Editor's Note: Commentary based on Fowler RA, Mittmann N, Geerts W, et al. Cost-effectiveness of dalteparin vs unfractionated heparin for the prevention of venous thromboembolism in critically ill patients. JAMA 2014;312:2135-45.

Background

Thromboprophylaxis with heparin is a key component in the care of critically ill patients given their high risk of venous thromboembolism (VTE). Low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH) are commonly used for thromboprophylaxis given their effectiveness and safety. The Prophylaxis for Thromboembolism in Critical Care (PROTECT) trial demonstrated similar rates of deep vein thrombosis (DVT), but reduced rates of pulmonary embolism (PE) and heparin-induced thrombocytopenia (HIT) in patients receiving LMWH compared to UFH.¹ No prospective, large-scale study has assessed the cost-effectiveness of an LMWH versus UFH thromboprophylactic strategy in critically ill patients. In this study, Fowler et al. performed a prospective economic evaluation to compare costs associated with LMWH (dalteparin) and UFH for VTE prophylaxis in critically ill patients.²

Methods

The cost-effectiveness of LMWH (dalteparin) versus UFH prophylaxis in critically ill patients, using a health care payer perspective and in-hospital time horizon, was assessed in parallel with the PROTECT trial. A total of 3,746 patients at least 18 years of age, weighing greater than 45 kilograms, with an expected intensive care unit (ICU) stay of 72 hours or more, eligible to receive LMWH or UFH, were enrolled in the PROTECT trial. There were 1,873 patients randomized to dalteparin and 1,873 to UFH. In addition to clinical outcomes (rates of VTE), this investigation measured patient-, resource-, and institution-specific costs associated with LMWH and UFH use. Furthermore, a sensitivity analysis was performed to estimate how cost-effectiveness would change with differences in costs of LMWH and UFH.

Results

The mean age of the study population was 61 years. In the study population, 76% were admitted to the ICU for critical illness, and 90% required mechanical ventilation. Following exclusion of 22 patients who did not meet initial inclusion criteria, a total of 1,862 patients in each group were used to determine cost calculations.

The mean cost per patient receiving UFH was higher ($63,290) than for patients receiving LMWH ($61,800), though this cost difference ($1,490) did not achieve statistical significance (Table 1). Patients receiving UFH had significantly higher rates of PE compared with LMWH (2.3 vs. 1.3%, P=0.01), resulting in more diagnostic imaging for suspected VTE (6,390 vs. 6,172 total radiologic investigations obtained) and therapeutic anticoagulation (7,084 vs. 6021 total doses). There were no differences in major bleeding rates, related procedures, or transfusions. Patients who received UFH spent more total days in the ICU and hospital (67,720 vs. 66,832 days), which corresponded to higher personnel and fixed daily hospital costs.

A sensitivity analysis was also performed, and demonstrated that LMWH was the least costly strategy until its acquisition cost rose from $8 to $179 per dose.

Table 1: Summary of Key Findings²

	LMWH	UFH	P Value
Mean cost per patient ($)	61,800	63,290	0.53
Number of radiologic investigations	6172	6390
Doses of therapeutic anticoagulation	6021	7084

Conclusion

In this prospective economic evaluation study comparing VTE prophylaxis strategies in critically ill patients, LMWH use resulted in lower cost per patient than UFH use, though this difference was not statistically significant. LMWH was associated with similar rates of DVT as UFH, but lower rates of PE and HIT. Accounting for all other economic (patient, resource, institution) costs, the cost of LMWH would have to increase 20-fold compared to UFH to become the more expensive prophylactic strategy.

Commentary/Perspective

A recent meta-analysis of thromboprophylaxis in critically ill patients illustrated that LMWH use, when compared to UFH, is associated with lower rates of PE and similar rates of DVT, major bleeding, and death.³ Additionally, in the PROTECT trial, fewer patients receiving LMWH had HIT (hazard ratio 0.27, P = 0.046).¹ The acquisition cost of once-daily LMWH is more expensive than twice-daily UFH. In this study, the median cost of LMWH for all countries was $8 (and $24.34 in the U.S.) compared to just $3.29 (and $3.23 in the U.S.) for UFH. However, differences in the clinical effects of LMWH and UFH may influence downstream costs. Thus, economic analyses of these two VTE prophylactic strategies account for and characterize such potential costs.

This investigation was prospectively designed and collected pre-specified (patient, resource, institutional) costs at centers along-side a randomized, blinded, large-scale trial. Overall, the mean and median cost of care per patient receiving LMWH was lower than UFH, though this difference was not statistically significant. Cost reduction in patients receiving LMWH was primarily explained by decreases in rates of HIT, thrombosis, hospital length of stay, and resultant resource use. Previously, Shorr et al. designed a decision model to assess the cost-effectiveness of LMWH for DVT prophylaxis in hospitalized medical patients and estimated that routine LMWH use saved $89 per patient despite higher acquisition costs.⁴ Using a similar model, LMWH use for DVT prophylaxis in critically ill patients saved, on average, $300 per individual.⁵ Other studies have also demonstrated VTE prophylaxis with LMWH to have a more favorable economic profile than UFH in different populations.^6,7

The American College of Chest Physicians Evidenced-Based Clinical Practice Guidelines and National Institute of Health and Care Excellence (NICE) recommend either LMWH or UFH for critically ill patients and LMWH for patients at highest risk of VTE.^8,9 The findings by Fowler et al. complement these clinical practice guidelines by demonstrating that the use of LMWH for VTE prophylaxis may be less costly than the use of UFH in critically ill patients. Clinical practice guidelines should consider advocating for greater LMWH use for VTE prophylaxis in the critically ill, given its greater effect and similar-to-lower cost profile compared to UFH.

References

1. Protect Investigators for the Canadian Critical Care Trials Group, the Australian New Zealand Intensive Care Society Clinical Trials G, Cook D, et al. Dalteparin versus unfractionated heparin in critically ill patients. N Engl J Med 2011;364:1305-14.
2. Fowler RA, Mittmann N, Geerts W, et al. Cost-effectiveness of dalteparin vs unfractionated heparin for the prevention of venous thromboembolism in critically ill patients. JAMA 2014;312:2135-45.
3. Alhazzani W, Lim W, Jaeschke RZ, et al. Heparin thromboprophylaxis in medical-surgical critically ill patients: a systematic review and meta-analysis of randomized trials. Crit Care Med 2013;41:2088-98.
4. Shorr AF, Jackson WL, Weiss BM, Moores LK. Low-molecular weight heparin for deep vein thrombosis prophylaxis in hospitalized medical patients: results from a cost-effectiveness analysis. Blood Coagul Fibrinolysis 2007;18:309-16.
5. Shorr AF, Ramage AS. Enoxaparin for thromboprophylaxis after major trauma: potential cost implications. Critical Care Med 2001;29:1659-65.
6. Wilbur K, Lynd LD, Sadatsafavi M. Low-molecular-weight heparin versus unfractionated heparin for prophylaxis of venous thromboembolism in medicine patients--a pharmacoeconomic analysis. Clin Appl Thromb Hemost 2011;17:454-65.
7. Schadlich PK, Kentsch M, Weber M, et al. Cost effectiveness of enoxaparin as prophylaxis against venous thromboembolic complications in acutely ill medical inpatients: modelling study from the hospital perspective in Germany. PharmacoEconomics 2006;24:571-91.
8. Guyatt GH, Akl EA, Crowther M, et al. Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:7S-47S.
9. National Institute for Health and Care Excellence. Venous thromboembolism: reducing the risk: reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to hospital (NICE website). 2013. Available at: http://www.nice.org.uk/guidance/cg92. Accessed 12/8/2014.

Keywords: Anticoagulants, Cost-Benefit Analysis, Critical Care, Critical Illness, Dalteparin, Diagnostic Imaging, Heparin, Heparin, Low-Molecular-Weight, Hospital Costs, Intensive Care Units, Prospective Studies, Pulmonary Embolism, Respiration, Artificial, Thrombocytopenia, Thromboembolism, Venous Thromboembolism, Venous Thrombosis

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