Selecting an Agent for Prophylaxis of Venous Thromboembolism
Selecting an Agent for Prophylaxis of Venous Thromboembolism
Q: It has become very common to use expensive low-molecular-weight heparins (LMWHs) for prophylaxis of deep venous thrombosis (DVT) in hospitalized medical and surgical patients. How can optimal prophylaxis be maintained while controlling the pharmacy expenses that result from the use of effective but costly antithrombotic agents?
A: Over the past decade, the use of LMWHs has expanded exponentially as data and experience with the drugs have accumulated. As a result, hospital expenditures have increased dramatically, prompting many hospitals to evaluate LMWHs for potential formulary restriction or therapeutic interchange.
The prevention of thrombotic complications is essential in the hospital setting, as venous thromboembolism (VTE), including DVT and pulmonary embolism (PE), is a major cause of morbidity and mortality in hospitalized patients, with 5–10% of all inpatient deaths associated with PE. The frequency of VTE is 150-fold higher in hospitalized patients than in nonhospitalized individuals. An estimated 75% of all fatal PEs occur in medical patients, who account for 60% of all hospital admissions. Early mortality rates of 3.8% and 38.9% in patients experiencing DVT and PE, respectively, have been reported. Patients undergoing major orthopedic surgery have an increased risk of fatal PE. Approximately 50–60% of patients undergoing total hip or knee replacement or surgery for hip fracture without prophylaxis will develop DVT, and up to 13% will die from PE. At the most basic level, the mean length of hospital stay increases from 5.4 days in patients who do not develop a DVT or PE to 11.5 and 12.4 days, respectively, in those who develop these complications (p < 0.0001 for both comparisons).
In 2001, dalteparin was selected as the formulary LMWH at Baptist Hospital of East Tennessee (BHET), a 320-bed community hospital in Knoxville, Tennessee. Dalteparin was therapeutically interchanged for enoxaparin for all anticoagulant treatment and prophylaxis indications at BHET. After the merger of Pharmacia and Pfizer in 2003, three factors led to a gradual erosion of dalteparin use at BHET: (1) reduced support of dalteparin purchases from the newly merged company representatives, (2) continued drug purchasing support from the manufacturer of enoxaparin, and (3) the increasing preference by cardiologists for enoxaparin over dalteparin in the treatment of acute coronary syndrome (ACS).
The importance of controlling the increasing LMWH acquisition costs at BHET while continuing optimal medical and surgical anticoagulation and prophylaxis gave rise to a dilemma. To resolve it, the BHET pharmacy department reevaluated available LMWHs by reviewing their pharmacokinetics and pharmacodynamics, clinical trial data, adverse effects, and pricing to develop a conversion plan. The BHET pharmacy department's conversion proposal specified that tinzaparin sodium was to be the formulary LMWH indicated for sole use in the treatment of DVT and PE (175 IU/kg subcutaneously daily) and for medical and surgical DVT prophylaxis (see below for dosage). In addition, the proposed conversion allowed the use of enoxaparin sodium 1 mg/kg subcutaneously every 12 hours to treat ACS. In October 2004, the BHET pharmacy and therapeutics (P&T) committee approved the conversion; shortly afterward, the medical executive committee gave its official authorization.
The most controversial area debated during the P&T committee's discussion about the proposal was the use of tinzaparin in the prophylaxis of DVT and PE. Although many medications are routinely used for indications not included in FDA-approved labeling, it is essential to thoroughly evaluate available data for efficacy and safety. Since tinzaparin had been marketed in Europe, several trials, including a direct comparison with enoxaparin for the prophylaxis of DVT and PE, had been completed.
The prophylactic dosage of tinzaparin indicated in our conversion plan was based on data published by Planes et al. Data from this randomized, double-blind controlled trial in 499 patients demonstrated equivalent safety and efficacy of tinzaparin and enoxaparin after total hip replacement. Patients received either tinzaparin sodium 4500 IU or enoxaparin sodium 40 mg subcutaneously 12 hours before surgery, followed by a second dose 12 hours after surgery, and continued once daily for 15 days. DVT occurred in 20.1% of enoxaparin-treated patients and 21.7% of the tinzaparintreated group. The proximal DVT rate was 10.5% for enoxaparin and 9.5% for tinzaparin. Bilateral venography was the method of detection for DVT and was performed between days 10 and 14, unless clinical symptoms occurred before that time. The difference in DVT rates between groups was not significant. One PE occurred in each group. No difference in bleeding complications between groups was noted.
Since the absolute risk of DVT is higher in patients undergoing hip surgery than in other hospitalized patients, we reasoned that tinzaparin sodium 4500 IU subcutaneously daily would be appropriate for most patients who would otherwise receive subcutaneous enoxaparin sodium 40 mg once daily. The only tinzaparin sodium dosage evaluated in knee- replacement patients is 75 IU/kg subcutaneously daily. Knee-replacement patients were excluded from our proposal; these patients usually receive subcutaneous enoxaparin sodium 30 mg every 12 hours or tinzaparin sodium 75 IU/kg daily at BHET.
In summer 2005, a formal evaluation of the therapeutic interchange was performed. In all, 723 records of patients receiving tinzaparin were reviewed: 650 patients for medical prophylaxis and 73 for surgical prophylaxis. Four DVTs were recorded (0.55%) following the conversion to tinzaparin. No PEs were documented in the patient records reviewed. Three other DVTs were considered to be unrelated to tinzaparin prophylaxis, as they occurred after only one dose given after a hospital stay exceeding eight days. The median length of prophylaxis with tinzaparin was 5.41 doses.
Since the therapeutic interchange, LMWH expenditures have been consistently decreasing. From the third quarter to the end of the fourth quarter of 2004, LMWH costs decreased 7.6%, from $150,589 to $139,083. From the beginning of the first quarter to the end of the second quarter of 2005, LMWH expenditures decreased by 16%, from $128,435 to $107,842, resulting in an annualized cost saving of over $130,000 due to maximized discounts on tinzaparin purchases.
The success of the therapeutic interchange shows that optimal prophylaxis of DVT and PE can be achieved while reducing costs. Our results further indicate that our conversion to the primary use of a single LMWH for DVT and PE prophylaxis in medical and surgical patients has been successful from a benefit—cost perspective. The use of tinzaparin for the prophylaxis of DVT and PE has resulted in the continued highly effective prevention of DVT and PE at BHET. Other institutions can use similar methods to help optimize the use of LMWHs in their particular practice settings.
The Management Consultation column gives readers an opportunity to obtain advice on common management problems from pharmacists practicing in health systems.
AJHP readers are invited to submit questions for this column. Selected questions will be forwarded to one or two experts in the field, who will prepare brief responses for publication. Questions should be narrow in scope, such that they can be answered in approximately 500 words. Responses will be sent to the inquirer before publication. Readers are also invited to comment on the answers of consultants; such comments will be considered for the Letters column.
Suggestions for topics should be submitted to AJHP, 7272 Wisconsin Avenue, Bethesda, MD 20814 (301-664-8601 or ajhp@ashp.org
Q: It has become very common to use expensive low-molecular-weight heparins (LMWHs) for prophylaxis of deep venous thrombosis (DVT) in hospitalized medical and surgical patients. How can optimal prophylaxis be maintained while controlling the pharmacy expenses that result from the use of effective but costly antithrombotic agents?
A: Over the past decade, the use of LMWHs has expanded exponentially as data and experience with the drugs have accumulated. As a result, hospital expenditures have increased dramatically, prompting many hospitals to evaluate LMWHs for potential formulary restriction or therapeutic interchange.
The prevention of thrombotic complications is essential in the hospital setting, as venous thromboembolism (VTE), including DVT and pulmonary embolism (PE), is a major cause of morbidity and mortality in hospitalized patients, with 5–10% of all inpatient deaths associated with PE. The frequency of VTE is 150-fold higher in hospitalized patients than in nonhospitalized individuals. An estimated 75% of all fatal PEs occur in medical patients, who account for 60% of all hospital admissions. Early mortality rates of 3.8% and 38.9% in patients experiencing DVT and PE, respectively, have been reported. Patients undergoing major orthopedic surgery have an increased risk of fatal PE. Approximately 50–60% of patients undergoing total hip or knee replacement or surgery for hip fracture without prophylaxis will develop DVT, and up to 13% will die from PE. At the most basic level, the mean length of hospital stay increases from 5.4 days in patients who do not develop a DVT or PE to 11.5 and 12.4 days, respectively, in those who develop these complications (p < 0.0001 for both comparisons).
In 2001, dalteparin was selected as the formulary LMWH at Baptist Hospital of East Tennessee (BHET), a 320-bed community hospital in Knoxville, Tennessee. Dalteparin was therapeutically interchanged for enoxaparin for all anticoagulant treatment and prophylaxis indications at BHET. After the merger of Pharmacia and Pfizer in 2003, three factors led to a gradual erosion of dalteparin use at BHET: (1) reduced support of dalteparin purchases from the newly merged company representatives, (2) continued drug purchasing support from the manufacturer of enoxaparin, and (3) the increasing preference by cardiologists for enoxaparin over dalteparin in the treatment of acute coronary syndrome (ACS).
The importance of controlling the increasing LMWH acquisition costs at BHET while continuing optimal medical and surgical anticoagulation and prophylaxis gave rise to a dilemma. To resolve it, the BHET pharmacy department reevaluated available LMWHs by reviewing their pharmacokinetics and pharmacodynamics, clinical trial data, adverse effects, and pricing to develop a conversion plan. The BHET pharmacy department's conversion proposal specified that tinzaparin sodium was to be the formulary LMWH indicated for sole use in the treatment of DVT and PE (175 IU/kg subcutaneously daily) and for medical and surgical DVT prophylaxis (see below for dosage). In addition, the proposed conversion allowed the use of enoxaparin sodium 1 mg/kg subcutaneously every 12 hours to treat ACS. In October 2004, the BHET pharmacy and therapeutics (P&T) committee approved the conversion; shortly afterward, the medical executive committee gave its official authorization.
The most controversial area debated during the P&T committee's discussion about the proposal was the use of tinzaparin in the prophylaxis of DVT and PE. Although many medications are routinely used for indications not included in FDA-approved labeling, it is essential to thoroughly evaluate available data for efficacy and safety. Since tinzaparin had been marketed in Europe, several trials, including a direct comparison with enoxaparin for the prophylaxis of DVT and PE, had been completed.
The prophylactic dosage of tinzaparin indicated in our conversion plan was based on data published by Planes et al. Data from this randomized, double-blind controlled trial in 499 patients demonstrated equivalent safety and efficacy of tinzaparin and enoxaparin after total hip replacement. Patients received either tinzaparin sodium 4500 IU or enoxaparin sodium 40 mg subcutaneously 12 hours before surgery, followed by a second dose 12 hours after surgery, and continued once daily for 15 days. DVT occurred in 20.1% of enoxaparin-treated patients and 21.7% of the tinzaparintreated group. The proximal DVT rate was 10.5% for enoxaparin and 9.5% for tinzaparin. Bilateral venography was the method of detection for DVT and was performed between days 10 and 14, unless clinical symptoms occurred before that time. The difference in DVT rates between groups was not significant. One PE occurred in each group. No difference in bleeding complications between groups was noted.
Since the absolute risk of DVT is higher in patients undergoing hip surgery than in other hospitalized patients, we reasoned that tinzaparin sodium 4500 IU subcutaneously daily would be appropriate for most patients who would otherwise receive subcutaneous enoxaparin sodium 40 mg once daily. The only tinzaparin sodium dosage evaluated in knee- replacement patients is 75 IU/kg subcutaneously daily. Knee-replacement patients were excluded from our proposal; these patients usually receive subcutaneous enoxaparin sodium 30 mg every 12 hours or tinzaparin sodium 75 IU/kg daily at BHET.
In summer 2005, a formal evaluation of the therapeutic interchange was performed. In all, 723 records of patients receiving tinzaparin were reviewed: 650 patients for medical prophylaxis and 73 for surgical prophylaxis. Four DVTs were recorded (0.55%) following the conversion to tinzaparin. No PEs were documented in the patient records reviewed. Three other DVTs were considered to be unrelated to tinzaparin prophylaxis, as they occurred after only one dose given after a hospital stay exceeding eight days. The median length of prophylaxis with tinzaparin was 5.41 doses.
Since the therapeutic interchange, LMWH expenditures have been consistently decreasing. From the third quarter to the end of the fourth quarter of 2004, LMWH costs decreased 7.6%, from $150,589 to $139,083. From the beginning of the first quarter to the end of the second quarter of 2005, LMWH expenditures decreased by 16%, from $128,435 to $107,842, resulting in an annualized cost saving of over $130,000 due to maximized discounts on tinzaparin purchases.
The success of the therapeutic interchange shows that optimal prophylaxis of DVT and PE can be achieved while reducing costs. Our results further indicate that our conversion to the primary use of a single LMWH for DVT and PE prophylaxis in medical and surgical patients has been successful from a benefit—cost perspective. The use of tinzaparin for the prophylaxis of DVT and PE has resulted in the continued highly effective prevention of DVT and PE at BHET. Other institutions can use similar methods to help optimize the use of LMWHs in their particular practice settings.
The Management Consultation column gives readers an opportunity to obtain advice on common management problems from pharmacists practicing in health systems.
AJHP readers are invited to submit questions for this column. Selected questions will be forwarded to one or two experts in the field, who will prepare brief responses for publication. Questions should be narrow in scope, such that they can be answered in approximately 500 words. Responses will be sent to the inquirer before publication. Readers are also invited to comment on the answers of consultants; such comments will be considered for the Letters column.
Suggestions for topics should be submitted to AJHP, 7272 Wisconsin Avenue, Bethesda, MD 20814 (301-664-8601 or ajhp@ashp.org
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