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Venous thromboembolism: Initiation of anticoagulation

Venous thromboembolism: Initiation of anticoagulation
Authors:
Gregory YH Lip, MD, FRCPE, FESC, FACC
Russell D Hull, MBBS, MSc
Section Editors:
Jess Mandel, MD, MACP, ATSF, FRCP
James D Douketis, MD, FRCPC, FACP, FCCP
Deputy Editor:
Geraldine Finlay, MD
Literature review current through: Dec 2022. | This topic last updated: Oct 13, 2022.

INTRODUCTION — Venous thromboembolism (VTE) is comprised of two entities, deep vein thrombosis (DVT) and pulmonary embolism (PE). VTE has significant morbidity and mortality for both the inpatient and outpatient population. The risk of recurrent thrombosis and embolization is highest in the first few days and weeks following diagnosis. Thus, initial anticoagulation during the first few days (ie, 0 to 10 days) is critical in the prevention of recurrence and VTE-related death.

The agents used, timing, duration, and dosing of initial anticoagulation for the treatment of VTE are discussed in this topic. The indications and overview of VTE treatment, as well as long-term (3 to 12 months) and extended (indefinite) anticoagulation for patients with VTE are discussed separately. (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)", section on 'Patients at high risk of bleeding' and "Venous thromboembolism: Anticoagulation after initial management" and "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation".)

The approach to anticoagulation outlined in this topic is, in general, consistent with strategies outlined by several international societies including the American College of Chest Physicians, the American College of Physicians, the European Society of Cardiology, the European Respiratory Society, and others [1-4].

NOMENCLATURE — For the purposes of discussion in this topic, the following terms apply:

Initial anticoagulation refers to anticoagulant therapy that is administered immediately following diagnosis of acute VTE; it is often given over the first few days (typically from 0 to 10 days) while planning for long-term anticoagulation. Long-term anticoagulant therapy is typically administered for a finite period beyond the initial period, usually three to six months and occasionally up to 12 months. Extended anticoagulation usually refers to therapy that is administered indefinitely. (See "Venous thromboembolism: Anticoagulation after initial management" and "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation".)

Factor Xa and direct thrombin inhibitors have a variety of names including newer/novel oral anticoagulants, non-vitamin K antagonist oral anticoagulants (NOAs, NOACs), direct oral anticoagulants (DOACs), and target-specific oral anticoagulants (TOACs, TSOACs) [5]. Throughout this topic we refer to these agents by their pharmacologic class, factor Xa and direct thrombin inhibitors. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".)

INDICATIONS — Details of the indications for anticoagulation, including those for patients with isolated distal DVT and subsegmental PE are discussed separately. (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)", section on 'Anticoagulant therapy' and "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults".)

BLEEDING RISK — In all patients, the decision to anticoagulate should be individualized and the benefits of VTE prevention carefully weighed against the risk of bleeding (table 1 and table 2). Risk factors for bleeding that influence whether to anticoagulate are discussed in detail separately. (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)", section on 'Assessing bleeding risk' and "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation", section on 'Assessing the risk of bleeding'.)

SELECTION OF AGENT — Initial anticoagulation refers to systemic anticoagulation administered immediately following the diagnosis of deep vein thrombosis (DVT) or pulmonary embolism (PE; typically first 0 to 10 days). It is often administered while a decision regarding long-term anticoagulation is being made. When the decision is made to administer anticoagulant therapy, it should be started immediately since a delay may potentially increase the risk of life-threatening embolization [6,7].

Options for initial anticoagulation include the following:

Low molecular weight (LMW) heparin (see 'Low molecular weight heparin' below)

Fondaparinux (see 'Fondaparinux' below)

Unfractionated heparin (UFH) (see 'Unfractionated heparin' below)

Oral factor Xa inhibitors or direct thrombin inhibitors (see 'Direct factor Xa and thrombin inhibitors' below)

Our approach is generally consistent with that of other experts including the American College of Chest Physicians, and Thrombosis Canada [4,8-10].

General population — With the exception of patients who are pregnant, have active cancer, or have severely impaired renal function (eg, creatinine clearance [CrCl] <30 mL/minute) we and others suggest the following approach (table 3) [4,8]:

For most patients with VTE who are hemodynamically stable, we suggest subcutaneous LMW heparin or fondaparinux, or the oral factor Xa inhibitors, rivaroxaban or apixaban, rather than intravenous UFH. This preference is based upon limited data that suggest that LMW heparin and fondaparinux are superior to UFH, and data that also suggest that the DOACs have similar efficacy to LMW heparin/warfarin. However, in practice, a decision between these agents is usually made based upon clinician experience as well as the risks of bleeding, patient comorbidities, preferences, cost, and convenience (table 3). As examples:

DOACsRivaroxaban and apixaban are the only DOACs that have been studied and approved by regulatory agencies as monotherapy (ie, no pretreatment with heparin is necessary) for the treatment of patients with VTE. They may be preferred in those who wish to avoid the burden of injections in whom convenience or oral medication is a personal preference. Importantly, LMW heparin (or UFH) should be administered if there is a delay in obtaining these anticoagulants (eg, availability needs to be assured). (See 'Direct factor Xa and thrombin inhibitors' below.)

When prescribing the direct thrombin inhibitor dabigatran, or the factor Xa inhibitor edoxaban, we suggest that a short course of heparin (typically LMW heparin) be administered for five days prior to transitioning to oral therapy (ie, sequential therapy also known as dual therapy, although the agents should not be administered together) since their efficacy as monotherapeutic agents has not been studied or approved. Importantly, these agents should not be administered simultaneously.

Importantly, these DOAC agents are not suitable for the treatment of hemodynamically unstable PE or massive iliofemoral DVT (eg, phlegmasia cerulea dolens) where their efficacy has not been adequately studied and their use may interfere with potential therapy (eg, thrombolytic therapy). (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)", section on 'Phlegmasia cerulea dolens' and "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults", section on 'Hemodynamically unstable patients'.)

LMW heparin – Subcutaneous LMW heparin may be preferred in those in whom oral anticoagulation is not feasible (eg, poor oral intake, malabsorption) or contraindicated (eg, pregnancy). (See 'Low molecular weight heparin' below.)

Fondaparinux – Subcutaneous fondaparinux is an acceptable alternative to subcutaneous LMW heparin (eg, heparin-induced thrombocytopenia [HIT]). (See 'Fondaparinux' below.)

Intravenous (IV) UFH – IV UFH must be administered in the inpatient setting and is therefore not suitable as an outpatient therapy. IV UFH is our preferred agent for select populations of patients discussed below. (See 'Unfractionated heparin' below and 'Renal failure' below and 'Hemodynamic instability' below and 'Extensive clot burden' below and 'Anticipated need for discontinuation or reversal' below and 'Obesity or poor subcutaneous absorption' below.)

Subcutaneous UFH may be an alternative to IV UFH, administered in a weight-based fixed-dose regimen (333 IU/kg initial, then 250 IU/kg subcutaneous twice a day) without activated thromboplastin time monitoring.

Warfarin cannot be administered as the only initial anticoagulant for the treatment of patients with VTE. However, when chosen as the long-term anticoagulant it must be co-administered with heparin so that full anticoagulation is assured. (See 'Transitioning to maintenance therapy' below.)

Special populations — When choosing an initial anticoagulant, patients with malignancy, pregnant women, outpatients, and those with a history of heparin-induced thrombocytopenia (HIT) deserve special consideration (table 3).

Renal failure — IV UFH is our preferred anticoagulant in those with severe renal failure (eg, CrCl <30 mL/minute) since renal adjustment is not required for therapeutic anticoagulation. (See 'Unfractionated heparin' below.)

Hemodynamic instability — IV UFH is our preferred anticoagulant in those who are hemodynamically unstable since thrombolysis, interventional procedure, or surgery may need to be considered in this population. (See 'Unfractionated heparin' below.)

Extensive clot burden — IV UFH is our preferred anticoagulant for those patients with extensive DVT or with phlegmasia cerulea dolens, or those with massive or submassive PE which is based upon an anticipated need for a procedural or surgical intervention. In addition, the DOACs and LMW heparin have not been adequately tested in this population. (See 'Unfractionated heparin' below.)

Anticipated need for discontinuation or reversal — Since IV UFH has a short half-life (three to five hours) and a known reversibility agent (protamine sulfate), it is our preferred anticoagulant for those patients in whom there is a high likelihood that anticoagulation will need to be discontinued or reversed (eg, patients at risk of bleeding or in need of a procedural or surgical intervention). (See 'Unfractionated heparin' below.)

Obesity or poor subcutaneous absorption — There is no preferred agent in patients who are obese. However, therapeutic anticoagulation can be assured with IV UFH. IV UFH may also be an alternative to subcutaneous LMW heparin when subcutaneous absorption is potentially poor (eg, massive edema, anasarca).

Malignancy — For most patients with active malignancy and acute VTE who have a reasonable life expectancy and adequate renal function (CrCl ≥30 mL/minute), low molecular weight (LMW) heparin is the preferred agent for initial anticoagulation, rather than other agents. Initial agents in this population are discussed in more detail separately. (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy".)

Pregnancy — For pregnant women with acute VTE, adjusted-dose subcutaneous LMW heparin is the preferred agent for initial anticoagulation because it has a more favorable safety profile, especially when compared with warfarin. (See "Deep vein thrombosis and pulmonary embolism in pregnancy: Treatment" and "Use of anticoagulants during pregnancy and postpartum".)

Heparin-induced thrombocytopenia — Patients with acute VTE may have a prior history of HIT or may develop HIT during parenteral therapy with heparin. For both populations, heparin is contraindicated (ie, UFH, LMW heparin, heparin flushes, heparin-bonded catheters, and heparin-containing medications) and non-heparin anticoagulants are preferred. The diagnosis and management of patients with HIT are discussed in detail separately. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia" and "Management of heparin-induced thrombocytopenia".)

OUTPATIENT ANTICOAGULATION — Not all patients who have acute VTE need to be admitted to the hospital for initial anticoagulation. Several randomized trials and meta-analyses, most of which have compared outpatient therapy with subcutaneous low molecular weight heparin with inpatient therapy with intravenous unfractionated heparin suggest that, in select populations, anticoagulation at home is safe and effective. Patient selection is critical when considering outpatient therapy for patients with deep vein thrombosis and/or pulmonary embolism, the details of which are discussed separately (table 4). (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)", section on 'Outpatient versus inpatient therapy' and "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults", section on 'Outpatient anticoagulation'.)

ANTICOAGULANT AGENTS — For patients with VTE, the greatest risk of embolization is during the first few days following the diagnosis, particularly if patients are not anticoagulated. Thus, anticoagulant therapy should be started immediately as a delay may potentially increase the risk of life-threatening embolization. Baseline coagulation tests (prothrombin time, international normalized ratio [INR], activated partial thromboplastin time [aPTT]) should be drawn prior to the initiation of anticoagulation to guide therapy. The timing, duration, and dose of initial anticoagulation vary with the agent selected and are discussed in the sections below.

Low molecular weight heparin — Low molecular weight (LMW) heparin is our preferred anticoagulant for those with active cancer or pregnancy, for those in whom warfarin, dabigatran, or edoxaban is chosen as the agent for long-term use, as well as for those in whom it is anticipated that therapeutic anticoagulation cannot be assured via the oral route (eg, malabsorption, vomiting). For those in whom rivaroxaban or apixaban are chosen as the oral agent for long-term use, LMW heparin is not necessary unless these agents are unavailable or delayed. (See 'Selection of agent' above.)

Dosing — The initial therapeutic dose of LMW heparin (eg, enoxaparin, dalteparin, tinzaparin) varies by product. Dosing is typically weight-based and renally-adjusted, and all are administered subcutaneously. Typical starting doses are:

Enoxaparin 1 mg/kg twice daily (preferred); alternatively, 1.5 mg/kg once daily can be used in selected non-obese inpatients; for home treatment, the twice daily regimen is better studied and therefore preferred by many experts [11,12]

Dalteparin 200 units/kg once daily or 100 units/kg twice daily (eg, patients with absorption concerns)

Tinzaparin 175 units/kg once daily

Nadroparin 171 units/kg once daily or 86 units/kg twice daily (not available in the United States)

Dosing for patients with renal insufficiency are listed in the tables (table 5). (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'LMW heparin'.)

Efficacy — Evidence from several randomized trials and meta-analyses have reported that, compared with intravenous (IV) and subcutaneous unfractionated heparin (UFH), subcutaneous LMW heparin has higher rates of thrombus regression and lower rates of recurrent thrombosis, major bleeding, and mortality [8,13-27]. However, the data are fraught with methodologic flaws, including publication bias in favor of LMW heparin. None of the different formulations appear to be superior to the other [28]. Data that support the use of LMW heparin include the following:

In a 2017 meta-analysis of 29 studies that compared LMW heparin with IV or subcutaneous UFH in patients with acute VTE (deep vein thrombosis [DVT] and/or pulmonary embolism [PE]), at three months LMW heparin was associated with the following [27]:

Fewer thrombotic complications (eg, recurrence, extension, embolization) (3.7 versus 5.1 percent; odds ratio [OR] 0.70, 95% CI 0.56-0.90)

Improved thrombus regression (51 versus 42 percent; OR 0.71, 95% CI 0.61-0.82)

Reduced rates of major hemorrhage (1.5 versus 2.1 percent; OR 0.69, 95% CI 0.5-0.95)

Non-significant reduction in mortality (4.8 versus 5.7 percent; OR 0.84, 95% CI 0.70-1.01)

An older meta-analysis of 13 studies of patients with acute VTE performed between 1980 and 1994 reported that, compared with UFH, LMW heparin was associated with a lower rate of both recurrent VTE (2.7 versus 7 percent) and major bleeding (0.9 versus 3.2 percent) [16].

A 1999 meta-analysis of 11 trials of patients with acute DVT found a lower mortality rate at three to six months among patients treated with LMW heparin, compared with those receiving UFH (OR 0.71, 95% CI 0.53-0.94) [20]. Differences in recurrent thromboembolism and bleeding complications were not different between the two treatments.

Once daily regimens of LMW heparin appear to be as effective as twice daily regimens. Meta-analyses of trials directly comparing once versus twice daily administration found no convincing differences in recurrent thrombosis, major hemorrhage, or mortality [18,19,29-35]. One large randomized trial of 900 patients with symptomatic DVT, a third of whom also had PE, compared the LMW heparin enoxaparin, administered as a standard twice daily regimen (1 mg/kg twice daily), with a lower once daily regimen (1.5 mg/kg per day) [18]. Although rates of recurrence (3 versus 4 percent) and hemorrhage (1 versus 2 percent) were lower with the twice daily regimen, the difference was not significant and may have been explained by the lower total daily dose administered in the once daily treatment group. In another meta-analysis, once daily regimens were associated lower rates of major bleeding but at the expense of an increased rate of VTE recurrence [35]. Except for enoxaparin, we prefer, when once daily dosing is being considered, that it be administered at the same total daily dose as a twice daily schedule.

The LMW heparins have a number of advantages over unfractionated heparin [36,37]. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Advantages and limitations'.)

Greater bioavailability when given by subcutaneous injection

Duration of the anticoagulant effect is longer, permitting once or twice daily administration

Fixed dosing is feasible because the anticoagulant response (anti-Xa activity) correlates well with body weight

Laboratory monitoring is not necessary (correlation between anti-Xa activity and bleeding or recurrent thrombosis is poor)

Lower risk of heparin-induced thrombocytopenia (HIT)

Use as an outpatient therapy

Disadvantages of LMW heparin compared with UFH include the higher cost, and, although protamine is an antidote for hemorrhage, its effect is incomplete. In addition, efficacy is less certain in the obese population, in patients with renal failure, and in older patients who are underweight (<45 kg). LMW heparin should be avoided or dose adjustments made in these circumstances (table 5). (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Other complications' and "Heparin and LMW heparin: Dosing and adverse effects", section on 'LMW heparin standard dosing'.)

LMW heparin also appears to be as effective as once daily subcutaneous fondaparinux. (See 'Fondaparinux' below.)

Trials directly comparing LMW heparin with oral factor Xa and direct thrombin inhibitors as initial therapies for acute DVT have not been performed. (See 'Direct factor Xa and thrombin inhibitors' below and "Venous thromboembolism: Anticoagulation after initial management", section on 'Direct thrombin and factor Xa inhibitors'.)

Fondaparinux — As an alternative to LMW heparin, fondaparinux is an acceptable anticoagulant for most nonpregnant patients with newly diagnosed VTE (eg, patients with HIT). (See 'Selection of agent' above.)

Dosing — Fondaparinux is typically dosed according to patient weight as 5 mg once daily (<50 kg), 7.5 mg once daily (50 to 100 kg), and 10 mg (>100 kg). Fondaparinux is renally excreted. Further information on dosing and adverse effects are discussed in detail separately. (See "Fondaparinux: Dosing and adverse effects", section on 'Pharmacology'.)

Efficacy — Although subcutaneous fondaparinux is less well studied than either LMW heparin or UFH in this setting, fondaparinux appears to have a similar efficacy and safety profile to LMW heparin [38]. One multicenter trial of 2205 patients with acute DVT were randomized to receive fondaparinux, 7.5 mg subcutaneously once daily (5 mg in patients weighing <50 kg; 10 mg >100 kg), or enoxaparin 1 mg/kg subcutaneously twice daily with warfarin, for at least five days. There was no difference in the rate of recurrent thromboembolism (4 percent), major bleeding (1 percent), or mortality rates (3 versus 4 percent) between the two treatments. A meta-analysis of pentasaccharides that included fondaparinux also reported similar efficacy when fondaparinux was given in combination with warfarin [39]. (See 'Selection of agent' above.)

Subcutaneous fondaparinux and IV UFH also appear to have similar effects on mortality, recurrent thromboembolism, and major bleeding. This was demonstrated by a trial that randomly assigned 2213 patients with acute PE to receive either subcutaneous fondaparinux or IV UFH [40]. The trial found no difference in mortality (5.2 versus 4.3 percent with IV UFH), recurrent thromboembolic events (3.8 versus 5 percent with IV UFH), or major bleeding (2 versus 2.3 percent with IV UFH).

Dosing and adverse effects of fondaparinux are discussed in detail separately. (See "Fondaparinux: Dosing and adverse effects".)

Unfractionated heparin — Intravenous unfractionated heparin (UFH) is our preferred anticoagulant for patients with severe renal failure (eg, CrCl <30 mL/minute) and for patients in whom there is a high likelihood that acute reversal of anticoagulation will be needed (eg, procedure or at increased risk of bleeding) as well as those with hemodynamic instability especially if thrombolysis is being considered, and extensive clot burden (eg, phlegmasia cerulea dolens, submassive PE). It may also be an alternative to LMW heparin in patients suspected to have poor subcutaneous absorption (eg, edema or obesity). (See 'Selection of agent' above and 'Renal failure' above and 'Hemodynamic instability' above and 'Extensive clot burden' above and 'Anticipated need for discontinuation or reversal' above and 'Obesity or poor subcutaneous absorption' above.)

Dosing — Initial dosing of subcutaneous and IV UFH is also weight based, but unaffected by renal insufficiency. We prefer weight-based protocols (table 6) rather than fixed-dose protocols (table 7A-B) because they make pharmacologic sense and improve time spent within the therapeutic range for the aPTT (target range 1.5 to 2.5 times the control) [41-43].

The use of IV UFH protocols may increase the time spent in the therapeutic range for the aPTT. Achieving and maintaining a therapeutic aPTT range can be challenging [44-47]. As an example, one observational study reported that 60 percent of treated patients failed to achieve an adequate aPTT response during the initial 24 hours of therapy and that 30 to 40 percent of patients remained subtherapeutic over the next three to four days [45]. These observations led to protocols designed to efficiently achieve and maintain target aPTT goals. Commonly used protocols are:

Weight-based (table 6) [42]

Non-weight based (table 7A-B) [43]

The preference for weight-based protocols is primarily based upon a randomized trial of a mixed population of patients requiring IV UFH for several different indications (venous and arterial thrombosis, unstable angina). In that trial, a weight-based heparin dosing nomogram (table 7A-B) was compared with a non-weight-based nomogram to maintain an aPTT ratio of 1.5 to 2.3 times control values (table 6) [42]. Patients treated with the weight-adjusted regimen received a starting bolus dose of 80 units/kg followed by an 18 units/kg per hour infusion; subsequent adjustments were made every six hours. Patients in the standard-care group received a bolus of 5000 units followed by a 1000 units/hour infusion; subsequent fixed-dose adjustments were made every six hours. A higher percentage of patients in the weight-adjusted group achieved a therapeutic aPTT within 24 hours (97 versus 77 percent) without an increase in major bleeding. Recurrent thromboembolism was more frequent in the non-weight-based group (relative risk 5.0, 95% CI 1.1-21.9). This protocol is generalizable and widely used routinely in clinical practice. However, data still suggest that a large proportion of patients anticoagulated for PE, for example, remain outside of the therapeutic range during the first 48 hours (up to one-third) [48].

Although not routine, weight-adjusted subcutaneous UFH has been used for patients who decline IV access and have a contraindication to LMW heparin (eg, severe renal insufficiency) or other anticoagulants [24]. Typically, subcutaneous UFH is given as a weight-based dosing of 333 units/kg loading dose followed by 250 units/kg every 12 hours [9].

Optimal dosing of UFH in patients with obesity is unknown. Most physicians use ideal body weight to guide dosing and increase the aPTT accordingly to the target. The clinical efficacy of this approach is unknown. (See "Intensive care unit management of patients with obesity", section on 'Anticoagulants'.)

Additional therapeutic uses of UFH are discussed in detail separately. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Unfractionated heparin'.)

Efficacy — In the past, IV UFH was the gold standard for initial anticoagulation in patients with DVT until LMW heparin became available. Compared with LMW heparin, use of IV UFH is associated with slightly higher rates of recurrent thrombosis and major bleeding. Comparative studies between LMW heparin and IV UFH are discussed in detail separately. (See 'Selection of agent' above and 'Low molecular weight heparin' above.)

The efficacy of IV UFH depends upon achieving a critical therapeutic level as soon as possible, preferably within the first 24 hours of treatment, usually via a continuous IV infusion [21,42,49-53]. The critical therapeutic level of heparin, as measured by the aPTT, is a target aPTT ratio range of 1.5 to 2.5 times the control. This corresponds to a heparin level of 0.3 to 0.7 units/mL, when measured by an anti-Xa assay [10,54]. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Dosing and monitoring'.)

Studies that support this target range include the following:

One older prospective study of patients with acute DVT reported that, compared with an aPTT ratio >1.5, patients who had an aPTT ratio <1.5 times the control for three days had a threefold increase in the risk of recurrent thrombosis [49].

A pooled analysis of three randomized trials examined therapeutic or subtherapeutic UFH (mostly IV UFH) for acute proximal DVT [53]. Compared with patients whose aPTT exceeded the therapeutic threshold by 24 hours, failure to achieve a therapeutic aPTT during that time was associated with an increased rate of recurrent thrombosis (23 percent versus 4 percent).

Although there is a strong correlation between subtherapeutic aPTT values and recurrent thromboembolism, the relationship between supratherapeutic aPTT (ie, an aPTT ratio 2.5 or more) and bleeding is less definite [43]. Nonetheless, aiming for a therapeutic range with the avoidance of periods of both subtherapeutic and supratherapeutic levels is prudent.

The advantages of IV UFH compared with LMW heparin include its lower cost and its safe use in those with renal insufficiency. An additional advantage of the IV formulation is its short half-life, particularly for patients in whom there is a potential need for acute discontinuation (eg, surgery). Disadvantages are that infusions of UFH require hospital admission, and both subcutaneous and IV UFH are associated with a higher potential for HIT. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Other complications'.)

Data that support efficacy of subcutaneous UFH include the following:

One meta-analysis of 16 randomized trials of patients with VTE, when compared with continuous IV UFH for initial anticoagulation, subcutaneous UFH resulted in similar rates of recurrence (5.7 versus 3.5 percent), mortality (0.3 percent each), and major bleeding (4.4 versus 4.8 percent) [27].

Another meta-analyses [8] of four randomized trials [21,23,24,55] demonstrated that LMW heparin and subcutaneous UFH have similar effects on mortality (4.3 versus 4 percent with subcutaneous UFH), recurrent thromboembolic events (3.3 versus 4 percent with subcutaneous UFH), and major bleeding (2.3 versus 1.8 percent with subcutaneous UFH).

Direct factor Xa and thrombin inhibitors — Oral factor Xa (rivaroxaban, apixaban, edoxaban) or direct thrombin inhibitors (dabigatran) are attractive candidates as initial oral anticoagulants in patients with acute VTE due to their quick onset of action (peak efficacy one to four hours after ingestion). Rivaroxaban and apixaban were evaluated as anticoagulants without prior administration of heparin (ie, monotherapy); as such they may be used as the sole initial anticoagulant. However, anticoagulant therapy with heparin should not be delayed while the decision is being made to treat with one of these agents and assurance needs to be obtained that the drug is available immediately (as an inpatient or outpatient). In contrast, in trials that evaluated dabigatran and edoxaban, all patients were treated with five days of heparin prior to their administration (ie, sequential therapy); as such, we prefer that a short course of heparin (typically LMW heparin) be administered alone before transitioning to either dabigatran or edoxaban. (See 'Selection of agent' above.)

Dosing — Typical initial doses in those with normal renal function are:

Rivaroxaban 15 mg twice daily (for the first three weeks)

Apixaban 10 mg twice daily (for first seven days)

Edoxaban 60 mg once daily (and 30 mg once daily in patients with a body weight below 60 kg) (after an initial 5 to 10 days of parenteral anticoagulation)

Dabigatran 150 mg twice daily (after an initial 5 to 10 days of parenteral anticoagulation)

In keeping with the clinical trials that demonstrated their efficacy, in patients who are receiving heparin as the initial anticoagulant, we prefer that oral factor Xa or direct thrombin inhibitors be given within 6 to 12 hours following the last dose of subcutaneous LMW heparin when administered as a twice daily regimen, or within 12 to 24 hours for once daily regimens. Infusions of UFH can be immediately discontinued following the administration of these oral agents. (See "Venous thromboembolism: Anticoagulation after initial management", section on 'Agents for long-term anticoagulation'.)

Many of these agents are renally excreted such that patients with severe renal insufficiency should not be considered for these agents. The distribution of agent and anticoagulant effect in the obese population is unknown. Maintenance doses for long-term anticoagulation and further details regarding dosing in renal insufficiency are discussed in UpToDate Lexicomp monographs and in additional topics. (See "Management of bleeding in patients receiving direct oral anticoagulants" and "Venous thromboembolism: Anticoagulation after initial management", section on 'Direct thrombin and factor Xa inhibitors' and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Chronic kidney disease'.)

The efficacy and safety of factor Xa and direct thrombin inhibitors as anticoagulants for extensive DVT (eg, patients with phlegmasia cerulea dolens) or hemodynamically significant pulmonary embolism are unknown, and, as such, they should not be used in these patients who may receive thrombolytic therapy. Similarly, we prefer that these agents not be administered in patients who are pregnant, because their safety and efficacy is unproven in this population. (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)", section on 'Phlegmasia cerulea dolens' and "Approach to thrombolytic (fibrinolytic) therapy in acute pulmonary embolism: Patient selection and administration" and "Deep vein thrombosis and pulmonary embolism in pregnancy: Treatment".)

Efficacy — Randomized trials of these oral agents in patients with acute VTE examined efficacy and safety in the context of long-term anticoagulation with the same oral agent for three months or more. When compared with conventional courses of LMW heparin or IV UFH followed by long-term anticoagulation with warfarin, these agents had similar rates of recurrent thrombosis and major hemorrhage [56-59]. However, trials that reported efficacy for dabigatran (direct thrombin inhibitor) and edoxaban (factor Xa inhibitor) used a minimum of five days of anticoagulation with LMW heparin or UFH prior to their administration for long-term oral therapy (ie, sequential therapy) [58,59]. In contrast, trials of rivaroxaban and apixaban reported efficacy of both agents as the sole initial anticoagulant (monotherapy). Although short periods (<48 hours) of heparin were allowed prior to randomization, our experience with these agents is in keeping with the data that suggest monotherapy with these agents is safe and effective. Details of the trials that reported the safety and efficacy of these agents for the long-term treatment of VTE are discussed separately. (See "Venous thromboembolism: Anticoagulation after initial management", section on 'Direct thrombin and factor Xa inhibitors'.)

DURATION OF THERAPY FOR HEPARIN — The initial duration of heparin therapy varies depending upon the oral agent chosen and whether or not thrombolysis is anticipated:

Factor Xa and direct thrombin inhibitors – When factor Xa and direct thrombin inhibitors are chosen, co-administration with heparin is not warranted. However, short courses of heparin are acceptable in those on rivaroxaban and apixaban, while typically five days is required for those on dabigatran and edoxaban. (See 'Direct factor Xa and thrombin inhibitors' above.)

Warfarin – When administered together with warfarin on day 1, there is no benefit to prolonged courses of systemic heparin beyond a therapeutic INR (table 8). Randomized trials have reported that shorter courses of heparin therapy (typically four to five days) plus initiation of warfarin on day 1 is as effective as longer courses of heparin (10 to 14 days) with the delayed initiation of warfarin (eg, starting day 5 to 10) [41,55,60]. As an example, in one randomized trial of patients treated with parenteral heparin for proximal DVT, the initiation of warfarin on day 1 of therapy was associated with an equivalent three-month rate of recurrent VTE when compared with warfarin started on day 5 to 10 of therapy (7 percent each) [60]. This approach has the added advantage of minimizing the total number of days that a patient requires anticoagulation with heparin, thereby reducing the risk of HIT [36]. In clinical practice, the same approach is acceptable for patients taking subcutaneous LMW heparin, UFH, and fondaparinux.

Anticipated thrombolysis – Since a small proportion of patients with heavy clot burden in the lower extremity or submassive pulmonary embolus (PE) may need thrombolysis, IV UFH is usually administered for an ill-define period (sometimes up to 48 hours) until it is assessed by the clinician that thrombolysis is not indicated. There are no guidelines to facilitate the duration of heparin under these circumstances. (See "Approach to thrombolytic (fibrinolytic) therapy in acute pulmonary embolism: Patient selection and administration".)

Details of transitioning to long-term maintenance therapy are discussed separately. (See 'Transitioning to maintenance therapy' below.)

EMPIRIC ANTICOAGULATION — The decision to empirically anticoagulate while waiting for diagnostic test results depends upon the clinical suspicion for VTE (table 9), the expected timing of diagnostic tests, and the bleeding risk. Our strategy is similar for patients with deep vein thrombosis (DVT) and/or pulmonary embolism and is discussed separately. (See "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults", section on 'Empiric anticoagulation'.)

The diagnosis of DVT is also discussed separately. (See "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity".)

TRANSITIONING TO MAINTENANCE THERAPY — Therapeutic anticoagulation should be ensured during the transition from initial to long-term (maintenance) therapy (table 10). The optimal transition strategy varies with the long-term anticoagulant chosen and is discussed separately. (See "Venous thromboembolism: Anticoagulation after initial management", section on 'Agents for long-term anticoagulation' and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Transitioning between anticoagulants'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Superficial vein thrombosis, deep vein thrombosis, and pulmonary embolism" and "Society guideline links: Anticoagulation".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (See "Patient education: Deep vein thrombosis (DVT) (Beyond the Basics)".)

Beyond the Basics topics (see "Patient education: Deep vein thrombosis (DVT) (Beyond the Basics)" and "Patient education: Warfarin (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Nomenclature – Initial anticoagulation refers to anticoagulant therapy that is administered immediately following diagnosis of acute venous thromboembolism (VTE); it is often given over the first few days (typically from 0 to 10 days) while planning for long-term anticoagulation. Anticoagulation should be started immediately as a delay increases the risk of embolization and death. (See 'Nomenclature' above.)

Bleeding risk – Every patient with acute VTE should be assessed for the risk of bleeding prior to anticoagulation. Most clinicians agree that anticoagulation should be administered to patients with a low risk of bleeding and avoided in those at high risk (table 1 and table 2). For patients with a moderate risk of bleeding, the decision to anticoagulate must be individualized according to the values and preferences of the patient as well as the risk-benefit ratio as assessed by the clinician. (See 'Bleeding risk' above and "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)", section on 'Assessing bleeding risk' and "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Mitigating bleeding risk' and "Risks and prevention of bleeding with oral anticoagulants" and "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation", section on 'Assessing the risk of bleeding'.)

First-line anticoagulant – For most patients with acute VTE, we suggest subcutaneous low molecular weight (LMW) heparin, subcutaneous fondaparinux, or the oral factor Xa inhibitors, rivaroxaban or apixaban, rather than intravenous (IV) unfractionated heparin (UFH) (Grade 2C). A decision between these agents is usually made based upon clinician experience as well as the risks of bleeding, patient comorbidities, preferences, cost, and convenience (table 3 and table 5). Dosing for each agent is individualized. (See 'Selection of agent' above and 'Low molecular weight heparin' above and 'Fondaparinux' above and 'Direct factor Xa and thrombin inhibitors' above.)

Special populations – Other populations require special consideration:

Renal failure or poor absorption – For most patients with acute VTE who have severe renal failure (eg, creatinine clearance <30 mL/minute), hemodynamic instability, or massive iliofemoral deep vein thrombosis, or for patients in whom there is a high likelihood of needing to acutely discontinue or reverse anticoagulation, we suggest IV UFH rather than LMW heparin (Grade 2C). IV UFH may also be an alternative to LMW heparin when subcutaneous absorption is potentially poor (eg, massive edema, anasarca). A weight-based protocol is preferably used to administer UFH at a dose sufficient to prolong the activated partial thromboplastin time (aPTT), with a target aPTT ratio of 1.5 to 2.5 over the control (table 6). (See 'Selection of agent' above and 'Unfractionated heparin' above.)

Others

For pregnant females, LMW heparin is the preferred initial anticoagulant. (See "Deep vein thrombosis and pulmonary embolism in pregnancy: Treatment".)

For patients with malignancy, first-line agents include LMW heparin and select direct oral anticoagulants. (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy".)

For patients with heparin-induced thrombocytopenia, heparin is contraindicated, and immediate anticoagulation with a non-heparin anticoagulant (eg, argatroban, danaparoid, fondaparinux, bivalirudin) is indicated. (See "Management of heparin-induced thrombocytopenia".)

Outpatient therapy – Outpatient rather than inpatient anticoagulation can be considered in select patients (table 4). (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)", section on 'Outpatient versus inpatient therapy' and "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults", section on 'Outpatient anticoagulation'.)

Empiric anticoagulation – The decision to empirically anticoagulate while waiting for diagnostic test results depends upon the clinical suspicion for VTE (table 9), the expected timing of diagnostic tests, and the bleeding risk. (See "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults", section on 'Empiric anticoagulation' and 'Empiric anticoagulation' above.)

Transitioning to maintenance – Full anticoagulation should be ensured during the transition from initial to long-term (maintenance) therapy when switching agents. (See "Venous thromboembolism: Anticoagulation after initial management", section on 'Agents for long-term anticoagulation' and 'Transitioning to maintenance therapy' above and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Transitioning between anticoagulants'.)

  1. Raja AS, Greenberg JO, Qaseem A, et al. Evaluation of Patients With Suspected Acute Pulmonary Embolism: Best Practice Advice From the Clinical Guidelines Committee of the American College of Physicians. Ann Intern Med 2015; 163:701.
  2. Ortel TL, Neumann I, Ageno W, et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv 2020; 4:4693.
  3. Konstantinides SV, Meyer G, Becattini C, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). Eur Respir J 2019; 54.
  4. Stevens SM, Woller SC, Kreuziger LB, et al. Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline and Expert Panel Report. Chest 2021; 160:e545.
  5. Husted S, de Caterina R, Andreotti F, et al. Non-vitamin K antagonist oral anticoagulants (NOACs): No longer new or novel. Thromb Haemost 2014; 111:781.
  6. den Exter PL, van Es J, Erkens PM, et al. Impact of delay in clinical presentation on the diagnostic management and prognosis of patients with suspected pulmonary embolism. Am J Respir Crit Care Med 2013; 187:1369.
  7. Smith SB, Geske JB, Maguire JM, et al. Early anticoagulation is associated with reduced mortality for acute pulmonary embolism. Chest 2010; 137:1382.
  8. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e419S.
  9. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e152S.
  10. Garcia DA, Baglin TP, Weitz JI, et al. Parenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e24S.
  11. Hacobian M, Shetty R, Niles CM, et al. Once daily enoxaparin for outpatient treatment of acute venous thromboembolism: a case-control study. Clin Appl Thromb Hemost 2010; 16:21.
  12. Chong BH, Brighton TA, Baker RI, et al. Once-daily enoxaparin in the outpatient setting versus unfractionated heparin in hospital for the treatment of symptomatic deep-vein thrombosis. J Thromb Thrombolysis 2005; 19:173.
  13. Segal JB, Streiff MB, Hofmann LV, et al. Management of venous thromboembolism: a systematic review for a practice guideline. Ann Intern Med 2007; 146:211.
  14. Kakkar VV, Hoppenstead DA, Fareed J, et al. Randomized trial of different regimens of heparins and in vivo thrombin generation in acute deep vein thrombosis. Blood 2002; 99:1965.
  15. Lensing AW, Prins MH, Davidson BL, Hirsh J. Treatment of deep venous thrombosis with low-molecular-weight heparins. A meta-analysis. Arch Intern Med 1995; 155:601.
  16. 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; 100:269.
  17. Dolovich LR, Ginsberg JS, Douketis JD, et al. A meta-analysis comparing 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; 160:181.
  18. 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; 134:191.
  19. Breddin HK, Hach-Wunderle V, Nakov R, et al. Effects of a low-molecular-weight heparin on thrombus regression and recurrent thromboembolism in patients with deep-vein thrombosis. N Engl J Med 2001; 344:626.
  20. Gould MK, Dembitzer AD, Doyle RL, et al. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A meta-analysis of randomized, controlled trials. Ann Intern Med 1999; 130:800.
  21. Prandoni P, Carnovali M, Marchiori A, Galilei Investigators. Subcutaneous adjusted-dose unfractionated heparin vs fixed-dose low-molecular-weight heparin in the initial treatment of venous thromboembolism. Arch Intern Med 2004; 164:1077.
  22. Faivre R, Neuhart Y, Kieffer Y, et al. [A new treatment of deep venous thrombosis: low molecular weight heparin fractions. Randomized study]. Presse Med 1988; 17:197.
  23. Lopaciuk S, Meissner AJ, Filipecki S, et al. Subcutaneous low molecular weight heparin versus subcutaneous unfractionated heparin in the treatment of deep vein thrombosis: a Polish multicenter trial. Thromb Haemost 1992; 68:14.
  24. Kearon C, Ginsberg JS, Julian JA, et al. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. JAMA 2006; 296:935.
  25. Castellucci LA, Cameron C, Le Gal G, et al. Clinical and safety outcomes associated with treatment of acute venous thromboembolism: a systematic review and meta-analysis. JAMA 2014; 312:1122.
  26. Quinlan DJ, McQuillan A, Eikelboom JW. Low-molecular-weight heparin compared with intravenous unfractionated heparin for treatment of pulmonary embolism: a meta-analysis of randomized, controlled trials. Ann Intern Med 2004; 140:175.
  27. Robertson L, Jones LE. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for the initial treatment of venous thromboembolism. Cochrane Database Syst Rev 2017; 2:CD001100.
  28. Wells PS, Anderson DR, Rodger MA, 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; 165:733.
  29. Couturaud F, Julian JA, Kearon C. Low molecular weight heparin administered once versus twice daily in patients with venous thromboembolism: a meta-analysis. Thromb Haemost 2001; 86:980.
  30. Bhutia S, Wong PF. Once versus twice daily low molecular weight heparin for the initial treatment of venous thromboembolism. Cochrane Database Syst Rev 2013; :CD003074.
  31. van Dongen CJ, MacGillavry MR, Prins MH. Once versus twice daily LMWH for the initial treatment of venous thromboembolism. Cochrane Database Syst Rev 2005; :CD003074.
  32. Charbonnier BA, Fiessinger JN, Banga JD, et al. Comparison of a once daily with a twice daily subcutaneous low molecular weight heparin regimen in the treatment of deep vein thrombosis. FRAXODI group. Thromb Haemost 1998; 79:897.
  33. Holmoström M, Berglund MC, Granquist S, et al. Fragmin once or twice daily subcutaneously in the treatment of deep venous thrombosis of the leg. Thromb Res 1992; 67:49.
  34. Siegbahn A, Y-Hassan S, Boberg J, 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.
  35. Trujillo-Santos J, Bergmann JF, Bortoluzzi C, et al. Once versus twice daily enoxaparin for the initial treatment of acute venous thromboembolism. J Thromb Haemost 2017; 15:429.
  36. Linkins LA, Dans AL, Moores LK, et al. Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e495S.
  37. Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997; 337:688.
  38. Büller HR, Davidson BL, Decousus H, et al. Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial. Ann Intern Med 2004; 140:867.
  39. Brandao GM, Junqueira DR, Rollo HA, Sobreira ML. Pentasaccharides for the treatment of deep vein thrombosis. Cochrane Database Syst Rev 2017; 12:CD011782.
  40. Büller HR, Davidson BL, Decousus H, et al. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med 2003; 349:1695.
  41. Leroyer C, Bressollette L, Oger E, et al. Early versus delayed introduction of oral vitamin K antagonists in combination with low-molecular-weight heparin in the treatment of deep vein thrombosis. a randomized clinical trial. The ANTENOX Study Group. Haemostasis 1998; 28:70.
  42. Raschke RA, Reilly BM, Guidry JR, et al. The weight-based heparin dosing nomogram compared with a "standard care" nomogram. A randomized controlled trial. Ann Intern Med 1993; 119:874.
  43. Hull RD, Raskob GE, Rosenbloom D, et al. Optimal therapeutic level of heparin therapy in patients with venous thrombosis. Arch Intern Med 1992; 152:1589.
  44. Fennerty AG, Thomas P, Backhouse G, et al. Audit of control of heparin treatment. Br Med J (Clin Res Ed) 1985; 290:27.
  45. Wheeler AP, Jaquiss RD, Newman JH. Physician practices in the treatment of pulmonary embolism and deep venous thrombosis. Arch Intern Med 1988; 148:1321.
  46. Cruickshank MK, Levine MN, Hirsh J, et al. A standard heparin nomogram for the management of heparin therapy. Arch Intern Med 1991; 151:333.
  47. Hylek EM, Regan S, Henault LE, et al. Challenges to the effective use of unfractionated heparin in the hospitalized management of acute thrombosis. Arch Intern Med 2003; 163:621.
  48. Prucnal CK, Jansson PS, Deadmon E, et al. Analysis of Partial Thromboplastin Times in Patients With Pulmonary Embolism During the First 48 Hours of Anticoagulation With Unfractionated Heparin. Acad Emerg Med 2020; 27:117.
  49. Basu D, Gallus A, Hirsh J, Cade J. A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. N Engl J Med 1972; 287:324.
  50. Hull RD, Raskob GE, Hirsh J, et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis. N Engl J Med 1986; 315:1109.
  51. Brandjes DP, Heijboer H, Büller HR, et al. Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis. N Engl J Med 1992; 327:1485.
  52. Hull RD, Raskob GE, Brant RF, et al. The importance of initial heparin treatment on long-term clinical outcomes of antithrombotic therapy. The emerging theme of delayed recurrence. Arch Intern Med 1997; 157:2317.
  53. Hull RD, Raskob GE, Brant RF, 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; 157:2562.
  54. Hirsh J, Raschke R. Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126:188S.
  55. Gallus A, Jackaman J, Tillett J, et al. Safety and efficacy of warfarin started early after submassive venous thrombosis or pulmonary embolism. Lancet 1986; 2:1293.
  56. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363:2499.
  57. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013; 369:799.
  58. Hokusai-VTE Investigators, Büller HR, Décousus H, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369:1406.
  59. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361:2342.
  60. Hull RD, Raskob GE, Rosenbloom D, et al. Heparin for 5 days as compared with 10 days in the initial treatment of proximal venous thrombosis. N Engl J Med 1990; 322:1260.
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References