The Relative Effectiveness of Pumps Over MDI and Structured Education (REPOSE): study protocol for a cluster randomised controlled trial

Introduction People with type 1 diabetes (T1DM) require insulin therapy to sustain life, and need optimal glycaemic control to prevent diabetic ketoacidosis and serious long-term complications. Insulin is generally administered using multiple daily injections but can also be delivered using an infusion pump (continuous subcutaneous insulin infusion), a more costly option with benefits for some patients. The UK National Institute for Health and Care Excellence (NICE) recommend the use of pumps for patients with the greatest need, citing insufficient evidence to approve extension to a wider population. Far fewer UK adults use pumps than in comparable countries. Previous trials of pump therapy have been small and of short duration and failed to control for training in insulin adjustment. This paper describes the protocol for a large randomised controlled trial comparing pump therapy with multiple daily injections, where both groups are provided with high-quality structured education. Methods and analysis A multicentre, parallel group, cluster randomised controlled trial among 280 adults with T1DM. All participants attended the week-long dose adjustment for normal eating (DAFNE) structured education course, and receive either multiple daily injections or pump therapy for 2 years. The trial incorporates a detailed mixed-methods psychosocial evaluation and cost-effectiveness analysis. The primary outcome will be the change in glycosylated haemoglobin (HbA1c) at 24 months in those participants whose baseline HbA1c is at or above 7.5% (58 mmol/mol). The key secondary outcome will be the proportion of participants reaching the NICE target of an HbA1c of 7.5% (58 mmol/mol) or less at 24 months. Ethics and dissemination The protocol was approved by the Research Ethics Committee North West, Liverpool East and received Medicines and Healthcare products Regulatory Agency (MHRA) clinical trials authorisation. Each participating centre gave National Health Service R&D approval. We shall disseminate study findings to study participants and through peer reviewed publications and conference presentations, including lay user groups. Trial registration number ISRCTN 61215213

The captopril-digoxin multicenter resarch group study on the comparative steps of captopril and digoxin in patients with mildmoderate heart failure: Implications for therapy

It is argued that the basis of therapy in a patient with mild-to-moderate congestive heart failure should be a combination of a diuretic and a converting enzyme inhibitor, with the further addition of digoxin if necessary.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44603/1/10557_2005_Article_BF01881521.pd

Present and future pharmacotherapeutic agents in heart failure: an evolving paradigm

Many conditions culminate in heart failure (HF), a multi-organ systemic syndrome with an intrinsically poor prognosis. Pharmacotherapeutic agents that correct neurohormonal dysregulation and haemodynamic instability have occupied the forefront of developments within the treatment of HF in the past. Indeed, multiple trials aimed to validate these agents in the 1980s and early 1990s, resulting in a large and robust evidence-base supporting their use clinically. An established treatment paradigm now exists for the treatment of HF with reduced ejection fraction (HFrEF), but there have been very few notable developments in recent years. HF remains a significant health concern with an increasing incidence as the population ages. We may indeed be entering the surgical era for HF treatment, but these therapies remain expensive and inaccessible to many. Newer pharmacotherapeutic agents are slowly emerging, many targeting alternative therapeutic pathways, but with mixed results. Metabolic modulation and manipulation of the nitrate/nitrite/nitric oxide pathway have shown promise and could provide the answers to fill the therapeutic gap between medical interventions and surgery, but further definitive trials are warranted. We review the significant evidence base behind the current medical treatments for HFrEF, the physiology of metabolic impairment in HF, and discuss two promising novel agents, perhexiline and nitrite

Oxidative stress in type 2 diabetes: the role of fasting and postprandial glycaemia

Oxidative stress, through the production of reactive oxygen species (ROS), has been proposed as the root cause underlying the development of insulin resistance, β-cell dysfunction, impaired glucose tolerance and type 2 diabetes mellitus (T2DM). It has also been implicated in the progression of long-term diabetes complications, including microvascular and macrovascular dysfunction. Excess nourishment and a sedentary lifestyle leads to glucose and fatty acid overload, resulting in production of ROS. Additionally, reaction of glucose with plasma proteins forms advanced glycation end products, triggering production of ROS. These ROS initiate a chain reaction leading to reduced nitric oxide availability, increased markers of inflammation and chemical modification of lipoproteins, all of which may increase the risk of atherogenesis. With the postulation that hyperglycaemia and fluctuations in blood glucose lead to generation of ROS, it follows that aggressive treatment of fasting and postprandial hyperglycaemia is important for prevention of micro and macrovascular complications in T2DM

ACE Inhibition and Endothelial Function: Main Findings of PERFECT, a Sub-Study of the EUROPA Trial

Background: ACE inhibition results in secondary prevention of coronary artery disease (CAD) through different mechanisms including improvement of endothelial dysfunction. The Perindopril-Function of the Endothelium in Coronary artery disease Trial (PERFECT) evaluated whether long-term administration of perindopril improves endothelial dysfunction. Methods: PERFECT is a 3-year double blind randomised placebo controlled trial to determine the effect of perindopril 8 mg once daily on brachial artery endothelial function in patients with stable CAD without clinical heart failure. Endothelial function in response to ischaemia was assessed using ultrasound. Primary endpoint was difference in flow-mediated vasodilatation (FMD) assessed at 36 months. Results: In 20 centers, 333 patients randomly received perindopril or matching placebo. Ischemia-induced FMD was 2.7% (SD 2.6). In the perindopril group FMD went from 2.6% at baseline to 3.3% at 36 months and in the placebo group from 2.8 to 3.0%. Change in FMD after 36 month treatment was 0.55% (95% confidence interval −0.36, 1.47; p = 0.23) higher in perindopril than in placebo group. The rate of change in FMD per 6 months was 0.14% (SE 0.05, p = 0.02) in perindopril and 0.02% (SE 0.05, p = 0.74) in placebo group (0.12% difference in rate of change p = 0.07). Conclusion: Perindopril resulted in a modest, albeit not statistically significant, improvement in FMD

Management of cardiac health in trastuzumab-treated patients with breast cancer: updated United Kingdom National Cancer Research Institute recommendations for monitoring

More women are living with and surviving breast cancer, because of improvements in breast cancer care. Trastuzumab (Herceptin®▾) has significantly improved outcomes for women with HER2-positive tumours. Concerns about the cardiac effects of trastuzumab (which fundamentally differ from the permanent myocyte loss associated with anthracyclines) led to the development of cardiac guidelines for adjuvant trials, which are used to monitor patient safety in clinical practice. Clinical experience has shown that the trial protocols are not truly applicable to the breast cancer population as a whole, and exclude some women from receiving trastuzumab, even though they might benefit from treatment without long-term adverse cardiac sequelae. Consequently, five oncologists who recruited patients to trastuzumab trials, some cardiologists with whom they work, and a cardiovascular lead general practitioner reviewed the current cardiac guidelines in the light of recent safety data and their experience with adjuvant trastuzumab. The group devised recommendations that promote proactive pharmacological management of cardiac function in trastuzumab-treated patients, and that apply to all patients who are likely to receive standard cytotoxic chemotherapy. Key recommendations include: a monitoring schedule that assesses baseline and on-treatment cardiac function and potentially reduces the overall number of assessments required; intervention strategies with cardiovascular medication to improve cardiac status before, during, and after treatment; simplified rules for starting, interrupting and discontinuing trastuzumab; and a multidisciplinary approach to breast cancer care

“Escape” of aldosterone production in patients with left ventricular dysfunction treated with an angiotensin converting enzyme inhibitor: Implications for therapy

Despite the findings in randomized trials of a significant effect of angiotensin-converting enzyme (ACE) inhibitors in reducing morbidity and mortality of patients with symptomatic left ventricular dysfunction, the morbidity and mortality of these patients remains relatively high. One potential strategy to further improve morbidity and mortality in these patients is blockade of aldosterone. Many clinicians have assumed that ACE inhibitors would block both angiotensin II and aldosterone. However, there are data to suggest that aldosterone production may “escape” despite the use of an ACE inhibitor. An escape of aldosterone production has several important consequences, including: sodium retention, potassium and magnesium loss, myocardial collagen production, ventricular hypertrophy, myocardial norepinephrine release, endothelial dysfunction, and a decrease in serum high density lipoprotein cholesterol. Due to the potential importance of these mechanisms, the finding that there is a significant correlation between aldosterone production and mortality in patients with heart failure, as well as evidence that an aldosterone antagonist, spironolactone, when administered to patients with heart failure treated with conventional therapy including an ACE inhibitor results in increased diuresis and symptomatic improvement, an international prospective multicenter study has been organized, the Randomized Aldactone Evaluation Study (RALES Pilot Study), to evaluate the safety of blocking the effects of aldosterone in patients with heart failure treated with an ACE inhibitor.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44631/1/10557_2004_Article_BF00877755.pd