Drug Criteria & Outcomes: Tinzaparin formulary evaluation: DVT treatment
Drug Criteria & Outcomes: Tinzaparin formulary evaluation: DVT treatment
By Lisa Patel, PharmD
Auburn (AL) University*
* Written on clinical rotation at Huntsville Hospital, Huntsville, AL
The deep vein thrombosis (DVT)-related, Food and Drug Administration (FDA)-approved indications for enoxaparin (Lovenox, Aventis) include:
• prevention of DVT in patients undergoing hip replacement, knee replacement, or abdominal surgery who are at risk for thromboembolic complications;
• inpatient or outpatient treatment of acute DVT with or without pulmonary embolism when administered in conjunction with warfarin sodium;
• prevention of DVT in medical patients at risk for thromboembolic complications due to severely restricted mobility during acute illness; and
• other indications, including prevention of ischemic complications of unstable angina and myocardial infarction.
The DVT-related, FDA-approved indication for tinzaparin (Innohep, DuPont) includes:
• Treatment of DVT with or without pulmonary embolism when administered in conjunction with warfarin sodium. The safety and effectiveness of tinzaparin were established in hospitalized patients.
Mechanism of action
When binding to antithrombin III (the body’s natural anticoagulant), low-molecular-weight heparin (LMWH) products cause a conformational change that increases the activity of antithrombin III. Antithrombin III can bind thrombin and prevent its effect on the coagulation system. Because less than 50% of the LMWH chains are capable of binding both antithrombin and thrombin, LMWH inhibits antifactor Xa to a greater degree than antifactor IIa. Factor Xa catalyzes the conversion of prothrombin (Factor II) to thrombin (Factor IIa). Antifactor-Xa activity correlates with antithrombotic efficacy, and antifactor IIa correlates with bleeding. Thus, LMWH products theoretically have less chance of causing bleeding than unfractionated heparins.
LMWH products also inhibit thrombin, which converts fibrinogen to fibrin (the main constituent of a thrombus). Inhibition of Factors Xa and IIa does not dissolve clots, but helps to prevent DVT and clot extension, while natural mechanisms resolve the thrombus. LMWH does not bind as extensively to plasma proteins, macrophages, or endothelial cells, resulting in a more predictable response pattern as compared to unfractionated heparin. Other actions of LMWH, of which the clinical significance has not been determined, include stimulation of endothelial cell growth factor, activation of lipoprotein lipase, suppression of aldosterone secretion, inhibition of smooth muscle cell proliferation, and induction of platelet aggregation.1,2
Pharmacokinetic data
LMWH products have similar molecular profiles, but structural variations create differences in biologic actions.3,4 (See Table 1, below.) Biological properties and extent of antifactor-Xa activity vary widely among available products. For this reason, all different LMWHs should be considered separate products. Although LMWH levels cannot be measured directly, antifactor-Xa activity, antifactor-IIa activity, and tissue factor pathway inhibitor (TFPI) can be measured as indicators of LMWH clinical activity.5
Depolymerization of specific LMWH products results in the loss of molecules that are greater than 18 saccharide units and molecular changes that confer varying chemical and biological profiles to each LMWH product. This smaller molecule results in a product that inhibits Factor IIa to a lesser degree compared to unfractionated heparin.6 As stated earlier, an increase in the antifactor-Xa/IIa ratio theoretically would result in a decreased chance of bleeding. Thus, enoxaparin with an antifactor-Xa/IIa ratio of 3.9 compared to a tinzaparin value of 1.9 theoretically should result in fewer bleeding episodes. No studies comparing the two drugs for DVT treatment exist; thus, this pharmacokinetic difference is difficult to relate to clinical practice. One study involving 440 patients that compared tinzaparin (4,500 antifactor IU Xa) and enoxaparin (40 mg) for prophylaxis of DVT after hip surgery identified four patients in the enoxaparin group and two patients in the tinzaparin group who experienced major bleeding.7 Minor bleeding occurred in 21 patients in the enoxaparin group and in 13 patients in the tinzaparin group. This study showed a lower incidence of bleeding with tinzaparin; however, the difference was not statistically significant.
Because of its increased duration of action, tinzaparin can be given once a day vs. once-to-twice daily for enoxaparin (depending on its indication). This is an important pharmacokinetic difference in terms of cost and convenience.
Dosing
Recommended dose for treatment of DVT:3,4
Tinzaparin dose:
• 175 IU/kg SC QD
Enoxaparin dose:
• 1 mg/kg/dose Q12H
• 1.5 mg/kg/dose Q24H
These doses are indicated as "bridge" therapy to warfarin until a stable international normalized ratio (INR) is achieved. The 1.5 mg/kg Q24H dose of enoxaparin is indicated for inpatient therapy only.
Duration of therapy
Average duration of therapy for LMWH is 6-7 days. Warfarin therapy should be started between days 1-3 of LMWH therapy. Treatment with LMWH should continue until a therapeutic INR (between 2-3 for two consecutive days) can be achieved.
Renal impairment
Dose with caution in patients with severe renal impairment. In patients with moderate renal failure (CrCl 30-80 mL/min), antifactor-Xa clearance was similar to clearance in healthy patients. For patients with severe renal impairment (CrCl < 30 mL/min), clearance was 30% lower in enoxaparin patients and 24% lower in tinzaparin patients compared to controls. Although no recommendations have been made, dosage adjustments or alternate therapy should be considered in patients with severe renal impairment.3,4,8
Geriatric dosing
Because LMWHs are eliminated renally, elderly patients may have decreased elimination. Dose modification, however, is not necessary unless severe renal impairment exists.
Pediatric dosing
At this time, neither tinzaparin nor enoxaparin is approved by the FDA for use in pediatric patients.
As indicated in Table 2, below, tinzaparin and enoxaparin have similar adverse effect profiles.3,4 Slight differences in incidence of common side effects were not statistically significant in a trial comparing prophylaxis doses of tinzaparin and enoxaparin.7 In one tinzaparin study, major bleeding was reported as 0.5% with 175 antifactor Xa IU/kg daily for six days and 3% with unfractionated heparin. Incidence of minor bleeding was equal at 3% for both groups.8 Studies with enoxaparin report a 2% rate of major bleeding.4 Injection-site pain or irritation also is a common adverse effect, and case reports of skin necrosis have been reported with both tinzaparin and enoxaparin.3,4
Contraindications
Contraindications to outpatient therapy with LMWH include (see Table 3, below):3,4
- history of heparin-induced thrombocytopenia;
- presence of current thrombocytopenia;
- history of two or more episodes of DVT or PE;
- concurrent pulmonary embolism;
- significant comorbidity;
- contraindications to anticoagulants;
- inherited or acquired clotting or bleeding disorders;
- active bleeding;
- pregnant or lactating women;
- morbid obesity (actual body weight > 150 kg);
- renal insufficiency;
- inability to understand instructions or attend follow-up visits;
- history of protein C, protein S, or antithrombin III deficiency;
- potential for noncompliance; and
- lack of home support.
Precautions
Precautions that should be exercised when using tinzaparin and enoxaparin are detailed in Table 4, below.3,4
Monitoring and management
Labs. Routine laboratory monitoring with aPT and aPTT is not necessary with LMWH products. Monitoring may become necessary if complications such as overdose or bleeding occur. Therapy with these agents can be monitored with measurements of antifactor-Xa activity per mL. Recommended target plasma range usually is 0.5-1.0 antifactor-Xa units, with peaks measured 3-4 hours after dose.9 Complete blood counts (CBC) with platelets, hematocrit, and hemoglobin, and stool tests for occult blood should be assessed periodically.3,4,8
Overdose
Overdose with these products may result in bleeding complications. Patients with cases of minor bleeding or increased bruising should be monitored. Injected enoxaparin and tinzaparin can be neutralized with slow IV injection of protamine sulfate 1% solution (1 mg protamine sulfate for each mg of enoxaparin or each 100 antifactor Xa IU of tinzaparin should be administered). An additional 0.5 mg of protamine sulfate per 1 mg of enoxaparin or 100 antifactor Xa IU of tinzaparin can be given if the aPTT (measured 1-2 hours after initial protamine infusion) continues to be increased. Additional doses of 1 mg protamine sulfate per 1 mg of enoxaparin have been given in case reports that suggest that additional doses be based on patient response rather than laboratory values. Administration of protamine sulfate does not result in 100% neutralization of antifactor Xa. Protamine sulfate achieves maximal neutralization at 60% with both LMWH products.3,4
Both tinzaparin and enoxaparin interact with the agents listed in Table 5, below.3,4,8 Use of these agents should be discontinued prior to LMWH therapy. If discontinuation is not possible, patients should be monitored closely for increased risk of bleeding. GI bleeding is a concern with these interactions.
Efficacy
A summary of important trials examining the efficacy of these drugs for DVT treatment is provided below.
Tinzaparin:
• The American-Canadian Thrombosis Study was a multicenter, randomized double-blind clinical trial that compared IV unfractionated heparin (UFH) and tinzaparin in patients with acute DVT.10 Of 432 patients, 219 were in the UFH group and 213 were in the LMWH group. Patients at least 18 years of age with proximal DVT documented by venography were included. In addition to exclusion of patients with previously listed contraindications to LMWH therapy, patients who received warfarin, LMWH, or heparinoids in the seven days prior to the study, patients who received therapeutic doses of SC heparin within 12 hours prior to the study, patients who were receiving IV heparin, and patients who did not sign informed consent documents were excluded.
Subcutaneous tinzaparin (175 IU/kg) was found to be at least as efficacious as IV UFH for DVT treatment. UFH was dosed with an initial IV bolus dose of 5,000 USP units followed by continuous infusion of 40,320 or 29,760 units Q24H, depending on whether the patient had designated risk factors for bleeding. UFH dose was adjusted based on laboratory values of aPTT. Statistically significant differences were observed with recurrence of thromboembolism and major bleeding. Major bleeding with long-term warfarin therapy was higher with tinzaparin. The significance of this difference was not determined. Results of this study are illustrated in Table 6, below.
Use of a standardized heparin protocol that achieves therapeutic levels in greater than 90% of patients during the first 24 hours was one strength of the study, because subtherapeutic doses of heparin can result in high rates of recurrent thromboembolism. Baseline characteristics of patients in the groups were similar, and both fatal and nonfatal outcomes of the study were identified at various centers rather than at one center.
Two hundred patients from this same multicenter, double-blind, randomized study were evaluated for the treatment of PE and underlying DVT.11 Patients were included based on presence of high-probability lung scan findings and regionally normal findings on chest radiographs. The treatment regimens were the same as those in the previous study group. Of the 200 patients with PE and underlying DVT, 97 patients were in the tinzaparin group, and 103 were in the UFH group. None of the tinzaparin patients had a recurrence of thromboembolism, while seven of the UFH patients experienced recurrence. Major bleeding occurred in one LMWH patient and two UFH patients; minor bleeding occurred in two LMWH patients and three UHF patients. Thrombocytopenia occurred with three LMWH patients and one UFH patient, while death occurred in nine UFH patients and six LMWH patients. Results were not specified as being statistically significant. However, it was concluded that tinzaparin is at least as efficacious as UFH therapy.
• The Tinzaparin or Standard Heparin: Evaluations in Pulmonary Embolism (THESEE) Study was a multicenter, randomized, unblinded clinical trial comparing once-daily tinzaparin and IV UFH.12 For study inclusion, pulmonary embolism had to be documented objectively by pulmonary angiography, by ventilation-perfusion lung scanning indicating a high probability of pulmonary embolism, or by scanning with indeterminate results that were accompanied by DVT, which was confirmed by venography or compression ultrasonography.
The primary outcome measurements were death, symptomatic recurrent thromboembolism, or major bleeding measured eight days into the study. The endpoints were assessed again at day 90. Patients were excluded if they were thought to have a massive pulmonary embolism requiring thrombolytic therapy or pulmonary embolectomy, active bleeding, disorders contraindicating anticoagulation therapy, a therapeutic dose of anticoagulation therapy for more than 24 hours before entering the study, life expectancy of less than three months, severe hepatic or renal failure, likelihood of noncompliance, or pregnancy. Of 612 patients in the study, 308 patients were assigned to the UFH group and 304 patients received LMWH. Nine patients from each group reached at least one primary endpoint within the first eight days. By day 90, 22 and 18 patients from the UFH and tinzaparin groups, respectively, reached at least one of the clinical endpoints. None of these results showed a statistically significant difference; therefore, tinzaparin was proven to be at least as effective as UFH in DVT patients with PE. Selection criteria used in this study may have caused patients at higher risk for recurrences, bleeding, and death to be excluded. Results of this trial are presented in Table 7, below.
Enoxaparin:
• A New England Journal of Medicine study conducted by Levine et al compared treatment of DVT with LMWH in outpatient settings with UFH administered in the hospital.13 The study included patients with acute proximal DVT confirmed by sonography or ultrasonography. Patients with contraindications to LMWH therapy or to outpatient therapy with LMWH and patients who had previous treatment with UFH for more than 48 hours or who did not provide informed consent were excluded. Of the 500 patients who met these criteria, 247 were assigned to the LMWH group and 253 were assigned to the UFH group. Results of this trial are presented in Table 8, below.
• A parallel-group, randomized, partially blinded, multicenter international trial conducted by Merli et al compared enoxaparin 1.0 mg/kg Q12H, enoxaparin 1.5 mg/kg Q24H, and UFH dosed according to institutional protocol in the treatment of DVT.14 Patients had to be more than 18 years old to enter the study. Inclusion required symptomatic lower-extremity DVT. Exclusion criteria were related to contraindications to LMWH or warfarin therapy. Of the 900 patients who met the criteria, 290 were randomized to the UFH group, 298 to the once-daily enoxaparin (E1) group, and 312 to twice-daily enoxaparin (E2) group. Only 20 of the 136 patients who did not complete the study discontinued due to adverse effects (six with UFH, nine with E1, and five with E2). Twice-daily enoxaparin had more favorable results vs. both groups in every endpoint. Although differences in thromboembolism, major hemorrhage, and thrombocytopenia were not statistically significant, occurrences with E2 still were lower. Results of this study are presented in Table 9, below.
• Another study compared enoxaparin (given in a fixed dose of 1 mg/kg Q12H) and UFH (given as an initial continuous infusion of 500 U/kg per 24H).15 Patients were included in the study if they were older than 18 years with a proximal DVT proved by bilateral ascending venography. Exclusion criteria for the patients included associated severe pulmonary embolism requiring thrombolytic therapy, contraindications to anticoagulants, use of curative heparin therapy for more than 24 hours, recent surgery, pregnancy, previous implantation of vena cava filter, previously well-documented deficiency in coagulation inhibitors, and history of heparin-induced thrombocytopenia. Of the 134 patients who met the study criteria, 67 were randomized to the UFH group and 67 to the enoxaparin group. All patients were examined daily during the first 10 days of the study. Venograms from day 0 and day 10 were assessed and showed a significant difference favoring enoxaparin. In the UFH group, five venograms were found to have worsened, 34 were unchanged, and 18 improved, compared to one worsened, 24 unchanged, and 35 improved in the enoxaparin group. No patients in either group experienced major bleeding or recurrent DVT. Minor bleeding occurred in four enoxaparin patients and no UFH patients. According to this study, enoxaparin was more effective than UFH. Differences in outcomes measured were statistically significant.
• Both tinzaparin and enoxaparin have been shown to be more efficacious than UFH heparin in the treatment of DVT. Because no trials compare the two agents for this indication, direct comparison cannot be made. However, clinical experience demonstrates that both agents have been used efficaciously with similar safety profiles.
Cost
Treating patients with LMWH products allows patients to be discharged early or to be treated at home. This will decrease the number of hospital days and, thus, decrease cost.16 Tables 10 and 11, below, present drug cost information for enoxaparin and tinzaparin.
Enoxaparin:
1 mg/kg/dose Q12H
• For a 60 kg patient with a dose of 1 mg/kg Q12H, the patient should receive a 60 mg dose Q12H, which would result in a daily price of $46.78 ($23.39 x 2). For an average six-day course of therapy, enoxaparin would cost $280.68 ($46.78 x 6).
• For a 75 kg patient, calculated in the same manner, a six-day course of therapy costs $374.16.
1.5 mg/kg/dose Q24H
• For a 60 kg patient with a dose of 1.5 mg/kg Q24H, the patient should receive a 90 mg dose, which would result in a daily price of $38.97. For an average six-day course of therapy, enoxaparin would cost $233.82 ($38.97 x 6).
• For a 75 kg patient, calculated in the same manner, a six-day course of therapy costs $303.90.
Tinzaparin:
175 IU/kg SC QD
• A 60 kg patient with a dose of 175 IU/kg Q24H requires 10,500 IU per dose. A six-day regimen requires 63,000 IU or two 2 mL vials. The cost per vial is $52.34. Thus, a six-day course of therapy with tinzaparin would be $104.68 ($52.34 x 2).
• A 75 kg patient requires 78,750 IU, which also is two mL vials. A six-day course of therapy for this patient also would be $104.68.
Cost comparison
• The cost difference between enoxaparin and tinzaparin for an average six-day regimen for a 60 kg patient is $176 ($280.68-$104.68) for outpatient therapy. The cost difference for a 75 kg patient is $269.48 ($374.16-$104.68).
• Use of tinzaparin for DVT treatment can significantly reduce the cost of therapy. The direct drug cost saving of tinzaparin over enoxaparin is less with the once-daily (inpatient) dose of enoxaparin compared to the twice-daily dose. However, cost of hospitalization also must be considered with use of the inpatient dose.
• Because tinzaparin is available only in one vial size (40,000 IU/2 mL vial), the potential for drug wastage with weight-based dosing exists. However, individual tinzaparin doses can be drawn up in plastic syringes, and are stable for 10-15 days under refrigeration or at room temperature.17 By preparing specific doses from the 2 mL vial, drug wastage can be reduced, and cost savings can be realized to a greater extent.
Conclusion
The major differences in tinzaparin and enoxaparin are those of a pharmacokinetic nature. The difference in the antifactor-Xa/IIa ratio theoretically could account for differences in anticoagulation efficacy, as well as differences in the incidence of bleeding. Pharmacokinetic differences do exist and are reflected by differences in the respective dosage regimens of each LMWH. Both tinzaparin and enoxaparin have proven to be efficacious in clinical trials for DVT treatment compared to UFH. Comparable rates of adverse events and efficacy have been noted.
Thus, the pharmacokinetic differences have not translated to improved clinical response. However, enoxaparin demonstrates more experience in clinical trials than tinzaparin.
LMWH products proven efficacious can be given at recommended product-specific doses. However, LMWHs should be considered separate anticoagulation products and should not be interchanged on a dose-per-dose basis. Although no head-to-head trials have been conducted for these products for DVT treatment, both agents have been proved safe and effective.
Thus, cost and experience become important factors in the decision to add tinzaparin to the formulary. The potential for significant cost reductions with the use of tinzaparin supports the consideration of its addition to the formulary/DVT outpatient protocol.
References
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2. Tapson V. Deep venous thrombosis: Outpatient therapy with low-molecular-weight heparin. Manag Care 1999; 8(Suppl):S2-S6.
3. DuPont Pharmaceutical Co. Tinzaparin product compendium. Wilmington, DE: 2000.
4. Rhone-Poulenc Rorer Pharmaceuticals. Enoxaparin package insert. Collegeville, PA: 1999.
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6. Helena B, et al. Preclinical differentiation of low-molecular-weight heparins. Sem Thromb Hemost 1999; 25(Suppl 3):63-72.
7. Planes A, et al. Prevention of deep vein thrombosis after hip replacement — Comparison between two low-molecular heparins, tinzaparin and enoxaparin. Thromb Haemost 1999; 81:22-25.
8. Enoxaparin [monograph in electronic version]. Micromedex Healthcare Series. Englewood, CO: Micromedex; 2001.
9. Low-molecular-weight heparin for venous thromboembolism. Drug Ther Bull 1998; 36:25-29.
10. Hull R, et al. Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med 1992; 326:975-982.
11. Hull R, et al. Low-molecular-weight heparin vs. heparin in the treatment of patients with pulmonary embolism. Arch Intern Med 2000; 160:229-236.
12. Simonneau G, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. N Engl J Med 1997; 337:663-669.
13. Levine M, et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996; 334:677-681.
14. Merli G, et al. Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease. Ann Intern Med 2001; 134:191-202.
15. Simonneau G, et al. Subcutaneous low-molecular-weight heparin compared with continuous intravenous unfractionated heparin in the treatment of proximal deep vein thrombosis. Arch Intern Med 1993; 153:1541-1546.
16. Personal communication. Cindy Hall, buyer, Pharmacy Department, Huntsville Hospital System; May 2001.
17. Innohep-DuPont Pharmaceuticals. Available at http://www.innohep.com. Accessed Nov. 2, 2001.
18. Liezorovicz A, et al. Prevention of perioperative deep vein thrombosis in general surgery: A multicentre double blind trial comparing two doses of Logiparin and standard heparin. Br J Surg 1991; 78:412-416.
19. Siegbahn A, et al. Subcutaneous treatment of deep venous thrombosis with low-molecular-weight heparin: A dose finding study with LMWH-Novo. Thromb Res 1989; 55:767-778.
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