livingston, KA, Ross, AB, Jacques, PF, Koecher, K, McKeown, NM
Nutrients. 2018;(8)
Abstract
Consumption of whole grains have been associated with reduced risk of chronic diseases in many observational studies; yet, results of intervention studies are mixed. We aimed to use evidence mapping to capture the methodological and reporting variability in whole grain intervention studies that may contribute to this inconsistency. We conducted a reproducible search in OVID Medline for whole grain human intervention studies (published 1946 to February 2018). After screening based on a priori criteria, we identified 202 publications describing a total of 213 unique trials. Over half (55%) were acute trials, lasting ≤1 day, 30% were moderate duration studies (up to 6 weeks) and 15% were of longer duration (more than 6 weeks). The majority of acute trials (75%) examined measures of glycaemia and/or insulinemia, while most of the longer trials included measures of cardiometabolic health (71%), appetite/satiety (57%) and weight/adiposity (56%). Among the moderate and long duration trials, there was a wide range of how whole grains were described but only 10 publications referenced an established definition. Only 55% of trials reported the actual amount of whole grains (in grams or servings), while 36% reported the amount of food/product and 9% did not report a dose at all. Of the interventions that provided a mixture of whole grains, less than half (46%) reported the distribution of the different grain types. Reporting of subject compliance also varied and only 22% used independent biomarkers of whole grain intake. This evidence map highlights the need to standardize both study protocols and reporting practices to support effective synthesis of study results and provide a stronger foundation to better inform nutrition scientists and public health policy.
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Is it possible for people with severe mental illness to sit less and move more? A systematic review of interventions to increase physical activity or reduce sedentary behaviour.
Ashdown-Franks, G, Williams, J, Vancampfort, D, Firth, J, Schuch, F, Hubbard, K, Craig, T, Gaughran, F, Stubbs, B
Schizophrenia research. 2018;:3-16
Abstract
Individuals with severe mental illness (SMI) (schizophrenia-spectrum, bipolar disorder and major depressive disorder) die 10-20 years prematurely due to physical disorders such as cardiovascular disease. Physical activity (PA) is effective in preventing and managing these conditions in the general population, however individuals with SMI engage in substantially less PA and more sedentary behaviour (SB) compared to healthy counterparts. Furthermore, the effectiveness of intervening to increase PA or reduce SB in SMI populations is unknown. Therefore, we systematically reviewed studies measuring changes in PA or SB following behavioural interventions in people with SMI. A systematic search of major databases was conducted from inception until 1/3/2018 for behavioural interventions reporting changes in PA or SB in people with SMI. From 3018 initial hits, 32 articles were eligible, including 16 controlled trials (CT's; Treatment n = 1025, Control n = 1162) and 16 uncontrolled trials (n = 655). Of 16 CTs, seven (47%) reported significant improvements in PA, although only one found changes with an objective measure. Of 16 uncontrolled trials, 3 (20%) found improvements in PA (one with objective measurement). No intervention study had a primary aim of changing SB, nor did any note changes in SB using an objective measure. In conclusion, there is inconsistent and low quality evidence to show that interventions can be effective in changing PA or SB in this population. Future robust randomized controlled trials, using objectively-measured PA/SB as the primary outcome, are required to determine which behavioural interventions are effective in improving the sedentary lifestyles associated with SMI. Systematic review registration- PROSPERO registration number CRD42017069399.
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Emerging Trends in Clinical Research: With Implications for Population Health and Health Policy.
Chin-Yee, B, Subramanian, SV, Verma, AA, Laupacis, A, Razak, F
The Milbank quarterly. 2018;(2):369-401
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Abstract
UNLABELLED Policy Points: Significant advances in clinical medicine that have broader societal relevance may be less accessible to population health researchers and policymakers because of increased specialization within fields. We describe important recent clinical advances and discuss their broader societal impact. These advances include more expansive strategies for disease prevention, the rise of precision medicine, applications of human microbiome research, and new and highly successful treatments for hepatitis C infection. These recent developments in clinical research raise important issues surrounding health care costs and equitable resource allocation that necessitate an ongoing dialogue among the fields of clinical medicine, population health, and health policy. CONTEXT Developments in clinical medicine have important implications for population health, and there is a need for interdisciplinary engagement among clinical medicine, the social sciences, and public health research. The aim of this article is to help bridge the divide between these fields by exploring major recent advances in clinical medicine that have important implications for population health. METHODS We reviewed the most cited articles published from 2010 to 2015 in 5 high-impact clinical journals and selected 5 randomized controlled trials and 2 related clinical practice guidelines that are broadly relevant to population health and policy. FINDINGS We discuss the following themes: (1) expanding indications for drug therapy and the inherent medicalization of the population as highlighted by studies and clinical guidelines supporting lower blood pressure targets or widespread statin use; (2) the tension in nutritional research between quantifying the impact of isolated nutrients and studying specific foods and dietary patterns, for example, the role of the Mediterranean diet in the primary prevention of cardiovascular disease; (3) the issue of high medication costs and the challenge of providing equitable access raised by the development of new and effective treatments for hepatitis C infection; (4) emerging clinical applications of research on the human microbiome as illustrated by fecal transplant to treat Clostridium difficile infections; and (5) the promise and limitations of precision medicine as demonstrated by the rise of novel targeted therapies in oncology. CONCLUSIONS These developments in clinical science hold promise for improving individual and population health and raise important questions about resource allocation, the role of prevention, and health disparities.
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Patient-Reported Outcome Measures for Use in Clinical Trials and Clinical Practice in Inflammatory Bowel Diseases: A Systematic Review.
de Jong, MJ, Huibregtse, R, Masclee, AAM, Jonkers, DMAE, Pierik, MJ
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2018;(5):648-663.e3
Abstract
BACKGROUND & AIMS Mucosal inflammation must be carefully monitored to improve the long-term outcomes of patients with inflammatory bowel diseases (IBD). Patient-reported outcome measures (PROMs) are used increasingly to monitor disease activity in clinical practice and as endpoints in clinical trials. We performed a systematic review to provide an overview of the available PROMs on IBD activity and to evaluate their diagnostic value. METHODS A systematic search of the PubMed, Medline, Cochrane library, and Embase databases using defined keywords, identified 973 articles. These were screened by 2 independent reviewers, and 37 articles on development or validation of PROMs to assess IBD activity were identified for further analysis. Based on the recommendations of the Food and Drug Administration (FDA), the following measurement properties were evaluated: content, construct, and criterion validity; reliability; and responsiveness to change. In addition, data on ease of use in clinical practice were collected. RESULTS Seventeen articles presenting 20 different PROMs were included the final analysis, although none met all the FDA-recommended criteria. Only 2 PROMs (patient-reported Harvey Bradshaw Index and Simple Clinical Colitis Activity Index scores) reported patient involvement during its development. Only 6 PROMs (patient-reported global assessment, patient assessment of disease activity, mobile health index for Crohn's disease, mobile health index for ulcerative colitis, patient-reported outcome derived from the Mayo score, and the 6-point Mayo score) were validated as markers of IBD activity, using findings from endoscopy as the reference standard; these PROMs identified patients with mucosal inflammation with area under the curve values of 0.63-0.82. The mobile health index for CD and UC scores had the best measurement properties for use in clinical practice and in clinical trials. CONCLUSIONS In a systematic review, we identified more than 20 PROMS that have been developed and tested for their ability to determine IBD activity. Further studies are needed to determine their accuracy and whether they can be used effectively in routine practice, clinical trials, telemedicine systems, and value-based healthcare programs.
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How to set the stage for a full-fledged clinical trial testing 'incremental haemodialysis'.
Casino, FG, Basile, C
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2018;(7):1103-1109
Abstract
Most people who make the transition to maintenance haemodialysis (HD) therapy are treated with a fixed dose of thrice-weekly HD (3HD/week) regimen without consideration of their residual kidney function (RKF). The RKF provides an effective and naturally continuous clearance of both small and middle molecules, plays a major role in metabolic homeostasis, nutritional status and cardiovascular health, and aids in fluid management. The RKF is associated with better patient survival and greater health-related quality of life. Its preservation is instrumental to the prescription of incremental (1HD/week to 2HD/week) HD. The recently heightened interest in incremental HD has been hindered by the current limitations of the urea kinetic model (UKM), which tend to overestimate the needed dialysis dose in the presence of a substantial RKF. A recent paper by Casino and Basile suggested a variable target model (VTM), which gives more clinical weight to the RKF and allows less frequent HD treatments at lower RKF as opposed to the fixed target model, based on the wrong concept of the clinical equivalence between renal and dialysis clearance. A randomized controlled trial (RCT) enrolling incident patients and comparing incremental HD (prescribed according to the VTM) with the standard 3HD/week schedule and focused on hard outcomes, such as survival and health-related quality of life of patients, is urgently needed. The first step in designing such a study is to compute the 'adequacy lines' and the associated fitting equations necessary for the most appropriate allocation of the patients in the two arms and their correct and safe follow-up. In conclusion, the potentially important clinical and financial implications of the incremental HD render it highly promising and warrant RCTs. The UKM is the keystone for conducting such studies.
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Changes in the use of end points in clinical trials for elderly cancer patients over time.
Le Saux, O, Falandry, C, Gan, HK, You, B, Freyer, G, Péron, J
Annals of oncology : official journal of the European Society for Medical Oncology. 2017;(10):2606-2611
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Abstract
BACKGROUND Physicians need well-addressed clinical trials assessing benefits and harm of treatments to avoid under-treatment or over-treatment of elderly patients. The main objectives of this report were to present an overview of end points used in clinical trials dedicated to elderly patients; and to assess the evolution in chosen end points before and after the creation of the International Society of Geriatric Oncology in the early 2000s. PATIENTS AND METHODS All phases I, II and III trials dedicated to the treatment of cancer among elderly patients published between 2001 and 2004 and between 2011 and 2014 were reviewed. All phase III clinical trials assessing cancer treatments among adults in the same periods were also reviewed to identify subgroup analyses of elderly patients among these trials. RESULTS Among phase III trials dedicated to elderly patients, overall survival was a common primary end point. Interestingly, tumor centered end points were very common in the first time period and very uncommon in the second time period, whereas composite end points were very uncommon in the first time period but very common in the second time period. Concerningly, disease-specific survival was very infrequently reported in dedicated clinical trials of elderly patients despite their importance in evaluating competing risk of death from non-oncology causes. The use of patient-reported outcomes (PROs) as a primary end point remained very uncommon but the reporting of PROs as a secondary end point tended to increase in the second time period, from 19% to 33% (P = 0.10). Functional status was infrequently reported. CONCLUSION During the past decade, the use of clinically meaningful end points such as PROs and functional status in elderly patients remained moderate. Yet, the use of PROs as a secondary end point tended to increase between the two time periods.
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A core outcomes set for clinical trials of interventions for young adults with type 1 diabetes: an international, multi-perspective Delphi consensus study.
Byrne, M, O'Connell, A, Egan, AM, Dinneen, SF, Hynes, L, O'Hara, MC, Holt, RIG, Willaing, I, Vallis, M, Hendrieckx, C, et al
Trials. 2017;(1):602
Abstract
BACKGROUND Achieving consensus from a range of relevant stakeholders about an agreed set of core outcomes to be measured and reported as a minimum in clinical trials has the potential to enhance evidence synthesis and make findings more relevant and applicable. Intervention research to improve outcomes for young adults with type 1 diabetes (T1DM) is hampered by inconsistent use of outcome measures. This population frequently struggles to manage their condition and reports suboptimal clinical outcomes. Our aim was to conduct an international, e-Delphi consensus study to identify a core outcome set (COS) that key stakeholders (young adults with T1DM, diabetes health professionals, diabetes researchers and diabetes policy makers) consider as essential outcomes for future intervention research. METHODS Using a list of 87 outcomes generated from a published systematic review, we administered two online surveys to a sample of international key stakeholders. Participants in the first survey (survey 1; n = 132) and the second survey (survey 2; n = 81) rated the importance of the outcomes. Survey 2 participants received information on total mean rating for each outcome and a reminder of their personal outcome ratings from Survey 1. Survey 2 results were discussed at a consensus meeting and participants (n = 12: three young adults with T1DM, four diabetes health professionals, four diabetes researchers and one diabetes policy maker) voted on outcomes. Final core outcomes were included provided that 70% of consensus group participants voted for their inclusion. RESULTS Eight core outcomes were agreed for inclusion in the final COS: measures of diabetes-related stress; diabetes-related quality of life; number of severe hypoglycaemic events; self-management behaviour; number of instances of diabetic ketoacidosis (DKA); objectively measured glycated haemoglobin (HbA1C); level of clinic engagement; and perceived level of control over diabetes. CONCLUSIONS This study is the first to identify a COS for inclusion in future intervention trials to improve outcomes for young adults with T1DM. Use of this COS will improve the quality of future research and increase opportunities for evidence synthesis. Future research is necessary to identify the most robust outcome measure instruments.
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Low FODMAP in 2017: Lessons learned from clinical trials and mechanistic studies.
Eswaran, S
Neurogastroenterology and motility. 2017;(4)
Abstract
Given the prevalence of irritable bowel syndrome (IBS) and the suboptimal response to most therapeutic approaches, there has been increasing interest in and adoption of dietary treatment strategies, such as the low Fermentable Oligo-, Di-, & Mono-Saccharides and Polyols (FODMAP) diet. FODMAPs are a diverse group of carbohydrates that exert effects in the gastrointestinal tract not only via fermentation but likely via alterations in the microbiota, metabolome, permeability, and intestinal immunity as well. Clinical evidence for efficacy of this diet is mounting, but there are significant questions regarding short- and long-term safety and effects on the microbiota and nutrition that remain unanswered. This review article interprets the recent findings reported in this issue of Neurogastroenterology and Motility and summarizes the mechanistic and clinical efficacy data of the low FODMAP diet in IBS patients to date.