Selection of patients with symptomatic diabetic neuropathy for clinical trials

Two hundred and fourteen patients with prima-facie evidence of symptomatic diabetic neuropathy were considered for inclusion in a clinical trial. Only 50 patients (24%) fulfilled all the clinical and electrophysiological criteria for entry. One hundred and nine patients (51%) were excluded on clinical grounds alone. Reasons for exclusion included the presence of alternative causes of neuropathy (15%), peripheral vascular disease (10%), proximal or asymmetrical neuropathies (11%), renal impairment (5%), nerve entrapment (4%), cerebrovascular disease (2%) and amputations (2%) with miscellaneous conditions accounting for the remaining 2%. Of the 105 patients who satisfied the clinical entry requirements another 55 patients (26%) were excluded by electrophysiological criteria. Peroneal motor nerve conduction velocity was unrecordable or unacceptably reduced (less than 30 m/s) in 42% of these patients, sensory nerve potentials were unrecordable in 8% and median nerve compression was evident in another 3%. The selection of cohorts for clinical trials in diabetic neuropathy involves careful consideration of clinical and electrophysiological features of the patients and exclusion of alternative causes of neuropathy.     

Translation of clinical trials into clinical practice

The results of well-conducted clinical trials should be translated into practice but there is good evidence that this is not happening. There are a number of reasons for this - ignorance of doctors and patients, uncertainty as to the applicability of trials to individual patients, indolence and inefficiency on the part of practitioners, and financial considerations. More attention needs to be paid to correct all these factors.     

Liraglutide: from clinical trials to clinical practice

Liraglutide, a once-daily glucagon-like peptide-1 receptor agonist, is approved for use as monotherapy in the USA and Japan (but not in Europe or Canada) and in combination with selected oral agents (all regions) for the treatment of patients with type 2 diabetes. Guidance from local advisory bodies is emerging on the most appropriate place for liraglutide in the treatment pathway. It is apparent from its phase 3 clinical trial programme that liraglutide provides superior glycaemic control compared with that achieved with other antidiabetic agents used early in the treatment pathway (e.g. glimepiride and sitagliptin). Key additional benefits include a low incidence of hypoglycaemia and clinically relevant weight loss, although these benefits may be ameliorated by concomitant sulphonylurea (SU) treatment and, in the case of hypoglycaemia, reduction of the SU dose may be necessary. Overall, the profile of liraglutide is similar and, in some aspects, superior to twice-daily exenatide. The implementation of liraglutide therapy is straightforward, with simple dose titration from the starting dose of 0.6 to 1.2 mg/day after 1 week; some patients may benefit from additional titration to 1.8 mg/day. Treatment is self-administered by subcutaneous injection. This contrasts with other agents used early in the treatment pathway, but clinical data suggest patients' overall treatment satisfaction with liraglutide is similar (1.2 mg) or better (1.8 mg) than that with sitagliptin despite differing administration methods. Some patients may experience nausea when initiating liraglutide treatment, but the titration regimen is designed to improve tolerability and clinical data indicate nausea is transient.     

Pitavastatin - from clinical trials to clinical practice

Managing dyslipidaemia is central to the management of cardiovascular disease. Most statins can reduce the 5-year incidence of major vascular events by 20%. In Europe, however, up to 53% of statin-treated patients fail to attain their low-density lipoprotein-cholesterol (LDL-C) target and residual risk remains high, even when targets are reached. Reasons for this include under-treatment due to insufficient starting doses/failure to uptitrate; poor persistence with therapy due to adverse events (AEs) or drug-drug interactions (DDIs); and failure to treat non-LDL-C risk factors, such as high triglycerides (TGs) and low high-density lipoprotein-C (HDL-C). Phase III and IV studies demonstrate that pitavastatin 1-4 mg has a similar or greater lipid-lowering efficacy to atorvastatin 10-20 mg, simvastatin 20-40 mg and pravastatin 10-40 mg, and is well-tolerated with a low incidence of adverse events (AEs). The SmPC recommends a usual starting dose of 1 mg, with dose-escalation if required. However, since the lower doses (1-2 mg) bring the majority of people with hypercholesterolaemia or combined dyslipidaemia to LDL-C target, the need for pitavastatin uptitration and the risk of under-treatment is low. In addition to reducing LDL-C, pitavastatin has a sustained beneficial effect on other atherogenic lipids, including TGs and HDL-C. Recent studies reveal that pitavastatin reduces coronary atheroma plaque volume as efficiently as atorvastatin and can improve the composition of coronary plaques, effects that are likely to reduce the risk of CV endpoints in patients with acute coronary syndrome. Moreover, pitavastatin has a number of pleiotropic effects that can reduce inflammation and lipid oxidation, improve endothelial function, reduce the metabolic changes associated with adiposity, and improve glucose metabolism and renal function. Compared to other statins, pitavastatin has a unique metabolic profile that could reduce the risk of DDIs, thereby providing a clear benefit in patients receiving polypharmacy. Overall, pitavastatin is a well tolerated and effective treatment for patients with hypercholesterolaemia and combined dyslipidaemia, especially in those with low HDL-C, and it should help improve LDL-C-target attainment rates by reducing the risk of under-treatment, minimising AE rates, and reducing the risk of DDIs in people requiring polypharmacy. Future and ongoing studies will directly compare the effects of pitavastatin vs. other statins on hard clinical endpoints.     

Peak flow monitoring in clinical practice and clinical asthma trials

PURPOSE OF REVIEW: This review summarizes recent reports on peak expiratory flow (PEF) monitoring in clinical asthma trials and clinical practice. RECENT FINDINGS: In clinical trials, summary measures such as average morning PEF provide only a fraction of the available information about asthma control and treatment response. New statistical models should improve the yield from PEF datasets. Improved criteria are needed for the diagnosis of exacerbations, and these may be developed from quality-control analysis of existing datasets. In clinical practice we must reduce the burden of monitoring and increase the ease of interpretation of PEF data. Electronic monitoring, with short message service or Internet communication, may assist with both. There is a need for standardized user-friendly PEF charts and simple statistically appropriate interpretative tools, which will facilitate the development of clinical algorithms and individualized written action plans. Normal values for diurnal variability should be updated to reflect twice daily monitoring. SUMMARY: Current use of PEF data is limited by the burden of monitoring and the continuing use of interpretative tools that were originally developed for their practical feasibility rather than their clinical validity. Both of these problems may be improved by giving attention to methods for recording, displaying and analysing PEF data.     

Issues in extrapolating from clinical trials to clinical practice and outcomes

Extrapolation of clinical trial results to clinical practice requires consideration of whether the trial patients were representative of clinical practice, whether the trial therapy studied was optimal, whether the sample size was adequate, and the impact of adjunctive treatments.
In thrombolytic trials in particular, regional variations in attitudes to coronary angiography may have affected outcomes. Clinical trial results need to be interpreted in the light of the cost effectiveness of the application.
The assessment of clinical outcomes depends on interplay between the structure and process of care, patient factors and chance. Large standardised databases are necessary to assess clinical practice and outcomes.     

Reconciling subject differences in recruitment to clinical trials and clinical practice

The special interest group on Reconciling Subject Differences was centered around the issue that the results from randomized clinical trials do not predict response to therapies in clinical practice, and around the hypothesis that this might be explained by differences in subjects selected for clinical trials compared to those treated in routine practice.     

ACE for whom? Implications for clinical practice of post-infarct trials.

OBJECTIVE--To determine how many lives would be saved if patients were routinely treated with ACE inhibitors after myocardial infarction according to the criteria of four recent major clinical trials, and to estimate the costs and benefits of these approaches. DESIGN--Retrospective survey. SETTING--The Nottingham Health District. PATIENTS--Data from 7855 patients admitted between 1989 and 1990 were combined and the selection criteria of four major clinical trials (AIRE, SAVE, GISSI-3, and ISIS-4) were applied. RESULTS--Of the patients admitted in Nottingham with confirmed myocardial infarcts 39% were eligible for AIRE and 8% for SAVE. In patients with suspected myocardial infarction as defined by the major trials, 60% would have been eligible for GISSI-3 and 63% for ISIS-4. Treating appropriate patients in accordance with these trials would have saved 20 (AIRE), 3 (SAVE), 4 (GISSI-3) and 5 (ISIS-4) lives each year in Nottingham at a drug cost of 5400 pounds, 33 pounds 791, 2730 pounds, and 4116 pounds per life per year saved respectively. CONCLUSIONS--Short-term treatment with ACE inhibition appears to be cheaper but such an approach would save fewer lives. The AIRE study is the most applicable to current clinical practice but ACE inhibitors should be offered routinely to patients satisfying the criteria of any of the four major clinical trials.     

Diabetic gastrointestinal autonomic neuropathy: Current status and new achievements for everyday clinical practice

Gastrointestinal symptoms occur frequently among patients with diabetes mellitus and are associated with considerable morbidity. Diabetic gastrointestinal autonomic neuropathy represents a complex disorder with multifactorial pathogenesis, which is still not well understood. It appears to involve a spectrum of metabolic and cellular changes that affect gastrointestinal motor and sensory control. It may affect any organ in the digestive system. Clinical manifestations are often underestimated, and therefore autonomic neuropathy should be suspected in all diabetic patients with unexplained gastrointestinal symptoms. Advances in technology have now enabled assessment of gastrointestinal motor function. Moreover, novel pharmacological approaches, along with endoscopic and surgical treatment options, contribute to improved outcomes. This review summarises the progress achieved in diabetic gastrointestinal autonomic neuropathy during the last years, focusing on clinical issues of practical importance to the everyday clinician.     

最新临床研究带给心源性脑栓塞预防的启示

缺血性卒中（ischemic stroke,IS）是病因和发病机制高度异质性的一组疾病。从1996年TOAST分型到2009年的ASCO分型,均将心源性脑栓塞（cardiac embolism,CE）作为一个单独的疾病,而不使用“脑栓塞”这一诊断名称。因为动脉粥样硬化导致的动脉一动脉栓塞,实质上属于动脉粥样硬化性脑梗死。大量循证医学证据汪实,CE的抗栓预防措施有别于非心源性卒中,     

Randomized trials of directional coronary atherectomy: Implications for clinical practice and future investigation

Objectives. This study compared and contrasted the randomized trials of directional atherectomy and coronary angioplasty for de novo native coronary artery lesions.Background. The results of two randomized trials, the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT) and the Canadian Coronary Atherectomy Trial (CCAT), comparing initial and intermediate-term outcome of directional coronary atherectomy and conventional coronary angioplasty in de novo native vessels, have been reported. In CAVEAT any coronary artery segment that could be by either technique was included; in CCAT only nonostial proximal left anterior descending coronary artery stenoses were studied.Methods. The primary end point was 6-month angiographic restenosis. Clinical outcome end points at 6 months included death, myocardial infarction, emergency bypass surgery and abrupt closure.Results. Initial angiographic success rates were significantly improved with directional coronary atherectomy compared with conventional angioplasty (89% vs. 80% for CAVEAT; 98% vs. 91% for CCAT). Also, the initial improvement in minimal lumen diameter and final immediate postprocedural residual diameter stenosis were better with atherectomy. In CCAT, there was no difference in initial complications; in CAVEAT, non-Q wave myocardial infarction rates and abrupt closure were increased with atherectomy. Despite improved success rates and better lumen achieved with atherectomy, in CCAT there was no difference in angiographic restenosis (46% for directional atherectomy vs. 43% for angioplasty). In CAVEAT, in a prespecified subset analysis involving the proximal left anterior descending coronary artery, restenosis was both significantly and clinically less for directional atherectomy (51% vs. 63%). For non-left anterior descending coronary artery segments, there was no difference.Conclusions. These studies document the difference between achievement of an excellent initial angiographic result and the longer term issue of clinical restenosis. Widespread use of directional coronary atherectomy to treat lesions that would be well treated by angioplasty in an attempt to decrease restenosis rates substantially does not appear indicated by the data. In individual lesions, directional atherectomy should be selected with the view toward optimizing initial results. Further trials are needed to determine whether more aggressive or better targeted directional coronary atherectomy may improve not only the initial gain but the long-term outcome as well.