Investigation of the effect of Interleukin-1 receptor antagonist (IL-1ra) on markers of inflammation in non-ST elevation acute coronary syndromes (The MRC-ILA-HEART Study)

Background

Point of care testing (PoCT) may be a useful adjunct in the management of chronic conditions in general practice (GP). The provision of pathology test results at the time of the consultation could lead to enhanced clinical management, better health outcomes, greater convenience and satisfaction for patients and general practitioners (GPs), and savings in costs and time. It could also result in inappropriate testing, increased consultations and poor health outcomes resulting from inaccurate results. Currently there are very few randomised controlled trials (RCTs) in GP that have investigated these aspects of PoCT.

Design/Methods

The Point of Care Testing in General Practice Trial (PoCT Trial) was an Australian Government funded multi-centre, cluster randomised controlled trial to determine the safety, clinical effectiveness, cost effectiveness and satisfaction of PoCT in a GP setting. The PoCT Trial covered an 18 month period with the intervention consisting of the use of PoCT for seven tests used in the management of patients with diabetes, hyperlipidaemia and patients on anticoagulant therapy. The primary outcome measure was the proportion of patients within target range, a measure of therapeutic control. In addition, the PoCT Trial investigated the safety of PoCT, impact of PoCT on patient compliance to medication, stakeholder satisfaction, cost effectiveness of PoCT versus laboratory testing, and influence of geographic location.

Discussion

The paper provides an overview of the Trial Design, the rationale for the research methodology chosen and how the Trial was implemented in a GP environment. The evaluation protocol and data collection processes took into account the large number of patients, the broad range of practice types distributed over a large geographic area, and the inclusion of pathology test results from multiple pathology laboratories. The evaluation protocol developed reflects the complexity of the Trial setting, the Trial Design and the approach taken within the funding provided. The PoCT Trial is regarded as a pragmatic RCT, evaluating the effectiveness of implementing PoCT in GP and every effort was made to ensure that, in these circumstances, internal and external validity was maintained.

Trial Registration

12612605000272695     

i-STAT – Combining Chemistry and Haematology in PoCT

Point-of-care testing (PoCT) is traditionally considered a branch or offshoot of clinical chemistry. The appearance on the market of small, light, inexpensive, multi-purpose, point-of-care analysers, which combine a number of widely differing analytes, has to some degree upset this paradigm. Such analysers, however, are invaluable in some clinical settings.Specialties other than clinical chemistry may have differing views on traditional test management, particularly with regard to quality control (QC), quality assurance (QA), and training. These views must be considered when designing an overall PoCT management plan. Test management issues should be resolved by taking the view that it is a ‘point-of-care’ test, and by looking at the specific test technology and method involved, rather than by just assuming it is a ‘haematology’ or a ‘chemistry’ test.Clinical users of a combined PoCT system are principally interested in the generation of good quality results. To avoid confusion, any advice given to clinical staff regarding their analysers should be clear, concise, and above all else, consistent.     

Existing and Emerging Technologies for Point-of-Care Testing

The volume of point-of-care testing (PoCT) has steadily increased over the 40 or so years since its widespread introduction. That growth is likely to continue, driven by changes in healthcare delivery which are aimed at delivering less costly care closer to the patient’s home. In the developing world there is the challenge of more effective care for infectious diseases and PoCT may play a much greater role here in the future. PoCT technologies can be split into two categories, but in both, testing is generally performed by technologies first devised more than two decades ago. These technologies have undoubtedly been refined and improved to deliver easier-to-use devices with incremental improvements in analytical performance. Of the two major categories the first is small handheld devices, providing qualitative or quantitative determination of an increasing range of analytes. The dominant technologies here are glucose biosensor strips and lateral flow strips using immobilised antibodies to determine a range of parameters including cardiac markers and infectious pathogens. The second category of devices are larger, often bench-top devices which are essentially laboratory instruments which have been reduced in both size and complexity. These include critical care analysers and, more recently, small haematology and immunology analysers. New emerging devices include those that are utilising molecular techniques such as PCR to provide infectious disease testing in a sufficiently small device to be used at the point of care. This area is likely to grow with many devices being developed and likely to reach the commercial market in the next few years.     

The National QAAMS Program – A Practical Example of PoCT Working in the Community

The Quality Assurance for Aboriginal and Torres Strait Islander Medical Services (QAAMS) Program is the largest and longest-standing national point-of-care testing (PoCT) program in Australia. With a focus on PoCT for diabetes management, it now operates in 115 Indigenous medical services and has been funded continuously by the Australian Government for 11 years. A recent independent evaluation of the QAAMS Program concluded that the program continues to meet best practice standards for Indigenous healthcare, diabetes management and PoCT.     

Integrating PoCT into Clinical Care

In South Australia, the Integrated Cardiovascular Clinical Network SA (iCCnet SA) is the provider which enacts the recommendations and policies of the state-wide cardiac clinical network working parties in rural and remote areas by developing appropriate clinical tools.Pathology tests play a significant role in contributing to best practice for patient diagnosis and management. As most South Australian country hospitals do not have timely access to pathology results, point-of-care testing (PoCT) for troponin and N-terminal pro-brain natriuretic peptide (NT-proBNP) has been integrated into clinical pathways for the management of possible acute coronary syndrome (ACS) and suspected heart failure patients respectively. Compared with control hospitals of similar size and resources, preliminary results from an iCCnet SA regional hospital showed improved patient outcomes for ACS: 30-day readmission rates were reduced from 10.4% to 4.2% (p = 0.03) and there was a corresponding trend in the reduction of in-hospital death rates from 15.8% to 9.8% (p = 0.1).The establishment of iCCnet SA has improved outcomes for rural patients presenting to hospital with symptoms suggestive of ACS by facilitating the uptake of evidence-based acute cardiac care. Implementation of PoCT equipment into clinical care requires a systematic approach that engages all stakeholders involved in patient care. Provider clinical networks, such as iCCnet SA, provide a structure for effective working relationships between health professionals. PoCT has been critical to the success of the network, but it needs to be implemented within an integrated system of care to produce optimal outcomes.     

Evolution of Point-of-Care Testing in Australia

Currently no mandatory standards or guidelines exist for Point-of-Care Testing (PoCT) in Australia. In 2001, a report on the role and value of ‘near patient testing’ in general practice outlined work that was required to assist the Australian Government to decide how to manage PoCT. Phillips Fox reported that adoption of mandatory accreditation requirements was not justified by the level of risk associated with PoCT.If implemented appropriately, PoCT could be useful with frontline management of chronic disease, relieving stress on general practice and expanding the reach of pathology.Interim PoCT standards in general practice were developed by a Quality Use of Pathology committee, and formed an accreditation framework for the PoCT in General Practice Trial. This trial concluded that PoCT has a role in supporting the primary healthcare team to manage chronic disease patients.While results of the trial are still being considered, the potential impact of funding PoCT in general practice is being treated as part of the wider review of pathology funding currently taking place in Australia.Although Australia has local models from which to draw experience, it has yet to decide the quality framework it would adopt if it was to roll out PoCT in general practice. The quality framework that Australia adopts for PoCT must achieve high quality pathology results that enhance clinical care.     

Quality control issues in point of care testing

* Quality Control (QC) in Point of Care Testing (PoCT) is often thought of as a complex issue; however intelligent system analysis can simplify matters and greatly increase the chances of a well controlled system. What we want to achieve is a QC program which adequately controls the PoCT system, but does not excessively contribute to the operating costs or complexity of maintaining a PoCT instrument, or network of instruments. * Don't neglect effective pre-analytical work: good documentation, operator training, monitoring, and analyser maintenance programs are essential, as for any analyser. * Look closely at your analyser: Is it a "laboratory type" instrument or cartridge or strip based? Can it perform multiple test types or a single test only? How is it calibrated? Does it have built in self-check capabilities or an electronic check cartridge? Is the sample in contact with the instrument? What are the cartridge/strip/reagent storage requirements? * Establish where the analysis is taking place and which system component is involved. * Tailor your QC program to target this component, but still check the system as a whole. * A common approach is to check cartridges/strips on delivery and run a QA sample at least monthly to check storage conditions and operator performance. If there is no independent electronic instrument check, daily QC checks are also recommended. * Don't be afraid to stray beyond conventional QC models if necessary. Some PoCT systems are not adequately controlled by the application of conventional QC alone.     

Point-of-Care Testing and Creatinine Measurement

This paper reviews the current status of point-of-care testing (PoCT) devices that are available for measuring whole blood or serum/plasma creatinine globally and within Australasia. Information on non-analytical specifications and analytical performance is provided using data sourced from recently published literature, external quality assurance programs and evaluative work by the author's unit. The limitations of current devices are summarised.     

Proteasome inhibition: a novel approach to cancer therapy

The central role of the proteasome in controlling the expression of regulators of cell proliferation and survival has led to interest in developing proteasome inhibitors as novel anticancer agents. In vitro and in vivo studies have shown that proteasome inhibitors have activity against a variety of tumor types. One of these agents, PS-341, has been tested in phase I trials in a variety of tumor types; in these trials, PS-341 treatment was well tolerated and preliminary evidence of biological activity was observed in some patients. Phase II trials in several hematological malignancies and solid tumor types are now in progress.     

Tuberculosis Vaccines and Prevention of Infection

SUMMARY

Tuberculosis (TB) is a leading cause of death worldwide despite the availability of effective chemotherapy for over 60 years. Although Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccination protects against active TB disease in some populations, its efficacy is suboptimal. Development of an effective TB vaccine is a top global priority that has been hampered by an incomplete understanding of protective immunity to TB. Thus far, preventing TB disease, rather than infection, has been the primary target for vaccine development. Several areas of research highlight the importance of including preinfection vaccines in the development pipeline. First, epidemiology and mathematical modeling studies indicate that a preinfection vaccine would have a high population-level impact for control of TB disease. Second, immunology studies support the rationale for targeting prevention of infection, with evidence that host responses may be more effective during acute infection than during chronic infection. Third, natural history studies indicate that resistance to TB infection occurs in a small percentage of the population. Fourth, case-control studies of BCG indicate that it may provide protection from infection. Fifth, prevention-of-infection trials would have smaller sample sizes and a shorter duration than disease prevention trials and would enable opportunities to search for correlates of immunity as well as serve as a criterion for selecting a vaccine product for testing in a larger TB disease prevention trial. Together, these points support expanding the focus of TB vaccine development efforts to include prevention of infection as a primary goal along with vaccines or other interventions that reduce the rate of transmission and reactivation.     

Aromatase inhibitors in gynecologic cancers

The female genital tract is hormonally responsive, and consequently some tumors, which arise within in it, may be treated at least in part, with hormonal manipulation. The range of responses in clinical trials and case reports will be reviewed. Many of these diseases are too rare for clinical trial testing, and in some cases evidence is anecdotal at best. Recurrences of ovarian cancer have been treated with tamoxifen and megesterol acetate with variable response rates from 0 to 56%. The favorable toxicity profile of aromatase inhibitors led to trials of these agents for the treatment of relapsed epithelial ovarian cancer. These agents have proved tolerable with minor response rates but a significant disease stabilization rate, which may be prolonged in a minority of cases. It is unclear if these responses may be predicted by estrogen receptor expression or aromatase expression. Anastrazole has also been tried in combination with an EGFR receptor-inhibitor, again showing minor responses but possibly an increase in TTT in some patients. Granulosa cell tumors of the ovary are rare, hormonally sensitive tumors, with reported responses to a variety of hormonal manipulations, including aromatase inhibition. In addition, combined endocrine blockade, including aromatase inhibition, has been tried with reports of success. Endometrial cancers, particularly type I lesions, are often treated with hormonal manipulation, most commonly with progestins, but also with antiestrogens such as tamoxifen. A trial of aromatase inhibition in the treatment of recurrent endometrial cancer showed minimal responses. Endometrial stromal sarcoma, an uncommon uterine malignancy, has shown response to hormonal treatments, with multiple case reports of efficacy of aromatase inhibition. Despite the rarity of some of these tumor types, rare tumor study groups, such as within the Gynecologic Oncology Group, should make an effort to prospectively define the utility of these treatments.     

Coenzyme Q10 in cardiovascular disease

In this review we summarise the current state of knowledge of the therapeutic efficacy and mechanisms of action of CoQ₁₀ in cardiovascular disease. Our conclusions are: 1. There is promising evidence of a beneficial effect of CoQ₁₀ when given alone or in addition to standard therapies in hypertension and in heart failure, but less extensive evidence in ischemic heart disease. 2. Large scale multi-centre prospective randomised trials are indicated in all these areas but there are difficulties in funding such trials. 3. Presently, due to the notable absence of clinically significant side effects and likely therapeutic benefit, CoQ₁₀ can be considered a safe adjunct to standard therapies in cardiovascular disease.     

Antibiotic treatment of atherosclerosis

PURPOSE OF REVIEW: Several lines of evidence have demonstrated an association between a variety of chronic bacterial infections and atherosclerotic cardiovascular disease. This has led to the proposal that antibiotic therapy might be helpful in the secondary prevention of atherosclerosis. A variety of smaller pilot studies have been reported testing this hypothesis and several large multicenter trials are also underway. The purpose of this review is to summarize the results of these studies and comment on their implications for the treatment of atherosclerosis. RECENT FINDINGS: Most of the antibiotic studies to date have been secondary prevention studies that have targeted patients exposed to Chlamydia pneumoniae. Most have used either azithromycin or roxithromycin with treatment courses ranging from a few days to 3 months. Several small studies of coronary artery disease patients have shown significant promise for reducing cardiovascular events such as death, myocardial infarction, or admission for unstable angina. However, other studies have not been so positive. Weekly Intervention with Zithromax for Atherosclerosis and its Related Disorders, WIZARD, the largest study to date, in which stable post-myocardial infarction patients were randomized to receive a 3-month course of azithromycin or placebo, demonstrated a significant reduction in death and myocardial infarction by 6 months, but this benefit was not sustained throughout the remaining course of follow-up. The Azithromycin and Coronary Events (ACES) and Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) trials are ongoing and are testing the effect of more prolonged treatment duration. SUMMARY: A variety of antibiotic trials for the secondary prevention of atherosclerosis have been performed. Several pilot studies have shown significant positive clinical effects, but, thus far, no large randomized trial has confirmed those findings. Some concerns over the antibiotics chosen and the duration of treatment have been raised. Other trials are underway to address some of those concerns. In the meantime, no recommendation for the use of antibiotic therapy for the secondary prevention of atherosclerosis can yet be made.     

Do stroke models model stroke?

Stroke is one of the leading causes of death worldwide and the biggest reason for long-term disability. Basic research has formed the modern understanding of stroke pathophysiology, and has revealed important molecular, cellular and systemic mechanisms. However, despite decades of research, most translational stroke trials that aim to introduce basic research findings into clinical treatment strategies – most notably in the field of neuroprotection – have failed. Among other obstacles, poor methodological and statistical standards, negative publication bias, and incomplete preclinical testing have been proposed as ‘translational roadblocks’. In this article, we introduce the models commonly used in preclinical stroke research, discuss some of the causes of failed translational success and review potential remedies. We further introduce the concept of modeling ‘care’ of stroke patients, because current preclinical research models the disorder but does not model care or state-of-the-art clinical testing. Stringent statistical methods and controlled preclinical trials have been suggested to counteract weaknesses in preclinical research. We conclude that preclinical stroke research requires (1) appropriate modeling of the disorder, (2) appropriate modeling of the care of stroke patients and (3) an approach to preclinical testing that is similar to clinical testing, including Phase 3 randomized controlled preclinical trials as necessary additional steps before new therapies enter clinical testing.     

Superoxide dismutase and catalase as therapeutic agents for human diseases. A critical review

The list of human and animal diseases for which oxygen radical scavenging therapy is being recommended continues to grow, based primarily on inferential evidence suggesting a potential role for oxygen-derived free radicals in various types of pathophysiology. Some distinct advances in pharmacologic manipulation of protein scavengers have been made which could ultimately greatly enhance the use of these reagents as drugs, as well as some innovative techniques for drug delivery (direct injection via endoscopy, iontophoresis). Unfortunately, most of the therapeutic reports in the literature, almost all of which are based on usage of standard (native) SOD and/or catalase, are still anecdotal and/or uncontrolled. A review of the human disease/treatment literature suggests that further tightening of the scientific design of such trials is still badly needed; hopefully better experimental design will be applied when products such as PEG conjugates or genetically engineered polymers are ready for testing.     

The immune recognition of malaria antigens

Owing to the demonstration that the immune response of inbred mice to some defined malaria antigens is influenced by the major histocompatibility complex (MHC), and the finding that only a minority of individuals living in malaria-endemic areas appear to recognize such antigens, there are fears that synthetic subunit malaria vaccines will be poorly immunogenic in a substantial proportion of the target population. Such fears have been reinforced by the results of the first two human malaria vaccine trials. In this review Eleanor Riley, Olle Olerup and Marita Troye-Blomberg summarize the experimental evidence for MHC-related genetic restriction of malaria immunity and discuss some alternative explanations for nonresponsiveness in populations living in malaria-endemic areas.     

Evidence-Based Laboratory Medicine: Is It Working in Practice?

The principles of Evidence-Based Medicine have been established for about two decades, with the need for evidence-based clinical practice now being accepted in most health systems around the world. These principles can be employed in laboratory medicine. The key steps in evidence-based practice, namely (i) formulating the question; (ii) searching for evidence; (iii) appraising evidence; (iv) applying evidence; and (v) assessing the experience are all accepted but, as yet, translation into daily clinical and laboratory practice has been slow. Furthermore, the demand for evidence-based laboratory medicine (EBLM) has been slow to develop.There are many contrasting observations about laboratory medicine, for example (i) there is too much testing vs insufficient testing; (ii) testing is expensive vs laboratories are expected to generate income; and (iii) test results have little impact on outcomes vs test results are crucial to clinical decision making. However, there is little evidence to support any of these observations. Integrating the principles of EBLM into routine practice will help to resolve some of these issues by identifying (a) where laboratory medicine fits into the care pathway; (b) where testing is appropriate; (c) the nature and quality of evidence required to demonstrate the clinical utility of a test; (d) how the test result impacts on clinical actions; (e) where changes in the care pathway will occur; and (f) where benefit/value can be achieved. These answers will help to establish the culture of EBLM in clinical and laboratory practice.     

Les essais cliniques en médecine nucléaire

The EU clinical trials directive (2001/20/EC) was published on the 4th April 2001 and was transposed into French law in 2004. This new clinical trial regulation has modified considerably the research area including clinical trials conducted with radiopharmaceutical medicinal products. This new regulation aims at ensuring the protection of the health and safety of clinical trial participants, the ethical soundness and the reliability and robustness of data generated in clinical trials. In practice, the sponsor has to submit a clinical trial application to the Afssaps for authorization and to the concerned Ethics Committee for a positive opinion. The content of the clinical trial application regarding the investigational medicinal product is very detailed and a heavy technical dossier could be required in order to justify the quality of the medicinal product used in the clinical trial. Furthermore, pharmacy and radiopharmacy required specific authorizations for preparing these medicinal products. This new regulation could refrain nuclear medicine from conducting clinical trials.     

Fibric acid derivatives in cardiovascular disease prevention: results from the large clinical trials

PURPOSE OF REVIEW: Results from five large placebo-controlled trials with second-generation fibrates have shown varying success in reducing cardiovascular events. This review focuses on a number of extended analyses from these trials that may relate to the success or failure of fibrate therapy and indicate who might likely benefit from this therapy. RECENT FINDINGS: Results have been far from uniform and several trials have been adversely impacted by high off-trial statin use. Collective evidence suggests, however, that fibrates have optimum cardiovascular benefit in diabetes or other manifestations of insulin resistance. Much of this evidence comes from posttrial analysis in subgroups with more sharply defined clinical characteristics than in the overall trial population. Analyses also suggest that different fibrates have a different range of favorable clinical properties, that the cardiovascular benefit of fibrates may not be readily measured or mostly predicted by changes in traditional lipid measurements, and that other nonlipid properties of fibrates as peroxisome proliferator-activated receptor agents might explain some of the benefit of these drugs. SUMMARY: Results of major clinical endpoint trials with fibrates, although not uniformly positive, provide substantial evidence for a selective therapeutic role of these drugs in cardiovascular event reduction in diabetes or insulin resistance.