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Randomised trials top the hierarchy of evidence. To provide the best evidence to guide surgical practice, randomised trials must answer clinically important questions, have important and objective outcome measurement and be sufficiently powered to detect important differences between interventions. Investigators who adhere to these principles are more likely to succeed during the conduct of their trials.
OBJECTIVE: To identify and evaluate studies of interventions in primary care aimed at reducing medication related adverse events that result in morbidity, hospital admission, and/or mortality. METHODS: Fourteen electronic databases were systematically searched for published and unpublished data. Bibliographies of retrieved papers were searched and experts and first authors contacted in an attempt to locate additional studies. There were no restrictions on language of publication. All interventions applied in primary care settings which aimed to improve patient safety by reducing adverse events resulting from medication overuse or misuse were considered. Randomised controlled trials, controlled trials, controlled before and after studies, and interrupted time series studies were eligible for inclusion. Study quality assessment and data extraction were undertaken using the Cochrane Effective Practice and Organisation of Care data collection checklist and template. Meta-analysis was performed using a random effects model. RESULTS: 159 studies were initially identified, of which 38 satisfied our inclusion criteria. These were categorised as follows: 17 pharmacist-led interventions (of which 15 reported hospital admissions as an outcome); eight interventions led by other primary healthcare professionals that reported preventable drug related morbidity as an outcome; and 13 complex interventions that included a component of medication review aimed at reducing falls in the elderly (the outcome being falls). Meta-analysis found that pharmacist-led interventions are effective at reducing hospital admissions (OR 0.64 (95% CI 0.43 to 0.96)), but restricting analysis to the randomised controlled trials failed to demonstrate significant benefit (OR 0.92 (95% CI 0.81 to 1.05)). Pooling the results of studies in the other categories did not demonstrate any significant effect. CONCLUSIONS: There is relatively weak evidence to indicate that pharmacist-led medication reviews are effective in reducing hospital admissions. There is currently no evidence for the effectiveness of other interventions which aim at reducing admissions or preventable drug related morbidity. More randomised controlled trials of primary care based pharmacist-led interventions are needed to decide whether or not this intervention is effective in reducing hospital admissions.
Travoprost is a synthetic ester prodrug of a prostaglandin F(2alpha) analogue used in the treatment of open-angle glaucoma and ocular hypertension. Intraocular travoprost 0.004% once daily was significantly more effective at reducing intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension than placebo or timolol 0.5% twice daily and was at least as effective as latanoprost 0.005% once daily in randomised, double-blind studies. When used as adjunctive therapy with timolol 0.5% twice daily in patients with elevated IOP not adequately controlled by timolol alone, travoprost 0.004% showed significant additional IOP reduction in a randomised double-blind trial. Travoprost 0.004% was well tolerated in clinical trials. The majority of adverse events such as ocular hyperaemia and eyelash changes were mild and resolved without treatment.
Ethinylestradiol/chlormadinone acetate 0.03/2mg (EE/CMA) is a combined monophasic contraceptive pill with antiandrogenic properties. In a large, noncomparative, multicentre trial (< or =24 cycles of treatment per woman) and two (6- and 12-cycle) postmarketing surveillance studies, EE/CMA was effective in preventing pregnancy. EE/CMA was significantly more effective than EE/levonorgestrel 0.03/0.15 mg/day in treating women with mild-to-moderate papulopustular acne of the face and related disorders in a randomised, single-blind, multicentre trial. EE/CMA was well tolerated in clinical trials and the postmarketing surveillance studies. Adverse events were those commonly reported with oral contraceptives. As expected, the most common menstrual disturbances were breakthrough bleeding, spotting and amenorrhoea.
OBJECTIVE: To determine the extent of application of the intention to treat principle in the chronic suppurative otitis media (CSOM) randomised controlled trials. DESIGN: Data were extracted from 28 CSOM randomised controlled trials. MAIN OUTCOME MEASURES: Conceptual and methodological approaches of dealing with protocol deviations with respect to withdrawal, missing response and non-compliance. RESULTS: Of the 28 CSOM trials included in this study, only one (4%) trial mentioned intention-to-treat (ITT) analysis. However, 10(36%) other trials which did not mention ITT, had no protocol deviations and thus carried out an ITT analysis by default. It is highly likely that a biased treatment effect existed in the trial that mentioned ITT since the authors undertook a complete case analysis disregarding the 22% protocol deviators. There were no attempts in any of the trials to impute for missing responses and carrying out a sensitivity analysis. For trials with a big percentage of protocol deviations, the validity of their results are brought to question. CONCLUSIONS: In practice, not all those entered into a randomised-controlled trial will complete the trial. Thus intention-to-treat analysis is an important aspect of randomised controlled trials of health care interventions which tries to bridge this gap. It is important for authors to explicitly state the protocol deviations, the methods used to handle them and the potential effect with reference to bias and study outcome.
Following the publication of a randomised controlled trial of Arnica in hand surgery, a number of reports of apparently beneficial effects of Arnica came to the author's attention. Many of these apparent responses could have been due to other factors including the use of herbal (non-diluted) Arnica, placebo response and natural course of disease.
Memantine, an uncompetitive antagonist with moderate affinity for NMDA receptors, demonstrates voltage-dependency and relatively fast on/off receptor kinetics. Memantine 20 mg/day significantly slowed the rate of deterioration in outpatients with moderate to severe Alzheimer's disease in a 28-week US randomised, double-blind, placebo-controlled, multicentre study. Memantine 10 mg/day improved measures of dementia in care-dependent inpatients with Alzheimer's disease or vascular dementia in a 12-week randomised, double-blind study. Significantly more memantine than placebo recipients were responders according to Clinical Global Impression of Change scores and the Behavioural Rating Scale for Geriatric Patients Care Dependence subscale. Memantine 20 mg/day significantly improved cognition-related outcomes (cognitive subscale of the Alzheimer's Disease Assessment Scale) in patients with vascular dementia in two 28-week randomised, double-blind, placebo-controlled, multicentre trials. No statistically significant between-group difference was seen in other primary endpoints. Adverse events (incidence in memantine recipients greater than in placebo recipients) occurring in patients with moderately severe to severe dementia included diarrhoea, insomnia, dizziness, headache and hallucination.
Removal of uraemic toxins can be increased by online haemodiafiltration. At present, it is unclear whether online haemodia-filtration ultimately improves clinical outcomes in chronic haemodialysis patients. The Dutch 'Convective transport study' (CONTRAST) is an ongoing trial comparing standard haemodialysis with online haemodiafiltration. This randomised controlled trial will provide substantial clinical evidence on the effects of haemodiafiltration on fatal and non-fatal cardiovascular events and all-cause mortality, compared with standard haemodialysis.
BACKGROUND: Combining radiation and hormone therapy (administration of selective estrogen receptor modulators) has become common clinical practice in recent years for receptor positive breast cancer. Little is known about a possible interaction of both treatment modalities if they are given simultaneously. Tamoxifen (antiestrogen molecule, triphenylethylene derivative) may theoretically render cancer cells less responsive to radiotherapy arresting hormone-receptor-positive cells in G0/G1 phase and increase the risk of breast and lung fibrosis stimulating the secretion of transforming growth factor beta in human fibroblasts. PURPOSE: This article reviews the published data to assess the impact of sequencing of hormonal and radiation therapy on outcomes in breast cancer. METHODS: Computerised searches for publications debating the sequencing of hormonal therapy relative to radiation therapy were done using MEDLINE data. RESULTS: Results of tamoxifen experiments with cell culture regarding radioprotection of tumour clonogens are conflicting. In contrast to in vitro results, in animal studies no protective effect of tamoxifen was observed. In one in vitro study, letrozole (non-steroid selective aromatase inhibitor) had a radiosensitizing effect on breast-cancer lines. No randomised clinical trials to date have studied sequencing of tamoxifen or other selective estrogen receptor modulators and radiotherapy. Results from retrospective clinical studies which included treatment arms with and without tamoxifen showed reduction in tumour recurrence with tamoxifen. Some of these studies have noted increased risk of lung and breast fibrosis with tamoxifen with radiotherapy. Results of three articles examined the effect of tamoxifen sequence showed no adverse effect on local control or survival in sequential versus concurrent tamoxifen and radiation patients. One of the three studies also assessed the risk of complications with respect to the timing of tamoxifen with radiotherapy. There was no difference in the rates of complications between the two groups. The association of radiation and selective aromatase inhibitors or aromatase inactivators has not been addressed in clinical studies. CONCLUSIONS: Combined application of tamoxifen and radiotherapy improves survival and local control in breast cancer. Available clinical studies do not indicate that the simultaneous application of tamoxifen and radiotherapy is disadvantageous, as was suggested by some of the in vitro studies. The risk of subcutaneous breast and lung fibrosis might be slightly increased if tamoxifen is given simultaneously with radiotherapy. Both treatment modalities should be started early after surgery. There is no sufficient evidence to withhold tamoxifen administration during irradiation of breast cancer. The issue of optimal sequencing of hormonal and radiotherapy should be addressed in randomised clinical trials.
Atherothrombotic cardiovascular disease is a leading cause of death in women, especially in the postmenopause. It is controversial whether postmenopausal hormone replacement therapy is protective with regard to cardiovascular disease. On the one hand, observational studies consistently show that the risk of cardiovascular disease is 35 to 50% lower among users of hormonal replacement than among non-users. In addition, hormonal replacement is associated with an improvement of the lipid profile and several other potentially beneficial effects. On the other hand, two recent placebo-controlled randomised trials did not find evidence in favour of cardiovascular protection by hormonal replacement. This discrepancy may be explained by insufficient adjustment for lifestyle factors in observational studies and insufficient consideration of methodological flaws in experimental studies, both of which lead to an overestimation of the protective effect of hormonal replacement. Hormonal replacement may affect the pathophysiology of atherothrombosis in several ways, both positive and negative. Progress in this field requires the isolation of the positive effects.
The clinical application of a new method for using the insect growth regulator, pyriproxyfen, for controlling flea populations in cat-owning homes is evaluated for the first time. In a multicentric, controlled and randomised trial, 107 flea-infested cats were treated with a minimum dose of 10 mg/kg bodyweight pyriproxyfen as a 10 per cent spot-on application on two occasions, with a three-month interval between doses. For comparison, 99 cats received lufenuron suspension orally, once a month, for six months. Flea counts decreased significantly over time in each group and were significantly lower in the pyriproxyfen group than in cats treated with the reference product. The percentage of 'zero-flea' cats increased from 49 per cent on day 30 to 88 per cent on day 180 in the pyriproxyfen group and from 30 to 71 per cent in the lufenuron group at the same time points (P<0.05). Appropriately timed topical applications of pyriproxyfen, therefore, offer a method of flea control in the domestic environment.
Local control and sphincter preservation are the two challenges of anal canal cancer treatment. These tumors are radio- and chemo-sensitive and treatment moved from surgical approach, with abdominoperineal resection, to definitive radiation therapy with or without concurrent chemotherapy. Randomised trials proved the benefit of combined modality with chemoradiotherapy and of mitomycine C (MMC) compared with radiotherapy alone, with a toxic death rate of about 2%. Indications of chemoradiotherapy are locally advanced tumor T2 > or = 4 cm, T3-4 or N1-3 but the best modalities of combined treatment are still under debate. Standard chemotherapy is 5 flurouracile (5FU) + MMC, but cisplatinum (CDDP) is an effective and well tolerated substitute for MMC. Favourable results with CDDP-containing regimen in term of toxicity and carcinologic control have been reported in phase II and retrospective studies. Total radiation dose, overall duration of radiation therapy, duration of the gap and indications of additional boost are not clear, but it is demonstrated that overall duration of treatment should be as short as possible to improve the therapeutic radio. Phase II and III studies are ongoing, to evaluate the best chemotherapy regimen between 5FU+MMC and 5FU+CDDP, the benefit of neoadjuvant or maintenance chemotherapy and the interest of increased total dose. Next future could be the utilisation of oral 5FU. This article is a review of past randomised trials, phases II and retrospective study on radiochemotherapy of anal canal carcinoma.
Anaemia is a key component of diabetic nephropathy, but its importance has only recently been recognised. Recombinant human erythropoietin (epoetin) is an established treatment for renal anaemia, and may help to reduce complications associated with diabetic nephropathy, such as cardiovascular disease. The limited experience with the use of epoetin in this patient group prompts the urgent need for clinical data on anaemia correction in early diabetic nephropathy, particularly with regard to benefits on cardiovascular risk reduction. The Anaemia CORrection in Diabetes (ACORD) study will investigate the effects of anaemia correction on cardiac structure and function in patients with early diabetic nephropathy. This 15-month multicentre study will recruit 160 adult patients with diabetes, mild or moderate chronic kidney disease (with creatinine clearance >or=30 ml/min at screening) and moderate anaemia (haemoglobin [Hb], 10.5-13.0 g/dl). Patients will be randomised to one of two groups: the early treatment group will receive subcutaneous epoetin beta (NeoRecormon) at study entry to maintain target Hb levels of 13-15 g/dl, while the control group will reflect current practice and will not receive epoetin therapy until Hb levels decline below 10.5 g/dl. The primary efficacy variable, change in left ventricular mass index, will be evaluated at 15 months following randomisation; secondary efficacy variables will include changes in cardiac structure and function over the study period. The ACORD study should provide valuable information on the benefits of anaemia correction in patients with early diabetic nephropathy. The study will also increase awareness of the importance of treating anaemia associated with diabetes.
Operative treatment of intra-articular calcaneal fractures with anatomical reduction and early mobilisation has lead to a considerable improvement of the functional results of these severe injuries over the recent two decades. New tendencies like modified approaches tailored according to the vascular anatomy, arthroscopic control of joint reduction in conjunction with open or percutaneous procedures, early flap coverage for severe open fractures or closed fractures with full thickness skin necrosis, the use of interlocking plates that further minimises the need of bone grafting and subtalar arthrolysis at the time of hardware removal for fibrous overgrowth have the potential for further improvement of the outcome. The observation from several comparative studies that operative treatment leads to superior results in displaced intra-articular calcaneal fractures has been qualified in a recent prospective, randomised multicentre trial. This paper presents and the authors' experience with the demanding operative treatment of these fractures together with new developments aiming at improving the clinical results.
The "evidence" in EBM must be of high quality in order to be useful, but this is not always the case. Even the "gold standard" of evidence-based medicine, the randomised clinical trial, is bedevilled by low inclusion rates and potentially important recruitment biases. "Real world" trials often do not give the same results as these highly artificial controlled clinical studies. Meta-analysis, the next most important level of evidence in EBM, may be unreliable, sometimes giving different results to subsequent large randomised trials. There is a bias in the hypotheses tested in large clinical trials, as the costs involved are usually covered by commercially interested companies. For this reason, trials of non-patentable compounds or therapies of no commercial interest may not be performed. The process of journal review and publication is capricious, slow and may have a selection bias towards positive studies, meaning that communication channels for the "evidence" are often unsatisfactory. For many rarer conditions and situations, there is simply no "high level" evidence, such as in paediatrics and subspecialty surgery.
The atrio-bi-ventricular pacing has been used for hemodynamic improvement since 1994, and the MUSTIC trial is the first controlled study assessing this concept. It collected 67 patients with severe and stable heart failure with optimised medical therapy, with sinus rhythm and without any traditional indication for pacing. After two periods of three months with blinded randomisation and cross-over, the bi-ventricular pacing mode showed its superiority to the inactive mode concerning all study endpoints, for example with an improvement of the functional capacity of 23% assessed by the 6-minutes-walk test. Thus the MUSTIC trial opens up the way for morbidity and mortality studies.
Randomised, double-blind, placebo-controlled clinical trials are human experiments in which the process of randomisation and blinded observation greatly simplify the interpretation of the results. However, epidemiological issues when properly addressed allow the optimal preparation of the study with anticipation of factors to be included in the analysis which are independent of the randomisation process but can affect the results, for example, the effect of age, dose, time since vaccination and exposure to other diseases. Alternative methods of estimating vaccine efficacy may be necessary in some settings, and such methods may have limitations which must be acknowledged in interpretation. This paper reviews some recently published studies of vaccine efficacy for the application of epidemiological principles in design and analysis.
Angiotensin converting-enzyme inhibition (ACEI) is a widely accepted treatment during established renal diseases and beneficial effects have also been reported in IgA nephropathy (IgAN). Immunosuppression with myco-phenolate mofetil (MMF) has recently been introduced in the treatment of immune-mediated renal diseases showing promising results. Preliminary clinical reports are also suggestive that MMF is effective in severe forms of IgAN. We propose a randomised prospective trial aimed to compare long-term renal survival of early IgAN in the course of ACEI therapy with or without MMF immunosuppression.