Informing disinvestment with limited evidence: cobalamin deficiency in the fatigued.

OBJECTIVES: Health technology reassessment and disinvestment can be difficult due to uncertainties regarding available evidence. Pathology testing to investigate cobalamin (vitamin B12) deficiency is a strong case in point. We conducted a 3-month economic evaluation of five strategies for diagnosing and treating cobalamin deficiency in adult patients hypothetically presenting with new unexplained fatigue in the primary care setting. The first consultation per patient was considered. Screening tests other than serum cobalamin were not included. METHODS: A cost-effectiveness analysis was undertaken using a decision tree to represent the diagnostic / treatment pathways, with relevant cost and utility scores assigned to different stages in the evaluation process. Input parameter values were estimated from published evidence, supplemented by expert opinion, with sensitivity analysis undertaken to represent parameter uncertainty. RESULTS: Ordering serum vitamin B12 to assess cobalamin deficiency among patients with unexplained fatigue was not cost-effective in any patient population, irrespective of pretest prevalence of this deficiency. For patients with a pretest prevalence above 1 percent, treating all with oral vitamin B12 supplements without testing was most cost-effective, whereas watchful waiting with symptoms monitoring was most cost-effective for patients with lower pretest prevalence probabilities. CONCLUSIONS: Substantial evidence gaps exist for parameter estimation: questionable cobalamin deficiency levels in the fatigued; debatable treatment methods; unknown natural history of the condition. Despite this, we reveal a robust path for disinvestment decision making in the face of a paradox between the evidence required to inform disinvestment compared with its paucity in informing initial funding decisions.

Effect of cocoa on blood pressure.

BACKGROUND: High blood pressure is an important risk factor for cardiovascular disease attributing to about 50% of cardiovascular events worldwide and 37% of cardiovascular related deaths in Western populations. Epidemiological studies suggest that cocoa rich products reduce the risk of cardiovascular disease. Flavanols found in cocoa have been shown to increase the formation of endothelial nitric oxide which promotes vasodilation and therefore blood pressure reduction. Previous meta-analyses have shown that cocoa-rich foods may reduce blood pressure. Recently additional trials had conflicting results. OBJECTIVES: To determine the effect of flavanol-rich chocolate or cocoa products on blood pressure in people with or without hypertension. SEARCH METHODS: We searched the following electronic databases from inception to November 2011: Cochrane Hypertension Group Specialised Register, CENTRAL, MEDLINE and EMBASE. In addition we searched international trial registries, and the reference lists of review articles and included trials. SELECTION CRITERIA: Randomised controlled trials (RCT) investigating the effects of chocolate or cocoa products on systolic and diastolic blood pressure in adults for a minimum of two weeks duration. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed the risk of bias in each trial in consultation with a third author. Random effects meta-analyses on all studies fitting the inclusion criteria were conducted using Review Manager version 5.1 and Stata version 12. Heterogeneity was explored by subgroup analyses and univariate meta-regression analysis of several variables including dosage of flavanol content (total or monomers) in chocolate or cocoa products, blinding, baseline blood pressure, theobromine content, sugar content, body-mass-index (BMI), duration and age. MAIN RESULTS: Twenty studies met the inclusion criteria. Meta-analyses of the 20 studies involving 856 mainly healthy participants revealed a statistically significant blood pressure reducing effect of flavanol-rich cocoa products compared with control in short-term trials of 2-18 weeks duration: Mean difference SBP (95%CI): -2.77 (-4.72, -0.82) mm Hg, p=0.005, n=20; mean difference DBP (95%CI): - 2.20 (-3.46, -0.93) mm Hg, p=0.006, n=19 available for DBP.Trials provided participants with 30-1080 mg of flavanols (mean=545.5 mg) in 3.6-105 g of cocoa products per day in the active intervention group. In half of the trials (n=10) the active group consumed 500-750 mg of flavanols per day. The control group received either a flavanol-free product (n=12) or a low-flavanol containing cocoa powder (6.4 and 41 mg flavanols, n=8). Subgroup meta-analysis of trials with a flavanol-free control group revealed a significant blood pressure reducing effect, in contrast to trials using a low-flavanol product in the control group. This analysis may have been confounded by trial duration and the level of blinding of participants.Trial duration was short (mean 4.4 weeks, range 2-8 weeks, n=19, and one trial of 18 weeks). A significant blood pressure reducing effect was evident in trials of 2 weeks duration (n=9), but not in trials of >2 weeks duration (n=11). It is important to note that seven out of the nine trials (78%) of 2 weeks duration also had a flavanol-free control group. Therefore, subgroup analysis by duration might be confounded by flavanol dosage used in the control groups, and the level of blinding of participants.Adverse effects including gastrointestinal complaints and distaste of the trial product were reported by 5% of patients in the active cocoa intervention group and 1% of patients in the control groups. AUTHORS' CONCLUSIONS: Flavanol-rich chocolate and cocoa products may have a small but statistically significant effect in lowering blood pressure by 2-3 mm Hg in the short term.Our findings are limited by the heterogeneity between trials, which was explored by univariate meta-regression and subgroup analyses. Subgroup meta-analysis of trials using a flavanol-free control group revealed a significant blood pressure reducing effect of cocoa, whereas analysis of trials using a low-flavanol control product did not. While it appears that shorter trials of 2 weeks duration were more effective, analysis may be confounded by type of control and unblinding of participants, as the majority of 2-week trials also used a flavanol-free control and unblinding of participants. Results of these and other subgroup analyses based on, for example, age of participants, should be interpreted with caution and need to be confirmed or refuted in trials using direct randomized comparison.Long-term trials investigating the effect of cocoa products are needed to determine whether or not blood pressure is reduced on a chronic basis by daily ingestion of cocoa. Furthermore, long-term trials investigating the effect of cocoa on clinical outcomes are also needed to assess whether cocoa has an effect on cardiovascular events and to assess potential adverse effects associated with chronic ingestion of cocoa products.

Clinical software packages can be improved to help general practitioners increase the provision of preventive care.

Despite the importance of prevention in general practice, electronic clinical record systems used in Australian general practice do not present a comprehensive overview of each patient's preventive care status to general practitioners or patients. Data relevant to prevention is scattered between different parts of the patient's record. On-screen reminders to general practitioners are simplistic and easily overlooked, and no reminders are sent automatically to patients. There is no structured means to note a patient's refusal or ineligibility for a particular preventive activity. Electronic clinical record systems should be enhanced to allow patients to be invited automatically, at appropriate times, to review and respond to comprehensive information and advice about preventive care that is recommended for them. Users of electronic clinical record systems will need to lobby their software vendors to have the proposed enhancements made.

Patient acceptance and perceived utility of pre-consultation prevention summaries and reminders in general practice: pilot study.

BACKGROUND: Patients attending general practices receive only about sixty per cent of the preventive services that are indicated for them. This pilot study explores patient acceptability and perceived utility of automatically generated prevention summary and reminder sheets provided to patients immediately before consultations with their general practitioners. METHODS: Adult patients attending a general practitioner in a practice in Adelaide and a general practitioner in a practice in Melbourne, Australia for consultations in January and February 2009 received automatically-generated prevention summary and reminder sheets that highlighted indicated preventive activities that were due to be performed, and that encouraged the patient to discuss these with the general practitioner in the consultation. Patients completed a post-consultation questionnaire and were interviewed about their experience of receiving the sheets. RESULTS: Sixty patients, median age 53 years (interquartile range 40-74) years, and 58% female, were recruited. Seventy eight per cent of patients found the sheets clear and easy to understand, 75% found them very or quite useful, 72% reported they had addressed with their general practitioner all of the preventive activities that were listed on the sheets as being due to be performed. A further 13% indicated that they had addressed most or some of the activities. 78% of patients said that they would like to keep receiving the sheets. Themes emerging from interviews with patients included: patient knowledge was enhanced; patient conceptions of health and the GP consultation were broadened; the consultation was enhanced; patient pro-activity was encouraged; patients were encouraged to plan their health care; the intervention was suitable for a variety of patients. CONCLUSIONS: Most patients reported that they found the prevention summary and reminder sheets acceptable and useful. The actual increase in performance of preventive activities that may result from this new intervention needs to be tested in randomised controlled trials.

General practice perspectives on a bowel cancer screening quality improvement intervention using the Consolidated Framework for Implementation Research.

INTRODUCTION: An understanding of contextual factors that influence whether general practitioners advise their patients to be screened for colorectal cancer (CRC) might guide interventions to increase screening participation from its persistently low rate. We report on the use of a theory-based tool to explore contextual factors that might influence implementation of a novel quality improvement (QI) intervention to increase CRC screening in general practice (CRC-QI). The objective was to identify and incorporate strategies into the intervention that will enable flexible implementation across different practice settings. STUDY TYPE: A qualitative study to explore contextual facilitators of, and barriers to, the implementation of a novel CRC-QI intervention. METHODS: Eighteen staff, from three self-nominated general practices, participated in focus group discussions. The Consolidated Framework for Implementation Research (CFIR), which included constructs relevant to CRC screening in primary care, guided the formative evaluation. Findings were aligned to the CFIR model using a deductive thematic analysis. RESULTS: Contextual facilitators of, and barriers to, the implementation of the CRC-QI intervention were identified in each CFIR domain and CRC-relevant construct. Five consistent themes were identified that potentially influence elements of the CRC-QI intervention: priority setting and incentives, information technology, patient-level barriers, clinical practice, and the National Bowel Cancer Screening Program (NBCSP). Participants proposed that incentive payments and NBCSP policy changes (outer-setting strategies) would facilitate organisational change (inner-setting strategies) and the effective implementation of the CRC-QI intervention. CONCLUSION: There may be an opportunity to better engage general practice in CRC screening via outer-setting constructs that support existing clinical practice. For example, improvements to the National Cancer Screening Register and Quality Improvement Incentive - Practice Incentives Program (PIP) could be made without altering the NBCSP design.

Does chocolate reduce blood pressure? A meta-analysis.

BACKGROUND: Dark chocolate and flavanol-rich cocoa products have attracted interest as an alternative treatment option for hypertension, a known risk factor for cardiovascular disease. Previous meta-analyses concluded that cocoa-rich foods may reduce blood pressure. Recently, several additional trials have been conducted with conflicting results. Our study summarises current evidence on the effect of flavanol-rich cocoa products on blood pressure in hypertensive and normotensive individuals. METHODS: We searched Medline, Cochrane and international trial registries between 1955 and 2009 for randomised controlled trials investigating the effect of cocoa as food or drink compared with placebo on systolic and diastolic blood pressure (SBP/DBP) for a minimum duration of 2 weeks. We conducted random effects meta-analysis of all studies fitting the inclusion criteria, as well as subgroup analysis by baseline blood pressure (hypertensive/normotensive). Meta-regression analysis explored the association between type of treatment, dosage, duration or baseline blood pressure and blood pressure outcome. Statistical significance was set at P < 0.05. RESULTS: Fifteen trial arms of 13 assessed studies met the inclusion criteria. Pooled meta-analysis of all trials revealed a significant blood pressure-reducing effect of cocoa-chocolate compared with control (mean BP change +/- SE: SBP: -3.2 +/- 1.9 mmHg, P = 0.001; DBP: -2.0 +/- 1.3 mmHg, P = 0.003). However, subgroup meta-analysis was significant only for the hypertensive or prehypertensive subgroups (SBP: -5.0 +/- 3.0 mmHg; P = 0.0009; DBP: -2.7 +/- 2.2 mm Hg, P = 0.01), while BP was not significantly reduced in the normotensive subgroups (SBP: -1.6 +/- 2.3 mmHg, P = 0.17; DBP: -1.3 +/- 1.6 mmHg, P = 0.12). Nine trials used chocolate containing 50% to 70% cocoa compared with white chocolate or other cocoa-free controls, while six trials compared high- with low-flavanol cocoa products. Daily flavanol dosages ranged from 30 mg to 1000 mg in the active treatment groups, and interventions ran for 2 to 18 weeks. Meta-regression analysis found study design and type of control to be borderline significant but possibly indirect predictors for blood pressure outcome. CONCLUSION: Our meta-analysis suggests that dark chocolate is superior to placebo in reducing systolic hypertension or diastolic prehypertension. Flavanol-rich chocolate did not significantly reduce mean blood pressure below 140 mmHg systolic or 80 mmHg diastolic.

Dark chocolate or tomato extract for prehypertension: a randomised controlled trial.

BACKGROUND: Flavanol-rich chocolate and lycopene-rich tomato extract have attracted interest as potential alternative treatment options for hypertension, a known risk factor for cardiovascular morbidity and mortality. Treatment of prehypertension (SBP 120-139/DBP 80-89 mmHg) may forestall progression to hypertension. However, there has been only limited research into non-pharmacological treatment options for prehypertension. We investigated the effect of dark chocolate or tomato extract on blood pressure, and their acceptability as an ongoing treatment option in a prehypertensive population. METHODS: Our trial consisted of two phases: a randomised controlled three-group-parallel trial over 12 weeks (phase 1) followed by a crossover of the two active treatment arms over an additional 12-week period (phase 2). Group 1 received a 50 g daily dose of dark chocolate with 70% cocoa containing 750 mg polyphenols, group 2 were allocated one tomato extract capsule containing 15 mg lycopene per day, and group 3 received one placebo capsule daily over 8 weeks followed by a 4-week washout period. In phase 2 the active treatment groups were crossed over to receive the alternative treatment. Median blood pressure, weight, and abdominal circumference were measured 4-weekly, and other characteristics including physical activity, general health, energy, mood, and acceptability of treatment were assessed by questionnaire at 0, 8 and 20 weeks. We analysed changes over time using a linear mixed model, and one time point differences using Kruskal-Wallis, Fisher's-Exact, or t-tests. RESULTS: Thirty-six prehypertensive healthy adult volunteers completed the 6-month trial. Blood pressure changes over time within groups and between groups were not significant and independent of treatment. Weight and other characteristics did not change significantly during the trial. However, a marked difference in acceptability between the two treatment forms (chocolate or capsule) was revealed (p < 0.0001). Half of the participants allocated to the chocolate treatment found it hard to eat 50 g of dark chocolate every day and 20% considered it an unacceptable long-term treatment option, whereas all participants found it easy and acceptable to take a capsule each day for blood pressure. CONCLUSION: Our study did not find a blood pressure lowering effect of dark chocolate or tomato extract in a prehypertensive population. Practicability of chocolate as a long-term treatment option may be limited. TRIAL REGISTRATION: http://www.anzctr.org.au Identifier: ACTRN12609000047291.

Effect of garlic on blood pressure: a systematic review and meta-analysis.

BACKGROUND: Non-pharmacological treatment options for hypertension have the potential to reduce the risk of cardiovascular disease at a population level. Animal studies have suggested that garlic reduces blood pressure, but primary studies in humans and non-systematic reviews have reported mixed results. With interest in complementary medicine for hypertension increasing, it is timely to update a systematic review and meta-analysis from 1994 of studies investigating the effect of garlic preparations on blood pressure. METHODS: We searched the Medline and Embase databases for studies published between 1955 and October 2007. Randomised controlled trials with true placebo groups, using garlic-only preparations, and reporting mean systolic and/or diastolic blood pressure (SBP/DBP) and standard deviations were included in the meta-analysis. We also conducted subgroup meta-analysis by baseline blood pressure (hypertensive/normotensive), for the first time. Meta-regression analysis was performed to test the associations between blood pressure outcomes and duration of treatment, dosage, and blood pressure at start of treatment. RESULTS: Eleven of 25 studies included in the systematic review were suitable for meta-analysis. Meta-analysis of all studies showed a mean decrease of 4.6 +/- 2.8 mm Hg for SBP in the garlic group compared to placebo (n = 10; p = 0.001), while the mean decrease in the hypertensive subgroup was 8.4 +/- 2.8 mm Hg for SBP (n = 4; p < 0.001), and 7.3 +/- 1.5 mm Hg for DBP (n = 3; p < 0.001). Regression analysis revealed a significant association between blood pressure at the start of the intervention and the level of blood pressure reduction (SBP: R = 0.057; p = 0.03; DBP: R = -0.315; p = 0.02). CONCLUSION: Our meta-analysis suggests that garlic preparations are superior to placebo in reducing blood pressure in individuals with hypertension.

Aged garlic extract lowers blood pressure in patients with treated but uncontrolled hypertension: a randomised controlled trial.

OBJECTIVE: To assess the effect, tolerability and acceptability of aged garlic extract as an adjunct treatment to existing antihypertensive medication in patients with treated, but uncontrolled, hypertension. DESIGN: A double-blind parallel randomised placebo-controlled trial involving 50 patients whose routine clinical records in general practice documented treated but uncontrolled hypertension. The active treatment group received four capsules of aged garlic extract (960 mg containing 2.4 mg S-allylcysteine) daily for 12 weeks, and the control group received matching placebos. The primary outcome measures were systolic and diastolic blood pressure at baseline, 4, 8 and 12 weeks, and change over time. We also assessed tolerability during the trial and acceptability at 12 weeks. RESULTS: In patients with uncontrolled hypertension (SBP ≥ 140 mmHg at baseline), systolic blood pressure was on average 10.2 ± 4.3 mmHg (p=0.03) lower in the garlic group compared with controls over the 12-week treatment period. Changes in blood pressure between the groups were not significant in patients with SBP<140 mmHg at baseline. Aged garlic extract was generally well tolerated and acceptability of trial treatment was high (92%). CONCLUSION: Our trial suggests that aged garlic extract is superior to placebo in lowering systolic blood pressure similarly to current first line medications in patients with treated but uncontrolled hypertension.