Deep vein thrombosis (DVT) is a pervasive LOW-MOLECULAR-WEIGHT HEPARIN IN THE TREATMENT OF ACUTE DEEP VEIN THROMBOSIS AND PULMONARY EMBOLISM *

Transcription

1 LOW-MOLECULAR-WEIGHT HEPARIN IN THE TREATMENT OF ACUTE DEEP VEIN THROMBOSIS AND PULMONARY EMBOLISM * Geno J. Merli, MD ABSTRACT There are more than hospital admissions each year for deep vein thrombosis (DVT) in the United States. Moreover, there are approximately readmissions for recurrent venous thromboembolic events, with an average length of hospital stay between 5 days and 7 days. This article reviews the clinical evidence related to inpatient and outpatient treatment options and their efficacies in achieving therapeutic goals for the clinical management of DVT. It also reports the medical evidence relating to eligibility criteria and dosing, as well as the American College of Chest Physicians recommendations regarding duration of therapy. (Advanced Studies in Medicine. 2002;2(12): ) *Based on a presentation given by Dr Merli at the American College of Physicians Annual Session. The Ludwig A. Kind Professor of Medicine, Director of the Division of Internal Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania. Address correspondence to: Geno J. Merli, MD, Director, Division of Internal Medicine, Jefferson Medical College, Thomas Jefferson University, Walnut Towers, 1025 Walnut St, 8th Floor, Room 822, Philadelphia, PA Deep vein thrombosis (DVT) is a pervasive health problem, affecting 2 million people in the United States annually. 1 As many as deaths are caused by pulmonary embolism (PE) every year. As many as pulmonary emboli will occur with approximately deaths from these thrombotic events. Secondary complications such as postphlebitic syndrome and pulmonary hypertension contribute significantly to long-term morbidity and mortality in this patient population. While the death toll is tragic, the financial burden is significant; the cost of care for patients with DVT is an estimated $1.5 billion annually. 2 Clinical evidence documents the prevalence of undetected PE in patients with acute DVT. In a study of 622 patients with acute DVT but without PE, Meignan et al 3 reported that radionuclide lung scanning revealed abnormalities in 82% of the patients; PE was thought to be present in 40% to 50% of the patients. These findings have strong implications for the clinical management of DVT, with the goals of preventing thrombus extension, thrombus embolization, early and late thrombus recurrence, and possibly postthrombotic syndrome (although clinical evidence in this last area is inconclusive). Prompt administration of anticoagulant therapy is essential to preventing clot propogation and pulmonary emboli. Clinical evidence suggests that if patients achieve a therapeutic activated partial thromboplastin time quickly with heparin, the less recurrent disease occurs subsequently. 4 An examination of the current armamentarium for treating DVT may offer insights as to which treatment modalities are most efficacious. Figure 1 illustrates the efficacy of various approaches to DVT clinical management in accomplishing treatment goals, according to the current medical literature. In the United States, many physicians are placing inferior vena cava filters in patients who have extensive thrombosis in the deep femoral system up to the iliacs, in addition to administering anticoagulation therapies. However, using inferior vena cava filters in such circumstances in advance has not been supported Advanced Studies in Medicine 445

2 by the medical literature. In terms of anticoagulation therapies, both heparin and low-molecular-weight heparin (LMWH) have proven effective in preventing embolization and extension as well as reducing recurrence. Hypothetically, LMWH and heparin may also prevent postthrombotic syndrome. LMWH may restore patency, but at this time insufficient clinical evidence exists to confirm these suppositions. Thrombolysis has proven effective in achieving 4 of the 5 treatment goals, but the extent to which it prevents embolization is questionable at this point. Following is a review of the clinical evidence related to the treatment options and their efficacies in achieving therapeutic goals for the clinical management of DVT. Excluded from the following trials were patients with hereditary or acquired coagulation disorders, creatinine clearance less than 30 cc/min, pregnancy, or cancer and unspecified concomitant chemotherapy. ENOXAPARIN VERSUS UNFRACTIONATED HEPARIN A report by Simonneau 5 et al shows that thromboembolic disease recurred in 1.5% (N=67) of patients in an enoxaparin treatment arm, as compared to 10.4% (N=67) of subjects in the heparin group. In a study, de Valk et al 6 compared the efficacy and safety of 2 subcutaneous doses of danaparoid, a long-acting agent, with that of continuous intravenous administration of unfractionated heparin (UFH) in the treatment of 209 patients believed to have venous thromboembolism (VTE). Patients were randomly assigned to either low-dose danaparoid (intravenous loading dose of 1250 U followed by 1250 U administered subcutaneously twice daily [N=65]); high-dose danaparoid (intravenous loading dose of 2000 U followed by 2000 U administered subcutaneously twice daily [N= 63]); or UFH (intravenous loading dose of 2500 U followed by dose-adjusted continuous infusion [N=60]). Treatment lasted at least 5 days. A significant reduction in recurrence or extension of VTE was seen in patients receiving high-dose danaparoid (8 of 63 [13%]), as compared with patients receiving intravenous UFH (17 of 60 [28%]; relative risk was 0.45 [0.21 to 0.96 (95% confidence interval [CI]). Occurrence of major and minor bleeding was similar in the 3 groups. A report from Lindmarker 7 showed dalteparin sodium administered at 200 units/kg once per day to a maximum of units resulted in fewer instances of recurrent thromboembolic disease (12%), as compared to heparin (17%). All 3 investigators report no differences between LMWH and heparin in major bleeding episodes. Additional evidence suggesting that LMWH therapy results in fewer recurrences of DVT and PE has been reported by Hull in the New England Journal of Medicine. 8 This double-blind clinical trial compared fixed-dose subcutaneous LMWH (tinzaparin), once daily with adjusted-dose intravenous heparin, given by continuous infusion for the initial treatment of patients with proximal-vein thrombosis. Six of 213 patients who received tinzaparin 175 units/kg (2.8%) and 15 of 219 patients who received intravenous heparin (6.9%) experienced new episodes of VTE (P =.07). Major bleeding associated with initial therapy occurred in 1 patient receiving tinzaparin (0.5%) and in 11 patients receiving intravenous heparin (5.0%), showing a reduction in risk of 91% (P =.006). However, this apparent protection against major bleeding was lost during longterm therapy. Another clinical trial comparing reviparin with UFH 9 showed no statistically signifi- Figure 1.Therapeutic Goals and Treatment Options for DVT Goals of Supportive IVC therapy care filter Heparin LMWH Thrombolysis Prevent? embolization Prevent extension Reduce recurrence Restore patency? Prevent postthrombotic?? syndrome DVT = deep vein thrombosis; IVC = inferior vena cava; LMWH = low-molecularweight heparin. 446 Vol. 2, No. 12 August 2002

3 cant difference between the 2 drugs in the measure of return episodes of VTE. (Table 1) A landmark study by Levine et al in 1996 evaluated the safety and efficacy of enoxaparin administered to outpatients. 10 Patients with acute proximal DVT were randomly assigned to receive either intravenous standard heparin in the hospital (253 patients) or LMWH (247 patients received 1 mg of enoxaparin per kilogram of body weight subcutaneously twice daily) administered primarily at home. The study design allowed outpatients taking LMWH to go home immediately and hospitalized patients taking LMWH to be discharged early. All the patients received warfarin starting on the second day. Of the 247 patients receiving LMWH, 13 (5.3%) had recurrent thromboembolism, as compared with 17 (6.7%, 95% CI) of the 253 patients receiving standard heparin. Five patients (2%) receiving LMWH had major bleeding, as compared with 3 patients (1.2%) receiving standard heparin. In a separate study reported simultaneously, Koopman et al 11 also demonstrated the safety and efficacy of outpatient administration of LMWH. Patients were randomly assigned to 1 of 2 study arms: adjusted-dose intravenous standard heparin administered in the hospital (198 patients), or fixed-dose subcutaneous LMWH administered at home (202 patients). Seventeen (8.6%) of the 198 patients who received standard heparin and 14 (6.9%) of the 202 patients who received LMWH experienced recurrent thromboembolism (95% CI). Major bleeding occurred in 4 patients (2.0%) assigned to standard heparin and in 1 patient (0.5%, 95% CI) assigned to low-molecular-weight heparin, as shown in Table 2. However, despite such convincing clinical evidence, many physicians in the United States are not using LMWH to treat patients with thromboembolic disease. Table 3 shows findings from 3 separate metaanalyses of safety and efficacy of LMWH, as compared with UFH Outcomes for recurrent VTE, major bleeds, and mortality were consistently better for LMWH, as compared to UFH. Once-a-day administration was compared to twice-a-day dosing of LMWH and UFH in a randomized controlled trial of patients with proximal and distal clots. 15 Investigators found that once-a-day dosing with enoxaparin 1.5 mg/kg was equally as safe and efficacious as 1 mg/kg q 12h and constant infusion IV of heparin; in both regimens, safety and efficacy were comparable to that of standard heparin therapy. While most of the medical evidence regarding the safety and efficacy of LMWH focuses on the treatment of DVT, only limited data are available on the use of LMWH to treat acute symptomatic PE. Table 1. Clinical Outcomes Trials: LMWH Treatment of DVT/PE Study Group RTE DVT PE Maj Bld Hull 8 Tinzaparin 6 (3%) 3 (1%) 3 (1%) 1 (0.5%) (213) UFH 15 (7%) 6 (3%) 9 (4%) 11 (5%) (219) Columbus 21 Reviparin 27 (5%) 17 (3%) 10 (2%) 16 (3%) (510) UFH 25 (5%) 13 (3%) 12 (2%) 12 (2%) (511) LMWH = low-molecular-weight heparin; DVT = deep vein thrombosis; PE = pulmonary embolism; RTE = recurrent thromboembolism; Maj Bld = major bleeding; UFH = unfractionated heparin. Table 2. Efficacy: Suitable Proximal DVT 10 Levine et al 10 Koopman et al 11 Enoxaparin UFH Nadroparin UFH (n = 247) (n = 253) (n = 202) (n = 198) RTE Major bleeding Death Hospital (days) 1.1* *120 (48%) were exclusively treated in the outpatient setting. DVT = deep vein thrombosis; UFH = unfractionated heparin; RTE = recurrent thromboembolism. Table adapted with permission from reference 10. Advanced Studies in Medicine 447

4 This subgroup of patients was selected for analysis in a random controlled trial of 612 patients with symptomatic PE who did not require thrombolytic therapy or embolectomy. 9 Patients were randomly assigned to either SC LMWH (tinzaparin) once daily, or IV UFH. In the first 8 days of treatment, 2.9% of 308 patients assigned to receive UFH reached at least 1 of the endpoints, as compared with 3.0% of 304 patients assigned to LMWH (95% CI). By day 90 of the study, 7.1% of patients assigned to UFH and 5.9% of patients assigned to LMWH had reached at least 1 of the following endpoints: death, recurrent thromboembolism, or major bleed (P =.54). However, the risk of major bleeding was similar in the 2 treatment groups throughout the study. These findings suggest that initial treatment of PE with LMWH is at least as safe and effective as is treatment with UFH. Looking at randomized trials of dalteparin, another formulation of LMWH currently in use, studies by Lindmarker et al, 7 Fiessinger et al, 16 and Luomanmaki et al 17 found no significant differences between dalteparin and UFH for the variables of morbidity, PE/DVT, major bleeding, or thrombocytopenia. In conclusion, a composite of all relevant study findings suggests that LMWH outcomes for recurrent thromboembolic disease and major bleeding are superior to those for UFH (Figure 2). Yet within the United States healthcare system, UFH is used more widely than is LMWH, largely due to lack of protocol development for outpatient care with LMWH. Table 3. Meta Analyses of LMWH vs IV UFH DVT Treatment Leizorovicz et al 12 Lensing et al 13 Siragusa et al d 23 mo follow-up 3 6 mo follow-up 90 d follow-up VTE n = 2045 n = 1086 n = 1228 recurrence 2.82% vs 4.63% 3.1% vs 6.6% 2.5% vs 4.5% RR 0.66 ( ) RR 0.47 ( ) RR 0.5 ( ) P =.09 P <.01 P <.02 Major n = 2045 n = 1512 n = 1694 bleed 2.43% vs 4.04% 0.8% vs 2.8% 2.2% vs 4.7% RR 0.65 ( ) RR 0.32 ( ) RR 0.44 ( ) P =.15 P<.005 P =.04 Mortality n = 2045 n = 1086 n = % vs 4.83% 3.9% vs 7.1% 3.3% vs 5.9% RR 0.72 ( ) RR 0.53 ( ) RR 0.51 ( ) P =.16 P<.04 P =.01 LMWH = low-molecular-weight heparin; UFH = unfractionated heparin; DVT = deep vein thrombosis; VTE = venous thromboembolism; RR = relative risk. Figure 2. Clinical Efficacy: LMWH vs UFH Venous Thromboembolism 22 CRITERIA FOR SELECTING PATIENTS FOR OUTPATIENT ANTICOAGULATION THERAPY Figure 3 offers a graphic illustration of combined clinical evidence regarding the incidence of major bleeding and recurrent thromboembolism in patients who are given UFH and in patients who receive LMWH. Based upon these study findings and their exclusion criteria, the following should be LMWH = low-molecular-weight heparin; UFH = unfractionated heparin. Reprinted with permission from reference Vol. 2, No. 12 August 2002

5 considered as absolute contraindications for outpatient treatment with LMWH: Active bleeding Cardiopulmonary instability Hereditary bleeding disorders History of heparin induced thrombocytopenia Allergy to heparin. Figure 3. LMWH vs IV UFH Social and medical relative contraindications for outpatient treatment with LMWH include the following: Geographic inaccessibility Potential for medication noncompliance Inability to support cost of drug Pregnancy Hereditary or acquired thrombotic disorders Peptic ulcer disease, gastrointestinal, or genitourinary bleeding within 6 weeks Uncompensated comorbidities Concomitant medical problems (eg, CrCl < 30 cc/min) Pulmonary embolism (hemodynamically stable). This was placed under the relative risk category because many US physicians are not clinically comfortable with treating patients with uncomplicated PE on an outpatient basis. Koopman et al 11 reported that 69% of the patients were eligible for outpatient treatment of DVT; Levine et al 10 and Yusen et al 18 respectively reported that only 33% and 18% of the subjects met the criteria to be treated at home. Within our facility at Thomas Jefferson University, we find that approximately 45% of patients meet eligibility criteria for outpatient anticoagulation therapy. LMWH = low-molecular-weight heparin; UFH = unfractionated heparin. Table 4. Once- vs Twice-Daily Dosing DOSING REGIMENS Whether to administer once- or twice-a-day dosing of therapy remains controversial. Table 4 summarizes the incidence of major bleeding and recurrent DVT under various dosing regimens, but it is important to stress that these studies did not exclude patients on the basis of weight. However, in studies where dosing was fixed and not adjusted on actual body weight, outcomes for primary endpoints were less favorable (Table 5). In our study of once- versus twice-daily dosing Major Author WT Bleed RVTE Simonneau 5 No limit 0 1/67 (enoxaparin) (1%) q12h Hull 8 No limit 0.5% 6/213 (tinzaparin) (3%) qd Levine 10 No limit 2% 13/247 (enoxaparin) (5.3%) q12h RVTE = recurrent venous thromboembolism. Advanced Studies in Medicine 449

6 with enoxaparin 15 in which no weight limits were placed upon subjects, we found no significant difference in the outcomes of recurrent VTED or major bleeding within the qd and q12h study arms. However, in a subgroup analysis there was a higher incidence of recurrent VTED in obese patients and in patients with cancer who received qd dosing than for those patients who received q12h dosing, but the variance was not statistically significant. Nonetheless, it Table 5. Once- vs Twice-Daily Dosing Major Author WT Bleed RVTE Koopman 11 Fixed dose 0.5% 14/202 (nadroparin) (6.9%) q12h Lindmarker 7 Fixed dose 0% 11/91 (dalteparin) (12%) qd de Valk 6 Fixed dose 1% 8/63 (danaparoid) (13%) q12h Columbus 21 Fixed dose 1.9% 27/510 (reviparin) (5.3%) q12h does raise some questions surrounding dosing, which again surface in reports from Partsch et al. 19 This study of the safety and efficacy of dalteparin showed 5.3% (N=67) of subjects within the qd (200 units/kg) study arm experienced major bleeds and 5.3% experienced recurrent PE. In the 12 h D (100 units/kg) study arm, 1.5% (N=64) experienced major bleeds and 1.6% experienced recurrent PE. Protocol for outpatient anticoagulation therapy at Thomas Jefferson University is based on recommendations from the American College of Chest Physicians (ACCP) consensus conference. 20 The ACCP recommendations, as detailed in Table 6, call for administration of warfarin initiated on day 1 or day 2 with continuation of LMWH for at least 5 days, until an international normalized ratio (INR) value of 2 to 3 is achieved for 2 consecutive days. In summary, UFH has long been the mainstay of therapy for DVT and PE. However, over the last 10 years, LMWHs have been replacing this therapy for treating thrombotic events. LMWHs are better absorbed, have a longer half-life, and do not require monitoring. 19 A number of studies have demonstrated the safety and efficacy of LMWHs in treating patients with thromboembolic events. LMWHs have changed the paradigm of care for thromboembolic disease: outpatient treatment or shorter hospital stay for inpatients. RVTE = recurrent venous thromboembolism. REFERENCES Table 6.ACCP Duration of Therapy 26 3 to 6 months First event with reversible or time-limited risk factor > 6 months Idiopathic VTE, first event 12 months to lifetime First event with Cancer until resolved Anticardiolipin antibody Antithrombin deficiency Recurrent event, idiopathic or with thrombophilia Data adapted with permission from reference Hirsh J, Hoak J. Management of deep vein thrombosis and pulmonary embolism: a statement for healthcare professionals from the council on thrombosis (in constitution with the council on cardiovascular radiology), American Heart Association. Circulation 1996;93: Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet. 1999;353: Meignan M, Rosso J, Gauthier H, et al. Systematic lung scans reveal a high frequency of silent pulmonary embolism in patients with proximal deep venous thrombosis. Arch Intern Med. 2000;160: Hull RD, Raskob GE, Brant R, et al. Relation between the time to achieve the lower limit of the APTT therapeutic range and recurrent venous thromboembolism during heparin treatment for deep vein thrombosis. Arch Intern Med. 1997;157: Vol. 2, No. 12 August 2002

7 5. Simonneau G, Charbonnier B, Decousus H, 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: devalk HW, Banga JD, Wester JW, et al. Comparing subcutaneous danaparoid with intravenous unfractionated heparin for the treatment of venous thromboembolism. A randomized controlled trial. Ann Intern Med. 1995;123(1): Lindmarker P, Holmstrom M, Granqvist S, et al. Comparison of once-daily subcutaneous Fragmin with continuous intravenous unfractionated heparin in the treatment of deep vein thrombosis. Thromb Haemost. 1994;72: Hull RD, Raskob GE, Pineo GF, et al. Subcutaneous lowmolecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med. 1992;326(15): Simonneau G, Sors H, Charbonnier B, et al, for the THE- SEE Study Group. A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. N Engl J Med. 1997;337(10): Levine M, Gent M, Hirsh J, 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(11): Koopman MMW, Prandoni P, Piovella F, et al, for The Tasman Study Group. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. N Engl J Med. 1996; 334(11): Leizorovicz A, Simonneau G, Decousus H, et al. Comparison of efficacy and safety of low molecular weight heparins and unfractionated heparin in initial treatment of deep venous thrombosis: a meta-analysis. BMJ. 1994;309(6950): Lensing AW, Prins MH, Davidson BL, et al. Treatment of deep venous thrombosis with low-molecular-weight heparins. A meta-analysis. Arch Intern Med. 1995;155: Siragusa S, Cosmi B, Piovella F, et al. Low-molecular-weight heparins and unfractionated heparin in the treatment of patients with acute venous thromboembolism: results of a meta-analysis. Am J Med. 1996;100: Merli G, Spiro TE, Olsson CG, et al. Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease. Ann Intern Med. 2001;134: Fiessinger JN, Lopez-Fernandez M, Gatterer E, et al. Oncedaily subcutaneous dalteparin, a low molecular weight heparin, for the initial treatment of acute deep vein thrombosis. Thromb Haemost. 1996;76: Luomanmaki K, Grankvist S, Hallert C, et al. A multicentre comparison of once-daily subcutaneous dalteparin (low-molecular-weight heparin) and continuous intravenous heparin in the treatment of deep vein thromobosis. J Intern Med. 1996;240(2): Yusen RD, Haraden BM, Gage BF, et al. Criteria for outpatient management of proximal lower extremity deep venous thrombosis. Chest. 1999;115(4): Partsch H, Kechavarz B, Mostbeck A, et al. Frequency of pulmonary embolism in patients who have iliofemoral deep vein thrombosis and are treated with once- or twice-daily low-molecular-weight heparin. J Vasc Surg. 1996; 24(5): Hyers TM, Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thromboembolic disease. Chest. 2001;119 (suppl 1):176S-193S. 21. The Columbus Investigators. Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med. 1997;337: Dolovich LR, Ginsberg JS, Douketis JD, et al. A meta-analysis comparig low-molecular-weight heparins with unfractionated heparin in the treatment of venous thromboembolism: examining some unanswered questions regarding location of treatment, product type, and dosing frequency. Arch Intern Med. 2000;160(2): Duroux P. A Collaborative European Multicentre Study: a randomized trial of subcutaneous low-molecular-weight heparin (CY216) compared with intravenous unfractionated heparin in the treatment of deep vein thrombosis. Thromb Haemost. 1991;65: Prandoni P, Lensing AW, Buller HR, et al. Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep vein thrombosis. Lancet. 1992;339: Lopaciuk S, Meissner AJ, Filipecki S, et al. Subcutaneous low-molecular-weight heparin in the treatment of deep vein thrombosis: a Polish multicenter trial. Thromb Haemost. 1992;68: Hyers TM, Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thromboembolic disease. Chest. 2001; 119(suppl 1);176S-193S. Advanced Studies in Medicine 451