Phil Shackley

The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial

BACKGROUND Carbamazepine is widely accepted as a drug of first choice for patients with partial onset seizures. Several newer drugs possess efficacy against these seizure types but previous randomised controlled trials have failed to inform a choice between these drugs. We aimed to assess efficacy with regards to longer-term outcomes, quality of life, and health economic outcomes. METHODS SANAD was an unblinded randomised controlled trial in hospital-based outpatient clinics in the UK. Arm A recruited 1721 patients for whom carbamazepine was deemed to be standard treatment, and they were randomly assigned to receive carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate. Primary outcomes were time to treatment failure, and time to 12-months remission, and assessment was by both intention to treat and per protocol. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN38354748. FINDINGS For time to treatment failure, lamotrigine was significantly better than carbamazepine (hazard ratio [HR] 0.78 [95% CI 0.63-0.97]), gabapentin (0.65 [0.52-0.80]), and topiramate (0.64 [0.52-0.79]), and had a non-significant advantage compared with oxcarbazepine (1.15 [0.86-1.54]). For time to 12-month remission carbamazepine was significantly better than gabapentin (0.75 [0.63-0.90]), and estimates suggest a non-significant advantage for carbamazepine against lamotrigine (0.91 [0.77-1.09]), topiramate (0.86 [0.72-1.03]), and oxcarbazepine (0.92 [0.73-1.18]). In a per-protocol analysis, at 2 and 4 years the difference (95% CI) in the proportion achieving a 12-month remission (lamotrigine-carbamazepine) is 0 (-8 to 7) and 5 (-3 to 12), suggesting non-inferiority of lamotrigine compared with carbamazepine. INTERPRETATION Lamotrigine is clinically better than carbamazepine, the standard drug treatment, for time to treatment failure outcomes and is therefore a cost-effective alternative for patients diagnosed with partial onset seizures.

The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial.

BACKGROUND Valproate is widely accepted as a drug of first choice for patients with generalised onset seizures, and its broad spectrum of efficacy means it is recommended for patients with seizures that are difficult to classify. Lamotrigine and topiramate are also thought to possess broad spectrum activity. The SANAD study aimed to compare the longer-term effects of these drugs in patients with generalised onset seizures or seizures that are difficult to classify. METHODS SANAD was an unblinded randomised controlled trial in hospital-based outpatient clinics in the UK. Arm B of the study recruited 716 patients for whom valproate was considered to be standard treatment. Patients were randomly assigned to valproate, lamotrigine, or topiramate between Jan 12, 1999, and Aug 31, 2004, and follow-up data were obtained up to Jan 13, 2006. Primary outcomes were time to treatment failure, and time to 1-year remission, and analysis was by both intention to treat and per protocol. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN38354748. FINDINGS For time to treatment failure, valproate was significantly better than topiramate (hazard ratio 1.57 [95% CI 1.19-2.08]), but there was no significant difference between valproate and lamotrigine (1.25 [0.94-1.68]). For patients with an idiopathic generalised epilepsy, valproate was significantly better than both lamotrigine (1.55 [1.07-2.24] and topiramate (1.89 [1.32-2.70]). For time to 12-month remission valproate was significantly better than lamotrigine overall (0.76 [0.62-0.94]), and for the subgroup with an idiopathic generalised epilepsy 0.68 (0.53-0.89). But there was no significant difference between valproate and topiramate in either the analysis overall or for the subgroup with an idiopathic generalised epilepsy. INTERPRETATION Valproate is better tolerated than topiramate and more efficacious than lamotrigine, and should remain the drug of first choice for many patients with generalised and unclassified epilepsies. However, because of known potential adverse effects of valproate during pregnancy, the benefits for seizure control in women of childbearing years should be considered.

Methodological issues in the application of conjoint analysis in health care

This paper adds to an increasing literature on methodological questions addressed in the application of conjoint analysis (CA) in health care. Three issues are addressed: ordering effects; internal validity; and internal consistency. The results of an application of CA in a primary care setting provide no evidence that the ordering of scenarios was important. Evidence was found of both internal validity and internal consistency. In addition, individual preferences were found to be determined by experiences, which raise potentially important questions regarding the elicitation and use of such preferences in economic evaluation.

Randomized controlled trial and cost-effectiveness analysis of silver-donating antimicrobial dressings for venous leg ulcers (VULCAN trial)

Antimicrobial silver dressings are used beneath graduated compression in the treatment of venous ulceration. There is little information on whether their use is effective. This was a prospective randomized trial and cost‐effectiveness analysis of silver‐donating versus non‐silver low‐adherence dressings in the treatment of venous leg ulcers.

Botulinum Toxin for the Upper Limb After Stroke (BoTULS) Trial Effect on Impairment, Activity Limitation, and Pain

Background and Purpose— Botulinum toxin is increasingly used to treat upper limb spasticity due to stroke, but its impact on arm function is unclear. We evaluated botulinum toxin for upper limb spasticity and function poststroke. Methods— Three hundred thirty-three patients with stroke with upper limb spasticity and reduced arm function participated in a multicenter randomized controlled trial. The intervention group received botulinum toxin type A injection(s) plus a 4-week therapy program. The control group received the therapy program alone. Repeat injection(s) and therapy were available at 3, 6, and 9 months. The primary outcome was upper limb function at 1 month (Action Research Arm Test). Secondary outcomes included measures of impairment, activity limitation, and pain at 1, 3, and 12 months. Outcome assessments were blinded and analysis was by intention to treat. Results— There was no significant difference in achievement of improved arm function (Action Research Arm Test) at 1 month (intervention group: 42 of 167 [25.1%], control group 30 of 154 [19.5%]; P=0.232). Significant differences in favor of the intervention group were seen in muscle tone at 1 month; upper limb strength at 3 months; basic arm functional tasks (hand hygiene, facilitation of dressing) at 1, 3, and 12 months; and pain at 12 months. Conclusions— Botulinum toxin type A is unlikely to be useful for improving active upper limb function (eg, reaching and grasping) in the majority of patients with spasticity after stroke, but it may improve basic upper limb tasks (hand hygiene, facilitation of dressing) and pain.

Do ordering effects matter in willingness-to-pay studies of health care?

Willingness-to-pay studies are increasingly being used in the evaluation of health care programmes. However, there are methodological issues that need to be resolved before the potential of willingness-to-pay can be fully exploited as a tool for the economic evaluation of health care programmes. Of particular methodological interest are the consequences of varying the order in which willingness-to-pay questions are presented to respondents in contingent valuation studies. This paper examines the possibility of ordering effects in willingness-to-pay studies in health care. That is, when asking willingness-to-pay questions about three health care programmes within a single survey, does the order the programmes are presented have an impact on the reported willingness-to-pay? Ordering effects are observed in the ranking of the programmes, in the proportion of zero values reported and in the WTP for one of the programmes. The results suggest that the best explanation for the ordering effects is one of fading glow, whereby the first programme in any sequence captures much of the utility associated with giving.

A prospective randomised controlled trial and economic modelling of antimicrobial silver dressings versus non-adherent control dressings for venous leg ulcers: the VULCAN trial.

OBJECTIVE To examine the effectiveness and cost-effectiveness of antimicrobial silver-donating dressings for venous leg ulcers compared with simple non-adherent (also known as low-adherent) dressings. DESIGN A pragmatic, prospective randomised controlled trial (RCT) and cost-effectiveness analysis of silver-donating versus low-adherent dressings in the treatment of venous leg ulcers. A non-randomised observational group was also recruited. SETTING Primary and secondary care services in the north and south of England (Sheffield and Exeter). PARTICIPANTS Consenting patients with active ulceration of the lower leg that had been present for a period of greater than 6 weeks. INTERVENTIONS Patients were randomised to receive either a silver-donating or non-silver low-adherent dressing applied beneath compression bandages or hosiery. The choice of dressing within these groups was left to clinician preference. Evaluation was by clinical assessment, supplemented by evaluation of quality of life and cost-effectiveness. MAIN OUTCOME MEASURES The primary outcome measure was complete ulcer healing at 12 weeks in the index limb. Secondary measures were costs and quality-adjusted life-years (QALYs), cost-effectiveness, time to healing, and recurrence rate at 6 months and 1 year. RESULTS In total, 304 participants were recruited to the clinical trial: 213 to the RCT and 91 to the observational arm. Within the RCT 107 were randomised to antimicrobial dressings and 106 to the control dressings. There were no significant differences (p > 0.05) between the two groups for the primary outcome measure of proportion of ulcers healed at 12 weeks (59.6% for silver and 56.7% for control dressings). The overall median time to healing was also not significantly different between the two groups (p = 0.408). A total of 24 patients had recurrent ulcers within 1 year; the recurrence rates of 11.6% (n = 11) for the antimicrobial and 14.4% (n = 13) for the control dressings were not significant. Mean utility valuations for both the EuroQol 5 dimensions (EQ-5D) quality of life questionnaire and Short Form 6 dimensions (SF-6D) utility index showed no differences for either group at 1, 3, 6 or 12 months. Compared with the control group, the antimicrobial group had an incremental cost of 97.85 pounds and an incremental QALY gain of 0.0002, giving an incremental cost-effectiveness ratio for the antimicrobial dressings of 489,250 pounds. Cost-effectiveness modelling of the results of the RCT showed that antimicrobial dressings were not cost-effective. CONCLUSIONS No significant differences in either primary or secondary end points were found between the use of antimicrobial silver-donating dressings and the control group of low-adherent dressings. Modelling showed that antimicrobial silver dressings were not cost-effective. TRIAL REGISTRATION Current Controlled Trials ISRCTN72485131.

What is the Role of the Consumer in Health Care

Recent government policy in the UK National Health Service (NHS) has carried with it an implicit assumption that greater consumer involvement in health care is both desirable and beneficial. This may be the case in theory, but in practice there are substantial barriers to consumers becoming more involved in health care. Following a consideration of the role the government envisages for consumers in the NHS, the extent to which it is possible for consumers to fulfil this role, and more fundamentally whether they want to fulfil it, are discussed. It is argued that because of the extent of the breakdown of consumer sovereignty in health care, the doctor–patient (agency) relationship assumes a particularly important role. The theory of agency and its application to health care is then discussed and a number of important issues highlighted. A review of the literature on the extent of consumer involvement in health care precedes the conclusion in which the key issues raised in the article are brought together.

Evaluation of the cost-effectiveness of root canal treatment using conventional approaches versus replacement with an implant.

AIM To evaluate the cost-effectiveness of root canal treatment for a maxillary incisor tooth with a pulp infection, in comparison with extraction and replacement with a bridge, denture or implant supported restoration. METHODOLOGY A Markov model was built to simulate the lifetime path of restorations placed on the maxillary incisor following the initial treatment decision. It was assumed that the goal of treatment was the preservation of a fixed platform support for a crown without involving the adjacent teeth. Consequently, the model estimates the lifetime costs and the total longevity of tooth and implant supported crowns at the maxillary incisor site. The model considers the initial treatment decisions, and the various subsequent treatment decisions that might be taken if initial restorations fail. RESULTS Root canal treatment extended the life of the tooth at an additional cost of pound5-8 per year of tooth life. Provision of orthograde re-treatment, if the root canal treatment fails returns further extension of the expected life of the tooth at a cost of pound12-15 per year. Surgical re-treatment is not cost-effective; it is cheaper, per year, to extend the life of the crown by replacement with a single implant restoration if orthograde endodontic treatment fails. CONCLUSION Modelling the available clinical and cost data indicates that, root canal treatment is highly cost-effective as a first line intervention. Orthograde re-treatment is also cost-effective, if a root treatment subsequently fails, but surgical re-treatment is not. Implants may have a role as a third line intervention if re-treatment fails.

The impact of information on non-health attributes on willingness to pay for multiple health care programmes

Despite the acceptance that health gain is the most important attribute of health care, other aspects of health care may affect utility. The aim of this paper is to report an experiment to test the impact of providing different levels of information in the context of the EuroWill study, a joint contingent valuation (CV) of multiple health programmes. Three hundred and three respondents were simultaneously asked for their willingness-to-pay (WTP) for three health care programmes: more heart operations, a new breast cancer treatment and a helicopter ambulance service. To test for the impact of variation in information, three versions of one of the programmes (heart) were provided. Results show that WTP for all three programmes tended to be significantly higher for respondents who were provided additional positive information about the heart programme. Our results show that CV of health care programmes, which only take into account medical outcomes, may lead to the value of such programmes not being adequately estimated, and that the impact of information may even be more decisive in the context of joint evaluation of multiple, rather than single, programmes.