PHARMACQECONOMICS

Cost-Effectiveness of Enoxaparin versus Low-Dose Heparin for Prophylaxis Against Venous Thrombosis

after Major Trauma

John W. Devlin, Pharm.D., Antonio Petitta, B.Sc.Pharm., M.B.A., Alexander D. Shepard, M.D., and Farouck N. Obeid, M.D.

We attempted to determine health and economic outcomes from the perspective of an integrated health system of administering enoxaparin 30 mg twice/day versus heparin 5000 U twicejday for prophylaxis against venous thrombosis after major trauma. A decision-analytic model was developed from best literature evidence, institutional data, and expert opinion. We assumed that 40% of proximal deep vein thromboses (DVTs) and 5% of distal DVTs are diagnosed and confirmed with initial or repeat duplex scanning; 50% of undiagnosed proximal DVTs result in pulmonary embolism; 2% and 1% of undiagnosed proximal DVTs will lead to readmission for DVT and pulmonary embolism, respectively, and pulmonary embolism-related mortality rates range from &30%. Length of hospital stay data and 1996 institutional drug use and acquisition cost data were used to estimate the cost of enoxaparin and heparin therapy. Diagnosis and treatment costs for DVT and pulmonary embolism were derived from institutional charge data using cost:charge ratios. A second analysis of patients with lower extremity fractures was completed. One-way and multiway sensitivity analyses were performed. For 1000 mixed trauma patients receiving enoxaparin versus heparin, our model showed that 62.2 (95% CI -113 to -12) DVTs or pulmonary emboli would be avoided, resulting in 67.6 (8 to 130) life-years saved at a net cost increase of $104,764 (-$329,300 to $159,600). Enoxaparin versus heparin resulted in a cost of $1684 (-$3600 to $9800) for each DVT or pulmonary embolus avoided and a discounted cosaife-year saved of $2303 (-$8100 to $19,000). For 1000 patients with lower extremity fractures, enoxaparin versus heparin resulted in a cost of $751 (-$4200 to $3300) for each DVT or pulmonary embolus avoided and a discounted cost/life-year saved of $1017 (-$10,200 to $6300). Although enoxaparin increases overall health care costs, it is associated with a cosdadditional life-year saved of only $2300, which is generally lower than the commonly used hurdle rate of $30,000/life-year saved. The cost-effectiveness ratio is more favorable in patients with lower extremity fractures than in the general mixed trauma population. (Pharmacotherapy 1998; 18(6): 1335-1342)

Patients admitted to the hospital with major trauma are at increased risk for developing a venous thromboembolic complication such as deep vein thrombosis (DVT) or pulmonary

embolism.'-3 A case series revealed DVT by contrast venography in 58% of patients after trauma.' Pulmonary embolism is the third most common cause of death in patients who survive

1336 PHARMACOTHERAPY Volume 18, Number 6, 1998

Table 1. Model Assumptions AssumD tions Best Low High Epidemiologic Assumptions

Number of patients Overall DVT frequency Heparin 5000 U S.C. b.i.d.12 Enoxaparin 30 mg S.C. b.i.d."

Heparin 5000 U S.C. b.i.d.12 Enoxaparin 30 mg S . C . b.i.d.12

% proximal DVT frequency

% proximal DVT clinically diagnosed1F18 % distal DVT clinically diagnosed1s18 % clinically suspected DVT confirmed by duplex scanning (sensitivity)'

% clinically suspected DVT undergoing repeat duplex scanning'

% clinically suspected DVT with negative duplex scan undergoing venography'

% positive venography (sensitivity)' % undiagnosed proximal DVT leading to

% undiagnosed proximal DVT leading to

% patients undergoing VQ scan requiring

% undiagnosed proximal DVT leading to

% patients with no DVT falsely diagnosed

% patients with no DVT falsely diagnosed

Mortality for diagnosed PE1a22 Mortality for undiagnosed PEIaZ2 Life exDectancvU

readmission for DVTI9.

~ ~ 1 6 , c. d

pulmonary angiography

readmission for PEC,

with DVT18

with PEls2l

1000

0.44 (O.49la 0.31 (O.39la

0.33 (0.37)" 0.20 (0.13Y 0.40 0.05

0.95

0.05

0.1 1 .o

0.02

0.5

0.13

0.01

0.1

0.02 0.08 0.3

30

0.40b 0.27b

0.28b 0.07b 0.32 0.04

0.92

0.02

0.05 1.0

0.01,

0.4

0.1

0.002

0.08

0.01 0.03 0.15

20

0.48b 0.41b

0.40b , 0.26b

0.48 0.07

0.98

0.08

0.3 1.0

0.04

0.6

0.23

0.02

0.13

0.03 0.1 0.4

40

the first 24 hours after t r a ~ m a . ~ Risk factors associated with venous thromboembolism in these patients include age, surgery, blood trans- fusion, long bone or pelvic fracture, and neuro- trauma. Patients who develop venous thrombo- embolism usually require anticoagulation therapy, which can prolong hospitalization and increase the risk for adverse events such as bleeding.2

At most institutions. low-dose subcutaneous From the Department of Pharmacy Services, Detroit

Receiving Hospital and University Health Center (Dr. Devlin); Ambulatory Pharmacy Services, Henry Ford Health System (Mr. Petitta); and the Divisions of Vascular Surgery (Dr. Shepard) and Trauma Surgery (Dr. Obeid), Department of Surgery, Henry Ford Hospital, Detroit, Michigan.

Presented in part at the annual meeting of the American College of Clinical Pharmacy, Phoenix, Arizona, November

Address reprint requests to John W. Devlin, Pharm.D., BCPS, Department of Pharmacy Services, Detroit Receiving Hospital and University Health Center, 4201 St. Antoine, Detroit, MI 48201-4162.

9-12,1997.

heparin is the most frequently administered prophylactic agent against venous thrombosis for trauma patients because of its proved efficacy in decreasing the frequency of these complications and its low acquisition Patients with a relative contraindication to heparin therapy (intracranial hemorrhage, spinal cord injury, bleeding diathesis, severe thrombocytopenia) usually receive prophylaxis with lower extremity intermittent pneumatic compression devices. These are cumbersome, however, and not applicable in some patients, such as those with lower extremity trauma or peripheral arterial occlusive disease.5- '9

In controlled trials, low-molecular-weight heparins (LMWHs) were more efficacious than low-dose heparin in preventing DVT after both knee and hip replacement surgery.", l1 In a randomized, double-blind, controlled trial comparing low-dose heparin with the LMWH

ENOXAPARIN VERSUS HEPARIN PROPHYLAXIS AFTER TRAUMA Devlin et al 1337

Table 1. Model Assumptions (continued) Assumptions Best Low High Cost assumptions'

DVT prophylaxis with heparin ($)',g 7.65 6.14 9.22 DVT prophylaxis with enoxaparin ($)' ,h 196.80 157.44 236.16 DVT index admission, added hospital stay 0 0 3652' PE index admission, added hospital stay ($) 0 0 67445 Duplex scan ($) Venogram ($)

368 294 442 1580 1264 1896

Chest radiograph ($) 66 53 79 VQ scan ($) Electrocardiogram ($) Pulmonary angiogram ($)

1046 837 1883 30 24 36

3190 2552 3828 Anticoagulation therapy, DVT ($)k 43 1 300 550 Anticoagulation therapy, PE ($)k DVT readmission (total cost, $)I

503 400 600 4090 3272 4908

PE readmission (total cost, $)" 7286 5828 8743 DVT = deep vein thrombosis; PE = pulmonary embolism. "Values for lower extremity fracture subanalysis are from reference 12. bRange based on calculated SEM from reference 12. 'Institutional data, Henry Ford Hospital, Detroit, Michigan. dExpert opinion, Henry Ford Hospital, Detroit, Michigan. 'Based on total patient cost data converted from patient charges using appropriate cost:charge ratio. Same assumptions apply as for above epidemiologic assumptions. 'Median length of prophylaxis against venous thrombosis calculated from 18-month retrospective analysis for all patients admitted to our hospital with an ISS of 9 or above, with no evidence of intracranial bleeding, who received subcutaneous heparin for more than 24 hours at any time during admission. gBased on our hospital's acquisition cost ($0.36) + 3-ml syringe ($0.12) for a dose of 5000 U. hBased on the hospital's acquisition cost ($12.30) for a dose of 30 mg. 'Assume (a) average length of hospital stay for DVT = 6.7 days (HFH data, (b) codday for semiprivate ward bed = $545. jAssume (a) average length of hospital stay for pulmonary embolism = 8.3 days (HFH data); each patient will spend 2 days in ICU with the remainder of stay in a semiprivate ward bed, (b) codday for ICU bed = $166, (c) codday for semiprivate ward bed = $545. kAssume (a) all patients with diagnosis of a DVT will receive heparin 1400 Uhour by continuous intravenous infusion to maintain partial thromboplastin time (PTT) 1.5-2 times the normal range, (b) all patients with DVT or pulmonary embolism will receive intravenous heparin for the duration of the hospital stay, (c) cost of heparin therapy includes 25,000 U in 250 ml D5W bag = $1.06, three PTT/day @ $15 each, and one platelet count @ $12 each, (d) cost of warfarin step-down anticoagulation (assuming average dosage 5 mgday) = $52.25. 'Assume e and j. "Assume i and j ,

enoxaparin for prophylaxis against venous thrombosis in patients with major trauma, the overall frequency of venographically proven DVT was lower in the enoxaparin-treated group. l2

These results led us to rethink our current strategy of providing low-dose heparin therapy to patients admitted to our institution with major trauma. Despite the potential advantages of enoxaparin in this population, we have not yet revised our thromboprophylactic guidelines to include LMWHs. This is largely because the acquisition cost of these agents is 20-30 times higher than that of unfractionated heparin.

Methods

To determine if cost savings associated with fewer DVTs and pulmonary emboli in enoxaparin-

treated patients justifies the drug's dramatically higher cost, we performed a cost-effectiveness analysis, from the perspective of an integrated health system, to compare low-dose heparin with enoxaparin as prophylaxis against venous thrombosis for patients hospitalized with major trauma.

Henry Ford Hospital is a large, urban, tertiary care teaching hospital that is certified by the American College of Surgeons as a level 1 trauma center. In 1995, 25% (448/1806) of patients admitted for trauma had an Injury Severity Score (ISS) of 9 or greater (mean * SD 14 * 8.2, range 9-75). The ISS is calculated by adding the sum of the squares of the highest abnormal abbreviated injury scale scores from up to three different body regions, and predicts the probability of ~urviva1.l~ Patients with an ISS of 9 or above are

1338 PHARMACOTHERAPY Volume 18, Number 6, 1998

i r n t d r i n : - ( I ) heparin (H) so0011 sc bid OR (2) enoxsparin (E) 30mg sc bid

0

generally considered to have experienced moderate to severe trauma. For admissions in 1995 with such a score, 73% were classified as blunt and the rest penetrating traumas. Major sites of injury were chest and abdomen (55%), extremity (18%), head (14%), spine (Soh), and other (5%).

For our analysis, we adapted an approach of clinical policy analysis published elsewhere. l4

We used the same treatments that were reported in a controlled clinical trial: heparin 5000 U and enoxaparin 30 mg, both subcutaneously every 12 hours.12 Important health and economic outcomes affected by these treatments were identified.

The frequency of clinically diagnosed DVT and pulmonary embolism during the index admission as well as number of subsequent rehospitalizations for either condition were health outcomes. Costs of prophylactic therapy, diagnostic work-up for a suspected DVT or pulmonary embolism, and related hospitalization and treatment were economic factors. To estimate the magnitude of outcomes for the two treatments, we made a series of assumptions based on the best available literature, retrospective cost and use data from our institution, and expert opinion (Table 1). Best l i terature evidence was obtain'ed by searching MEDLINE for the years 1980-1995 using the following key words: deep vein thrombosis, pulmonary embolus, prophylaxis, trauma, heparin, low-molecular-weight heparin, randomized controlled trial, and cost-effective- ness analysis.

Although trauma patients receiving enoxaparirl

False Negative P k u ~ Go To Figure 2 DVT Diagnosis (Pulmonary Embolus)

n a Clinical Diagnosis Patient Discharged Not Confirmed Fmm Hospital survival

Falsc Positive DVTDiagnosis ~~~l~~ scan Not Confirmed

m n u Patient Discharged From HospiW Survival

a 0 Confirm Clinical Clinical Diagnosis Patient Discharged

NO DVT Falw Positive

prophylaxis experience fewer DVTs than those receiving unfractionated heparin, the method of detection in one study'' did not match current practice at Henry Ford Hospital. Ascending venography, the gold standard for diagnosing DVT, is rarely performed at most institution^.'^ Instead, because duplex scanning is less expensive, easier, and less risky and nearly as accurate, it has rapidly besome the first-line diagnostic test of choice in most centers.24 It is a combination of real time B-mode ultrasonography and Doppler-derived blood flow analysis. The anatomic and physiologic information obtained includes a two-dimensional image of the interrogated vein and assessment of intraluminal blood flow, which are sensitive indicators for DVT. When duplex scanning is negative but a high index of suspicion remains that DV/T is present, the scan is usually repeated in 48-72 hours before considering ascending venography.

Furthermoie, unlike methods used in the other study,12 our trauma patiems are not routinely screened for DVT, but instead undergo study only when a DVT is clinically suspected. Lack of routine screening undoubtedly leads to the detec- tion of fewer DVTs, as less than 5% of distal and 40% of proximal DVTs are clinically apparent.15-18

The surprisingly low frequency of pulmonary embolism in the earlier study (1 patient) ,12

compared with other case series is likely attributable to their surveillance screening. In clinical practice, lack of surveillance with duplex scanning or venography places patients at greater risk of pulmonary embolism should they develop

Diagnosis Confirmed DVT Treated Confirmed With IV Heparin Survival

rl I

m u a TNS Positive Confmed DVT

TmIed With IV Heparin S w i v a l Venography

Diagnosis NotConfirmcd I

I Please Go To Figure 2 No Venography (Pulmonary Embolus)

n u a

ENOXAPARIN VERSUS HEPARIN PROPHYLAXIS AFTER TRAUMA Devlin et al 1339

... From Figure 1 , Patients at Risk for PE

a clinically silent proximal DVT. Both disorders may become manifest during either the index admission or sometime after discharge, and require rehospitalization for anticoagulation therapy.

In an effort to portray present clinical practice at large, urban trauma centers such as ours as accurately as possible, we developed a decision tree outlining prophylaxis, diagnosis, and treatment of DVT and pulmonary embolism in patients admitted with trauma (Figures 1 and 2 ) . I t is similar to those used in other cost- effectiveness analyses examining prophylaxis against venous thrombosis. 19-21

The first branch represents the known probability of developing a DVT in a patient admitted with an ISS of 9 or greater in whom intracranial bleeding has been ruled out. The next four branches reflect management of patients with and without DVT who receive diagnoses that are true positive, false negative, false positive, and true negative. We estimated 5% of distal and 40% of proximal DVTs to be clinically apparent. 15-18 Furthermore, we estimated 10% of patients would have a false positive diagnosis of DVT but assumed DVT would be ruled out in all of them by duplex scanning." We estimated 2% of all patients would develop a DVT after discharge from the index hospitalization and require rehospitalization for anticoagulation therapy. We assumed all clinically suspected DVTs would be confirmed or rejected by duplex scanning with sensitivity of 95%. Venography, with a sensitivity of loo%, would be performed only if repeat duplex scan was negative and DVT was sti l l strongly suspected.

PE Not Clinically Detected a

Death a

It was estimated that 50% of proximal DVTs not diagnosed during the index hospitalization would lead to pulmonary embolism during that hospitalization, and that 1% of these patients would require readmission for treatment of pulmonary 25 Furthermore, 2% of patients without DVT were estimated to be falsely diagnosed with pulmonary embolism, all of which would be ruled out by diagnostic work- up.'' All patients with suspected pulmonary embolism were assumed to have an electro- cardiogram, two-view chest film, and ventilation- perfusion lung scan (V-Q). We estimated that 13.2% of these patients would require subsequent pulmonary angiography.

Whereas pulmonary embolism (nonfatal) occurred in only one patient in the earlier trial,12 its effects, both undiagnosed and diagnosed, on mortality were included in our analysis. Based on published analyses, it was estimated that survival probability when it was undiagnosed was 0.70 and when diagnosed (and treated) was 0.9 2.

Life expectancy for the trauma population admitted to our hospital was conservatively estimated using recently published data for the African-American male population in urban Detroit.23 Survival in the model for all patients without pulmonary embolism was assumed to be 100%. Future life-years were discounted at a rate of 3%/year. , The median length of venous thromboprophylaxis

(8 days, range 1-46 days), used to calculate the cost of prophylaxidpatient, was derived from an l&month (January 1995-June 1996) retrospective analysis of all patients admitted to our institution with an ISS of 9 or above, having no evidence of

0 Confirm Clinical Diagnosis False-Positive Clinical Through v/Q scan afdor Diagnosis Not Confirmedl Diagnosis of PE Pulmonary AWiokVPhY Patient Discharged From Hospital Survival

No Pulmonary n a Embolus

True-Negative Clinical Patient Discharged

Confirm Clinical Diagnosis Through v/Q Scan and/or Survival Confirmed PE Treated

PE clinically Detected Pulmonary h@OWPhY With IV Heparin a n

Death

Pulmonary Embolus a

1340 PHARMACOTHERAPY Volume 18, Number 6, 1998

Table 2 . Summary of Outcomes (1000 patients) Projected Outcomes Enoxaparin Heparin Difference 95th Certainty Range" Health outcomes

DVT index hospitalization 35.6 70.4 -34.8 -65 to -7 PE index hospitalization 15.9 40.4 -24.5 -6 to0 DVT hospital readmission 5.5 7.4 -1.9 -48 to -2 PE hospital readmission 2.7 3.7 -1.0 -3 to 0 Total DVT and PE 59.7 121.9 -62.2 -113 to -12 PE-related deaths 2.1 4.3 -2.2 -4 to 0 Life-years saved 67.6 8 to 130 Discounted life-years saved 46.6 ' 6 to 84

Drug costs for prophylaxis against venous

Diagnosis and treatment costs for DVT

Diagnosis and treatment costs for PE during

Diagnosis and treatment costs for DVT

Economic outcomes

thrombosis ($1 196,800 7650 189,150 151,800 to 226,300

during index hospitalization ($) 59,744 83,385 -23,641 -215,700 to -9600

index hospitalization ($) 58,426 104,272 -45,846 -338,500 to -7500

requiring hospital readmission ($1 22,451 30,331 -7880 -25,700 to 600 Diagnosis and treatment costs for PE r requiring hospital readmission ($) 19,997 27,016 -7019 -22,300 to 300

Total cost ($1 357,418 252,654 J ' 104,764 -329,300 to 159,600

Cost-effectiveness Total cost/DVT/F'E avoided 1684 , -3600 to 9800 Codlife-vear saved 2303 -8100 to 19.000

~ ____~ _ _ _ _ _ ~ ~ _ _ _ _ _ ~

DVT = deep veinthromboz PE = pulmonary embolism. "Represents estimated 2.5th and 97.5th percentiles for the distribution of possible values of the difference based on the Monte Carlo multiway sensitivity analysis using ranges specified and 10,000 iterations.

intracranial bleeding, who received subcutaneous heparin for more than 24 hours.

We assumed all patients who developed DVT or pulmonary embolism would receive heparin followed by warfarin. Insertion of a vena caval (Greenfield) filter was not considered, as filters are rarely used in our trauma patients, and the likelihood of such patients requiring them is evenly distributed between heparin and enoxaparin prophylaxis groups. A standard dosage of heparin 1400 U/hour was derived from a heparin drug use evaluation completed at our institution that examined the average dosage to maintain activated partial thromboplastin time between 50 and 72 seconds in patients treated for DVT or pulmonary embolism. In addition, based on the results of this review, patients would have an average of three partial thromboplastin time or prothrombin time draws/day and one platelet count every 3 days. A standard dosage of warfarin 5 mg/day was adopted from other a n a l y s e ~ . ' ~ ? ~ ~

Because of limited institutional data, we conservatively estimated that DVT or pulmonary embolism occurring during the index admission would not lengthen hospitalization. We did, however, use the most dire scenario that a DVT or pulmonary embolism diagnosed and treated in

our model would be additive to the hospital length of stay as the high estimate. All other cost assumptions are detailed in the footnotes accompanying Table 1.

All charges were converted to costs by obtaining appropriate cost:charge ratios for each depart- ment. Nursing costs related to drug administration were not factored into our analysis as each agent is administered twice/day, and thus neither one would be likely to affect nursing staffing levels. Costs were not discounted since they were assumed to occur within year 1.26

We estimated the overall uncertainty of the model by Monte Carlo multiway sensitivity analysis with spreadsheet forecasting software (Crystal Ball; Decisioneering Inc., Boulder, CO) . The Monte Carlo simulation allowed each assumption to vary randomly across its range of values while performing 10,000 iterations. One- way sensitivity analysis was conducted for variables that provided the greatest contribution to overall model variability.

Since patients with lower extremity fractures in the previous study were at greater risk for venous thromboembolism than trauma patients without such fractures,12 we completed a second analysis specifically for this population. The frequency of

ENOXAPARIN VERSUS HEPARIN PROPHYLAXIS AFTER TRAUMA Devlin et al 1341

proximal and distal DVTs in that study for such patients was substituted in the above decision analysis. All other assumptions remained the same.

Results

The results for each outcome under baseline assumptions are shown in Table 2, with 95% certainty ranges from multiway sensitivity analysis. The 95% certainty ranges represent values that lie between percentile 2.5 and percentile 97.5 of the 10,000 predicted values for each outcome. The health outcomes component of the model shows that 62.2 (95% CI -113 to -12) DVTs or pulmonary emboli will be avoided for every 1000 mixed trauma patients treated with enoxaparin versus heparin. Avoidance of these events prevents 2.2 (-4 to 0 ) deaths and results in 67.6 (8 to130) life-years saved.

The economic outcomes component shows that enoxaparin will increase the cost of prophylaxis by $189,150 ($151,800 to 225,300) and decrease other health care costs by $84,000, resulting in a net cost increase of $104,764 (-$329,300 to $159,600) for every 1000 patients. Combining health and economic outcomes results in a cost of $1684 (-$3600 to $9800) for each DVT or pulmonary embolism avoided and a discounted cost/life-year saved of $2303 (-$8100 to $19,000).

For 1000 patients with lower extremity fractures, enoxaparin versus heparin resulted in a cost of $751 (-$4200 to $3300) for each DVT or pulmonary embolism avoided and a discounted cost/life-year saved of $1017 (-$10,200 to $6300).

Assumptions that provided the largest contribution to overall variability in cost/life-year saved were hospitalization costs for increased length of stay associated with embolic events during the index admission, and percentage of DVTs that are proximal for patients receiving heparin prophylaxis. One-way sensitivity analysis of these three variables showed that when the cost of increased length of stay and percentage of proximal DVTs for heparin-treated patients varied from their minimum to maximum values, cost/life-year saved ranged from $2303 to -$488, $2303 to -$1336, and $1341 to -$4103, respectively

Discussion

A1 t hou g h anti th ro mb o tic prophylaxis with enoxaparin versus heparin for patients admitted to our institution will increase overall health care

costs, the cosdadditional life-year saved of $2300 is substantially lower than the generally accepted generic hurdle rate of $30,000/life-year saved. Our analysis showed that enoxaparin is even more cost-effective for patients with lower extremity fractures. Sensitivity analysis found that costs for increased length of stay for DVT and pulmonary embolism during index hospital- ization was a major contributor to the variability in the model. Since data related to length of stay for these disorders were unavailable, we conservatively chose zero as the baseline value so as to not overestimate the impact of the newer agent. In reality, however, this number is likely to be greater than zero. When longer hospital- ization is completely additive to the index hospitalization, enoxaparin becomes cost saving.

Although we developed our decision analysis from common clinical practice; based our model assumptions on best available literature evidence, institutional data, and expert opinion; and applied well-established pharmacoeconomic principles, some factors not considered in the analysis may have influenced our results. For example, although only clinically significant DVT and pulmonary embolism were included as outcomes (unlike the study that included all DVTs detected by surveillance venography12), the frequency of both disorders may have been overestimated. The rate a t which patients develop proximal DVT is a major contributor to the variability. If in actual practice this rate is lower than used here, the actual cost/life-year saved would be greater.

For some assumptions, such as the number of patients readmitted with DVT or pulmonary embolism, we used opinions of two senior attending trauma surgeons, as neither literature nor institutional data were available. Although a nonsignificant trend (p=O. 12) for more clinically detectable major bleeding events in patients treated with enoxaparin (5/129, 3.9%) rather than heparin (1/136, 0.6%) were reported,12 we excluded bleeding from our analysis because of low overall reported frequency (1.7%), lack of a significant difference between agents, and the fact that only 2/6 bleeding events required discon- tinuation of prophylactic therapy. Similarly, other trials comparing enoxaparin and heparin reported no difference in the frequency of major bleeding between groups, with a trend for greater bleeding in heparin-treated patient^.^^-^'% 27, 28

In conclusion, enoxaparin, despite having a significantly greater acquisition cost than unfrac- tionated heparin, is a cost-effective alternative as

1342 PHARMACOTHERAPY Volume 18, Number 6,1998

prophylaxis against venous thrombosis for patients admitted with major trauma, particularly those with lower extremity fractures.

References 1. Geerts WH, Code KI, Jay RM, et al. A prospective study of

venous thromboembolism after major trauma. N Engl J Med 1994;331:1601-6.

2. Rogers FB. Venous thromboembolism in trauma patients. Surg Clin North Am 1995;75:279-91.

3. Shackford SR, Moser KM. Deep vein thrombosis and pulmonary embolism in trauma patients. J Intensive Care Med 1988;3:87-98.

4. OMalley KF, Ross SE. Pulmonary embolism in major trauma patients. J Trauma 1990;30:748-50.

5. Knudson MM, Lewis FR, Clinton A, Atkinson K, Megerman J. Prevention of venous thromboembolism in trauma patients. J Trauma 1994;37:480-7.

6. Dennis JW, Menawat S, Von Thron J, et al. Efficacy of deep venous thrombosis prophylaxis in trauma patients and identification of high risk groups. J Trauma 1993;35:132-9.

7. Clagett GP, Anderson FA Jr, Heit J, Levine MN, Wheeler HC. Prevention of venous thromboembolism. Chest 1995;108(suppl): 312s-34.

8. GerSin K, Grindlinger GA, Lee V, Dennis RC, Wedel SK, Cachecho R. The efficacy of sequential compression devices in multiple trauma patients with severe head injury. J Trauma 1994;37:205-8.

9. Comerota AJ, Katz ML, White JV. Why does prophylaxis with external pneumatic compression for deep vein thrombosis fail? Am J Surg 1992;164:265-8.

10. Turpie AGG, Levine MN, Hirsh J , et al. A randomized controlled trial of a low-molecular heparin (enoxapprin) to prevent deep-vein thrombosis in patients undergoing elective hip surgery. N Engl J Med 1986;315:925-9.

11. Levine MN, Hirsch J, Gent M, et al. Prevention of deep vein thrombosis after elective hip surgery: a randomized trial comparing low molecular weight heparin with standard unfractionated heparin. Ann Intern Med 1991;114545-51.

12. Geerts WH, Jay RM, Code KI, et al. A comparison of low-dose heparin with low-molecular weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med 1996;335:701-7.

13. Baker SP, ONeill B, Haddon W, Long WB. The injury severity score: a method for describing patients with multiple injuries and evaluating emergency care. J Trauma 1974;14:187-96.

14. Ward RE, Gheorghiade M, Young JB, et al. Economic outcomes of withdrawal of digoxin therapy in adult patients

with stable congestive heart failure. J Am Coll Cardiol

15. Gallus AS. Venous thromboembolism: incidence and clinical risk factors. In: Madden JL, Hume M, eds. Venous thrombo- embolism: prevention and treatment. East Norwalk, CT: Appleton-Century-Crofts, 1976: 1-32.

16. Kakkar VV, Flane C, Howe CT, et al. Natural history of postoperative deep vein thrombosis. Lancet 1969;2:230-3.

17. Lensing AWA, Pradoni P. Distribution of venous thrombi in symptomatic patients. Thromb Haemost 1991;65:1730.

18. Oster G, Tuden RL, Colditz GA. A cost-effectiveness analysis of prophylaxis against deep-vejn thrombosis in major orthopedic surgery. JAMA 1987;257:203-8.

19. Anderson DR, OBrien BJ, Levine MN, et al. Efficacy and cost of low-molecular-weight heparin compared with standard heparin for the prevention of deep vein thrombosis after total hip arthroplasty. Ann Intern Med 1993;119:1105-12.

20. OBrien BJ, Anderson DR, Goeree R. Cost-effectiveness of enoxaparin versus warfarin prophylaxis against deep-vein thrombosis after total hip replacement. Can Med Assoc J 1994;150:1083-90.

21. Drummond M, Aristides M, Davies L, e t al. Economic evaluation of standard heparin and enoxaparin for prophylaxis against deep vein thrombosis in elective hip surgery. Br J/Surg 1994;8 1 : 1 742-6,

22. Lensing AW, Hirsch J , Buller HR. Diagnosis of venous thrombosis. In: Coleman RW, Hirsh J, Marder VJ, Salzman EW, eds. Hemostasis and thrombosis: basic principles and clinical practice. Philadelphia: JB Lippincott, 1994: 1297-1321.

23. Anonymous. Challenge of a lifetime. Ann Arbor: Michigan Department of Public Health, 1995.

24. Kearon C, Julian JA, Newman TE. Noninvasive diagnosis of deep vein thrombosis. Ann Intern Med 1998;128:663-77.

25. Hawkins DW, Langley PC, Krueger KP. Pharmacoeconornic model of enoxaparin versus heparin for prevention of deep vein thrombosis after total hip replacement. Am J Health-Syst Pharm 1997;54:1185-90.

26. Petitta A, Kaatz S, Estrada C, Effendi A, Anandan JV. The transition to medication system performance indicators. Top Hosp Pharm Manage 1995;14:20-6.

27. Colewell CW, Spiro TE, Trowbridge AA, e t al. Use of enoxaparin, a low-molecular-weight heparin and unfractionated heparin for the prevention of deep vein thrombosis after elective hip replacement. J Bone Joint Surg 1994;76A:3-14.

28. Planes A, Vochelle N , Mazas F, et al. Prevention of postoperative venous thrombosis: a randomized trial comparing unfractionated heparin with low molecular weight heparin in patients undergoing total hip replacement. Thromb Haemost 1988;60:407-10.

1995;26:93-101.