Economic evaluation of atorvastatin for prevention of recurrent stroke based on the SPARCL trial.

OBJECTIVES: This study evaluated the economic implications of results obtained by the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. METHODS: To enable long-term projection of the trial results, a discrete event simulation of the course of clinical care after a recent stroke or transient ischemic attack (TIA) was developed. It generates pairs of identical patients; both receive usual care, one receives atorvastatin in addition. Their clinical course is simulated based on their risk of stroke, cardiovascular events, and case fatality rates taken from SPARCL, life expectancy from Saskatchewan Health data, and utility weights from literature. Costs, from a US health-care payer perspective in 2005 US dollars, were estimated for a within-trial 5-year period; survival and quality-adjusted life-years (QALYs) were extrapolated over a patient's lifetime; all discounted at 3%/year. RESULTS: The prevention of stroke, coronary, and other cardiovascular events expected with atorvastatin translates to mean gains of 0.155 life-years gained and 0.172 QALYs per patient over their lifetime. Reducing associated medical costs ($8405 vs. $11,237) but increasing drug costs ($13,984 vs. $8752) results in net $2400/patient, or $13,916/QALY gained. Probabilistic sensitivity analysis indicates no simulations yield ratios above $50,000/QALY. CONCLUSION: Prescribing atorvastatin for patients with prior stroke or TIA is expected to provide health benefits at an acceptable cost in the United States.

Treating relapsing multiple sclerosis with subcutaneous versus intramuscular interferon-beta-1a: modelling the clinical and economic implications.

The EVIDENCE trial concluded that administering high-dose/high-frequency subcutaneous (SC) interferon-beta-1a (IFNb1a) was more effective in preventing relapses among patients with relapsing multiple sclerosis (MS) than low-dose weekly intramuscular (IM) IFNb1a after 64 weeks. This analysis utilized discrete-event simulation (DES) to model the potential longer-term clinical and economic implications of this trial. A DES predicting the course of relapsing MS and incorporating the effect of IFNb1a therapy was developed. The model began by randomly reading in actual patient data from the trial to create 1000 patients. Each simulated patient was replicated - one was assigned to receive SC IFNb1a three times a week and the other to receive IM IFNb1a once a week. During the simulation, patients may (i) experience relapses, with associated short- and long-term impacts on costs and disability; (ii) develop new T2 lesions detected by a magnetic resonance imaging scan; (iii) discontinue treatment because of adverse events or lack of response; (iv) advance to secondary progressive MS; or (v) die. Model inputs were mainly obtained from the EVIDENCE trial, but were taken from published literature if they could not be obtained from the trial. Direct medical costs ($US, year 2006 values) to the US payers were primarily obtained by updating a published cost analysis. Costs and benefits were discounted at 3% per annum. Extensive sensitivity analyses were conducted to test the robustness of the model results. Based on 100 replications of 1000 patient pairs over 4 years, SC IFNb1a was predicted to enable more patients to avoid relapse (216 vs 147). Total mean costs per patient (discounted) were $US79 890 with SC IFNb1a versus $US74 485 with IM administration, a net increase of $US5405 per patient. However, SC IFNb1a was estimated to prevent 0.50 relapses and save 23 relapse-free days per patient, yielding incremental cost-effectiveness ratios of $US10 755 per relapse prevented and $US232 per relapse-free day gained. Sensitivity analyses revealed that the result was most sensitive to the treatment efficacy, model time horizon and cost of IFNb1a treatment. Based on the results observed in the EVIDENCE trial, the model predicted that SC IFNb1a would yield greater health benefits over 4 years than IM IFNb1a, at a cost that would seem to be a reasonable trade-off.

Prevention and management of hyperphosphatemia with sevelamer in Canada: health and economic consequences.

BACKGROUND: Sevelamer hydrochloride (Renagel) binds phosphate in patients with end-stage renal disease without the use of exogenous calcium and may reduce the progression of coronary vascular calcification. This intervention was shown to be cost-effective in the United States. This paper presents the Canadian adaptation. METHODS: A discrete event simulation of the long-term cardiovascular implications of 1 year of phosphate binding in a prevalent hemodialysis population was used to estimate the cost-effectiveness of sevelamer use in Canada based on the demographics, comorbidities, physiological and renal characteristics. Initial calcification score and expected changes over 1 year were derived using regression equations developed from a clinical trial and translated to cardiovascular disease risk based on equations developed from a long-term cohort study. Direct medical costs from a Canadian Medicare perspective were taken from Ontario data. Ten replications of 10,000 patients over 13 years (discounting at 3%) were done for the base case and extensive sensitivity analyses were conducted. RESULTS: The cardioprotective effect of sevelamer over 1 year is estimated to prevent 10 cardiovascular events and gain 18 life-years compared with calcium carbonate in 100 patients over a lifetime. These benefits are obtained at a net cost of CAD$2,096; an incremental cost-effectiveness ratio of CAD$12,384 per discounted life-year gained. Sensitivity analyses showed that the time horizon and efficacy were the most important factors. CONCLUSION: The results of this study provide evidence that use of sevelamer in Canada would be economically sound.

Cost-effectiveness of clopidogrel in acute coronary syndromes in Canada: a long-term analysis based on the CURE trial.

BACKGROUND: Cardiovascular diseases account for nearly 20% of all hospitalizations in Canada and consume 12% of the total cost of all illnesses. With increasing trends of cardiovascular disease and increasing costs of care, development of cost-effective strategies is vital. The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial demonstrated the effectiveness of clopidogrel plus acetylsalicylic acid (ASA) compared with ASA alone in reducing cardiovascular events in patients with acute coronary syndromes and, in addition, patients undergoing percutaneous coronary intervention in the Percutaneous Coronary Intervention in CURE (PCI-CURE) trial. OBJECTIVE: To assess the cost-effectiveness of clopidogrel in the Canadian health care system. METHODS: Estimates of hospitalization costs were based on the 2003 cost schedules released by the Health Funding and Costing Branch of the Alberta Health and Wellness, as well as on the Case Mix Group classification system. Life expectancy beyond the trial was estimated from the Saskatchewan Health Database. Cost-effectiveness was expressed as the incremental cost-effectiveness ratio, and bootstrap methods were used to estimate the joint distribution of costs and effectiveness. RESULTS: Clopidogrel was shown to be cost-effective, with incremental cost-effectiveness ratios less than $10,000 per event prevented and less than $4,000 per life-year gained. The probability of clopidogrel resulting in cost per life-year gained of less than $20,000 was 0.975 for CURE patients and 0.904 for PCI-CURE patients. CONCLUSIONS: The economic analysis demonstrated that clopidogrel combination therapy is not only cost-effective as antiplatelet therapy compared with ASA alone, but it is also cost-effective compared with other commonly used and openly reimbursed cardiovascular therapies in the Canadian health care system.

The emerging infectious challenge of clostridium difficile-associated disease in Massachusetts hospitals: clinical and economic consequences.

OBJECTIVE: To estimate the clinical and economic burden of Clostridium difficile-associated disease (CDAD) in Massachusetts over 2 years. DESIGN: A retrospective analysis of Massachusetts hospital discharge data from 1999-2003 was conducted. Cases of CDAD in 2000 were identified using code 008.45 from the International Classification of Diseases, Ninth Revision, Clinical Modification; patients were excluded if they had a hospitalization in the prior year during which a diagnosis of CDAD was recorded. Hospitalizations for CDAD during 2001 and 2002 were examined. For primary case patients (ie, those for which CDAD was the principal diagnosis), all inpatient costs were deemed to be related, whereas for secondary case patients, all-patient refined diagnosis-related group assignment, case severity level, and length of stay (LOS) were used to calculate incremental costs attributable to CDAD. Costs were adjusted to the national level and reported in 2005 US dollars. RESULTS: The CDAD cohort consisted of 3,692 patients; 59% were women, and the mean age was 70 years. This group represented 1% of all patients hospitalized in Massachusetts in 2000 (96% of hospitals treated at least 1 case; range, 1-257 cases). Of patients who received a first hospital diagnosis of CDAD in 2000, a total of 28% were primary case patients; their mean LOS was 6.4 days, and the mean cost per stay was $10,212. For secondary case patients, the mean CDAD-related incremental LOS was 2.95 days, and the mean incremental cost per stay was $13,675 per patient. Of patients with CDAD who survived their index stay in 2000, a total of 455 (14%) had at least 1 readmission for CDAD within the subsequent 2 years (mean number of readmissions, 1.4 per patient; range, 1-7 readmissions), with a mean time to first readmission of 3 months. Over 2 years, a total of 55,380 inpatient-days and $51.2 million were consumed by CDAD management. CONCLUSION: CDAD is widespread in Massachusetts hospitals. Rehospitalization with CDAD, if it occurs, generally happens within a few months and happens multiple times for some patients. Based on this study's findings, a conservative estimate of the annual US cost for CDAD management is $3.2 billion dollars.

Cost-benefit analysis of preventing sudden cardiac deaths with an implantable cardioverter defibrillator versus amiodarone.

OBJECTIVES: To conduct a cost-benefit assessment of prevention of sudden cardiac deaths with an implantable cardioverter defibrillator (ICD) versus amiodarone from the perspective of the health-care systems in the UK and France. METHODS: Course after implantation with an ICD or taking amiodarone was modeled using discrete event simulation; 1000 pairs of identical patients were simulated 100 times for each analysis. Rates of life-threatening arrhythmia and death from other causes were assumed identical, but the case fatality of arrhythmia and hospitalization differ between treatments. Rates were based on published data, primarily from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). Direct medical costs (in 2004 Euros) and lives saved were estimated over 5 years. The monetary value of a life (UK euro2.1 million, France euro2.0 million) was applied to this benefit and examined relative to the net investment required. RESULTS: ICDs decreased deaths during the 5 years from 37.0% to 29.7% at a net cost of euro26,222 to euro20,008 per patient, yielding cost-benefit ratios of 0.17 (UK) and 0.14 (France)-more than a 5 to 1 return on investment. Sensitivity analyses showed ICDs represent value for money whenever a life is valued at least at euro274,000. CONCLUSION: In these European countries where society values a life at more than euro2 million, ICDs are a worthwhile investment compared with amiodarone for primary prevention of sudden cardiac deaths in patients with heart failure.

Budgetary impact of treating acute bipolar mania in hospitalized patients with quetiapine: an economic analysis of clinical trials.

OBJECTIVE: To present a tool that allows estimation of the budget impact of treatments for acute mania in bipolar I disorder from a US healthcare payer perspective. METHODS: Using discrete event simulation, the course of individuals is simulated beginning with hospitalization. Discharge depends on symptom level measured by the Young Mania Rating Scale (YMRS). The treatment effect is determined using time-dependent regression equations derived from trial data, and decision rules obtained from clinical experts. Outcomes include: time to response and symptom resolution; proportion of subjects reaching each outcome; number of adverse events. Costs were obtained from hospital discharge databases, the National Medicare Physician Fee Schedule and RedBook. Different scenarios are examined, each describing the proportion of subjects on the various treatments (lithium, divalproex sodium, olanzapine, risperidone, and quetiapine--monotherapy and in combination with lithium). Analyses are intention-to-treat over 100 days, corresponding to follow-up in mania trials. Despite its flexibility and structural adaptability, the model has some important limitations related to the characteristics of the clinical trials. These include focus on inpatient management of acute mania, use of the YMRS as the model driver, polypharmacy restricted to two-drug regimens, no explicit consideration of titration and dose changes, and relatively short time horizon. RESULTS: Scenarios with a greater proportion of quetiapine users (5% vs. 40% and 100%) result in a smaller impact on the healthcare budget (6912, 6277, and 5525 dollars per patient, respectively) and improvements in patient outcomes (e.g., 43%, 47%, and 54% responding at day 21; 74%, 77%, and 80% remitting by day 84). Sensitivity analyses showed that the budget impact is influenced by drug prices, discharge criteria and side-effect management. CONCLUSION: Results suggest that increased use of quetiapine for bipolar mania in the US is economically justified and improves health outcomes. In addition, this model illustrates that discrete event simulation is a useful and versatile tool for budget impact analyses.

Setting up annual OSHA training--bloodborne pathogen standard.

While monitoring actual performance will always be of paramount importance, laboratory managers must also be vigilant about protecting their employees. In Part One of this two-part series discussing OSHA training procedures, columnist Judith O'Brien examines the necessary precautions related to bloodborne pathogens.

The time course of subsequent hospitalizations and associated costs in survivors of an ischemic stroke in Canada.

BACKGROUND: Documentation of the hospitalizations rates following a stroke provides the inputs required for planning health services and to evaluate the economic efficiency of any new therapies. METHODS: Hospitalization rates by cause were examined using administrative data on 18,695 patients diagnosed with ischemic stroke (first or subsequent, excluding transient ischemic attack) in Saskatchewan, Canada between 1990 and 1995. Medical history was available retrospectively to January 1980 and follow-up was complete to March 2000. Analyses evaluated the rate and timing of all-cause and cardiovascular hospitalizations within discrete periods in the five years following the index stroke. Cardiovascular hospitalizations included patients with a primary diagnosis of ischemic stroke, transient ischemic attack, myocardial infarction, stable or unstable angina, heart failure or peripheral arterial disease. RESULTS: One-third (36%) of patients were identified by a hospitalized stroke. Mean age was 70.5 years, 48.0% were male, half had a history of stroke or a transient ischemic attack at the time of their index stroke. Three-quarters of the patients (72.7%) were hospitalized at least once during a mean follow-up of 4.6 years, accruing CAD $24 million in the first year alone. Of all hospitalizations, 20.4% were related to cardiovascular disease and 1.6% to bleeds. In the month following index stroke, 12.5% were admitted, an average of 1.04 times per patient hospitalized. Strokes accounted for 33% of all hospitalizations in the first month. The rate diminished steadily throughout the year and stabilized in the second year when approximately one-third of patients required hospitalization, at a rate of about one hospitalization for every two patient-years. Mean lengths of stay ranged from nine days to nearly 40 days. Close-fitting Weibull functions allow highly specific probability estimates. Other cardiovascular risk factors significantly increased hospitalization rates. CONCLUSION: After stroke, there are frequent hospitalizations accounting for substantial additional costs. Though these rates drop after one year, they remain high over time. The number of other cardiovascular causes of hospitalization confirms that stroke is a manifestation of disseminated atherothrombotic disease.

Managing meningococcal disease in the United States: Hospital case characteristics and costs by age.

OBJECTIVE: Meningococcal disease occurs worldwide. Approximately 1400 to 2800 cases are reported in the United States annually. The goal of this analysis was to examine hospitalized cases of meningitis and meningococcemia to identify case characteristics, resource use, and inpatient care costs. METHODS: International Classification of Diseases-9th Revision-Clinical Modification diagnosis codes 036.0-036.9 were used to identify cases from roughly 1000 hospitals in four all payer state discharge databases. Multiyear data (1999-2001) were examined to identify demographics, admission month, health service utilization, and hospital costs by age group: infant (<1 years), children (1-10 years), adolescent (11-17 years), young adult (18-22 years), adults (23-49 years), and adults (> or =50 years). Cost estimates include accommodations, ancillary and physician services, reported in 2003 US dollars. RESULTS: Of 1654 cases of meningococcal disease identified, meningococcemia was coded for 51%. Adults accounted for 33% of the cases. The highest rate of admissions occurred from January through March and 62% were admitted via the Emergency Department. Inpatient case fatality rate was 6.4%; 71% of those who died had meningococcemia. The mean length of stay was 9 days. Of survivors, 91% were discharged home (1% with intravenous medications and 11% with other home health-care services) while 7% required further subacute inpatient care. The average cost per hospitalization was estimated at 23,294 dollars per patient. Infants had the lowest average cost per stay (16,793 dollars) and adolescents had the highest (28,202 dollars). CONCLUSIONS: The presence of meningococcemia results in a greater death rate, longer length of stay, and increased care costs. Meningococcal disease has substantial economic, as well as profound clinical consequences for patients of all ages.

Structural determinants of rotavirus subgroup specificity mapped by cryo-electron microscopy.

The rotavirus double-layered particle (DLP) is a molecular machine that transcribes 11 genomic segments of double-stranded RNA into full-length mRNA segments during viral replication. DLPs from the human Wa strain of virus, belonging to subgroup II (SG II), possess a significantly reduced level of transcriptase activity compared to bovine UK DLPs that belong to subgroup I (SG I). Cryo-electron microscopy and icosahedral image analysis was used to define the structural basis for this difference in transcriptase activity and to derive three-dimensional density maps of bovine UK and human Wa DLPs at 26 angstroms and 28 angstroms resolution, respectively. The two rotavirus strains had the same diameter, T = 13 l icosahedral lattice symmetry and size of the VP6 trimers on the surface of the DLPs. However, the Wa particles displayed a remarkable absence of VP6 trimers surrounding each 5-fold vertex position. To further explore these structural differences, three-dimensional reconstructions were generated of DLPs decorated with Fab fragments derived from subgroup-specific monoclonal antibodies. The X-ray structures of VP6 and a generic Fab fragment were then docked into the cryo-electron microscopy density maps, which allowed us to propose at "pseudo-atomic" resolution the locations of the amino acid residues defining the subgroup-specific epitopes. Our results demonstrate a correlation between the structure of the VP6 layer and the transcriptase activity of the particles, and suggest that the stability of VP6 trimers, specifically those at the icosahedral 5-fold axes, may be critical for mRNA synthesis. Thus, subgroup specificity of rotavirus may reflect differences in the architecture of the double-layered particle, with resultant consequences for viral mRNA synthesis.

Economic implications of extended-release metoprolol succinate for heart failure in the MERIT-HF trial: a US perspective of the MERIT-HF trial.

BACKGROUND: The MERIT-HF trial demonstrated improved survival and fewer hospitalizations for worsening heart failure with extended-release (ER) metoprolol succinate in patients with heart failure. This study sought to estimate the economic implications of this trial from a US perspective. METHODS AND RESULTS: A discrete event simulation was developed to examine the course of patients with heart failure. Characteristics of the population modeled, probabilities of hospitalization and death with standard therapy, and risk reductions with ER metoprolol succinate were obtained from Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF) and evaluated in weekly cycles. Direct medical costs were estimated from US databases in 2001 US dollars. Uncertainty in inputs was incorporated and analyses were carried out to estimate events prevented total and net costs. The model predicts that ER metoprolol succinate will prevent approximately 7 deaths and 15 hospitalizations from heart failure per 100 patients over 2 years. Compared with standard therapy alone, this translates to a cost reduction between $395 and $1112 per patient, depending on whether the costs of hospitalizations for other causes are included. Savings were maintained in 90% of the simulations. CONCLUSION: This analysis predicts that the positive effect of ER metoprolol succinate on mortality and morbidity demonstrated in MERIT-HF leads to substantial savings.