The cost of teriflunomide in the treatment of relapsing-remitting multiple sclerosis.

AIMS: Teriflunomide, used globally to treat multiple sclerosis (MS) and widely subsidised for this indication including in Australia and New Zealand, is the main metabolite of leflunomide, an older immune-modulating drug. Leflunomide therefore represents a potential alternative therapy for MS. Teriflunomide is about 50-500 times more expensive than leflunomide, depending on prices in each jurisdiction. I wished to study how this situation arose. METHODS: Web search to obtain the publicly available minutes of eight international regulatory bodies that have approved teriflunomide for the governments of the US, Canada, Europe, England, Scotland, Australia (TGA and PBS) and New Zealand, and examination of the processes and minuted discussions concerning the metabolic, efficacy, toxicity and cost relationship between teriflunomide and leflunomide. RESULTS: The relationship between the two drugs and their relative efficacy or toxicity in MS was considered by three of eight agencies (Food and Drug Administration (FDA), European Medicines Agency (EMA) and the Canadian Agency for Drugs and Technology in Health (CADTH)). The remaining agencies accepted teriflunomide applications at face value, assessed cost-effectiveness against contemporaneous drugs used for treating MS, and did not discuss the potential role of leflunomide as a therapy for MS. No agency minuted the implications of the cost difference. CONCLUSIONS: Efficacy for leflunomide in MS is likely but unproven. The sponsor presented a case for teriflunomide that was within the established procedures for drug agencies in establishing cost-effectiveness, and agencies did not stray from their normal procedures. As a result, an opportunity to decrease the cost of treating MS has been missed. Though off-label use of leflunomide is possible, this is unlikely without a publicly-funded trial to demonstrate non-inferiority with regard to efficacy and safety.

Effect of medical thromboprophylaxis on mortality from pulmonary embolus and major bleedingy.

BACKGROUND: Several studies have failed to discover a beneficial effect of medical thromboprophylaxis on mortality. AIMS: To examine the relative influence of acute fatal pulmonary embolism (PE) and fatal major haemorrhage on overall mortality in medical patients treated with low molecular weight heparin (LMWP) for prophylaxis. METHODS: The author compared deaths from the above factors using data from a recent Cochrane Collaboration meta-analysis. Data from trials satisfying the criteria of the Cochrane analysis plus additional exclusions to avoid bias were pooled to produce point estimates of mortality from PE and major bleeds to estimate net mortality benefit. Estimates were then subject to limited sensitivity analysis based on reported epidemiological data. RESULTS: Reported PE and major bleeds were 0.44 per cent and 0.27 per cent, respectively. The corresponding case-specific mortality rates were 30.8 per cent and 12.8 per cent and the relative risk reduction (RRR) for PE was 23.2 per cent. Estimated deaths from major bleeds exceeded PE deaths avoided by a small margin (3/100,000 patients given prophylaxis). This excess increased to 30/100,000 when more plausible literature values for PE case fatality rates were applied. CONCLUSION: Medical thromboprophylaxis has a finely balanced effect on mortality but may increase it. Such an effect would explain the failure to discover a mortality benefit from medical thromboprophylaxis. Further work, including a formal meta-analysis and additional clinical studies, is required to confirm this picture.

Potential cost to Western Australia of proposed patient co-payments according to healthcare organisational structure: A preliminary analysis.

BACKGROUND: The Australian federal government has proposed an AUD $7 patient co-payment for a general practitioner (GP) consultation. One effect of the co-payment may be that patients will seek assistance at public hospital emergency departments (EDs), where currently there is no user charge. AIMS: We studied the possible financial impact of patient diversion on the Western Australia (WA) health budget. METHOD: We constructed a spreadsheet model of changes in annual cash flows including the co-payment, GP fees for service, and rates of diversion to emergency departments with additional marginal costs for ED attendance. RESULTS: Changes in WA cash flows are the aggregate of marginal ED costs of treating diverted patients and added expenditure in fees paid to rural doctors who also man local emergency centres. The estimated costs to WA are AUD $6.3 million, $35.9 million and $87.4 million at 1, 5, and 10 per cent diversion, respectively. Commonwealth receipts increase and expenditure on Medicare benefits declines. CONCLUSION: A diversion of patients from GP surgeries to ED in WA caused by the co-payment will result in increased costs to the state, which may be substantial, and will reduce net costs to the Commonwealth.

Current state of medical thromboprophylaxis in Australia.

BACKGROUND: Australia has two published national guidelines for general medical thromboprophylaxis (MT), but the two differ in detail and the basis for patient selection remains uncertain. Several aspects of current guidelines are controversial, as is the proposed design of a dedicated prescribing box in the National Inpatient Medication Chart. AIM: To discuss and comment on the current standing of medical thromboprophylaxis in Australia. METHOD: We have marshalled literature known to us from our previous published research, and have applied this knowledge to discuss shortcomings, which, in our opinion, exist in current medical thromboprophylaxis practice, and to suggest solutions. CONCLUSION: Australian guidelines are flawed because they are based on unsuitable evidence (incidence of subclinical thrombotic disease) and define eligibility broadly, such that about 80 per cent of patients are considered eligible. They urge that prescribers should "consider" prophylaxis without supplying an adequate basis for doing so. They do not provide grounds for assessing the balance between hazard (in the form of major bleeds) and benefit (thrombotic events avoided). Other clinical factors promoting unnecessary use of medical thromboprophylaxis include the use of age as a risk factor and proposed inclusion of a new DVT prophylaxis section in the National Inpatient Medication Chart (NIMC), which implicitly discourages non-prescription of prophylaxis.

Measures of risk and their relationship to the relative size of a high-risk group: application to medical thromboprophylaxis.

BACKGROUND: The aim of this study was to establish the meaning of "high-risk" when the subgroup so defined by risk factor analysis is a substantial proportion of the population. This is clinically important when patients, deemed to be at high risk as a result of risk factor analysis, become eligible for a clinical intervention to decrease the risk, especially if the intervention has adverse effects. One example in clinical practice is the assessment of eligibility for medical thromboprophylaxis. METHODS: Equations were derived relating risk and the proportion of the population (F) deemed to be at high risk on risk factor analysis, based on the formula for weighted average. The equations were validated for the population of medical inpatients at high- or low-risk of thromobembolic events using a spreadsheet model of thrombosis risk containing known risk factors for venous thromboembolism in this population. RESULTS: The validated equations define an upper limit of absolute and incremental risk (risk relative to the whole population) in the high-risk group that is a function of or equal to 1/F, respectively. The added risk in the high-risk group declines to zero as F tends to 1, because it must be balanced by the diminishing risk in the progressively smaller low-risk group while maintaining the population average. CONCLUSION: The results of this study have implications for the validity of the published eligibility criteria for medical thromboprophylaxis.

Eligibility for medical thromboprophylaxis based on risk-factor weights, and clinical thrombotic event rates.

OBJECTIVES: To measure eligibility for medical thromboprophylaxis using two Australasian guidelines - the Australia and New Zealand Working Party Guidelines [WPG] and the National Health and Medical Research Council Guidelines [NHMRCG]) - and proposed new guidelines based on risk-factor weights; and to measure the incidence of clinical venous thromboembolism (VTE) events in medical patients ("ensuing VTE"). DESIGN, SETTING AND PATIENTS: Prospective case-note audit in an acute medical ward of Southland Hospital, a regional hospital in Invercargill, New Zealand, among all 595 patients who were discharged consecutively from 21 November 2010 to 7 March 2011. Of these, 245 were excluded on clinical grounds or because they were under the care of the authors. MAIN OUTCOME MEASURES: The primary outcome was eligibility for prophylaxis under each guideline. Secondary outcomes included incidence of ensuing VTEs, use of thromboprophylaxis, drug acquisition costs with each guideline, and bedside practicability of a guideline based on risk-factor weights. RESULTS: Nineteen per cent of patients were eligible under the new guidelines, compared with 80%, 88% and 36% under the WPG and two interpetations of the NHMRCG, respectively. One patient had an ensuing VTE. The new guideline had lower drug acquisition costs and was suitable for bedside use. CONCLUSIONS: Clinical VTE events are rare in medical patients, and medical VTE thromboprophylaxis needs to be more focused. The new guideline has performance characteristics th@satisfy this need.

The Cockroft and Gault formula for estimation of creatinine clearance: a friendly deconstruction.

AIMS: To review the derivation of the Cockroft and Gault formula for estimating creatinine clearance from serum creatinine in a historical context. METHOD: The derivation described by Cockroft and Gault was reviewed, and an alternative formula was sought using the data reported in the paper. RESULTS: Cockroft and Gault used 24 hour urine creatinine data expressed as mg/kg body weight and mathematical manipulation of a linear regression equation which introduced body weight as an independent variable into the formula. This involved a circular logic and may have been mathematically invalid. A more logical equation not containing body weight was derived from the data. CONCLUSION: The Cockcroft and Gault formula has been validated by long usage but the derivation appears logically insecure. Nevertheless, its role in estimating renal function at the bedside is established.

Genesis of medical thromboprophylaxis guidelines in Australia: a need for transparency and standardisation in guideline development.

Clinical guidelines are recommendations based on systematic identification and synthesis of the best available scientific evidence. The National Health and Medical Research Council (NHMRC) has published standards for guideline development. According to the NHMRC standards, guideline development must be a transparent and independent process, with full disclosure of any potential competing interests. Australian guidelines for prevention of venous thromboembolism have been published by an autonomous group. Several features of the processes used to produce and distribute these guidelines, such as pharmaceutical sponsorship, do not meet NHMRC endorsement standards. The guidelines may overstate the need for thrombo-prophylaxis in medical patients, and thus expose some patients to an unnecessary risk of bleeding complications. Despite this, these guidelines have been taken up avidly by national and state bodies responsible for safety and quality in health care, and mandated national application has been proposed.

Rational thromboprophylaxis in medical inpatients: not quite there yet.

Routine thromboprophylaxis in hospitalised medical patients is based on trials that predominantly use asymptomatic deep vein thrombosis (DVT) as the endpoint. As asymptomatic DVT is 10-30-fold more common than symptomatic DVT, this exaggerates estimates of benefit and cost-effectiveness. Based on symptomatic disease, the number needed to treat per venous thromboembolism (VTE) prevented is high (150-1600), and the true cost-effectiveness of thromboprophylaxis for symptomatic event reduction is uncertain. The incidence of major bleeding among patients receiving prophylaxis is at least equal to the reduction in clinical VTE. Routine thromboprophylaxis in hospitalised medical patients is not warranted, and better patient selection is needed.

The national inpatient medication chart: critical audit of design and performance at a tertiary hospital.

OBJECTIVE: To compare the national inpatient medication chart (NIMC) with the chart previously used at Royal Perth Hospital (RPH) in Western Australia, and with charts used at 13 other hospitals across Australia; and to audit NIMC performance in practice and to assess its design characteristics. DESIGN: Audit of patient prescribing documents extended to include a comparison with aggregated pilot study data and the previous RPH chart. Assessment of design features by inspection, based on their likely effect on medication safety. SETTING: A tertiary public hospital. MAIN OUTCOME MEASURES: Compliance with the requirements of chart fields, measured as the percentage of correct entries according to predetermined criteria as required by the WA Office of Safety and Quality in Health Care. RESULTS: Average compliance was 56% (95% CI, 43%-67%). Differences in compliance after introduction of the NIMC were variable and only one was classified as "major". The number of charts required per admission increased from 3.1 for the previous RPH chart to 6.3 for the NIMC, and chart replacement was required after 2.9 days for the NIMC compared with 5.5 days for the previous RPH chart. Of seven advantages of the NIMC claimed by the WA Director General of Health in a letter to doctors, five (71%) were not confirmed in practice. Ten notable design features of the NIMC with a potential adverse influence on medication safety were identified. CONCLUSIONS: The NIMC contains adverse design features and is inferior to the medication chart previously in use at RPH. The purported advantages of introducing a national standard chart were not experienced at RPH.

Cost effectiveness of trastuzumab in the adjuvant treatment of early breast cancer: a lifetime model.

BACKGROUND: Recent randomised trials have demonstrated a statistically significant effect of trastuzumab on disease-free survival when used as adjuvant therapy for human epidermal growth factor receptor 2 protein (HER2)-positive resectable early stage breast cancer, with a treatment course lasting either 9 or 52 weeks. However, the cost effectiveness of adjuvant trastuzumab with respect to mortality remains uncertain, especially in an Australian setting. OBJECTIVE: To estimate the cost effectiveness of trastuzumab in Australia, in a cohort of 50-year-old patients with HER2-positive breast cancer over a lifetime, using (i) disease-free survival and cardiotoxicity data from recent randomised trials; (ii) information on long-term survival of patients with treated primary breast cancer; and (iii) costs of treating local and distant relapses and disease from causes other than breast cancer. METHODS: A Markov model consisting of four health states (remission, loco-regional recurrence, metastatic disease and death) was developed. Transition probabilities corresponded to patterns of relapse and metastases seen in recent trials. The model was run until age 100 years to allow calculation of average survival. Outcome measures were life-years and QALYs (calculated using utility weights reported in the literature). The model was calibrated to reflect literature evidence that the risk of breast cancer recurrence following primary treatment diminishes progressively to zero after about 20 years. It was assumed that the morbidity benefit of trastuzumab observed in trials would be present for 5 years but would then diminish progressively to zero after 8 years. Costs (year 2005 values) and benefits were discounted at 3% per annum. RESULTS: For every 1000 patients treated with a 52-week course of trastuzumab, there were 136 fewer breast cancer deaths (relative risk reduction 28%). The incremental cost-effectiveness ratios (ICERs) were Australian dollars ($ A)13 730 per year of life saved (YOLS) and $ A22 793 per QALY. The net incremental cost was $ A56.3 million ($ A414 012/cancer death avoided). Cost effectiveness declined (ICER = $ A27 734/QALY) in older patients (age 65 years at treatment initiation). The ICER was driven mainly by the drug acquisition costs, the assumption of the duration of benefit and the discount rate. Cost offsets from reduced costs of treating recurrent or metastatic breast cancer during follow-up were present but these factors were of less importance according to sensitivity analyses. The 9-week treatment schedule approached economic dominance (ICER = $ A1700/QALY) because of decreased costs, improved relative risk for prevention of metastases and more cancer deaths avoided (196). CONCLUSION: The results suggest that trastuzumab as adjuvant therapy for early breast cancer may be cost effective when given over either 52 or 9 weeks at current acquisition costs in Australia. However, the overall budget impact of the 52-week course is significant, and the 9-week course appears economically attractive.