Economic analyses of venous thromboembolism prevention strategies in hospitalized patients: a systematic review

Venous thromboembolism occurs in up to 40% of hospitalized medical and surgical patients in the absence of prophylactic anticoagulation [1, 2]. Even with prophylaxis, the risk of venous thromboembolism in critically ill patients approaches 10% and has serious consequences: untreated pulmonary embolism has a mortality rate approaching 25% [3‐5]. Among critically ill patients, those developing venous thromboembolism have longer intensive care unit and hospital stays, longer duration of mechanical ventilation, and higher hospital mortality [6]. Consequently, venous thromboembolism not only is associated with serious morbidity and mortality, but also has major implications for healthcare resource utilization.

Appropriate use of prophylaxis to prevent venous thromboembolism in patients at risk has been identified as one of the most important patient-safety interventions for hospitals [7]. However, substantial variability is found in the use of such prophylaxis in practice. Prevention is most commonly achieved with anticoagulant drugs. Because important decisions about pharmacologic interventions are made with knowledge of their economic consequences, formal economic analyses are useful tools to guide clinicians and policy makers about the value of drug interventions and their consequences [8, 9]. However, many evaluations of new drugs do not occur prospectively with efficacy studies, and many are sponsored by the manufacturers, raising the possibility of bias.

We performed a systematic review of economic analyses of venous thromboembolism-prevention strategies in acutely ill hospitalized patients. Our objectives were to review and critically appraise the economic evaluations of a broad spectrum of strategies in diverse patient groups to help inform clinicians and policy makers about the cost-effectiveness of various approaches to venous thromboembolism prophylaxis.

In this systematic review of economic analyses of venous thromboembolism-prevention strategies in hospitalized patients, we found that all of the high-quality studies focused on pharmacologic prophylaxis. Low-molecular-weight heparins were the most commonly studied "new" class of medication and were generally reported to be the dominant or economically attractive strategy in comparison with placebo, unfractionated heparin, or warfarin, among medical and surgical patients. However, among orthopedic patients, fondaparinux was favored over low-molecular-weight heparins. The two newest agents, dabigatran and rivaroxaban, are favored in the two most recent orthopedic surgery evaluations included in this review. Among the various strategies compared, the new agent had a favorable cost-efficacy ratio in 97% of the studies, and most of these studies were sponsored by the manufacturers of the new agent.

Few systematic reviews of economic analyses comparing different modes of venous-thromboembolism prophylaxis in hospitalized patients have been conducted. In 1994, one such review of cost-efficacy analyses of low-molecular-weight heparins, unfractionated heparin, and warfarin in the prevention and treatment of venous thromboembolism in surgical patients, concluded that low-molecular-weight heparin was more efficacious and cost-effective after total hip arthroplasty [34]. Most recently, a trial comparing low-molecular-weight heparin with unfractionated heparin in hospitalized patients found low-molecular-weight heparin to be cost saving compared with unfractionated heparin and that low-molecular-weight heparin was associated with a lower venous thromboembolism readmission rate at 30 and 90 days [59]. Our review includes 37 subsequently published analyses, focusing on both medical and surgical patient populations, and comparing newer pharmacologic agents for venous thromboembolism prophylaxis, such as fondaparinux, dabigatran, and rivaroxaban.

In this review, low-molecular-weight heparins appeared to offer superior prophylaxis efficacy compared with warfarin, unfractionated heparin, and placebo for orthopedic, general surgical, and medical patients. Fondaparinux was found to be economically more attractive for venous thromboembolism prevention compared with heparins because of greater efficacy in surgical and orthopedic patients, but may also be associated with increased bleeding. Among 11 economic analyses comparing enoxaparin with fondaparinux, all found that fondaparinux was economically attractive. More than half of these studies were either directly sponsored by the manufacturers of fondaparinux, or were based on original randomized controlled trials funded by the manufacturer.

Historically, many economic evaluations of new drugs have been sponsored by the drug manufacturer. However, this introduces the potential for bias in model construction and interpretation of the results. In a retrospective analysis of 107 trials in five leading medical journals with regard to outcome and sources of funding, studies sponsored by pharmaceutical companies were much less likely to favor traditional therapy over new drug treatment [60, 61]. It is not surprising that new agents are incrementally efficacious; this is the nature of progress in medicine. However, new agents, typically still under patent protection, are virtually always substantially more expensive than comparator drugs. In our systematic review, 25 of the 39 studies were funded by pharmaceutical companies, and, with the exception of a single study [28], each of these found the sponsored drug more economically attractive than the comparator drug. Such consistency in incremental cost-effectiveness among more-expensive drugs is striking. Importantly, we could not detect a consistent bias in outcome between sponsored and nonsponsored evaluations; however, only a minority of evaluations did not receive sponsorship.

Strengths of our review include adherence to rigorous systematic review methods, which consisted of a comprehensive search strategy, broad eligibility criteria, and study selection by two independent adjudicators using a priori criteria to minimize selection bias. Economic analyses are susceptible to investigator bias, often due to retrospective decision-model generation and retrospective acquisition of cost-and-effect data. To reduce this risk, we included only economic evaluations that incorporated outcome data from prospective randomized controlled trials. We conducted data abstraction and critical appraisal in duplicate, by using established criteria for assessing economic evaluations. We also addressed the relation of recency to market and for-profit sponsorship in influencing the reporting of economic evaluations. This review also has limitations. Many of the analyses within studies that we included come from a limited number of trials and cost-comparison models. For example, five studies used outcome data from the MEDENOX trial [20, 22‐24, 33]. If most of the data are derived from a limited number of efficacy trials and cost models, similar results are likely to be found across economic evaluations. Although the studies included in this review received high ratings of internal validity, studies varied widely with respect to patient population, time-horizon of therapy, and payer perspective, making generalizability to other health care difficult. In addition, many evaluations rely on radiologic as opposed to clinical venous thromboembolism detection, which may overestimate the real-life clinical consequences of venous thromboembolism. Side effects of thromboprophylaxis may be underestimated, as randomized controlled trials often exclude patients at higher risk of bleeding. Furthermore, trials are generally underpowered to detect differences in rare drug-specific complications such as heparin-induced thrombocytopenia. This may lead to an overestimation of cost-efficacy, as reported in the economic evaluations in this review. Finally, our review included a predominance of orthopedic, general surgery, and medical patients, and thus, our findings may not generalizable to other patient populations.

Among economic analyses in this review, incremental cost-effectiveness ratios were commonly expressed in costs per venous thromboembolism events avoided, and they ranged from $500 to $8,000 per venous thromboembolism event avoided. These ranges are difficult to interpret, as no firmly established willingness-to-pay benchmarks exist for venous thromboembolism prevention. Costs per life-year or quality-adjusted life-year gained were less commonly reported, making economic comparisons of venous thromboembolism-prevention strategies and other interventions in healthcare similarly challenging. Comparing and combining ICERs performed with country-specific costs is challenging, as patient, disease, provider, and health-care system factors may influence transferability. We have not adjusted costs based on country-specific purchasing power parity but have adjusted based on changes in gross domestic product over time, and country-specific exchange rates [62].

An informative economic analysis should include both benefits and harms of interventions and the full associated costs over a relevant time horizon. Full costs of venous thromboembolism prophylaxis were not included in some studies. The common complications of venous thromboembolism prophylaxis include prophylaxis failure, leading to thrombotic events, bleeding, and heparin-induced thrombocytopenia [1]. All 39 studies evaluated in this systematic review accounted for breakthrough thrombotic events; however, only half included bleeding complications (Table 3), and none fully accounted for heparin-induced thrombocytopenia. The omission of these potentially serious complications may considerably affect the cost-comparison data of the individual studies. Most studies ascertained costs retrospectively and from the literature. This is often less complete or less accurate compared with prospective determination alongside a randomized controlled trial. Finally, none of the studies included in this review was prospectively designed before results of the randomized controlled trials were published; accordingly, they may be at risk for subjective decision-tree construction and interpretation.

Few studies have evaluated the cost-effectiveness of mechanical venous thromboembolism-prevention strategies, and none of the existing studies met our eligibility criteria. The UK National Institute for Health and Clinical Excellence have recommended considering graduated compression stockings in most patients, although economic evaluations of mechanical venous thromboembolism prophylaxis have generally been of low quality [63]. The paucity of rigorous evidence about the cost effectiveness of mechanical prophylaxis is striking. However, this may be explained by the fact that manufacturers of mechanical devices are often not required to furnish either effectiveness or cost data to regulatory bodies before their introduction and marketing.

In this systematic review of economic analyses of venous thromboembolism-prevention strategies in hospitalized patients, we found that low-molecular-weight heparins appear to be the most economically attractive strategy for venous thromboembolism prevention among the majority of medical and surgical patients, whereas fondaparinux is more economically attractive for orthopedic patients. The studies, however, may be at risk of overestimating efficacy and underestimating side effects such as bleeding. Approximately two thirds of all evaluations were directly funded by the manufacturer of the new drug, and such drugs were more likely to be found economically attractive in comparison to other strategies. Limited opportunity for peer-reviewed and independent funding for economic evaluations unfortunately leads to reliance on industry sponsorship in this field. In the future, we recommend that high-quality, prospective, cost-effectiveness analysis be planned alongside the intervention trials and that these be designed, conducted, analyzed, and reported independent of industry sponsors.

Dr. Fowler is a Career Scientist of the Ontario Ministry of Health and Long-term Care and an incoming Clinician Scientist of Heart and Stroke Foundation of Canada. Dr. Cook holds a Canada Research Chair from the Canadian Institutes of Health Research.