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(Chest. 2004;125:1642-1650.)
© 2004 American College of Chest Physicians

Costs and Clinical Outcomes Associated With Low-Molecular-Weight Heparin vs Unfractionated Heparin for Perioperative Bridging in Patients Receiving Long-term Oral Anticoagulant Therapy*

Alex C. Spyropoulos, MD; Floyd J. Frost, PhD; Judith S. Hurley, MS, RD and Melissa Roberts, MS

* From the Clinical Thrombosis Center (Dr. Spyropoulos), Lovelace Health Systems; and the Center for Pharmacoeconomic and Outcomes Research (Dr. Frost, and Ms. Hurley and Ms. Roberts), Lovelace Respiratory Research Institute, Albuquerque, NM.

Correspondence to: Alex C. Spyropoulos, MD, Medical Director, Clinical Thrombosis Center, Lovelace Sandia Health Systems, 5400 Gibson Blvd SE, Albuquerque, NM 87108; e-mail: alex.spyropoulos{at}lovelacesandia.com


   Abstract
TOP
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 Conclusions
 References
 
Study objectives: There have been no health-care cost evaluations comparing the use of low-molecular-weight heparin (LMWH) to unfractionated heparin (UH) as "bridge therapy" in the perioperative period in patients receiving long-term oral anticoagulant (OAC) therapy who need interruption of therapy to undergo an elective surgical procedure. We performed a retrospective analysis of the medical and administrative records of health plan members in a managed care organization who underwent bridge therapy perioperatively with either IV UH, administered in a hospital setting, or LMWH, administered primarily in the outpatient setting using disease management guidelines.

Design: A retrospective analysis of medical and administrative records of treated health plan members meeting inclusion/exclusion criteria during the two study periods (ie, from 1994 to 1996 and from 1998 to 2000).

Setting: Staff-model health maintenance organization serving New Mexico.

Patients: The UH group included persons receiving long-term warfarin therapy from 1994 to 1996 (26 patients), and the LMWH group included persons receiving long-term warfarin therapy from 1998 to 2000 (40 patients) with perioperative use of heparin (either UH or LMWH) as bridge therapy for an elective surgical procedure.

Interventions: Costs were calculated for the period from 10 days before the procedure through 30 days after the procedure. The rates of adverse events (ie, valvular or mural thrombus, intracranial event, transient ischemic attack, peripheral arterial event, venous thromboembolic event, major and minor bleeding, thrombocytopenia, and death) occurring 1 to 30 days postprocedure were determined.

Measurements and results: The groups were similar in age, sex, Charlson score, indication for long-term warfarin therapy (ie, arterial/cardiac vs venous), mean international normalized ratio prior to procedure, procedure duration, use of intraprocedural anticoagulant agents or thrombolytic agents, and use of general anesthesia during the procedure (all p > 0.05). A total of 34.6% of UH patients and 40.0% of LMWH patients experienced one or more clinical adverse events within 30 days of the postoperative period, a difference that was not statistically significant (p = 0.67). The mean total health-care costs were $31,625 in the UH group and $18,511 in the LMWH group (p < 0.01). The mean inpatient costs were $28,515 in the UH group and $14,330 in the LMWH group (p < 0.01). Outpatient surgery costs ($1,159 vs $53, respectively; p = 0.01) and pharmacy costs ($639 vs $133, respectively; p < 0.01) were higher in the LMWH group.

Conclusions: The mean total health-care costs in the perioperative period were significantly lower (by $13,114) in patients receiving long-term OAC therapy using LMWH compared to those receiving it using UH for an elective surgical procedure. The cost savings associated with LMWH use were accomplished through the avoidance or minimization of inpatient stays and no increase in the overall rate of clinical adverse events in the postoperative period.

Key Words: enoxaparin • low-molecular-weight heparin • managed care • oral anticoagulant therapy • outpatient treatment • perioperative bridging • pharmacoeconomic evaluation


   Introduction
TOP
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 Conclusions
 References
 
The optimal perioperative management of at-risk patients on long-term oral anticoagulant (OAC) therapy remains problematic. Although most patients can safely undergo procedures such as diagnostic endoscopy, cataract surgery, arthrocentesis, and oral surgery/dental extractions without an alteration of OAC therapy in the periprocedural period,1 the conventional care for the perioperative management of high-risk patients requiring continuous anticoagulant therapy involves the use of IV unfractionated heparin (UH) as "bridge therapy" during periods of subtherapeutic levels of oral anticoagulation.2 Consensus guidelines34567 for the management of anticoagulation therapy in the perioperative period, especially with the use of IV or subcutaneous UH, are based on expert opinion or mathematical modeling. In the preoperative period, this is accomplished in conjunction with the cessation of OAC therapy until a safe target international normalized ratio (INR) is reached to minimize the bleeding risk associated with the procedure (usually an INR of < 1.5). In the postoperative period, therapy with IV or subcutaneous UH is resumed along with OAC therapy until a previously defined therapeutic INR is reached (usually 2.0).34567

Although the safety and efficacy of therapy using low-molecular-weight heparin (LMWH) compares favorably with therapy using UH with regard to postoperative deep venous thrombosis prophylaxis, the treatment of venous thromboembolism, and the treatment of acute coronary syndromes,8910 there are limited clinical data concerning its use in the perioperative or periprocedural period in patients receiving long-term OAC requiring the temporary cessation of therapy to undergo an elective procedure. Observational cohort studies and comparative, nonrandomized case series11121314 involving relatively small sample sizes have reported good clinical outcomes with the use of LMWH in the periprocedural and perioperative period, with one study14 revealing a similar safety and efficacy profile to that of therapy with IV UH. Some guidelines715 concerning the perioperative management of the patient receiving long-term anticoagulation therapy, including the latest consensus statements from the American College of Chest Physicians,7 make specific mention of LMWH as a treatment option with a grade C recommendation.

Pharmacoeconomic analyses support the cost-effectiveness, cost savings, or economic dominance of the use of LMWH over that of UH for the inpatient treatment of venous thrombosis, the outpatient management of uncomplicated deep vein thrombosis, thromboprophylaxis in orthopedic surgery, and the management of acute coronary syndromes.16171819 Most of these analyses161719 support the notion that the cost savings from LMWH therapy stem from shifting costs from the inpatient to the less expensive outpatient environment or from the greater effectiveness of treatment.

To date, there have been no cost evaluations comparing the use of LMWH to that of UH in the perioperative period for the patient receiving long-term OAC therapy requiring the temporary interruption of therapy to undergo an elective surgical procedure. Therefore, we conducted a retrospective study, the primary objective of which was to compare the health-care costs of patients who were treated on a mostly outpatient basis with the LMWH enoxaparin to the health-care costs of patients who were treated with IV UH as hospital inpatients.


   Patients and Methods
TOP
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 Conclusions
 References
 
Study Site
This study was conducted among members of the Lovelace Health Plan, which is the insurance component of Lovelace Health Systems. Lovelace Health Systems is a fully integrated managed care organization and health-care delivery system serving New Mexico, the facilities of which include a 210-bed acute care hospital, nine primary care centers, and two multispecialty outpatient centers. The Lovelace Health Plan had between 150,000 and 240,000 members per year during the study period.

Disease management guidelines for the perioperative management of anticoagulation therapy for nonemergent surgical procedures for at-risk patients receiving long-term OAC utilizing the LMWH agent enoxaparin, usually in the outpatient setting, were instituted at Lovelace Health Systems in March 1997 and were implemented through a pharmacist-managed anticoagulation clinic. Patients who were eligible for perioperative anticoagulant bridging therapy with enoxaparin included those receiving long-term OAC therapy for cardiac disease (ie, patients with high-risk atrial fibrillation, and those patients with mechanical and bioprosthetic heart valves) and noncardiac disease (ie, patients at high risk for venous thromboembolism and arterial thromboembolism). Patients with high-risk atrial fibrillation included those with concomitant prosthetic valves, a previous thromboembolic event within 6 months of undergoing the elective procedure, severe left ventricular dysfunction, a history of hypertension, and age >= 75 years. Patients with a high risk of venous thromboembolism included those with active malignancy, a history of thrombophilia, or recurrent disease.

Study Design
This was a retrospective study that compared total health-care costs and rates of adverse clinical outcomes in two groups of at-risk patients receiving long-term warfarin therapy who received bridge therapy in the perioperative period with UH or LMWH for an elective surgical procedure during the temporary cessation of warfarin therapy. Costs were examined for the bridging episode, which was defined as the period from 10 days before the procedure through 30 days after the procedure. Adverse clinical events that occurred following the procedure were identified from day 1 through day 30 postprocedure. The study protocol was reviewed by the Lovelace Institutional Review Board and was given exempt status.

Study Population
Inclusion and exclusion criteria were applied to both the UH group and the LMWH group with the aim of ensuring that the two study groups included patients with comparable risk profiles. All study patients met the following inclusion criteria: (1) had received long-term OAC therapy with intent-to-treat for >= 3 months for venous or arterial thromboembolic disease, atrial fibrillation, or cardiac valvular disease; (2) had undergone an elective surgical procedure in which UH or LMWH therapy was used in the perioperative period; and (3) were >= 18 years old on the date of the procedure. All patients had a goal INR of 2.5 for routine intensity warfarin therapy, and a goal INR of 3.0 for high-intensity therapy.

The UH group included patients who had been treated with weight-adjusted IV UH (adjusted to keep the activated partial thromboplastin time between 1.5 times to 2.5 times control values) in the hospital between January 1, 1994, and December 31, 1996. During this time, there were no anticoagulation management guidelines for the use of LMWH. As 1997 represented a transition year for the implementation of these guidelines, this group of patients was excluded from the analysis.

The LMWH group included patients who had been treated with the LMWH agent enoxaparin mostly on an outpatient basis between January 1, 1998, and December 31, 2000. During this time, perioperative anticoagulation management guidelines, which defined at-risk patients who were suitable candidates for LMWH therapy, were in use at Lovelace Health Systems. The guidelines specify that warfarin therapy be discontinued at least 4 days prior to the patient undergoing the procedure and that enoxaparin therapy be started at least 2 days prior to the patient undergoing the procedure at a therapeutic dose of 1 mg/kg subcutaneously bid. A prophylactic dose of 30 mg then was administered on the evening of surgery if the patient was deemed to have adequate hemostasis. Otherwise, the usual therapeutic dose of enoxaparin was administered concomitantly with the patient’s maintenance dose of warfarin the morning after surgery and was continued until the INR was in the therapeutic range (ie, > 2.0 for most cases) for >= 2 consecutive days.

Patients were excluded from the study for the following reasons: (1) had been receiving OAC therapy for < 3 months; (2) had undergone an urgent or emergent surgical procedure rather than an elective procedure; (3) had severe chronic renal insufficiency (serum creatinine level, > 2.5 mg/dL; or creatinine clearance level, < 30 mL/min); (4) had underlying cirrhosis or severe liver disease (baseline INR, > 1.5); (5) had a body weight of > 330 lb; (6) had experienced a major bleeding episode from any source within 3 months of the elective surgical procedure; or (7) were hospitalized for a reason other than the elective surgical procedure.

Identification of Subjects
Potential study subjects first were identified using health plan administrative data. For the UH group, we used outpatient pharmacy claims to identify all health plan members from 1994 to 1996 who had filled prescriptions for warfarin. Using inpatient claims, we then identified the subset of patients who were hospitalized during the study period, were at least 18 years old at the time of hospitalization, and whose hospitalization included a surgical procedure that potentially required bridging therapy. We then reviewed the paper medical chart to determine whether the patient received bridge therapy with heparin and met the study eligibility criteria.

For the LMWH group, after first identifying patients who had filled prescriptions for warfarin on an outpatient basis between 1998 and 2000, we identified the subset of patients who had filled those prescriptions with enoxaparin. We also reviewed the anticoagulation therapy clinic records to identify additional patients who had received bridge therapy not captured by prescription drug claims for LMWH. The paper medical charts of all potential LMWH group patients then were reviewed to determine whether the patient had received bridge therapy with LMWH for an elective surgical procedure, and to ascertain the status of all other inclusionary and exclusionary study criteria.

Data Collection
Medical Records:
A data abstraction instrument and detailed instructions for abstracting data were developed. A team of four experienced medical record reviewers and one medical student reviewed the medical records and abstracted data onto the data collection form. The record reviewers were trained in the study protocol and were supervised by a research nurse with extensive experience conducting medical record abstraction for research projects. All data collection forms were reviewed by the nurse supervisor for completeness and consistency. The abstracted data were entered into computer-readable format and were formatted with appropriate variables (SAS; SAS Institute; Cary, NC). We obtained information on patient demographic and clinical characteristics, indication for anticoagulation therapy (ie, arterial/cardiac and venous), comorbidities, procedure details, bridging therapy regimen, and postprocedure adverse events by conducting a review of medical records and abstracting pertinent data.

Clinical Data:
Information describing adverse events was extracted from medical records. Adverse events of interest were as follows: death from any cause; venous thromboembolic event (deep vein thrombosis confirmed by Doppler ultrasound, venography, or spiral CT scan, or pulmonary embolism confirmed by high-probability ventilation/perfusion scan, pulmonary arteriography, or spiral CT scan); cardiac valvular or mural thrombus confirmed by echocardiography; intracranial event confirmed by CT scan or MRI; suspected transient ischemic attack; peripheral arterial thromboembolic event confirmed by arteriography; major bleed (defined as retroperitoneal bleeding, intracranial bleeding, intraocular bleeding, a postprocedural drop in hemoglobin level of > 2 g/dL; a clinically apparent bleed necessitating the transfusion of >= 2 U packed RBCs; or any bleeding resulting in a hospital visit or surgical intervention); minor bleed (defined as epistaxis, hematuria, ecchymoses, either spontaneous or around the surgical wound site, and other bleeding not defined as major); and significant thrombocytopenia (ie, platelet count of < 100,000 cells/µL or a drop in platelet count of > 50% from baseline, with or without heparin-associated antiplatelet antibodies). To adjust for comorbidities, a comorbidity score was calculated using the adaptation by Deyo et al20 of the Charlson index. The Charlson index is a weighted score that is calculated based on the presence or absence of 17 categories of comorbidities that predict the likelihood of death in hospitalized patients. The score was calculated based on International Classification of Diseases, ninth revision, diagnosis codes in the inpatient and outpatient claims records for the year prior to the study window.

Administrative Data:
We obtained cost data for the bridging episode from administrative claims. These data are housed in the Lovelace Patient Database that is maintained by the Lovelace Respiratory Research Institute Center for Pharmacoeconomic and Outcomes Research. We extracted charges for inpatient care, outpatient care, and outpatient drug dispensing for the period from 10 days preprocedure through 30 days postprocedure. We calculated the outpatient costs for the following subcategories: primary care; specialty care; outpatient surgery; laboratory tests; radiology; emergency department care; and all other outpatient care. We calculated pharmacy costs by summing the average wholesale price of LMWH and all other outpatient drugs dispensed during the bridging episode.

Statistical Analysis
We determined the mean total health-care costs, as well as the costs for inpatient care, total outpatient care, subcategories of outpatient care, LMWH drug costs, and all other drug costs. We also calculated the rates of adverse events. For the cost data, we used both the t test, which assumes that the data have an underlying normal distribution, and the Wilcoxon rank sum nonparametric test, which has no underlying distribution assumptions. The nonparametric test is an appropriate one for our cost and clinical data, due to the small sample sizes and uncertainty about the underlying distributions of the data for each treatment group. The reported p values are for a two-tailed test statistic. No p value is reported for which sample sizes were not large enough for a meaningful measure of difference.

Multiple regression analysis was performed to further determine the predictive value of a heparin regimen on total health-care costs. The dependent variable, total health-care costs, was transformed using the natural logarithm function. Independent variables in the model were as follows: UH group; sex; age; arterial/cardiac risk (ie, indication for long-term OAC therapy); occurrence of an adverse event; and a proxy for more complex surgery (ie, duration of surgical procedure > 120 min). All analyses were performed using a statistical software package (SAS, version 8.0; SAS Institute).


   Results
TOP
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 Conclusions
 References
 
We identified 90 potential patients for the UH group and 71 potential patients for the LMWH group who had been receiving long-term OAC therapy prior to undergoing an elective surgical procedure. A review of medical records resulted in 64 patients being found to be ineligible for inclusion in the UH group (31 had not been receiving OAC therapy for 3 months prior to the procedure, and 33 did not receive heparin in the perioperative period) and 31 patients being found to be ineligible for inclusion in the LMWH group (14 had not received OAC therapy for 3 months prior to undergoing the procedure, 14 did not receive heparin in the perioperative period, 1 person had a body weight of > 330 lb, and the procedure was performed outside Lovelace Health Systems and the chart was therefore unavailable for 2 patients). A total of 26 patients were eligible for inclusion in the UH group, and 40 patients were eligible for inclusion in the LMWH group.

Patient demographic and clinical characteristics of the UH and LMWH groups are shown in Table 1 . The groups were similar in age, sex distribution, indication for long-term warfarin therapy (ie, arterial/cardiac vs venous status), mean INR prior to the surgical procedure, and Charlson score (all p > 0.05).


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  		Table 1. Demographic and Clinical Characteristics of UH and LMWH Groups*

 
The characteristics of the surgical procedures are shown in Table 2 . A total of 11.3% of all patients received antiplatelet medications in the week prior to undergoing the procedure, but small sample size did not permit a test of the difference between groups. There were no differences between groups in the use of other medications of interest in the week prior to undergoing the procedure (ie, chemotherapeutic agents, corticosteroids, vitamin K, and nonsteroidal anti-inflammatory agents). There were also no differences in the proportion of surgical procedures classified as orthopedic, cardiothoracic, or general surgery (sample size was too small to detect differences in the proportions of other types of surgical procedures). Intraprocedural anticoagulant agents and thrombolytic agents were used in 26.9% of UH patients and in 10.0% of LMWH patients, but the difference was not statistically significant. The occurrence of major surgery, defined as a procedure duration of >= 45 min, was similar in both groups (84.6% vs 75%, respectively; p = 0.36). The majority of both UH and LMWH patients received general anesthesia (73.1% and 62.5% respectively; p = 0.38). Warfarin therapy was restarted within 24 h postprocedure in the minority of patients in both groups (23.1% vs 25.0%, respectively; p = 0.87). All 26 patients in the UH group and 19 patients (47.5%) in the LMWH group were hospitalized during heparin bridge therapy in the perioperative period. The mean length of stay in the hospital was 6.54 days for UH patients and 6.21 for LMWH patients.


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  		Table 2. Characteristics of the Bridged Medical Procedure in UH and LMWH Groups*

 
Adverse Events
The occurrence of adverse events is shown in Table 3 . There was no difference in the overall rate of events, with 34.6% of patients in the UH group and 40.0% in the LMWH group experiencing an adverse event within 30 days postprocedure (p = 0.67). One patient in each group experienced two adverse events. Due to the small sample size, we were unable to determine whether the rates of types of adverse events differed between groups, but we describe the events below.


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  		Table 3. Occurrence of Clinical Adverse Events Within 30 Days Postprocedure*

 
Thromboembolic events occurred in the UH group only, and they included one intracranial event, one transient ischemic attack, and one deep vein thrombosis. There were three major bleed events, (11.5%) in the UH group, all associated with a drop in hemoglobin of > 2 g/dL or a transfusion of >= 2 U packed RBCs in the immediate postoperative period. There were six major bleed events (15.0%) in the LMWH group. One was associated with a drop in hemoglobin of > 2 g/dL or a transfusion of >= 2 U packed RBCs in the immediate postoperative period, one retroperitoneal bleeding event, and four events in which bleeding resulted in rehospitalization or surgical intervention. A total of 25.0% of LMWH patients and 7.7% of UH patients experienced a minor bleed, most due to surgical site hematoma or bleeding around the surgical wound site. A total of 7.7% of UH patients and 2.5% of LMWH patients experienced significant thrombocytopenia. No deaths occurred during the follow-up period.

Health-Care Costs
Mean health-care costs for the bridge therapy period (ie, 10 days preprocedure through 30 days postprocedure) and statistical test results for differences in costs between the two treatment groups are shown in Table 4 . There were significant differences in costs between groups for total health care, inpatient care, and outpatient pharmacy, but not for total outpatient care. The mean total health-care costs were $31,625 in the UH group (95% confidence interval [CI], $22,966 to $40,285) and $18,511 in the LMWH group (95% CI, $8,355 to $28,668), a difference of $13,114 in favor of the LMWH group (p <.01). Inpatients costs were $28,515 in the UH group (95% CI, $20,399 to $36,631) vs $14,330 in the LMWH group (95% CI, $4,074 to $24,586; p < 0.01). Total outpatient costs were $3,532 for the LMWH group (95% CI, $2,328 to $47,737) vs $2,978 for the UH group (95% CI, $1,454 to $4,501; p = 0.08). Two subcategories of outpatient care costs were significantly different between groups, outpatient surgery, and "other care" (both p < 0.01). Outpatient pharmacy costs were $133 for the UH group (95% CI, $80 to $186) and $649 for the LMWH group (95% CI, $460 to $838; p < 0.01).


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  		Table 4. Mean Health-Care Costs and No. of Drug Fills for Bridging Therapy Episode*

 
In a multivariate regression model in which the log transformation of mean total health-care costs was the dependent variable, the predictors of higher costs during the bridging episode were the following: (1) being in the UH group, (2) having an arterial/cardiac indication for long-term OA therapy, (3) having a procedure > 2 h in duration, and (4) having any postprocedure adverse event (Table 5 ). The model had an adjusted R2 value of 0.53.


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  		Table 5. Predictors of Higher Health-Care Costs*

 

   Discussion
TOP
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
Conclusions
 References
 
The present study evaluated total health-care costs and short-term clinical outcomes in the setting of an integrated health-care delivery system in two groups of patients receiving long-term OAC therapy who required the temporary cessation of therapy and perioperative use of heparin to undergo an elective surgical procedure. In the UH group, patients received bridge therapy perioperatively in the hospital, while in the LMWH group patients received bridge therapy perioperatively on a mostly outpatient basis. The patients in the LMWH group received bridge therapy using explicit disease management guidelines under the auspices of a pharmacist-managed anticoagulation clinic. Previously published reports212223 suggest the potential for large health system-wide cost savings from the use of outpatient-based approaches to anticoagulant therapy management, assuming that there are no differences in clinical outcomes.

To our knowledge, this is the first pharmacoeconomic evaluation in an integrated health-care delivery system of a mostly outpatient-based bridging approach using LMWH and disease management guidelines in the perioperative management of the patient receiving long-term OAC therapy. The comparison group consisted of patients who received bridge therapy with conventional UH anticoagulant therapy. Both groups were similar in terms of demographic and clinical characteristics, including the indication for long-term warfarin therapy and comorbidity status, as reflected by the Charlson score. The two groups were also similar in the occurrence of major surgery (duration, > 45 min), use of general anesthesia, and the reinitiation of warfarin within 24 h postoperatively.

The results of our study reveal substantial mean total health-care cost savings ($13,114) in favor of the LMWH group. Costs were based on charges in administrative claims accrued during the bridging episode. The lower costs in the LMWH group resulted from the lower costs for inpatient care, despite higher costs for outpatient surgery and outpatient pharmacy. In addition, cost savings were achieved even though almost half of the patients in the LMWH group were hospitalized, which reflects a "real-world" experience with the perioperative management of at-risk patients with thromboembolic disease. In a multivariate regression model, arterial/cardiac risk was associated with increased costs, while age was not. Two outcome variables in the model (ie, surgery lasting >= 2 h and experiencing an adverse event) also were associated with increased costs, as would be expected. After adjusting for the effect of existing risk (arterial/cardiac), duration of procedure, and occurrence of an adverse event, the model showed that the use of UH still had a statistically significant association with increased costs.

Other studies2425 of perioperative bridging therapy using LMWH have reported cost avoidance or mean cost savings of $4,540 to $6,864 (US dollars) due to the reduction or avoidance of hospital length of stay. The majority of these studies have included patients who received bridge therapy with LMWH only in the postoperative setting during the transition to long-term warfarin therapy. As such, the cost savings of $13,114 in the present analysis, which includes the preoperative and postoperative use of LMWH as bridge therapy with the possibility of further avoidance of hospital bed-days, corresponds well with these figures. The limitations of the previous studies include a nongeneralizable patient population (ie, the LMWH group of patients mostly included those with only postoperative initiation of LMWH therapy along with warfarin in the setting of cardiac surgery), lack of a comparison group, reliance on estimated or extrapolated costs, and incomplete descriptions of the methods for cost and outcome assessments.

Our study also revealed no difference in the overall rate of clinical adverse events between the UH group and LMWH group (34.6% vs 40.0%, respectively; p = 0.67). The rate of thromboembolic complications in the UH group (three events among 26 patients) is higher than that reported in previous studies11121314 of perioperative bridging therapy using LMWH, although most studies represented small case series. One possible factor leading to increased rates of thrombotic events with IV UH use may be the difficulty of achieving adequate dosing in the perioperative period, despite the use of a weight-based nomogram. Montalescot et al14 reported a 9% therapeutic rate during the second study day in patients who were treated postoperatively during cardiac valve replacement using weight-adjusted IV UH therapy as a bridge to warfarin therapy vs an 87% therapeutic rate in those patients treated with LMWH (p < .0001), with > 91% of patients being subtherapeutic with a regimen of IV UH.

Of interest is that none of the 11 patients with mechanical heart valves in our LMWH (enoxaparin) group experienced a thrombotic event (results not shown), which is especially interesting in light of the previous labeling changes warning that enoxaparin is not recommended for thromboprophylaxis in patients with prosthetic heart valves.

The postprocedure rates of major bleeding events seen here (UH group, 11.5%; LMWH group, 15.0%) are higher than the rate predicted by mathematical modeling (3%) or described in previous perioperative bridging studies41112131426 in patients receiving long-term OAC therapy using LMWH (range, 0 to 6.6%). A possible reason for this was our strict use of well-established definitions of major and minor bleeding events, the ability to capture major bleeding events that resulted in rehospitalization or surgical intervention (four of six events in the LMWH group), and the overall high proportion of major surgeries (ie, orthopedic, cardiothoracic, and general surgery) and use of general anesthesia in both patient groups. One well-designed, prospective, multicenter study26 revealed a higher rate of major bleeding events (6.6%) than those reported in previous studies, mostly in the immediate postoperative period, suggesting that previous reports may have been conservative in the estimation of perioperative bleeding risk.

Last, there was a higher than expected incidence of significant thrombocytopenia in both heparin groups (UH group, 7.7%; LMWH group, 2.5% [representing a total of three patients]). Although the true incidence of heparin-induced thrombocytopenia could not be ascertained in the absence of serologic studies, previous studies27 have suggested a lower incidence of serologic conversion and clinical heparin-induced thrombocytopenia in patients treated with LMWH vs those treated with UH for postoperative thromboprophylaxis.

Our study has several limitations. First, in this retrospective study, the two groups underwent perioperative heparin bridging in different years. The UH group underwent bridging from 1994 to 1996. Prior to 1997, LMWH heparin was not available, and UH was used exclusively. Beginning in March 1997, disease management protocols using LMWH in the perioperative period were phased into use in our health-care system using well-defined risk categories. Although it is possible that patients with a lower thrombotic risk received bridge therapy with LMWH in our study, the two study groups were similar in demographic and clinical characteristics, including comorbidity status. It is also possible that other changes in the delivery of health care occurred during the study years that affected the delivery and quality of health care for those patients receiving bridge therapy, such as improved surgical techniques and decreased operating times. However, important indicators for postoperative adverse events, such as the occurrence of major surgery, the use of intraprocedural anticoagulant agents or thrombolytic agents, the use of general anesthesia, and the resumption of OAC therapy within 24 h postoperatively, were tested for and found to not be statistically significantly different between groups. Second, we did not adjust for cost inflation across the study years (from 1994 to 2000) to standardize costs. Not adjusting costs, however, biases in the direction of a more conservative estimate of cost savings with LMWH use. Adjusting the inpatient costs of the UH group for inflation would have served to increase the costs of the UH group, with the result that LMWH use would have been associated with an even greater cost savings. Third, although there was no difference in the rates of total adverse events between groups, we did not have sufficient numbers to determine whether there were differences in the rates of subcategories of adverse clinical events (eg, arterial events, venous events, major bleeds, minor bleeds, and thrombocytopenia).

Between January 1998 and March 2002, a total of 137 patients receiving long-term OAC therapy received bridge therapy perioperatively with LMWH in our health-care delivery system (data on file). Applying a cost savings figure of $13,114 per episode of bridge therapy, as seen in our present study, results in an estimated savings of nearly $1.8 million due to the use of an outpatient LMWH bridging protocol during this time period. This figure is based on patient health-care charges and does not adjust for the fixed costs associated with operating the clinical thrombosis center.


   Conclusions
TOP
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Conclusions
References
 
Our study revealed that perioperative or periprocedural use of LMWH, mostly in the outpatient setting, in at-risk patients receiving long-term OAC therapy requiring the interruption of therapy to undergo elective surgery or an elective procedure, substantially reduces costs compared with the inpatient use of IV UH. The use of LMWH in conjunction with perioperative disease management guidelines resulted in a shift of health-care utilization from more expensive inpatient care to less expensive outpatient care and prescription drugs. This shift in utilization was achieved with comparable rates of adverse outcomes in both groups.


   Acknowledgements
 
The study team is grateful to Hans Petersen, MS, for the collection of administrative data, to Ann Von Worley, BSN, RN, for the supervision of medical record review tasks, and to Dana Golden, Adrian Miranda, Debbie Tallman, RN, and Ann Marie Weaver for the abstraction of medical record data.


   Footnotes
 
Abbreviations: CI = confidence interval; INR = international normalized ratio; LMWH = low-molecular-weight heparin; OAC = oral anticoagulant; UH = unfractionated heparin

This study was presented as a poster abstract at the International Society of Thrombosis Hemostasis XIX Congress, Birmingham, UK, in July 2003.

Dr. Spyropoulos is on the Speaker’s Bureau and is a consultant for Aventis Pharmaceuticals. This research was supported by an unrestricted grant-in-aid from Aventis Pharmaceuticals.

Received for publication July 9, 2003. Accepted for publication January 20, 2004.


   References
TOP
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Conclusions
 References
 

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