Heparin Use in Deep Venous Thrombosis
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The primary objectives for the treatment of deep venous thrombosis (DVT) are to prevent pulmonary embolism (PE), reduce morbidity, and prevent or minimize the risk of developing the postphlebitic syndrome. Anticoagulation remains the mainstay of the initial treatment for DVT. The current guidelines recommend short-term anticoagulation with subcutaneous (SC) low-molecular-weight heparin (LMWH) (Grade 1A), intravenous (IV) unfractionated heparin (UFH) (Grade 1A), fixed-dose unfractionated heparin (FDUH) SC (Grade 1A), or fondaparinux SC (a synthetic factor Xa inhibitor) (Grade 1A). [1]
Heparin is a heterogeneous mixture of polysaccharide fragments with varying molecular weights but with similar biologic activity. The larger fragments exert their anticoagulant effect by interacting with antithrombin III (ATIII) to inhibit thrombin. ATIII, the body’s primary anticoagulant, inactivates thrombin and inhibits the activity of activated factor X in the coagulation process. The low-molecular-weight fragments exert their anticoagulant effect by inhibiting the activity of activated factor X. The hemorrhagic complications attributed to heparin are thought to arise from the larger higher-molecular-weight fragments.
Initial treatment with LMWH, UFH, or fondaparinux should continue for at least 5 days and until the international normalized ratio (INR) is >2 for 24 hours (Grade 1C). A vitamin K antagonist such as warfarin should be initiated together with LMWH, UFH, or fondaparinux on the first treatment day (Grade 1A). [1]
Go to Deep Venous Thrombosis and Thrombophlebitis for more complete information on this topic.
Traditionally, heparin has been used only for admitted patients with DVT. Regular UFH was the standard of care until the introduction of LMWH products. Heparin prevents extension of the thrombus and has been shown to significantly reduce (but not eliminate) the incidence of fatal and nonfatal PE as well as recurrent thrombosis.
The primary reason for the persistent, albeit reduced, risk of PE is primarily due to the fact that heparin has no effect on preexisting nonadherent thrombus. Moreover, heparin does not affect the size of existing thrombus and has no intrinsic thrombolytic activity. Heparin therapy is associated with complete lysis in fewer than 10% of patients studied with venography after treatment.
Heparin therapy has little effect on the risk of developing postthrombotic (postphlebitic) syndrome. The original thrombus causes venous valvular incompetence and altered venous return leading to a high incidence of chronic venous insufficiency and postthrombotic syndrome.
Warfarin therapy is overlapped with heparin for 4-5 days until the INR is therapeutically elevated to 2-3. Heparin must be overlapped with oral warfarin because of the initial transient hypercoagulable state induced by warfarin. This effect is related to the differential half-lives of protein C, protein S, and the vitamin K–dependent clotting factors II, VII, IX, and X. Long-term anticoagulation is definitely indicated for patients with recurrent venous thrombosis and/or persistent or irreversible risk factors.
When intravenous UFH is initiated for DVT anticoagulation, the goal is to achieve and maintain an elevated activated partial thromboplastin time (aPTT) of at least 1.5 times control. Heparin pharmacokinetics are complex, and the half-life is 60-90 minutes. A protocol for IV heparin use is as follows:
Give an initial bolus of 80 U/kg.
Initiate a constant maintenance infusion of 18 U/kg.
Check the aPTT or heparin activity level 6 hours after the bolus, and adjust the infusion rate accordingly.
Continue to check the aPTT or heparin activity level every 6 hours, until 2 successive values are therapeutic.
Monitor the aPTT or heparin activity level, hematocrit, and platelet count every 24 hours.
A study by Kearon et al concluded that FDUH is as safe and effective as LMWH in patients with acute DVT and is suitable for outpatient treatment. [2] In this randomized, primarily outpatient, open-label, adjudicator-blinded, noninferiority trial of 708 adult patients with objectively confirmed DVT, FDUH SC was compared with LMWH (enoxaparin or dalteparin). In the UFH group, 333 units/kg of UFH SC was administered initially, followed by a fixed dose of 250 U/kg twice daily. This was overlapped with oral warfarin for 5 days until the INR was considered therapeutic. In the LMWH group, 100 IU/kg of the LMWH was administered twice daily. [2]
Recurrent venous thromboembolism (VTE) occurred in 13 patients in the UFH group (3.8%) compared with 12 patients in the LMWH group (3.4%; absolute difference, 0.4%). [2] Major bleeding during the first 10 days of treatment occurred in 1.1% of the UFH group versus 1.4% in the LMWH group (absolute difference, –0.3).
Heparin-induced thrombocytopenia is not infrequent. In this condition, platelet aggregation induced by heparin may trigger venous or arterial thrombosis with significant morbidity and mortality. Unfortunately, it is not possible to predict which subset of patients will develop thrombosis. All patients who develop thrombocytopenia while taking heparin are at risk. Alternatives include the substitution of porcine for bovine heparin, the use of LMWH, or initiation of therapy with warfarin alone. Go to Heparin-Induced Thrombocytopenia for more complete information on this topic.
LMWH is prepared by selectively treating UFH to isolate the low-molecular-weight (< 9,000 Da) fragments. Its activity is measured in units of factor X inactivation, and monitoring of the aPTT is not required. The dose is weight adjusted. [3, 4, 5]
The increased bioavailability and prolonged half-life of LMWH allows for outpatient treatment of DVT using once-daily or twice-daily subcutaneous treatment regimens. Outpatient treatment of acute DVT with LMWH has been successfully evaluated in a number of studies and is currently the treatment of choice if the patient is eligible. In general, outpatient management is not recommended if the patient has proven or suspected concomitant PE, significant comorbidities, extensive iliofemoral DVT, morbid obesity, renal failure, or poor follow-up (see Exclusion Criteria for Outpatient DVT Management, below).
Several LMWH preparations are available. Enoxaparin, dalteparin, tinzaparin, and nadroparin are discussed here. Enoxaparin, dalteparin, and tinzaparin have received US Food and Drug Administration (FDA) approval for the treatment of DVT in the United States; enoxaparin is approved for inpatient and outpatient treatment of DVT. Nadroparin is approved for DVT treatment in Canada.
The efficacy and safety of LMWH for the initial treatment of DVT have been well established in several trials.
Mismetti and colleagues, in a systematic meta-analysis of original source data, concluded that the efficacy and safety of enoxaparin was not significantly modified by the presence or absence of initial PE at baseline. [6] PE is recognized as a sequela of DVT, and most cases of PE are recognized to arise from DVT of the lower extremities. Previous meta-analyses of published trials could not evaluate the efficacy and safety of LMWH if PE was present in addition to DVT, because they reviewed only published summarized data.
Mismetti et al reported enoxaparin 1 mg/kg twice daily was noninferior to UFH in the treatment of DVT with or without a coexisting PE. [6] In addition, although not statistically significant, a trend favoring enoxaparin over UFH was also observed in the incidence of major bleeding and all-cause mortality at 3 months.
Although LMWH is not inferior to UFH in the treatment of DVT, the clinician must recognize that, despite adequate anticoagulant therapy, the recurrence rate for DVT and/or PE when enoxaparin is used is reportedly still 4.5%. With UFH, the recurrence rate for DVT, PE, or both was 4.4%, 1.8%, and 5.7%, respectively. The incidence of DVT and PE recurrence in patients presenting with DVT and an initial symptomatic PE is much higher, approaching 8.2% in the UFH group compared with 4.8% in patients with DVT alone.
When comparing the efficacy of enoxaparin versus UFH, no significant difference between patients with and without an initial symptomatic PE was noted. However, the risk of recurrent PE was also higher in patients with an initial symptomatic PE despite adequate anticoagulant therapy. Therefore, a recurrent VTE event must be considered in patients who present to the emergency department with recurrent symptoms despite adequate anticoagulant therapy. Incidentally, the group of patients presenting with DVT and symptomatic PE were found more often to be women with a previous history of VTE, and thus, inherently at greater risk for VTE recurrence.
Van Dongen and colleagues performed a meta-analysis to specifically evaluate the safety and efficacy of once-daily versus twice-daily dosing of enoxaparin for treatment of DVT and found no statistically significant differences between the 2 regimens. [7] The investigators had hypothesized that twice-daily dosing would be more effective and safer with fewer bleeding complications, as well as a higher frequency of dosing would allow more stability in anticoagulation. They therefore expected fewer complications with this group. However, when the data was pooled, the actual incidence of VTE recurrence between the groups was not statistically significant, complying with the predetermined equivalence criteria. [7]
In assessing discrepancies in thrombus size, no statistical difference was noted. However, although a lower mortality was observed in the twice-daily group and a lower incidence of hemorrhage was seen in the once-daily group, neither of these differences was statistically significant. [7] While admitting that the wide confidence interval led to decreased precision in these results, the Van Dongen et al concluded that once-daily dosing is as safe and efficacious as the standard twice-daily regimen.
Numerous questions have arisen about the use of enoxaparin in special patient populations, such as those with renal insufficiency, those who are pregnant, and those who are morbidly obese. Michota and Merli reviewed the efficacy, safety, and dosing of enoxaparin in DVT prophylaxis and in the treatment of VTE in special patient populations—the morbidly obese, pregnant women, those with renal insufficiency, and cancer patients. [8]
Given the prevalence of obesity, a problem that afflicts one third of Americans today, Michota and Merli reviewed its effect on enoxaparin dosing and found some evidence to suggest that weight-based dosing is feasible. [8] Morbid obesity was defined as body weight greater than 150 kg or a body mass index (BMI) greater than 50 kg/m2. [8] The authors noted there is a paucity of morbidly obese patients represented in the major clinical trials evaluating the LMWH agents and cited a British trial that demonstrated decreased anti-Xa activity with increased body weight when fixed dosing as opposed to weight-based enoxaparin dosing was used.
The relationship between intravascular volume, volume of distribution of the drug, and body weight is not linear. Therefore, weight-based dosing in the morbidly obese patient population might lead to an excessive rate of bleeding complications. However, other studies have shown that no significant increase in anti-Xa activity occurs when weight-based dosing of LMWH is used. In a cardiovascular trial, no increase in bleeding rates between obese and nonobese patients was documented when full weight-based dosing was used.
Michota and Merli concluded that in morbidly obese patients, although the general consensus suggests that weight-based dosing without a cap is currently recommended, a paucity of data supports it. Therefore, the investigators suggested that it is not unreasonable to initiate therapy with full weight-based dosing and to monitor the anti-Xa levels. [8] The therapeutic ranges for anti-Xa activity for the various LMWH compounds are listed the table below; the anti-Xa levels are drawn 4 hours after a subcutaneous dose.
Table 1. LMWH Therapeutic Peak Anti-Xa levels for VTE Therapy [8] (Open Table in a new window)
LMWH Regimen
Therapeutic Peak
Enoxaparin
1 mg/kg q12h hours
0.6-1 IU/mL
1.5 mg/kg daily
1-1.5 IU/mL
Tinzaparin 175 IU/kg qd
0.85-1 IU/mL
Dalteparin
100 IU/kg q12h hours
0.4-1.1 IU/mL
200 IU/kg qd
1-2 IU/mL
Enoxaparin dosing has also been poorly studied in patients with renal conditions. Higher peak anti-Xa levels as well as half-life prolongation correlate with decreasing creatinine clearance, because LMWH is renally cleared. Patients with renal failure may be at increased risk for bleeding secondary to excessive anticoagulation. Several trials have substantiated increased bleeding rates with UFH and LMWH among patients with renal insufficiency (creatinine clearance [CrCl] < 30 mL/min).
Although UFH has a dual clearance mechanism and is less susceptible to drug accumulation in renal insufficiency than LMWH, its greater adverse effect on platelet function and capillary permeability leads to a similar rate of bleeding problems. A negative linear correlation exists between anti-Xa activity and creatinine clearance. As a result, the FDA issued new dosing guidelines for enoxaparin of 1 mg/kg daily instead of twice a day. No revised dosing guidelines are available for the other LMWH agents. Michota and Merli also concluded that monitoring of anti-Xa levels is the safest approach in patients with chronic renal insufficiency. [8]
In pregnant patients with VTE, LMWH has clear advantages over UFH, including better bioavailability, lower incidence of heparin-induced thrombocytopenia and osteoporosis, and reduced monitoring requirements. Throughout pregnancy, the volume of distribution of LMWH is larger. Drug clearance is higher in early pregnancy and trends toward normal at delivery. Therefore, monitoring of anti-Xa levels is important.
Drug therapy should be initiated at the same dose as for nonpregnant patients, but the dose may have to be increased if anti-Xa levels fall below the therapeutic ranges outlined in the Table 1, above. [8] Therapy should be held during delivery but then restarted postpartum and continued while the patient is crossed over to a vitamin K antagonist.
In a Canadian study by Wells et al that compared tinzaparin (the only LMWH to have demonstrated statistical superiority to UFH in the prevention of DVT recurrence) with dalteparin, dalteparin found to be noninferior to tinzaparin. [9] The existing literature had predicted outcomes in favor of tinzaparin by a minimal but clinically important 4% combined end-point. However, with combined event rates of 4.8% for dalteparin and 5.4% for tinzaparin, tinzaparin was not found to be superior to dalteparin, and both therapies provided safe and efficacious outpatient treatment of acute DVT and PE. [9] Then, in December 2008, the FDA issued a communication that recommended considering alternatives to tinzaparin for treatment of DVT in patients older than 70 years with renal insufficiency because of an increased risk of death in that population. [10]
The Wells et al study was the first trial to compare drugs within the LMWH class, and it also was the first study to treat patients with acute DVT and PE solely on an outpatient basis. [9] However, the question of whether there is any significant clinical difference between these LMWH agents for the treatment of DVT or PE was only partially answered. The investigators estimated that the projected sample size needed to detect any significant difference between dalteparin and tinzaparin would exceed 30,000 patients. [9] Such a study is unlikely to be funded at the present time.
Currently, enoxaparin and other LMWHs are recommended for the treatment of DVT. However, these agents have some disadvantages. First, the data on once-daily or twice-daily dosing of enoxaparin are not clear. Second, the practical issues surrounding the administration of a weight-based 1 mg/kg dose from fixed-volume syringes of enoxaparin may be an issue for some patients. Third, the incidence of heparin-induced thrombocytopenia, although reduced with enoxaparin, is not completely eliminated.
The following factors are exclusion criteria for outpatient management of DVT:
Suspected or proven concomitant PE
Significant cardiovascular or pulmonary comorbidity
Ileofemoral DVT
Contraindications to anticoagulation
Familial or inherited disorder of coagulation – ATIII deficiency, prothrombin 20210A, protein C or protein S deficiency, or factor V Leiden
Familial bleeding disorder
Pregnancy
Morbid obesity >150 kg
Renal failure (creatinine >2 mg%)
Unavailable or unable to arrange close follow-up care and/or patient/family resistant to outpatient therapy
Unable to follow instructions
Homeless and/or no contact telephone
Geographic – too far from hospital
Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008 Jun. 133(6 Suppl):454S-545S. [Medline].
Kearon C, Ginsberg JS, Julian JA, Douketis J, Solymoss S, Ockelford P, et al. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. JAMA. 2006 Aug 23. 296(8):935-42. [Medline].
San Norberto García EM, Merino B, Taylor JH, Vizcaíno I, Vaquero C. Low-molecular-weight heparin for prevention of venous thromboembolism after varicose vein surgery in moderate-risk patients: a randomized, controlled trial. Ann Vasc Surg. 2013 Oct. 27(7):940-6. [Medline].
Deep venous thrombosis and pulmonary embolism. Part 1. Initial treatment: usually a low-molecular-weight heparin. Prescrire Int. 2013 Apr. 22(137):99-101, 103-4. [Medline].
Deep venous thrombosis and pulmonary embolism. Part 2–Prevention of recurrences: warfarin or low-molecular-weight heparin for at least 3 months. Prescrire Int. 2013 May. 22(138):129-33. [Medline].
Mismetti P, Quenet S, Levine M, Merli G, Decousus H, Derobert E, et al. Enoxaparin in the treatment of deep vein thrombosis with or without pulmonary embolism: an individual patient data meta-analysis. Chest. 2005 Oct. 128(4):2203-10. [Medline].
van Dongen CJ, MacGillavry MR, Prins MH. Once versus twice daily LMWH for the initial treatment of venous thromboembolism. Cochrane Database Syst Rev. 2005 Jul 20. CD003074. [Medline].
Michota F, Merli G. Anticoagulation in special patient populations: are special dosing considerations required?. Cleve Clin J Med. 2005 Apr. 72 Suppl 1:S37-42. [Medline].
Wells PS, Anderson DR, Rodger MA, Forgie MA, Florack P, Touchie D, et al. A randomized trial comparing 2 low-molecular-weight heparins for the outpatient treatment of deep vein thrombosis and pulmonary embolism. Arch Intern Med. 2005 Apr 11. 165(7):733-8. [Medline].
U.S. Food and Drug Administration. Communication about an Ongoing Safety Review of Innohep (tinzaparin sodium injection). Available at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm136254.htm. Accessed: October 29, 2010.
Lee AY, Kamphuisen PW, Meyer G, et al; CATCH Investigators. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: a randomized clinical trial. JAMA. 2015 Aug 18. 314(7):677-86. [Medline].
Minet C, Potton L, Bonadona A, et al. Venous thromboembolism in the ICU: main characteristics, diagnosis and thromboprophylaxis. Crit Care. 2015 Aug 18. 19:287. [Medline].
LMWH Regimen
Therapeutic Peak
Enoxaparin
1 mg/kg q12h hours
0.6-1 IU/mL
1.5 mg/kg daily
1-1.5 IU/mL
Tinzaparin 175 IU/kg qd
0.85-1 IU/mL
Dalteparin
100 IU/kg q12h hours
0.4-1.1 IU/mL
200 IU/kg qd
1-2 IU/mL
Donald Schreiber, MD, CM Associate Professor of Surgery (Emergency Medicine), Stanford University School of Medicine
Donald Schreiber, MD, CM is a member of the following medical societies: American College of Emergency Physicians
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Gary Setnik, MD Chair, Department of Emergency Medicine, Mount Auburn Hospital; Assistant Professor, Department of Emergency Medicine, Harvard Medical School
Gary Setnik, MD is a member of the following medical societies: American College of Emergency Physicians, Society for Academic Emergency Medicine, National Association of EMS Physicians
Disclosure: Medical Director for: SironaHealth.
Barry E Brenner, MD, PhD, FACEP Professor of Emergency Medicine, Professor of Internal Medicine, Program Director for Emergency Medicine, Sanz Laniado Medical Center, Netanya, Israel
Barry E Brenner, MD, PhD, FACEP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Chest Physicians, American College of Emergency Physicians, American College of Physicians, American Heart Association, American Thoracic Society, New York Academy of Medicine, New York Academy of Sciences, Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.
Francis Counselman, MD, FACEP Chair, Professor, Department of Emergency Medicine, Eastern Virginia Medical School
Francis Counselman, MD, FACEP is a member of the following medical societies: Alpha Omega Alpha, American College of Emergency Physicians, Norfolk Academy of Medicine, Association of Academic Chairs of Emergency Medicine, Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.
Heparin Use in Deep Venous Thrombosis
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