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PubMed1985

Metoprolol in acute myocardial infarction (MIAMI). A randomised placebo-controlled international trial. The MIAMI Trial Research Group.

The effect of metoprolol on mortality and morbidity after 15 days, was compared with that of placebo in a double-blind randomised international trial (the MIAMI trial) in patients with definite or suspected acute myocardial infarction (AMI). Treatment with intravenous metoprolol (15 mg) or placebo was started shortly after the patient's arrival in hospital within 24 h of the onset of symptoms, and then oral treatment (200 mg daily) was continued for the study period (15 days). Of the 5778 patients included, 2901 were allocated to placebo and 2877 to metoprolol. Definite AMI was confirmed in 4127 patients. There were 142 deaths in the placebo group (4.9%) and 123 deaths in the metoprolol group (4.3%), a difference of 13 per cent with 95 per cent confidence limits of -8 to +33 per cent, not statistically significant (P = 0.29). Previously recorded risk indicators of mortality were analysed in retrospect. These indicated that there was a category which showed higher risk which contained approximately 30% of all randomized patients. In these, the mortality rate in the metoprolol treated group was 29% less than in the placebo group. In the remaining lower risk categories there was no difference between the treatment groups. This subset analysis must be interpreted with caution in view of the findings from other similar studies. Positive effects were observed on the incidence of definite AMI and on serum enzyme activity in patients treated early (less than 7 h). There was no significant effect on ventricular fibrillation but the number of episodes tended to be lower in the metoprolol treated patients during the later phase (6-15 days; 24 vs 54 episodes). The incidence of supraventricular tachyarrhythmias, the use of cardiac glycosides and other antiarrhythmics, and the need for pain-relieving treatment were significantly diminished by metoprolol amongst all randomised patients. Adverse events associated with metoprolol were infrequent, expected, and relatively mild.

Aged↗
PubMed1986

A controlled assessment of propranolol in the treatment of neuroleptic-induced akathisia.

Twelve patients with neuroleptic-induced akathisia were treated in a randomised, double-blind, cross-over design with propranolol and matching placebo. Propranolol caused significant decrements in both subjective and objective ratings of akathisia, but not in anxiety scores. This confirms prior findings of the efficacy of propranolol in akathisia induced by neuroleptic treatment.

Adult↗
PubMed2003

Treating obsessive compulsive disorder: a new role for infectious diseases physicians?

BACKGROUND: Patients with psychiatric disorders are often seen by infectious disease physicians. Sometimes the psychiatric condition is the primary disorder, and the physician's main task is the early identification of the disorder and referral to specialist psychiatric services. On other occasions, the psychiatric condition will need to be addressed in addition to the infectious disease, and the physician aims to treat in conjunction with a psychiatrist. It is rare for referrals to be made from psychiatry to infectious diseases physicians. METHOD: A single case study is used to describe a modification of Danger Ideation Reduction Therapy (DIRT), a novel intervention for obsessive compulsive disorder (OCD). In our modification the infectious diseases physician plays a key, collaborative role in the psychological treatment of the patient. RESULTS: Although an uncontrolled trial, results from the modified DIRT protocol are encouraging and warrant replication in a randomised controlled trial. CONCLUSIONS: A collaborative approach by the infectious diseases physician, the microbiology laboratory and the psychologist can provide a valuable means of retaining patients with OCD in treatment and in the management of this common, disabling condition.

Adult↗
PubMed2004

Swedish Council on Technology Assessment in Health Care (SBU). Chapter 12. Future need for research.

Despite the extensive consequences of sickness absence, scientific research is both surprisingly scarce and theoretically and conceptually underdeveloped. There are few longitudinal studies, and even fewer intervention studies. The medical aspects in sickness insurance are seldom addressed, effects of factors at different structural levels are not considered,and the consequences of sick leave have barely been studied. Furthermore, little is known about the employer's role and the layperson's perspectives. Gender and ethnicity factors should be considered further. The concept of work ability needs to be defined, problematized, and operationalized. However, it is not only more, but mainly it is studies of better quality that are needed, e.g. longitudinal studies, international comparative studies, and randomised controlled trials. This would require multidisciplinary research groups, long-term research environments, international commitment, opportunities for good professional development within the field, and reliable basic data, including sick-listing diagnoses.

Absenteeism↗
PubMed2000

Comparison of analytical methods for cluster randomised trials: an example from a primary care setting.

BACKGROUND: Cluster randomisation is commonly used to evaluate educational and organisational interventions in primary care. We conducted a study where 66 general practices in the North East of Scotland were randomised to receive guidelines and access to a fast-track investigation service for two common urological conditions. Patients were identified from referral letters and recruited upon referral to secondary care. Although these urological conditions are common in secondary care, the number of referrals per general practice can be small; this created a number of issues for the analysis. METHODS: Three general approaches in the analysis of cluster randomised trials; the adjustment of standard tests; analysis at cluster level; and advanced statistical techniques (random effects models and generalised estimating equations) were applied to data from the above trial. The effect of the intervention on both a continuous and a dichotomous outcome was investigated. RESULTS: Spuriously low P values were obtained when conventional tests (which do not account for clustering in the data) were applied. Cluster level analysis of the dichotomous outcome with no account for cluster size resulted in a different conclusion compared with cluster level analysis with weighting, standard tests with adjustment and advanced statistical methods. DISCUSSION: Cluster randomised trials are becoming increasingly common in primary care. Where recruitment of individual patients is generated by referral from primary to secondary care it is likely that the trial will suffer from inherent weaknesses: not all clusters randomised contribute to the analysis; there is the likelihood of single size clusters and variable cluster sizes. Our analysis indicated that the different approaches produced consistent results across continuous outcomes, but for dichotomous outcomes in the cluster level analysis, failure to weight observations would have resulted in a different conclusion.

Cluster Analysis↗
PubMed2003

Randomised trials comparing chemotherapy regimens for advanced non-small cell lung cancer: biases and evolution over time.

We systematically evaluated the evidence from randomised trials comparing various chemotherapy regimens for advanced non-small cell lung cancer. Across 254 eligible trials (42661 patients), no regimens were compared in >6 studies. Twenty-six trials (10%) found statistically significant differences in survival between the compared arms. Only five reported the randomisation mode, and four reported adequate allocation concealment; nine performed unaccounted interim analyses. Statistical significance was more common in larger (P=0.003), more recent studies (P=0.031), and trials from countries with only one published eligible study (P=0.008). Increased reported median survival was independently associated with platinum and/or taxane and combination regimens, but also with the year of publication, smaller sample size, and larger representation of non-stage IV patients and patients with a better performance status. The proportion of enrolled patients with a performance status of 2 or worse decreased significantly over time (12.9% per decade, P<0.001). Randomised evidence in this field is fragmented and subject to considerable selection biases.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Chronic tendinopathy: effectiveness of eccentric exercise.

OBJECTIVES: To determine the effectiveness of eccentric exercise (EE) programmes in the treatment of common tendinopathies. DATA SOURCES: Relevant randomised controlled trials (RCTs) were sourced using the OVID website databases: MEDLINE (1966-Jan 2006), CINAHL (1982-Jan 2006), AMED (1985-Jan 2006), EMBASE (1988-Jan 2006), and all EBM reviews--Cochrane DSR, ACP Journal Club, DARE, and CCTR (Jan 2006). The Physiotherapy Evidence Database (PEDro) was also searched using the keyword: eccentric. REVIEW METHODS: The PEDro and van Tulder scales were employed to assess methodological quality. Levels of evidence were then obtained according to predefined thresholds: Strong--consistent findings among multiple high-quality RCTs. Moderate--consistent findings among multiple low-quality RCTs and/or clinically controlled trials (CCTs) and/or one high-quality RCT. Limited--one low-quality RCT and/or CCT. Conflicting--inconsistent findings among multiple trials (RCTs and/or CCTs). No evidence-no RCTs or CCTs. RESULTS: Twenty relevant studies were sourced, 11 of which met the inclusion criteria. These included studies of Achilles tendinopathy (AT), patella tendinopathy (PT) and tendinopathy of the common wrist extensor tendon of the lateral elbow (LET). Limited levels of evidence exist to suggest that EE has a positive effect on clinical outcomes such as pain, function and patient satisfaction/return to work when compared to various control interventions such as concentric exercise (CE), stretching, splinting, frictions and ultrasound. Levels of evidence were found to be variable across the tendinopathies investigated. CONCLUSIONS: This review demonstrates the dearth of high-quality research in support of the clinical effectiveness of EE over other treatments in the management of tendinopathies. Further adequately powered studies that include appropriate randomisation procedures, standardised outcome measures and long-term follow-up are required.

Chronic Disease↗
PubMed1999

What is meant by intention to treat analysis? Survey of published randomised controlled trials.

OBJECTIVES: To assess the methodological quality of intention to treat analysis as reported in randomised controlled trials in four large medical journals. DESIGN: Survey of all reports of randomised controlled trials published in 1997 in the BMJ, Lancet, JAMA, and New England Journal of Medicine. MAIN OUTCOME MEASURES: Methods of dealing with deviations from random allocation and missing data. RESULTS: 119 (48%) of the reports mentioned intention to treat analysis. Of these, 12 excluded any patients who did not start the allocated intervention and three did not analyse all randomised subjects as allocated. Five reports explicitly stated that there were no deviations from random allocation. The remaining 99 reports seemed to analyse according to random allocation, but only 34 of these explicitly stated this. 89 (75%) trials had some missing data on the primary outcome variable. The methods used to deal with this were generally inadequate, potentially leading to a biased treatment effect. 29 (24%) trials had more than 10% of responses missing for the primary outcome, the methods of handling the missing responses were similar in this subset. CONCLUSIONS: The intention to treat approach is often inadequately described and inadequately applied. Authors should explicitly describe the handling of deviations from randomised allocation and missing responses and discuss the potential effect of any missing response. Readers should critically assess the validity of reported intention to treat analyses.

Data Collection↗
PubMed2000

Can unequal be more fair? A response to Andrew Avins.

In this paper, we respond to Andrew Avins's recent review of methods whose use he advocates in clinical trials, to make them more ethical. He recommends in particular, "unbalanced randomisation". However, we argue that, before such a recommendation can be made, it is important to establish why unequal randomisation might offer ethical advantages over equal randomisation, other things being equal. It is important to make a pragmatic distinction between trials of treatments that are already routinely available and trials of restricted treatments. We conclude that unequal randomisation could, indeed, be an ethical compromise between protecting the interests of participants and those of society.

England↗
PubMed1996

The role of radiotherapy in endometrial carcinoma.

The purpose of this work is to describe the role of radiotherapy in endometrial carcinoma. Endometrial carcinoma is a common, invasive gynaecologic malignancy that kills thousands of women throughout the world each year. This tumour is especially common in developed countries. The use of radiotherapy in these patients may consist of preoperative irradiation, irradiation alone or postoperative irradiation. The use of irradiation has changed significantly over time and the use of a specific radiotherapy modality depends on many factors, including local geographic practice patterns. The evolving use of pre and postoperative irradiation will be described. Whole abdominal irradiation and the use of irradiation alone in medically inoperable patients will be discussed. Current prospective randomised studies within the United States will be presented and discussed.

Abdomen↗
PubMed2002

Chemoradiation schedules--what radiotherapy?

UNLABELLED: Synchronous chemoradiation (SCRT) is playing an increasing role in the primary and multimodality management of cancer in many disease sites. Current schedules have been in the main empirically derived, and the addition of chemotherapy has in some cases led to a compromise in the total dose or scheduling of radiotherapy. Non-randomised phase II studies abound, but there are few well designed phase III randomised studies with comprehensive acute toxicity data and mature follow-up. In many sites long-term survival is unusual. So severe morbidity and long term functional outcome is poorly documented. It is therefore difficult to assess the real benefit of SCRT. This review uses the endpoints of local control and overall survival from randomised trials in small and non-small cell lung cancer, head and neck cancer, oesophageal cancer, rectal and anal cancer. We explore the evidence for total dose; fractionation; fraction size; the effects of a gap in treatment; and scheduling of radiation in SCRT. CONCLUSIONS: An optimal schedule of SCRT has not yet been derived. The enhanced acute toxicity and persistent high risk of local failure in many disease settings with current SCRT schedules demand that more effective and less toxic treatment strategies must be identified in the future. These schedules should be tested in randomised trials with the emphasis on meticulous reporting of acute toxicity endpoint and documenting the field sizes or proportions of critical organs within the high dose area if we are to derive the optimal therapeutic ratio.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

[Clinical studies in rehabilitation research--problems and solutions from biometrical perspective].

Methodology of clinical studies is highly sophisticated in drug research. But clinical trials are also necessary to demonstrate efficacy and safety of rehabilitation treatment. The call for evidence based medicine has also reached rehabilitation. However, in rehabilitation medicine it is much more difficult to design and conduct clinical trials with a high methodological standard. Among the reasons are: A comparable control group is necessary because spontaneous healing and unspecific measures contribute to therapeutic success, too. But what could "placebo rehabilitation" look like? The masking of therapies (blinded studies) will hardly ever be possible. Therefore, it is more difficult to achieve the same treatment and observation for the treatment and control group. Treatments in rehabilitation take longer to become effective than a drug and maybe the success will disappear after some time. Therefore, long-term trials and follow-ups are necessary. Such studies are expensive, need a strong organisation, and drop-outs are unavoidable. An appropriate outcome variable does not always exist. "Return to work" is an important, reliable and valid variable, but it delivers only one bit of information per patient. As a consequence, smaller progress in rehabilitation can only be demonstrated with large sample sizes. Outcome variables based on time enable studies with reasonable sample sizes. Sometimes it is more difficult to obtain acceptance of randomisation in rehabilitation patients than in acute patients. Some rehabilitation hospitals have only recently begun to take an interest in controlled clinical trials, hence are not so experienced. Nevertheless, controlled clinical trials delivering convincing results are possible in rehabilitation medicine as well. But biometrical consultation is necessary e.g. for study design, study conduction and evaluation. Most important points are the methodology of the study design and its practicability. Especially in these topics rehabilitation physicians and biometrician have to cooperate.

Biometry↗
PubMed2006

[Interactions between radiation and hormonal therapy in breast cancer: simultaneous or sequential treatment].

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.

Animals↗
PubMed2001

[Hormonal supplements for postmenopausal women: no evidence of protection against cardiovascular disease].

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.

Aged↗
PubMed2001

Field efficacy of a 10 per cent pyriproxyfen spot-on for the prevention of flea infestations on cats.

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.

Administration, Cutaneous↗
PubMed2005

[Chemoradiotherapy and anal canal cancer].

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.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

[Calcaneal fractures--the most frequent tarsal fractures].

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.

Arthroscopy↗
PubMed1994

Treatment of Langerhans cell histiocytosis--evolution and current approaches.

Optimal treatment of Langerhans cell histiocytosis remains problematic. The absence of controlled studies and the lack of standard diagnostic and evaluation criteria have impeded therapeutic progress even though knowledge of basic aspects of LCH have advanced. Historical analysis of outcome suggests little improvement until very recently, but marked differences in outcome according to extent of disease. Consequently, major and now successful efforts have been made to stratify LCH patients into different 'risk groups'. Recent findings suggest that combination chemotherapy for multisystem disease is beneficial and that VP-16 is a useful new agent for treating LCH, despite controversies regarding its side effects. The first randomised international treatment study, LCH-1, being conducted by the Histiocyte Society, should resolve some of these controversies. Other experimental therapies may be considered for children with severe, unresponsive LCH.

Biological Factors↗