Limited Clinical Trial Evidence Research Articles

Obesity pharmacotherapy in older adults: a narrative review of evidence.

The prevalence of obesity in older adults (people aged >60 years) is increasing in line with the demographic shift in global populations. Despite knowledge of obesity-related complications in younger adults (increased risk of type 2 diabetes, liver and cardiovascular disease and malignancy), these considerations may be outweighed, in older adults, by concerns regarding weight-loss induced reduction in skeletal muscle and bone mass, and the awareness of the 'obesity paradox'. Obesity in the elderly contributes to various obesity-related complications from cardiometabolic disease and cancer, to functional decline, worsening cognition, and quality of life, that will have already suffered an age-related decline. Lifestyle interventions remain the cornerstone of obesity management in older adults, with emphasis on resistance training for muscle strength and bone mineral density preservation. However, in older adults with obesity refractory to lifestyle strategies, pharmacotherapy, using anti-obesity medicines (AOMs), can be a useful adjunct. Recent evidence suggests that intentional weight loss in older adults with overweight and obesity is effective and safe, hence a diminishing reluctance to use AOMs in this more vulnerable population. Despite nine AOMs being currently approved for the treatment of obesity, limited clinical trial evidence in older adults predominantly focuses on incretin therapy with glucagon-like peptide-1 receptor agonists (liraglutide, semaglutide, and tirzepatide). AOMs enhance weight loss and reduce cardiometabolic events, while maintaining muscle mass. Future randomised controlled trials should specifically evaluate the effectiveness of novel AOMs for long-term weight management in older adults with obesity, carefully considering the impact on body composition and functional ability, as well as health economics.

Alzheimer's disease with frailty: Prevalence, screening, assessment, intervention strategies and challenges.

Alzheimer's disease (AD) is a neurodegenerative disorder that affects millions worldwide and is expected to surge in prevalence due to aging populations. Frailty, characterized by muscle function decline, becomes more prevalent with age, imposing substantial burdens on patients and caregivers. This paper aimed to comprehensively review the current literature on AD coupled with frailty, encompassing prevalence, screening, assessment, and treatment while delving into the field's challenges and future trajectories. Frailty and AD coexist in more than 30% of cases, with hazard ratios above 120% indicating a mutually detrimental association.Various screening tools have emerged for both frailty and AD, including the Fried Frailty Phenotype (FP), FRAIL scale, Edmonton Frailty Scale (EFS), Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Clock Drawing Test (CDT), and General Practitioner Assessment of Cognition (GPCOG). However, none has solidified its role as the definitive gold standard. The convergence of electronic health records and brain aging biomarkers heralds a new era in AD with frailty screening and assessment. In terms of intervention, non-pharmacological strategies spanning nutrition, horticulture, exercise, and social interaction, along with pharmacological approaches involving acetylcholinesterase inhibitors (AChEIs), N-methyl-D-aspartate (NMDA) receptor antagonists, and anti-amyloid beta-protein medications, constituted cornerstones for treating AD coupled with frailty. Technological interventions like repetitive transcranial magnetic stimulation (rTMS) also entered the fold. Notably, multi-domain non-pharmacological interventions wield considerable potential in enhancing cognition and mitigating disability. However, the long-term efficacy and safety of pharmacological interventions necessitate further validation. Diagnosing and managing AD with frailty present several daunting challenges, encompassing low rates of early co-diagnosis, limited clinical trial evidence, and scarce integrated, pioneering service delivery models. These challenges demand heightened attention through robust research and pragmatic implementation.

Clip Closure Does Not Reduce Risk of Bleeding After Resection of Large Serrated Polyps: Results From a Randomized Trial

Serrated polyps are important colorectal cancer precursors and are most commonly located in the proximal colon, where post-polypectomy bleeding rates are higher. There is limited clinical trial evidence to guide best practices for resection of large serrated polyps (LSPs). In a multicenter trial, patients with large (≥20 mm) non-pedunculated polyps undergoing endoscopic mucosal resection (EMR) were randomized to clipping of the resection base or no clipping. This analysis is stratified by histologic subtype of study polyp(s), categorized as serrated [sessile serrated lesions (SSLs) or hyperplastic polyps (HPs)] or adenomatous, comparing clip vs control groups. The primary outcome was severe post-procedure bleeding within 30 days of colonoscopy. A total of 179 participants with 199 LSPs (191 SSLs and 8 HPs) and 730 participants with 771 adenomatous polyps were included in the study. Overall, 5 patients with LSPs (2.8%) experienced post-procedure bleeding compared with 42 (5.8%) of those with adenomas. There was no difference in post-procedure bleeding rates between patients in the clip vs control group among those with LSPs (2.3% vs 3.3%, respectively, difference 1.0%; P= NS). However, among those with adenomatous polyps, clipping was associated with a lower risk of post-procedure bleeding (3.9% vs 7.6%, difference 3.7%; P= .03) and overall serious adverse events (5.5% vs 10.6%, difference 5.1%; P= .01). The post-procedure bleeding risk for LSPs removed via EMR is low, and there is no discernable benefit of prophylactic clipping of the resection base in this group. This study indicates that the benefit of endoscopic clipping following EMR may be specific for >2 cm adenomatous polyps located in the proximal colon. gov, Number: NCT01936948.

ID: 3521647 EFFECT OF CLIP CLOSURE ON OUTCOMES AFTER RESECTION OF LARGE SERRATED POLYPS: RESULTS FROM A RANDOMIZED TRIAL

Serrated polyps, particularly sessile serrated lesions (SSL), are important colorectal cancer precursors. Endoscopic management of serrated polyps often differs from that of adenomatous polyps due to morphology and other specific endoscopic features. SSLs are most commonly located in the proximal colon, where post-polypectomy bleeding rates are higher. There is limited clinical trial evidence to guide best practices for resection of large serrated polyps.

Use of Mechanical Circulatory Support Devices Among Patients With Acute Myocardial Infarction Complicated by Cardiogenic Shock

Mechanical circulatory support (MCS) devices, including intravascular microaxial left ventricular assist devices (LVADs) and intra-aortic balloon pumps (IABPs), are used in patients who undergo percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) complicated by cardiogenic shock despite limited evidence of their clinical benefit. To examine trends in the use of MCS devices among patients who underwent PCI for AMI with cardiogenic shock, hospital-level use variation, and factors associated with use. This cross-sectional study used the CathPCI and Chest Pain-MI Registries of the American College of Cardiology National Cardiovascular Data Registry. Patients who underwent PCI for AMI complicated by cardiogenic shock between October 1, 2015, and December 31, 2017, were identified from both registries. Data were analyzed from October 2018 to August 2020. Therapies to provide hemodynamic support were categorized as intravascular microaxial LVAD, IABP, TandemHeart, extracorporeal membrane oxygenation, LVAD, other devices, combined IABP and intravascular microaxial LVAD, combined IABP and other device (defined as TandemHeart, extracorporeal membrane oxygenation, LVAD, or another MCS device), or medical therapy only. Use of MCS devices overall and specific MCS devices, including intravascular microaxial LVAD, at both patient and hospital levels and variables associated with use. Among the 28 304 patients included in the study, the mean (SD) age was 65.4 (12.6) years and 18 968 were men (67.0%). The overall MCS device use was constant from the fourth quarter of 2015 to the fourth quarter of 2017, although use of intravascular microaxial LVADs significantly increased (from 4.1% to 9.8%; P < .001), whereas use of IABPs significantly decreased (from 34.8% to 30.0%; P < .001). A significant hospital-level variation in MCS device use was found. The median (interquartile range [IQR]) proportion of patients who received MCS devices was 42% (30%-54%), and the median proportion of patients who received intravascular microaxial LVADs was 1% (0%-10%). In multivariable analyses, cardiac arrest at first medical contact or during hospitalization (odds ratio [OR], 1.82; 95% CI, 1.58-2.09) and severe left main and/or proximal left anterior descending coronary artery stenosis (OR, 1.36; 95% CI, 1.20-1.54) were patient characteristics that were associated with higher odds of receiving intravascular microaxial LVADs only compared with IABPs only. This study found that, among patients who underwent PCI for AMI complicated by cardiogenic shock, overall use of MCS devices was constant, and a 2.5-fold increase in intravascular microaxial LVAD use was found along with a corresponding decrease in IABP use and a significant hospital-level variation in MCS device use. These trends were observed despite limited clinical trial evidence of improved outcomes associated with device use.

Effectiveness of Contact Precautions to Prevent Transmission of Methicillin-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococci in Intensive Care Units.

Contact precautions for endemic methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) are under increasing scrutiny, in part due to limited clinical trial evidence. We retrospectively analyzed data from the Strategies to Reduce Transmission of Antimicrobial Resistant Bacteria in Intensive Care Units (STAR*ICU) trial to model the use of contact precautions in individual intensive care units (ICUs). Data included admission and discharge times and surveillance test results. We used a transmission model to estimate key epidemiological parameters, including the effect of contact precautions on transmission. Finally, we performed multivariate meta-regression to identify ICU-level factors associated with contact precaution effects. We found that 21% of admissions (n = 2194) were placed on contact precautions, with most for MRSA and VRE. We found little evidence that contact precautions reduced MRSA transmission. The estimated change in transmission attributed to contact precautions was -16% (95% credible interval, -38% to 15%). VRE transmission was higher than MRSA transmission due to contact precautions, but not significantly. In our meta-regression, we did not identify associations between ICU-level factors and estimated contact precaution effects. Importation and transmission were higher for VRE than for MRSA, but clearance rates were lower for VRE than for MRSA. We found little evidence that contact precautions implemented during the STAR*ICU trial reduced transmission of MRSA or VRE. We did find important differences in the transmission dynamics between MRSA and VRE. Differences in organism and healthcare setting may impact the efficacy of contact precautions.

Salvage chemotherapy in the treatment of metastatic melanoma after progression on immunotherapy.

e22019 Background: Immune-checkpoint inhibitors (ICI) have dramatically altered the prognosis of metastatic melanoma (MM); however, fifty percent of patients will not respond to ICI. For these patients, the next choice of treatment includes targeted therapy or a clinical trial if eligible. If these treatment choices have already been utilized or are not available to the patient, there may be value in attempting a course of salvage chemotherapy (CTX). Limited clinical trial evidence has demonstrated unexpected efficacy of CTX after prior progression on ipilimumab, offering higher disease control rates than expected from what is seen in first-line chemotherapy. The phenomenon of a “priming” effect of ICI on CTX efficacy has been shown in patients of various solid tumors after progression on anti-PD1/PD-L1 therapy. The purpose of this retrospective analysis is to evaluate the efficacy of salvage CTX after prior ICI therapy for patients with MM. Patients with ocular melanoma were excluded, as this tumor subtype is known to have reduced response to immunotherapy. Methods: By retrospective analysis, patients were included under an IRB approved waiver of consent. We identified patients with MM treated with ICI therapy between Jan, 2011 and July, 2019 who were subsequently treated with salvage CTX as a result of progression of disease (POD). Salvage CTX included dacarbazine, carboplatin, temozolomide, paclitaxel, or a combination. We assessed response rate, duration of response, and time to progression (TTP) from the onset of salvage CTX. Results: A total of 22 patients who satisfied the above criteria were identified. The majority of this population had a course of single agent ICI as well as a course of combination ICI prior to salvage CTX (72.7%, n = 16/22). 13 (59.1%) patients had POD on salvage CTX with a median TTP of 10.9 weeks. 9 (40.9%) patients responded to salvage CTX. 3 (13.6%) patients achieved a complete response, 4 (18.2%) patients achieved a partial response and 2 (9.1%) patients achieved stable disease. Mean durability of response was 53.6 weeks, ranging from 7-194 weeks. Conclusions: ICI “priming” prior to salvage CTX efficacy may improve disease responsiveness to CTX. This sequence of therapy may offer patients another reasonable treatment option. Despite the small sample size of this study, a prospective clinical trial in MM exploring CTX following ICI progression should be considered.

COMPRESSION SCREWS IN THE TREATMENT OF FRACTURES: A SCOPING REVIEW

The purpose of this scoping review was to identify and describe the current body of evidence on internal fracture fixation devices that require compression screws. Electronic literature searches were conducted and 665 unique studies were included. Investigations on avulsion fractures represented a small proportion of these studies (45 studies), the remainder being those on patients with fractures with vascular compromise risk. The most common type of avulsion injury investigated was tibial avulsion fractures, followed by fifth metatarsal and calcaneal avulsions. For vascular compromised fractures, greater than half of the studies were on femoral neck injuries while scaphoid injury studies also represented a substantial proportion of this evidence base. Most of the studies were case series and there was limited randomized clinical trial evidence. A total of 429 studies provided sufficient information on the devices used in their investigation; DePuy-Synthes and Acumed ranked as the top two companies in cumulative publications over the last decade. There is a large body of evidence on internal fixation compression screw devices used in the management of fractures; however, the literature is generally dominated by non-comparative research studies. Opportunities to improve the evidence base are large. Manufacturer priority on evidence-based product development is key to ongoing research inquiry.

Cost-effectiveness of mirabegron compared to tolterodine ER 4 mg for overactive bladder in Canada.

This analysis compared the cost-effectiveness of once-daily regimens of mirabegron 50 mg and generic tolterodine ER 4 mg in a hypothetical cohort of previously treated patients with overactive bladder (OAB) in Canada. A Markov model was developed to represent different health states according to OAB symptoms (frequency, incontinence), presence/absence of adverse events (AEs; dry mouth, constipation, blurred vision), and treatment status (on-treatment, discontinue treatment, restart previous treatment). The time horizon used was one year, with monthly transitions between health states. The model was populated using data from a phase 3, placebo-controlled trial of mirabegron that included tolterodine as an active comparator (SCORPIO), as well as other published literature and expert opinion. Cost-effectiveness was calculated from Canadian public payer (based on Quebec list prices) and societal perspectives. The incremental one-year cost per patient for mirabegron over tolterodine was $182 CAD and $157 CAD from the payer and societal perspectives, respectively. The incremental quality-adjusted life year (QALY) gain for mirabegron was 0.0066 when using EQ-5D health-state utilities. Mirabegron was cost-effective compared with tolterodine, from both payer and societal perspectives, and remained cost-effective vs. tolterodine across the majority of sensitivity analyses. The model was based on limited clinical trial evidence supplemented with expert opinion and assumptions; a select number of OAB symptoms, AEs, and direct and indirect medical costs associated with OAB; and a timeframe of only one year. From the payer and societal perspectives, the health economic model indicates that in Canada, mirabegron is a cost-effective treatment strategy compared with tolterodine, leading to improved health outcomes (QALYs) at an acceptable incremental cost.

The Beneficial Effects of Quercetin, Curcumin, and Resveratrol in Obesity.

Over the past two decades, obesity has been one of the major public health concerns in most countries. In the search for new molecules that could be used for the treatment of obesity, good perspectives have been opened up for polyphenols, a class of natural bioactive phytochemicals. Experimental and limited clinical trial evidence supports that some polyphenols such as quercetin, curcumin, and resveratrol have potential benefit functions on obesity treatment. This brief review focuses on the main functions of the above-named polyphenols on adipose tissue. These polyphenols may play beneficial effects on adipose tissue under obese condition by alleviating intracellular oxidative stress, reducing chronic low-grade inflammation, inhibiting adipogenesis and lipogenesis, and suppressing the differentiation of preadipocytes to mature adipocytes.

Give Serious Thought Before Starting Antipsychotics in Delirious Elders

Give Serious Thought Before Starting Antipsychotics in Delirious Elders

Fixed-dose combination therapy of nebivolol and valsartan for the treatment of hypertension

ABSTRACTRecent large clinical trials have refuted earlier suggestions from the Joint National Committee 8 committee that less aggressive targets for blood pressure control were all that could be justified in most hypertensive patients. It now does appear that in fact “lower is better,” with blood pressure targets < 120/80 mm Hg appropriate for many hypertensive patients. Two drug combinations are often indicated as initial therapy if a 20/10 mm Hg or greater blood pressure reduction is necessary to reach target. Combinations consisting of β-blockers and renin-angiotensin-aldosterone system inhibitors have previously been deemed “less effective,” based on partially overlapping mechanisms of action and limited clinical trial evidence. Nebivolol is a vasodilating β1-selective blocker and β3- adrenoceptor agonist; β3-adrenoceptor activation increases nitric oxide concentrations and thus explains the vasodilatory effect. A recent 8-week randomized trial (N=4,161) in individuals with stage 1-2 hypertension demonstrated that single-pill fixed dose combinations (FDC) of nebivolol and valsartan, an angiotensin II subtype 1 receptor blocker, were more effective in reducing blood pressure than the corresponding monotherapies, with comparable tolerability. In addition, an ABPM-biomarkers substudy from that trial (n=805) demonstrated that the FDC prevented a valsartan-induced increase in plasma renin activity, and that the nebivolol/valsartan 20/320 mg/day dose reduced plasma aldosterone concentration significantly more than valsartan 320 mg/day. This article will describe the properties of nebivolol that make it unique and separate it from other β-blockers, and will further support the pharmacological advantages of this particular combination.

Therapeutic Potential and Critical Analysis of the PCSK9 Monoclonal Antibodies Evolocumab and Alirocumab

To review the mechanism of action for PCSK9 monoclonal antibodies and critically evaluate the therapeutic potential of evolocumab and alirocumab in the treatment of hypercholesterolemia. Ovid MEDLINE search from 1980 to August 2015 using the terms PCSK9, evolocumab, and alirocumab with forward and backward citation tracking. English-language trials and studies assessing the mechanism, efficacy, or safety of PCSK9 monoclonal antibodies were included. PCSK9 monoclonal antibodies have a potent ability to reduce low-density lipoprotein (LDL) by almost 50% in controlled trials: -47.49% (95% CI = -69.6% to -25.4%). They have an acceptable safety profile with no significant elevations in Creatine Kinase (CK) (odds ratio [OR] = 0.72; 95% CI = 0.54 to 0.96) or serious adverse events (OR = 1.01; 95% CI = 0.87 to 1.18), and preliminary evidence suggests reductions in myocardial infarction (OR = 0.49; 95% CI = 0.26 to 0.93). Although it is effective in several familial hypercholesterolemia (FH) patient types, it does not work in homozygous patients with dual allele LDL receptor negative polymorphisms or those who are homozygous for autosomal recessive hypercholesterolemia. Although not preferred over statins because of limited clinical trial evidence of cardiovascular event reductions, dosing convenience, and expense, PCSK9 monoclonal antibodies will have a prominent role to play in the treatment of hypercholesterolemia, especially in patients needing large LDL reductions, including patients with many types of FH.

The Cost-Effectiveness of Low-Cost Essential Antihypertensive Medicines for Hypertension Control in China: A Modelling Study.

BackgroundHypertension is China’s leading cardiovascular disease risk factor. Improved hypertension control in China would result in result in enormous health gains in the world’s largest population. A computer simulation model projected the cost-effectiveness of hypertension treatment in Chinese adults, assuming a range of essential medicines list drug costs.Methods and FindingsThe Cardiovascular Disease Policy Model-China, a Markov-style computer simulation model, simulated hypertension screening, essential medicines program implementation, hypertension control program administration, drug treatment and monitoring costs, disease-related costs, and quality-adjusted life years (QALYs) gained by preventing cardiovascular disease or lost because of drug side effects in untreated hypertensive adults aged 35–84 y over 2015–2025. Cost-effectiveness was assessed in cardiovascular disease patients (secondary prevention) and for two blood pressure ranges in primary prevention (stage one, 140–159/90–99 mm Hg; stage two, ≥160/≥100 mm Hg). Treatment of isolated systolic hypertension and combined systolic and diastolic hypertension were modeled as a reduction in systolic blood pressure; treatment of isolated diastolic hypertension was modeled as a reduction in diastolic blood pressure. One-way and probabilistic sensitivity analyses explored ranges of antihypertensive drug effectiveness and costs, monitoring frequency, medication adherence, side effect severity, background hypertension prevalence, antihypertensive medication treatment, case fatality, incidence and prevalence, and cardiovascular disease treatment costs. Median antihypertensive costs from Shanghai and Yunnan province were entered into the model in order to estimate the effects of very low and high drug prices. Incremental cost-effectiveness ratios less than the per capita gross domestic product of China (11,900 international dollars [Int$] in 2015) were considered cost-effective. Treating hypertensive adults with prior cardiovascular disease for secondary prevention was projected to be cost saving in the main simulation and 100% of probabilistic simulation results. Treating all hypertension for primary and secondary prevention would prevent about 800,000 cardiovascular disease events annually (95% uncertainty interval, 0.6 to 1.0 million) and was borderline cost-effective incremental to treating only cardiovascular disease and stage two patients (2015 Int$13,000 per QALY gained [95% uncertainty interval, Int$10,000 to Int$18,000]). Of all one-way sensitivity analyses, assuming adherence to taking medications as low as 25%, high Shanghai drug costs, or low medication efficacy led to the most unfavorable results (treating all hypertension, about Int$47,000, Int$37,000, and Int$27,000 per QALY were gained, respectively). The strengths of this study were the use of a recent Chinese national health survey, vital statistics, health care costs, and cohort study outcomes data as model inputs and reliance on clinical-trial-based estimates of coronary heart disease and stroke risk reduction due to antihypertensive medication treatment. The limitations of the study were the use of several sources of data, limited clinical trial evidence for medication effectiveness and harms in the youngest and oldest age groups, lack of information about geographic and ethnic subgroups, lack of specific information about indirect costs borne by patients, and uncertainty about the future epidemiology of cardiovascular diseases in China.ConclusionsExpanded hypertension treatment has the potential to prevent about 800,000 cardiovascular disease events annually and be borderline cost-effective in China, provided low-cost essential antihypertensive medicines programs can be implemented.

Abstract 938: Circulating biomarkers of gut barrier function: Correlates and responses to calcium supplementation among sporadic colorectal adenoma patients in a dose-response randomized controlled trial

Abstract Gut barrier dysfunction contributes to several gastrointestinal disorders, including inflammatory bowel diseases and colorectal cancer, but factors associated with intestinal hyperpermeability have rarely been assessed in human populations, and there is very limited clinical trial evidence on whether gut barrier function may be modified by dietary factors. To address these gaps, we 1) evaluated factors associated with baseline circulating biomarkers of gut barrier function, and 2) tested the effect of calcium on these biomarkers over a 4-month treatment period among patients with previous colorectal adenoma in a randomized, double-blinded, placebo-controlled clinical trial (n = 193). Patients were randomized to placebo (n = 66), 1.0 g calcium (n = 64), or 2.0 g calcium (n = 63) daily. Circulating levels of anti-flagellin and anti-lipopolysaccharide (LPS) immunoglobulins (Igs) as markers of colonic hyperpermeability were measured at baseline and at 4-month follow-up via ELISA. At baseline, mean levels of anti-flagellin and anti-LPS IgA but not IgG were higher among men and those with a larger body mass index (BMI), a larger waist circumference, and higher levels of plasma C-reactive protein. Mean anti-flagellin IgG levels were higher among those with higher proinflammatory cytokine scores. We did not observe effects of calcium on anti-flagellin or anti-LPS Igs: the relative change of a combined permeability score (defined as the sum of the optical densities of all biomarkers) from baseline to follow-up was 0.07 (95% confidence interval [CI] -0.13, 0.27) for each treatment group relative to the placebo group (p-values ≥ 0.5). Our results suggest that 1) men and those with a larger BMI or waist circumference may have greater gut permeability, 2) markers of gut permeability and systemic inflammation may be directly associated with one another, and 3) supplemental calcium administered for 4 months may not modify circulating levels of biomarkers of gut barrier function. Citation Format: Baiyu Yang, Roberd M. Bostick, Andrew T. Gewirtz, Hao Quang Tran, Veronika Fedirko. Circulating biomarkers of gut barrier function: Correlates and responses to calcium supplementation among sporadic colorectal adenoma patients in a dose-response randomized controlled trial. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 938. doi:10.1158/1538-7445.AM2015-938

Managing Antithrombotic Therapy in Patients With Both Atrial Fibrillation and Coronary Heart Disease

PurposeAtrial fibrillation (AF) and coronary heart disease (CHD) commonly occur together. Previous consensus guidelines were published before the wide availability of novel oral anticoagulants (NOACs) and newer P2Y12 antiplatelet agents. We examine recent evidence to guide management in 3 categories of patients with AF and CHD: patients with stable CHD, nonstented patients with recent acute coronary syndrome, and patients with a coronary stent requiring dual-antiplatelet therapy. MethodsWe conducted a literature search by evaluation of PubMed and other data sources including international meeting reports. We critically reviewed recent clinical trial and relevant registry evidence to update European and US consensus documents. FindingsOral anticoagulation with warfarin or NOACs is required to prevent embolic stroke in AF, and antiplatelet therapy is insufficient for this purpose. Antiplatelet therapy using monotherapy with aspirin is the standard of care in stable CHD. Dual-antiplatelet therapy with aspirin and clopidogrel or a new P2Y12 inhibitor (dual-antiplatelet therapy) is needed to reduce coronary events after an acute coronary syndrome or after percutaneous coronary intervention. Combinations of these agents increase the risk of bleeding, and limited clinical trial evidence suggests that withdrawal of aspirin may reduce bleeding without increasing coronary events. ImplicationsAvailable clinical trials and registries provide remarkably little evidence to guide difficult clinical decision making in patients with combined AF and CHD. In patients on triple antithrombotic therapy with vitamin K antagonists, aspirin, and clopidogrel, a single clinical trial indicates that withdrawal of aspirin may reduce bleeding risk without increasing the risk of coronary thrombosis. It is unclear whether this evidence applies to combinations of NOACs and newer P2Y12 inhibitors. Clinical trials of combinations of the newer antithrombotic agents are urgently needed to guide clinical care.

A randomised controlled trial of an enhanced interdisciplinary community based group program for people with Parkinson’s disease: study rationale and protocol

Parkinson's disease (PD) is a progressive, chronic neurodegenerative disorder for which there is no known cure. Physical exercise programs may be used to assist with the physical management of PD. Several studies have demonstrated that community based physical therapy programs are effective in reducing physical aspects of disability among people with PD. While multidisciplinary therapy interventions may have the potential to reduce disability and improve the quality of life of people with PD, there is very limited clinical trial evidence to support or refute the use of a community based multidisciplinary or interdisciplinary programs for people with PD. A two group randomized trial is being undertaken within a community rehabilitation service in Brisbane, Australia. Community dwelling adults with a diagnosis of Idiopathic Parkinson's disease are being recruited. Eligible participants are randomly allocated to a standard exercise rehabilitation group program or an intervention group which incorporates physical, cognitive and speech activities in a multi-tasking framework. Outcomes will be measured at 6-week intervals for a period of six months. Primary outcome measures are the Montreal Cognitive Assessment (MoCA) and the Timed Up and Go (TUG) cognitive test. Secondary outcomes include changes in health related quality of life, communication, social participation, mobility, strength and balance, and carer burden measures. This study will determine the immediate and long-term effectiveness of a unique multifocal, interdisciplinary, dual-tasking approach to the management of PD as compared to an exercise only program. We anticipate that the results of this study will have implications for the development of cost effective evidence based best practice for the treatment of people with PD living in the community.

Bipolar and Substance Use Disorder Comorbidity: Diagnostic and Treatment Considerations

Both bipolar I and bipolar II disorders are highly comorbid with substance use disorders, and this comorbidity is associated with more severe illness course and early mortality. There is overdiagnosis of bipolar disorder in substance-misusing populations, but careful, structured diagnostic evaluation using family and other third-party confirmation can decrease this likelihood. Limited data for the use of pharmacological interventions to decrease drug and alcohol use in patients with bipolar disorder are available; nevertheless, the Food and Drug Administration-approved treatments for addictions, especially for nicotine and opiate dependence, may still be effective in patients with bipolar disorder. There is limited clinical trial evidence for treating mood episodes in patients with comorbid conditions; current substance use diagnoses do not lead to worse mood outcomes prospectively, suggesting that treatment should not be withheld from this group. Because the health consequences of substance misuse can be so grave, clinicians must be prepared to engage patients in treatment aimed to change behavior.

Efficacy and safety of bevacizumab in combination with docetaxel for the first-line treatment of elderly patients with locally recurrent or metastatic breast cancer: Results from AVADO

BackgroundOncologic treatment in elderly patients is challenging, due to comorbidities, often impaired organ function, limited clinical trial evidence, inadequate guidelines and no consistent ‘elderly’ definition. We report exploratory sub-analyses of safety and efficacy in elderly patients, defined as ⩾65years old, in AVastin And DOcetaxel (AVADO) receiving first-line bevacizumab plus docetaxel for metastatic breast cancer (mBC). Patients and methodsPatients with HER2-negative, locally recurrent or mBC were randomised to 3-weekly docetaxel (100mg/m2) with placebo, bevacizumab 7.5mg/kg or bevacizumab 15mg/kg, for 9 cycles or until disease progression or unacceptable toxicity. Patients had no prior chemotherapy for mBC. ResultsProgression-free survival (PFS) was increased with bevacizumab in the elderly subpopulation (n=127), the effect being greater with higher dose (hazard ratio=0.63 [95% confidence interval (CI) 0.383–1.032] versus 0.76 [95% CI: 0.46–1.262], respectively). PFS was numerically similar in the elderly and overall populations, but the former failed to achieve statistical significance. Overall response rates for docetaxel plus placebo, bevacizumab 7.5mg/kg and 15mg/kg were 44.7%, 36.6% and 50.0%, respectively. Effects on survival were not statistically significant. Bevacizumab was well tolerated in elderly patients, the most common adverse effects were neutropenia and febrile neutropenia; there was no excess of grade⩾3 cardiovascular events. There was no clear correlation between baseline hypertension and its development during study treatment. ConclusionsIn this exploratory sub-analysis in AVADO, bevacizumab plus docetaxel showed efficacy in elderly patients similar to the overall study population. There were no unexpected safety signals in patients aged 65years or older.

Medicinal plants and dementia therapy: herbal hopes for brain aging?

An escalating "epidemic" of diseases like Alzheimer's has not yet been met by effective symptomatic treatments or preventative strategies. Among a few current prescription drugs are cholinesterase inhibitors including galantamine, originating from the snowdrop. Research into ethnobotanicals for memory or cognition has burgeoned in recent years. Based on a multi-faceted review of medicinal plants or phytochemicals, including traditional uses, relevant bioactivities, psychological and clinical evidence on efficacy and safety, this overview focuses on those for which there is promising clinical trial evidence in people with dementia, together with at least one other of these lines of supporting evidence. With respect to cognitive function, such plants reviewed include sage, Ginkgo biloba, and complex mixtures of other traditional remedies. Behavioral and psychological symptoms of dementia (BPSD) challenge carers and lead to institutionalization. Symptoms can be alleviated by some plant species (e.g., lemon balm and lavender alleviate agitation in people with dementia; St John's wort treats depression in the normal population). The ultimate goal of disease prevention is considered from the perspective of limited epidemiological and clinical trial evidence to date. The potential value of numerous plant extracts or chemicals (e.g., curcumin) with neuroprotective but as yet no clinical data are reviewed. Given intense clinical need and carer concerns, which lead to exploration of such alternatives as herbal medicines, the following research priorities are indicated: investigating botanical agents which enhance cognition in populations with mild memory impairment or at earliest disease stages, and those for BPSD in people with dementia at more advanced stages; establishing an ongoing authoritative database on herbal medicine for dementia; and further epidemiological and follow up studies of promising phytopharmaceuticals or related nutraceuticals for disease prevention.