as patients become disabled and require more health care services over the ensuing months and years. ACS represent an acute event that can have continuing costs, and thus differs from and is more complicated than a single form of therapy or diagnostic test (Table 1). When considering a new therapy for ACS, there is generally a clear starting point but often no clear stopping point (other than death). The natural history of ACS may vary substan- tially, as may management. The patient may be stable but then decompensate, resulting in a hospitalization and intensified therapy, presumably with a somewhat worse health state and associated costs. The goal of therapy is to return the patients to their baseline health state and maintain them there. Economic considerations should include direct cost as well as indirect costs, which may be substantial due to lost productivity. ACS may also have a considerable impact on how people feel (quality of life) and how they function (health status). A good design for an outcomes study in heart failure should take into account all of these possibilities. BACKGROUND ON ECONOMIC ANALYSES In an environment in which society cannot afford all possible medical services, all forms of care compete for resources based on effectiveness and cost. A comparison of cost between contending therapies can involve a simulation in which costs and outcome are estimated from nonrandomized comparisons and randomized controlled trials. Even within randomized trials, an economic analysis can range from a simulation to a very detailed component of the trial with extensive primary data collection. For any of these designs, the simplest type of economic study is a comparison of costs or a cost-mini- mization study. Such a study is useful when it is reasonable to assume that the two treat- ments offer similar outcomes. When effectiveness cannot be assumed to be the same for competing therapies, there are three related forms of economic analyses that can be used to study the relationship of cost to outcome: cost-effectiveness, cost-utility, and cost-benefit. Cost-effectiveness analysis assumes that there is one overall measure of effectiveness, often survival (2). This method breaks down when there are multiple measures of effectiveness. For instance, one form of therapy may increase the risk of death, but offers improved symp- tomatic status. This may, in principle, be addressed through cost-utility analysis, in which all measures of effectiveness are incorporated into one measure, utility (2). A 706 Weintraub Table 1 What is Different About the Economics of ACS? Episode in a chronic disease rather than a procedure. Clear starting point. No clear stopping point. Disease course may vary widely. Management may vary widely. Boundaries of what to include may be difficult. Indirect costs may be substantial. Health status may be affected significantly. third and somewhat less popular form of analysis is cost-benefit analysis, in which measures of both cost and effectiveness are reduced to dollars or other currency (2). We can begin to understand the approach of cost-effectiveness analysis by consider- ing competing therapies, A and B, to treat the same condition (Fig. 1). In panel 1, ther- apy A is less effective but more expensive than therapy B. In this setting, B is said to dominate A. Similarly, in panel 4, A is more effective and less expensive than B. In this setting, A would dominate B. Commonly, however, the more effective therapy or test is also more expensive. Thus, in panel 2, A is more effective but also more expensive. Sim- ilarly, in panel 3, B is more effective but also more expensive. When a therapy is both more effective and more expensive than the competing therapy, cost-effectiveness analy- sis can help decision makers choose whether to allocate resources to the more effective service. The perspective in these analyses can have an important impact on their structure and outcome. For instance, an analysis from a hospital’s perspective might not include the long-term consequences of a particular clinical strategy, whereas this issue may be most important to the patient and the payer. The perspective of all of the various stakeholders may be viewed in aggregate as “society”. To be most useful in serving societal goals, cost and cost-effectiveness analyses should be performed from a societal perspective, in which an attempt to measure all of the costs and measures of outcome associated with a particular treatment is made. These costs should include those incurred by the patient, the costs of medical resources that could have been used for other patients, and any loss of income that the patient sustained because of poor health, as well as the loss of income for those who may have provided informal care to the patient. Outcome should include events, quality of life, and survival. By looking at the sum of all of these costs in rela- tion to outcome, a policy maker could decide, for example, whether the public good ben- efited more by allocating limited health care resources to preventive services or a new therapy for ACS. Economics of Acute Coronary Syndromes 707 Fig. 1. Decision matrix. DETERMINING COSTS Nomenclature for Costs Economists are more concerned with how society chooses to allocate limited resources rather than what something costs per se (3). Cost may be used to sum resource use of several type, permitting an economic comparison of services with a common scale. Accounting methods are used to develop costs from resource use; a summary of accounting names is shown in Table 2. Costs must be considered from one of several possible perspectives (4). For hospi- tals, costs are their expenses related to providing a service. For payers, the cost is what the providers charge, plus their administrative expenses. In principle, cost studies often seek to determine societal costs, which can be used in cost-effectiveness analyses to gain the widest perspective. However, societal costs are never directly measurable, and thus combinations of cost proxies from one or several stakeholders, where measurable, are often used as estimates. Costs are classified as direct or indirect (5). Varying definitions of indirect costs may lead to uncertainty categorizing a particular cost. Theoretically, direct costs are those incurred by a stakeholder for a therapy or test, and indirect related costs are those incurred by other societal groups. More commonly, direct costs relate to the provision of medical care, while indirect costs are other societal costs. Medical costs can also be divided into three components: in-hospital direct costs, fol- low-up direct costs, and indirect costs. Inpatient costs are comprised of hospital costs (e.g., room, laboratory testing, pharmacy, etc.) and physician professional billings. Fol- low-up direct costs include physician office visits, outpatient testing, medications, home health providers, and additional hospitalizations. In this setting, indirect costs reflect lost patient or business opportunity and may be referred to as productivity costs (6). A final way of thinking about costs is that direct costs are realistically linked to a particular service, while indirect costs are not. This type of indirect cost is also called overhead (7). 708 Weintraub Table 2 Nomenclature for Costs Cost perspective: Provider, i.e., hospital or professional. Payer, i.e., insurance carrier. Patient. Cost category: Direct costs. Indirect costs. Accounting method: Top-down. Bottom-up. Costs per service: Average cost. Marginal (incremental) cost. The appropriate length of time over which to measure costs is dependent upon the procedures being studied and outcomes being measured. The cost of a hospitalization for ACS could be considered the initial hospitalization alone. Alternatively, the cost for a hospitalization for ACS could be considered to include the “induced” cost related to that hospitalization during a period of follow-up (8). Often in the United States, hospital provider costs are used as a proxy for societal costs. What a hospital charges for a service is not its cost (9). Measuring hospital cost is difficult and has been approached by using what is called either top-down or bottom- up accounting (10). Top-down costing involves dividing all the money spent on a hos- pitalization or procedures by the number of episodes of care of the particular type performed. In contrast, a bottom-up approach involves individually costing all resources used for a service, i.e., supplies, equipment depreciation and facilities, salaries, etc. All methods involve a set of assumptions and limitations. When considering the cost of a specific procedure using top-down costing, it must be assumed that costs in the depart- ment in which the procedure is provided can be separated from costs in other depart- ments. There may also be variability within a department. Bottom-up methods also are limited by the ability to account for all resources consumed and to appropriately apply costs. Another issue involved in measuring hospital costs is average vs marginal or incre- mental cost (11). Average cost is calculated by dividing all costs for a therapy or test by the number of that particular type. In contrast, the marginal cost is the cost of the next similar procedure. Average costs include all resources used, including overhead, whose costs would not be decreased if not utilized. Marginal costing accepts fixed costs as a given and focuses only on variable costs or those additional resources consumed by each additional patient. Variable costs are analytically separated from fixed costs by estab- lishing the perspective and time-frame as fixed. For instance, facilities’ costs are com- monly considered fixed, but how should marginal personnel costs be assigned? If an older test such as Swan Ganz catheters decreases as echocardiography becomes more common, how is the decrease in intensive care unit (ICU) nurse activity and increase in echocardiography technician activity reflected? Because of these difficulties, most cost and cost-effectiveness studies use average costs. Cost Measurement There is a detailed approach to top-down costing based on the UB92 summary of hos- pital charges, which is commonly used in the United States (12). The UB92 is a uniform billing statement used by all third party carriers. The relationship between costs and charges, in the form of global specific cost to charge ratios, must be developed using American Hospital Association guidelines and then filed annually with Health Care Financing Administration (HCFA) in a Hospital Cost Report, which is in the public domain. An alternative approach is to use bottom-up cost accounting and assign cost weights to each type of resource used (13). The sum of resources times their cost weights yields total cost. However, the methods are sufficiently laborious that they are rarely used. Another approach is to use a payer perspective (14). In the United States, Medicare diagnosis-related group (DRG) reimbursement rates can be used to define cost. Similar methods are available in other countries. The use of DRGs to assign cost does not account for variation in cost within that DRG and may not even reflect average resource use. Economics of Acute Coronary Syndromes 709 To assess professional costs, it is not sufficient to consider only the primary physicians’ fees alone, as other professionals provide services (15,16). The goal must be to capture all of the professional services for an episode of care. In the United States, there has been an effort to rationalize physician payments by developing a set of scales for services (17). This system, the resource-based relative value scale (RBRVS), was developed over time to try to assess the relative time, physical, and cognitive efforts associated with physician services (17). Each service is assigned a number called the relative value unit (RVU). If the profile of physician services for a procedure or hospitalization is known, then RVUs for each service may be used to develop a proxy for the physician costs. The total RVUs may be converted to a dollar figure by a conversion factor from Medicare or private insur- ance carriers. Developing a profile of professional services is quite laborious and rarely undertaken. An alternative approach is to use published data in which professional serv- ices by DRG are estimated as a percent share of hospital costs (18). Determining the costs of outpatient services presents different challenges in assess- ing resource utilization, including direct and indirect medical costs. Direct costs include physician office visits, medications, procedures and testing, rehabilitation, nursing home stays, and home health services, as well as patient out of pocket expenses, includ- ing travel. Services can be assigned a cost using the Medicare Fee schedule as discussed above. Medication costs can be estimated from compiled prices by sampling pharma- cies or using published wholesale pharmaceutical prices. Indirect productivity costs include missed time from work by the patient or family members. In any case, it is not possible to directly measure all of the indirect costs. For instance, if an executive in a company has a myocardial infarction and is out of work for 6 wk, there may or may not be loss of pay, but the effect on the business cannot readily be determined. Indirect costs, if measured at all, are often confined to family loss of income, and the numbers must be examined with both interest and skepticism. Inflation and Discounting Costs in the future should be deflated by multiplying by a constant to convert from any one year to another, based on the medical inflation rate or the general inflation rate of the consumer price index (CPI) (19). The medical inflation rate is generally larger than of the overall CPI and will give somewhat different figures. Future costs should also be discounted to reflect the opportunity costs of current dollars, i.e., future costs should be expressed at their present value (20). For instance, if a policy maker were given the alternative of spending $1000 now or $1000 in 5 yr to treat a given condition and obtain the same outcome, the decision would always be the latter. Costs are gener- ally discounted at a rate of 3–5%/yr (20). COMPARING COSTS TO OUTCOME Determination of Patient Utility and Quality Adjusted Life Years In the treatment of ACS, it is unusual for one measurement of outcome to be of suf- ficient clinical importance that all other outcome measures may be ignored in clinical decision making. While death generally overwhelms all other outcome measures in importance, these patients may also suffer from considerable disability. Thus, a therapy may be justified based on improved health status alone, even if not life saving. Improved health status should not be thought of as independent of a disease process. 710 Weintraub The relationship of health status to disease process, with a focus on ACS is shown in Fig. 2 (21). Health status includes, symptoms, functional limitations, and the reaction to these limitations, which we may call quality of life. Decreased health status is dependent on the severity of the disease process. To incorporate health status measures into a cost-effectiveness analysis, an overall measure of health status is needed. In prin- ciple, this task may be accomplished through the determination of patient utility. The utility of a therapy or test is the sum of benefits, both positive and negative, that accrues to a patient over time as the result of the procedure (22). More technically, util- ity is a measure of patients’ preferences for one health state over another. We may con- sider the assessment of utility beginning with a decision tree (Fig. 3), which takes a patient at a specific point and then considers, in principal, all possible events up to some Economics of Acute Coronary Syndromes 711 Fig. 2. Measures of health status and their relationship to disease status or severity. Fig. 3. Idealized decision tree for a decision on diagnostic strategy or therapeutic choice. 712 Weintraub point in the future. In this model, nodes with squares represent choices, and nodes with circles represent chance events. In the simplified model shown, a single choice is made, and for each choice, there are two possible outcomes. Each outcome is called a health state. Each health state has a utility and a probability of occurrence. The utility of choice A in Fig. 3 is the sum of the utility of health state 1, times its probability plus the util- ity of health state 2, times its probability. Unlike this simplified model, for any one treat- ment, there may be multiple possible health states; it is generally difficult to determine the probability and utility health states. Utility changes over time, corresponding to changes in health state. The utility of two alternative treatments after suffering an ACS are compared in Fig. 4. After initiating therapy A, the patient may feel well and utility rises. A recurrent symptomatic period between yr 1 and 2 causes utility to fall. With successful treatment, utility rises again. For therapy B, there is no episode of recurrent symptoms, and utility gradually rises. Ultimately, the patients get to the same point, but the patient who has the episode of recurrent heart failure suffers a period of decreased utility. Utility measurement reflects patient preference. One patient may dislike the disability of chest pain enough to be will- ing to undergo more aggressive therapy with revascularization. Another patient may dis- like the difficulties involved with more aggressive care enough to be willing to put up with more functional limitation. Utility may be measured indirectly using either a validated survey, such as the Health Utilities Index (23) or the EuroQol (24) or by directly assessing patient preference. The patient preference methods, Standard Gamble and Time Trade-off (2), ask patients to directly evaluate their current state of health and then evaluate what they would give up or risk to achieve perfect health. The patient preference methods are probably superior to surveys because the evaluation of a patient’s view of his/her own state of health is measured directly, but they are more difficult to administer. In the Time Trade-Off Fig. 4. Theoretical time course of utility for two different therapies for heart failure. With therapy A, there is a dip in utility followed by recovery, while for therapy B, utility gradually rises. Economics of Acute Coronary Syndromes 713 approach, patients weigh the fraction of expected survival they are willing to give up to live in perfect health. With the Standard Gamble, patients weigh what risk of death they are willing to take to live in perfect health. The Standard Gamble is probably superior because it includes the element of risk (2). Utility alone does not provide a final summary measure of outcome, because it does not include life expectancy. A summary measure can be created by combining utility and survival to obtain quality-adjusted life years (QALYs) (Fig. 5) (21,25). Survival, as with cost presented above, is generally discounted, which means that patients value a year of survival at the present time more than a year of survival in the future. The “true” dis- count rate for survival is unknown. Values in the literature for the discount rate have var- ied from 2% to 10%, with 3% being the most popular, and it should be discounted at the same rate as cost (20). Thus, with a discount rate of 3%, next year’s survival is 3% less important than this year’s survival. QALYs is the best summary measure of outcome in a cost-utility analysis because, it incorporates patient value, risk aversion, expected survival, and a discount rate. Cost-Effectiveness and Cost-Utility Analysis Cost-effectiveness is defined as the change in cost per unit increase in effectiveness. If the summary effectiveness measure is in QALYs, then the marginal or incremental cost-effectiveness of therapy or test A compared to therapy or test B is defined as: COST A – COST B /QALYs A – QALYs B . The cost-effectiveness ratio combines the three important outcome measures of utility, survival, and cost (Fig. 5). Cost-effectiveness analysis involves multiple assumptions in measuring both cost and outcome, which introduces uncertainty or error. Uncertainty in clinical microeconom- ics is generally approached through sensitivity analysis. With sensitivity analysis, meas- urements in which there is uncertainty are varied between appropriate ranges, and the analysis is repeated. However, the appropriate ranges for the variables for sensitivity Fig. 5. Interrelationship between survival, utility, and cost to create a cost-utility analysis. analysis may not be clear. Sensitivity analysis offers a sense of the stability of the cost- effectiveness ratio; in some studies the variation in the ratio with sensitivity analysis may be small, while in others it may be sufficiently large that the original point estimate may have little meaning. Therapies that appear cost-effective using only the central point esti- mate may not seem as cost-effective when the underlying assumptions are varied, or a ratio that was marginally cost-effective may seem quite cost-effective when the assump- tions are varied; this may be especially true concerning the cost of a new therapy which may decline over time. In studies in which cost and effectiveness are directly measured, the variability of the cost-effectiveness ratio can be expressed with a 95% confidence interval (CI) determined by boot-strap analysis. COST-EFFECTIVENESS OF THERAPY IN ACS Clinical trials and subsequent economic evaluations have been carried out in most areas of medical decision making concerning ACS. These studies are discussed below and summarized in Table 3. Coronary Care Patients with an acute myocardial infarction, whether ST-segment elevation or not, often suffer life-threatening complications that require rapid high-level intervention. Consequently, the standard of care is generally to admit patients with an acute myocar- dial infarction to a coronary care unit. Admission to these units is costly and relatively few patients benefit from the units’ advanced capabilities. The value of this triage for specific groups of patients can be illuminated through an economic analysis. To address this issue, Tosteson and colleagues made use of clinical and resource uti- lization data from 12,139 emergency department patients who presented with acute chest pain (26). They compared a coronary care unit with admission to an intermediate care facility with central electrocardiographic monitoring and personnel to detect and treat in-hospital complications. Information on the effectiveness of coronary care units is sparse, particularly in this setting of alternatives with some of the same capabilities. Based on data from the Multicenter Chest Pain Study, the authors estimated that mor- tality for patients with an acute myocardial infarction would be 15% higher for admis- sion to an intermediate care unit compared with a coronary care unit (27). Using this assumption, the value of admission to a coronary care unit varied depending on the age of the patient and the initial probability of an acute myocardial infarction. In 1992 dol- lars, for patients who were 55–64 yr old and had a 1% probability of infarction, admis- sion to a coronary care unit had a cost-effectiveness ratio of $1.4 million/yr of life saved, while the same age patients with a 99% probability of an infarction had a cost-effec- tiveness ratio of $15,000/yr of life saved. The cost-effectiveness ratio was less than $75,000/yr of life saved if the probability of infarction exceeded 20%. The cost-effec- tiveness of coronary care units was less favorable for younger patients because of their lower underlying risk of a life-threatening complication. Pharmacologic Reperfusion With the advent of information about the efficacy of thrombolytic therapy for the treatment of patients with suspected acute myocardial infarction, interest turned to the economic value of this intervention. Since the two largest and earliest trials of 714 Weintraub [...]... al A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group (ESSENCE) N Engl J Med 1997;337:447–452 50 Mark DB, Cowper PA, Berkowitz SD, et al Economic assessment of low-molecular-weight heparin (enoxaparin) versus unfractionated heparin in acute coronary syndrome... experiences of 24 individuals while trying to quit smoking Based on a Twelve Step philosophy, this book outlines a three-month, one-day-at-a-time program to begin recovery from nicotine addiction No-Nag, No-Guilt: Do-It-Your-Own Way Guide to Quitting Smoking (Tom Ferguson, Random House, Inc publishers, 1998) Dr Ferguson is an experienced medical writer who avoids anti-smoking rhetoric Instead, he offers... 1982;96 :102 109 10 Finkler SA, Ward DM Essentials of cost accounting for Health Care Organizations 2nd edition Aspen Publication, 1999, pp 11–43 11 Hlatky MA, Lipscomb J, Nelson C, et al Resource use and cost of initial coronary revascularization: coronary angioplasty versus coronary bypass surgery Circulation 1990;82(Suppl IV):IV-208–IV-213 12 Weintraub WS, Mauldin PD, Talley JD, et al Determinants of. .. ML, Vos J, Martens LL Cost-utility analysis of thrombolytic therapy Eur Heart J 1991;12:694–699 31 Midgette AS, Wong JB, Beshansky JR, Porath A, Fleming C, Pauker SG Cost-effectiveness of streptokinase for acute myocardial infarction: a combined meta-analysis and decision analysis of the effects of infarct location and of likelihood of infarction Med Decis Making 1994;14 :108 –117 32 Herve C, Castiel... the setting of PCI, but especially so in patients undergoing PCI in the setting of ACS Treatment of high risk patients undergoing coronary revascularization reduces the short-term risk of the composite of death, myocardial infarction or coronary revascularization (51) An economic analysis of the Early Postmenopausal Intervention Cohort (EPIC) trial found that the use of this therapy for high-risk patients... Economic impact of GPIIB/IIIA blockade after high-risk angioplasty: results from the RESTORE trial Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis J Am Coll Cardiol 1999;34 :106 1 106 6 55 Weintraub WS, Culler SD, Kosinski A, et al Economics, health-related quality of life, and cost-effectiveness methods for the TACTICS (Treat Angina With Aggrastat [tirofiban]] and Determine Cost of Therapy... restrict their smoking near the patient • Schedule follow-up visit Follow-up contact should occur 1 wk after the Quit Day SHORT-TERM COPING STRATEGIES • Remove all smoking-related paraphernalia (ashtrays, lighters, etc.) from the home, office, and car • Keep cigarettes out of easy reach (in an out -of- the-way kitchen cupboard, in the garage, in the trunk of the car) • Be prepared to ask others to modify their... health care costs (54) Neither of these studies directly examined the use of these agents in patients with acute ischemic syndromes TACTICS-TIMI 18 trial has specifically addressed this issue (55) Economics of Acute Coronary Syndromes 719 Invasive vs Conservative Strategies in Non-ST-Segment Elevation ACS The relative value of an invasive strategy with early catheterization and possible revascularization... V Cost-benefit analysis of thrombolytic therapy Eur Heart J 1990;11 :100 6 101 0 33 Mark DB, Hlatky MA, Califf RM, et al Cost effectiveness of thrombolytic therapy with tissue plasminogen activator as compared with streptokinase for acute myocardial infarction N Engl J Med 1995; 332:1418–1424 34 Kalish SC, Gurwitz JH, Krumholz HM, Avorn J A cost-effectiveness model of thrombolytic therapy for acute myocardial... studies of patient charges for rehabilitation services and averted medical expenses for hospitalizations after rehabilitation Cardiac rehabilitation participants had an incremental life expectancy of 0.202 yr In 1988, the average cost of rehabilitation and exercise testing was $1485, partially offset by averted cardiac rehospitalizations of $850/patient A cost-effectiveness value of $2130/yr of life . either top-down or bottom- up accounting (10) . Top-down costing involves dividing all the money spent on a hos- pitalization or procedures by the number of episodes of care of the particular. a cost-effec- tiveness ratio of $15,000/yr of life saved. The cost-effectiveness ratio was less than $75,000/yr of life saved if the probability of infarction exceeded 20%. The cost-effec- tiveness. al. A comparison of low-molecular-weight heparin with unfrac- tionated heparin for unstable coronary artery disease. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events