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The Economics of Venous Thromboembolism Prophylaxis^*

A Primer for Clinicians

^* From the Pulmonary and Critical Care Medicine Division (Dr. Davidson), Swedish Medical Center and University of Washington School of Medicine, Seattle, WA; Pharmaceutical Outcomes Research and Policy Program (Dr. Sullivan), University of Washington, Seattle, WA; Sir Mortimer B. Davis Jewish General Hospital (Dr. Kahn), Montreal, QC, Canada; Aarhus University Hospital (County) (Dr. Borris), Aarhus, Denmark; Academic Medical Center (Dr. Bossuyt), Amsterdam, the Netherlands; and College of Public Health (Dr. Raskob), University of Oklahoma Health Sciences Center, Oklahoma City, OK.

Correspondence to: Bruce L. Davidson, MD, MPH, FCCP, 801 Broadway, Suite 915, Seattle, WA 98122; e-mail: brucedavidson{at}pobox.com

	Abstract

TOP Abstract Introduction Relevance of Cost-effectiveness... Efficacy, Safety, and... Factors With Economic Impact... Outcomes in Economic Evaluations... Challenges in Building the... Interpreting Cost-effectiveness... References

 
Cost-effectiveness information can help health-system participants make decisions about diagnostic or therapeutic innovations that are more expensive but incrementally safe and effective. However, these analyses cannot help decide whether a less expensive approach is "sufficient" and funds ought to be allocated to other medical issues entirely. At present, formulary committees are commonly determining that medications are "mostly equivalent" in efficacy and safety and choosing individual medications or classes of medications based on cost. Clinicians may not agree with these decisions and will need to understand their rationale. For prophylaxis of venous thromboembolism after hip and knee replacement and hip fracture surgery, many preventive modalities are available with different safety and efficacy profiles and different costs. It is possible to list the important safety and efficacy outcomes of prophylaxis, estimate their incidences and costs, and "model" comparisons of one modality vs another, in order to help decide whether one is preferable.

Key Words: cost-effectiveness • deep-vein thrombosis • health economics • pulmonary embolism • venous thromboembolism

	Introduction

TOP Abstract Introduction Relevance of Cost-effectiveness... Efficacy, Safety, and... Factors With Economic Impact... Outcomes in Economic Evaluations... Challenges in Building the... Interpreting Cost-effectiveness... References

 
Cost-effective patient treatment is desirable because lack of financial resources contributes to the inability of society to fully protect against disease. To gauge the cost-effectiveness of different medical interventions including diagnostic tests, disease treatments, and preventive treatments, a separate methodology has been devised: the economic evaluation of health-care interventions. This discipline is subject to a number of unintentional potential biases, in part because of its dependence on cost determinations, which are nearly always relative and subject to both judgment and significant market fluctuations.

In the current environment, in which cost is an important factor for determining which drugs (sometimes classes of drugs) will be made available to patients (or classes of patients) on inpatient and outpatient formularies, individual clinicians can play a role if they understand the elements of cost-effectiveness analysis sufficiently well to critically evaluate proposals and decisions made by formulary committees. The latter may have less clinical insight and responsibility than the clinician, but the clinician may nevertheless be bound by their decisions. In settings where these decisions are so "final" that they might deny potentially beneficial therapy to a patient in need, reviewing the rationale for such decisions has become a responsibility tantamount to understanding the risks and benefits of drugs and procedures.

With respect to prevention of venous thromboembolism (VTE), ie, pulmonary embolism (PE) and deep-vein thrombosis (DVT), this article will present considerations for determining the benefits and costs of thrombosis and bleeding outcomes in a well-characterized patient group at high VTE risk: those undergoing hip and knee replacement and hip fracture surgery. Short-term as well as long-term costs and benefits, an example of how one estimates outcome rates in the absence of specific hard data, and suggestions about how to interpret the results of a model will be presented.

	Relevance of Cost-effectiveness Analysis

TOP Abstract Introduction Relevance of Cost-effectiveness... Efficacy, Safety, and... Factors With Economic Impact... Outcomes in Economic Evaluations... Challenges in Building the... Interpreting Cost-effectiveness... References

 
A recent cost-effectiveness analysis in the New England Journal of Medicine comparing aspirin vs the platelet adenosine diphosphate-receptor antagonist clopidigrel for secondary prevention of coronary heart disease concluded that "increased prescription of aspirin for secondary prevention of coronary heart disease is attractive from a cost-effectiveness perspective. Because clopidogrel is more costly, its incremental cost effectiveness is currently unattractive, unless its use is restricted to patients who are ineligible for aspirin".¹ To this, an invited editorialist responded,

The implications of the conclusions of Gaspoz et al are deeply troubling to me ... To abandon the search for improved therapies by describing them as unattractive on the basis of cost would represent an enormous disservice to our patients and would distinguish attempts to improve patient care from the quest for better automobiles, audio systems, or computers, or from any other area of human endeavor. Surely the search for better drug therapy is at least as important as the search for improved audio performance! . . If organized medicine, in contrast to third-party payers, takes the position that increments in therapeutic benefit must be achieved at costs similar to those of current therapy, however cheap that therapy, then we are destined to be trapped at our current level of therapeutic efficacy forever—a very unattractive prospect.²

These comments illustrate the range of conclusions that might be drawn from cost-effectiveness analyses. At present, hospital pharmacies and pharmacy benefit programs of health insurance providers are often given fixed budgets for drug costs. This practice, termed silo or global budgeting, means that paying for expensive drugs beyond some anticipated level leads to budget shortfalls in other areas unless cutbacks are made or additional funds provided. Commodity products, such as aspirin and unfractionated heparin, will inevitably be less expensive, hence potentially preferred, compared to more recently developed, "improved" products with comparable adverse effect profiles (such as low-molecular-weight heparins [LMWHs] or the pentasaccharide fondaparinux). The issue critical in decision making ought to be whether the "improvement" in drug warrants the increase in cost. To properly evaluate this question, both the costs and benefits require estimation. Where an existing drug is effective, for example, the cost associated with an improvement in efficacy can be modeled using the clinical trial results from the efficacy comparison.

A previously published cost-effectiveness model³ (from 1987) for VTE prophylaxis in perioperative orthopedic surgery joint replacement patients compared several methods vs no prophylaxis other than diagnosis and treatment of VTE when it became clinically evident. This model, and several subsequent iterations with different prophylactic measures,^{4 5 6 7} found that any type of prophylaxis is cost saving (not merely more efficacious) compared to no prophylaxis at all. Moreover, short-term use of LMWHs in this setting, as well as extended (eg, 30-day) prophylaxis with LMWHs appeared cost-effective in some studies.^{8 9}

Limitations of this model³ were that the risk of VTE was included solely for the period of hospitalization but not beyond, the cost of side effects (primarily bleeding complications from prophylactic therapy) were not included, and the cost of long-term consequences of VTE (eg, postthrombotic syndrome) were not included. Epidemiologic studies and clinical trials^{9 10} have been persuasive that the risk of clinically evident VTE continues to accumulate beyond the day of hospital discharge (currently often the third postoperative day) in joint replacement and hip fracture patients. Major bleeding, variously defined from study to study but with an incidence of approximately 2 to 5% in patients receiving joint replacement,^{11 12 13 14 15 16} does carry a cost for prolonged hospitalization, transfusions and their complications, and occasionally invasive procedures to achieve hemostasis. Finally, while the incidence of postthrombotic syndrome in orthopedic surgical patients after postoperative DVT (fully treated) is controversial, it is agreed that the long-term management of postthrombotic syndrome does carry a cost that might be avoidable had the initial DVT not occurred.^{17 18} Estimating the incidences and costs for these outcomes ought to be part of determining the cost-effectiveness of prophylactic therapy.

With respect to VTE prophylaxis, evaluating cost-effectiveness is further relevant for several reasons. An injected anticoagulant (unfractionated heparin) and an oral anticoagulant (warfarin) have dominated clinical practice for a number of years, so clinicians have become quite experienced with their use, including use in particularly fragile populations (those with renal or hepatic insufficiency, the very frail, even actively bleeding patients). However, despite being quite inexpensive, prophylactic unfractionated heparin carries the risk of heparin-induced thrombocytopenia. Warfarin carries the risk of bleeding, which can be major and devastating even within the therapeutic range,¹⁹ and the certain knowledge that each patient’s dosage must be individually titrated and monitored over time. Advocates of newer anticoagulants who are urging their adoption point to this collection of disadvantages, while guardians of the pharmacy budgets seek to analyze the cost-effectiveness of newer drugs.

	Efficacy, Safety, and Acquisition Costs of VTE Prophylaxis in Hip and Knee Replacement and Hip Fracture Patients

TOP Abstract Introduction Relevance of Cost-effectiveness... Efficacy, Safety, and... Factors With Economic Impact... Outcomes in Economic Evaluations... Challenges in Building the... Interpreting Cost-effectiveness... References

 
The American College of Chest Physicians consensus committee recently updated prior recommendations for VTE prophylaxis, concluding that LMWH and warfarin were recommended for these patient groups.²⁰ Other methods, such as aspirin (not recommended) and mechanical methods (perhaps to be used in combination) were also reviewed. Subsequent to the publication of the recommendations in January 2001, data have been published on the first of a series of synthetic pentasaccharides, fondaparinux. This drug binds to antithrombin III and inhibits activated factor X as does unfractionated heparin and LMWHs but, unlike them, shows zero antithrombin (anti-IIa) activity, activity previously believed to be the critically important mode of anticoagulant action.²¹ The clinical trials^{11 12 13 14 15 16 21} that studied fondaparinux have engendered some controversy with respect to timing of dosing and bleeding rates, but individually, and in a meta-analysis,²² clearly show substantially improved efficacy without a significantly increased risk of bleeding.

Prophylactic methods also differ with respect to purchase cost and related expense. The lead author believes the acquisition costs listed herein, obtained by personally surveying several hospitals, are generally accurate in at least some of the United States at the time of this writing. A once-daily injection of 2.5 mg of fondaparinux in an achievable discounted situation costs a hospital approximately $30. Two 30-mg syringes of enoxaparin per day cost approximately $24; for physicians using the European regimen of 40 mg qd, the daily cost is approximately $16. The LMWH dalteparin dosed at 5,000 U qd costs approximately $13 a day. Warfarin costs the patient $0.30 per pill, but each visit to an anticoagulation clinic for international normalized ratio measurement can be reimbursed by the health system (eg, Medicare) at a "room fee" of $60. Knee-high intermittent pneumatic compression devices are not of use when a patient is ambulating (as patients are encouraged to do), and cost approximately $18 for a recycled sterilized pair (one-time cost) and approximately $8 per day for rental of the cycling inflation device.

	Factors With Economic Impact in Prevention of VTE in Hip and Knee Replacement and Hip Fracture Patients

TOP Abstract Introduction Relevance of Cost-effectiveness... Efficacy, Safety, and... Factors With Economic Impact... Outcomes in Economic Evaluations... Challenges in Building the... Interpreting Cost-effectiveness... References

 
Each drug or method is associated with an absolute risk reduction vs some comparator (usually an active comparator rather than placebo) for an untoward outcome (usually a clot seen at venography or symptomatic VTE), as well as a complication rate (eg, major bleeding) and a financial cost for acquisition, administration and, in the case of warfarin, monitoring of the drug. The risk reduction and complication rates are obtained from one or more clinical studies.

Patients with symptomatic VTE after failed prophylaxis require treatment. This might be as simple as LMWH followed by warfarin, all administered in outpatient status for 3 months, or as complex as admission for severe illness that results in death consequent to PE or other complications. For each type of patient and all in between, there will be direct costs, as well as indirect ones for missed work, etc. The latter are considerably more difficult to measure, but their inclusion is important if the analysis is from a societal perspective, rather than from the perspective of the insurer.²³

The optimal duration of prophylaxis in these patients, which can affect cost as well as safety and efficacy, is uncertain for several reasons. Clinical trial results regularly add to the evidence but cannot provide the "truth" about optimal duration; instead, they provide data for the time periods they have chosen to study. Moreover, results are inconsistent across types of surgery. In the report of one methodologically strong study,²⁴ prophylaxis for 1 month, compared to 1 week, reduced the rate of thrombosis in patients with hip replacement but not patients with knee replacement. The ideal model for cost-effectiveness analyses would allow different durations of therapy to be compared.

Symptomatic VTE appears to carry the long-term risks of both recurrence and organ-specific complications. For DVT, this includes postthrombotic syndrome with associated chronic venous insufficiency and venous ulcers; for PE, chronic thromboembolic pulmonary hypertension. The incidence of postthrombotic syndrome after symptomatic DVT has been reported as 5.6% at 90 days and 24% at 5 years.¹⁷ After asymptomatic DVT, the DVT type most often discovered in patients receiving joint replacement studied by venography during antithrombotic drug development, the incidence of postthrombotic syndrome has been reported (after a course of therapeutic anticoagulation) to be 24% in one study²⁵ and 4% in another study.²⁶ A prospective study of the incidence of chronic thromboembolic pulmonary hypertension has not been published; the incidence is likely between 0.5% and 3%.

	Outcomes in Economic Evaluations of VTE Prophylaxis

TOP Abstract Introduction Relevance of Cost-effectiveness... Efficacy, Safety, and... Factors With Economic Impact... Outcomes in Economic Evaluations... Challenges in Building the... Interpreting Cost-effectiveness... References

 
An improved system for modeling costs would include acute VTE outcomes beyond hospital discharge, possibly up to 3 months, since VTE events after hip replacement may continue that long, and even longer for postthrombotic syndrome. They should include costs for symptomatic events rather than asymptomatic events, since patients and their clinicians are unaware of the latter. For this reason, costs of diagnosing and treating symptomatic VTE, symptomatic bleeding, and symptomatic postthrombotic syndrome should be included, but not costs of venography, of asymptomatic clots identified by venography, or self-limited episodes of epistaxis, oozing from a surgical wound, or other similar minor bleeding.

	Challenges in Building the Economic Evaluation Model for VTE Prophylaxis

TOP Abstract Introduction Relevance of Cost-effectiveness... Efficacy, Safety, and... Factors With Economic Impact... Outcomes in Economic Evaluations... Challenges in Building the... Interpreting Cost-effectiveness... References

 
Providing incidence rates and costs for this type of cost-effectiveness model are not always straightforward. For example, given the wide disparity between two reports^{25 26} for postthrombotic syndrome rates after asymptomatic (but treated) VTE in orthopedic surgical patients, the incidence rate to be "plugged into a model" is not apparent. A weighted average of the two reported series (12%) seems a reasonable approach.

How should cost figures for treatment of symptomatic VTE (ie, prophylaxis failure) be assigned? Whether a patient is treated in hospital (even for a day or two, which triggers payment of the entire Medicare diagnosis-related group amount) or as an outpatient is often due to fluctuating patient circumstance and physician preference rather than a decision based on data culled from journal articles. The incidence and costs associated with diagnostic workups for suspected VTE that do not bear fruit, hence do not lead to treatment, are not easily ascertained.

The incidence of symptomatic VTE in the months following hip fracture surgery is likewise not evident from large studies. Instead, one could propose extrapolating from hip replacement data. For example, in the large Pulmonary Embolism Prevention clinical trial,²⁷ the incidence of symptomatic PE for patients with hip fracture compared to patients with hip replacement was 2.6% to 1.5%, a ratio of 1.7. One could use this factor to multiply the observed rate of symptomatic VTE over several weeks from available hip replacement trials to obtain an estimated rate for VTE after similar duration observation of patients with hip fracture.

Given the estimates inherent in arriving at costs from estimated or extrapolated incidence rates, fluctuating prices, aggregated payment claims databases, etc, how robust can conclusions be? A sensitivity analysis is usually performed to address this question. This type of analysis would take key variables (such as the incidence of postthrombotic syndrome, or the cost of a prophylactic drug) and widely vary their values over a credible range, eg by 50%, or to the extremes of a 95% confidence interval for an estimate, to see if the overall conclusion changes. These estimates can be provided in a "torpedo" diagram, so named because of horizontal bars of varying width, each for a different variable, one on top of another, symmetric with respect to the origin, presented on a figure.

	Interpreting Cost-effectiveness Analyses

TOP Abstract Introduction Relevance of Cost-effectiveness... Efficacy, Safety, and... Factors With Economic Impact... Outcomes in Economic Evaluations... Challenges in Building the... Interpreting Cost-effectiveness... References

 
Cost-effectiveness analyses are usually a beginning for discussion, rather than the end of it, because, as emphasized in this article, they represent estimates. Moreover, even if prepared by unbiased scientists, they are often sponsored by proponents of a particular treatment, eg, a prophylaxis advocate or pharmaceutical company, an entity usually not taking into account other competitors for funds in the same health system (eg, more effective early diagnosis of curable lung cancer).

Since medical practice should employ available safe and effective methods to prevent and ameliorate disease, clinicians can generally adopt the posture that substantial improvements in therapy that are safe should be used if they appear reasonably cost-effective. If the relative effectiveness of two interventions are known, one can be weighed against the other with respect to costs to determine if the more effective intervention costs more and, if so, how much more. If these types of analyses point toward superior effectiveness or safety, or both, at equivalent or lower cost, the onus should fall on the health system to justify denying a considerably more effective, equally safe, cost-neutral alternative. If the cost of such an alternative is considerably more, the decision becomes more complex and may require individualizing the better but more expensive therapy, directing it to selected patients. The concept of rationing therapy in this way is one of the most disagreeable aspects of medicine.

	Footnotes

 
This research was supported by an unrestricted educational grant from Sanofi Synthelabo Group.

Dr. Davidson has received an honorarium from the American College of Chest Physicians for the preparation of this article.

Abbreviations: DVT = deep-vein thrombosis; LMWH = low-molecular-weight heparin; PE = pulmonary embolism; VTE = venous thromboembolism

	References

TOP Abstract Introduction Relevance of Cost-effectiveness... Efficacy, Safety, and... Factors With Economic Impact... Outcomes in Economic Evaluations... Challenges in Building the... Interpreting Cost-effectiveness... References

 

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