Venous thromboembolism: Initiation of anticoagulation

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. This period is often termed the "initiation phase" of anticoagulant therapy [1,2].

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 treatment phase (also called "long-term") (3 to 12 months) and extended phase (indefinite) anticoagulation for patients with VTE are discussed separately. (See "Overview of the treatment of lower extremity deep vein thrombosis (DVT)", section on 'IVC filters' 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 [1,3-5].

NOMENCLATURE — 

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

●Initiation phase (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 treatment phase ("long-term") anticoagulation. Treatment phase 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 phase 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".)

●Parenteral anticoagulants used for initiation phase (initial) anticoagulation include unfractionated heparin, low molecular weight heparin and fondaparinux. The generic term "heparin" is used in this chapter to refer to these medications collectively. In special circumstances, other parenteral agents (eg, argatroban or bivalirudin) may be employed.

●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) [6]. Throughout this topic we refer to these agents by their pharmacologic class, factor Xa and direct thrombin inhibitors, consistent with the Internation Society on Thrombosis and Haemostasis nomenclature [7].(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 "Acute pulmonary embolism in adults: Treatment overview and prognosis" and "Overview of the treatment of lower extremity deep vein thrombosis (DVT)", section on 'Anticoagulant agent and duration'.)

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. Risk factors for bleeding that influence whether to anticoagulate are discussed in detail separately. (See "Overview of the treatment of lower extremity deep vein thrombosis (DVT)", section on 'Pretreatment assessment of bleeding risk'.)

SELECTION OF AGENT — 

Initiation phase (initial) anticoagulation refers to systemic anticoagulation administered immediately following the diagnosis of deep vein thrombosis (DVT) or pulmonary embolism (PE; typically the first 0 to 10 days). It is often administered while a decision regarding treatment phase (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 [8,9].

Options for initiation phase (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)

●Selected oral factor Xa 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 [1,10-12].

Treatment approaches — The choice of agent used for the treatment phase of anticoagulation (from about day 10 through 3 to 12 months) determines the strategy used through the initiation phase. There are four basic approaches (table 1):

●Monotherapy (oral initiation) – Apixaban and rivaroxaban have higher doses used during the initiation phase (10 mg twice daily for seven days for apixaban, 15 mg twice daily for 21 days for rivaroxaban), which preclude the requirement for initial heparin therapy.

●Sequential therapy – Dabigatran and edoxaban do not have a higher dose studied for initiation, so a parenteral agent such as LMW heparin must be used for at least five days, after which the patient can be transitioned to dabigatran or edoxaban for the treatment phase. Medications are not given concomitantly (no overlap).

●Overlapping therapy – When warfarin is chosen for the treatment phase, it is generally started on the same day, following initial parenteral anticoagulant administration. Both agents are overlapped until at least five days of concomitant therapy have taken place, and the parenteral agent is not stopped until the INR has been 2.0 or greater for at least 24 hours.

●Parenteral monotherapy – Certain patients (such as those unable to use an oral agent, and selected patients with cancer-associated thrombosis) use LMW heparin for initiation phase therapy, and then continue this for the ongoing treatment phase. Depending on the specific LMW heparin used, the daily dose may be adjusted after the first 30 days of administration.

General population — With the exception of patients who are pregnant or have severely impaired kidney function (eg, creatinine clearance [CrCl] <30 mL/minute), we and others suggest the following approach (table 2) [1,10].

For most patients with VTE who are hemodynamically stable, we suggest the oral factor Xa inhibitors, rivaroxaban or apixaban. This preference is based upon data that suggest that the oral factor Xa inhibitors have similar efficacy to LMW heparin/warfarin. However, in practice, the decision between available agents is usually made based upon clinician experience as well as the risks of bleeding, patient comorbidities, preferences, cost, and convenience (table 2). As examples:

●Oral factor Xa inhibitors (monotherapy) – Rivaroxaban 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). Note that the labeling of rivaroxaban utilizes a higher dose for 21 days before reverting to the treatment phase dose on day 22 of therapy. (See 'Direct factor Xa and thrombin inhibitors' below.)

●Oral factor Xa inhibitors/oral direct thrombin inhibitors (sequential therapy) – When prescribing the oral factor Xa inhibitor edoxaban or the direct thrombin inhibitor dabigatran, 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, and no initiation phase dose is available. Importantly, these agents should not be administered simultaneously (the heparin should be administered first, then changed to the oral agent to begin the treatment phase of anticoagulation). This is in contrast to warfarin, which is given in overlap with parenteral therapy.

Importantly, oral factor Xa inhibitors or oral direct thrombin inhibitors are not suitable for the initial 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 interventional therapy (eg, thrombolytic therapy). A heparin is generally used initially, and selection of treatment phase therapy takes place following interventions or stabilization of the patient. (See "Acute pulmonary embolism in adults: Treatment overview and prognosis", section on 'High-risk PE (unstable)' and "Overview of the treatment of lower extremity deep vein thrombosis (DVT)", section on 'Thrombolytic therapy and thrombectomy'.)

●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 UFH – Intravenous UFH must be administered in the inpatient setting and is therefore not suitable as an outpatient therapy. Intravenous UFH is our preferred agent for select populations of patients discussed below. (See 'Unfractionated heparin' below and 'Kidney 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 intravenous 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 treatment phase (long-term) anticoagulant it must be coadministered with heparin so that full anticoagulation is assured. (See 'Transitioning to treatment phase (long-term) 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 2).

Kidney failure — Intravenous UFH is our preferred anticoagulant in those with severe kidney failure (eg, CrCl <30 mL/minute) since renal adjustment is not required for therapeutic anticoagulation. (See 'Unfractionated heparin' below.) Apixaban is also labeled for use in all stages of kidney disease. Observational data suggests similar efficacy and safety to UFH transitioned to warfarin [13,14].

Kidney adjustment for LMW heparins (table 3) and DOACs are provided separately. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Dosing in CKD' and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Chronic kidney disease'.)

Hemodynamic instability — Intravenous 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 — Intravenous 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 intravenous UFH has a short half-life (three to five hours) and a known reversal 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 — Initial therapeutic anticoagulation can be assured with intravenous UFH. Intravenous UFH may also be an alternative to subcutaneous LMW heparin when subcutaneous absorption is potentially poor (eg, massive edema, anasarca). Guidance statements support use of apixaban and rivaroxaban in patients with obesity [15].

Malignancy — For most patients with active malignancy and acute VTE who have a reasonable life expectancy and adequate kidney function (CrCl ≥30 mL/minute), oral factor Xa inhibitor or low molecular weight (LMW) heparin is appropriate. 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 "Venous thromboembolism in pregnancy and postpartum: Treatment" and "Anticoagulation during pregnancy and postpartum: Agent selection and dosing".)

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 — 

A large percentage of patients who have acute VTE do not 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 "Acute pulmonary embolism in adults: Treatment overview and prognosis", section on 'Outpatient anticoagulation' and "Overview of the treatment of lower extremity deep vein thrombosis (DVT)", section on 'Outpatient therapy'.)

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 pregnant patients, and 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 (total body weight [TBW]) 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 [16,17]

●Dalteparin 200 units/kg once daily or 100 units/kg twice daily (eg, patients with absorption concerns); after one month, the dose is reduced to 150 units/kg once daily

●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 kidney function impairment and obesity are listed in the tables (table 3 and 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 and subcutaneous unfractionated heparin (UFH), subcutaneous LMW heparin has higher rates of thrombus regression and lower rates of recurrent thrombosis, major bleeding, and mortality [10,18-32]. 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 [33]. Data that support the use of LMW heparin include the following:

●In a 2017 meta-analysis of 29 studies that compared LMW heparin with intravenous 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 [32]:

•Fewer thrombotic complications (eg, recurrence, extension, embolization) (3.7 versus 5.1 percent; odds ratio [OR] 0.7, 95% CI 0.56-0.9)

•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 0.7-1.01)

●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) [21].

●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) [25]. 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 [23,24,34-40]. 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) [23]. 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 [40]. 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. Trials of LMW heparin used for both initiation phase and subsequent treatment phase therapy in patients with cancer utilized dose adjustment, which varies by agent [41].

The LMW heparins have a number of advantages over unfractionated heparin [42,43]. (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 higher cost, and, although protamine is an antidote for hemorrhage, its effect is incomplete. In addition, safety and efficacy are less certain in the obese population, in patients with kidney failure, and in older patients who are underweight (<45 kg). LMW heparin should be avoided or dose adjustments made in these circumstances (table 3). (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.)

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 [44]. 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 [45]. (See 'Selection of agent' above.)

Subcutaneous fondaparinux and intravenous 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 intravenous UFH [46]. The trial found no difference in mortality (5.2 versus 4.3 percent with intravenous UFH), recurrent thromboembolic events (3.8 versus 5 percent with intravenous UFH), or major bleeding (2 versus 2.3 percent with intravenous 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 kidney 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 'Kidney 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 intravenous and subcutaneous UFH is weight-based but unaffected by kidney function impairment. 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'.)

●Intravenous UFH – For intravenous UFH infusions, we prefer weight-based protocols (table 6) rather than non-weight based protocols because they increase time spent within the therapeutic range [47-49].

The preference for weight-based protocols is primarily based upon a randomized trial of a mixed population of patients requiring intravenous UFH for several different indications (venous and arterial thrombosis, unstable angina). In that trial, a weight-based heparin dosing nomogram (table 6) was compared with a non-weight-based nomogram to maintain a therapeutic aPTT ratio [48]. 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, 95% CI 1.1-21.9). This protocol (table 6) is generalizable and widely used in clinical practice. However, despite weight-based protocols, a large proportion of patients anticoagulated for PE, for example, remain outside of the therapeutic range during the first 48 hours (up to two-thirds) [50].

In many institutions, titration of heparin protocols is based on anti-Xa activity rather than aPTT. Anti-Xa has fewer confounding factors when compared with aPTT but is typically more expensive and results may not be available as rapidly [51]. Use of coagulation tests is discussed separately. (See "Clinical use of coagulation tests", section on 'Monitoring heparins'.)

●Subcutaneous UFH – Weight-adjusted subcutaneous UFH is rarely needed for patients who decline intravenous access and have a contraindication to LMW heparin (eg, severe kidney function impairment) or other anticoagulants [29]. Two strategies are variably used: a fixed-dose strategy or an aPTT-adjusted dose strategy. While data support both approaches, the ACCP suggest a fixed-dose strategy.

•In the fixed-dose strategy, subcutaneous UFH is given as a weight-based dosing of 333 units/kg loading dose followed by 250 units/kg every 12 hours for the duration of treatment [11,29]. Rarely, we obtain a random aPTT to ensure therapeutic levels (eg, inpatients).

•In the dose-adjusted strategy, subsequent dosing is then titrated to achieve a therapeutic aPTT [26,52]. The first aPTT is generally measured six hours after the second dose. Most adjustments should be an increase or decrease of 10 to 30 percent. The aPTT may be measured six hours after the second injection that follows each dose adjustment. Once a stable dose is achieved, the aPTT may be measured after three to four days of treatment and then every few weeks.

In rare circumstances, a transition from intravenous UFH to subcutaneous UFH is needed. The transition is traditionally done after the patient has received intravenous UFH for 5 to 10 days and a loading dose of subcutaneous UFH is not needed [52]. In this situation, the first aPTT can be checked six hours after the first subcutaneous UFH dose and then six hours after every dose adjustment until a stable dose that produces the desired therapeutic level is achieved. This approach may be more commonly used in pregnancy [52]. (See "Anticoagulation during pregnancy and postpartum: Agent selection and dosing".)

However, long-term use of this approach is challenging since syringes are not prefilled, UFH vials are difficult to obtain in retail pharmacies, and each injection requires a high volume (eg, a single dose may be >1 mL and need to be injected at two or more sites).

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

The efficacy of intravenous UFH depends upon achieving a critical therapeutic level as soon as possible, preferably within the first 24 hours of treatment, usually via a continuous intravenous infusion [12,26,48,53-58]. Monitoring the therapeutic level of heparin is discussed separately. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Dosing and monitoring' and "Clinical use of coagulation tests", section on 'Monitoring heparins'.)

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 [53].

●A pooled analysis of three randomized trials examined therapeutic or subtherapeutic UFH (mostly intravenous UFH) for acute proximal DVT [57]. 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) and bleeding is less definite [49]. Nonetheless, aiming for a therapeutic range with the avoidance of periods of both subtherapeutic and supratherapeutic levels is prudent.

The advantages of intravenous UFH compared with LMW heparin include its lower dependence on renal elimination, although patients with severe renal insufficiency have higher risk for bleeding than those with normal kidney function, regardless of agent [59]. An additional advantage of the intravenous 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 intravenous 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 intravenous 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) [32].

●Another meta-analyses [10] of four randomized trials [26,28,29,60] 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), are attractive candidates as initiation phase (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 for the subsequent treatment phase. (See 'Selection of agent' above.)

Dosing — Typical initial doses in those with normal kidney 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 (note for dabigatran and edoxaban, this transition should not occur until five days of parenteral therapy have been completed). 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 treatment phase (long-term) anticoagulation'.)

Many of these agents are renally excreted such that patients with severe kidney impairment should not be considered for these agents; though apixaban is approved by the Federal (FDA) for use at all levels of renal dysfunction [13,14]. Evidence has been developing regarding the use of oral factor Xa inhibitors in patients with obesity, and a guidance statement supports use of apixaban and rivaroxaban [15]. Maintenance doses for long-term anticoagulation and further details regarding dosing in kidney function impairment are discussed in the UpToDate drug interactions program 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'.)

In patients with extensive DVT (eg, patients with phlegmasia cerulea dolens) or hemodynamically significant pulmonary embolism, initial heparin therapy is preferred by the authors given a larger body of supportive evidence and the use of heparin anticoagulation in most studies of patients receiving interventional therapies. As such, oral factor Xa inhibitors and oral direct thrombin inhibitors should not be used in patients who may receive thrombolytic therapy; though they are frequently appropriate for treatment phase anticoagulation following interventions and patient stabilization. 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 "Acute pulmonary embolism in adults: Thrombolytic therapy in intermediate- and high-risk patients" and "Venous thromboembolism in pregnancy and postpartum: Treatment" and "Overview of the treatment of lower extremity deep vein thrombosis (DVT)", section on 'Thrombolytic therapy and thrombectomy'.)

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 intravenous UFH followed by long-term anticoagulation with warfarin, these agents had similar rates of recurrent thrombosis and major hemorrhage [61-64]. 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) [63,64]. 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 apixaban or rivaroxaban are chosen, coadministration with heparin is not warranted as the initial higher dose of these agents can be used for initiation therapy. However, short courses of heparin are acceptable in those on rivaroxaban and apixaban; it is debatable whether time on heparin can be counted toward the seven days of higher dose therapy for apixaban, or the 21 days for rivaroxaban. The authors consider time on parenteral therapy as equivalent to the time on higher dose initiation therapy. Five days of parenteral therapy is required for those who will use dabigatran or edoxaban, as they have no higher initiation phase dosing. (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 7). Randomized trials have reported that shorter courses of heparin therapy (typically ~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) [47,60,65]. 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) [65]. 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 [42]. 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 (intermediate high-risk) pulmonary embolus (PE) may need thrombolysis, intravenous 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 "Acute pulmonary embolism in adults: Thrombolytic therapy in intermediate- and high-risk patients".)

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

EMPIRIC ANTICOAGULATION — 

The decision to empirically anticoagulate while waiting for diagnostic test results depends upon the clinical suspicion for VTE (table 8), 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 "Acute pulmonary embolism in adults: Treatment overview and prognosis", section on 'Empiric anticoagulation or thrombolysis'.)

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 TREATMENT PHASE (LONG-TERM) THERAPY — 

Therapeutic anticoagulation should be ensured during the transition from initiation phase (initial) to treatment phase (long-term) therapy as detailed above (table 1). 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 treatment phase (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 – Initiation phase (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 prohibitively high risk. (See 'Bleeding risk' above and "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Mitigating bleeding risk' and "Risks and prevention of bleeding with oral anticoagulants" and "Overview of the treatment of lower extremity deep vein thrombosis (DVT)", section on 'Pretreatment assessment of bleeding risk'.)

●First-line anticoagulant – For most patients with DVT or stable low- and intermediate-risk PE, who are without comorbidities, we suggest rivaroxaban or apixaban rather than other anticoagulation regimens (Grade 2C). Rivaroxaban and apixaban are oral agents and can be given both as initiation phase therapy (at a higher dose) and continued at standard dose throughout the treatment phase. Other anticoagulants are reasonable alternatives and may be preferred in specific settings and comorbidities (table 2 and table 3). 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:

•Severe disease and high bleeding risk – For most patients with acute VTE who have 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 intravenous UFH rather than LMW heparin (Grade 2C).

•Kidney failure – UFH, or alternatively apixaban, are options for initiation phase (initial) anticoagulation in patients with severe renal insufficiency or renal failure.

•Obesity or poor absorption –Intravenous 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 "Venous thromboembolism in pregnancy and postpartum: Treatment".)

For patients with malignancy, first-line agents include oral factor Xa inhibitors and LMW heparin. (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 anticoagulation is safe when criteria are met (table 4). Outpatient rather than inpatient anticoagulation is frequently possible in patients without compelling indications for hospitalization. (See "Acute pulmonary embolism in adults: Treatment overview and prognosis", section on 'Outpatient anticoagulation' and "Overview of the treatment of lower extremity deep vein thrombosis (DVT)", section on 'Outpatient therapy'.)

●Empiric anticoagulation – The decision to empirically anticoagulate while waiting for diagnostic test results depends upon the clinical suspicion for VTE (table 8), the expected timing of diagnostic tests, and the bleeding risk. (See 'Empiric anticoagulation' above and "Acute pulmonary embolism in adults: Treatment overview and prognosis", section on 'Empiric anticoagulation or thrombolysis'.)

●Transitioning to treatment phase (long-term) therapy – Full anticoagulation should be ensured during the transition from initial to treatment phase (long-term) therapy. The approach varies according to the agent chosen for the treatment phase. (See "Venous thromboembolism: Anticoagulation after initial management", section on 'Agents for treatment phase (long-term) anticoagulation' and 'Transitioning to treatment phase (long-term) therapy' above and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Transitioning between anticoagulants'.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Russell D Hull, MBBS, MSc, who contributed to earlier versions of this topic review.