Rapid development of a de novo intracranial aneurysm following carotid occlusion.

Carotid occlusion is a therapeutic intervention for specific intracranial vascular conditions, including giant, traumatic and intracavernous aneurysms. The long-term complications include de novo aneurysm formation at a distant site due to hemodynamic changes in the circle of Willis. The time frame for de novo aneurysm formation has been described in years with a mean of 9.6 years. There is no formalised radiological surveillance program following carotid occlusion. We describe the rapid development of a de novo posterior communicating artery aneurysm following contralateral carotid occlusion for a traumatic intracavernous aneurysm and suggest the need for a formalised radiological follow-up program following carotid occlusion.

Six minute walk distance is greater when performed in a group than alone.

OBJECTIVE: To investigate whether the distance covered in the six minute walk test was affected by walking with a group of others in comparison with performing the test alone. METHODS: Eight healthy men (mean (SD) age 21.0 (0.9) years) and eight healthy women (mean (SD) age 20.8 (2.0) years) performed in random order two six minute walk tests either alone or in a group of four on two separate occasions one week apart. RESULTS: Distance covered increased significantly from a mean of 653 (61) m in the individual male tests to 735 (79) m in the male group tests (p<0.05), and 616 (75) m in the individual female tests to 701 (54) m in the female group tests (p<0.01). The men increased the distance walked in six minutes by 12.5% and the women by 13.7% when they performed the test as a group. CONCLUSION: Performing the six minute walk test in a group facilitates its execution.

Effect of clinical risk stratification on cost-effectiveness of the implantable cardioverter-defibrillator: the Canadian implantable defibrillator study.

BACKGROUND: Three randomized clinical trials showed that implantable cardioverter-defibrillators (ICDs) reduce the risk of death in survivors of ventricular tachyarrhythmias, but the cost per year of life gained is high. A substudy of the Canadian Implantable Defibrillator Study (CIDS) showed that 3 clinical factors, age >/=70 years, left ventricular ejection fraction /=2 of 3 risk factors. Incremental cost-effectiveness of ICD therapy was computed as the ratio of the difference in mean cost to the difference in life expectancy between the 2 groups. Over 6.3 years, the mean cost per patient in the ICD group was Canadian (C) $87 715 versus $38 600 in the amiodarone group (C$1 approximately US$0.67). Life expectancy for the ICD group was 4.58 years versus 4.35 years for amiodarone, for an incremental cost-effectiveness of ICD therapy of C$213 543 per life-year gained. The cost per life-year gained in patients with >/=2 factors was C$65 195, compared with C$916 659 with <2 risk factors. CONCLUSIONS: The cost-effectiveness of ICD therapy varies by patient risk factor status. The use of ICD therapy in patients who have >/=2 risk factors of age >/=70 years, left ventricular ejection fraction

Cost-effectiveness of the implantable cardioverter-defibrillator: results from the Canadian Implantable Defibrillator Study (CIDS).

BACKGROUND: In the Canadian Implantable Defibrillator Study (CIDS), we assessed the cost-effectiveness of the implantable cardioverter-defibrillator (ICD) in reducing the risk of death in survivors of previous ventricular tachycardia (VT) or fibrillation (VF). METHODS AND RESULTS: Healthcare resource use was collected prospectively on the first 430 patients enrolled in CIDS (n=212 ICD, n=218 amiodarone). Mean cost per patient, adjusted for censoring, was computed for each group based on initial therapy assignment. Incremental cost-effectiveness of ICD therapy was computed as the ratio of the difference in cost (ICD minus amiodarone) to the difference in life expectancy (both discounted at 3% per year). All costs are in 1999 Canadian dollars (C$1 approximately US$0.65). Over 6.3 years, mean cost per patient in the ICD group was C$87 715 versus C$38 600 in the amiodarone group (difference C$49 115; 95% CI C$25 502 to C$69 508). Life expectancy for the ICD group was 4.58 years versus 4.35 years for amiodarone (difference 0.23, 95% CI -0.09 to 0.55), for incremental cost-effectiveness of ICD therapy of C$213 543 per life-year gained. ICD benefit was greater in patients with low left ventricular ejection fraction (<35%), and cost-effectiveness in this group was more attractive (C$108 484). Alternative extrapolations of survival benefit and costs to 12 years indicated cost-effectiveness in the range of C$100 000 to C$150 000 per life-year gained. CONCLUSIONS: At C$213 543, the value for the money offered by ICD therapy is not attractive by currently accepted standards. Further research is warranted to identify the indications and patient subgroups for whom ICDs are a cost-effective use of resources.

Optimizing the electrical stimulation of retinal ganglion cells.

Epiretinal prostheses aim to restore visual perception in the blind through electrical stimulation of surviving retinal ganglion cells (RGCs). While the effects of several waveform parameters (e.g., phase duration) on stimulation efficacy have been described, their relative influence remains unclear. Further, morphological differences between RGC classes represent a key source of variability that has not been accounted for in previous studies. Here we investigate the effect of electrical stimulus waveform parameters on activation of an anatomically homogenous RGC population and describe a technique for identifying optimal stimulus parameters to minimize the required stimulus charge. Responses of rat A2-type RGCs to a broad array of biphasic stimulation parameters, delivered via an epiretinal stimulating electrode (200 × 200 µ m) were recorded using whole-cell current clamp techniques. The data demonstrate that for rectangular charge-balanced stimuli, phase duration and polarity have the largest effect on threshold current amplitude-cells were most responsive to cathodic-first pulses of short phase duration. Waveform asymmetry and increases in interphase interval further reduced thresholds. Using optimal waveform parameters, we observed a drop in stimulus efficacy with increasing stimulation frequency. This was more pronounced for large cells. Our results demonstrate that careful choice of electrical waveform parameters can significantly improve the efficacy of electrical stimulation and the efficacy of implantable neurostimulators for the retina.

Organization of callosal linkages in visual area V2 of macaque monkey.

In visual area V2 of the macaque monkey callosal cells accumulate in finger-like bands that extend 7-8 mm from the V1/V2 border, or approximately half the width of area V2. The present study investigated whether or not callosal connections in area V2 link loci that are located at the same distance from the V1/V2 border in both hemispheres. We analyzed the patterns of retrograde labeling in V2 resulting from restricted injections of fluorescent tracers placed at different distances from the V1/V2 border in contralateral area V2. The results show that varying the distance of V2 tracer injections from the V1/V2 border led to a corresponding variation in the location of labeled callosal cells in contralateral V2. Injections into V2 placed on or close to the V1 border produced labeled cells that accumulated on or close to the V1 border in contralateral V2, whereas injections into V2 placed away from the V1 border produced labeled cells that accumulated mainly away from the V1 border. These results provide evidence that callosal fibers in V2 preferentially link loci that are located at similar distances from the V1/V2 border in both hemispheres. Relating this connectivity pattern to the topographic map of V2 suggests that callosal fibers link topographically mirror-symmetrical regions of V2, i.e., callosal fibers near the V1/V2 border interconnect areas representing visual fields on, or close to, the vertical meridian, whereas callosal connections from regions away from the V1/V2 border interconnect visuotopically mismatched visual fields that extend onto opposite hemifields.

Distribution of neurons projecting to the superior colliculus correlates with thick cytochrome oxidase stripes in macaque visual area V2.

In visual area V2 of macaque monkeys, cytochrome oxidase (CO) histochemistry reveals a pattern of alternating densely labeled thick and thin stripe compartments and lightly labeled interstripe compartments. This modular organization has been associated with functionally separate pathways in the visual system. We examined this idea further by comparing the pattern of CO stripes with the distribution of neurons in V2 that project to the superior colliculus. Visually evoked activity in the superior colliculus is known to be greatly reduced by blocking magnocellular but not parvocellular layers of the lateral geniculate nucleus (LGN). From previous evidence that V2 thick stripes are closely associated with the magnocellular LGN pathway, we predicted that a significant proportion of V2 neurons projecting to the superior colliculus would reside in the thick stripes. To test this prediction, the tangential distribution of retrogradely labeled corticotectal cells in V2 was compared with the pattern of CO stripes. We found that neurons projecting to the superior colliculus accumulated preferentially into band-like clusters that were in alignment with alternate CO dense stripes. These stripes were identified as thick stripes on the basis of their physical appearance and/or by their affinity to the monoclonal antibody Cat-301. A significantly smaller proportion of labeled cells was observed in thin and interstripe compartments. These data provide further evidence that the spatial distribution of subcortically projecting neurons can correlate with the internal modular organization of visual areas. Moreover, they support the notion that CO compartments in V2 are associated with functionally different pathways.

Solubilized HLA class I antigen enzyme-linked immunoassay to identify HLA-typing reagents.

The objective of this study was to evaluate the use of sHLA in a solid-phase EIA as a rapid and sensitive way to identify potential IgG HLA class-I-typing reagents. To evaluate the efficacy of the sHLA EIA, we used the assay to screen 259 HLA-A, -B, and -C antisera that our laboratory had procured using the standard NIH LCA. A positive result obtained by the sHLA EIA, which was defined as an EIA ratio of 3 SD above the mean of 91 anti-HLA-negative sera, revealed that 91% (79 of 87) of the A-locus-typing reagents were positive, 96% (150 of 156) of the B-locus antisera were positive, and only 75% (12 of 16) of the C-locus reagents were positive. The typing reagents that were negative by EIA (n = 18) fell into two categories. First, 38% (7 of 18) were negative by sHLA EIA, as they were IgM-typing reagents (NIH LCA reactivity ameliorated by DTT). The second group of the 11 remaining typing reagents had a mean EIA ratio of 1.0 +/- 0.246 (mean +/- 1 SD), which was significantly (P < 0.001) higher than the mean of the 91 negative controls that were used to establish the negative cutoff. The overall sensitivity of the sHLA EIA to detect HLA class-I-directed IgG was 97.2%.

Clinical economics review: cost-effectiveness of treatment alternatives for gastro-oesophageal reflux disease.

Gastro-oesophageal reflux disease is a chronic recurring disorder, which is widespread, especially in Western societies. Faced with increasing health costs and finite resources, an increasingly important part of evaluating new treatments is economic appraisal. In this paper, we review critically the published economic studies of the cost-effectiveness of treatments for gastro-oesophageal reflux disease. Proton pump inhibitors are considered the best choice for the management of grades II-IV oesophagitis and are more cost-effective than H2-receptor antagonists because of their fast healing of oesophagitis, early relief of symptoms, and prevention of recurrent oesophagitis and development of complications.

Cost-benefit analyses in the health-care literature: don't judge a study by its label.

OBJECTIVES: To assess whether health-care related economic evaluations labeled as "cost benefit analyses" (CBA) meet a contemporary definition of CBA methodology and to assess the prevalence of methods used for assigning monetary units to health outcomes. DATA SOURCES: Medline, Current Contents, and HSTAR databases and reference lists of review articles, 1991-1995. STUDY SELECTION: Economic analyses labeled as CBAs were included. Agreement on study selection was assessed. STUDY EVALUATION: CBA studies were classified according to standard definitions of economic analytical techniques. For those valuing health outcomes in monetary units (bona fide CBAs), the method of valuation was classified. RESULTS: 53% of 95 studies were reclassified as cost comparisons because health outcomes were not appraised. Among the 32% considered bona fide CBAs, the human capital approach was employed to value health states in monetary units in 70%. Contingent valuation methods were employed infrequently (13%). CONCLUSIONS: Studies labeled as CBAs in the health-care literature often offer only partial program evaluation. Decisions based only on resource costs are unlikely to improve efficiency in resource allocation. Among bona fide CBAs, the human capital approach was most commonly used to valuing health, despite its limitations. The results of health-care related CBAs should be interpreted with extreme caution.

An economic evaluation of transdermal glyceryl trinitrate in the prevention of intravenous infusion failure.

A common cause of peripheral intravenous infusion failure is due to the patient developing phlebitis or extravasation. Recent clinical trials indicate that the use of transdermal glyceryl trinitrate (GTN patches) can reduce the incidence of infusion failure and hence the costs of re-infusion. In this study we conduct an economic evaluation of this new pharmaceutical application to determine whether the use of such patches results in hospital resource cost savings. Time-to-first infusion failure probabilities from a placebo-controlled trial are used to model the sequential failure problem as a Markov process. Using estimated staff and materials costs for first and subsequent infusions, we calculate the expected cost per infused patient to time t for treatment and control groups. Using this simple comparative cost method, results indicate that the net impact on hospital resources from patch usage is dependent upon the total required length of infusion time. Analysis of infusion time thresholds indicates that for patients requiring long-term (t greater than 50 hours) periods of infusion the use of patches is likely to generate resource savings. We conclude that to realize such resource savings clinical decisions to infuse with GTN patches should incorporate the prior probability that the total required length of infusion time exceeds 50 hours.

Are health states "timeless"? The case of the standard gamble method.

The standard gamble method, as currently recommended for use in health care program evaluation, provides an individual's preference score or "utility weight" for living in a given health state for the rest of the individual's life. Many researchers interpret this value as a time-independent or "timeless" one and order health states on a scale of zero (death) to one (full health), regardless of the time spent in the health state. This article examines whether preference scores for a severe pain health state are "timeless," or in other words whether the utility independence assumption is satisfied. Our study results suggest that for the majority of respondents, the preference scores are not independent of time.

Economic evaluation of donepezil for the treatment of Alzheimer's disease in Canada.

BACKGROUND: Donepezil is a new drug recently approved in the United States and Canada for the treatment of Alzheimer's disease (AD). We estimated the cost-effectiveness of donepezil 5 mg daily as an adjunct to usual care in the management of persons with mild-to-moderate AD defined as a Mini-Mental Health State Examination (MMSE) score in the range 10 to 26. METHODS: Treatment effect data as MMSE change-over-baseline scores were obtained from a 30-week placebo-controlled trial of donepezil. MMSE scores beyond observed trial data were estimated using a Markov model with 10 cycles of 24 weeks based on the placebo MMSE progression observed in the trial. Data from AD subjects in the Canadian Study of Health and Aging were used to estimate costs of nursing home care, community services, medications, and caregiver time as a function of MMSE score. A clinic-based cohort study from Alberta was used to estimate the distribution of AD patients by MMSE score presenting for treatment. The effectiveness measure for the economic model was expected time (over 5 years) spent with nonsevere AD (MMSE > or = 10). RESULTS: Over 5 years of treatment, donepezil is predicted to reduce health care costs by CA$929 per patient but increase caregiver time costs by CA$48 per patient for an overall cost saving to society of CA$882 per patient. Patients not receiving donepezil are predicted to spend 2.21 years of the 5 years in nonsevere AD compared with 2.41 years for treated patients (a gain of just over 2 months). Sensitivity analysis reveals that cost savings per patient increase if more AD patients are assumed to survive to 5 years; however, if donepezil treatment continues when patients' MMSE score falls below 10, the incremental cost is higher for treatment at CA$1554 per patient. CONCLUSION: Based on the limited available data, our model predicts that the use of donepezil for mild-to-moderate AD in Canada is associated with lower 5-year costs and less time spent with severe AD when compared with the alternative of usual care with no donepezil therapy. As more reliable long-term data become available, these predictions should be confirmed and/or updated.

Cost-Effectiveness of tolterodine for patients with urge incontinence who discontinue initial therapy with oxybutynin: a Canadian perspective.

BACKGROUND: Tolterodine is a novel muscarinic receptor antagonist for the treatment of overactive bladder. OBJECTIVE: The purpose of this study was to examine the cost-effectiveness of tolterodine for patients with urge incontinence (UI) who discontinue initial therapy with oxybutynin in a Canadian setting. METHODS: We compared 2 treatment strategies for the management of adult patients with UI: (1) generic oxybutynin with no further treatment for patients who discontinue and (2) generic oxybutynin with switch to tolterodine (2 mg BID) for patients who discontinue. We developed a 1-year Markov model (4-week cycle length) with transitions between disease states of normal, mild, moderate, and severe. Transition probabilities over 12 weeks were obtained from randomized trial data, and drug discontinuation rates were obtained from Quebec prescription claims data. Outcome measures were time in "normal" health state and quality-adjusted life-years (QALYs) using EuroQol-5D utility scores from a survey of Swedish patients with overactive bladder. Costs to the health care payer and patient out-of-pocket costs (in Canadian dollars) were included. RESULTS: For patients who discontinue oxybutynin, the use of tolterodine is associated with approximately 6 months per year in a normal health or mild disease state, compared with approximately 3 months for those who do not receive further drug therapy after discontinuation. Tolterodine use resulted in an annual additional cost per patient of Can $163. The incremental cost per QALY was Can $9,982 and appeared to be robust to alternative model parameter assumptions. CONCLUSION: Use of tolterodine in patients with UI who discontinue initial therapy with generic oxybutynin lies within currently accepted benchmarks for cost-effectiveness.

The retinal input to calbindin-D28k-defined subdivisions in macaque inferior pulvinar.

Several studies have provided evidence for direct retinal input to the pulvinar of macaques monkeys, but there is no general agreement regarding the extent of this projection. Moreover, it is not known how retinal input correlates with chemoarchitectonic subdivisions recently recognized within the large, classical divisions of the pulvinar. The potential implications of this correlation have become more evident after reports that chemoarchitectonic subdivisions of the inferior pulvinar (PI) have specific patterns of connections with cortical visual areas. We have therefore re-examined the retino-PI projection using intraocular injections of horseradish peroxides, and correlated it with pulvinar subdivisions revealed using an antibody for calbindin-D28k. Retinal projections were found preferentially within the medial subdivision of the PI, with some involvement of the posterior and central calbindin-D28k defined subdivisions.

Willingness to accept risk in the treatment of rheumatic disease.

STUDY OBJECTIVE: The aim was to assess patients willingness to accept mortal risk in the drug treatment of chronic rheumatic disease. DESIGN: A non-random sample of consecutive patients were interviewed with a standardised survey instrument. SETTING: The study took place in the Royal National Hospital for Rheumatic Diseases, Bath, UK. PATIENTS: 100 consecutive in- and out-patients aged 65 or less were interviewed, 50 with rheumatoid arthritis and 50 with ankylosing spondylitis. Mean age was 48 years with mean disease duration of 14 years. The rheumatoid arthritis group was mainly female (84%), v 26% in the ankylosing spondylitis group. MEASUREMENTS AND MAIN RESULTS: Risk preferences were elicited using the method of standard gamble in the context of a hypothetical new drug. Patients indicated the maximum percentage probability of mortality they regarded as acceptable to achieve four different levels of benefit: total cure (20.7%), relief of pain (16.9%), relief of stiffness (13.1%), return to normal functioning (14.5%). Rheumatoid arthritis patients displayed a higher (p less than 0.05) willingness to accept risk than ankylosing spondylitis patients for all gambles except relief of stiffness. Analysis of variance indicated that willingness to accept risk decreases with the duration of disease and increases with reductions in self assessed health status. CONCLUSIONS: Evaluative methods such as standard gamble can elicit useful risk-benefit preference data from patients to assist those who manage clinical risks.

The Nottingham Health Profile as a measure of quality of life following combined heart and lung transplantation.

This paper reports on the use of the Nottingham Health Profile as a measure of patient quality of life before and after combined heart and lung transplantation at Harefield Hospital. A total of 125 profiles from 48 patients were analysed. In both section 1 and section 2 of the profile, large and statistically significant (p less than 0.05) improvements in quality of life were associated with transplantation. The profile proved easy to use either as part of an interview during assessment for transplantation or as a postal follow-up postoperatively.

Statistical versus quantitative significance in the socioeconomic evaluation of medicines.

This article examines the twin concepts of the statistical significance and quantitative importance of observed differences in studies comparing medicines in terms of economic parameters such as cost-effectiveness and measures of health-related quality of life (HRQOL). Central to the design and interpretation of any comparative study, such as a randomised controlled trial, is some prior judgement about the order of magnitude of a difference that would make one switch from one therapy to another. Starting with current definitions of clinically important differences we argue by analogy that the importance of differences in HRQOL require a shift of focus from the physician to the patient for preferences and judgements concerning what is important to them. Whether an intervention offers sufficient value for money (cost effectiveness or cost utility) to warrant resources being reallocated to it is a collective decision requiring the input of public preferences about the relative importance of alternative therapies and health benefits. Ultimately, the importance of the health benefits offered by a new drug is revealed by societal willingness-to-pay. This may be stated implicitly through committees using cost-effectiveness 'league tables' for decision making, or explicitly by consumer surveys of willingness-to-pay in the context of cost-benefit analysis and stemming from the theoretical foundation of welfare economics.

Cost effectiveness of the prevention and treatment of deep vein thrombosis and pulmonary embolism.

The purpose of this article is to review and critically appraise the cost-effectiveness analyses that have compared various modalities for the prevention and treatment of deep vein thrombosis (DVT) and pulmonary embolism. Studies were identified by MEDLINE search and review of bibliographies of retrieved articles. Original economic analyses for the prevention or treatment of venous thromboembolism published in the English language literature were included in the analysis. In addition to collecting clinical and economic data, the methodological quality of the studies was evaluated using predefined criteria. Separate analyses were performed for studies of the prevention, and of the treatment, of venous thromboembolism following general surgery and following total hip arthroplasty. Fourteen cost-effectiveness analyses involving thromboembolic prophylaxis following total hip arthroplasty and 7 following general surgery met the eligibility criteria for this analysis. Each of the total hip arthroplasty studies containing a 'no intervention arm' determined that effective forms of prophylaxis not only reduced the rates of venous thromboembolic complications, but were less costly than a strategy of not providing venous thromboembolic prophylaxis. Six of 7 studies found low-molecular-weight (LMW) heparin to be more effective, and 4 of 7 found it to be less costly, than either unfractionated heparin or warfarin for the prevention of venous thrombosis following total hip arthroplasty. Following general surgical procedures, 6 of 7 studies found prophylaxis to be both more effective and less costly than no prophylaxis. Two studies also concluded that LMW heparin was more effective and less costly than unfractionated heparin for the prevention of DVT after general surgery. In general, the studies included in this overview were of high methodological quality with 11 of 15 studies fulfilling 4 or more of the 6 criteria for sound cost-effectiveness analyses. Effective venous thromboembolic prophylaxis results in fewer complications and is less costly than no prophylaxis following general surgery and total hip arthroplasty. LMW heparin was reported to be more efficacious and cost effective than unfractionated heparin following general surgery, and unfractionated heparin and warfarin following total hip arthroplasty. However, these findings must be regarded with caution in view of recent clinical trials and a meta-analysis reporting that the efficacy of LMW heparin and unfractionated heparin are similar following general surgery, and the efficacy of LMW heparin and warfarin are similar following total hip arthroplasty. Conclusions about the most cost-effective treatment for DVT await the publication of cost analyses from clinical trials comparing outpatient subcutaneous LMW heparin with inpatient therapy with intravenous unfractionated heparin.

Assessing the economic value of a new antidepressant. A willingness-to-pay approach.

Using the method of willingness to pay (WTP), this study assesses the value of a new antidepressant, moclobemide, relative to that of tricyclic antidepressants (TCAs), which have equivalent efficacy but less favourable adverse effect profiles. From a published meta-analysis of controlled clinical trials, we identified 7 adverse effects, the risk of which differed significantly between moclobemide and TCAs. We obtained risk reduction data and descriptions of adverse effects from interviews with 95 individuals who had mild to moderate depression and who had been taking one or more TCAs in the previous year. Using a visual analogue scale, respondents ranked and rated each adverse effect. Participants were then asked (using the scenario of additional out-of-pocket drug payment) to quantify the maximum amount that they would pay for a new drug that reduced each adverse effect by the specified probability. Blurred vision and tremor were ranked and rated as the most bothersome adverse effects, with dry mouth being the least bothersome. On average, respondents were willing to pay an additional $Can22 per month [95% confidence interval (CI) 16-28] to reduce the risk of blurred vision from 10 to 5%. The lowest WTP value was for reducing the risk of dry mouth from 40 to 15%, at $Can11 per month (95% CI 8-15). Although not measured directly, we derived 2 estimates of WTP for multiple (i.e. all 7) risk reductions. We obtained upper and lower WTP limits of $Can118 and $Can36 per month, respectively, depending upon aggregation assumptions. Compared with the TCAs amitriptyline and imipramine, the net cost of moclobemide is greater, but the overall net benefit (WTP minus cost) is ambiguous given uncertainty about WTP aggregation over adverse effects. However, compared with the TCAs desipramine and clomipramine, the net benefit of moclobemide is unambiguously positive. We conclude that the WTP approach is a potentially valuable tool that requires more development for use in healthcare economic evaluation.