TRIALS update, may 22
Written by admin on May 25th, 2008 | Filed under: clinical practice UPDATE
Competing Risk and Heterogeneity of Treatment Effect in Clinical Trials
It has been demonstrated that patients enrolled in clinical trials frequently have a large degree of variation in their baseline risk for the outcome of interest. Thus, some have suggested that clinical trial results should routinely be stratified by outcome risk using risk models, since the summary results may otherwise be misleading. However, variation in competing risk is another dimension of risk heterogeneity that may also underlie treatment effect heterogeneity. Understanding the effects of competing risk heterogeneity may be especially important for pragmatic comparative effectiveness trials, which seek to include traditionally excluded patients, such as the elderly or complex patients with multiple comorbidities. Indeed, the observed effect of an intervention is dependent on the ratio of outcome risk to competing risk, and these risks–which may or may not be correlated–may vary considerably in patients enrolled in a trial. Further, the effects of competing risk on treatment effect heterogeneity can be amplified by even a small degree of treatment related harm. Stratification of trial results along both the competing and the outcome risk dimensions may be necessary if pragmatic comparative effectiveness trials are to provide the clinically useful information their advocates intend.
GENetic and clinical Predictors Of treatment response in Depression: the GenPod randomised trial protocol
Background: The most effective pharmacological treatments for depression inhibit the transporters that reuptake serotonin (Selective Serotonin Reuptake Inhibitors - SSRIs) and noradrenaline (Noradrenaline Reuptake Inhibitors - NaRIs) into the presynaptic terminal. There is evidence to suggest that noradrenaline and serotonin enhancing drugs work through separate mechanisms to produce their clinical antidepressant action. Although most of the current evidence suggests there is little difference in overall efficacy between SSRIs and NaRIs, there are patients who respond to one class of compounds and not another. This suggests that treatment response could be predicted by genetic and/or clinical characteristics. Firstly, this study aims to investigate the influence of a polymorphism (SLC6A4) in the 5HT transporter in altering response to SSRI medication. Secondly, the study will investigate whether those with more severe depression have a better response to NaRIs than SSRIs. Methods/design: The GenPod trial is a multi-centre randomised controlled trial. GPs refer patients aged between 18-74 years presenting with a new episode of depression, who do not have any medical contraindications to antidepressant medication and who have no history of psychosis or alcohol/substance abuse. Patients are interviewed to ascertain their suitability for the study. Eligible participants (with a primary diagnosis of depression according to ICD10 criteria and a Beck Depression Inventory (BDI) score >14) are randomised to receive one of two antidepressant treatments, either the SSRI Citalopram or the NaRI Reboxetine, stratified according to severity. Follow-up assessments take place at 2, 6 and 12 weeks following randomisation. Primary outcome is measured at 6 weeks by the BDI. Outcomes will be analysed on an intention-to-treat basis and will use multiple regression models to compare treatments.DiscussionThe results of the trial will provide information about targeting antidepressant treatment for individual patients; in turn this may increase prescribing efficacy, thereby speeding recovery and reducing the cost to the NHS. It will also help to understand the different roles that noradrenaline and serotonin might play in the biology of depression. The trial is expected to report in the Autumn of 2008.
GALA: an international multicentre randomised trial comparing general anaesthesia versus local anaesthesia for carotid surgery
Background: Patients who have severe narrowing at or near the origin of the internal carotid artery as a result of atherosclerosis have a high risk of ischaemic stroke ipsilateral to the arterial lesion. Previous trials have shown that carotid endarterectomy improves long-term outcomes, particularly when performed soon after a prior transient ischaemic attack or mild ischaemic stroke. However, complications may occur during or soon after surgery, the most serious of which is stroke, which can be fatal. It has been suggested that performing the operation under local anaesthesia, rather than general anaesthesia, may be safer. Therefore, a prospective, randomised trial of local versus general anaesthesia for carotid endarterectomy was proposed to determine whether type of anaesthesia influences peri-operative morbidity and mortality, quality of life and longer term outcome in terms of stroke-free survival. Methods/design A two-arm, parallel group, multicentre randomised controlled trial with a recruitment target of 5000 patients. For entry into the study, in the opinion of the responsible clinician, the patient requiring an endarterectomy must be suitable for either local or general anaesthesia, and have no clear indication for either type. All patients with symptomatic or asymptomatic internal carotid stenosis for whom open surgery is advised are eligible. There is no upper age limit. Exclusion criteria are: no informed consent; definite preference for local or general anaesthetic by the clinician or patient; patient unlikely to be able to co-operate with awake testing during local anaesthesia; patient requiring simultaneous bilateral carotid endarterectomy; carotid endarterectomy combined with another operation such as coronary bypass surgery; and, the patient has been randomised into the trial previously. Patients are randomised to local or general anaesthesia by the central trial office. The primary outcome is the proportion of patients alive, stroke free (including retinal infarction) and without myocardial infarction 30 days post-surgery. Secondary outcomes include the proportion of patients alive and stroke free at one year; health related quality of life at 30 days; surgical adverse events, re-operation and re-admission rates; the relative cost of the two methods of anaesthesia; length of stay and intensive and high dependency bed occupancy. Trial registration Current Controlled Trials ISRCTN00525237
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