Managing older people with atrial fibrillation and preventing stroke: a review of anticoagulation approaches.

INTRODUCTION: Oral anticoagulants (OACs) are the cornerstone of stroke prevention in atrial fibrillation (AF), but prescribing decisions in older people are complicated. Clinicians must assess the net clinical benefit of OAC in the context of multiple chronic conditions, polypharmacy, frailty and life expectancy. The under-representation of high-risk, older adult sub-populations in clinical trials presents the challenge of choosing the right OAC, where a 'one-size-fits-all' approach cannot be taken. AREAS COVERED: This review discusses OAC approaches for stroke prevention in older people with AF and presents a prescribing aid to support clinicians' decision-making. High-risk older adults with multiple chronic conditions, specifically chronic kidney disease, dementia/cognitive impairment, previous stroke/transient ischemic attack or intracranial hemorrhage, polypharmacy, frailty, low body weight, high falls risk, and those aged ≥75 years are considered. EXPERT OPINION: Non-vitamin K antagonist OACs are the preferred first-line OAC in older adults with AF, including high-risk subpopulations, after individual assessment of stroke and bleeding risk, except those with mechanical heart valves and moderate-to-severe mitral stenosis. Head-to-head comparisons of NOACs are not available, therefore the choice of drug (and dose) should be based on an individual's risk (stroke and bleeding) and incorporate their treatment preferences. Treatment decisions must be person-centered and principles of shared decision-making applied.

Beyond Antiretroviral Treatment: Patterns and Factors Associated With Composite Medication Adherence Before and During the COVID-19 Pandemic in Patients With HIV With Multiple Chronic Conditions.

BACKGROUND: Polypharmacy for multiple chronic conditions (MCCs) poses an increasing challenge in people with HIV (PWH). This research explores medication adherence in PWH with MCCs before and during COVID-19. SETTING: Kaiser Permanente Mid-Atlantic States. METHODS: Medical and pharmacy records of a continuously enrolled cohort (September 2018-September 2021) of adult PWH were used. To estimate medication adherence, monthly proportion of days covered (PDC) was measured individually for antiretrovirals (ARVs), diabetes medications (DMs), renin-angiotensin antagonists (RASMs), and statins (SMs) and combined into composite measures (CMs) with and without ARVs. Descriptive statistics, time-series models, and multivariable population-averaged panel general estimating equations were used to profile trends, effects, and factors associated with adherence. RESULTS: The cohort (n = 543) was predominantly 51-64 years old (59.3%), Black (73.1%), male (69.2%), and commercially insured (65.4%). Two-thirds (63.7%) of patients were taking medications in 2 medication groups (ie, ARVs and either DMs, RASMs, or SMs), 28.9% were taking medications in 3 medication groups, and 7.4% were taking medications in all 4 medication groups. Overall, PDC for CMs without ARVs was 77.2% and 70.2% with ARVs. After March 2020, negative monthly trends in PDC were observed for CMs without ARVs (ß = -0.1%, P = 0.003) and with ARVs (ß = -0.3%, P = 0.001). For CMs with ARVs, Black race (aOR = 0.5; P < 0.001; ref: White) and taking medications for 3 medication groups (aOR = 0.8; P < 0.02; ref: 2) were associated with lower adherence. CONCLUSION: Decreasing medication adherence trends were observed during the COVID-19 pandemic with variations among population subgroups. Opportunity exists to improve medication adherence for non-White populations and those taking medications for MCCs beyond ARVs.

Polypharmacy and prescription medication use in a population-based sample of adolescent and young adult cancer survivors.

PURPOSE: We examined prescription medication use and identified correlates of polypharmacy-taking multiple medications-in adolescent and young adult cancer survivors (AYAs), who experience early-onset chronic conditions. METHODS: Our cross-sectional study pooled data (2008-2017) from the national Medical Expenditure Panel Survey. We estimated prevalence of polypharmacy (≥ 5 unique prescription medications over an approximate 1-year period) in AYAs (age 18-39 years with a history of cancer) and age- and sex-matched controls, overall and by sociodemographics, clinical factors, and health indicators. We compared survivors' and controls' medication use across therapeutic classes. To identify correlates of polypharmacy among AYAs, we included factors with p < 0.20 in bivariable analysis in a multivariable logistic regression model. RESULTS: AYAs (n = 601) had a higher prevalence of polypharmacy than controls (n = 2,402), overall (31.5% vs. 15.9%, p < .01) and by all sociodemographics, clinical factors, and health indicators. A majority of AYAs with multiple chronic conditions (58.8%, 95% CI 47.3-70.4) or disability (61.3%, 95% CI 52.6-70.0) had polypharmacy. Patterns of AYAs' medication use across therapeutic classes were consistent with their chronic conditions. Nearly one-third used opioid/narcotic analgesics (32.2% vs. 13.7% of controls, p < 0.01). Among AYAs, multiple chronic conditions (aOR 4.68, 95% CI 2.23-9.83) and disability (aOR 3.70, 95% CI 2.23-6.14) were correlated with polypharmacy. CONCLUSIONS: Chronic conditions and disabilities, including aftereffects of cancer treatment, may drive polypharmacy in AYAs. Future research should examine adverse outcomes of polypharmacy and opioid/narcotic use in AYAs. IMPLICATIONS FOR CANCER SURVIVORS: AYAs with chronic conditions or disabilities should be monitored for polypharmacy.

The role of senolytics in osteoporosis and other skeletal pathologies.

The skeletal system undergoes irreversible structural deterioration with aging, leading to increased fracture risk and detrimental changes in mobility, posture, and gait. This state of low bone mass and microarchitectural changes, diagnosed as osteoporosis, affects millions of individuals worldwide and has high clinical and economic burdens. Recently, pre-clinical studies have linked the onset of age-related bone loss with an accumulation of senescent cells in the bone microenvironment. These senescent cells appear to be causal to age-related bone loss, as targeted clearance of these cells leads to improved bone mass and microarchitecture in old mice. Additionally, other pathologies leading to bone loss that result from DNA damage, such as cancer treatments, have shown improvements after clearance of senescent cells. The development of new therapies that clear senescent cells, termed "senolytics", is currently underway and may allow for the modulation of bone loss that results from states of high senescent cell burden, such as aging.

Polypharmacy and Cognition Function Among Rural Adults.

BACKGROUND: Polypharmacy (using≥5 medications) is associated with poor health outcomes. Mixed results from past studies surrounding chronic medication use, control of chronic conditions, and their effects on cognitive performance warrant further attention. OBJECTIVE: Investigate a link between polypharmacy and cognition function in rural-dwelling adults in Texas, USA. METHODS: Project FRONTIER (Facing Rural Obstacles to Healthcare Now Through Intervention, Education & Research) is a cross-sectional epidemiological study using community-based participatory research in three counties of Texas. Residents age > 40 were eligible for inclusion. The primary outcome is cognitive impairment, and exposures of interest are polypharmacy; comorbidities; and diabetes, hypertension, and depression medication. Logistic regression was used to assess association. RESULTS: Six hundred eighty-nine individuals participated; the mean age was 61, and the majority were female (68.7%).The median number of medications taken by participants was 3.3 (IQR: 0-5); the rate of polypharmacy was 29.6%. Anti-hypertensive agents were the most common medications (15%) used. Polypharmacy users were 2.84 times more likely to have cognitive impairment [OR: 2.84, 95%CI (1.32-6.09)] than those using < 5 medications. Participants on hypertensive medications had 1.85 times higher odds [OR: 1.85, 95%CI (1.14-3.01)] of having cognitive impairment than those who did not have cognitive impairment. CONCLUSION: Polypharmacy increases the odds of cognitive impairment. The odds of presenting with cognitive impairment increased as the number of medications increased. Additionally, we identified a large, concerning number of participants with pharmacotherapy and poor chronic disease management. A larger study should examine medication adherence among rural elders to manage chronic disease and any healthcare barriers to adherence.

Economic Evaluations of Interventions to Optimize Medication Use in Older Adults with Polypharmacy and Multimorbidity: A Systematic Review.

PURPOSE: To conduct a systematic review of the economic impact of interventions intended at optimizing medication use in older adults with multimorbidity and polypharmacy. METHODS: We searched Ovid-Medline, Embase, CINAHL, Ageline, Cochrane, and Web of Science, for articles published between 2004 and 2020 that studied older adults with multimorbidity and polypharmacy. The intervention studied had to be aimed at optimizing medication use and present results on costs. RESULTS: Out of 3,871 studies identified by the search strategy, eleven studies were included. The interventions involved different provider types, with a majority described as a multidisciplinary team involving a pharmacist and a general practitioner, in the decision-making process. Interventions were generally associated with a reduction in medication expenditure. The benefits of the intervention in terms of clinical outcomes remain limited. Five studies were cost-benefit analyses, which had a net benefit that was either null or positive. Cost-utility and cost-effectiveness analyses resulted in incremental cost-effectiveness ratios that were generally within the willingness-to-pay thresholds of the countries in which the studies were conducted. However, the quality of the studies was generally low. Omission of key cost elements of economic evaluations, including intervention cost and payer perspective, limited interpretability. CONCLUSION: Interventions to optimize medication use may provide benefits that outweigh their implementation costs, but the evidence remains limited. There is a need to identify and address barriers to the scaling-up of such interventions, starting with the current incentive structures for pharmacists, physicians, and patients.

The use of geroprotectors to prevent multimorbidity: Opportunities and challenges.

Over 60 % of people over the age of 65 will suffer from multiple diseases concomitantly but the common approach is to treat each disease separately. As age-associated diseases have common underlying mechanisms there is potential to tackle many diseases with the same pharmacological intervention. These are known as geroprotectors and could overcome the problems related to polypharmacy seen with the use of the single disease model. With some geroprotectors now reaching the end stage of preclinical studies and early clinical trials, there is a need to review the evidence and assess how they can be translated practically and effectively into routine practice. Despite promising evidence, there are many gaps and challenges in our understanding that must be addressed to make geroprotective medicine effective in the treatment of age-associated multimorbidity. Here we highlight the key barriers to clinical translation and discuss whether geroprotectors such as metformin, rapamycin and senolytics can tackle all age-associated diseases at the same dose, or whether a more nuanced approach is required. The evidence suggests that geroprotectors' mode of action may differ in different tissues or in response to different inducers of accelerating ageing, suggesting that a blunt 'one drug for many diseases' approach may not work. We make the case for the use of artificial intelligence to better understand multimorbidity, allowing identification of clusters and networks of diseases that are significantly associated beyond chance and the underpinning molecular pathway of ageing causal to each cluster. This will allow us to better understand the development of multimorbidity, select a more homogenous group of patients for intervention, match them with the appropriate geroprotector and identify biomarkers specific to the cluster.

A systematically collated library of prescribing safety indicators for people with chronic kidney disease.

BACKGROUND: People with chronic kidney disease (CKD) have high levels of co-morbidity and polypharmacy placing them at increased risk of prescribing-related harm. Tools for assessing prescribing safety in the general population using prescribing safety indicators (PSIs) have been established. However, people with CKD pose different prescribing challenges to people without kidney disease. Therefore, PSIs designed for use in the general population may not include all PSIs relevant to a CKD population. The aim of this study was to systematically collate a library of PSIs relevant to people with CKD. METHODS: A systematic literature search identified papers reporting PSIs. CKD-specific PSIs were extracted and categorised by Anatomical Therapeutic Chemical (ATC) classification codes. Duplicate PSIs were removed to create a final list of CKD-specific PSIs. RESULTS: Nine thousand, eight hundred fifty-two papers were identified by the systematic literature search, of which 511 proceeded to full text screening and 196 papers were identified as reporting PSIs. Following categorisation by ATC code and duplicate removal, 841 unique PSIs formed the final set of CKD-specific PSIs. The five ATC drug classes containing the largest proportion of CKD-specific PSIs were: Cardiovascular system (26%); Nervous system (13.4%); Blood and blood forming organs (12.4%); Alimentary and metabolism (12%); and Anti-infectives for systemic use (11.3%). CONCLUSION: CKD-specific PSIs could be used alone or alongside general PSIs to assess the safety and quality of prescribing within a CKD population.

Polypharmacy and mobility outcomes.

Polypharmacy is known to be associated with negative consequences of mobility related conditions such as falls, functional decline and disability. This systematic review highlights the effectiveness of deprescribing interventions on mobility related conditions in older adults in the community dwelling reported taking five or more medications daily.

Thoughtful Prescribing and Deprescribing.

Polypharmacy, the use of five or more medications, is common in older adults. It can lead to the use of potentially inappropriate medications and severe adverse outcomes. Deprescribing is an essential step of the thoughtful prescribing process and it can decrease the use of potentially inappropriate medications. Studies have demonstrated that deprescribing is feasible in the clinical setting, especially when it incorporates patient preferences, shared decision making, and an interdisciplinary team. Medication-specific algorithms can facilitate deprescribing in the clinical setting.

Overview of High Yield Geriatrics Assessment for Clinic and Hospital.

Geriatric assessment is a comprehensive, multifaceted, and interdisciplinary evaluation of medical, socioeconomic, environmental, and functional concerns unique to older adults; it can be focused or broadened according to the needs of the patient and the concerns of clinical providers. Herein, the authors present a high-yield framework that can be used to assess older adult patients across a variety of settings.

CE: Mitigating the Dangers of Polypharmacy in Community-Dwelling Older Adults.

Polypharmacy, the use by a patient of multiple medications, contributes to adverse drug events, hospitalizations, geriatric syndromes, and increased health care costs. In the United States, polypharmacy is increasingly widespread, particularly among community-dwelling adults over age 62. In 2005-2006, 31% of such adults used five or more prescription drugs and 8.4% used medication combinations associated with potential interactions. By 2010-2011, 36% used five or more prescription drugs and 15% used potentially problematic drug combinations. Reducing the dangers of polypharmacy, however, requires clinicians to broaden their focus, considering not only the number of drugs a patient takes, but also the prescription of potentially inappropriate medications and potential prescribing omissions. This article explores the factors that contribute to polypharmacy and discusses its negative physiological, psychological, and economic effects. It also describes strategies for reducing polypharmacy, including both "explicit" approaches, which are grounded in the findings of literature reviews and expert opinion, and "implicit" approaches, which are based on the provider's interpretation of clinical data and the patient's medication regimen.

Optimising pharmacotherapy in older cancer patients with polypharmacy.

OBJECTIVE: Polypharmacy is frequent among older cancer patients and increases the risk of potential drug-related problems (DRPs). DRPs are associated with adverse drug events, drug-drug interactions and hospitalisations. Since no standardised polypharmacy assessment methods for oncology patients exist, we aimed to develop one that can be integrated into routine care. METHODS: Based on the Systematic Tool to Reduce Inappropriate Prescribing (STRIP), we developed OncoSTRIP, which includes a polypharmacy anamnesis, a concise geriatric assessment, a polypharmacy analysis taking life expectancy into account and an optimised treatment plan. Patients ≥65 years with ≥5 chronic drugs visiting our outpatient oncology clinic were eligible for the polypharmacy assessment. RESULTS: OncoSTRIP was integrated into routine care of our older cancer patients. In 47 of 60 patients (78%), potential DRPs (n = 101) were found. In total, 85 optimisations were recommended, with an acceptance rate of 41%. It was possible to reduce the number of potential DRPs by 41% and the number of patients with at least one potential DRP by 30%. Mean time spent per patient was 71 min. CONCLUSIONS: Polypharmacy assessment of older cancer patients identifies many pharmacotherapeutic optimisations. With OncoSTRIP, polypharmacy assessments can be integrated into routine care.

Optimising medication management for polymedicated home-dwelling older adults with multiple chronic conditions: a mixed-methods study protocol.

INTRODUCTION: Optimal medication management is one of the basic conditions necessary for home-dwelling older adults living with multiple chronic conditions (OAMCC) to be able to remain at home and preserve their quality of life. Currently, the reasons for such high numbers of emergency department visits and the very significant rate of hospitalisations for OAMCC, due to medication-related problems (MRPs), is poorly explored. This study aims to reveal the current state of the medication management practices of polymedicated, home-dwelling OAMCC and to make proposals for improving clinical and medication pathways through an innovative and integrated model for supporting medication management and preventing adverse health outcomes. METHODS AND ANALYSIS: A mixed-methods study will address the medication management of polymedicated, home-dwelling OAMCC. Its explanatory sequential design will involve two major phases conducted sequentially over time. The quantitative phase will consist of retrospectively exploiting the last 5 years of electronic patient records from a local hospital (N ≈ 50 000) in order to identify the different profiles-made up of patient-related, medication-related and environment-related factors-of the polymedicated, home-dwelling OAMCC at risk of hospitalisation, emergency department visits, hospital readmission (notably for MRPs), institutionalisation or early death. The qualitative study will involve: (a) obtaining and understanding the medication management practices and experiences of the identified profiles extracted from the hospital data of OAMCC who will be interviewed at home (N ≈ 30); (b) collecting and analysing the perspectives of the formal and informal caregivers involved in medication management at home in order to cross-reference perspectives about this important dimension of care at home. Finally, the mixed-methods findings will enable the development of an innovative, integrated model of medication management based on the Agency for Clinical Innovation framework and Bodenheimer and Sinsky's quadruple aim. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Human Research Ethics Committee of the Canton Vaud (2018-02196). Findings will be disseminated in peer-reviewed journals, professional conferences and other knowledge transfer activities with primary healthcare providers, hospital care units, informal caregivers' and patients' associations.

Prescribing patterns of polypharmacy in Korean pediatric patients.

BACKGROUND: Several studies have examined the risk and health outcomes related to polypharmacy among the elderly. However, information regarding polypharmacy among pediatric patients is lacking. OBJECTIVE: The aim of this study was to investigate the prevalence of polypharmacy and its related factors among the pediatric population of South Korea. METHODS: We used national claim data from the Health Insurance Review and Assessment Service-Pediatric Patients Sample (HIRA-PPS) in Korea originating from 2012 through 2016. Polypharmacy was defined as a daily average of two or more drugs used yearly. Complex chronic conditions (CCCs) were examined to evaluate concomitant chronic diseases in pediatric patients. Age-specific contraindications and potential drug-drug interactions were assessed according to criteria established by the Korea Institute of Drug Safety & Risk Management (KIDS). Descriptive statistics and logistic regression were conducted to analyze the status of polypharmacy and its associated risk factors in pediatric patients. RESULTS: The 5-year prevalence of pediatric polypharmacy in pediatric patients was 3.7%. The prevalence of polypharmacy was much higher in younger pediatric patients: 9.5% for patients between the ages of 1-7 years, 0.9% for ages 6-11 years, and 1.1% for ages 12-19 years. Pediatric patients with CCCs, Medical Aid benefits, or a hospital admission history had a significantly higher prevalence of polypharmacy when compared to their counterparts without those conditions. The most commonly prescribed drugs were respiratory agents (29%) followed by anti-allergic drugs (18.7%), central nervous system agents (15.9%), antibiotics (10.1%), and gastrointestinal drugs (7.7%). There was a positive correlation between the daily average number of inappropriate prescriptions and the degree of polypharmacy, especially in pediatric patients between the ages of 1-7 years. Contraindications and potential drug-drug interactions occurred in 11.0% and 10.1% of patients exposed to polypharmacy, respectively. CONCLUSIONS: One in ten pediatric patients under the age of 7 years was prescribed two or more concurrent drugs on average per day. Furthermore, pediatric patients exposed to polypharmacy showed an increased risk of inappropriate drug use. The implementation of a medication review system that considers pediatric patient polypharmacy exposure would reduce inappropriate drug use and prevent unwanted adverse outcomes.

Geriatric patients: compliance issues and ways of its optimization

The aim of the study is to increase the effectiveness of diseases treatment in elderly patients. The work is based on the study of the nature and the role of compliance disorders, optimizing the effectiveness with the use of therapeutic complex of pharmacotherapy associated with psychotherapeutic component. As a result of the analysis of morbidity in elderly age and the nature of compliance in elderly patients, an optimal therapeutic complex was proposed, which consists of rational pharmacological load and psychotherapeutic intervention, aimed at informing a patient about the disease, methods of its treatment, as well as at creating an effective therapeutic alliance which provides proper medical care and prevents self-treatment in such patients.

Polypharmacy: Evaluating Risks and Deprescribing.

Polypharmacy, defined as regular use of at least five medications, is common in older adults and younger at-risk populations and increases the risk of adverse medical outcomes. There are several risk factors that can lead to polypharmacy. Patient-related factors include having multiple medical conditions managed by multiple subspecialist physicians, having chronic mental health conditions, and residing in a long-term care facility. Systems-level factors include poorly updated medical records, automated refill services, and prescribing to meet disease-specific quality metrics. Tools that help identify potentially inappropriate medication use include the Beers, STOPP (screening tool of older people's prescriptions), and START (screening tool to alert to right treatment) criteria, and the Medication Appropriateness Index. No one tool or strategy has been shown to be superior in improving patient-related outcomes and decreasing polypharmacy risks. Monitoring patients' active medication lists and deprescribing any unnecessary medications are recommended to reduce pill burden, the risks of adverse drug events, and financial hardship. Physicians should view deprescribing as a therapeutic intervention similar to initiating clinically appropriate therapy. When deprescribing, physicians should consider patient/ caregiver perspectives on goals of therapy, including views on medications and chronic conditions and preferences and priorities regarding prescribing to slow disease progression, prevent health decline, and address symptoms. Point-of-care tools can aid physicians in deprescribing and help patients understand the need to decrease medication burden to reduce the risks of polypharmacy.

Medication patterns in older adults with multimorbidity: a cluster analysis of primary care patients.

BACKGROUND: Older adults suffer from various chronic conditions which make them particularly vulnerable. The proper management of multiple drug use is therefore crucial. The aim of our study was to describe drug prescription and medication patterns in this population. METHODS: A cross-sectional study in Barcelona (Spain) using electronic health records from 50 primary healthcare centres. Participants were aged 65 to 94 years, presenting multimorbidity (≥2 chronic diseases), and had been prescribed at least 1 drug for 6 months or longer during 2009. We calculated the prevalence of prescribed drugs and identified medication patterns using multiple correspondence analysis and k-means clustering. Analyses were stratified by sex and age (65-79, 80-94 years). RESULTS: We studied 164,513 patients (66.8% women) prescribed a median of 4 drugs (interquartile range [IQR] = 3-7) in the 65-79 age-group and 6 drugs (IQR = 4-8) in the 80-94 age-group. A minimum of 45.9% of patients aged 65-79 years, and 61.8% of those aged 80-94 years, were prescribed 5 or more drugs. We identified 6 medication patterns, a non-specific one and 5 encompassing 8 anatomical groups (alimentary tract and metabolism, blood, cardiovascular, dermatological, musculo-skeletal, neurological, respiratory, and sensory organ). CONCLUSIONS: Drug prescription is widespread among the elderly. Six medication patterns were identified, 5 of which were related to one or more anatomical group, with associations among drugs from different systems. Overall, guidelines do not accurately reflect the situation of the elderly multimorbid, new strategies for managing multiple drug uses are needed to optimize prescribing in these patients.

Barriers and enablers for deprescribing among older, multimorbid patients with polypharmacy: an explorative study from Switzerland.

BACKGROUND: Polypharmacy is an increasing problem, leading to increased morbidity and mortality, especially in older, multimorbid patients. Consequently, there is a need for reduction of polypharmacy. The aim of this study was to explore attitudes, beliefs, and concerns towards deprescribing among older, multimorbid patients with polypharmacy who chose not to pursue at least one of their GP's offers to deprescribe. METHODS: Exploratory study using telephone interviews among patients of a cluster-randomized study in Northern Switzerland. The interview included a qualitative part consisting of questions in five pre-defined key areas of attitudes, beliefs, and concerns about deprescribing and an open explorative question. The quantitative part consisted of a rating of pre-defined statements in these areas. RESULTS: Twenty-two of 87 older, multimorbid patients with polypharmacy, to whom their GP offered a drug change, did not pursue all offers. Nineteen of these 22 were interviewed by telephone. The 19 patients were on average 76.9 (SD 10.0) years old, 74% female, and took 8.9 (SD 2.6) drugs per day. Drugs for acid-related disorders, analgesics and anti-inflammatory drugs were the three most common drug groups where patient involvement and the shared-decision-making (SDM) process led to the joint decision to not pursue the GPs offer. Eighteen of 19 patients fully trusted their GP, 17 of 19 participated in SDM even before this study and 8 of 19 perceived polypharmacy as a substantial burden. Conservatism/inertia and fragmented medical care were the main barriers towards deprescribing. No patient felt devalued as a consequence of the deprescribing offer. Our exploratory findings were supported by patients' ratings of predefined statements. CONCLUSION: We identified patient involvement in deprescribing and coordination of care as key issues for deprescribing among older multimorbid patients with polypharmacy. GPs concerns regarding patients' devaluation should not prevent them from actively discussing the reduction of drugs. TRIAL REGISTRATION: ISRCTN16560559 .