Quality-adjusted life years in cancer: pros, cons, and alternatives.

High and rising cancer treatment costs have forced a discussion about the use of cost-effectiveness analyses and other approaches to assess the value of cancer care. Oncologists have traditionally resisted using economic considerations in day-to-day medical considerations, though unavoidably their decisions have important resource implications, and increasingly economic realities are impacting their actions. In this paper, we summarise the use of the quality-adjusted life years to assess the value of cancer care and suggest potential ways to improve upon value measurement in cancer coverage and reimbursement decisions.

Factors associated with failure to correct the international normalised ratio following fresh frozen plasma administration among patients treated for warfarin-related major bleeding. An analysis of electronic health records.

This study assessed the frequency and factors associated with failure to correct international normalised ratio (INR) in patients administered fresh frozen plasma (FFP) for warfarin-related major bleeding. This retrospective database analysis used electronic health records from an integrated health system. Patients who received FFP between 01/01/2004 and 01/31/2010, and who met the following criteria were selected: major haemorrhage diagnosis the day before to the day after initial FFP administration; INR ≥2 on the day before or the day of FFP and another INR result available; warfarin prescription within 90 days. INR correction (defined as INR ≤1.3) was evaluated at the last available test up to one day following FFP. A total of 414 patients met selection criteria (mean age 75 years, 53% male, mean Charlson score 2.5). Patients presented with gastrointestinal bleeding (58%), intracranial haemorrhage (38%) and other bleed types (4%). The INR of 67% of patients remained uncorrected at the last available test up to one day following receipt of FFP. In logistic regression analysis, the INR of patients who were older, those with a Charlson score of 4 or greater, and those with non-ICH bleeds (odds ratio vs. intracranial bleeding 0.48; 95% confidence interval 0.31-0.76) were more likely to remain uncorrected within one day following FFP administration. In an alternative definition of correction, (INR ≤1.5), 39% of patients' INRs remained uncorrected. For a substantial proportion of patients, the INRs remain inadequately or uncorrected following FFP administration, with estimates varying depending on the INR threshold used.

Failure to correct International Normalized Ratio and mortality among patients with warfarin-related major bleeding: an analysis of electronic health records.

BACKGROUND: Delayed correction of blood clotting times as measured by the International Normalized Ratio (INR) is associated with adverse outcomes among certain patients with warfarin-related major bleeding. However, there are limited data on the association between INR correction and mortality. OBJECTIVE: To assess factors associated with 30-day mortality and time to death in patients receiving fresh frozen plasma (FFP) for warfarin-associated major bleeding. METHODS: A retrospective database analysis was undertaken with electronic health record data from a large integrated health system. Patients met the following criteria: major hemorrhage diagnosis; INR ≥ 2 on the day before or day of receipt of FFP; and prescription fill for warfarin within 90 days. INR correction (defined as INR ≤ 1.3) was evaluated at the last available test 1 day following the start of FFP administration. Kaplan-Meier curves and Cox proportional hazards models were constructed to assess mortality. RESULTS: Four hundred and five patients met the selection criteria (mean age of 75 years, 54% male), and 67% remained uncorrected at 1 day following the start of FFP administration. Among all patients, 11% died within 30 days of hospital admission. An uncorrected INR was not associated with a higher risk of 30-day mortality for patients overall, but was statistically significant for the subgroup with intracranial hemorrhage (ICH) (adjusted odds ratio 2.55; 95% confidence interval 1.04-6.28). CONCLUSIONS: Among the subgroup of major bleeding patients with warfarin-associated ICH, those not correcting to either INR ≤ 1.3 or INR ≤ 1.5 with the use of FFP have an increased rate of mortality at 30 days.

Cost-effectiveness of migraine prevention: the case of topiramate in the UK.

The aim of this study was to assess the cost-effectiveness of topiramate vs. no preventive treatment in the UK. Model inputs included baseline migraine frequency, treatment discontinuation and response, preventive and acute medical cost per attack [2005 GBP ( pound)] and gain in health utility. Outcomes included monthly migraines averted, acute and preventive treatment costs and cost per quality-adjusted life year (QALY). Topiramate was associated with 1.8 fewer monthly migraines and a QALY gain of 0.0384. The incremental cost of topiramate vs. no preventive treatment was about 10 UK pounds per migraine averted and 5700 UK pounds per QALY. Results are sensitive to baseline monthly migraine frequency, triptan use rate and the gain in utility. Incorporating savings from reduced work loss (about 36 UK pounds per month) suggests that topiramate would be cost saving compared with no preventive treatment. This analysis suggests that topiramate is a cost-effective treatment for migraine prevention compared with no preventive treatment.

Predictors of hospital length of stay and cost in patients with intracerebral hemorrhage.

We used the 2002 Healthcare Cost and Utilization Project Nationwide Inpatient Sample to assess hospital length of stay (LOS) and cost among adults with a principal diagnosis of intracerebral hemorrhage (n = 13,239). Sixty-nine percent of patients were aged > or =65 years, and 31% died during hospitalization. Mean LOS (cost) was 7.7 days (15,256 dollars) (survivors: 9.6 days, 17,442 dollars). Patient, hospital, and payer characteristics accounted for 69.1% of variation in cost per discharge.

Patterns of use of antithrombotic therapy and quality of anticoagulation among patients with non-valvular atrial fibrillation in clinical practice.

We conducted a retrospective cohort study of thromboprophylaxis rates and the quality of anticoagulation control among patients with atrial fibrillation (AF) using a large, geographically diverse database of electronic medical records. The study population consisted of 13,709 AF patients treated in US outpatient physician practices. Approximately two-thirds were prescribed warfarin alone or in combination with another drug. Older patients, males, and those with congestive heart failure (CHF) or prior stroke were more likely to receive antithrombotic therapy. Among 6454 patients treated with warfarin who had at least two valid prothrombin time/international normalised ratio test results, approximately half of study days were spent in target range. Female sex, CHF and residence in the Northeast were associated with more time out of range. Our study confirms that, in routine medical practice, warfarin is not prescribed for substantial numbers of eligible patients, and anticoagulation control with warfarin is suboptimal for many of those at risk for thromboembolism.

Adherence to calcium channel blocker therapy in older adults: a comparison of amlodipine and felodipine.

The efficacy of dihydropyridine calcium channel blockers for treating hypertension appears to be similar, but a variety of factors, including patient characteristics, tolerability and pharmacokinetic properties, may influence treatment adherence and outcome. We aimed to evaluate treatment adherence in clinical practice among older hypertensive adults (50+ years) prescribed amlodipine or felodipine for the first time as part of the California Medicaid (Medi-Cal) program. We used a retrospective, matched, cohort-analysis design. Over 1 year, patients prescribed amlodipine were 21% less likely to discontinue study treatment than those prescribed felodipine. Discontinuation tended to occur early, with 20% and 30% of amlodipine and felodipine patients, respectively, discontinuing treatment after one prescription. A non-significant difference in favour of amlodipine was demonstrated for anti-anginal medication use among patients taking these drugs at baseline. This study suggests that use of amlodipine may be associated with improved adherence, compared with felodipine, among older out-patients in the Medi-Cal program.

Cost-effectiveness results from the US Carvedilol Heart Failure Trials Program.

OBJECTIVE: To evaluate the cost-effectiveness of carvedilol, a beta-blocker that is approved for use in the US for the treatment of heart failure, based on data from Phase III clinical trials. METHODS: We conducted an economic evaluation alongside the US Carvedilol Heart Failure Trials Program, which consisted of four concurrent, randomized, double-blind, placebo-controlled clinical trials; the mean duration of follow-up across these four trials was 6.5 months (the program was terminated prematurely based on a finding of a 65% mortality benefit). Using data from these trials, we examined the cost-effectiveness of carvedilol in terms of the estimated cost per death averted among patients randomized to such therapy versus those receiving placebo. Attention was focused on the cost of carvediol therapy plus the cost of cardiovascular-related inpatient care. Costs of care were estimated by combining infomation on healthcare utilization from the clinical trials with secondary sources of cost data. RESULTS: Patients randomized to receive carvedilol had lower mean +/- SD estimated costs of cardiovascular-related inpatient care over 6.5 months compared with those receiving placebo ($1912 +/- $7595 vs. $4463 +/- $20,565, respectively). As mortality alsowas lower among carvedilol patients, the estimated cost per death averted was negative. The probability that carvedilol would both increase survival and decrease costs of cardiovascular-related care over a 6.5-month period was estimated to be 0.98. CONCLUSIONS: Data from the US Carvedilol Heart Failure Trials Program indicate that carvedilol reduces mortality in patients with heart failure; our study suggests that it also may be cost-saving over a period of approximately six months.

A general model of the effects of sleep medications on the risk and cost of motor vehicle accidents and its application to France.

BACKGROUND: Although various prescription drugs may be equally effective in promoting sleep, some may lead to substantial impairment in psychomotor functioning and an increased risk of motor vehicle accidents. OBJECTIVE: To develop a general model to evaluate the potential effects of sleep medications on motor vehicle accidents and costs, and apply the model to the French setting. METHODS: Impairment in driving performance, as evaluated by randomised controlled open-road studies using the standard deviation of a vehicle's lateral position (SDLP), a measure of weaving, was expressed in terms of equivalent blood alcohol (ethanol) concentration (BAC). Epidemiological data were then used to relate BAC to the excess risk of motor vehicle accidents. Although a non-impairing medication would not increase risk, a medication that produces mild impairment in driving performance (a change of 2.5 cm in SDLP, equivalent to 0.05% BAC) would increase motor vehicle accident risk by 25%. One that leads to moderate impairment (an SDLP change of 4.5 cm, equivalent to 0.08% BAC) would roughly double this risk, and a severely impairing medication (an SDLP change of 7 cm, equivalent to 0.12% BAC) would result in up to a 5-fold increase in motor vehicle accident risk. For application to the French setting, a hypothetical cohort of 100,000 adult drivers with insomnia was assumed to be treated for 14 days either with zaleplon 10 mg, a new sleep medication that has been shown not to significantly impair driving performance, or zopiclone 7.5 mg, which has been shown to cause moderate impairment. RESULTS: Compared with zaleplon, use of zopiclone over 14 days in France would be expected to result in 503 excess accidents per 100,000 drivers at an additional cost of 158 French francs (31 US dollars) per person (1996 values). CONCLUSIONS: Our model illustrates the extent to which non-impairing sleep medications could reduce the burden posed by motor vehicle accidents. Our model is designed to be general, and thus can serve as the basis for similar investigations.

Potential short-term economic benefits of improved glycemic control: a managed care perspective.

OBJECTIVE: There are limited data relating glycemic control to medical costs among patients with diabetes. The goal of this study was to examine the potential impact of improved glycemic control on selected short-term complications of diabetes and associated costs in a managed care setting. RESEARCH DESIGN AND METHODS: Using a retrospective cohort design and automated databases from January 1994 to 30 June 1998, adult members of the Fallon Clinic who were diagnosed with diabetes were identified and assigned to one of three study groups based on each patient's mean HbA1c level: good control (<8%), fair control (8-10%), and poor control (> 10%) groups. Inpatient (hospital or skilled nursing facility) admissions for selected acute (short-term) complications, represented by selected infections, hyperglycemia, hypoglycemia, and electrolyte disturbances, and the associated medical charges were evaluated across the three HbA1c groups. Multivariate analyses were used to control for differences in several potential confounding factors among the study groups. All findings were expressed on a 3-year basis. RESULTS: Of 2,394 patients with diabetes, approximately 10% (251) had at least one inpatient stay for a short-term complication, accounting for 447 admissions. Over 3 years, the adjusted rate of inpatient treatment ranged from 13 per 100 patients with good glycemic control to 16 per 100 patients with fair glycemic control and 31 per 100 patients with poor glycemic control (P < 0.05). The corresponding mean adjusted charges were approximately $970, $1,380, and $3,040, respectively Among the 30% of the study population with long-term diabetic complications, the results were more marked; the adjusted admissions per 100 patients (mean charges) were estimated to be 30 ($2,610), 38 ($3,810), and 74 ($8,320) over 3 years for patients with an HbA1c of <8, 8-10, and > 10%, respectively. CONCLUSIONS: In typical practice, better glycemic control is associated with a reduced rate of admission for selected short-term complications and, therefore, reduced medical charges for these complications over a 3-year period. The potential short-term economic benefits are important to consider when making decisions regarding the adoption and use of new interventions for the management of diabetes.

The net cost of Alzheimer disease and related dementia: a population-based study of Georgia Medicaid recipients.

The objective of this study was to estimate the direct medical cost of Alzheimer disease (AD) and related dementia to the Georgia Medicaid program. A retrospective, cross-sectional, matched control group design was used. AD cases 50 years of age and older were identified by using International Classification of Diseases (9th edition, Clinical Modification) diagnosis codes from 1994 Georgia Medicaid administrative claims files. For every case, three age- and gender-matched non-AD controls were selected. Differences in average recipient Medicaid expenditures between cases and controls were estimated using weighted least squares regression analysis, adjusting for age, gender, race, Charlson comorbidity index, Medicare eligibility, and months of Medicaid eligibility. A total of 8,671 AD cases were identified (prevalence, 4.4%). The average adjusted annual Medicaid expenditure per AD recipient was $14,492 (U.S.). The net (i.e., excess) average annual Medicaid cost per AD recipient (i.e., the difference in adjusted mean expenditures between cases and controls) was estimated to be approximately $8,200. Excessive nursing home expenditures accounted for most of the additional cost of treating dementia (> 85%), although inpatient hospital, physician, outpatient, and prescription drug expenditures also were higher among patients with AD. Based on these estimates, Georgia Medicaid is projected to spend almost $70 million annually for AD and related dementia. The excessive cost attributable to AD poses a significant burden to the Georgia Medicaid program.

The economic cost of Alzheimer's disease and related dementias to the California Medicaid program ("Medi-Cal") in 1995.

Although state Medicaid programs may bear a large portion of the costs of Alzheimer's disease (AD), current information on spending is not available. Using a health insurance claims database for a 10% random sample of California Medicaid ("Medi-Cal") recipients 60+ years of age, the authors estimated the excess cost of AD to Medi-Cal in 1995 as the difference in expenditures between an AD cohort (those with AD or related dementias) and an age- and sex-matched cohort without AD. Among 62,450 recipients, 2,575 (4.1%) were found to have AD or related dementias, and their average payments were approximately $7,700 higher (P<0.01) than those for the comparison group. These estimates suggest that Medi-Cal spends about $200 million on AD and related dementias annually, a burden that represents nearly 10% of state spending on elderly patients.

Cholesterol-reduction intervention study (CRIS): a randomized trial to assess effectiveness and costs in clinical practice.

BACKGROUND: The 1988 US National Cholesterol Education Program Expert Panel Report recommended initial treatment with niacin or bile acid sequestrants, followed by other agents if needed, to lower low-density lipoprotein cholesterol (LDL-C) levels in hypercholesterolemic patients who require drug therapy. It is unknown how the effectiveness and costs of such an approach ("stepped care") compare in typical clinical practice to those of initial therapy with lovastatin. PATIENTS AND METHODS: We randomly assigned 612 patients, aged 20 to 70 years, who met 1988 National Cholesterol Education Program guidelines for drug treatment of elevated LDL-C level and had not previously used cholesterol-lowering medication, to either a stepped-care regimen or initial therapy with lovastatin (both n=306). The study, conducted at Southern California Kaiser Permanente, was designed to approximate typical practice: provider compliance with treatment plans was encouraged but not enforced, and patients paid for medication as they customarily would. RESULTS: At 1 year, the decline in mean LDL-C level was significantly greater among patients assigned to initial treatment with lovastatin (22% vs 15% for stepped care; P<.001), as was the number who attained goal LDL-C level (

A multinational economic evaluation of rhDNase in the treatment of cystic fibrosis.

Economic evaluations of pharmaceuticals are increasingly being conducted in conjunction with randomized phase III clinical trials to meet the demand for pharmacoeconomic data when new products are launched. While the need for such data is often global, the trials in which relevant information may be collected are often conducted in only one or a limited number of countries. A critical issue is how data from pivotal clinical trials in one setting can serve as the basis for pharmacoeconomic evaluations in others. We address this issue and report on four economic evaluations that we undertook in conjunction with a recent U.S. phase III clinical trial of recombinant human deoxyribonuclease (rhDNase), which is used to improve pulmonary function in patients with cystic fibrosis (CF). The objective of these evaluations was to estimate the potential impact of rhDNase therapy in France, Germany, Italy, and the United Kingdom on the direct costs of medical care for the treatment of respiratory tract infections (RTIs) in patients with CF. Analyses of economic impact were undertaken both with and without adjustment for differences in practice patterns between the United States and the countries of interest. Our findings suggest that rhDNase therapy may reduce the cost of RTI-related care by between US$600 and US$1,100 over a 24-week period; the cost of rhDNase is not included in these figures, as a price was unavailable when our analyses were undertaken. Despite methodologic challenges, economic evaluations that meet the information needs of decision makers in diverse countries can nonetheless be undertaken in conjunction with phase III clinical trials.

Cost-effectiveness of enoxaparin vs low-dose warfarin in the prevention of deep-vein thrombosis after total hip replacement surgery.

BACKGROUND: Enoxaparin sodium, a low-molecular-weight heparin, was recently approved for use in the United States to prevent deep-vein thrombosis after total hip replacement surgery. Its cost-effectiveness relative to prophylaxis with low-dose warfarin sodium is unknown. METHODS: A decision-analytic model was developed to compare two strategies of prophylaxis for deep-vein thrombosis with a strategy of not using prophylaxis in a hypothetical cohort of 10,000 patients undergoing total hip replacement surgery. For each of these strategies, we estimated the expected number of cases of confirmed deep-vein thrombosis or pulmonary embolism, the expected number of thromboembolic deaths, and the expected costs of venous thromboembolic care, including prophylaxis, diagnosis, and treatment. Data were drawn primarily from the published literature. RESULTS: Compared with no prophylaxis, the use of low-dose warfarin would be expected to reduce the number of cases of confirmed deep-vein thrombosis from about 1000 (per 10,000 patients) to 420 and the number of thromboembolic deaths from about 250 to 110. Expected costs of care related to deep-vein thrombosis also would be reduced from approximately $530 to $330 per patient. Prophylaxis with enoxaparin would be expected to reduce further the number of cases of confirmed deep-vein thrombosis and the number of thromboembolic deaths (to 250 and 70, respectively) but increase costs of care by approximately $50 per patient. The cost-effectiveness of enoxaparin (relative to low-dose warfarin) is estimated to be approximately $12,000 per death averted. CONCLUSION: Although enoxaparin is more costly than low-dose warfarin, its cost-effectiveness in total hip replacement compares favorably with that of other generally accepted medical interventions.

A randomized trial to assess effectiveness and cost in clinical practice: rationale and design of the Cholesterol Reduction Intervention Study (CRIS).

To compare the effectiveness and costs of two alternative approaches to the treatment of hypercholesterolemia, a prospective randomized trial is being undertaken at Southern California Kaiser Permanente, a large health maintenance organization. Six hundred and twelve patients with postdiet LDL cholesterol (LDL-C) levels in the range of 190-230 mg/dl (or 160-230 mg/dl for those with coronary heart disease or two or more coronary risk factors) were randomized to a stepped-care regimen (initial treatment with niacin followed by other agents if needed) or to initial use of lovastatin, an HMG-CoA reductase inhibitor. All patients are being followed for 1 year. The study seeks to approximate conditions of typical clinical practice: provider compliance with these plans of treatment is encouraged but not enforced and patients pay for medication as they customarily would. Principal outcomes of interest include the proportion of participants who achieve goal LDL-C at one year, the mean change in total cholesterol and LDL-C levels between baseline and the end of follow-up, and the costs of cholesterol-lowering therapy.

Prevention of deep-vein thrombosis following total hip replacement surgery with enoxaparin versus unfractionated heparin: a pharmacoeconomic evaluation.

OBJECTIVE: To compare the use of healthcare services in patients receiving enoxaparin, a low molecular weight heparin versus those receiving unfractionated heparin as prophylaxis against deep-vein thrombosis (DVT) following total hip replacement surgery. DESIGN: Economic evaluation undertaken in conjunction with a randomized, open-label, parallel group, Phase III clinical trial. SETTING: 32 US acute-care hospitals. PATIENTS: 607 patients undergoing elective total hip replacement. INTERVENTIONS: Enoxaparin 30 mg q12h, enoxaparin 40 mg qd, or unfractionated heparin 5000 units q8h started within 24 hours following surgery and continued for 7 days. MAIN OUTCOME MEASURES: (1) Use of selected tests and treatments for DVT; (2) use of selected tests and treatments related to postoperative bleeding; (3) length of stay in hospital; and (4) readmissions to hospital within 14 days. RESULTS: Although the use of selected tests and treatments related to DVT or postoperative bleeding did not differ significantly between the three treatment groups, mean length of stay in the hospital (following the start of study therapy) was shorter among patients receiving enoxaparin 30 mg (9.5 days; p = 0.01) or 40 mg (9.9 days; p < 0.05) than those receiving unfractionated heparin (11.3 days). There was also a trend toward fewer hospital readmissions in both of the enoxaparin groups. CONCLUSIONS: Compared with unfractionated heparin, use of enoxaparin following total hip replacement may decrease the risk of DVT and length of hospital stay.

Methodological issues in economic assessments of new therapies. The case of colony-stimulating factors.

Pharmacoeconomic evaluations estimate the value of medical interventions by comparing their clinical consequences and costs. Economic analyses, based on resource use data collected during 3 clinical trials of lenograstim, were performed as part of a lenograstim economic evaluation programme. Undertaking economic evaluations alongside clinical trials presents a number of methodological challenges, since the trials may be performed in atypical settings, have inappropriate follow-up, or use end-points that are not useful for economic evaluation. This paper reports on how these challenges were met in the lenograstim economic evaluation programme. In particular, it was decided that the evaluations would be based on an intent-to-treat perspective, with the same period of follow-up (for costs) for both lenograstim and vehicle groups.

Pharmacoeconomic evaluation of lenograstim. Conclusions and future directions.

To evaluate the safety and efficacy of lenograstim, a new recombinant human granulocyte colony-stimulating factor (rHuG-CSF), as an adjunct to cancer chemotherapy, 3 phase III randomised clinical trials were recently conducted in Europe in patients with inflammatory breast cancer, non-Hodgkin's lymphoma, and small cell lung cancer. To explore the economic implications of lenograstim therapy, a multinational pharmacoeconomics programme was undertaken using data collected during these clinical trials. This programme consisted of concurrent prospective economic evaluations undertaken by study teams in France (non-Hodgkin's lymphoma), Germany and Italy (a combined evaluation in inflammatory breast cancer) and the UK (small cell lung cancer). In these studies, attention was focused on the direct costs of medical care-principally the costs of cancer chemotherapy as well as its associated morbidity. In 2 of the pharmacoeconomic evaluations (i.e. the French, German/Italian), lenograstim was found to generate cost savings as a result of reductions in morbidity associated with chemotherapy. However, the cost of lenograstim therapy would be likely to exceed these savings, leading to an overall increase in the costs of cancer treatment. Whether the use of lenograstim is cost-effective will therefore largely depend on its impact on patient survival and quality of life, and current practical use. These issues are the focus of additional clinical studies currently underway. In addition, new research is focusing on the clinical benefits of lenograstim in other areas of oncology and haematology. Further pharmacoeconomic studies in these areas are also warranted.