Critical concepts in cost-effectiveness for cardiovascular specialists

Critical concepts in cost-effectiveness for cardiovascular specialists Robert M. Califf, MD, and Eric L. Eisenstein, DBA Durham, NC

We are entering a new era of therapeutics in medicine. The number of new effective therapies will continue to increase at a faster rate than the already overwhelming pace of recent therapeutic development. Genomics and proteomics will radically shorten the time between identification of a pathophysiologic pathway and development of a molecule or device that can be used therapeutically. These applications, made possible by enhanced understanding of biologic processes, will increase the number of new therapies and will also be substantially more potent in altering the biology of the target disease. This change is occurring at a time when the health system is straining under the pressure of increasing costs of new medical products. The reaction to this pressure has been to devise proscriptive approaches to the independence of practitioners as they make treatment recommendations. In a rational world, health system decisions would be made based on the value (health benefit) of a proposed therapeutic approach relative to its cost. The only evident alternative would be to give preferences to those who exert the most political pressure or have the most money. Cardiovascular therapies have the most detailed information about cost and effectiveness, which is why cardiovascular practitioners must lead the application of costeffectiveness data.

The current situation Coronary heart disease remains the largest cause of death and disability both on a global basis and in the United States.1 Because of the aging of the population, the incidence of new cardiovascular events will continue to increase in the United States at least through the next 20 years,2 while in developing countries an epidemic of atherosclerosis is occurring because of lifestyle changes. Therefore decisions made concerning routine treatments of coronary heart disease have a major impact on the national health and the national budget. At the local level, the purchasing of pharmaceutical From the Division of Cardiology, Department of Medicine, Duke University Medical Center. Reprint requests: Robert M. Califf, MD, Duke Clinical Research Institute, P.O. Box 17969, Durham, NC 27715. Am Heart J 2000;140:S143-7. Copyright © 2000 by Mosby, Inc. 0002-8703/00/$12.00 + 0 4/0/111610 doi:10.1067/mhj.2000.111610

agents has changed substantially. In the recent past, physicians wrote prescriptions with little overview and review. Pharmacy and Therapeutics Committees were relatively autonomous and represented the views of prescribing physicians regarding therapies that should be used. We have entered an era in which the Pharmacy and Therapeutics Committee’s budget is carefully managed because it can be manipulated as a line item. Unfortunately, this “silo” mentality prevents an integrated assessment of what can be achieved by more effective prescribing. Thus when a new pharmaceutical agent might achieve savings in other parts of the health care system, it is difficult to identify those savings or to make the argument for their use on the basis of financial benefit to an integrated health system. Increasingly, hospital systems, health systems, managed care organizations, and federal programs are developing consolidated approaches for managing pharmaceutical choices and expenses. On an outpatient basis, pharmaceutical benefits managers now handle a large portion of the management of prescription benefits for insurance companies and managed care organizations. By “carving out” the benefit, these pharmaceutical benefits managers are able to provide an efficiency based on an economy of scale and just-intime distribution; however, because they make their profit by reducing the cost of pharmaceutical agents, many have questioned their ability to fairly judge new product advances.3 Although the press has focused on the use of the human genome to predict disease, an understanding of the manner in which genes produce proteins and the function of those proteins (proteomics) is likely to have an even greater effect on therapeutics. The ability to identify and manufacture biologically active proteins will increase dramatically, making the number of new biologically active substances much larger. This escalation of therapeutic advances will accelerate the pressure on organized Pharmacy and Therapeutics Committees and pharmaceutical benefits managers. This dynamic at the local and regional level has essentially made pharmaceutical costs a “zero-sum game.” Given the number of strikingly beneficial drugs and biologics that will be available in the near future, an old agent will likely need to be dropped when a new one is added. The question then is what criteria should determine which therapies should be used and how they should be used.

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Assessment tools When a product intended to benefit patients is evaluated, the basic equation for assessment is simple: compare the costs of the therapy with its effectiveness in terms of human health. Specifically, the formula calls for comparing the costs of two treatments with their effectiveness: CE =

Cnew – Cstandard Enew – Estandard

where C = costs and E = effectiveness. Unfortunately, this information is rarely available at the time the hospital formulary is considering the two therapies, nor is adequate information available for most drugs that are already commonly in use. The assessment of cost is not as simple as it might seem.4 To be used in a cost-effectiveness analysis, cost must be measured in terms not only of the therapy alone but also of the total cost of care for the medical problem. Thus a treatment that may be more expensive in the short run may save money “downstream” by reducing expensive complications of the illness. On the other hand, a less expensive treatment could induce additional costs downstream because of a lack of effectiveness. This phenomenon is most evident today in terms of the benefits of treatment for heart failure that keep patients out of the hospital. The cost of angiotensinconverting enzyme inhibitors, for example, may be totally offset by the reduction in hospitalizations for compliant patients with heart failure. Therefore in addition to hospital costs, outpatient costs should also be captured within a relevant time frame. Evaluating effectiveness is at least as difficult as assessing cost. Many medical products reach the market on the basis of small studies in limited populations with surrogate end points. For the purposes of analysis of cost-effectiveness, the clinical benefit must be measured in tangible human outcomes (survival, clinical events, and quality of life). The studies used to make these estimates must also be representative of the population treated in practice. Unfortunately, we currently have little societal agreement on how to account for improvement in quality of life in the absence of increased longevity or how to consider worse quality of life in the context of better survival. Progress is being made in understanding the concept of “quality-adjusted life years,”5 but few clinicians are willing to accept these measures for direct decision making comparing one product with another. Information on cost and effectiveness must be measured not only for the treatment of interest but also for the alternative treatment. In the case of a new type of treatment, the comparison should be the normal treatment of the disease. In the case of a therapy designed to replace an existing therapy, an accurate estimate of the cost of the old treatment must be available.

The time horizon of a cost-effectiveness analysis is critical. For therapies that change survival, the relevant time point is the lifetime of the patient. Because no one advocates withholding new therapies until a new generation of patients exists, life expectancy must be estimated by modeling expected longevity. This modeling requires a number of assumptions that must be made in an unbiased manner. Cost-effectiveness assessments must be based on empirical data. A conundrum in the field is that an observational study is, by its nature, not controlled and highly subject to confounding, whereas the results of a controlled clinical trial may not be able to be generalized. Clinical trials are frequently criticized by those evaluating cost and effectiveness because they often have protocol-based visits and evaluations that are not done in routine practice, because placebo-controlled studies induce different patient and physician behavior, and because multiple characteristics that would not prohibit treatment in practice are commonly used as exclusion criteria in trials. We believe that the ideal approach is to conduct outcome-based clinical trials that include the population intended to be treated and that require multiple procedures that are not a routine part of clinical practice.6 Perhaps the most dangerous practice is the local cost-effectiveness study. Because many physicians, pharmacists, and administrators are suspicious that the results of a multicenter trial may not pertain to their particular environment, it seems reasonable to them to evaluate the experience in their individual hospital or managed care organization by comparing those who received the treatment with those who did not. This approach is unreliable because it provides an opportunity for treatment selection bias to produce spurious results and because the sample size will be too small to draw conclusions. These very problems are the reason that large, multicenter trials are required to measure typical treatment effects. What may be less appreciated is that the sample size to measure a difference in cost may exceed the sample size required to measure a clinical difference because of the skewed distribution of cost data.7 Assuming that we have an agreed-upon assessment of cost relative to an increase in survival, how do we determine whether the benefit is worth the additional cost? Unfortunately, we do not have societal agreement on this issue. The only solid benchmark pertains to renal dialysis. In July 1972, a law was passed by Congress guaranteeing medical coverage for patients with this need. Although the estimates are extremely rough, several studies have estimated that the cost for dialysis is between $35,000 and $60,000 per year of life saved.8,9 A reasonable case can be made that it would be unfair to deny a treatment to a patient with another disease if its cost was less than the cost for each year of

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life saved by dialysis, because dialysis is considered a national right. The most commonly misunderstood fundamental concept is that of incremental cost-effectiveness. In most areas of life, to receive a benefit, we expect to pay more. The decision to purchase something usually is not based on an expectation of saving money; rather, we want to know whether the purchase is worth the price. Yet most clinicians (and politicians) continue to hope that investing in medical care will save money. Consider most approaches to preventive medicine: most primary prevention measures (better diet, exercise, etc) do not eliminate the risk of diseases but rather defer the disease until later in life. Ultimately, the cost to society is greater, but in most cases, we consider the additional health benefit worth the extra cost.

Rules of assessment Because the evaluation of cost-effectiveness typically requires both modeling of abstract data and direct comparison with alternative approaches, there has been considerable concern about whether such evaluations are being done fairly. The New England Journal of Medicine initially decided to forego publishing any cost-effectiveness analyses funded by industry because of concerns about bias. This policy was rapidly retracted, and a set of guidelines was published.10 The guidelines require that industry-funded studies be underwritten by a grant to a not-for-profit entity, not to an individual or group. Authors should not receive direct salary from a sponsor or competitor or have equity interest in the sponsor or an ongoing consultancy or scientific advisory-board relationship with the sponsor. Authors must state in writing that they had independence as they designed the study, interpreted the data, wrote the report, and made decisions regarding publication, regardless of the results of the analyses. The investigators must retain access to the database, and the manuscript must contain all data used in the analyses, the assumptions on which the analyses are based, and the model used in the analyses. Finally, the model used to calculate life expectancy must be lucid enough for a nonprofessional reader to comprehend.

Data with abciximab The sequence of clinical trials with abciximab provides an example of cost-effectiveness data developed directly from large clinical trials. These trials were developed with the prospective construct that analyzing costs as part of the trial would provide a basis for rationalizing the use of abciximab in clinical practice. Each trial was designed to enroll typical patients undergoing percutaneous intervention (PCI) so that the results would be generalizable. Costs were estimated

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directly from hospital bills and from records of followup visits. Life expectancy was calculated with data for the duration of available follow-up and then extrapolation from the survival of similar patients monitored in the Duke Databank for Cardiovascular Diseases.11, 12 The details of these trials are covered in other sections of this supplement; this review will focus on the costeffectiveness issues. Although it could be argued that the reduction in ischemic events seen in the clinical trials of abciximab derive from the class effect shared by all GPIIb/IIIa inhibitors, the main reason to focus on abciximab is that it is the only GPIIb/IIIa inhibitor that has been proven to reduce mortality. The EPIC trial compared abciximab with placebo in patients at high risk who were undergoing coronary angioplasty.13 The trial was designed at a time when the effects of blockade of the glycoprotein (GP)IIb/IIIa receptor were entirely unknown. The major finding was a reduction in ischemic events at the primary designated end point time of 30 days. Fortunately, the blind was maintained, and a surprising continued divergence of the event curves was observed in long-term follow-up.14 Although these findings raised the intriguing possibility that abciximab might improve survival, this was not the major hypothesis of the EPIC trial, and thus the cost analysis focused on the issue of cost offsets.15 Indeed, the incremental cost of adding abciximab to an interventional procedure was partially offset by a reduction in ischemic complications, but an increase in bleeding complications added to the cost. Because of the increase in bleeding in EPIC, the EPILOG trial was designed to examine outcomes with abciximab and a lower dose of heparin, with meticulous attention paid to groin care in an effort to reduce bleeding complications.16 The trial showed that the benefit could indeed be maintained, and the bleeding complications could be reduced to the rate of complications of heparin alone in the setting of PCI. Just as the EPILOG trial was finished, interventional cardiologists turned to stenting because of the demonstrated benefit of preventing abrupt vessel closure and late restenosis. The joint impact on cost of widespread use of stents and abciximab met considerable resistance, and the obvious questions were: Are the two treatments additive or synergistic? Do they counteract each other? Does one eliminate the need for the other? Accordingly, the EPISTENT study was designed, randomly allocating patients to stenting, abciximab, or both.17 The result of the trial was surprising to many. Stenting reduced restenosis as expected but had no effect on periprocedural myocardial necrosis. Abciximab reduced periprocedural myocardial necrosis but had no effect on restenosis. For the 30-day end point of major adverse cardiac events, therefore, the combination of stenting and abciximab was superior to either alone. However, one of the most important findings in

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Figure

Mortality benefit with abciximab in patients undergoing PCI.

Table CE league table New technology

Existing technology

Patient population

Cost/YOLS

PTCA Exercise stress test β-blockers t-PA CABG Hypertension screening

Medical therapy No testing No therapy Streptokinase Medical therapy No screening

Men age 55 with severe angina Age 60 with mild pain and no left ventricular dysfunction Hypertensive age 35-64, no heart disease and 95 mm Hg Anterior MI, age 41-60 Two-vessel coronary artery disease Asymptomatic woman age 20

$8,900 $15,600 $16,800 $60,000 $90,200 $104,600

Data from Mark 20 and Tengs.21 Costs adjusted to 1998 dollars with the Consumer Price Index. YOLS, Years of life saved; PTCA, Percutaneous transluminal coronary angioplasty; t-PA, tissue-type plasminogen activator; MI, myocardial infarction; CABG, coronary artery bypass grafting.

the EPISTENT trial was that at one year, mortality was lower in patients randomized to receive both abciximab and stent deployment than it was in those patients randomized to either abciximab or stents individually.18 When the costs of the treatment approaches were added up, the combination of stents and abciximab cost an extra $932 compared with stenting alone and an extra $582 compared with abciximab alone without stenting. Considering the extra years of life added, this amounts to approximately $6213 per year of life saved compared with stenting alone and $5291 per year of life saved compared with abciximab alone: considerably better than many other therapies. The league table (Table) gives perspective for some other commonly used interventions. This positive but unanticipated finding from EPISTENT occurred at a time when all the follow-up data from other trials of abciximab were being compiled. The systematic overview of all trials using the bolus and

12-hour infusion of abciximab showed a significant reduction in mortality that was sustained over the duration of follow-up (Figure). The combined results of the overview and the EPISTENT trial as a single trial provide convincing evidence of the impact of abciximab on survival. The costeffectiveness analysis clearly demonstrates that the additional benefit is achieved at a cost within the range of “economically attractive” medical care. Despite these demonstrated benefits, the use of GPIIb/IIIa inhibitors including abciximab, eptifibatide, and tirofiban remains approximately 50% for PCI procedures.

Interface of cost-effectiveness with medical errors Recently, the Institute of Medicine in the United States has focused attention on medical errors as an issue to be addressed by the medical community.19 An error is defined as failure to execute the correct plan in

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the care of a patient or failure to have the correct plan. This definition, borrowed from other high-risk industries such as the aerospace industry and automobile safety systems, leaves many issues of medical practice at risk of being termed medical errors. A fundamental question to be addressed is when failure to use a treatment that has been shown to provide a clinical benefit constitutes an error. In the case of GPIIb/IIIa inhibitors in PCI, the evidence of benefit is overwhelming, yet many cardiologists have argued that reductions in measures of myocardial necrosis do not constitute proof of enough benefit to justify routine use. One measure that might be suggested as proof is the agreement by major professional societies or governmental organizations that the treatment is recommended in a Clinical Practice Guideline. Indeed, the recently published American College of Cardiology/ American Heart Association Guidelines on Unstable Angina place the use of GPIIb/IIIa inhibitors as a Class I indication when PCI is used. The next level of discussion concerns the perspective of incremental cost-effectiveness. Is it the right plan to use a therapy that costs more than the societal benchmark for the benefit when there are not enough resources to pay for all effective treatments? The evidence for the use of abciximab in PCI is beyond dispute, particularly when compared with the many other commonly used therapies. The demonstrated economic attractiveness of GPIIb/IIIa inhibitors raises the question of whether failure to use them is a medical error. This question will be a topic of hot debate over the next several years.

Conclusion The incremental effectiveness and cost of therapeutic approaches can be measured, and these measures will be needed to make difficult decisions in our new therapeutic environment. Coronary heart disease, as the leading cause of death and disability, will likely be a testing ground for concepts about how to make decisions based on incremental cost-effectiveness. In a series of clinical trials, abciximab has improved clinical outcomes including survival at a cost below the commonly quoted threshold of renal dialysis. Yet a substantial number of patients are undergoing PCI without the benefit of this effective treatment. The debate about whether failure to act on such medical evidence will be a “medical error” will be vibrant.

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