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.     

Measuring clinical performance using routinely collected clinical data

Following the well-publicized problems with paediatric cardiac surgery at the Bristol Royal Infirmary, there is wide public interest in measures of hospital performance. The Kennedy report on the BRI events suggested that such measures should be meaningful to the public, case-mix-adjusted, and based on data collected as part of routine clinical care. We have found that it is possible to predict in-hospital mortality (a measure readily understood by the public) using simple routine data-age, mode of admission, sex, and routine blood test results. The clinical data items can be obtained at a single venesection, are commonly collected in the routine care of patients, are already stored on hospital core IT systems, and so place no extra burden on the clinical staff providing care. Such risk models could provide a metric for use in evidence-based clinical performance management. National application is logistically feasible.     

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.     

Loose connections between peer-reviewed clinical journals and clinical practice

Many important advances in medical care are first reported in the biomedical literature, but physicians find the literature overwhelming and, therefore, are often unaware of advances. This article examines the ways in which peer-reviewed clinical journals contribute to this problem and proposes some solutions for both their editors and clinical readers. Peer-reviewed clinical journals impede the dissemination of validated advances to practitioners by mixing a few rigorous studies (communications from scientists to practitioners) with many preliminary investigations (communications from scientists to scientists). Journals wishing to improve communication with practitioners should feature rigorous studies of the nature, cause, prognosis, diagnosis, prevention, and treatment of disease and should feature sound clinical review articles (communications from practitioners to practitioners). Additional strategies for improving communication between medical scientists and practitioners include improving publication standards for clinical journals, proving more informative abstracts for clinical articles, fostering the development of derivative literature services, and enhancing practitioners' skills in critically appraising the medical literature.     

Quantitative assessment of rheumatoid arthritis in standard clinical care: turning clinical care into clinical science

Patient questionnaires are a valuable method of monitoring the health status of patients with musculoskeletal conditions as part of daily clinical practice. Quantitative clinical monitoring improves the physician's ability to detect and document changes in patients' health conditions and thus leads to greater precision in clinical decisions. Furthermore, routine data collection on consecutive patients facilitates the analysis of groups of patients, providing more information than can be obtained from randomized clinical trials.     

Pulmonary embolism: from clinical presentation to clinical probability assessment

The rehabilitation of clinical assessment of venous thromboembolism (VTE) is certainly one of the major breakthroughs of the last decade in the field of pulmonary embolism (PE) diagnosis. Although the value of isolated clinical findings in suspected PE is limited due to the poor sensitivity and specificity of its symptoms and signs, their combination, whether empiric or explicit through prediction rules, allows a fairly accurate assessment of the likelihood of the disease in a given patient. This allows the identification of a large subset of patients with a low prevalence of the disease in whom a combination of noninvasive tests rules out PE effectively despite these tests' limited individual sensitivity. The best validated example is the combination of a low probability lung scan and a normal venous compression ultrasound in a patient with low clinical probability of PE, which is associated to a low 1 to 2% 3-month risk of VTE in such patients left untreated by anticoagulants. Finally, clinical assessment contributes significantly to the cost savings associated with modern noninvasive strategies.     

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.     

Measurement of somatic neuropathy for clinical practice and clinical trials

Distal sensory polyneuropathy is a common and unpleasant complication of diabetes mellitus. It is the main initiating factor for foot ulceration. The increasing prevalence of diabetes has important associated health implications, both in terms of morbidity and mortality, and results in the consumption of scarce medical resources. Identification of somatic neuropathy in clinical practice is therefore important for targeted educational and other interventions. In this article, we describe methods for detecting somatic neuropathy in clinical practice and highlight those tests that are proven to be predictors of foot ulceration. The approach for detecting and characterizing somatic neuropathy for clinical trials, however, differs significantly. These methods must ideally have high levels of reproducibility, sensitivity, and specificity. Currently, several neurophysiologic tests are employed in clinical trials in order to accurately characterize diabetic neuropathy. The recent introduction of the computer-assisted programs for the measurement of sensory modalities for clinical trials has been a major advance. Due to their invasive nature and associated morbidity, nerve biopsy studies are no longer used in clinical trials. Recently, using magnetic resonance imaging (MRI), significant spinal cord atrophy has been demonstrated in established neuropathy. If this observation proves to be an early feature, then a relatively rapid, noninvasive MRI technique may be used in the future to characterize diabetic neuropathy.     

Summary of ceftaroline fosamil clinical trial studies and clinical safety

In October 2010, the new cephalosporin, ceftaroline fosamil, was approved by the US Food and Drug Administration for therapy of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSIs). The active metabolite, ceftaroline, demonstrates in vitro activity against typical bacterial pathogens most often associated with CABP or ABSSSIs, including resistant Gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus. The efficacy and safety of ceftaroline fosamil was assessed in 2 large phase 3 programs of randomized, double-blind, clinical trials for CABP and ABSSSIs. For both indications, therapy with ceftaroline fosamil was observed to be noninferior to the comparator agents (ceftriaxone for CABP and vancomycin plus aztreonam for ABSSSIs) at both a standard test of cure assessment time (8-15 days after discontinuation of study drug) and an early assessment time point (day 3 or 4 of study). In the integrated analysis of the trials for CABP (FOCUS 1 and 2), clinical cure rates for the ceftaroline group were numerically higher than those for the ceftriaxone group (for the clinically evaluable population 84.3% vs 77.7%; difference: 6.6%; 95% confidence interval, 1.6%-11.8%). Among patients with CABP caused by S. pneumoniae, clinical cure rates were markedly higher in the ceftaroline treatment group than in the ceftriaxone treatment group (59 of 69 [85.5%] vs 48 of 70 [68.6%], respectively). For the ABSSSI studies (CANVAS 1 and 2), microbiologically evaluable (ME) success rates were similar between the treatment groups. Notably, the clinical cure rates in ME patients with methicillin-resistant S. aureus ABSSSIs were 142 of 152 (93.4%) and 115 of 122 (94.3%), for ceftaroline and vancomycin plus aztreonam, respectively, and did not differ from those achieved in infections due to methicillin-susceptible S. aureus (93.0%-94.5%). Ceftaroline fosamil was well tolerated, with a safety profile similar to the comparator agents used in these phase 3 trials.